Intelligent Drug Development Trials and Errors in Clinical Research

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Intelligent Drug Development
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Intelligent Drug
Development
Trials and Errors in Clinical Research
Michael Tansey
3
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3
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Library of Congress Cataloging-in-Publication Data
Tansey, Michael, author.
Intelligent drug development : trials and errors in clinical research /
Michael Tansey.
p. ; cm.
Includes bibliographical references.
ISBN 978–0–19–997458–0 (alk. paper)
I. Title.
[DNLM: 1. Drug Approval—methods. 2. Clinical Protocols. 3. Clinical
Trials as Topic—ethics. 4. Clinical Trials as Topic—methods. QV 771]
RM301.27
615.1072ʹ4—dc23
2013042467
978–0–19–997458–0
987654321
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CONTENTS
Acknowledgments vii
PART ONE: Setting the Scene Introduction: Cutting the Gordian Knot 3
1. Aiming for Excellence 9
PART Two: Planning: From Chaos to Cosmos 2. The Target Product Profile and Its Uses 31
3. Planning the Individual Clinical Trial 47
PART Three: The Practicable Protocol
4. Distilling the Essence of the Protocol: The Protocol Synopsis 57
5. Redistillation: Eliminating Impurities by Carrying out Protocol
Feasibility 68
6. The Optimal Blend: The Approved Synopsis and the Final Protocol 90
PART Four: The Sponsor, The Physician, and The Patient: The Eternal
Clinical Trial Triangle
7. Of Chickens and Eggs: The Sponsor’s Dilemma 103
8. Clinician or Clinical Trialist: The Physician’s Dilemma 123
9. What about the Customer? The Patient’s Dilemma 176
PART Five: And Another Thing . . .
10. About Time: Making Meetings Matter 187
11. The Brain-Scrambling, Fit-Inducing, Mind-Numbing Technicolor Laser
Show 202
References 213
Index 217
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A c k no w l ed g ments
Naming everyone who has contributed to the ideas expressed in this book would
take even longer and be more tedious than the worst Oscar acceptance speech. I have
learned something of value from just about everybody with whom I have come in
contact, even if the lesson has been what not to do. Another problem with naming
people is that I have no clear recollection as to who first came up with many of these
ideas. What I do know is that they are the positive results of many collaborative
activities in which I have taken part.
Some selective acknowledgements must be made, however, because it is unlikely
that I would have ever taken part in these activities if it were not for those who,
against great odds, did their best to pry me away from the narrow world of received
wisdom. The masters at the Oratory school, who taught and encouraged interest
in subjects outside the standard syllabus. The dean (I think) of the medical school
at St. Andrews who expressed dismay at those attending university just to “learn
a trade” led me to study history. The English weather, which drove me to look for
an opportunity elsewhere, and Professor Lionel Opie, who provided that opportunity at Groote Schuur Hospital and the University of Cape Town and taught me the
discipline needed for clinical research. Bill Bogie, who put my value as an academic
physician newly arrived in the pharmaceutical industry into perspective (none) and
then, with Kurt Hellwich, provided me with a solid foundation for my career in drug
development. Göran Ando, who suggested at our first meeting that my career prospects were not very favorable, for suggesting that a timeline should slip, and then
taught me, among many valuable lessons over the years, that anything can be done.
And of course my parents, who gave me every opportunity, and those close to me
who have supported me.
To everyone, thank you.
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Intelligent Drug Development
PART ONE
Setting the Scene
Introduction
Cutting the Gordian Knot
In the 4th century B.C., in the city of Gordium in Phrygia, there was a knot so complex that
nobody had been able to undo it. It was said that whoever undid the knot would become the
ruler of Asia.
Alexander the Great simply cut the knot with his sword and went on to rule Asia as far
as the Indus.
T
ime and money have always been important, intertwined factors in the context
of drug development, but never more important than they are now, especially
time. There are many reasons why. Competition has never been as keenly felt. Fewer,
larger companies spend huge amounts of money on research and development
(R&D) and, for the most part, have the same targets. Worldwide, first launches of
new medical entities (NME) are decreasing. In the 10 years from 2001 to 2010, the
number fell from 31 to 21, and only one-third of these launches were by major companies, defined as those spending more than two billion dollars on R&D in 2009
(2011 CMR International R&D Factbook). Investment in innovative biotechnology
has done little to change this so far. Market exclusivity (meaning the time during
which a new entity has no competition on the market) has diminished to the point of
being weeks, rather than the 10 years enjoyed by Imperial Chemical Industries (ICI)
with the first beta blocker.
A recent estimate for the loss of revenue for each day that a drug is in clinical
trials is between $600,000 and $8,000,000 (J. Hess and S. Litalien, Cutting Edge
White Paper). The five-month market advantage that celecoxib had over rofecoxib
was worth between $500,000,000 and $750,000,000 and established a competitive
edge that was never lost. So it doesn’t take a genius to appreciate the importance of
time above other things because, unlike other things, time can never be recovered.
Given these pressures, it would seem that making any improvement that would
give a competitive advantage would be a priority. Although all the elements of
drug development, from discovery to regulatory submission, are interdependent
and important, the clinical phase of development is crucial for success or failure.
Everything else becomes irrelevant if clinical benefit for the patient cannot be demonstrated. The careful, efficient management of this phase is essential to ensure that
reliable data can be generated rapidly and cost-effectively. It should come as a surprise, then, that performance measurements for the clinical trial process show a continuing and steady worsening. A good dose of antidepressants is needed to be able to
read them with equanimity. This is a small but relevant sample:
• About 80% of trials do not meet their original enrollment times. (J. Hess and
S. Litalien, Cutting Edge White Paper).
• Clinical trials last, on average, between 30%–42% longer than planned (J. Hess
and S. Litalien, Cutting Edge White Paper).
• Phase III trials run over schedule by an average of 6.2 months (J. Hess and
S. Litalien, Cutting Edge White Paper).
• Between 2005 and 2011, the increase in recruitment time was 29% for Phase II
studies and 20% for Phase III studies (2011 CMR International R&D Factbook).
• Development costs during delays can exceed $35,000 per day (Datamonitor
Report, “Launch Strategies” [DMHC2304], August 2007).
What is clear from these and other metrics is that companies are taking longer and
wasting more money to complete clinical studies. Larger companies might be able to
survive the consequences of these inefficiencies, such as loss of revenue and declining stock market value, but for small single-product companies they can be fatal.
All this is happening despite extensive redesign efforts involving experienced
consultants (at great expense); specialist companies providing expert solutions for
all the key issues faced in the trial process (never without expense); pervasive and
increasing (and expensive) use of technology to manage data and automate processes; and thousands of (relatively inexpensive) publications covering all aspects of
clinical development.
New ideas and technology are essential for progress and have been an essential
component in every area of scientific advance. So why is clinical development continuing to take longer and cost more? Perhaps the answer lies in what is being overlooked.
Scientific innovation is not the only way to higher R&D productivity. Attention to
the familiar management areas of cost, speed, and decision-making can still reap
rewards.
—E. David, T. Tramontin, and R. Zemmel. McKinsey Pharmaceutical R&D
Compendium 2010
To this list, I would add common sense and quality, but perhaps they are implicit in
the concept. But what does this mean in practice?
I hate quotations. Tell me what you know.
—Ralph Waldo Emerson, poet and essayist
[4]
Setting the Scene
So here is what I know about cost, speed, common sense, quality, and decision-making
in drug development and clinical trials, and why I wrote this book.
Drug development in the pharmaceutical industry is hampered by the following
unspoken but pervasive principles:
• if it is simple, complicate it;
• if it is complicated, make it unworkable;
• if there is a sensible solution to a problem, find a company policy to prevent its
application;
• if no such policy exists, invent a suitable regulation;
• season liberally with bureaucracy;
• keep doing the same thing again and again, irrespective of the outcome.
There are understandable (though not excusable) reasons why this is so. Drug development is regulated, complicated, and enveloped in uncertainty every step of the
way. Heavy regulation and penalties for noncompliance have engendered an attitude of caution and unnecessary over-complexity that can obscure the fundamental objectives; the regulations become an end in themselves. All this is reflected in
over-elaborate bureaucratic and increasingly inefficient processes. Complexity also
derives from the numerous pharmaceutical-related disciplines, some internal and
others outsourced, that are interdependent and have to be coordinated. Each individual clinical trial involves contractual, regulatory, and ethics approval at each site
and in each country. These processes are often sequential, always time-consuming,
and sometimes beyond direct control, leading to uncertainty. Finally, the complexity
and uncertainty are compounded because all patient-related activities have to be carried out through independent third parties.
There are, therefore, a lot of trees in the clinical research forest, with several possible paths through them and obstacles beyond our control. And yet it is possible to
see the wood; there are many parts of the trial process over which companies have
enough control to be able to minimize or even eliminate uncertainty, but they consistently fail to do so.
Why? The main reason is that ways of doing things are entrenched, and little
encouragement is given to those who want to do things differently. As part of the
pervasive resistance to change, there are the standard excuses: “this is how it has
always been done”; “there just isn’t time right now”; “even if there was time, this isn’t
the right project”; “and who are you to want to change things anyway?” Add to this
the propagation of poor practices by inadequately trained or inexperienced staff with
inappropriate levels of responsibility, and the results are predictable. In this environment, anyone naïve enough to think that new ideas will be welcome soon learns to
take the path of least resistance. On the other hand, the creativity used to justify
repetition of failed processes and rejection of new ideas would, if properly directed,
solve every problem confronting humankind from climate change to hangovers.
This is not just a problem for big pharmaceutical companies with their reputations for monolithic operational and decision-making processes so slow that sloths
appear hyperactive in comparison. Experience in a spectrum of companies, from
Introduction
[5]
some of the largest to some of the smallest, has taught me that it is as much of a
problem for mid-size and even tiny, virtual startup companies, despite the myth that
these are much more innovative, nimble, and unencumbered by bureaucracy. The
virtues and sins ascribed to companies by virtue of their size alone is nothing more
than mindless typecasting; the distribution curve for good and bad practices is the
same in each category and entirely dependent on the qualities and attitudes of the
people involved.
In summary, there is a blind spot for the lumbering, inefficient, and often mindless processes that form the core of the industry’s received wisdom, and its reluctance
to adopt alternatives. As a result, the drug development process has become more
and more complex, inefficient, and time-consuming, resembling a latter-day Gordian
knot. The objective of this book is to show how the knot can be unraveled, if not with
a single stroke, at least by a few well-aimed blows, to make drug development
•
•
•
•
faster;
more efficient;
of higher quality;
more cost-effective.
Furthermore, this is relatively straightforward, involving the consistent application
of simple approaches based on common sense to management areas that are, for the
most part, familiar. The intent is to stimulate everyone involved in clinical trials to
take an intelligent approach (the intelligence to which I refer in the title of this book
is that of the reader, not mine) by suggesting ways of doing things that everyone
can adapt and modify according to need. Since the suggested approaches are not
dependent on either a particular company structure or any specific technology, they
can be tailor-made for any company, department, or team, whatever the size. The
approaches are
• ones of principles rather than directives (though specific processes are given in
detail);
• global in concept;
• objective-oriented;
• based on clear and detailed planning;
• aimed primarily at registration studies, though equally valid for post-registration
studies of all kinds, including non-interventional studies;
• flexible in that they are not structure- or technology-dependent;
• of relevance to anyone involved in clinical research, including investors who want
to see their money used effectively;
• above all, ones of common sense, simplification, and elimination of random
motion.
One thing that I would like to emphasize is that very few, if any, of the individual
components of my book are either new or original. What they represent is the distillation of the most effective approaches to clinical research that I have experienced.
[6]
Setting the Scene
However, given how issues in clinical development are currently addressed, implementing the elements described in this book would indeed provide both a new and
an original approach in most cases.
Like any process, clinical development comprises a number of actions, some carried out in parallel and others sequentially, which are interdependent. Because of
this interdependence, the most successful outcome will result only if all of the key
factors described in the book are addressed in every trial, rather than picking the odd
one here and there. Improving individual aspects will always bring improvement, but
the whole is always greater than the sum of its parts. That is not to say that the book
is exhaustive; the principles described can be applied to other aspects and improve
performance even more.
I am looking for a lot of men who have an infinite capacity to not know what can’t
be done.
—Henry Ford, industrialist and founder of the Ford Motor Company
One reaction that (from my own experience) will almost certainly occur frequently
as the book is read is “It can’t be done!” Certainly there will be instances when the
reader can think of solutions better adapted to their particular circumstances, or
even better solutions period. The more often that happens, the better. There might
also be specific aspects that cannot be implemented in a given institution or country, at least not as described, because of local regulations. But for the most part,
I have found that “It can’t be done!” is a euphemism for “I don’t want to do it.”
One thing is certain. It can be done because it has been done, successfully.
Pharmacia implemented a number of the practices described here (as part of a much
broader companywide initiative) with the result that the company rapidly achieved
the leading position among its peers in clinical study cycle times. Figure I.1 shows
800
700
600
Days
500
Pharmacia (PHA)
14 Major companies (ex PHA)
1
400
300
10
200
1
6
100
1
2
0
Total Study
Duration
Protocol
to First
Patient
Enrolled
Patient
Recruitment
Database
Locked
Key
Statistical
Analysis
Final
Integrated
Report
Figure I.1 Pharmacia reached a leading position in clinical study cycle times.
CMR global performance metrics 2001.
Introduction
[7]
the results early in the process; further significant improvements occurred over the
following two years before Pharmacia was taken over.
That the industry as a whole not only comes nowhere near achieving these metrics more than 10 years later but also accepts a worsening situation is a sad tribute
to its continuing reliance on long discredited and entrenched attitudes and practices.
A Few Definitions and Explanations
In this book, the term “pharmaceutical industry” is used to encompass all those
entities that develop drugs, whatever their size and irrespective of the type of molecule being developed. By definition, the term “pharmaceutical” encompasses all
substances used for medicinal purposes, and the general approach needed to reach
a clinical development objective (whether making a quick return for investors or,
at the other extreme, achieving successful commercialization) is the same in each
entity.
Numerous statistics are quoted. They are only as accurate as the methodology for
collecting them allows, and their variability reflects the different contexts in which
they are collected. The intention is not to present these data as hard and fast numbers but to provide support for the contentions that are being made.
Finally, a few words about what this book is not. It is very irritating to go to a
game expecting to see football and then finding out that it is baseball (though not as
irritating as listening to those who know that they are going to a football game and
who then complain because it is not baseball). To minimize the risk of the former
(the latter are beyond redemption), let me emphasize what this book is not. It is not
a detailed description of each step of the clinical trial process; it does not address
the underlying scientific basis of protocol design; it is most certainly not primarily
about good clinical practice (GCP); and it does not cover quality control, regulatory
affairs, or safety reporting. Books on these topics exist in abundance, and the present work should be viewed as an (important) adjunct to, not a replacement for, clinical trial manuals. While this is not intended to provide hard-and-fast rules, there is
an emphasis when I know that something done a certain way has been consistently
successful. But if you know a better way, please go to it.
In summary, the purpose of this book is to identify the basic essentials of clinical
development and to stimulate ways to address them simply, logically, and without
prejudice. The intended outcome is the rapid and cost-effective collection of accurate, relevant data, increasing the certainty that intended milestones will be reached
within planned timelines and budgets.
[8]
Setting the Scene
C h apter 1
Aiming for Excellence
We are what we repeatedly do. Excellence, then, is not an act, but a habit.
—Aristotle, Greek philosopher and scientist
Introduction
Clinical trial processes are what we repeatedly do in clinical research, but, unfortunately, the habit of excellence is not as prevalent as it might be. Processes are only
as good as the ways in which they are carried out, so this aspect is worth looking at
before examining the processes themselves.
Excellence means the very best that is achievable in a given situation with the
knowledge and resources available, and it is not to be confused with perfection,
which is rarely attainable, and trying to achieve it is a waste of time.
Although the rational implementation of the various approaches described
later can help to make the clinical development process significantly more efficient, this will not in itself achieve excellence. Implementation needs to take place
in a cultural, intellectual, and operational environment that lends the necessary
support. There are many possible components of such an environment, but one
can go far by
•
•
•
•
instituting some basic behavioral elements;
doing things as well as they can be done all the time;
simplifying processes;
not allowing regulations to develop into liabilities.
Behavior with Benefits: A Little Light Philosophy
I have included this section risking that it might be considered unnecessary and
patronizing by some. After all, everybody believes that their behavior is impeccable,
just as everybody is a perfect driver. It only takes a few people to behave badly to
poison an organization (or to injure others).
Laws control the lesser man. Right conduct controls the greater one.
—Chinese proverb
Good behavior is the last refuge of mediocrity.
—Henry S. Haskins, stockbroker who was expelled for alleged misconduct and
published his aphorisms anonymously
Can principles be applied that encourage positive, ethical, complex, and intelligent
behavior without retreating into the lowest common denominator of mediocrity?
One can argue the extent to which principles can help to achieve these objectives,
but what is undeniable is that, in their absence, the results can be extremely damaging.
This is exemplified not only by the poor performance metrics but also by the poor reputation* of the pharmaceutical industry in the public’s view. In a poll carried out by Harris
in 2010, only 11% of respondents considered pharmaceutical and drug companies to
be “generally honest and trustworthy.” The purpose of this chapter is to describe these
basic principles and to explain why they are important. They form not only the foundation on which rests the favorable outcome of the approaches described in subsequent
chapters, but also the foundation for a successful, efficient, and trustworthy company.
The principles define the ways in which people behave and approach their daily activities and relationships at work; in other words, they define a culture. The culture of a
company should determine how everybody is expected to behave, and it should establish
the environment in which this behavior can occur unimpeded. Successful implementation can come only from the top of the company, and it has to be managed assiduously.
An important aspect to consider here is the relationship of culture to organizational
structure. Undue emphasis is often put on structure and organizational charts. It is
certainly important to know the distribution of responsibilities, both for activities
and for people, but it is far more important to know how people will work together.
How people work together depends primarily on the culture, not on the organizational
structure, which often serves to prevent collaboration and fosters an isolationist mentality as managers build protective walls around their chart-centered fiefdoms.
Behavioral principles by which everyone agrees to be bound are therefore essential, provided that they can be applied successfully. Factors that contribute to success
include the following:
• The principles need to be rational, relevant, and clearly defined.
• Only behaviors essential for success should be included.
* A colleague in the industry once told me that he had a brother who sold military weapons. At social gatherings, his brother would be quite open about his job, while my colleague
concealed his occupation to avoid being criticized. This story may well be apocryphal, as
I have heard different versions of it since, but it nevertheless reflects the perceived relative
standing of the pharmaceutical industry.
[10]
Setting the Scene
• Communication of the principles has to be meticulous, with frequent
reinforcement.
• Senior management must set the example.
• Nobody is exempt.
• Assessment of behavior should be an integral and significant part of annual objectives and performance appraisals.
• Failure to comply with the principles implies a mismatch between an employee
and the company and should be addressed swiftly and openly.
Every company has a different emphasis on what is important and defines required
behaviors accordingly. I would argue that the following encompass most essential
elements:
•
•
•
•
•
•
•
Honesty;
Killing the blame culture: accountability and collaboration;
Going beyond the job description: trust, delegation, and initiative;
Open-mindedness: listening, learning, and adapting;
Setting the bar: measuring, benchmarking, and committing to the highest standards;
Allowing people to be themselves;
Keeping the patient in mind (at all times).
Honesty
It is very unlikely that any company, or individual, in the pharmaceutical industry
would ever admit to condoning or performing dishonest practices. Yet constant revelations of malpractice indicate otherwise. The pressures for positive outcomes are
intense, so that an honorable intention may be subverted either by force and fear of
retaliation or, more insidiously, by a creeping process of rationalization (or both) in
which dishonest behavior becomes accepted practice. Here are a few common examples, from my experience alone, in clinical trials.
• Deliberate incorporation of bias in study design.
• Carrying out underpowered studies, knowing that results are unlikely to be interpretable. Unless patients are advised that this is the case, their inclusion is unethical, and the study is in any case a waste of money. This is a common temptation
in early development, especially when funds are limited.
• Nevertheless interpreting these results, with whatever emphasis is most
self-serving.
• Resuscitating negative studies by presenting unspecified analyses of dredged data
as valid endpoints, rather than as hypotheses to be tested.
• Underplaying (even hiding) adverse events.
• Suggesting efficacy when none has been shown. Often done by emphasizing borderline statistical over clinically irrelevant differences or describing numerical differences as “trends” in the absence of statistical differences.
A i m i n g f or E x c e l l e n c e
[11]
• Publishing misleading articles by omitting confounding data.
• Inducing compliant opinion leaders to spin a slanted company point of view.
• Putting patients at risk by continuing to study compounds that are clearly ineffective or unsafe; a temptation for single-product companies to postpone the
inevitable.
• Failing to keep post-approval commitments.
Honesty extends not only to giving accurate information but also to not withholding
information (which are two different things). There is little information in a company that it is essential to keep secret (though ensuring that what is confidential
remains so is another hallmark of honesty). “Transparency” has been trumpeted so
often as part of “value systems” that it is now almost a meaningless platitude, in
most cases defined more by the degree of opacity than the amount of light that is
shed. The tactic of keeping information for personal gain is as old as it is despicable,
as is the tendency to hide or dress up bad news. The latter demeans everyone in the
company and simply fuels lack of motivation and an overactive rumor mill. Honesty
and transparency mean telling the truth truthfully.
Killing the Blame Culture
“It’s not my fault!”
One of the behaviors that does most to poison any environment is finger-pointing and
failure to accept accountability. This is most marked when hierarchies, departmental
silos, and internal competition take precedence over company objectives and customers. The inevitable consequences are fear of failure, an overwhelming need to hide mistakes and cover one’s back, doing what one is told without question, and a stifling of
independent thought and initiative. In such an environment, people spend more time
and energy explaining why something can’t be done than would be needed to solve the
problem. Eliminating this behavior is the essence of any well-managed company.
“Can I help?”
The alternative approach, which brings the most benefit to a culture, is one of collaboration and personal and communal accountability, in which everyone, whatever
his or her role, is considered to be essential to and therefore accountable for the success or failure of the company. This applies to all projects and activities, and goes well
beyond simply being a member of a team. The concept encompasses many behavioral
aspects, including trust, honesty, a broader outlook on the activities of others, and a
greater motivation for being involved.
A broader outlook on (and involvement in) the activities of others brings significant rewards by substituting understanding and reason for frustration and criticism.
[12]
Setting the Scene
One solution to the perennial tension between R&D and marketing, in which marketing is always asking for the impossible and R&D is never providing essential data,
provides a useful example. This was to appoint both a senior R&D executive and a
senior marketing executive to co-chair the overall development oversight committees, instead of just an R&D person as is the norm. The result (after some significant
initial misgivings) was greater all-around understanding, better aligned objectives,
and considerably less friction.
Some people interpret communal accountability as a way of dissipating blame
among a large number of people so that no single person is censured. This is the
opposite of the intent. Everyone concerned will always be held accountable, but the
emphasis is on addressing problems rather than on allocating blame. If people are
not afraid to identify things that go wrong, they are more likely to do so as soon as
possible and collaborate in correcting them quickly. In fact, the resultant attitude of
collaboration, within and across hierarchies and functional boundaries, is more than
likely to prevent mistakes and delays.
Going beyond the Job Description: Trust, Delegation, and
the Use of Initiative
In the managerial organization, the top people sit in judgment; in the innovative organization, it is their job to encourage ideas, no matter how unripe or crude.
—Peter F. Drucker, management innovator and consultant
A lot of people never use their initiative because nobody told them to.
—Banksy, graffiti artist and satirist
The tyranny of the job description, aided and abetted by the myriad boxes of the intricate organizational chart (­figure 1.1), serves organizations very poorly. The primary
purpose of a job description is to establish the minimum that an employee should
be capable of and responsible for in an organization. It should not be a box in which
an employee is locked and out of which he or she can’t escape (“That’s not in your job
description”). A significant proportion of company employees will be people who are
only comfortable and effective when locked in a box (“That’s not in my job description”).
Organizations cannot survive without a number of such people, who fulfill vital and
productive roles. To go beyond survival, however, it is essential to encourage those
who do not want their roles to be circumscribed, and to provide the necessary environment. It makes no sense to spend time, money, and effort employing good people
and then constraining them from using the full range of their talents.
Reining Henderson in may be the opposite of what should be done. Emphasis on
hierarchy and control, with its implicit lack of trust, leads to a putting-people-ina-box and defense-of-turf mentality, and it is symptomatic of poor management or
incompetent staff, or both. Lack of trust and control inevitably leads to a lessening of
standards, because why bother to do one’s best when someone else will check it and
correct it even when no correction is needed (those in control have to justify their
A i m i n g f or E x c e l l e n c e
[13]
Figure 1.1 www.CartoonStock.com.
existence). Although the balance between oversight and delegation is important and
challenging even with the best of employees, it is getting that balance right that
leads to the greatest productivity. Allowing people to use their initiative and giving
them responsibility unrelated to their level in the company (being senior to someone
is not necessarily synonymous with being superior) are the best ways to cultivate
motivation and a can-do, problem-solving attitude.
Open-Mindedness: Listening, Learning, and Adapting
Listening, learning, and adapting are the natural complements to trust, delegation,
and encouragement of initiative, and their value can’t be overstated. They require
open-mindedness, without which the innovative edge is lost. Every technological
advance, including so many things we take for granted (such as rail travel, the computer, the light bulb, television, and photocopying), has been declared impossible,
useless, or unlikely to catch on by people whose minds were closed. Without the flexibility allowed by listening and learning, the effective day-to-day management of any
organization takes place in a straitjacket. The following points may help to explain
the concept and underline the value of open-mindedness:
[14]
Setting the Scene
• Seniority does not automatically confer a monopoly on ideas or knowledge. There
is no one to whom one should not listen.
• Listening to opinions and discussing them seriously are an important part of
educating all parties concerned. Being listened to as an equal is a strong motivating factor, and it leads to further open-mindedness and a more inclusive way of
thinking.
• Ideas or opinions may be of no value, but the only way to come to that conclusion
is to listen carefully and then think about these ideas or opinions as if they were
your own. Being dismissive of those one does not respect, for whatever reason, is
a foolproof way of learning nothing.
• Listening to contrary views is the only way to come to a rational point of view,
but this is anathema to some. These people induce a culture of fear and retribution in which open discussion is suppressed, so that they are surrounded only by
yes-men and yes-women.
• Being the messenger of bad news is always unpleasant, but it is much more so
if no one listens, learns, and acts appropriately in response to the information.
Cultures in which the instant reaction is to look for someone to blame (see above)
suffer the consequences of delayed, distorted, or even suppressed reporting of
negative information, with the potential to put patients at risk or to threaten the
viability of a company.
• A central component of competent management is that, once a decision is made,
it should be supported by all and implemented effectively. This can only happen
when decisions are made on the basis of all relevant information, so that they
are rational and take into account all views and opinions, and there is reasonable
consensus, and those with contrary opinions feel they have at least been taken
seriously. Failure to listen is at the root of many poor decisions or the inability to
implement them properly.
• New information sometimes makes it necessary to change a decision. On other
occasions it may become apparent that a decision, however well thought out,
was just plain wrong. There is sometimes a reluctance to adapt in these situations on the basis that changing decisions is a sign of weakness, but all decisions can be influenced by subsequent events, mistakes do happen, and it is
a sign of intelligence and integrity to react accordingly. Only those unable to
adapt or those with a personal agenda avoid or criticize a well-reasoned U-turn.
Setting the Bar: Measuring, Benchmarking, and Committing
to the Highest Standards
“We’re doing a great job!” Or are we? Without a commitment to maintaining the highest standards at all times, the decline to mediocrity is inevitable. Making people feel
good by praising efforts irrespective of quality is one symptom of such a decline,
and only regular benchmarking can reveal how great a job is really being done. What
may be good locally may not be good elsewhere, and what was good yesterday may
A i m i n g f or E x c e l l e n c e
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not be good today. The purpose of benchmarking is to establish best practices, not
in order to copy them, but in order to do better. And after having done better, it is
even more important to benchmark again, as somebody else is certain to have done
better still in the meantime. In the 1980s, Chrysler set a standard by developing a
new car in just four years, a record. Almost immediately, Toyota reduced the time to
two years; the latest Camry was apparently developed in 17 months. Benchmarking,
listening, learning, and adapting to change are essential to prevent complacency and
self-congratulation from lowering standards. Without these, it is impossible to aim
for excellence.
The starting point, and the most important element of all, in determining standards is the quality of the people working in a company. It is essential to employ the
right people and then allow them to use all their talents.
An organization, no matter how well designed, is only as good as the people who
live and work in it.
—Dee Hock, founder of Visa credit card association and management
innovator
It is self-evident that without the right people success will be hard to come by, whatever the potential of a new compound. Drugs do not develop themselves, and failure
to achieve the relevant milestone (whatever it may be: a liquidity event, regulatory
approval, or commercial success) is as often due to mismanagement as to any failure
of the drug itself. And yet companies, from the smallest to the largest, continue to
employ staff for critical positions on the basis of criteria that do not reflect suitability for the role.
1. The right people are those with the relevant experience and track record, not
necessarily those who have distinguished themselves in other related spheres,
such as medical practice, or who have a certain educational background or
post-graduate degree. Education and distinction are valuable assets and may
indicate potential. However, the skills needed to develop and commercialize
drugs are very specific and can only be properly acquired in the pharmaceutical
industry environment with experienced support and training.
2. The number of experienced drug developers is limited, especially so in areas
where there are few large pharmaceutical companies. The high-profile companies can attract enough candidates to be selective, and larger companies have the
resources to train those with potential, but smaller companies have neither of
these advantages. The consequence is that they often employ bright but inexperienced staff who receive little guidance and whose errors are therefore entrenched,
compounded, and disseminated as they move from company to company. In these
circumstances, it is far better to use outside expertise, either until a suitable candidate is found or as a permanent solution.
3. Employing someone who is not competent to do the assigned work is a greater
risk than not employing anybody.
[16]
Setting the Scene
Letting People Be Themselves
The best strategy for building a competitive organization is to help individuals become more
of who they are.
—Marcus Buckingham, author and business consultant
The most important asset of any company is the people who work there, and people come in a wide rage of nationalities, social and educational backgrounds, and
cultures. It is precisely this variety that provides the basis for success, so the first
principle for establishing a company culture is to ensure that none of the positive
attributes are suppressed, allowing people to become more of who they are. Cultures
(national as well as corporate) run between two behavioral extremes: from “nothing
is allowed without specific permission,” much beloved by dictators and micromanagers, to “everything is allowed unless otherwise specified,” much beloved by anyone
with a modicum of initiative and creativity. The latter approach obviously allows the
most freedom and creativity, but the tricky part is how to curb counterproductive
behavior without eroding the positive aspects by imposing mindless uniformity and
mediocrity.
Remembering the Patient at All Times
The many hurdles that have to be overcome in drug development and the enticing
promise of commercial success can obscure the fact that there is only one customer
for the product: the patient. If there were no patients, there would not be a market
for drugs, or at least not for drugs as therapeutic agents. Being involved in drug
development therefore imposes first a responsibility to patients, and only then a
responsibility to safeguarding intellectual property. It is worth emphasizing this
aspect because of the many common practices, some of which were listed in the section on honesty, that are directly contrary to the best interests of patients and can
even put them at risk. The consequences of all actions for patients should always be
the primary consideration, whatever their short-term objectives.
Doing Things Right
Failure is not a single, cataclysmic event. You don’t fail overnight. Instead, failure is a few
errors in judgment, repeated every day.
—Jim Rohn, successful entrepreneur
In their paper “Toward a Theory of Medical Fallibility” (1976), the philosophers
Samuel Gorovitz and Alasdair MacIntyre described one way of classifying scientific errors as arising “. . . either from the limitations of the present state of natural science—that is, from ignorance—or from the willfulness or negligence of the
natural scientist—that is, from ineptitude.” This classification applies equally well
A i m i n g f or E x c e l l e n c e
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to errors arising in just about any walk of life, as exemplified by the surgeon Atul
Gawande in his book The Checklist Manifesto (2009). Subtitled How to Get Things
Right, this book illustrates the medical disasters that can occur if procedures that
are known to work are not followed (ineptitude), and the dramatic improvements
that result from simply having and rigorously following a checklist. A striking confirmation of the value of the checklist approach was seen in a study by Arriaga
et al. (2013) of simulated operating room crises; 23% of lifesaving process steps
were missed when no checklist was used, compared with only 6% when a checklist
was available.
The checklist approach is already used, to a lesser or greater extent, in several
aspects of drug development, sometimes as an actual list of actions to be completed
or document requirements, but also in the form of templates, which are just checklists in a different form. Checklists exist for many of the operational processes and
can be adapted or written to cover any eventuality. Investigators and their site staff
are often provided with cards summarizing key aspects of a protocol as reminders.
Patients may be provided with cards to remind them when to take trial medication,
when to carry out certain procedures, or when to show up for clinic visits. All of these
approaches are encompassed in the broader concept of the checklist, though not as
consistently or extensively as they might be.
Although checklists are an essential component of this approach to doing things
correctly, they almost certainly do not work in isolation within an organization. All
of the elements described in this chapter play a role, as exemplified by a program
called the Comprehensive Unit-based Safety Program (CUSP) (B. M. Kuehn, JAMA,
2012, 308: 1617–1618), which has helped to reduce central line infections in hospitals. Apart from the checklist, success has been ascribed to listening to and empowering those who are most involved (as opposed to taking a hierarchical approach), as
well as to aligning teams behind the objective, education, making execution mandatory, measuring outcomes, and acknowledging milestones.
Many may not find the checklist approach appealing, feeling that doing things
by rote constrains their intellectual creativity and initiative. After all, according
to Ralph Waldo Emerson, “A foolish consistency is the hobgoblin of little minds.”
The keyword there, of course, is “foolish.” Consider the act of breathing, one of the
things that everyone relies on for consistency. Unless the incredibly complex process of breathing is repeated consistently and properly every time, we will die. And
yet few ever think about breathing; it is taken for granted and allows us the wonderful freedom to pursue interesting and creative activities. So it is with the processes
that are necessary for drug development. They should be repeated consistently and
perfectly every time so that time, resources, and money are freed up to allow genuine creative activity in place of the time, resources, and money used up in trying to
fix things.
The issue is not primarily about checklists, therefore, as these are simply one
means to an end. The issue is about doing things correctly, and it applies to every
single aspect of drug development, from strategic planning to operational implementation. Whatever the approach taken, the important thing is to instill the notion that
not doing things correctly is unacceptable.
[18]
Setting the Scene
Late-Stage Failure, a Specific Example of the High Cost of Not Doing
Things Correctly
Estimates from a number of sources for Phase III failure rates over the past 10 years
or so range from 30% to 50% (PAREXEL Biopharmaceutical R&D Statistical
Sourcebook, 2012/2013: 256). Of the 83 Phase III failures documented between
2007 and 2010, 67% were due to failures of efficacy (J. Arrowsmith, Nature Reviews
Drug Discovery, 2011, 10[2]‌: 87). There is enough evidence to suggest that a significant proportion of this high percentage of failures can be attributed to a failure to
carry out Phase II properly (Deloitte Recap LLCs DEVELOPMENT optimizer 9/2011)
(table 1.1). A comparison of compounds from the more than 200 companies in the
Recap Portfolio Index that were terminated in Phase III between January 2000 and
May 2011, compared with those approved by the FDA in the same period, shows
significant differences in their respective Phase II programs.
Not only did the failed compounds have significantly fewer studies and patients
in Phase II than the compounds that were approved, but 66% of the failed compounds progressed to Phase III on the basis of negative or neutral data, compared
with 20% of the approved compounds. The clinical endpoints had to be changed for
88% of the failed drugs, but only for 45% of the approved drugs. Investment in Phase
III was heavy, and the time to final outcome was no different for the failures compared with the successes.
The temptation to cut corners in Phase II is considerable, especially for startup
companies with limited funding. The objective is all too often to include the minimum number of patients to obtain some data from which a speculative supportive
conclusion can be extrapolated, rather than to power for definitive data. The irony is
that these small, often single-compound startup companies are the very ones that
have the most to gain from doing things right. How investors and CEOs fail to understand that underfunding early phase proof-of-concept studies not only costs them
money but delays exit strategies is one of the mysteries of the industry. As stated by
Arrowsmith (Nature Reviews Drug Discovery, 2011, 10[2]‌: 87), “It is important to
avoid wishful thinking when making a Phase III decision [or any decision dependent
on early phase data . . . added by the author], and instead rely on high quality scientific
Table 1.1. Phase II and Phase III programs for compounds that failed
in Phase III compared with compounds approved by the FDA
Median No Phase II Trails
Median No Patients in Phase II
Median No Patients in Phase III
Time From IND to Outcome
Terminated Phase III or at
Filing (n = 33)
Approved by FDA (n = 64)
1.0*
69**
821
7.4
2.0*
171**
697
6.9
(Yrs)
* p = 0.0002 ** p = 0.03
Adapted from Deloitte Recap LLCs DEVELOPMENT optimizer 9/2011.
A i m i n g f or E x c e l l e n c e
[19]
evidence to support decision making. The evidence comes from fully testing mechanisms against each target indication using well-defined endpoints in the right population in Phase II. . . . There are pharma companies that have already demonstrated
that good science can deliver a steady flow of robust clinical proofs of concept.”
Failure to carry out definitive early phase studies due to under-powering (too few
patients), inadequate exploration of all aspects of the new compound (too few studies), and wrong clinical endpoints (poor understanding of the clinical relevance of
the mechanism of action) result in
• equivocal false-negative or false-positive results;
• abuse of trial subjects, whose participation has been pointless;
• decisions (whether to continue development or sell the compound) based on
rationalization and wishful thinking;
• high risk of later failure;
• long delay in reaching the decision that the drug has failed;
• further abuse of patients, as participation is not only pointless but may put them
at risk;
• unnecessary costs.
Looking at the consequences of just one limited example of not doing things correctly
illustrates just how extensive the damage can be if the problem is more generalized.
Keeping Things Simple
Things should be made as simple as possible, but no simpler.
—Albert Einstein, physicist and Nobel Prize winner
Simple, clear purpose and principles give rise to complex and intelligent behavior. Complex
rules and regulations give rise to simple and stupid behavior.
—Dee Hock
A common fallacy is that speeding up a process can only be achieved at the expense
of quality. In fact, error rates have little to do with speed and are mainly due to complexity, carelessness, and incompetence. Simplification is the basis for speed and efficiency, but the trend in the industry is to ever-increasing complexity. This is mainly
driven by the urge to cover all bets because of fear of not complying with an (often
imaginary) regulation, by the notion that more is better, and, in the case of protocols, by the desire to collect data beyond the needs of the study objective, all at the
expense of achieving the original objective. There are two aspects to simplification.
The first is making what needs to be done simpler. The second is the elimination of
all that does not need to be done. The principle is quite simple: When in doubt, take
it out.
The following are examples of unnecessary complications and their consequences
in relation to protocols, data collection, and clinical trial processes.
[20]
Setting the Scene
Protocols and Data Collection
The fate of protocols and case record forms (CRFs) over the 12 years from 2000 to
2011 provides a perfect example of unnecessary, avoidable complexity and its consequences. Analyses carried out by the Tufts Center for the Study of Drug Development
(table 1.2, K. Getz, November 2012) showed the following increases in the number
of procedures. The growth in complexity was greater in Phase I and II protocols than
in Phase III protocols, and it varied from therapeutic area to therapeutic area.
These increases in complexity may be explained by the fact that the “typical” protocol now averages seven objectives and 13 endpoints, “. . . with the number of less
essential endpoints per protocol nearly doubling the average level observed 10 years
ago” (“One In Five Procedures Generates Extraneous Clinical Trials Data,” Tufts
CSSD Impact Report, Vol. 14, No. 6, Nov./Dec. 2012). Not surprisingly, the length
of the CRF has had to keep pace, from an average 55 pages in the early 2000s to
about 180 pages in 2008–2009 (“Trends and Implications of Increasingly Complex
Protocol Designs,” Tufts Center for Study of Drug Development, 2009).
The negative consequences may be significant. During the period 2000–2003
to 2004–2007, enrollment rates dropped by 21%, cycle times were 75% longer for
the more complex protocols than for the simpler protocols, and volunteer retention
rates in trials fell by 30%. These phenomena have been attributed to the hurdles
imposed by increasing eligibility criteria and the burden of undergoing more procedures (“Rising Protocol Complexity, Execution Burden Varies Widely by Phase and
TA,” Tufts CSSD Impact Report, Vol. 12, No. 3, May/June 2010).
By themselves, these facts mean little. Increasing the amount of information
gathered in Phases I and II could be worth the extra effort, providing more definitive data to prevent the continued development of ineffective or potentially unsafe
drugs and allowing for leaner Phase III studies more representative of the general
population. Unfortunately, Phase III studies have not become leaner (they have just
become less fat compared to the others), and quantity is not synonymous with quality or necessity.
This is illustrated by the fact that only half the procedures support primary and
key secondary endpoints (“One In Five Procedures Generates Extraneous Clinical
Trials Data,” Tufts CSSD Impact Report, Vol. 14, No. 6, Nov./Dec. 2012), and
Table 1.2 Increase in the number of protocol procedures between
2000–2003 and 2008–2011.
Per Protocol
Unique procedures
(median)
Total procedures
2000–2003
2004–2007
2008–2011
% Increase
20.5
28.2
30.4
48%
105.9
158.1
166.6
57%
(median)
Adapted from K. Getz et al. Variability in protocol design complexity by phase and therapeutic area. Drug
Information Journal, 2011, 45(4): 413–420.
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[21]
between 15% and 30% of data are never used in a new drug application (Medidata
Insights Metrics Compendium, April 2012). There is also a financial penalty; the
cost of procedures to evaluate procedures associated with lesser endpoints is
estimated to be about 18% of the average trial budget (“One In Five Procedures
Generates Extraneous Clinical Trials Data,” Tufts CSSD Impact Report, Vol. 14, No.
6, Nov./Dec. 2012).
The validity of a study is not directly proportional to the amount and frequency
of data collection. On the contrary, the usefulness of a study is directly related to
the intelligent collection of relevant data at appropriate times. Simply collecting
unneeded data that may well never be analyzed is an enormous waste of time for
everyone involved, from patients to data managers, and the associated expenses
are significant. The following examples illustrate just how quickly the numbers
add up.
The first is a typical example of collecting data in a new trial because the same
data were collected in previous trials and, who knows, they might be useful. Or,
worse, it might illustrate the mindlessness of cutting and pasting from one protocol
to the next. This Phase III trial involved over 900 patients who were seen every week
for about a year on average. The protocol required that heart rate, blood pressure,
and temperature be measured every two weeks, despite the fact that there was no
pharmacological reason to believe that the drug would affect these variables, and the
fact that no effect on these variables had been observed in previous studies, including a large Phase III study. These seemingly trivial measurements amounted to about
90,000 separate numbers to be collected, written down, verified, corrected, entered
in the database, and forgotten.
The second example illustrates a universal phenomenon, namely the collection
of every possible detail relating to concomitant medications. There are specific concomitant medications that can influence the metabolism of trial drugs or confound
outcomes, for which detailed information is needed. The same is true of any drug
associated with a serious adverse event. But in general, all the information needed
about concomitant medication is the fact that it is being taken, and the relevant
dates. This approach is rarely followed. In the worst case I have seen, the form
required 12 items of information at each visit, in addition to site and patient identifiers. Whatever the amount of excess information collected per visit, it soon mounts
up, only to sit unused in the database at the end of the study.
The negative consequences of collecting unnecessary data are important:
•
•
•
•
•
•
•
•
Complexity increases.
The CRF becomes unwieldy and more difficult to complete.
Time is wasted in collecting and entering data.
The process incurs added costs.
The likelihood of errors increases.
Correcting errors takes time and increases costs.
The data may never be analyzed.
Frequent collection of unnecessary lab data can result in meaningless, random
shifts, requiring analysis and explanation.
[22]
Setting the Scene
Process Simplification
How often during your working hours do you think to yourself “Why on earth am
I doing this?” (or something to that effect). If you are asking, it is probably because
the activity appears to add no obvious value. How often have you done something
about it? Probably not often, because if everyone who asked the question then did
something, the development process would be more efficient than it is today.
An entire industry has grown up to help companies redesign and improve the
efficiency of their processes. To manage this sort of change effectively company-wide
takes commitment, time, money, and expertise, and is too involved to cover in detail
here. However, an understanding of the reasons why processes become complicated,
the types of unnecessary activities that result, and their consequences might help
not only in answering the question “Why am I doing this?” but also in providing the
impetus to do something about it.
Some causes of process complication
Culture, whether national or company-related, has a very potent influence on processes. The more hierarchical or authoritarian (or both) the culture, the greater the
likelihood of unnecessary layers of management and regulation. If, in addition, the
culture is one of finger-pointing and punishment, fear will lead the staff to construct
“safeguards.”
Inexperience can cause an excessive concern about doing things wrong, leading to
the adoption of excessive precautions.
Ignorance is not only due to inexperience; it can be found at all levels of a company, pervading the ways in which people are expected to work.
Risk-aversion inevitably leads to overuse of caution and over-interpretation
of rules.
Lack of standardization means that ways of doing things are reinvented each time,
and one way may not be compatible with another.
An organizational instead of process perspective can cause the concerns of a department (in effect, a silo) to take precedence over the objective and how it is achieved.
Quality control instead of quality assurance destroys the motivation to get things
right the first time and results in incessant checking.
Poor management lacks clear targets and effective coordination.
How these causes of complications manifest themselves
Designing a process for the exception, not the rule
The underlying causes are inexperience or risk-aversion, especially in heavily authoritarian cultures. The trigger is usually an unexpected or infrequent event to which
there is an overreaction, so that a relatively straightforward process is then modified
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[23]
to cope with this event should it recur (of course, it might not). The result is that the
new process, inevitably more cumbersome and time-consuming than the previous
one, is applied unnecessarily all the time. Processes are best designed to cope with
the norm, with fallback measures for exceptions.
One way to understand this is to think about the way department stores process
requests for store cards. In the vast majority of cases, this takes very little time;
lengthy credit assessments, which can take weeks, are only carried out if there is
something to suggest a poor credit rating or if exceptionally large sums are involved.
Multiple checks and signatures
What a colleague of mine called “Checking Pox” results from all of the causes listed,
whether singly or in combination. Whether due to lack of experience, lack of quality
assurance, risk-aversion, lack of trust, or hierarchical concerns, the result is multiple
review formal cycles and approvals, usually with lots (and lots) of signatures. During
these cycles, everyone involved feels compelled to comment, and trivia begins to
carry the same weight as any important observations. The result is rarely something
better, and often something worse.
Bottlenecks
Often the various approvals or process steps are overseen by a committee or an
individual. So everything is stalled until the committee or individual has acted.
Committees notoriously work according to fixed schedules and often push agenda
items to the next meeting if time runs out. The problem is compounded by poor
decision-making.
An example of how individuals (and culture) can cause bottlenecks occurred in
the Japanese subsidiary of a company for which I worked. We couldn’t understand
why there was often a delay, often very variable in length, for formal letters to be
sent from the Japanese office. It turned out that local company policy dictated that
all letters had to be stamped with the company seal, which was the responsibility of
one person and was kept in his desk. When he was absent (which was frequently),
the seal was locked away, and no one else was allowed to use it.
Handovers and sequential activities
When hierarchy and departmental concerns have priority over objectives, handovers
are the norm. There are many consequences: There is a reluctance to let go of something, so handovers cause delay; there is no incentive to do things well, as the next
group can fix whatever is wrong; any advantages derived from continuity of experience are lost in the handover; and, inevitably, activities become sequential instead of
being carried out in parallel.
[24]
Setting the Scene
Examples are plentiful. In many companies, there are groups that manage
clinical development through to “proof of concept” before handing over to different groups that will continue the development. The underlying idea is that
the proof-of-concept group has no vested interest in full development, and so
will be objective and kill the compound more quickly if necessary. In fact, with
rare well-managed exceptions, the opposite occurs: To justify their existence, the
proof-of-concept group will continue with various investigations well beyond
what is needed, and there is extreme reluctance to hand over projects that are
successful. I have sat through many a rationalization that proof of concept actually extends through Phase III. Once the transfer has occurred, the new group
starts without the considerable experience of the compound that the members of
the proof-of-concept group have acquired.
For examples of unnecessary sequential activities, one need look no further than
the clinical trial approval process, which involves getting regulatory, contractual,
and ethics approvals, though not necessarily in that order. In many countries, the
process is sequential, with each component involving several iterations as changes
(some vital for patient safety and others as trivial as changes in spelling) hold things
up until the next meeting. In one recent instance in the United Kingdom, the process took about six months after rapid approval by the Medicines and Healthcare
Products Regulatory Agency for a process that can be completed in less than two
months.
Conclusions
Processes are very important, but they are just means to an end, not ends in themselves. Concentrating on the process (or that part for which a person or group of
people is responsible) instead of the ultimate objective can result in the process taking on a life of its own. It then mutates and becomes even more complex so that, in
the end, time, resources, and efforts are wasted in trying to do something well that
needn’t have been done at all.
When you make a process simpler,
•
•
•
•
•
first and foremost, less time is needed;
fewer people are needed;
less money is wasted;
the quality of the result is higher;
everyone involved is happier.
Difficult though it is to overcome cultural and organizational obstacles to simplifying
processes, individuals can do a lot by
• questioning the status quo;
• ignoring their hierarchical status;
• putting team activities above departmental politics;
A i m i n g f or E x c e l l e n c e
[25]
• remembering that activity without purpose is random motion;
• concentrating on objectives and results.
Killing Good Clinical Practice: Turning Regulations
into a Liability
When confronted with a regulation, even the most sensible people suddenly seem
to become acutely risk-averse at the expense of common sense. The consequence is
a vicious spiral, starting with someone adding a few unnecessary embellishments
(“just to be on the safe side”) that are then mindlessly repeated and expanded
(“because this is how we do things”) until they become enshrined as a nonexistent
regulatory requirement (“because this is what the FDA/EMA wants”). There is no
better example of this effect than the response to good clinical practice (GCP). When
GCP started to be introduced in earnest in the 1980s, the objectives were clear and
rational: to ensure the safety of clinical trial subjects and the integrity of the data.
Since then, the requirements have been expanded, codified, and harmonized, but the
underlying objectives are unchanged.
What has changed in the interim is that the process, rather than the outcome, has
become the primary objective, with the focus on imagined GCP-related requirements
rather than the logical overall conduct of the clinical trial. The way in which companies approach the monitoring and source document verification in clinical trials is a
good illustration of the broader issue.
The International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) guidelines give three reasons
for monitoring, namely to assure patient safety, integrity of data, and compliance
with regulations and the protocol. The list of the monitor’s responsibilities is long
and inclusive; among these is the need to carry out source document verification
(SDV), in which data in the study CRF are compared with the data in the original
documents from which the data CRF were transcribed. The way in which monitoring procedures, including SDV, should be carried out is not specified, though there
are guidelines. These are clear in stating that “Statistically controlled sampling may
be an acceptable method for selecting data to be verified” (ICH-GCP [5.18.3]) and
that “. . . the monitor should compare a representative number of subject records and
other supportive documents with the investigator’s reports . . .” (FDA Guideline for
the Monitoring of Clinical Investigations, 1998) (author’s italics).
Despite this, SDV evolved into the fulltime obsession of clinical monitors in
which 100% of data were checked for all patients, and it became virtually synonymous with clinical trial monitoring. An unnecessary activity therefore took over
from an essential one. To make matters worse, the way in which monitoring visits
were structured, usually routinely every four to eight weeks, bore no relationship
to any specific needs. All this came about because of a baseless perception that it
is what the regulatory authorities wanted and that, without it, audits would fail,
without any thought as to the truth of this perception or the value of the activity.
Interestingly, studies by government and academic bodies perform far less SDV and
[26]
Setting the Scene
monitor much less frequently than pharmaceutical sponsors without any loss of
credibility.
In fact, far from adding value, this approach serves only to waste time and
money at the expense of more important aspects that should be addressed. A survey in Sweden in 2005 revealed that fully 25% of Phase III budgets was spent on
SDV (with an additional 25% spent on other GCP-related activities) (S. Funnings
et al., 2009). On the other hand, 20% of the budget was used to correct errors.
This may well reflect the lack of attention to other monitoring responsibilities; in
a recent report, monitors spent only 5% of their time talking to site staff (K. Getz,
March 2011).
In recent years, there has been a strong push to rationalize monitoring and
SDV, most recently by the FDA in a guidance document that emphasizes a centralized risk-based approach in place of the blanket site-based norm (FDA Guidance
for Industry, August 2011). This, together with the opportunity for more central
approaches afforded by the increasing use of electronic data capture, could save at
least 20% of costs (E. Eisenstein et al., 2008). Nevertheless, over 80% of companies still continue to carry out SDV on 100% of data (K. Getz, March 2011) despite
the cost, the lack of any evidence that it improves data quality, and the inaccuracies
inherent in the SDV process itself.
The most effective ways of ensuring that all of the monitor’s responsibilities are
fulfilled, that patients are not put at risk, that there is regulatory and protocol compliance, and that data are valid in cost- and time-effective ways are as follows:
• Have a comprehensive monitoring plan agreed upon with the investigator.
• Ensure the education of all involved at the site and any CROs involved.
• Spend as much time as needed onsite before the start of the study (upfront activities more than repay their costs).
• Put in place a system that alerts the monitor to any potential problem immediately.
• In any event, visit the site as soon as possible after the first patient or two are
entered.
• Visit the sites on the basis of needs or specific objectives, not at random, fixed
intervals.
• Be selective in SDV. Select a subset of patients and the data to be verified routinely, and only increase to 100% in all patients if there is a specific need.
Monitoring and SDV practices illustrate how the way in which GCP is understood
and applied not only subverts its original intent but has resulted in a clinical trial
process that has become progressively more bureaucratic, time-consuming, cumbersome, and expensive, without adding any value whatsoever to the outcome.
Reassessing GCP practices can often lift a considerable financial and resource
burden.
A i m i n g f or E x c e l l e n c e
[27]
PART two
Planning: From Chaos to Cosmos
Plans are nothing; planning is everything.
—Dwight D. Eisenhower, military commander and president of the United States
The nicest thing about not planning is that failure comes as a complete surprise, rather than
being preceded by a period of worry and depression.
—Sir John Harvey-Jones, chairman of ICI
Doing things is much more fun than thinking about doing things, which is why planning often takes second place to action. Another reason is that things always need to
be done in a hurry. Yet the first quotation comes from someone for whom action was
the sine qua non of his profession. Stifling the urge to get going in favor of taking the
time to plan carefully minimizes the risk of avoidable failure.
Why should that be, given that things rarely go according to plan? The answer is
that it is not the plan itself but the planning process that is essential, because the
process
•
•
•
•
•
•
•
•
•
•
defines what tasks need to be completed, by whom and by when;
identifies potential issues;
identifies bottlenecks;
shows the impact of delays;
facilitates contingency planning;
enables prioritization;
commits a team;
makes it more likely that all stakeholders are aligned;
is essential for good project management;
provides a baseline for monitoring, review, and management.
This does not mean that the perfect plan exists; the other extreme, planning ad nauseam, is almost as bad as not planning at all. Perfectionism must be balanced by
pragmatism or, as put by another famous general, George Patton, “A good plan implemented today is better than a perfect plan implemented tomorrow.” The uncertainty
INPUT
PLANNING LEVEL
PRIMARY OUTPUT
Portfolio strategy
Information on the compound
Competitor information*
Regulatory information*
Standard of care*
Market research*
Intellectual property*
Resources*
STRATEGIC PLANNING
Target Product Profile
Target Product Profile
TACTICAL PLANNING
Overall Project Plan
comprising
individual
Functional Plans
Clinical Development Plan
OPERATIONAL PLANNING
Individual studies
*Country by country
Figure II.1 The basic strategic, tactical, and operational components of a development plan.
inherent in drug development means that intelligent risk-taking is the norm, and
the planning process is aimed at reducing the level of uncertainty and identifying
and mitigating (though not eliminating) risk.
It is rare (though by no means unheard of) for the development of a compound to
get underway without a plan including strategic, tactical, and operational elements,
as shown simplistically in figure II.1.
Although they may have a lot of components in common, these plans vary enormously in detail, specificity, and rationality. Two of these components that, in different ways, have a profound effect on the outcome and are rarely addressed optimally
are the construction of the target product profile (TPP) and planning for individual
clinical trials.
[30]
Planning: From Chaos to Cosmos
C h apter 2
The Target Product Profile and Its Uses
If you don’t know where you’re going, you’ll end up somewhere else.
—Yogi Berra, renowned baseball player
T
he decision that a new chemical entity (NCE) is a serious candidate for development entails a financial commitment that is the most important one that a pharmaceutical or biotech company can make. The next most important set of decisions
is concerned with making sure that development is aimed at a rational and focused
set of objectives. Ending up "somewhere else" usually means failure. The two most
important activities to ensure ending up in the right place are
• preparing the Target Product Profile (TPP);
• managing the disparity between results and expectations: the gap analysis.
The Target Product Profile
Since just about every development plan has a TPP, there would seem to be nothing new to say, so why devote most of a chapter to this subject? The answer is
that the ways in which TPPs are prepared and the formats in which they appear
vary enormously. Few seem to be the result of an exhaustive process and, as with
most planning and preparatory activities, the process is just as important as the
outcome.
Objective
The objective is to provide a concise, structured basis for designing a development plan that (if successfully implemented) will lead to an uncomplicated
approval process and to the desired labeling and data sheets in all markets. The
TPP is a summary of requirements for an optimal but realistic profile of the
product.
Characteristics of the TPP
• It precisely defines the expectations for the compound, with an explanation for
these expectations, so that if they are not fulfilled, a rational analysis of the continuing viability of the compound can be carried out.
• It is well-researched and detailed, including competitor and commercial information, and anticipates the environment at the planned date of launch.
• Although written when there is little information about the drug in question, it
is based on a solid foundation of objective data and not on outlandish or wishful
thinking.
• It is a relatively fixed document and should only be amended when changes are
based on factors that could not have been foreseen when the TPP was originally
drafted, such as the introduction of a new class of drugs for the same indication
or a change in the standard of care. Unexpected or undesirable study results are
not in themselves valid reasons for changing the TPP.
• It provides the focus for all development activities.
Some Common Factors Limiting the Value of the TPP
“It can’t be done!”
And so it isn’t done properly. Much of the content is theoretical, though based on
a foundation of solid data and careful analysis. There is sometimes a reluctance to
commit to theoretical targets, especially by those who are uncomfortable with uncertainty. It is rare, however, that there are insufficient data or that there is no concept
of the properties that would make the compound clinically or commercially viable
to allow realistic targets to be set. These are targets, after all, and no one expects a
bull’s-eye every time.
There is no accompanying rationale
One implication is that the TPP has not been thought through carefully. The most
important aspect of the rationale is that it obliges those setting the target to focus
and think logically. The rationale also allows anyone to understand (and to question,
if necessary) the reasoning behind a given target. This becomes essential as a project
progresses and more people who were not present at the beginning of the project
become involved.
[32]
Planning: From Chaos to Cosmos
The TPP is incomplete and the data on which the targets were based
are not identified
Without relevant competitive and other data for side-by-side comparison, it is not
possible to understand the context of a target or potential advantages of reaching it.
Incomplete TPPs limit their strategic and operational value.
Targets reflect wishful thinking, not careful analysis
A recent TPP contained the following efficacy target: “A 50% improvement over
available therapy at time of launch.”
This may seem like an extreme example, but statements like this are not uncommon. This is an unhelpful, and possibly damaging, target. Although it is specific, it
seems unrealistic. Since in this case there is no rationale or context, it is difficult
not to conclude that this is wishful thinking. It is unhelpful because it may lead to
under-powering of studies and distorted marketing forecasts (to name just two of
many potential consequences).
Targets are vague and nonspecific
The same TPP quoted above includes this as the only safety target: “Safe and well
tolerated in long-term therapy.” This is so nonspecific that virtually any outcome will
do. This may be the intention, but the document should make that clear. Generic,
non-targeted statements like this one provide no strategic or operational guidance.
The TPP does not cover all functions
Most often, the TPP is centered around the clinical aspects; even when a broader outlook is taken, there are functions having a significant influence on the outcomes that
are omitted. The profile on which clinical and commercial viability depends reflects
the outcomes from all the functions involved.
The appendix at the end of this chapter lists some suggestions for TPP content. It
is not meant to be either definitive or fixed, as the emphasis will change according to
the type of compound and the medical and commercial contexts.
The TPP does not anticipate circumstances at the predicted time of launch
An essential part of the art of writing the TPP is the ability to look into the future.
A big failing is to define targets that reflect the current status and do not take into
account the changes that might occur between now and the time of launch. The
T h e Ta r g e t P r o d u c t P r of i l e a n d I t s U s e s
[33]
changes might be due to competitors, to regulators, or to the economic, political,
or commercial environments. The amount that can be predicted is obviously limited
but, at a minimum, good competitor intelligence is essential to prevent development
targets that turn out to be redundant because of changes in the standard of care.
The TPP keeps changing
Targets should not be changed unless change is essential because of unforeseen environmental changes. To use a sporting analogy, a target in an archery competition is
not changed just because few competitors can hit the bull’s-eye. On the other hand,
if a new super bow is invented that allows everyone to hit the bull’s-eye every time,
the target will almost certainly have to be changed.
Changing the TPP as the characteristics of the drug become better defined defeats
the objective of the document, which is to provide an optimal baseline for development and a baseline against which to measure actual outcomes. There is a need to
document actual outcomes, as described below in the section on gap analysis.
When and by Whom the TPP Should Be Written
The TPP should be written early enough to provide a basis for planning the first
developmental activities. The TPP and the activities needed to write it form the basis
for the project development plan (PDP) and the individual functional plans stemming from the PDP, including the clinical development plan (CDP).
Preparing the TPP (­figure 2.1) is arguably the most important activity in the
development process and therefore requires a significant degree of discipline by all
contributors. Since the ideal TPP covers all of the possible characteristics of a compound, it is essential that the most qualified people from all the relevant disciplines
should be involved, with senior management approval of the result.
Constructing the TPP
The TPP is intended to be a comprehensive document, spanning all functions whose
input is needed for the successful development, approval, and launch of a new compound. Since the TPP will form the basis for the development program, it must
include very specific information about each element of the desired label so that the
development of the product can address each element.
Content
A list of the elements to consider for a TPP is given in the appendix at the end of this
chapter. This list is intended to be illustrative and is neither exhaustive nor definitive.
[34]
Planning: From Chaos to Cosmos
Figure 2.1 The TPP functions as the scaffold for the development program.
Each TPP should reflect the requirements of the compound it is describing, the only
caveat being that the document should be as inclusive as possible.
Structure
Each section of the TPP (e.g., each efficacy or manufacturing statement) is best presented in tabular form for ease of use and can usually be defined by the following six
elements:
1. A succinct and unambiguous statement of the target, whether it be a label
claim, a specification for a device, or a desired manufacturing standard. How
the targets will be met will be detailed in the development plans.
2. A concise but detailed rationale for wanting each target. The overall rationale
therefore provides a comprehensive summary of the scientific and business considerations that form the basis for the TPP. This document is of most value if it
covers all development functions, providing appropriate scientific background,
T h e Ta r g e t P r o d u c t P r of i l e a n d I t s U s e s
[35]
3.
4.
5.
6.
the therapeutic environment, and the financial basis supporting the proposal. The
very act of writing the rationale helps to ensure that the objective has been the
result of a well-researched and thought-out process, and also serves as a reminder
later in development, when memories have faded, new staff become involved, or a
compound is licensed to another company. The rationale is probably best included
in a separate document, rather than in the TPP itself, as it is too long to include in
a table.
The use to which the target information will be put, such as
• proof of concept;
• label;
• publication;
• promotion;
• exit milestone (etc.).
Target measures, including outcome elements, and the number of the relevant
study if the outcome depends on a study.
Comparative or other data on which the target or statement is based, such as
competitor data (most important) and current knowledge of the compound.
Comments, such as caveats, links to other objectives or activities, or possible
competitive advantages, etc.
Table 2.1 shows imaginary sections relating to one efficacy and one safety measure
for a drug to treat rheumatoid arthritis (RA). The rationale as to why there might be
this level of efficacy in this population would be written separately.
Table 2.1 An example of efficacy and safety sections of a TPP.
Target Profile
Reason for Target Measures Comparative/
Target
Other Data
Efficacy:
Prescribing
Efficacy in
information increase over
treatment of signs
and
placebo in
and symptoms
publication.
At least 12%
Differentiation &
Comments
In Competitor Phase Efficacy in anti-TNF
III efficacy study
failures, in which
(ref), ACR 50 within Competitor not
achieving ACR 50 3 months achieved
tested.
of RA compared
within 3 months. in 12% active—and
Require
to placebo, in
Studies XX & YY,
6% placebo-treated
FDA-approved
anti-TNF failures.
Phase III
patients (no
definition of
Safety:
Publication.
anti-TNF failures).
≤ 1% incidence of Competitor 1%
anti-TNF failure.
No advantage
Equivalent to
serious infections. serious infections in expected.
Competitor.
Study XX
Phase III
product label.
Disadvantage if
worse.
Note: Only one statement is given for each, but there should be as many statements as necessary.
[36]
Planning: From Chaos to Cosmos
The Gap Analysis: Managing the Disparity between
Results and Expectations
Inevitably, the results of a development program will diverge from the intended targets, creating a data gap (­figure 2.2).
The formidable human capacity for rationalization ensures that disappointing
results are underemphasized, and even marginally positive results are exaggerated.
This anticipated data gap can therefore easily metamorphose into a perception gap
(­figure 2.3), the consequence of which can be complete surprise when the regulatory
authorities fail to share the same perception.
The metamorphosis occurs quite naturally in the absence of formal, continuous analyses and assessments of the divergence between reality and expectations.
Analysis is essential to
• ensure that a project continues to be viable from medical, regulatory, competitive,
and regulatory perspectives;
• allow for the planning and implementation of corrective actions.
There is little problem if results are unequivocally negative or positive; this is rarely
the case, and it is in the interpretation of the more common marginal results where
the problems arise and analysis is most important.
The Objective
The main objective is a formal system for understanding the consequences of any
disparity between the ideal profile and the actual profile as it emerges during the
course of development, so that the relevant action can be taken.
Start
Development
Target
Outcome
Actual
Outcome
DATA GAP
Figure 2.2 How the data gap develops.
T h e Ta r g e t P r o d u c t P r of i l e a n d I t s U s e s
[37]
Regulatory
Submission
Regulatory
or Market
Perception
Company
Perception
PERCEPTION GAP
Figure 2.3 The perception gap.
The Requirements
There are three essential elements:
1. a rational, ideal baseline profile; this is the TPP;
2. defined limits of divergence from the baseline below which action of some sort
(whether cancellation of the project at one extreme, or else new studies or approaches
at the other) needs to be taken: this is the minimal viability requirement (MVR);
3. the real, up-to-date, current profile, optimally in the format of a package insert.
Defining the MVR
Ways of approaching this include making it up as one goes along (because circumstances change and what might have been acceptable yesterday may no longer be
acceptable today) to defining the MVR at the same time as the TPP and modifying it
as necessary. There are pros and cons to each approach, but the most important thing
is to have an approach.
The danger of making up the MVR as one goes along is that there might be a temptation to tailor that requirement to the actual results (again, rationalization). The pro is that
it is more likely to reflect current reality than something written months or years ago.
Defining the MVR at the same time as the TPP has the advantage of being part of
the same intense, data-based analysis, with the rationale being carefully considered
and recorded. The two main disadvantages are
• that the requirements remain fixed despite a changing environment;
• the very real danger of the line of least resistance being followed so that the easiest minimal target is used in the development process.
[38]
Planning: From Chaos to Cosmos
Note that requirements for commercial success vary from country to country, so
that the most pragmatic approach is to set the TPP as the standard likely to result in
success in all the major markets (e.g., the United States, Europe, and Japan) and the
MVR as the fallback that will allow commercialization in enough markets to maintain the viability of the compound or device.
Table 2.2 shows how the MVR might be incorporated into the TPP.
The actual evolving profile
One way of comparing the actual profile with the target or minimal profiles could
be to add another column to the TPP and enter the relevant data. This is a perfectly
rational approach and provides side-by-side comparisons. The limitation is that it
has no further use.
An alternative, or additional, approach is to enter actual data into the standard
format of a package insert (synonymous with package leaflet, label, data sheet,
and summary of product characteristics). The advantage of this approach is that it
results in a close approximation to the package insert that might be submitted for
Table 2.2 An example of how the MVR can be incorporated into the TPP.
Target Profile
Reason for
Target
Target
Measures
MVR
Comparative/ Comments
Other Data
Efficacy:
Prescribing
At least 12%
Similar
In Competitor
Efficacy in
information
increase over
efficacy over Phase III
treatment
and
placebo in
placebo as
of signs and
publication.
achieving
Competitor, (ref) ACR
symptoms of
ACR 50
but also in
50 within
Competitor not
RA compared
within
anti-TNF
3 months
tested.
to placebo, in
3 months.
failures.
achieved in
Require
anti-TNF failures.
Study XXX
12% active—
FDA-approved
Phase III
and in 6%
definition
efficacy study
To be achieved
in anti-TNF
failures,
in which
placebo-treated of anti-TNF
patients (no
failure.
anti-TNF
≤ 1%
As for
failures)
Competitor
No advantage
Equivalent to
incidence
Target
1% serious
expected.
Competitor.
of serious
infections in
Disadvantage if
infections.
product label.
worse.
Safety:
Publication.
Study XX &
YY, Phase III
T h e Ta r g e t P r o d u c t P r of i l e a n d I t s U s e s
[39]
approval. There are two ways in which this can done, starting when the TPP is being
prepared:
1. Fill in a blank template as data become available.
2. Fill the template from the beginning to provide a target package insert (TPI) that
exactly mirrors the TPP. The TPI is amended as data are accumulated until eventually it is no longer a target but an actual package insert.
The relationship between the TPP and TPI, and their strategic and operational
importance in the development process, are illustrated with specific reference to
clinical development in ­figure 2.4. The concept applies equally to all the functions
represented in the PDP.
The Process
Objective
The objective is to determine on a continuing basis whether current data from all
development activities still support the development objectives (whether a liquidity event, registration, or commercialization) in order to allow appropriate decisions
(corrective actions, discontinuation of the project) to be made without delay.
How
New data are compared with relevant sections of the TPP, the MVR, and (optimally)
the TPI. Updating the package insert template is critical as it allows comparison with
the TPI and shows what the actual package insert might look like.
ACTUAL
PACKAGE
INSERT
REGISTRATION
DOSSIER
DATA
GAP
CLINICAL DATA
MODIFY
ACCORDINGLY
CLINICAL STUDIES
CLINICAL DEVELOPMENT PLAN
PROJECT DEVELOPMENT PLAN
TARGET PRODUCT PROFILE
TARGET
PACKAGE
INSERT
Figure 2.4 Interrelationship between the TPP, the TPI, and development strategy.
[40]
Planning: From Chaos to Cosmos
Who
Ideally, this should primarily be the responsibility of the body with immediate oversight of the whole project, with formal, periodic review by the senior strategic development management committee.
When and what
Continuous, routine review by the project oversight body is essential. All results and
potential issues with the registration and commercial objectives (including labeling)
should be reviewed. Additional activities that are consistent with the knowledge
gained from these studies can be proposed. The objective is not to promote continually changing strategies, but to converge toward one that is consistent with both the
business needs of the company and the information obtained during the development program.
If the data are critical, the review should be carried out as soon as possible,
with senior management involvement, and not delayed until the next routine
meeting.
For senior management, an accurate understanding of the actual product characteristics, as compared with the original targets, is especially critical at the initiation
of Phase III and prior to finalizing registration activities. Formal review at the following times serves the necessary purposes:
• at the start of Phase III, as the review is integral to making a go/no-go decision;
• twelve months and six months before the planned regulatory submission date, as
more and more data become available and any gaps are more apparent;
• one month before regulatory submission, as part of a process to ensure that the
dossier is fit for submission.
Key Points
• Clear development targets are essential for a successful outcome.
• The targets should be set as early as possible, when the decision is made to proceed to full development of a compound.
• The targets should be rational and realistic, based on all available data, and relevant for the anticipated commercialization date.
• The rationale for each target should be clearly recorded.
• Targets are needed for all development activities.
• The TPP is the document summarizing all the targets. It comprises a summary of
all relevant information.
• The definition of minimal requirements, below which the viability of the project
becomes unlikely, is essential for the evaluation of new data. The MVR can be
defined along with, and included in, the TPP.
T h e Ta r g e t P r o d u c t P r of i l e a n d I t s U s e s
[41]
• Writing a TPI using the contents of the TPP, and then modifying the document as
data become available, serves to both highlight the gaps between prediction and
reality and produce a definitive package insert in a rational way.
• Routine and formal reviews by relevant oversight bodies of the emerging differences between the original targets and the actual results are essential to ensure
that there are no false perceptions, that corrective actions can be taken, and that
the project remains medically and commercially viable.
APPENDIX
Suggested TPP Contents
These are for illustration only, with some sections containing more details than others, and are not intended to be exhaustive. They will vary according to the drug or
device. All elements considered essential for the success of the compound should be included.
At the beginning of development, most targets are predictions and the final outcomes are unknown. However, the reasoning behind the prediction is given in the
rationale, and any key factors that could influence the outcome or explanations of
how the targets will be achieved in practice, and their relevant requirements, are
summarized in the “Comments” column and detailed in the development plans.
Commercial
• intended brand positioning;
• intended markets (countries);
• selling price.
Toxicology and Other Nonclinical
Any toxicology considerations that are critical to the success of the product should
be presented in this section. Examples might include absence of any reproductive
toxicology findings or the need for any unique toxicology studies.
Clinical Pharmacology
Relevant clinical pharmacology properties that are essential to the success of the
project should be described in this section. Consider the following:
• ADME;
• PK targets: for example, “The pharmacokinetic profile must include a rapid onset
(x–y minutes) and long duration of action (a–b hours)”;
[42]
Planning: From Chaos to Cosmos
• compartments to be penetrated;
• concentrations in blood, abscesses, joints, CSF, etc.;
• P450 interactions, co-administered drugs, and the need for interaction studies
(or not);
• population subgroups such as age, gender, race, smokers, renal impairment,
hepatic impairment, and other diseases;
• relevant properties of competitors;
• properties of our compound likely to provide advantage.
Medical
• indications
Important variations may exist between the U.S., European, Japanese, and other
markets, so it is useful to provide specific definitions to ensure that all studies are
conducted in the targeted indication. Consider the following:
o
o
o
o
o
o
prior knowledge;
guidelines;
current labels and their variations;
trends in labels;
best label to have;
targets needed to achieve best label.
• target populations
The target population should be defined as specifically as possible. If special populations, such as pediatric patients, are of interest, disease categories should be qualified (e.g., moderate to severe).
Note that studies limited to specific populations may result in labeling limited to
those populations. Populations in which specific studies must be conducted should
also be presented in this section.
• dosage forms, doses, dose regimens, and routes of administration
For routes of administration, consider the following:
o routes of administration that might be desirable (oral, subcutaneous, intramuscular, intravenous, suppository, intranasal, depot, patch, intra-ocular);
o what is known that might affect them (half-life, food effects, absorption,
metabolism, clearance, etc.);
o routes that are feasible for the compound;
o routes used by competitors;
o routes essential for ease of patient use and compliance;
o routes offering an advantage.
T h e Ta r g e t P r o d u c t P r of i l e a n d I t s U s e s
[43]
• efficacy claims
o Specific endpoints and efficacy parameters should be clinically realistic and
focus on key criteria of medical, regulatory, and commercial importance.
o The endpoints should be central in making go/no-go decisions.
o Terms such as “better than” should be carefully described, both qualitatively
and quantitatively, specifying the extent of the signal required and the key
measures.
• safety claims
This is the most important section, and one that may confer significant advantages
over competitors. Yet this section is rarely completed in sufficient detail. Often,
terms such as “better than” are used without any quantitative or qualitative definition. If an important factor in the success of the product is safety superiority over a
competitor, the desired superiority and the specific competitor should be provided.
Also consider the following:
o key safety problems with existing treatments;
o medical issues in target populations that could generate additional risks (vomiting and electrolyte disturbances or dehydration, malabsorption, etc.);
o adverse events that might not occur, or occur less frequently, with the new
medication;
o ways in which these can be quantified;
o black boxes, contraindications, warnings, precautions, etc.
Outcomes Research
This includes but is not limited to cost-effectiveness, quality of life, and patient satisfaction, and should be presented in sufficient detail that these issues may be considered in the design of the development plan.
Manufacturing
This includes a significant number of factors the management of which is essential,
such as process yield, batch failure rates, manufacturing cycle times, required annual
volume, marginal costs, and eventual cost of goods. Requirements and timelines for
improving these can be included.
Pharmaceutical Development
Consider including requirements for trial supplies, even if these do not represent the
final targets, which should be included.
[44]
Planning: From Chaos to Cosmos
Product Characteristics
The desirable characteristics of the final formulation, dosage form, or device should
be included in this section, including packaging requirements, stability, shelf life,
need for refrigeration, and comparative factors with competitive products.
Device Characteristics
All aspects to do with manufacturing, usability, fault rate, reliability, efficacy, safety,
cost, regulatory needs, and competition should be included in this section.
Intellectual Property
This includes activities aimed at securing, expanding, and prolonging patent
protection.
Patient Perspectives
I have never seen patient-related contents in a TPP, but it is worth considering
including the following:
How patients feel
• symptoms, physical and mental
• emotions
How patients function
• limitations in activity
Attitude patients have toward disease
• social
• severity
• disease burden
T h e Ta r g e t P r o d u c t P r of i l e a n d I t s U s e s
[45]
Attitude toward the medication
•
•
•
•
Does it work?
Is it safe?
Is it convenient?
Should I be taking it?
Financial cost to the patient
[46]
Planning: From Chaos to Cosmos
C h apter 3
Planning the Individual Clinical Trial
Overview and Background
Objective
All sites should be ready to enroll by the planned study start date.
Steps and Timelines from Beginning to Write a Protocol until Start
of Study
Realistically, this can only be achieved if the process is initiated 52 weeks before the
planned start date (see ­figure 3.1).
The components of each step and the associated timelines are described below.
There may be considerable overlap of these steps, and the time needed to complete
each one can vary greatly from project to project or study to study. This chapter gives
an overview of the key activities and their timelines; details of how the activities are
carried out are described in subsequent chapters. As always, these are guidelines,
and flexibility is the key.
Step 1
Write and approve
Draft Protocol
Synopsis
Step 2
Carry out
feasibility and
finalize Synopsis
4 to 12 weeks
4 to 8 weeks
Step 3
Carry out Patient
and Site Selection
and complete full
Final Protocol
6 to 8 weeks
* Time to start of study if Step 1 starts 52 weeks before planned start date
Figure 3.1 Steps and timelines from protocol writing to study startup.
Step 4
Complete study
start-up activities
38 to 24 weeks*
Timelines and Milestones that Matter
Timelines are defined by the activities that need to be carried out and the time each
activity will take. Some of these activities are necessarily sequential, as the next
activity cannot start until the previous one has been completed. Some of these
rate-limiting activities are defined as milestones, and time to their successful completion is used as a relative measure of efficiency.
Metrics have a valuable role to play in process improvement, but a potential drawback is that people will concentrate disproportionately more effort on achieving what
they know is being measured, sometimes to the neglect of other activities. It is therefore
essential that what is being measured be a true and important measure of efficiency.
One of the most popular metrics to measure the efficiency of the clinical trial startup
process is how short the time is between availability of the final protocol and when the
first patient is randomized, the shorter the better. This metric, so often quoted, is the
most useless and misleading because the completion of the study depends not on when
the first patient was randomized but on when the last patient was randomized. The mad
rush to enter the first patient is therefore a futile endeavor unless everything is in place
to ensure that all, or most, sites can start randomizing patients by the planned start date.
Since it is self-evident that the later the last site is activated, the longer the study
will take, the planning emphasis should be on ensuring, as far as possible, that no
site starts after the planned start date. This is a key milestone on the path to completing a study on time, and it can only be reached successfully by allowing enough
time for all of the factors that cause delays to be taken into account.
Virtually anything can become rate-limiting with poor planning or bad luck (the
latter often correlating with the former), but startup delays are usually due to one or
a combination of the regulatory, ethical, or contractual processes. These need to be
considered together on a country-by-country and site-by-site basis, as the rules for
which needs to come first, or whether the processes can be carried out in parallel or
have to be sequential vary considerably.
Regulatory authorities
Even with defined timelines, the duration of regulatory review cannot be predicted
accurately in any country. Official times to approval range from 30 days in Singapore
to more than 240 days in China, with the median being around 60 days. However,
not only is the documentation required different from country to country, but in
some countries the contract has to be negotiated first, and questions or inadequate
documentation can prolong the process.
Ethics committees
As with regulatory times, official ethics approval times do not necessarily reflect reality. Time to approval can be as short as a few days to 120 days or more in India and the
Philippines. Ethics committees tend to meet according to a fixed timetable and often
[48]
Planning: From Chaos to Cosmos
do not meet during vacation times, so that missing a meeting date by one day can add
months to the process. Often answers or changes, significant or otherwise, resulting
from ethics committee comments may not be considered until the next scheduled
meeting. In many countries, including, for example, China, Japan, Mexico, the United
Kingdom, and Argentina, regulatory and ethics approvals are sequential.
Contracts
Anything involving money and lawyers will inevitably become convoluted and unnecessarily time-consuming, and clinical trial contracts illustrate this point perfectly. In
the worst cases, contracts can take over three months to negotiate.
The country with potentially the most time-wasting multiple sequential processes
for setting up a clinical trial at the time of writing is probably the United Kingdom.
Not only are there national and then local levels of approval, but there is an additional component, research and development (R&D) approval. In one evaluation, it
took 12 months for 14% of 84 centers just to get R&D approval, six months for 21%
to get local ethics approval, and at least three months for 31% of centers to get a
signed contract (A. Hackshaw, H. Farrant, and S. Bulley et al., 2008). In the end, it
took six months or more for 52% of 84 centers to be activated, while only 11 centers
completed all the steps in two months or less.
These representative examples (which do not include the time taken to write a
protocol and to find and set up sites properly) merely underline the point that the
planning process for the average Phase II and Phase III trial optimally requires one
year. The response to this statement is frequently the supposition that the clinical
trial start needs to be delayed for up to a year, since how can one possibly start the
process for a study when the previous studies, which will provide vital information or
may even result in the cessation of development, are still underway.
The answer is that even in the best cases, clinical trial planning requires assumptions,
sensible risk-taking, and contingency measures, and that anyone who is not able to
work in an environment of risk and uncertainty should not be doing drug development.
In fact, much of what is needed to start writing the protocol for a clinical trial is
not usually dependent on the results of previous studies:
•
•
•
•
•
the indication;
the endpoints;
sample size;
selection or eligibility criteria;
comparator drugs.
Information that may depend on an ongoing study may include the following:
• dose or dose range;
• dose intervals;
• safety profile.
P l a n n i n g t h e I n di v i d ua l C l i n i c a l T r ia l
[49]
Inevitably, there might occasionally need to be changes resulting from this information, but that is not an excuse for not going ahead. Uncertainty over the dose is not
a limiting factor either. A range of trial drug doses can be packed in advance in the
knowledge that some will be wasted, but that time has been saved.
This leads to another objection: cost. The approach described requires considerable investment during the startup phase in addition to the traditional costs, including the cost of extensive training of CRO and site staff over and above the traditional
“investigator meeting,” carrying out protocol feasibility and patient screening, and
possibly packing supplies that might not be used. These costs are so trivial compared
with the eventual gains, as shown in detail in subsequent chapters, that not providing the necessary investment is almost professional misconduct.
Step 1: From the Decision to Go Ahead to the Approved
Draft Protocol Synopsis
The time needed for this step is between 4 and 12 weeks.
The protocol synopsis describes in detail all the operational elements needed to carry out
a study. These elements are those that will form the operational core of the full protocol,
so that the synopsis can fulfill most of the functions of the full protocol. Unlike the full
protocol, however, the synopsis does not contain explanations, definitions, or appendices, so it is usually between five to seven pages long and is easier to understand and
amend. The process for writing the protocol synopsis is described in detail in c­ hapter 4.
By the end of Step 1, all the activities needed to write a definitive protocol, with
the exception of testing the feasibility of the protocol, have been completed, resulting in an approved draft protocol synopsis.
The time taken to write and approve a draft protocol synopsis will depend on how
extensive previous research in the given therapeutic area and the relevant indication
has been.
When there have been regulatory approvals for the given indication with publication of study designs and results, and especially if the company has previously
carried out similar studies, the maximum time needed, including approval time, is
four weeks, and could be less. At the other extreme, if a therapeutic area is new to a
company and there are few or no published data or guidelines, extensive consultations and review of available data will be needed. In these circumstances, it can take
up to three months to complete an approved draft.
By the time the draft protocol synopsis has been approved, it is essential, if timelines are to be kept short, that the following have also been completed:
• identification of potential countries and sites in which the study can be carried
out, based on known regulatory, bureaucratic, and protocol requirements (identification is not synonymous with country and site selection, which can only be
determined after the feasibility of the protocol has been tested; the process of
determining feasibility is described in c­ hapter 5);
[50]
Planning: From Chaos to Cosmos
•
•
•
•
selection of sites in which protocol feasibility will be carried out;
preparation of the questionnaire to be used for protocol feasibility;
finalization of the formal agreements with the sites for carrying out feasibility;
sending requests for proposals (RFPs) and select CRO, especially if help is needed
for the feasibility process;
• explaining the feasibility process and agreeing on timelines with sites and CRO;
• starting the process for formal agreements with potential sites to carry out
patient screening once feasibility is complete.
As the synopsis is being developed, it can progressively be used to initiate more and
more parallel activities even before it reaches completion. Many will require the final
synopsis or protocol for completion, but early initiation of activities in parallel, even
if some information is not yet available, goes a long way to shortening timelines.
A representative sample of these activities is given below:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
material needed for patient screening and site selection;
arranging meetings with regulatory bodies;
resource planning;
statistical analysis plan;
patient recruitment plan;
randomization plan;
ordering and packing of supplies;
preparing import licenses;
designing the case record form;
study insurance;
study manual;
database setup;
training materials;
dates for training and other meetings.
Step 2: From Approved Draft Protocol Synopsis to
Approved (Definitive) Protocol Synopsis
The time needed for this step is between 4 and 8 weeks.
The central activities in Step 2 (described in detail in ­chapter 5) are carrying out
protocol feasibility and amending and approving the definitive protocol synopsis.
Protocol feasibility involves ensuring that all the protocol-specified procedures can
be carried out and assessing that enough patients complying exactly with the eligibility criteria actually exist. If either the procedures or the eligibility criteria prove to
be limiting factors, they can be changed accordingly if such change does not interfere with the objectives of the study. The draft protocol synopsis is then modified
to reflect changes that optimize feasibility, resulting in the final, approved protocol
synopsis that forms the basis of the full protocol.
P l a n n i n g t h e I n di v i d ua l C l i n i c a l T r ia l
[51]
Limiting factors are the number of representative sites chosen for feasibility,
their geographical locations, and the amount of preparation (agreements, etc.) carried out in advance. This is an important step that needs to be carried out carefully
and balanced by pragmatism if it is to have any value; with good planning and a judicious mixture of face-to-face and remotely managed sessions, Step 2 should take no
longer than eight weeks.
Step 3: Completion and Approval of Final Protocol and
Initiation of Patient Screening and Site Selection
The time needed is up to but no longer than 8 weeks.
The Final Protocol
The time needed from the definitive protocol synopsis to the final protocol is 2 weeks (no more).
At this stage, all of the activities that could have been initiated in Step 1 can be completed using the definitive protocol synopsis. However, certain activities can only
be carried out using the final protocol, the completion of which (­chapter 6) is now a
priority. Much of the work to complete the final protocol should have been done in
parallel; many sections (such as ethics statements and definition of adverse events)
are generic, while the rationales for the non-generic components (such as the endpoints, the number of patients, the statistical approach, etc.) will have been written
though not included in the synopsis.
Patient Screening and Site Selection
The time needed for patient screening and site selection is between 6 and 8 weeks, in parallel with
protocol finalization.
Patient screening and site selection (­chapter 7) are the main objectives of Step 3.
Establishing the number of patients who exactly match the eligibility criteria of
the protocol available at each site is the basis for site selection; sites without a relevant minimum number of patients (or the likelihood of finding them) should not
be included. The process is protocol-specific and ensures that the number of real
patients is counted, as opposed to the number the investigator thinks he or she
has. Once the patient screening is complete, the recruitment plan for any additional
patients can be agreed on and the other elements of site selection can be carried out.
As with protocol feasibility, identifying and setting up agreements with all potential
sites well in advance is essential. Unlike protocol feasibility, patient screening and site
selection have to be carried out at every potential site, so that the logistics are more
complicated as more face-to-face meetings are necessary for a more accurate process.
[52]
Planning: From Chaos to Cosmos
Step 4: Completion of Study Startup Activities
The time that remains if activities began 52 weeks in advance is between 38 and 24 weeks.
During this phase, all of the activities that did not need the final protocol and that
started as far back as Step 1 can be completed. As a rule, these are not necessarily the
rate-limiting factors, especially if initiated early. Activities that more often tend to
delay study startup are those for which the final protocol is needed, especially if they
have to be completed sequentially:
•
•
•
•
regulatory approvals;
ethics committee approvals;
contracts;
import licenses, etc.
The importance of completing the procedures leading to the final protocol as
quickly and efficiently as possible is therefore inescapable; while many key activities can be initiated using the synopsis in its various stages of development, most
of the rate-limiting factors depend on the final protocol for completion. Since the
objective is to start the study on a given planned date with all, or as many as possible, of the sites activated, the earlier the whole process is started and the final protocol is available, the more likely it is that the study will be completed as planned.
The most important other activity during this time is the training and education
of investigators, site staff, and CRO staff. Training and education should address, as
appropriate to each audience, the essence of clinical trial practice, GCP, the disease,
the protocol, and the CRF, as described in more detail in ­chapter 8.
Key Points for Achieving the Optimal Outcome
• Start the whole clinical trial process as early as possible, even in the face of
uncertainty.
• Invest in the study planning and startup activities, even if some of the investment may be lost, because the net gain is worth much more.
• Carry out as many activities as possible in parallel.
• Rely on facts rather than received wisdom whenever possible, by applying strict
protocol feasibility, patient screening, and site selection procedures.
• The longer the time between the availability of the final protocol and the planned
study start date, the greater the chance that the study will be completed on time
as planned.
The advantages of the four-step approach include
• a robust protocol;
• only unavoidable amendments;
P l a n n i n g t h e I n di v i d ua l C l i n i c a l T r ia l
[53]
•
•
•
•
•
•
a trial that is feasible;
proper education of all those involved;
as many actual patients as possible identified and recruited;
a plan for further recruitment in place;
nonperforming investigators reduced to a minimum;
simultaneous startup of all sites.
Overall, the trial will proceed faster and more cost-effectively, despite (or because of)
the greater upfront investment of time and money.
[54]
Planning: From Chaos to Cosmos
P A R T T h ree
The Practicable Protocol
C h apter 4
Distilling the Essence of the Protocol:
The Protocol Synopsis
Objective and Rationale
The main objective is to get the preparatory phase of the trial, especially protocol
feasibility, up and running as rapidly and efficiently as possible.
Introduction
The protocol synopsis is the most important document for ensuring a successful
trial. It comprises all the elements essential for planning and carrying out a clinical
trial, and is quicker to write, easier to read, less likely to have inconsistencies, and
much easier to modify than a full protocol. A protocol synopsis is usually between
five and seven pages long, whereas a typical protocol can run from 60 pages (rarely
fewer) to 100 pages (sometimes more). The synopsis is therefore the ideal document
to use for all the early preparatory activities, as the full protocol adds no value for
planning and operational purposes. A fairly typical protocol synopsis template is
shown in the appendix at the end of this chapter.
Steps from Draft Synopsis to Final Protocol
Step 1
The first step is to get an approved draft protocol synopsis.
This version of the synopsis should be as complete as possible in every respect,
except for those changes that will need to be made as a result of feasibility testing.
It is, in effect, the penultimate version of the core of the final protocol. It should
go through as many iterations as needed until it reaches the stage at which it can
be approved, pending feasibility. At this stage, all aspects relating to the objectives,
design, endpoints, investigations, lab tests, and treatment and procedural schedules
should be final; otherwise, doing feasibility is a waste of time.
This chapter describes how to get to the approved draft protocol synopsis. There
are then two more steps that will be described in detail in the following chapters.
Step 2
The second step is the approved protocol synopsis. The draft synopsis has been
amended as needed to ensure optimal feasibility without diminishing the validity of
the study and has been approved. At this stage, the protocol is, in effect, locked and
ready to be implemented.
Step 3
The third step is The Final Protocol, which is not, as it sounds, an airport paperback novel with an embossed cover but the approved full protocol. This step involves
incorporating the contents of the approved protocol synopsis (­figure 4.1) into the
template for the full version of the protocol and having it approved for completeness and consistency. No aspect of the trial, as detailed in the approved protocol synopsis,
should be modified at this stage (see ­chapter 6 for rare exceptions).
PROTOCOL SYNOPSES
PROJECT
DEVELOPMENT PLAN
Target Product Profile
Target Product Label
CLINICAL
DEVELOPMENT PLAN
Contents
Indication
Rationale
Objectives
Design
End-Points
Selections Criteria
Target Populations
Treatment Schedule
Sample Size
Countries and sites
Statistical Analysis
Schedule of Events
Figure 4.1 The protocol synopsis is the final operational plan derived from the project and
clinical development plans.
[58]
The Practicable Protocol
Preparing the Approved Draft Protocol Synopsis
When?
Synopses should be written as soon as the objectives of the clinical trial program
have been defined in the clinical development plan.
How?
The process of writing the protocol synopsis is one in which no shortcuts can be taken
or corners cut, including, in a perfect world, no cutting and pasting from previous
synopses. The entire success of the clinical trial rests on the accuracy, completeness,
scientific and medical validity, statistical integrity, and feasibility of the synopsis.
It is very easy to produce a less-than-adequate synopsis. Among the tried and
tested methods for achieving this are the following:
Rush the process
Essential elements of the process (reading the literature, consultations, and reviews)
take time, and trying to compress the process inevitably results in a substandard
outcome. If the therapeutic area or indication is entirely new, up to three months
should be allowed, though four weeks should be enough if there has been a lot of
experience with the compound and the indication.
Make it up as you go along
Although there is always room for innovation, there is no need to reinvent all aspects
of the design every time. There is a wealth of literature and other information that
can help in trial design for most therapeutic areas and indications. Reports of failed
studies (unfortunately, not published often enough) are essential in showing what
not to do.
Sit in a corner and write it by yourself
Failure to include all relevant input is perhaps the most common sin. Relevant input
comes from
• those who provide the logistics and operational support;
• those with expertise in medical practice, trial design, data analysis, regulations,
ethics, and international considerations;
• those who are interested in the results.
T h e P r o t o c ol S y n op s i s
[59]
The list of those concerned is long and well documented, but whether the support
and expertise lie within a company or have to be sought outside, inclusion of the following is essential and often omitted:
Marketing
The commercial interests of the company (and the interests of investors) are as important as the scientific, therapeutic, and ethical interests, and if these are not served
at every stage of the development, then the studies are not fulfilling company needs.
Statisticians
Without a firm statistical base, the results of a study have little validity, and yet statisticians (­figure 4.2) are frequently excluded from much of the design phase.
Patients
All clinical trials revolve around patients, and yet the perspectives of patients are
rarely considered. These aspects cannot be addressed by physicians, whose perceptions
Figure 4.2 By permission of Professor N. Simonson.
[60]
The Practicable Protocol
of how patients feel can be far removed from reality. Consider discussing the study
with patient support or advocacy groups, as well as with individual patients.
Pharmaco-economic and quality-of-life measures
Except when specifically designed to measure these endpoints, little consideration is
given to the potential to generate data in traditional efficacy and safety trials.
Rank-and-file clinical investigators
They understand the practicalities of clinical trials.
Broad clinical and regulatory advice
This should be sought from all countries to be involved in a multinational study. All
too often there is an assumption that what is true in the country in which the company is situated is true for all countries.
Cut and paste
There are parts of a full protocol that are standard and form part of a template for all
studies (such as the Declaration of Helsinki or the definitions of the various types of
adverse events), or that are standard for a given compound and can be cut and pasted
from one protocol to the next (e.g., the brief description of the characteristics of the
compound). Beyond these and one or two other limited examples, cutting and pasting is a surefire way of introducing inconsistencies and non-sequiturs that are not
discovered until it is too late.
Rely entirely on the opinions of experts from academia
No one goes to a shoemaker to get tax advice, or to a tax adviser to have their shoes
repaired. And yet it is very common for the pharmaceutical and biotech industry to
consider all advice from consultants in the academic sphere as being gospel, to be
given precedence over opinions from within the industry.
Drug development for the purpose of regulatory approval and commercialization entails numerous additional considerations and differences that do not apply
to most of the research carried out in academic centers. Commercial drug development is a science and an art unto itself that can only be understood from experience.
The most dangerous combination in protocol development is the academic clinician
who has been involved in some clinical trials and has been to a few meetings with
T h e P r o t o c ol S y n op s i s
[61]
regulatory bodies (and who therefore knows all there is to know about every aspect
of drug development) and the industry sycophant who does not dare to disagree.
There are experienced physicians and trial units in academia comparable with
the best in industry, but they are the exceptions, and this is not about exceptions.
Differentiating those aspects for which it is essential to have academic input (and
these are not to be minimized) from those that are best addressed by experts from
within the industry is the only way to ensure a lean, focused protocol that addresses
only the essential objectives in a pragmatic way.
Be your own reviewer
In a perfect world, there would be time to let the protocol synopsis mature so that
each contributor could come back and review it at leisure. As this is not the case,
frequent review by others is essential because obvious errors are far from visible to
those who are steeped in the day-to-day activities.
Avoid a formal approval process
The value of a formal approval process is not, as so often is thought to be the case, because
it passes the responsibility to others to find and correct mistakes. The value lies in carrying out a more or less objective and disinterested assessment of all components of the
synopsis. Some ideas about the conduct of protocol approval are given in ­chapter 6.
Simply put, the objective is to ensure that the synopsis is as perfect as possible
before feasibility testing. All the components of the synopsis should be reviewed,
with the knowledge that there might be changes to the subject selection criteria and,
less frequently, to the schedule of events and the target countries.
Take the path of least resistance in assessing whether or not the protocol is feasible
Perhaps the most grievous and most frequently committed sin in the development
process is the absence of a properly conducted assessment of feasibility. The perfect
theoretical protocol is of no value unless it can be completed, preferably within the
planned timeline and budget, and the feasibility process, as described in the next
chapter, is the only way to ensure a reasonable chance of meeting these objectives.
Making Use of the Approved Draft Protocol Synopsis
Although multifunctional project teams usually disseminate information to all relevant lines from the start of a project, there is a general reluctance to commit money
and people before there are approved plans or protocols. Although this is understandable, it can be counterproductive, and there should be an effort to balance the
[62]
The Practicable Protocol
constraints of limited resources with the need to meet timelines and maintain a
competitive advantage. Waiting for a guarantee that protocols are now final and will
not change is both impractical and unrealistic.
Much of the following can be done even while the draft protocol synopsis is being
prepared, but even for people requiring more certainty, all can be initiated once the
draft protocol synopsis has been approved:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
detailed resource planning by all departments, affiliates, and vendors;
everything needed to assess protocol feasibility;
material needed for patient screening and site selection;
arranging meetings with regulatory bodies;
statistical analysis plan;
patient recruitment plan;
randomization plan;
ordering and packing of supplies;
preparing import licenses;
designing the case record form (CRF) (especially if electronic);
study insurance;
study manual;
starting the request for proposals (RFP) process with vendors;
drafting the analysis plan;
database setup;
training materials;
dates for training and other meetings.
In most cases, the slight risk that some of these aspects might change following the
feasibility assessment is well worth taking. In practice, and if the protocol preparation process has been professional and rigorous, the most likely changes will be in
the patient selection criteria.
Key Points
• The protocol synopsis contains all the essential details for carrying out a study
and forms the core of the full, formal protocol.
• Unlimited care and attention should be given to the preparation of the synopsis,
as it is central to the success of the study.
• Among the many caveats to be taken into account, the most important is failure
to include all relevant input.
• Approval of a draft protocol synopsis indicates that everything except the results
of feasibility testing have been finalized.
• Much of the preparation for the trial can be initiated as the draft protocol synopsis is being prepared, and almost all can be initiated once the draft synopsis has
been approved.
• The most important function of the approved draft protocol synopsis is to carry
out a feasibility check (see next chapter).
T h e P r o t o c ol S y n op s i s
[63]
APPENDIX
The following represents a typical protocol synopsis template. Sections should be
expanded as necessary.
TITLE
Project Code:
Therapeutic Area:
Substance Identifier:
Protocol Number:
Approved Protocol Summary:
Approval Date:
Clinical Person Responsible for Approval:
Included in clinicaltrials.gov Database:
Revisions of this Summary:
Summary of Study Design
Protocol Identifiers
Therapeutic Area:
Product:
Indication:
Protocol Number:
Title of Study:
Background Information and Study Rationale
Trial Objectives and Endpoints
Primary Objective:
Secondary Objective(s):
Primary Endpoint(s):
Secondary Endpoint(s):
Study Design and Methods
Study Design:
Treatment:
[64]
The Practicable Protocol
Yes → ☑ No → ☐
Yes → ☐ No → ☑
Version and Date
Statistical Methods:
Sample Size Determination:
Interim Analyses:
Subject Selection
Subject Inclusion Criteria (subjects must meet all of the following inclusion criteria
to be eligible for enrollment in the study):
1.
2.
3.
Subject Exclusion Criteria (the presence of any of the following will exclude a subject
from study enrollment):
1.
2.
3.
PROTOCOL SCOPE
Development Phase:
Target Region(s):
Target Countries:
Country/Region-specific Variations:
Enrollment Target:
Number of Subjects to Screen:
Number of Subjects per Site:
Number of Sites:
Cooperative Group Involvement:
Outsourcing:
CLINICAL SUPPLIES
Study Drug:
Short Title for Labeling of Study Drug:
Additional Study Drugs or Comparators:
Other Information:
T h e P r o t o c ol S y n op s i s
[65]
SCHEDULE OF EVENTS
Protocol
Activities and
Forms to Be
Completed
Screening
(day)
Treatment (day)
Footnotes for Schedule of Events
[66]
The Practicable Protocol
Follow-up
Period
End of
Treatment
TIMELINES
Planned Durations and Estimated Dates
Duration of Washout Period
_______
Duration of Run-in Period
_______
Duration of Enrollment Period _______
Date First Subject In:
Date Last Subject In:
Duration of Treatment Period
_______
Date Last Subject Off Treatment:
This is Date Last Subject Out (LSO) if no further follow-up
Duration of Follow-up (if relevant) ______
Date Last Subject Off Follow-Up:
Date LSO if there is post-treatment follow-up
Analyses and Reports
Date of Interim Analysis:
Date of Final Analysis:
Date of Final Study Report:
T h e P r o t o c ol S y n op s i s
[67]
C h apter 5
Redistillation: Eliminating Impurities by
Carrying out Protocol Feasibility
Objective
The main objective is to make sure that a protocol designed by a committee can be
carried out in the real world.
Protocol Feasibility and Why It Is Essential
Introduction
Protocol feasibility is the process for determining whether or not a proposed protocol is practicable from ethical, patient, and medical practice perspectives. If not,
the next step is to determine which parts need to be amended to make it practicable
without undermining the objective of the proposed study.
Once the operational core of the protocol has been drafted, the next essential
step is to find out if there are any aspects that are either completely impracticable
or impede the conduct of the study unnecessarily. Finding the balance between the
fully loaded protocol that could, if the study were ever finished, provide the perfect
answer for a tightly defined population, and the minimalist protocol that, although
easy to carry out, might be too nonspecific and even put patients at risk, is largely an
art dependent on experience. There are, however, many objective measures that can
be taken to reduce uncertainty to the minimum possible.
This process is called “protocol feasibility.” The term means exactly what it says
(finding out if it is possible to carry out the study described in the protocol), but it
has frequently become confused with or combined with other study startup activities that have nothing to do with protocol feasibility, to the detriment of all of them.
Even when the term is understood, the process for determining feasibility is rarely
performed rigorously in practice.
What Protocol Feasibility Includes
Protocol feasibility includes the collection of all relevant information to determine
whether or not the protocol can be carried out as planned, with subsequent modification of the protocol to bring it more in line with reality.
Although most of the effort of protocol feasibility is concentrated at the site level,
because the major factor is whether or not patients conforming to the protocol selection
criteria actually exist in numbers large enough to make the study possible, country-specific
aspects are also important and should be included in the feasibility process. It is surprising how parochial the thinking of even the most experienced clinical trialists can be, and
assumptions that what is good in my own country must be good in every country are
ubiquitous. Furthermore, it is pointless to carry out the site-level feasibility in countries
where the study cannot be carried out, for whatever reasons. So there are two parts to the
data-gathering part of protocol feasibility, with overlap between them:
Country-specific aspects, including
•
•
•
•
•
disease prevalence;
regulatory requirements and timelines;
commercial priorities;
ethical considerations;
medical practice and standard of care.
Site-specific aspects that address the disease, the patients, and how the disease is
managed, including
•
•
•
•
ethical considerations;
practicality of the protocol from a patient perspective;
availability of patients fulfilling the protocol selection criteria;
practicability of the protocol from an investigator’s point of view.
Once the data are available and the number of eligible patients is known, an analysis is
carried out to see if changes to the criteria result in more eligible patients being available
without affecting the integrity of the study. The protocol is then modified accordingly.
What Protocol Feasibility Is Not
• Country selection: Although appropriate countries may have been identified
because of disease prevalence or practical factors, a definitive selection can only
be made once the protocol is final.
• Site selection: Sites can only be selected once there are likely to be no more
changes to the protocol, because ethics approval and contractual negotiations
usually depend on a final protocol, and changes may be such as to exclude a previously acceptable site for practical reasons. The approach to site selection is very
similar, as described subsequently, except that now the site has to match the protocol, instead of the protocol being adapted to match reality.
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• Patient recruitment: Until the selection criteria have been agreed upon, it is
impossible to identify all eligible patients at a site, much less recruit them.
• A means of including important investigators and opinion leaders in the protocol
design process. By this stage, the core of the protocol should be as complete as
possible, and all relevant consultations should already have taken place.
What are the consequences of inadequate protocol feasibility testing?
The relevant metrics quantify the consequences very clearly. The metrics quoted in
the introduction are repeated here as they are relevant (as they are for site selection
and patient recruitment).
Most trials fail to meet their enrollment times (J. Hess and S. Litalien, Web-Based
Patient Recruitment, Cutting Edge White Paper).
• About 80% of trials do not meet their original enrollment times.
• Clinical trials last, on average, between 30% to 42% longer than planned.
• Phase III trials overrun by an average of 6.2 months.
The situation is getting worse
• Between 2005 and 2011, the increase in recruitment time was 29% for Phase
II studies and 20% for Phase III studies (CMR International R&D Factbook,
June 2011).
The day-to-day cost of delay is considerable
• Delays may cost $35,000 a day per trial (Datamonitor Report, “Launch Strategies”
[DMHC2304], August 2007).
The need for protocol amendments increases delays and costs (K. Getz, Protocol
Amendments: A Costly Solution, Applied Clinical Trials Online, May 1, 2011).
• 60% of protocols need amendments.
• On average, there were 2.3 amendments per protocol, though the average
increases as development progresses, so that Phase III protocols averaged 3.5
amendments.
• The average time for each protocol amendment was 65 days.
• The cost per amendment was greater than $450,000, mainly due to increases in
investigator site fees and vendor change orders, but not including internal, translation, and resubmission costs.
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• For a Phase III protocol, the delay could be up to 7.5 months (65 days × 3.5 amendments) and the cost over $1.75M.
Most amendments are probably the result of inadequate planning time, poor planning,
and incomplete feasibility testing (K. Getz, Protocol Amendments: A Costly Solution,
Applied Clinical Trials Online, May 1 2011).
• One-third of amendments were due to avoidable causes, according to the sponsors.
Yet “unavoidable” causes included elements that might have been anticipated.
• Between 30% and 52% of amendments (depending on the phase of development)
were submitted before the first patient entered the study.
What this means in practice is that one or more of the following will happen:
• The study can’t be done or can’t be done in time in one or more of the countries
selected.
• Patients complying with the eligibility criteria don’t exist in the numbers
expected, and recruitment slows down or grinds to a halt.
• Patients can’t carry out the protocol-mandated visits. The frequency, duration,
and timing of visits and the duration of the study may cause patients eligible to
take part to refuse, or to enroll and then skip visits or drop out altogether.
• The study procedures may be too uncomfortable, threatening, or even impossible*
for patients to carry out, also leading to dropouts.
• Initially, this results in increasing pressure on investigators, leading to strained
relationships and demotivation.
• Next come desperate rescue measures, including new recruitment initiatives and
the opening of new sites.
• The protocol will almost certainly have to be amended unnecessarily, possibly
more than once.
The consequences are significant. The delays in themselves cost money, while the
remedial measures cost even more money. The demotivating effect on investigators
and patients is hard to quantify, but is probably even more damaging. The most significant effect, however, is the potential to bias and invalidate the study as the power
is reduced by the failure to recruit the required number of patients and because of
missing data due to skipped visits, poor completion of procedures, and dropouts.
* I found out the burden a poor protocol places on patients the embarrassing way.
Knowing that I was visiting South Africa, where a colleague had an active site for a study in
dementia, he asked if I would visit the investigator to determine progress. At the entrance
to the hospital, an unsmiling man greeted me curtly and told me to follow him. He took
me to an office, told me to sit, and gave me the questionnaires that patients were expected
to complete at each visit. I was then instructed not to move until I had done so. This took
about 40 minutes of concentrated effort, at which point the investigator asked me (using
more robust language): “And you really expect demented patients to do that?”
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Why does this happen so consistently (especially since everyone does
“protocol feasibility”)?
It happens because protocol feasibility is not being done properly. This is an excellent
example of the clinical trial process that can be quantified and controlled, provided
that a rigorous and consistent approach is taken. Unfortunately, much of what is
called “protocol feasibility” is nothing more than random motion, with the inevitable
random results. These are the main reasons for failure.
Timing is generally too late and the process is rushed
Feasibility must be carried out as early as possible so that an approved protocol is
available six months before the planned study start date, and enough time must be
allowed for the process to be carried out properly. The protocol cannot, by definition,
be final until feasibility is complete.
The wrong sites are selected
For feasibility, sites must be selected because they are representative of the standard
of care needed and they have an adequate number of the relevant patients. Sites
should not be selected primarily in order to gratify an opinion leader, in response
to a marketing request, because the investigator is a friend, or because the site is
convenient. It is worth emphasizing that participation in feasibility does not mean
automatic participation in the study, though the prospect of participation may be a
powerful motivator to carry out the feasibility.
There is no formal, rigorous approach at all
It is surprising how often a vendor will claim to carry out feasibility, when in fact
all that happens is that a generic questionnaire is sent to random sites resulting in
nonspecific answers of no value. Another common approach is to ask investigators
for an opinion as to how many of their patients comply with the selection criteria (“because, of course, doctor knows his/her patients best”). Given that a “typical”
protocol may have about 35 criteria (Getz K. Tufts Center for the Study of Drug
Development. Slide for Presentation “Clinical Trial Complexity,” November 2012),
the answer is inevitably a guess. Furthermore, this approach does not provide information as to which of the criteria rendered patients ineligible.
The approach invites inaccuracy
The only approach that will produce consistent results is to go through the process face
to face with the site staff, with real, accurate data from all relevant patients at hand.
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Any approach based on asking site staff to fill in questionnaires (whether mailed, faxed,
or available on the Internet) on their own will inevitably be suboptimal. The exception
(there are always exceptions) is when a site’s staff have previously been trained face to
face and have proved to be reliable in providing the relevant data accurately.
Questions are either irrelevant or omitted
An analysis of protocol feasibility checklists shows that the two consistent errors
are inclusion of irrelevant questions (generally about site selection rather than feasibility) and, more important, omission of questions specific to the protocol-specific
selection criteria. The latter is much more important. Without the actual values for
all the selection criteria from all of the available patients with the relevant disease, it
is impossible to know what percentage is eligible and, if not, why not.
Sites are not adequately compensated
The feasibility process is time-consuming, and experienced staff members need to be
involved. Adequate compensation is essential. Although there are many alternative
ways of doing this, the process may involve planning and effort (possibly even a contract at some sites) and gives those who prefer the path of least resistance an excuse
for adopting a simpler approach or for guaranteeing that the site will be involved in
the trial, however unsuited the site may be.
Objectives are unclear and experience is lacking
Whether the process is carried out by company staff or delegated to a CRO, the process and the objectives must be clear and agreed on, and those involved must be well
trained and experienced. The further removed staff are from the center (for example,
CRAs in affiliates), the less likely they are to be trained and focused. CRO contracts
rarely specify the feasibility process in any detail, and provision of the relevant training for CRO staff is rarer still.
Feasibility results are not taken into account
Time constraints, inexperience, or lack of motivation often result in failure to fully
analyze the feasibility data, especially with regard to those aspects that, if modified,
could make the protocol more practicable.
There is a lack of oversight and approval
Protocols are often approved without any evidence that the feasibility process has
been carried out properly, that the results have been analyzed, and that the protocol
has been amended accordingly.
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[73]
An Early Effort and Important Lessons in What Not to Do
These lessons are well illustrated by my first attempt at something approaching feasibility testing.
The compound under investigation was a hypoglycemic agent. The objective was
to carry out protocol feasibility, patient identification, and site selection simultaneously by a process designed to be as simple as possible. Combining all three aspects
was felt to be the most efficient approach, as it would avoid having to repeat each
individual component. Potential investigators were given the selection criteria from
the finalized protocol (as well as a simple letter of intent) and asked to go through
the records of their diabetic patients and fill in a simple questionnaire by answering
one of two questions:
1. If the patient satisfied the criteria, would the patient agree, in principle, to
take part in a study? Ethics approval had not been given at this point, so no
study-related procedures could be carried out.
2. If the patient did not satisfy the criteria, which criteria were not satisfied?
Once the information was available, the intent was to
• decide if changing the selection criteria might increase the number of eligible
patients;
• select those sites that had the most patients;
• continue to contact eligible patients to get their agreement to take part.
Figure 5.1 shows a completed page from the questionnaire.
The outcome from this example is fairly representative of all the sites that
took part:
• Seven of the 13 patients did not satisfy the selection criteria.
• Four of these seven patients were ineligible because of one criterion: Their blood
sugar levels were above the protocol-specified cutoff.
• Six of the patients did satisfy the selection criteria.
• Two of these six patients had agreed in principle to take part in the study, with a
potential enrollment date given.
• The investigator was still in the process of contacting the other four patients.
So, even using this flawed process, there were positive gains. The site could contribute enough patients to warrant inclusion in the study, and it was possible that up to
six patients could have been enrolled (subject to the results of initial screenings) as
soon as the site was initiated, rather than waiting to start the recruitment process
after initiation. However, a further four patients might have been eligible if the
blood sugar level cutoff had been higher. Assessment of this criterion showed that
the entry blood sugar level was conservative and could have been raised without
putting patients at risk, thus increasing the number of eligible patients significantly.
[74]
The Practicable Protocol
Figure 5.1 A completed page from the protocol feasibility and patient selection questionnaire.
Fundamental mistakes
1. The patient process was carried out without first ensuring protocol feasibility.
As a result, either patients with blood sugar levels above the protocol cutoff level
would be lost (potentially as many as 30%), or the protocol would have to be
amended, wasting time and money.
2. The actual values for the various selection criteria (such as actual blood glucose
levels) were not recorded, so that the effect of adjusting these on patient eligibility could not be assessed.
3. The process was carried out too near to the planned study start date to allow time
for any changes without causing delays.
4. Potential investigators were sent a questionnaire and asked to fill it out themselves; in many cases, the replies were inaccurate or delayed, or both. It was also
impossible to determine how much effort the investigators made to identify all
possible patients.
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[75]
Preparing for Protocol Feasibility
Timing and Sequence of Events
Timing is crucial. To ensure that most sites can start more or less simultaneously, an
approved final protocol is needed at least five months before the planned study start
date. All feasibility activities should therefore be completed six months before the
planned date at the latest. Optimal timing can only be achieved if these activities are
carried out in parallel as far as possible:
•
•
•
•
•
•
•
•
•
•
drafting the protocol summary;
training of internal and CRO staff on the feasibility process;
selection of sites where feasibility will be conducted;
identification of potential countries and sites in which the study can be carried
out, based on known regulatory, bureaucratic, and protocol requirements (identification is not synonymous with country and site selection, which can only be
determined after the feasibility of the protocol has been tested);
selection of sites in which protocol feasibility will be carried out;
preparation of the questionnaire to be used for protocol feasibility;
finalization of the formal agreements with the sites for carrying out feasibility;
sending requests for proposals (RFPs) and selecting CRO, especially if help is
needed for the feasibility process;
explaining the feasibility process and agreeing on timelines with sites and CRO;
starting the process for formal agreements with potential sites to carry out
patient screening once feasibility is complete.
Considerations for Assessing Country-Specific Protocol Feasibility
Relevant country-specific aspects should have been addressed in the strategic development and clinical development plans, including information on
•
•
•
•
•
disease prevalence;
regulatory requirements and timelines;
commercial priorities;
ethical considerations;
medical practices and standards of care.
The first three of these are easy to address early on as they are very general, but
the countries identified initially should be reexamined once the details of individual study designs are known, especially regarding ethical and medical practice
and operational aspects, as these are protocol-specific. Logically, this information should be gathered before the site-specific activities are started, as it is more
relevant (though not essential) to carry out the latter at sites that might then
take part.
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The Practicable Protocol
Ethical considerations
While physicians and ethics committees will have views on these aspects that should
have been discussed widely as part of the study design process, there may be local
regulatory authority or legal requirements that preclude certain protocol designs
from being approved in a given country.
• Is the inclusion of a placebo arm allowed?
• Will a washout period be allowed, and if so, for how long? Will the duration considered ethical be long enough for prior therapy to be eliminated?
• Will switching a patient from current, approved therapy to trial drugs be considered as putting the patient at risk?
• Can the trial drug continue to be supplied indefinitely if necessary after the trial
is finished?
Medical practice and operational considerations
• Is the standard of care such that the data from this country will be relevant in
other countries?
• Are required concomitant medications approved and available?
• If necessary, can blood samples be exported?
• Are fully accredited laboratories available?
Preparation for Assessing Site-Specific Protocol Feasibility
Make sure that feasibility is an integral part of the CRO contract
Requests for proposals (RFPs) rarely include details of a definitive protocol feasibility
process. What passes for feasibility in most CROs will almost certainly not meet the
definition of the process as defined here. A nonspecific RFP will result in CRO costs
and manpower allocated to feasibility well below what is needed, without any commitment to a rigorous approach. The RFP is the starting point for ensuring that the
process, including necessary resources and training, are within the competence of
the CRO and are allotted costs appropriately.
Educate internal and CRO staff
Education in this context is specifically about the process of protocol feasibility,
including the management of investigator sites with respect to any ethical or contractual formalities. Ideally, this should be part of the fundamental education of
all relevant company staff, whether in the head office or in affiliates, and not part
of the study startup process. Realistically, this will not always be so, in which case,
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education should take place as soon as possible after the decision to carry out a
study is made and a study conduct team is formed. Education of affiliate-based staff
should proceed as soon as a preliminary list of countries that might take part is
drawn up.
All involved must be very clear about the rules relating to patient data, so that
there are no breaches of ethics regulations and, equally important, so that any concerns and barriers to the process, whether real or imagined, can be addressed and
overcome. On the whole, resistance comes mainly from within the sponsor organization and the CROs; resistance from sites is generally lower than anticipated.
For a multinational study, regional variations in regulations and attitudes must be
addressed. The various options, contractual or otherwise, for compensating site staff
must be understood.
When training is carried out early in the process, some of the protocol-specific
information might not be known, but this knowledge will be acquired as the protocol
summary evolves and, finally, from the feasibility questionnaire.
If the feasibility process is to be delegated to a CRO, all relevant details must be
included in the contract, including the requirement for training. One of the biggest
failings is the complete lack of specificity about protocol feasibility in the RFP used
by most companies.
Defining the Questions Needed to Determine Feasibility
The questions that can best be addressed by staff at an investigative site fall in to
three categories: ethics, operational practicalities, and availability of eligible patients.
Many of the questions might have been discussed internally or with consultants during the protocol design phase, but the most objective and well-informed answers will
come from a site.
Ethical aspects of the protocol
Although the country-specific ethical questions will have been answered, there may
well be aspects of specific concern to physicians and ethics committees that differ
from the national standards.
Practicality of the protocol from a patient perspective
Patients are unlikely to take part in studies that are disproportionately disruptive or
unpleasant. Topics to be discussed might include
• the duration of the study;
• frequency of visits;
• number, type, and frequency of procedures, especially if invasive or painful;
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The Practicable Protocol
• suitability and complexity of any questionnaires or other instruments or activities to be completed by patients (patient advocacy groups can provide useful information about the practicality of asking patients to complete questionnaires);
• dosing regimens, especially if parenteral, frequent, or involving large numbers of
tablets or outsize tablets.
Practicality of the protocol from the investigational site perspective
Eventually, individual sites will assess whether or not they have the competence,
time, and facilities (see ­chapter 8) needed to carry out the study. At this stage, the
representative feasibility sites can answer general questions about these aspects so
that the protocol can be modified if any part will not be manageable.
Availability of eligible patients
The objective is to establish the absolute number of patients being treated at the site
who comply with the selection criteria for the study, and the proportion they represent of all patients with the given disease being treated at the site. This is done by
collecting all qualitative and quantitative data relating to the selection criteria for all
patients with the relevant disease at the site, or, if there are so many patients that it
would take too long to assess them all, for a representative random sample.
A generic questionnaire would look like table 5.1, with enough columns to include
all inclusion and exclusion criteria and any other relevant data. Since the average protocol has up to 35 selection criteria, the questionnaire can be several pages in length.
There are two critical aspects to remember:
• The data provided should not include any information that could be used to identify a patient.
• The questionnaire must be designed to include actual values for each criterion
when applicable. For example, if there is a specific blood sugar level cutoff, then
the patients’ actual blood sugar levels must be recorded, not just the fact that the
Table 5.1 Very simplified generic representation of a protocol
feasibility questionnaire.
Patient Age Diagnosis Inclusion Inclusion Exclusion Exclusion Eligibility
Number
Criterion 1 Criterion 2 Criterion 1 Criterion 2
1
2
3
4 etc.
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patients did or did not satisfy the criterion. The reason why this is important will
become evident in the section on analysis of the data.
Selecting and Setting Up Sites for Protocol Feasibility
When should feasibility sites be selected?
The selection process should start as soon as the type of patient needed to address
the therapeutic objective (such as osteoarthritis of the hip, or SLE) is known. At this
stage, the exact selection criteria are irrelevant.
What are the criteria for choosing a site?
Always remembering that the primary objective is protocol feasibility, not site selection, criteria to take into account include the following:
• a large population of the relevant patients;
• sites “representative” of the practice in that therapeutic area (this can’t be defined
precisely, but the site should not be too specialized, as the patients seen there
might not be representative of the general population, or too general, in circumstances where more advanced or severe disease is required);
• prior clinical trial experience;
• enthusiasm and willingness to help;
• a straightforward and rapid contractual approach;
• an efficient patient record filing and retrieval system;
• cost;
• previous collaboration with the site.
Apart from the first two points, pragmatism requires that these criteria be applied
flexibly. An advantage of identifying these sites as soon as possible is that it allows
time for contracts to be completed if necessary.
What arrangements need to be made at the site?
• Discussing the process in detail with all the staff who will be involved (not just
with the physician responsible for the patients) goes a long way to decreasing
resistance, reducing misunderstandings, inducing enthusiasm, and getting
alignment. If possible, those involved in patient record management should be
included.
• A formal agreement outlining the process, the deliverables, and the fee diminishes the chance of later disagreement. This can range from a letter of agreement
[80]
The Practicable Protocol
(the simplest, preferred option and the most common solution) to a full-blown
contract. Insistence on the latter may sometimes preclude a site from taking part.
• Making sure that the details about how the data will be collected and used (see
below for more details) are clearly documented and understood is invaluable.
Detailing how to collect data reduces the error rate and ensures consistency
across sites, while knowing how the data will be used is important for practical
and ethical reasons.
• Thought should be given to ethical considerations. Given the nature of the process, ethics approval is neither usually considered to be needed nor usually asked
for, but involvement of the chair of the ethics committee can ensure that this
aspect is addressed objectively.
• Don’t forget to agree on who is responsible for each activity and by when it should
be completed. Ideal timelines should be as realistically tight as possible, and the
person(s) who will carry out the process should be appropriate to the task.
Data Collection and Analysis
Data Collection
Coordination and planning are the essential precursors to data collection, so that all
the relevant site staff and the patient records, whether in paper or electronic form,
are ready and accessible on the appointed days at a venue in which work can continue
uninterrupted.
The ideal approach is for a trained sponsor representative to be present in person,
either observing the process or helping to complete the questionnaire. This can be
done in much the same way as it is done during the source document verification process. Optimally, the questionnaire would be in a format allowing electronic data capture, but whether done electronically, on paper, or both ways, the result is the same.
Data collection proceeds in two phases. The first phase is to classify patients
according to the “major” selection criteria that are not open to modification. In this
way, a significant number of patients can be eliminated without the need to address
all the other selection criteria, saving a lot of time. Some examples of these criteria are
• treatment-naïve patients only;
• diseases with, or without, a specific complication, such as
o patients with systemic lupus and nephritis,
o hypertensives with left ventricular hypertrophy,
o diabetics with peripheral vascular disease;
• disease present for a less than Y months;
• disease present for a minimum of X years.
The total number of patients with the disease may be large, but by eliminating all but
those who comply with these types of broad, essential criteria, a more manageable
number can proceed to the second phase.
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The second phase of data collection consists of extracting the values for all of the
remaining selection criteria from the records of those patients who remain after the
first phase, always remembering that, when applicable, actual values must be recorded,
not just the fact that a patient did not meet the criterion.
In theory, all this could be done simply by sending the questionnaire to the site
(either electronically or on paper) and asking that it be completed. In practice, this
is a bad idea because the result is rarely either complete or accurate, unless the site
has done this recently (new staff won’t know what to do) and has shown itself to be
dependable.
If it is absolutely impossible to be onsite for the completion of the questionnaire,
a reasonable compromise is for it to be completed online in an interactive way so that
the sponsor can observe how the document is being completed.
The Analysis
The data are analyzed in order to determine the following:
1. how many patients meet all the criteria as defined in the draft protocol synopsis
as it stands;
2. whether changing one or more of the criteria, within limits that do not affect the
validity of the protocol, increases the number of eligible patients;
3. how many patients would become eligible if something could be done to bring
them into conformity with the criteria (e.g., if a patient is taking concomitant
medication that is not permitted, could that medication be discontinued and the
patient enrolled after a washout period).
The number of patients with the relevant medical condition identified at the start
of the process is progressively reduced as each inclusion or exclusion criterion is
applied, usually leaving a disappointingly small number who comply with all the criteria. The result looks like fi
­ gure 5.2.
In this simplified example, the study was in critically ill patients in intensive care.
Twelve eligibility criteria are listed. Altogether 49 patients were identified as being
possible trial candidates, but only seven of these satisfied all the criteria.
At this point, each criterion is scrutinized carefully: Can it be amended, or even
eliminated, without affecting the integrity of the protocol? In the case of the example shown in ­figure 5.2, there was some debate about the relevance of criteria 8 to 12.
The fact that it was important to keep these criteria was irrelevant, however, because
it turned out that they were not limiting factors. Even if it had been possible to eliminate all of them, the net gain would have been one patient (­figure 5.3).
Further analysis showed that only two criteria affected the numbers significantly: duration of antibiotic treatment, which could not be modified, and the
APACHE score. Eliminating the APACHE score altogether would have had a dramatic
effect (­figure 5.4).
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The Practicable Protocol
1
49
2
49
3
49
49
4
5
18
6
18
7
8
8
8
9
7
10
7
11
7
12
7
Figure 5.2 This semi-automated system, developed by Bernard Chan and Grahaem Brown
of Competitive Drug Development International Ltd. (www.cddi.co), simplifies the analysis
process considerably. Yes/No criteria are included by checking the relevant box, while criteria
with actual values can be modified by moving the slider next to each one. In this example,
the number of eligible patients is reduced to seven when all the original eligibility criteria are
applied.
Further consultation and review of the literature showed that, while having an
upper limit for the APACHE score was essential, the number of eligible patients
could be doubled (­figure 5.5), without changing the profile of the patients in a clinically relevant way, by increasing the score from the original level of 16 to 22.
The protocol synopsis was therefore amended to reflect this change.
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1
49
2
49
3
49
4
49
5
18
6
18
7
8
8
8
9
8
10
8
11
8
12
8
Figure 5.3 Elimination of criteria 8 to 12 does not increase the number of eligible patients
materially.
When, as often happens, there is no obvious way in which the protocol can be
amended without affecting the original objectives, there will clearly be a problem
finding patients. In these cases, two main choices remain:
1. Change some criteria with the knowledge that the protocol will be less than
perfect (e.g., by including patients who are less severely affected, or who have
had the disease for a longer period, or who are older, etc.).
[84]
The Practicable Protocol
1
49
2
49
3
49
4
49
5
49
49
6
32
7
32
8
9
29
10
29
11
12
29
27
Figure 5.4 Eliminating the APACHE score criterion altogether would increase eligibility
fourfold. This would have destroyed the study, however, because survival decreases with
increasing score.
2. Leave the protocol as it is and put in place an extensive and concerted patient
recruitment program. This is often needed if changes to the protocol would materially affect patient safety or the study objectives. The advantage of having carried
out feasibility is that the recruitment process, though expensive, can start now,
increasing the possibility of the trial finishing on time, rather than as a late rescue
measure, with even greater costs and significant delays in trial completion.
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1
49
2
49
3
48
4
48
5
29
6
29
7
16
8
16
9
15
10
15
11
15
12
15
Figure 5.5 Changing the upper limit of the APACHE score to 22 doubled the number of eligible
patients without affecting the homogeneity of the study population.
Some Excuses for Avoiding the Feasibility Process (and Why They Are
Simply Excuses)
The following are classic excuses used by sponsor staff. In general, virtually all of
the resistance to the process is inside the sponsor company, and not at the investigator site. Once the value of the process has been explained, and a suitable fee has
been proposed, most trialists are enthusiastic and become useful advocates for the
process.
[86]
The Practicable Protocol
“It is too expensive”
It is not too expensive when compared with the cost of an average study and the
costs of protocol amendments, delays in starting the study, extended recruitment
times, and the need for additional sites.
“We don’t have time”
This means that “we haven’t planned properly and made time.”
“We don’t have the staff”
They may not have the staff internally (though feasibility might be more important than some of the internal activities), but there are many CROs with staff
for hire.
“We have never done this before”
That is interesting. So, every study has come in on time and on budget?
“It is unethical”
The process is perfectly ethical if the correct procedures are adopted. Similar objections were common when source document verification (SDV), for which the overall
approach is very similar, was first introduced. Plus ça change . . .
“The trial sites are too busy”
This is usually stated without consulting the site, or without explaining the concept
properly. If a site is genuinely too busy, the process should be carried out somewhere
else. This may also indicate that the site is too busy to take part in the actual study.
“Setting up a contract with a site is a nightmare”
Planning is again important, though in practice, the full contractual process is not
needed. A surprising proportion of sites do not ask to be paid.
“This is unnecessary because doctors know their patients”
Any doctor (or healthcare professional) who claims to remember all of the clinical and investigational details of every patient with a given disease in their
Ca r r y i n g o u t P r o t o c ol Fea s i b i l i t y
[87]
care either has very few patients, or the most phenomenal recall, or very little
insight.
Technology and Protocol Feasibility
All one needs to carry out feasibility is a spreadsheet and time. Life is made easier by
having an electronic data entry system and an analysis tool that allows the effect of
modifying individual eligibility criteria to be seen immediately (as in the above example). But is the laborious system of identifying individual patients and going through
their records one by one still necessary in an electronic age? The answer is “Yes.”
In 2001, at the companywide launch of a completely redesigned development
process, a session on future innovation described how electronic medical records
(EMRs) would soon allow protocol feasibility, site selection, and patient recruitment
to be carried out at the touch of a button.
Over 10 years later, there are still relatively few centers worldwide with EMRs, a
situation that is unlikely to change very soon. In very limited situations, EMRs have
been used to great effect (B. D. Harper, Parexel Biopharmaceutical R&D Statistical
Sourcebook, 2011/2012), but, for the overwhelming number of studies, a review of
written rather than EMRs (or, at best, a mixture of the two) will continue to be the
norm for many years.
Key Points
• There are significant negative practical and economical consequences if protocol
feasibility is not carried out properly:
o protocol-specific patients may not exist in sufficient numbers or may not exist
at all;
o patients may refuse to take part;
o aspects of the protocol may be considered unethical in some countries, though
not in others;
o medical practice might distort the results;
o all these result in delays and added expenses due to protocol amendments and
slow recruitment.
• Reasons why protocol feasibility is done badly include
o not doing it at all ("we have lots of experience");
o not making feasibility an integral part of the study startup process;
o starting too late and rushing;
o untrained staff;
o choosing the wrong sites;
o expecting the feasibility to be done for nothing (though often it is);
o not focusing on the protocol, but mixing site and patient selection;
o asking the wrong questions or omitting important data;
o carrying out the process remotely, instead of face to face.
[88]
The Practicable Protocol
• Avoiding all these obstacles requires planning, budgeting, and training.
• Involve as many relevant site staff (investigators, coordinators, administrators,
medical records keepers, ethics committee members) as possible.
• It is essential to include all protocol-specific questions, remembering that protocol feasibility goes beyond patient eligibility criteria.
• Accuracy of data collection can only be guaranteed if all relevant patient medical
records are available and the data are collected in face-to-face collaboration with
site staff.
• Careful analysis of the data can identify potential modifications to the protocol
that increase feasibility, sometimes significantly.
• Confirmation that the process has been carried out and that the modifications
are appropriate should be an integral part of the protocol review process, and no
protocol should be approved unless feasibility has been carried out properly.
Ca r r y i n g o u t P r o t o c ol Fea s i b i l i t y
[89]
C h apter 6
The Optimal Blend: The Approved
Synopsis and the Final Protocol
Objective
The main objective is the rapid realization of a final protocol that accurately meets
the development objectives, reflects the results of protocol feasibility, and can be
implemented without unnecessary amendments.
To recapitulate, the steps to an approved protocol are as follows:
1. The approved draft protocol synopsis. This is the penultimate version of the
core of the final protocol and is used to assess protocol feasibility, as described
in ­chapter 4.
2. The approved protocol synopsis. The synopsis has been amended as appropriate
to ensure optimal feasibility without diminishing the validity of the study and
has been approved. At this stage, the protocol is, in effect, locked and ready to be
implemented.
3. The approved final protocol. This step involves incorporating the contents of the
approved protocol synopsis into the template for the full version of the protocol
and having it approved for completeness and consistency.
Unfortunately, approval of each step is essential, with its implications of time-wasting
micromanagement, formality, pedantry, and bureaucracy. How to minimize these aspects
while ensuring that the essential value of the approval process is maintained is described
later in this chapter. But first, we review the final steps to the definitive protocol.
The Approved Protocol Synopsis
The only difference between this version of the synopsis and the draft synopsis is
that all changes resulting from the feasibility process have been incorporated. The
protocol is now complete from a purely operational perspective. That begs the question: “Why go through the process of approving this version and not just go on to the
full, definitive protocol?”
The reason is that it is much quicker and simpler, and less likely to lead to inconsistencies, to amend the draft synopsis and get on with all that can be done, without
having to wait for the full protocol or having to plow through all the redundant
(from an operational perspective) material it contains. The synopsis and the protocol have differing important functions, so that finalizing both as soon as possible is
a priority.
Once approved, the protocol synopsis can be used to finalize all of those activities
that were initiated using the approved draft, as listed in c­ hapter 4. In most cases, the
only changes to the synopsis will be to the patient selection criteria, so that all of the
following can be accomplished:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
material needed for patient screening and site selection;
arranging meetings with regulatory bodies;
resource planning;
statistical analysis plan;
patient recruitment plan;
randomization plan;
ordering and packing of supplies;
preparing import licenses;
designing the case record form (especially if electronic);
study insurance;
study manual;
starting the request for proposals (RFP) process with vendors;
drafting the analysis plan;
database setup;
training materials;
dates for training and other meetings.
The most important additional activity for which the approved synopsis can be used is
site and patient selection, as described in c­ hapter 7.
The Approved Final Protocol
The process for turning the approved synopsis into a protocol should be rapid and
straightforward. This is often not perceived as being possible and, as a consequence,
the process is usually unnecessarily lengthy and convoluted. There is no reason why
an approved final protocol should not be available within a very short time (one to
two weeks) after the synopsis has been approved.
T h e A pp r o v e d S y n op s i s a n d t h e Fi n a l P r o t o c ol
[91]
It is very important to complete and approve the protocol rapidly as there are
essential steps in the trial initiation process for which only the full protocol is
acceptable:
• approval by regulatory authorities
• approval by ethics committees
• contractual negotiations
Given the time these activities can take (especially if sequential), the need for speed
in producing the approved protocol is self-evident.
Differences between the Synopsis and the Full Protocol
The main differences are that the protocol contains a lot of background information (such as a summary of the characteristics of the drug and its development so
far), explanatory details (such as the statistical methods used), definitions (such as
adverse events or specific laboratory tests), and ethical considerations (such as the
declaration of Helsinki). There is also an expanded section in which the visit-by-visit
trial activities are described in minute detail.
Planning for and Writing the Full Protocol
There is a widespread belief that (a) turning a synopsis into a protocol is complex and
time-consuming, and (b) the study design can change during the process. In the face
of this belief, the consequence is inevitably that the protocol takes longer than necessary to finalize and changes occur. Both of these issues can be avoided with sensible
planning and adherence to a logical process.
To avoid unnecessary delays, much of the content of the full protocol can, and
should, be prepared in parallel with the activities surrounding the synopsis.
The key principle is to prepare as much as possible as early as possible, while
being careful not to include sections with a high likelihood of needing amendment,
because each change increases the likelihood of inconsistencies in the document. The
latter sections should be relatively few if the process for writing and approving the
draft synopsis has been rigorous. There are, broadly, three types of protocol content:
• information that is generic and common to most protocols;
• information that is drug-related;
• study-specific objectives, instructions, and procedures, as detailed in the synopsis.
Even before the study is conceived, the protocol template can contain most, if not
all, of the generic information and, unless this is the first-ever clinical study with the
drug, much of the drug-related information.
[92]
The Practicable Protocol
Information that is generic and common to most protocols
This information is usually part of most generic protocol templates and may include
the following:
• adverse events:
o definitions;
o general reporting requirements;
o serious adverse events reporting;
o emergency unblinding and code breaking.
• trial administration:
o ethics committee review;
o informed consent;
o drug accountability;
o completion and management of data collection tools;
o monitoring the trial;
o exemptions to the protocol;
o record retention;
o quality assurance;
o criteria for termination of the study;
o protocol amendments.
• ethical considerations:
o patient privacy;
o declaration of Helsinki.
• regulatory aspects:
o sponsor responsibilities;
o responsibilities of trial monitors;
o responsibilities of investigators;
o documents needed prior to study initiation;
o contents of investigator file.
Information that is drug-related
This information, which is usually limited to the introduction and in which the characteristics of the disease and the drug are summarized, can be added to the protocol
template early in the development process. Once written for the first time, this background material can be used in subsequent protocols, with amendments when new
data are available.
It is important to remember that only a brief outline is needed; detail is provided
in the investigator brochure. Two common time-wasting failings are trying to write
an entire thesis for the introduction and, though less common, writing a new introduction for each protocol.
T h e A pp r o v e d S y n op s i s a n d t h e Fi n a l P r o t o c ol
[93]
Study-specific objectives, instructions, and procedures, as detailed in the synopsis
Although some details can only be included once the feasibility process is complete,
there is a lot that can be added section by section during the development of the
synopsis. For example, the following can usually be included in the draft of the final
protocol at the approved draft synopsis, unless major changes are anticipated as the
result of feasibility testing:
•
•
•
•
•
•
•
•
•
•
•
•
title of study;
rationale;
objectives;
design;
endpoints;
statistical methodology;
study drugs, dose, frequency, and mode of administration;
evaluation parameters;
schedule of events;
study visits and follow-up;
specific safety issues;
detailed explanation of some of the sections.
Each study will have protocol-specific procedures and investigations. Some of
these may not be standard and may require instructions on how they are to be
carried out or how to store samples and specimens. Instructions may also be
needed for the handling and storage of trial medications. Diseases might have
specific diagnostic criteria or classifications of severity. All of these instructions, criteria, and classifications can be included in the protocol at a relatively
early stage.
What remains to be done?
At this stage, it is time for the inclusion of those components of the protocol that
were left until last because they were the most likely to need amendment as a result
of protocol feasibility. The specific components will differ from protocol to protocol
and should be identified as early as possible.
There are two components that are best left to last, irrespective of anything
else:
• the patient selection criteria, as these usually have the greatest impact on
feasibility;
• the detailed description of the visit-by-visit trial activities, as revisions here are
one of the main reasons for inconsistency.
[94]
The Practicable Protocol
Two failings commonly responsible for delays and inaccuracies
1. Revision of the study design
There is usually no reason to change anything at this stage, though this does not
prevent changes being made with abandon. These are the most common reasons:
• Investigators who are shown the approved synopsis with a view to participating in the study express opinions that somebody feels compelled to include, even
though they are irrelevant to the fundamental conduct of the study.
• The approval processes are flawed, so that
o the protocol synopsis is approved even though it is inadequate;
o the full protocol approval process is a free-for-all with unclear objectives and
poor oversight.
There may be events that make it essential to modify the study design even as the
protocol is being finalized. These include
•
•
•
•
the unforeseen introduction of new procedures in clinical practice;
new diagnostic investigations or criteria;
new government regulations;
new standards of care.
These same factors are among those that might require a protocol amendment later
in the study.
2. Extreme cutting and pasting
Injudicious cutting and pasting is a significant cause of inconsistency within a protocol. For sections that need to be modified from one protocol to another, it is probably more efficient in the long run to rewrite the section, rather than copying and
then modifying it. This is especially true for sections whose contents are reflected in
several parts of the protocol, especially dosing regimens or the schedule of events.
Key Points
• The development flow for the approved synopsis and protocol, and their primary
uses before the study starts, are shown in fi
­ gure 6.1.
• Other than the format and additional content, there should be no difference
between the approved synopsis and the approved protocol.
• The full protocol can be finished and approved very shortly after the synopsis has
been approved.
• It is important to finalize the protocol as soon as possible.
T h e A pp r o v e d S y n op s i s a n d t h e Fi n a l P r o t o c ol
[95]
Project and Clinical Development Plans
Detailed resource planning
Ordering supplies
Generating the randomisation plan
Packing supplies
Starting RFP process with vendors
Designing the data capture instrument
(especially if electronic)
Drafting the analysis plan
Protocol feasibility
Feasibility Test
Complete the Full Protocol in Parallel
Approved Draft Synopsis
USES
m
m
m
Approved Synopsis
USES
Screening for patients
Site selection
Approved Protocol
USES
Approval by regulatory authorities
Approval by ethics committees
Contractual negotiations
Figure 6.1 Flowchart for protocol synopsis and full protocol development, showing the
temporal relationship and their uses.
Reviewing and Approving the Synopsis and the Protocol
General Considerations
Most companies have a process for reviewing and approving protocols, usually
involving a formal committee. The effectiveness and efficiency of the process depend
on several factors.
Involving the right people
This is self-evident, one would think, but it is often not the case. The composition
should reflect the objectives set out for review or approval, some suggestions for which
are made below. Important considerations are experience, flexibility, and knowledge.
Least important are seniority and not being too busy. In smaller companies, this can
[96]
The Practicable Protocol
be a problem, as there are so few competent people that they end up doing everything.
In these cases, getting outside help with reviewing is money well spent.
Management culture
Reviewers and approvers (who may be different people) should have ultimate
decision-making powers. A common practice of reviewing and approving the reviewers and approvers is a waste of time and symptomatic of any number of diseases,
including inability to delegate and mindless hierarchy.
Adherence to objectives
Any process should have clear objectives, and reviewing and approving synopses
are no exceptions. Non-adherence to the objectives is one major reason why meetings take forever and people get confused and frustrated (the other major reason is
lack of preparation). The person who wants to change commas when the discussion
centers around strategy is as well known as the person who suddenly questions the
entire rationale when the final touches are being added to a protocol. Another culprit
is the person who confuses his or her function with that of the project management
process (budgets, resources, timelines, etc.).
There is always the potential for overlap of activities between teams and committees, and this process is no exception. The study conduct team should have the
primary responsibility for carrying out, analyzing, and implementing the results
of the feasibility process, while the protocol approval process ensures that it has
been done and is reflected in the synopsis and the full protocol. The temptation by
approval committees to interfere in the operational side is tempting, especially as
there is usually cross-pollination of membership. This does not mean that relevant
observations and suggestions should not be made, just that care should be taken
that the approval team is not trying to do the work of the study conduct team, and
vice versa.
Preparation, planning, and flexibility
Flexibility is essential. Any process that depends entirely for decisions on a meeting
that occurs at a regular, fixed time is, by definition, a waste of time. The time needed
to get feedback from a review or to get a decision should not depend on some preordained meeting frequency.
Synopses evolve so that review should be a continuous process. Agreement
between the clinical team and the reviewers about frequency and turnaround times
should ensure that the process flows without interruption. Ad hoc meetings between
individuals or small groups are most efficient uses of time, though arranging (two
at the most) plenary meetings to consolidate all the different aspects when the
T h e A pp r o v e d S y n op s i s a n d t h e Fi n a l P r o t o c ol
[97]
document is nearly ready is essential. Decisions made at these full meetings can be
implemented and reviewed without need for another meeting.
Approval
Approval of a synopsis or protocol is perhaps best done with everyone together,
preferably in the same room, though teleconference and video-conference participation can be effective if managed professionally. This meeting should be
called specifically when documents are ready for approval, with an agreed timeline that gives the approvers time to read the documents and prepare properly.
A week should be more than enough time and allow for interim discussions to
take place. Unless there are major issues (in which case, the whole process has
failed), changes agreed to at the meeting can be made and approved without need
for a further meeting.
Specific Considerations
The draft protocol synopsis
Writing the draft synopsis is synonymous with writing the definitive study-specific
core of the protocol. It is the single most important step in reaching an approved
protocol, and the review and approval processes should reflect this. They should
address all the components needed to answer two questions:
1. Does this address the strategic and operational objectives and will it provide the
relevant answers?
2. Does it meet the expected scientific, medical, and ethical standards of the
company?
Each component of the synopsis is as important as every other one and should
not be approved unless considered to be definitive. The fact that changes might be
made as a result of the feasibility process is not a reason to submit a suboptimal
document.
The definitive protocol synopsis
The specific purpose of this approval process is to ensure that relevant changes based
on the results of the feasibility test have been made in the synopsis. Human nature
being what it is, there will inevitably be comments about other aspects of the protocol. Unless fundamental to the success of the study, further changes should be
discouraged.
[98]
The Practicable Protocol
The full protocol
At this stage, one of the prime objectives of the approval process is to ensure that it
reflects the content of the approved synopsis exactly. Reasons for rare exceptions to
this rule have been given above, but unless these have occurred, the other objectives
of the process are to ensure
•
•
•
•
coherence of the document;
consistency throughout;
legibility and ease of understanding;
compliance with company and regulatory standards.
Key Points
• Objective review of the modified protocol synopsis, before it is considered to be
definitive, confirms that the feasibility process has been carried out and that the
modifications are appropriate.
• The effectiveness and efficiency of the review and approval processes (and of any
process involving a committee) depend largely on
o including the right people;
o the best management culture;
o adherence to objectives;
o preparation;
o good planning and flexibility.
• There are different objectives for teams or committees reviewing or approving
the draft synopsis, the definitive synopsis, and the full protocol. Adherence to
these objectives helps to minimize needless repetition, confusion, and delays.
T h e A pp r o v e d S y n op s i s a n d t h e Fi n a l P r o t o c ol
[99]
PART FOUR
The Sponsor, The Physician, and The
Patient: The Eternal Clinical Trial Triangle
C h apter 7
Of Chickens and Eggs: The Sponsor’s
Dilemma
Q. Which comes first, the sites or the patients?
A. The patients. Find the patients and the sites will follow.
Objectives
The main objective is to select only those sites that have definitively identified the
required number of study-specific patients. To ensure that objective, whenever it is
feasible, these patients should be lined up and ready to be enrolled before the sites
are initiated.
Definition of Terms
Screening is the means for identifying potential volunteers for a trial by assessing
whether or not they satisfy the inclusion, exclusion, and other relevant criteria for a
given study. Screening and identification can be carried out long before a study is scheduled to start.
Recruitment is the formal process of getting agreement from patients that they
will take part in a study and getting their informed consent. Patients who give
informed consent can then be enrolled in the study. Some procedures to determine
eligibility may need to be carried out immediately before enrollment, so the fact that
a patient has been recruited does not automatically indicate that the patient will be
enrolled.
Enrollment is the process of entering a patient who has given consent into the
study by carrying out whatever initial procedure is needed. The initial procedure may
be randomization, a run-in phase, or dosing if the study is open label.
Why Site Selection and Patient Recruitment Continue
To Be the Greatest Hurdles to Efficient Clinical Trial
Conduct
If the matter is one that can be settled by observation, make the observation yourself.
Aristotle could have avoided the mistake of thinking that women have fewer teeth than men
by the simple device of asking Mrs. Aristotle to keep her mouth open while he counted.
—Bertrand Russell, philosopher
Everyone is aware of the uncertainty and inefficiency that characterize clinical
research. It is therefore hard to explain why those few aspects that can be quantified
with some degree of accuracy and certainty continue to be the very ones that are
usually approached subjectively and irrationally. No two aspects illustrate this paradox more vividly (and no two aspects are more responsible for time delays, wasted
money, and poor data) than poor clinical trial site selection and inadequate patient
screening and identification before the study starts.
Typically, sites are selected according to a number of criteria including, among
others:
•
•
•
•
•
•
•
•
•
commercial importance (key market or key opinion leader);
disease prevalence;
previous experience with site or investigator;
expertise of investigator;
resources at the site;
equipment at the site;
relationship to institution (preferred provider agreement);
ease of contract negotiation;
ethics committee schedule and flexibility.
The primary emphasis is rarely on the one key question: “Does the site have enough
patients?”
The answer to this question is the only one that really matters, because if a site
does not have the patients, none of the other factors are relevant. On the other hand,
if a site does have the patients, then often, other shortcomings can be addressed.
This question is not to be confused with the question: “Does the investigator claim
to have enough patients?” The answer to the latter is usually subject to “Lasagna’s
Law,” described below.
The reason for this emphasis on patient availability is that patient recruitment is
by far the most important cause of time and cost overruns in clinical trials. The evidence for this, confirming what everyone already knows, is consistent and disturbing.
[104]
The Sponsor, The Physician, and The Patient: The Eternal Clinical Trial Triangle
Some Consistent and Disturbing Data; the Extent of the Problem
In most years and in most geographical areas, fewer than 15% of trials were completed on time (­figure 7.1) and between 40% and 70% were delayed for more than
one month (­figure 7.2). Data published in 2013 suggest that, although 89% of studies achieve the planned enrollment, “Study timelines are typically extended to nearly
double their original duration to meet desired enrollment levels for all therapeutic
areas” (Tufts CSSD Impact Report, 15:1, January/February 2013).
CMR International data (CMR, Global Clinical Performance Metrics, 2001) for the
years 1997 to 2001 including 33 large pharmaceutical companies from around the
world showed that the mean time from first patient enrolled to last patient enrolled
was between 307 and 343 days (all Phase II and Phase III studies, all therapeutic
areas; mean number of studies included per year 589, range 490–686).
Thus, the mean time to recruit patients into a study was 10 to 11 months in the
five years up to 2001, and since then things have only become worse: Between 2005
and 2011, the increase in recruitment time was 29% for Phase II studies and 20% for
Phase III studies (CMR International R&D Factbook, June 2011).
In a survey carried out by CenterWatch among 950 U.S. study sites in 2009 (The
CenterWatch Monthly, 2009, Vol. 16, Issue 5), 41% of respondents gave patient
recruitment and enrollment as a factor most often causing study delays, a figure
almost identical to the percentage (43%) who gave the same reply in a similar survey of 306 study sites in Europe in 2006 (The CenterWatch Monthly, 2006, Vol. 13,
Issue 6). This opinion is reflected in that of sponsors, who attributed 46% of delays
to “poor recruitment once sites are live” (Clinical Trial Recruitment Best Practices
and Performance Benchmarks: The Wise Investments Survey, Veritas Medicine,
April 2006).
An associated phenomenon is that almost 50% of sites included in studies fail to
reach their recruitment targets (Tufts CSSD Impact Report, 15:1, January/February
30
Percent
25
20
USA
15
Europe
10
Latin America
5
0
Asia-Pacific
1997 2000 2001 2002 2003 2005 2006 2007 2009
Year
* Includes Canada in 2006
Figure 7.1 Percentage of studies completed on time in the major geographical areas between
1997 and 2009.
Source for all data CenterWatch, taken from Parexel Biopharmaceutical R&D Statistical Sourcebooks 2004/2005,
2006/2007, 2009/2010, and 2011/2012.
T h e Sp o n s or ’ s Di l e m m a
[105]
Percent
80
70
60
50
40
30
20
10
0
USA
Europe/Canada
Latin America
Asia-Pacific
1997 2000 2001 2002 2003 2005 2006 2007 2009
Year
Figure 7.2 Percentage of studies completed more than one month late in the major geographical
areas between 1997 and 2009.
Source for all data CenterWatch, taken from Parexel Biopharmaceutical R&D Statistical Sourcebooks 2004/2005,
2006/2007, 2009/2010, and 2011/2012.
2013); 11% of investigators in this survey are estimated to recruit no patients at
all, a conservative estimate compared with others who quote figures of over 30% of
investigators recruiting no patients or just one patient.
The relevance of these well-known facts lies in the very significant consequences.
The Consequences
Delays
Delays increase costs: the cost of internal staff who are tied up; the cost of vendors,
who will naturally milk the delays for all they are worth; the cost of losing competitive advantage and the cost of delayed returns on investments.
Delays also involve frustration for and loss of interest by investigators and their
staff, further compounding the problem and creating a vicious cycle of failure and
antagonism.
Costs
In addition to the high daily costs of managing a study (Datamonitor Report, “Launch
Strategies” [DMHC2304], August 2007), the other most immediately tangible costs
are those for the initiation and maintenance of nonperforming sites and for recruitment rescue activities. Initiation and maintenance can cost $9,981 and $23,849
respectively (Medidata CROCAS® database, 2012). That adds up to nearly $340,000
for every 10 nonperforming sites. Recruitment rescue activity costs depend on the
number of additional sites needed and the time it takes to find and activate them,
and it is estimated that such activities are needed in 20% to 50% of clinical trials
(G. Li, “Site Activation: The Key To More Efficient Clinical Trials,” PharmExec.com,
December 12, 2008, Advanstar Communications).
[106]
The Sponsor, The Physician, and The Patient: The Eternal Clinical Trial Triangle
Discontinuation of studies
Recruitment problems may be such that a study has to be discontinued, and they may
be the reason for 30% of Phase III terminations (Li and Gray, “Peformance-Based
Site Selection Reduces Costs and Shortens Enrollment Time,” Monitor, December
2011). The consequences of such terminations go beyond the immediate study
costs, time wasted, and ethical considerations; entire development programs can be
undermined.
Robustness and credibility of results
Recruitment difficulties contribute significantly to misleading outcomes. Studies are
frequently analyzed even if they are stopped without the planned number of patients
being recruited, one possible outcome of which is a false negative result. Reviews of
“negative” studies show that over half may have missed a relevant endpoint due to
being underpowered (J. A. Freiman, T. C. Chalmers, H. Smith Jr. et al., New England
Journal of Medicine, 1978; D. Moher et al., JAMA, 1994).
Reasons for These Continuing Problems
Patient recruitment is the primary concern of everybody involved in clinical trial
operations, but inexplicably few begin at the logical, obvious starting point: Go
where the patients are. The data are clear: The availability of qualified, eligible study
volunteers is the top factor in ensuring best site performance (Tufts CSSD Survey
of 3,516 sites, 2010), and the effectiveness of site evaluation as a patient recruitment activity is rated the highest of all recruitment activities (Clinical Trial Patient
Recruitment, Cutting Edge Information, 2010). Yet this activity is not carried out
effectively for a number of reasons, many of which are due to traditional practices
that people are reluctant to abandon.
The clinical trial site selection lottery
The process for identifying trial sites has become more and more sophisticated.
Vendors offer access to elaborate databases and analytical methods to help in pinpointing the most appropriate sites. Nevertheless, the final common pathway to
reaching a decision still usually involves a combination of the following:
1.
2.
3.
4.
5.
The investigator is a key opinion leader (KOL).
The investigator is important to the company.
Marketing wants the investigator to be included.
We have worked with the investigator before.
The investigator recruited well in a previous study.
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6. The investigator has carried out trials with similar drugs.
7. The investigator says that the requisite number of patients is available.
All of these criteria are valid if taken in context and not given undue emphasis.
However, no guarantee of success can be placed on these criteria as they give no
indication whatever that the investigator has the relevant patients in the numbers
required.
Criteria 1 to 3
These criteria are interlinked and are the most insidious. If the objective is to recruit
patients in order to get data, then none of these three criteria apply. If an investigator conforming to these criteria can also recruit the required patients (one does not
necessarily preclude the other), then so much the better, but experience dictates that
this is not necessarily the case.
KOLs are important, and opinion leaders with experience in using a new drug
are invaluable as advocates and advisers to the sponsor and the medical community.
Unless they have proven themselves as good clinical trialists and have the required
patients for the current study, it makes no sense to include them as investigators,
however. There are many other ways of involving important physicians, including
membership in the various advisory and trial oversight bodies, or involvement in
studies of specific interest (which are carefully chosen neither to be on any critical
path nor likely to affect the overall project).
Very occasionally, an investigator may be included for purely political reasons, but
with the full knowledge that the time, money, and resources involved will not necessarily result in useful data.
There is a marketing element to all development activities (whether the purists
like it or not), and marketing input is as essential for the success of a compound as
any other input. However, in many companies, marketers have a disproportionate
influence on the investigator selection process. This may be rational (to some extent)
for some post-marketing studies, but generally speaking, it is a bad idea if the objectives are lost as a consequence.
This sort of influence is particularly harmful when it limits the geographical
areas to be used for clinical trials; it is not only a fallacy that trials only have value
if done in major markets, but this concept can also severely limit patient availability. Consideration should always be given to the advantage of speed to regulatory
approval and to market, or to the competitive advantage of new indications in the
label, as a better strategy than simply including opinion leaders or conducting studies in major markets, where delays are more common.
Therefore, a carefully thought-out plan, with input from all interested parties, for
managing influential physicians and others important for the success of a compound
should be an integral part of every development plan.
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Criteria 4 to 6
These criteria carry more weight, in that they at least suggest that the investigator is
experienced and capable, but there is still no indication that the studies were carried
out with the identical trial population.
Criterion 7: and pigs might fly
This is the most important of all the criteria as it is the most commonly applied to
site identification and selection processes, and it is the one that causes the most
problems. Of the many factors taken into account in determining patient availability, the opinion of the investigators themselves carries disproportionate weight.
After all, this is the easy way out and, in principle, this is eminently logical. After
all, who knows the patients best? Well, yes. Perhaps this is so when it comes to the
medical management of patients, but it is clearly not when it comes to recruiting
them for studies.
Dr. Louis Lasagna (Clinical Pharmacology & Therapeutics, 1979) and others have
emphasized the principle, now known commonly as Lasagna’s Law (­figure 7.3), that
investigators overestimate the availability of patients who meet the selection criteria
and would be willing to enroll in a trial. There are many variations of Lasagna’s Law,
but the gist is that the number of patients purportedly available to take part in a
trial drops by 80% to 90% the day that the trial begins, only apparently to reappear
afterward.
In fact, it is very unlikely that patients satisfying the specific trial needs ever
exist in the numbers quoted by most investigators, without even taking into account
whether or not these patients want to participate.
So does that mean that investigators are dishonest? After all, according to
ICH-GCP [4.1.1], the investigator “should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects
within the agreed recruitment period.” The answer, unequivocally, in 99% of cases is
“No.” The estimates are generally given in good faith, but the numerous factors (specific selection criteria, treatment regimens, visit schedules, patient motivation, etc.)
Before
Study
After
Study
Number of
Patients
Study
Start!
During
Study
Figure 7.3 Graphical representation of Lasagna’s Law.
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that need to be considered confound predictions unless confronted in a systematic
way, which is time-consuming and rarely done spontaneously.
So who is at fault? In most cases, it is primarily the sponsor. Why? Because sponsors are the only ones who know exactly what is required, and they very rarely provide investigators with a timely, well thought-out and realistic recruitment plan.
Inadequate planning
An analysis published in 2006 (“Clinical Operations: Accelerating Trials, Allocating
Resources and Measuring Performance,” Cutting Edge Information, September
2006) showed that, on average, 29% of the total trial time was taken up by patient
enrollment, compared with 17% of the time for the treatment phase, while site
selection and contractual aspects take up only 12% of the time. In other words, the
amount of time being spent is in inverse proportion to that logically required for
optimal results, with inadequate planning time leading to protracted recruitment.
Adequate planning requires that an approved protocol synopsis, as described
above, must be available at least six months before the planned start date of the
study. This time is used to assess potential sites and to determine patient numbers
per site, as the basis for including a site in the study. A second important prerequisite
is that a full recruitment plan must be prepared before contact with investigators,
and the plan must be contractually agreed on with each investigator.
Reluctance to invest in pre-study activities
The activities to be described take additional time, resources, and money in the
startup phase, leading to some resistance in accepting this approach, but the overall
result is that less time, resources, and money are needed for the completed study.
The relative lack of investment upfront has been identified as a key issue. In a survey of 950 investigators (The CenterWatch Monthly, 2009, Vol. 16, Issue 5), 27%
replied that increased funding for patient recruitment would help to prevent delays
in future trials.
Delegation of pre-study activities
In the same survey, the most frequently identified factor that could prevent study
delays was a reduction in the number of intermediaries involved. This is understandable because it is rare for the sponsor to be involved in site selection. In one survey,
only 6% of sponsors carried out site and investigator evaluation themselves; in 84%
of cases, sponsors relied on CROs (47%) or sponsor-hired vendors (37%), while 5%
did not do it at all (Tufts CSSD Survey of 3,516 sites, 2010).
The problem is that, unless specifically trained and paid to carry out operational
procedures exactly as specified by the sponsor, which rarely happens, CROs proceed
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The Sponsor, The Physician, and The Patient: The Eternal Clinical Trial Triangle
according to their own standard operating procedures. These rarely put the necessary
emphasis on pre-study activities, especially not of the type described below, and contracts are heavily weighted toward routine activities during the treatment phase. In
many cases, CROs do not consider patient recruitment to be part of their function.
The way in which site selection and an assessment of patient availability are
most often carried out is that the vendor approaches some sites that appear to
fit the necessary clinical criteria with a version of the protocol that is neither
detailed nor definitive. As a consequence, even if patient records are examined
in detail, which is also not very common, the number of potential volunteers is
grossly overestimated.
Finding the Patients
The Key Question: How Long Will It Take to Recruit the Patients?
The most common answer to this question is “How many patients do you need?” This
is usually followed by a tortuous analysis, based on patients to be recruited per site
per month (rarely more than two), with an outcome that stretches the timelines to
infinity.
In fact, the number of patients needed should not be the primary determinant of
recruitment times. The more appropriate response to the question should be: “That
depends entirely on whether or not each site has the requisite number of patients.”
A revelation
This obvious fact was revealed to me (perhaps belatedly) in the late 1980s when discussing the PACK study (“Prevention of Atherotic Complications with Ketanserin
Trial Group,” British Medical Journal, 1989) with a member of the study’s executive
committee. I asked him how he went about recruiting the required 3,899 patients
with intermittent claudication. His reply was to the effect that it was relatively simple in that the patients already existed and could therefore be identified before the
start of the study. For the patients lined up in this way, enrollment was very rapid;
the recruitment period extended many months only because not all patients had
been identified in this way.
A look through the database ClinicalTrials.gov shows that (excluding oncology
studies for reasons that are given below) over half of the trials involve patients with
chronic diseases. This means that these patients exist right at this moment. Since they
exist right at this moment, it is possible to identify them right at this moment, long
before the start date for a study, and to have them ready and waiting for the day
when the site is initiated and enrollment can start.
This is so obvious that it seems gratuitous to write about it. The reason why it
is not gratuitous to write about it is because few companies make the most of this
situation.
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How to Screen and Identify Patients
The process entails the investigator collecting the records of all patients with the
relevant medical condition and going through them individually to see if they match
the specific criteria of the study protocol. It is almost identical to part of the protocol
feasibility process, except that all potential sites are involved.
When should the process start?
Patient screening and identification should start as early as possible before the targeted study start date, preferably six months before but certainly no less than four
months before. On no account should the process start until protocol feasibility has
been completed and the protocol summary finalized and approved.
Who should be involved?
Ideally, someone from the sponsor company should carry out the process face to
face with a designated person from each investigator site. If sponsor resources are
inadequate, it will be necessary to use a CRO or other vendor. This is always a riskier
option, but the risk can be minimized by careful training of those involved (especially some joint sessions with the sponsor representative) and by including the specific approach to patient screening and identification in the contract.
For larger multicenter trials, when it might not be feasible to have a sponsor representative at each site, the process can be carried out online, either by the site alone
or interactively, or it can be carried out by the site alone using spreadsheets. In these
cases, careful education of all involved is essential.
All potential sites should take part, and only sites that agree to the process should
be included.
Do I have to pay for this?
The process is time-consuming, and investigators and their support staff should be
paid a reasonable fee. The fee should compensate for the time taken, but should not
be high enough to constitute an end in itself. A simple contract or letter of agreement is generally accepted for this activity, without the need for the sort of protracted negotiations that study contracts provoke. In many cases, investigators forgo
the screening fee in anticipation of the income from carrying out the study.
What documents are needed?
1. The patient’s medical case record (electronic or paper).
2. A questionnaire or spreadsheet detailing all the finalized inclusion and exclusion
criteria for the study, with a conclusion as to the suitability of each patient.
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Great care should be taken in the preparation of this spreadsheet to ensure that all
the information needed for selection of a patient is included and recorded:
•
•
•
•
•
•
•
•
•
patient identifier;
inclusion criteria (specified individually);
exclusion criteria (specified individually);
patient eligibility;
date eligible patient contacted;
patient agrees or disagrees to take part;
date patient signs consent form;
if patient disagrees, what is the reason;
for ineligible patients, can something be done to make patient eligible (e.g., by
discontinuing certain medications).
3. Additional information about other aspects of site suitability (previous experience, resources, equipment, competing studies, etc.) may be included, but optimally these will have been determined before the search for patients.
The completed spreadsheet is, in effect, the screening log for the study and may provide useful information for the design of subsequent studies.
How are patient screening and identification carried out?
The process varies slightly depending on the type of disease being studied.
Chronic, preexisting diseases
• Since these patients already exist, it is possible to identify and get consent from
actual patients before the start of the study.
• Rate of enrollment is then limited only by investigator resource.
Newly diagnosed acute or acute on chronic diseases
• A similar process applies, except that the exact frequency with which real, relevant
patients are seen by the investigator is determined.
The process can be done retrospectively or prospectively, or by a combination of the
two methods. The retrospective approach is especially useful in the case of chronic
diseases, as real patients with the potential to be recruited can be identified, but it
is equally useful in the case of acute conditions, as the rate at which such patients
are seen at the clinic can be determined (though some conditions are seasonal). The
prospective approach may be used if current records are not specific enough for the
study population, or if that is the preferred approach.
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The retrospective approach
• The investigator is requested to search for the records of all patients with the
relevant medical condition.
• Patient screening is then carried out: Patient records are checked against the criteria in the spreadsheet, optimally with a sponsor representative, as well as the
investigator or coordinator.
• The actual number of existing chronic cases, or the pass-through rate of acute
cases, is noted.
• When non-eligible patients may become eligible (e.g., by discontinuing treatment
that is not allowed by the protocol), they should be taken into account.
The prospective approach
Using the same spreadsheet, new patients are assessed as they present to the clinic.
A potential weakness of this approach is that this relies entirely on site staff to
ensure that the questionnaire is filled in accurately.
Advance patient recruitment
The objective of the process, and the optimal outcome, is for the patients to be identified and for them to agree in principle to take part in parallel with the time-consuming
regulatory, ethical, and contractual approval processes. This is especially important
in countries where these processes are sequential, as the time lost is significant.
The site can contact those patients with chronic, preexisting diseases identified
by the screening process and, even before ethics approval has been given, ask them
if they would, in principle, be prepared to take part in the study. Patients can then
be recruited and lined up before the start of the study, once the contractual negotiations and the ethics approval have been completed (but not before).
Effect of the process on enrollment rates
At the end of the process described above, there will be an objective assessment of
the number of patients available to take part in the study at each site.
For chronic, preexisting diseases, the actual number of patients available at the
start of the study will be known. Enrollment time for the study will now be limited by
• the resources at each site and the number of trial patients that can be enrolled
and followed up per week;
• any delays in being able to initiate sites because of delays in regulatory, contractual, or ethics approvals (most of which should have been addressed by adequate
planning);
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The Sponsor, The Physician, and The Patient: The Eternal Clinical Trial Triangle
• internal problems such as insufficient drug supply;
• for less common chronic diseases, the number of additional patients that have to
be found (and for which there will be a detailed recruitment plan).
For newly diagnosed acute or acute on chronic conditions, patients can only be identified, recruited, and enrolled as they turn up, but if the screening process has been carried
out efficiently, the time needed for recruitment is predictable with reasonable accuracy.
The target enrollment timelines, from study initiation to last patient in, that have
been shown to be entirely feasible using this approach to include an average number
of patients per site are as follows:
• chronic diseases: 20 working days;
• acute, acute on chronic, newly diagnosed: 60 working days;
• oncology studies: 120 working days.
The reason to make an exception for oncology studies is that, frequently, the studies
are carried out by academic bodies with specific protocols that limit the amount of
sponsor involvement. The principles for patient identification are just as valid for
oncology studies, however, and should be applied whenever possible.
If all of the sites needed for a study can be ready to start by the due date or earlier,
which should be the objective of the planning process previously described, then in
theory, the enrollment times quoted above should be the target enrollment times for
the entire study, irrespective of the number of patients to be enrolled.
Caveats
Despite meticulously following the process described above, it is unlikely that all
will go according to plan. Here are some of the potential problems to consider and
for which compensatory factors (other strategies, additional patients, backup sites)
must be built into the plan.
Selection criteria may involve procedures that can only be done after ethics approval
Some selection criteria may involve the patient undergoing one or more tests. None
of these can be carried out until ethics approval has been given and the patient has
given informed, written consent. Inevitably, some patients will no longer be eligible
as a result of the tests.
Patients fail the protocol-mandated pre-study screens
Some screens have to be repeated immediately before the start of a study. Some
patients who completed the selection process successfully may no longer be eligible.
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Patients may change their minds
Patients may change their minds between agreeing in principle to take part and signing informed consent, or they may change their minds after reading the consent
form. Of course, patients can also change their minds after signing consent, but are
less likely to do so. Consideration of factors that motivate and inhibit patients are
important in mitigating this problem and are discussed below.
The patient throughput rate may change
For studies in newly diagnosed patients or in acute or acute on chronic conditions,
the process results in an expectation of recruitment rates predicted on previously
observed throughput, rather than on identification of actual patients. The throughput rate can change rapidly; this is especially true for seasonal conditions, but may
occur for other reasons, such as introduction of a new therapy, shift of treatment
from a specialist to a non-specialist environment, Murphy’s Law, etc.
Not all eligible patients will consent to take part
The rate at which patients with newly diagnosed or acute conditions were seen at
a site before the start of a study is not predictive of the number of patients who
will agree to take part. The proportion agreeing may vary from medical condition to
medical condition, investigator to investigator, or country to country. As a rule of
thumb (and without any objective data to support this), it is best to assume that at
least 25%, but no more than 40%, of patients will consent to take part.
All plans, but especially bad ones, can be derailed by the unexpected
The better the planning process, the fewer unpredicted events will occur. One basic
aspect of a good plan is that all of the disciplines involved in the conduct of a clinical
trial should be integrated and coordinated. The consequence of failing to follow this
simple, self-evident rule is perhaps not unexpected.
Shortly after the experimental patient identification exercise I described in
­chapter 5, we repeated the process for a study in a neurological condition for which
recruitment was difficult because of competing studies. This time, we had learned
from our mistakes and the feasibility and patient identification process was more
efficient. The investigator was chosen and the patients were lined up and waiting.
And then everyone continued to wait, and wait, and wait. We had somehow overlooked the need to inform the clinical supplies group in time that this investigator would be ready before the anticipated start date. So when a competing company
came along to conduct an almost identical study, the investigator seized the opportunity and immediately handed over all the patients.
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Additional recruitment strategies may be needed
Suitable patients are not necessarily seen in sufficient numbers at investigator sites.
The patient screening and identification process will make it clear whether this is the
case or not. Once this has been determined, alternatives must be explored.
A plethora of approaches have been devised to help in patient recruitment and
enrollment; Spilker and Cramer, in their detailed book (B. Spilker, J. A. Cramer,
Patient Recruitment in Clinical Trials, 1992), list at least 37 recruitment methods.
That list was compiled before the Internet era and is therefore far from exhaustive.
All of these methods are important and should be considered for the recruitment
plan, but always together with, and not instead of, the screening and identification
process. Some of the approaches are relatively cheap, but the cost-effectiveness of
others should always be weighed carefully.
Site Selection
Once a realistic minimum number of patients per site has been identified, the realistic number of sites needed to complete recruitment on time can be calculated. This
is the number (with perhaps with one or two in reserve) of sites that need be activated, with the certainty that costly and time-wasting non-performing sites have
been reduced to a minimum.
The most experienced, best trained, and adequately equipped site is useless without adequate patient numbers. On the other hand, if the patients exist at a given
site, many shortcomings can be corrected, especially if the planning process allows
enough time.
Despite the fact that everybody is aware of these facts, investigators continue
to be included irrespective of their ability to enroll patients. Up to 30% of sites still
recruit no patients or only one patient. The three main consequences of this are as
follows:
• false estimates of enrollment times, with time overruns for studies and entire
development programs (the most deleterious outcome);
• wasted time, resources, and money in setting up, maintaining, and closing
nonperforming sites;
• a site recruiting a single patient. This is often worse than if none were recruited,
in that a disproportionate effort and expense are needed. Most mistakes occur at
the beginning of enrollment, so that the data may need considerable attention,
are more likely to be unevaluable, or may even introduce bias.
In selecting a site, it is therefore paramount to decide, based on as much certainty
as the patient identification process allows, on a minimum number of patients that
the site should be able to enroll. Therefore, only sites that comply with the patient
identification process should be included in the first place. Taking part in the process
is only a first step, however, so it should therefore be made clear to all investigators who
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take part that this does not guarantee automatic selection into the study. Keeping this in
mind and addressing this aspect tactfully will go a long way to ensure no hard feelings and good future relationships should a site fail to meet the requirements.
In addition to the patient aspect, a number of equally important factors need to
be taken into account by the sponsor before choosing a site, including
•
•
•
•
•
•
•
•
•
•
•
clinical trial expertise;
therapeutic area knowledge;
credibility;
an unblemished clinical trial record;
experienced staff to support the investigator;
enough staff with the time to carry out the study;
equipment;
space;
competing studies;
experience of previous collaborations;
those intangible factors that make for a good working relationship.
At the same time, the investigator should consider whether or not he or she should
take part by going through the process described in detail in c­ hapter 8.
Preempting the Luddites
In keeping with the unfortunate human tendency to waste more time and energy
finding reasons not to do something than would be needed to go ahead and do it,
the initial reaction to this approach is often that this is all very well in theory, but it
can’t be done in practice. One or more of the following reasons is then given; they are
listed here in no particular order. If you get a sense of déjà vu, that is because this is a
virtual repetition of the excuses trotted out for not doing protocol feasibility.
It Is Unethical
Always the favorite of those who want an easy way out, this is a common opening
gambit. Interestingly, this was a common reaction when source document verification (SDV) was introduced: How could a sponsor possibly delve into patient records
without compromising patient confidentiality? The approach is no different.
Some investigators may feel uncomfortable contacting and talking to patients
about a possible trial before ethics approval is given, even though there is nothing
unethical about this either. In these cases, actual contact with patients will have to
await ethics approval, but it must be made clear that the site will only be included if
the required numbers of patients agree to take part.
Provided that everyone follows accepted practice meticulously, ethical issues
never interfere with this patient recruitment approach.
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The Sponsor, The Physician, and The Patient: The Eternal Clinical Trial Triangle
It Is an Expensive Added Cost
Developing a drug is very expensive, whichever way of calculating the cost you agree
with. In this context, the added cost of planning and executing this recruitment
approach would be trivial. The fact is that this initial investment, far from being an
added cost, can result in huge financial gains in the long run.
There can be little doubt about this considering the financial consequences of
delays in completing studies because of poor recruitment:
•
•
•
•
•
•
the cost of site visits to motivate investigators;
the cost of starting additional sites;
the cost of other rescue strategies;
the cost of monitoring sites for longer than planned;
the cost of managing non-productive sites;
the cost of competitive disadvantage due to delay in introduction to the market.
Investigators Don’t Want, or Don’t Have Time, to Do This
This is usually stated by those who have never explored the process with investigators (and another reason that was given for why SDV wouldn’t work). In practice, few
are unwilling to take part once the process is explained carefully, and most become
ardent supporters.
Payment for the extra work carried out especially coupled with the relief of avoiding protracted recruitment problems and running a successful study are powerful
inducers to acceptance. The increasing use of electronic records is helping by making
the process much less cumbersome and time-consuming.
Investigators who have applied the process successfully are excellent advocates if
needed to convince others who might have reservations.
I (the Sponsor) Don’t Have Time to Do This
If this is true, it is because planning was not carried out far enough in advance, either
to carry out the process using internal staff or, in the case of companies without
adequate resources, to train a CRO or other vendor to do this.
How Can I Plan So Far in Advance if Relevant Information Is Not Available?
It is certainly easier to design studies far in advance the further one is in the development of a compound. However, those who cannot live with some measure of uncertainty have no place in drug development, where uncertainty is the norm.
The uncertainty is usually manageable. A new protocol may not have the exact
doses, for example, if the dose-defining study is still underway, but the essential
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elements of a protocol can still be written on the basis of existing preclinical, pharmacological, historical, and early clinical data.
There will, of course, be times when the results of a previous study are needed for
the definition of essential design elements of the next study, in which case, some
of the process will have to run sequentially. Even then, it is worth the extra time to
ensure rapid recruitment and a shorter overall study time.
It Will Take Forever to Negotiate a Contract
Negotiating study contracts can be a long and frustrating process, but experience
shows that for the simple patient screening process, most investigators and institutions are much more flexible.
Sending a Questionnaire Is Just as Effective as the Face-to-Face
Approach
Yes, it can be, if the site staff are properly educated and motivated, the required
process is well explained and understood, the questionnaire has all the necessary questions, there is an agreed-on timeline, and everyone does what they are
supposed to do.
Most of those who claim to carry out careful screening to determine patient numbers use a questionnaire of one sort or another, but rarely with detailed, definitive
protocol questions. Few carry out the face-to-face approach. All too often, the consequences are that
•
•
•
•
questionnaires are returned poorly completed;
questionnaires are returned late (or not at all);
there is less certainty that the data are accurate;
not all of the patient record forms available may have been examined.
Don’t Take My Word for It
The only way to see if an approach works is to measure the outcome (­figure 7.4).
The figure shows the mean recruitment times, assessed independently, for a large
pharmaceutical company (dark bars) over the first two years after the approaches
described in this book (among others) were implemented. The recruitment times
relate to all Phase II and III studies in all indications. The light bar shows the average recruitment times for 33 peer companies, including the 14 major “big pharma”
companies.
Over the two years from the baseline measure, there was a 67% reduction in
recruitment time within the company, and even one year after implementation,
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The Sponsor, The Physician, and The Patient: The Eternal Clinical Trial Triangle
Recruitment Time, Days
Company
Peers (CMR)
300
281
250
200
150
186
100
163
50
0
62
Baseline
Year 1
Year 2
Figure 7.4 Mean recruitment times at baseline and at one and two years after implementation
of the patient and site selection described above. Data provided to Pharmacia Corporation
by CMR.
average recruitment time was 42% lower than for the peer companies. At that time,
the company ranked number one in having the fastest study time compared with the
14 major peers, overall duration being 35% shorter.
For changes to become apparent in a large, international company, it takes time,
as illustrated above. When the relevant approaches are implemented in the context
of a single study, the results can be dramatic (­figure 7.5).
The study was started without the patient screening and site selection process
described above. After nearly four months, only two patients had been enrolled,
although 25 sites had been activated. Rescue measures were instituted. Patient
50
45
40
35
30
25
20
15
10
5
0
Patients
Intervention
1
3
5
7
9 11 13 15 17 19 21 23 25 27 29 31 33 35 37
200
180
160
140
120
100
80
60
40
20
0
Patients
Sites
Sites
Weeks
Figure 7.5 Study rescue using patient screening and identification.
With permission from Dr. G. Brown, Competitive Drug Development International Ltd. (www.cddi.co).
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screening was carried out at existing sites, and new sites were added on the basis of
patient screening, contributing to a rapid increase in patient enrollment.
Key Points
• Patient availability at a site can be quantified with reasonable accuracy.
• If the disease being studied is chronic, the actual number of patients at the site
who comply with the protocol requirements can be determined.
• These patients can be lined up and ready in time for the planned study start date.
• If the disease being studied is acute, or the acute exacerbation of a chronic condition, the frequency with which patients complying exactly with the protocol
requirements present to the site can be determined.
• Sites that are unlikely to provide the required number of patients should not be
included in the trial.
• Assessment of patient availability at sites provides a firm basis for designing and
implementing rational recruitment strategies to make up for any shortfall in the
available numbers.
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C h apter 8
Clinician or Clinical Trialist: The
Physician’s Dilemma
Objective
The main objective is to help physicians carry out those aspects of clinical trials
described in this book.
Introduction
Each individual involved in conducting a trial should be qualified by education, training, and
experience to perform his or her respective task(s).
—[ICH-GCP 2.8]
It is hardly rational to expect people to do things properly unless they are shown how,
so that the importance of formal training and education for everyone involved with
the pharmaceutical industry should be self-evident. The perpetuation of bad habits
by those who are poorly trained and educated, whether in pharmaceutical companies
or at investigator sites, is one of the root causes of the inefficiencies in drug development. Yet, while few people (whether or not they actually educate people properly)
would dispute the importance of well-trained employees, it is uncommon for most
companies to insist that all of those upon whom they depend are properly trained
as well. Among those who are rarely trained to meet the required standards of excellence are CRO staff and investigators and their site staff.
Negotiations with CROs rarely involve an assessment of how the various tasks are
performed and whether or not they are carried out to the standards expected by the
sponsor staff. This is not to imply that sponsor employees are better at what they do
than CRO staff. What is true, however, is that sponsor employees should know how to
do things the way the sponsor wants them done, which in turn should correspond to
the sponsor’s notion of excellence. CROs will always profess to have all the processes
requested by a sponsor, so that a laissez-faire attitude pervades negotiations. However,
CROs quite understandably have their own ways of working, and unless alternatives
are specified contractually, what the CRO does is what the sponsor gets. The next logical
step after specifying what is wanted is to provide the necessary training for CRO staff.
Where education and training are most needed and are carried out most poorly
is in the case of clinical trial investigators. A survey from 2006 indicated that only
43% of those who had participated in clinical trials had received “formal” training
(“Investigator Certification Catches On,” The CenterWatch Monthly, 2006), and the
content of the training was not specified. While everyone involved in the clinical trial
process is equally important in ensuring success, investigators and their support staff
are clearly the first among equals. Only the investigator has access to patients and only
the investigator can collect and record patient data. The rate of patient recruitment,
accuracy of data, and, ultimately, the credibility of a clinical trial depend primarily on
the investigator. Yet the data show unequivocally that recruitment rates and errors
in data collection are two of the biggest problems in the clinical trial process. Not
only does this waste enormous sums of money, put trial results at risk, and delay
approval of new drugs, but, more important, it shows a contemptuous disregard for
the patients who volunteer and put themselves in discomfort and at risk to take part
in the studies. Although investigators are not exempt from blame (there is no excuse
for taking money and then delivering substandard results), it is the sponsor who must
take most responsibility for the current situation. Investigators who produce shoddy
work are hardly likely to be encouraged to change their ways by the industry norms of
ignoring the need to provide adequate education and paying in full despite the results.
Though most companies or individuals would never dream of paying for substandard work from any other contractor, almost all companies are reluctant to penalize
poor work from investigators for fear of losing their support (and their prescriptions),
especially if they are influential leaders of opinion. This attitude is well illustrated
by a study that had as its only objective to find out how patients managed a new
auto-injector that they had to use unsupervised at home. One investigator decided
that his patients couldn’t possibly manage anything so complex. He therefore injected
all the patients himself, so that the resultant data were valueless. The headquarters
clinical team, which funded the study, refused to pay, but the affiliate nevertheless
paid the investigator in full out of its own pocket, in itself a rare phenomenon.
Perfection will never be achieved, but the chance that studies will be carried
out properly can only increase if investigators and their staff are well educated
in the clinical trial process and, most important, understand the consequences
of not following the process. There is an almost universal notion* that physicians
* Fortunately, the notion is not entirely universal, as I found out when I joined Hoechst,
my first pharmaceutical company, fresh from a post-doctoral research fellowship and a
senior medical post in a university hospital. On my first day, the medical director welcomed
me with the statement that, although he was glad to have me on board, I had to realize that
I would be of no value whatsoever to the company for at least two years. I don’t think my
career would have been as interesting or successful without the in-depth and far-ranging
education I received from the company as a result of their hope that I might add value.
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are automatically imbued with all the knowledge necessary to manage all clinical
aspects of drug development, whether as company employees or as investigators.
However, to quote Dr. Robert Temple of the FDA’s Center for Drug Evaluation and
Research, from an interview about an investigator training program: “The qualities which make a great physician are not necessarily the qualities which make a
great investigator.”
A survey carried out in 2012 (Tufts CSSD Impact Report, March/April
2013) showed that the number of active investigators worldwide has reached
an all-time high, and that the proportion of community-based (as opposed to
hospital- or university-based) investigators has grown. What is of concern is that
there appears to be little accrual of experience in many of these sites. Although
these findings relate only to FDA-sponsored studies, it is unlikely that they do
not reflect the overall situation. In Asia, Europe, and Latin America (continents
in which there has been a significant increase in the numbers of investigators),
turnover is high; more than 50% of investigators “choose not to conduct trials in
the subsequent year.” An analysis by CenterWatch (K. Korieth and A. Andersen,
2012) showed that in 2010, over 80% of the principal investigators regulated by
the FDA only carried out one study, while 44% of investigators were new. Taken
in conjunction with the finding that the average number of countries involved in
a typical late-stage clinical study is 34, increasing to 70 countries for the top 20
companies (K. A. Getz and R. Zuckerman, 2010), it is inevitable that (a) a significant number of investigators involved in each study will be inexperienced, if not
novices, and (b) that there cannot be any consistency or homogeneity of approach
across the sites.
The need for consistent and relevant training and education of investigators and
their site staff is therefore self-evident. Experience in carrying out purely academic
trials is not enough. The highly regulated nature of the drug development environment requires that all who are involved understand the process not just from a
purely clinical point of view, but also from the perspective of the sponsors. There are,
of course, investigators with as much or more formal drug development-related clinical trial experience and know-how than their industry colleagues, but these investigators are very much in the minority and becoming proportionately fewer as time
goes on.
Traditionally, however, the only time investigators receive any sort of training
is in the run-up to a study, during the so-called investigator meeting. This nonspecific, uninformative name well reflects the nonspecific, uninformative nature of
the average meeting, which is seen by many as much as a shopping and sight-seeing
opportunity as an educational event. During this meeting, investigators and site
staff are informed about specifics of the protocol and the case record form, sometimes with a brief rundown on GCP and safety reporting to comply with regulations. There are two problems with this approach: first, by trying to cover several
different things in one go, it is rare that they are all covered properly and, second,
there is rarely any training on the process of carrying out clinical trials.
The latter is one of the most astounding phenomena in an industry replete with
astounding phenomena. Companies pay significant sums of money to investigators
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to carry out studies on which the success or failure of the company may depend. Yet
rarely do they ensure the competence of the investigator to carry out the study. Part
of the problem is that there is often the perception that the relevant training has been
carried out. When I ask if training in clinical trial processes has been given, more
often than not the answer is “Yes, we did GCP training.” Yet even GCP training is
clearly inadequate; complaints received for noncompliance and fraud have increased
by more than 225% since 2001 (FDA office of Compliance, quoted by D. Butas, 2012).
Knowing the regulatory requirements for conducting a trial ethically, safely, and
credibly is essential, but GCP has little to do with how clinical trials are managed in
practice. Given that most investigators and their staff have never had formal training in how to conduct clinical trials, and that the propagation of bad practice from
one study to another is the norm, as evidenced by the poor quality of data (for which
the investigator has sole responsibility), it should be clear that the emphasis on GCP
alone is a costly liability. Reliance on GCP alone is the same as expecting someone
who has never driven a car to learn the rules of the road and then be able to drive
expertly, without being taught how to drive a car. On the other hand, knowing how
to drive without knowing the rules of the road is equally dangerous. Knowledge and
intelligent application of both are needed; the same applies equally to GCP and operational skill in the conduct of clinical trials.
Another part of the problem is that many physicians, especially those who are senior
or who have been involved in several trials, do not believe that they need any training. As
part of the process of setting up a comprehensive educational initiative for Pharmacia,
I invited several senior investigators to act as a sounding board. They were almost unanimous in their opinion that the concept might have some merit for new investigators,
but it certainly would not be relevant for them. To make the point, they were then asked
10 pertinent questions relating to the clinical research process, few of which they could
answer. Over the next three years, nearly 10,000 investigators and their study coordinators, in over 40 countries, underwent the company educational initiative (earning CME
credits in some areas), contributing significantly to the improvements illustrated at the
end of the introduction to this book. Those participating in this initiative were overwhelmingly positive, not only because it improved their standards, but also because it
raised their profiles and made them generally more attractive as investigators.
In summary, it is essential that everyone at the investigator site involved in the
conduct of a clinical trial be fully educated and trained in all four relevant components, taking the time needed to ensure that each is covered in as much detail as
necessary and fully understood:
•
•
•
•
all operational aspects of the clinical trial process;
GCP;
the protocol and all related procedures;
the data capture instrument.
In this chapter, the objective is to set out, from the perspective of an investigator,
the essential minimum of GCP and clinical trial operational requirements relevant to
the clinical processes covered in this book, with emphasis on their rationale, their
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interrelationships, and the consequences of ignoring them. These should be seen
in the context of the broader picture that includes, among other things, regulatory,
safety, and quality assurance requirements.
It is important to remember that for each of the responsibilities or activities
described for an investigator, there is a corresponding responsibility or activity
required of the sponsor. The term “sponsor” as used here means either the sponsoring
company staff (as they have overall responsibility) or any of their agents, such as CROs.
To Be or Not To Be in the Study; That Is the First Question
Key Message
Before agreeing to take part and signing the contract or agreement, the investigator must give careful consideration to all the requirements of the specific trial. The
investigator should not agree to take part, and the sponsor should not include that
site, if there are any requirements that cannot be met or if mutual agreement on all
aspects cannot be reached.
Introduction
Recruiting investigators is not always easy, and important details can be overlooked
when someone shows interest. Both the sponsor and the investigator are responsible
for making sure that a site is suitable, though only the investigator and site staff
can provide the answers. If the investigator is not prepared to participate fully, then
they should not sign the contract. By entering into a contractual agreement with the
sponsor, the investigator will be expected to adhere to his or her regulatory responsibilities and to the requirements of the study protocol. Payment will (or should)
depend entirely upon fulfillment of these commitments.
The time it takes to sign a contract will vary according to the in-house processes
at different institutions. The investigator should find out in advance who needs to
sign and how long it generally takes at their institution—this should then be built
into the planning phase.
In coming to a decision, the investigator and the site staff should take into account
all the responsibilities of an investigator given in detail in section 4 of the ICH guidelines. They cover the following subjects:
4.1
4.2
4.3
4.4
4.5
4.6
Investigator’s Qualifications and Agreements
Adequate Resources
Medical Care of Trial Subjects
Communication with Ethics Committees
Compliance with Protocol
Investigational Product(s)
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4.7 Randomization and Unblinding
4.8 Informed Consent of Trial Subjects
4.9 Records and Reports
4.10 Progress Reports
4.11 Safety Reporting
4.12 Premature Suspension or Termination of a Trial
4.13 Final Report(s) by Investigator
It is the responsibility of the sponsor company, whether directly or through a vendor
(such as a CRO), to provide the relevant support and information so that the investigator can address all of these aspects.
It is equally important for the investigator to inform the sponsor of the answers
to these questions, so that the sponsor can make an independent assessment of the
suitability of the site.
For the purpose of making a decision about taking part, the investigator and the
coordinators and other site staff who will be involved should, in addition to accepting
the responsibilities outlined in the ICH guidelines, be able to give positive answers
to the following questions.
•
•
•
•
•
•
•
•
•
•
•
•
Am I familiar with the background information on the investigational compound?
Do I know the protocol and CRF backward, forward, and inside out?
Can the trial procedures be justified ethically and clinically?
Are enough patients going to be available in the time allowed?
Do I have enough experienced and well-trained staff?
Does everyone who will be involved have enough time?
Is enough space appropriate for study needs available?
What other resources, equipment, and infrastructure will I need?
How will I deal with the laboratory samples and tests?
Can I cope with unexpected or remotely possible events?
Do I agree with the payments and payment schedule?
Do I agree with the publication policy?
Am I familiar with the background information on the investigational compound?
The Investigator Brochure provides all the relevant details, especially the pharmacology, toxicology, and early data that can alert the investigator as to likely safety issues
and potential benefits, and how the product should be used. All of this information
is essential for understanding the purpose, merits, and ethical aspects of the study.
Do I know the protocol and CRF backward, forward, and inside out?
Often, only the protocol is discussed at this stage, but ideally, the investigator should
review the CRF (paper or electronic) at the same time. Only an in-depth understanding
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of these two documents allows the investigator to list all the relevant questions and
clarifications needed to address all of the other considerations for taking part in the
study. The reason to emphasize this is because protocol violations are, at 46%, the
major area of noncompliance (FDA Office of Scientific Investigations, 2010).
Can the trial procedures be justified ethically and clinically?
The investigator is responsible for getting approval to carry out the study from an
ethics committee. This step should only be taken if the investigator is satisfied that
the rationale for the study is sound, that the benefit/risk profile is appropriate for
the condition being treated, and the clinical trial procedures are justified.
Are enough patients going to be available in the time allowed?
Sponsors approach potential investigators because they have access to patients.
However, having a pool of patients is not enough. What is needed is the certainty
that the agreed number of patients conforming to the study selection criteria and
agreeing to take part are enrolled in the agreed timeframe. The investigator must
understand and agree to the procedure for determining whether or not the site has
enough eligible patients (described in detail below) because, if not, the investigator
will not be included in the study.
Key points to consider:
•
•
•
•
Without enough patients, the trial is of no value.
The investigator must therefore be able to recruit the required number of patients.
The investigator must be able to do this within the required timeframe.
If the agreed-to number of patients can’t be delivered on time, then the investigator should not take part.
• An important consideration is whether payment is on a per-patient basis. If the
trial is a multicenter one, recruitment is likely to be very competitive. Here, timing is essential, because if the investigator fails to recruit quickly, another institution may enroll all the patients.
Do I have enough experienced and well-trained staff?
ICH-GCP [4.2] states that it is the responsibility of the investigator to ensure that
“adequate resources” are available for the duration of the study. The investigator
should therefore consider all of the resources needed:
• coordinators;
• technicians;
• nurses;
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•
•
•
•
secretaries;
other physicians;
patient recruiters;
backup staff in case of absence due to illness, emergency, pregnancy, or holidays.
For all of these staff, the requirement is that they be
• adequate in number;
• not overburdened by participation in competing studies or because of clinical
responsibilities;
• experienced and well trained;
• able to carry out non-routine procedures if required by the protocol;
• provided with adequate motivation if asked to take on extra work and
responsibility;
• adequately funded.
If the current site setup doesn’t meet these requirements, the investigator should
discuss with the sponsor whether
• staff can be recruited in time;
• training can be provided;
• these activities will be funded.
Does everyone who will be involved have enough time?
Trial-related activities often take longer than planned, and time commitments are
notoriously difficult to determine and should never be underestimated. It might be
useful to discuss time issues (and others) with more experienced colleagues.
There are certain stages during which intensive efforts are required (e.g., ethics
committee submission, patient identification, and post-trial procedures). At other
stages, the time commitment is less. It is important to have an appreciation of what
needs to be done and when. Not all trials are the same. With appropriate planning
and a competent team, time can be managed efficiently and not be a factor that compromises the study.
The time needed will depend on many factors:
• type and complexity of the study;
• stage of the trial (startup, ethics submission, patient consent, etc.);
• resources available for delegation.
Many people will have to give their time and should be consulted, including
• the investigator;
• study coordinators;
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•
•
•
•
•
•
•
•
nurses;
secretaries;
other physicians or sub-investigators;
technicians;
pharmacy staff;
laboratory staff;
referring physicians;
the patients.
Especially time-consuming activities include the following, though often they are
not allocated anywhere near enough time with the expected consequences:
•
•
•
•
•
•
•
•
•
•
•
•
reading the Investigator Brochure (IB) and protocol;
planning and assessing if the study is feasible for that site;
training;
communication with all involved;
the patient identification process;
preparing and submitting a dossier to the ethics committee;
informing patients and getting consent;
enrolling patients and baseline procedures;
non-routine procedures that may have an impact;
completing the CRF (or checking it, if others do the work);
talking to the sponsor’s representatives and replying to queries;
closing the study.
Activities in any trial site and in any institution do not usually take place in isolation, so it is essential to consider the effects on time and resources of competing
activities.
At the institutional level:
• Are other trials being performed at the institution?
• Is there competition for
o patients;
o pharmacy time;
o laboratory time;
o equipment?
• Can potentially conflicting activities be coordinated?
At the site level:
• Is the investigator involved in more than one study?
• Is the investigator planning other studies in the future that will overlap with the
proposed study?
• Will there be competition for the same patient population, thus increasing
recruitment time?
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• Are there enough resources to cover all these studies?
• Can the investigator be certain that all of the commitments will be met?
Is enough space appropriate for study needs available?
The availability of space should not be taken for granted. Space is needed for
•
•
•
•
•
•
•
•
patient interviews;
team discussions;
monitor visits;
audits and inspections;
storage of files during the study;
archiving;
investigational product storage;
sample storage.
Storage space will need to be close to where the team is working. Patient files are
confidential, so storage needs to be secure. Paper CRF files can be very large and will
require a lot of space. When space has to be rented or paid for, the investigator must
ensure that the relevant costs are included in the contract.
What other resources, equipment, and infrastructure will I need?
Some resources that are essential for running a clinical trial may at first glance
appear to be obvious or trivial, but they nevertheless should be considered in detail
at this stage. These include
•
•
•
•
•
•
•
•
•
•
•
telephones;
fax machines;
computers and software;
Internet connections;
printers;
cupboards;
filing cabinets;
lab equipment;
sample storage equipment;
investigational product storage, including special storage conditions;
stationery.
In each case, the investigator should make sure that the sponsor agrees to buy,
lease, or provide what is needed and pay for the running expenses. It should also
be agreed what happens to the equipment at the end of the study. Local ethical
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and tax regulations must be taken into account if the equipment is to be left at
the site.
Institutional quirks should always be considered, as these may provide unexpected obstacles. One institution would not allow international calls, so a separate
line had to be installed. Another had disabled the sound system on the hospital computers, so that webinars and Skyping with that site were not possible.
The investigator should also ensure that someone is given responsibility for
sourcing appropriate facilities, assessing the costs, and preparing contingency plans
for equipment failure.
How will I deal with the laboratory samples and tests?
The routine for laboratory tests may to be taken for granted in many institutions: The
sample is sent off, the results are returned. However, the specific needs of a clinical
trial need to be taken into account. The investigator is advised to actively involve laboratory staff, whether in-house or remote from the site, in the planning phase of the
trial to get their advice and to ensure that trial-specific procedures can be accommodated. The sponsor should provide guidance, especially for non-routine procedures
and when central laboratories are involved.
It is important to consider the following:
• General considerations:
o costs;
o what to do if the hospital or clinic lab cannot be involved;
o training in non-standard procedures;
o ensuring that non-standard tests can be done locally;
o out-of-hours work (staff, cost);
o collection and storage of samples;
o turnaround time.
• Specialist equipment:
o What are the costs?
o Who will supply it?
o Who will operate it?
o Who will need to be trained to operate it?
o Who will train them?
o Who will maintain it?
o What happens to it at the end of the trial?
• Central and other external laboratories:
o costs;
o preparation and labeling of samples;
o packaging;
o compatibility of lab schedules with those of patients and trial sites;
o transportation;
o if the lab is in another country, customs and other regulations.
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• Laboratory results:
o method of communication;
o speed of communication;
o compatibility with electronic data capture.
Can I cope with unexpected or remotely possible events?
The very act of contingency planning, as with all planning, can help to deal with unexpected events, even if the actual event was not considered. At this stage, the investigator should consider whether or not the physical or political environment is likely to be
disruptive, and whether or not the disruption would interfere with the trial.
Potential infrastructure issues:
• Internet;
• telephone;
• electricity;
• transport.
The infrastructure can vary from country to country or even one part of a country to
another part, so that what is considered reliable in one cannot be taken for granted
in another.
Potential environmental issues:
• earthquakes;
• hurricanes;
• seasonal weather.
Hurricanes and other seasonal weather patterns are reasonably predictable, and the
record of how these disrupt institutions and the local infrastructure is a useful indication of the likely effect on a trial.
Potential political issues:
• strikes;
• civil war;
• international conflicts;
• unfriendly governments.
Clearly, these issues (or the likelihood of these issues arising) will make a country
undesirable for clinical studies in most instances, though sometimes the scarcity of
patients elsewhere may limit choices. While no one is going to place a study in the
middle of a hot war zone, it is important to analyze the situation objectively before
a country is rejected for any of the above reasons. Frequently, the situation reported
in the press bears little relationship to the facts of everyday life.
Potential staff issues:
• illness;
• family emergencies;
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• pregnancy;
• holidays.
If no backup is likely to be available, the investigator should get agreement from the
sponsor that they will pay for appropriate temporary staff.
Do I agree with the payments and payment schedule?
The proposed payment must cover all aspects of the trial, not just personal fees and
overheads. The investigator must therefore ensure that all expenses are covered, and
that there is a procedure for funding essential but unforeseen expenses.
Payment schedules and turnaround times for invoices should also be discussed, to
ensure that the investigator is never out of pocket. Investigators should not expect all of
their personal fees to be paid in advance; agreement should be reached as to how fees will
be prorated to take into account unfinished or poor quality work that does not meet the
requirements, standards, and timelines of the protocol, the guidelines, and the contract.
Do I agree with the publication policy?
Many investigators participate in trials in order to be an author when the results are
published. To avoid disappointment or conflict later, the publication policy of the
sponsor should be a consideration in whether or not to take part.
There are two considerations:
1. Who can publish what, and when?
2. Who can be an author?
1. Who can publish what and when?
Data generated in a clinical trial are the property of the sponsor. The investigator
always has access to data relating to her or his own patients, but agreement is needed
as to when these data can be published.
In a single center study, the publication is usually a collaborative effort between
the sponsor and the investigator. In a multicenter trial, however, the investigator
should always agree not to publish the data from his or her own patients before
the results of the whole study have been published (if at all). The reason is that the
results from one site will not be powered to show a definitive result, so that the publication could be misleading.
2. Who can be an author?
Investigators are often promised authorship if they recruit enough patients, and
some expect to be authors just for having taken part. However, it is worth considering
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and discussing the uniform requirements for manuscripts (International Committee
of Medical Journal Editors, 2013), because although not binding, many of the leading journals will not accept papers that do not conform to these requirements.
• Authorship credit should be based on (1) substantial contributions to conception
and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and
(3) final approval of the version to be published. Authors should meet conditions
1, 2, and 3.
• When a large, multicenter group has conducted the work, the group should
identify the individuals who accept direct responsibility for the manuscript.
These individuals should fully meet the criteria for authorship/contributorship
defined above, and editors will ask these individuals to complete journal-specific
author and conflict-of-interest disclosure forms. When submitting a manuscript
authored by a group, the corresponding author should clearly indicate the preferred citation and identify all individual authors, as well as the group name.
Journals generally list other members of the group in the acknowledgments. The
NLM indexes the group name and the names of individuals the group has identified as being directly responsible for the manuscript; it also lists the names of
collaborators if they are listed in acknowledgments.
• Acquisition of funding, collection of data, or general supervision of the research
group alone does not constitute authorship.
• All persons designated as authors should qualify for authorship, and all those who
qualify should be listed.
• Each author should have participated sufficiently in the work to take public
responsibility for appropriate portions of the content.
Main consequences of failing to consider all responsibilities and requirements
Although both the investigator and the sponsor will suffer, the consequences are
greater and longer lasting for the sponsor.
1. Missed deadlines, added expenses, delayed patient access to potential healthcare
benefits, loss of competitive advantage, and loss of revenue.
The usual cause is delay. This is often due to slow recruitment, though a robust
patient identification process should eliminate sites that are unlikely to find enough
patients in time. Other causes are poor ethics committee submissions and inadequate resources slowing down throughput.
2. Invalid trial results, and increased costs and resource needs.
These are the potential consequences of missing or poor quality data due to inadequate,
unmotivated, and untrained staff. Missing data can lower the power of a study, and poor
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quality data can be erroneous, leading in both cases to false study results. Managing poor
quality data also costs the sponsor time, money, and resources in trying to clean up the
data, while the investigator is obliged to waste time answering the consequent queries.
3. Loss of credibility, loss of fees, and exclusion from subsequent trials.
In the worst cases, the sponsor is justified in withholding payment to an investigator. In practice, this rarely happens, but it is almost certain that the investigator will
be excluded from subsequent trials. Poor reputations spread very rapidly, so that
other sponsors may shy away from the site as well.
Patient Screening
Prediction is very difficult, especially about the future.
—Niels Bohr, physicist and Nobel laureate
Key Messages
The successful, on-time completion of a clinical trial depends on enough suitable
patients being available and agreeing to take part. The only way to achieve this consistently is to assess the eligible patient pool at a site factually and objectively, and
then to have a realistic plan for recruiting additional patients if there is a shortfall.
Inclusion of the site in the study depends on the result of this assessment or
screening process, and it therefore follows that refusal to carry out the process
should preclude the site from taking part.
So as not to raise expectations and provoke justified annoyance, sponsors should
describe this process and make it very clear in the very first conversation with the investigator that no decision about including the site will be made until the results are known.
Introduction
Apart from common sense, there is a regulatory basis for this approach: “The investigator should be able to demonstrate (e.g., based on retrospective data) a potential
for recruiting the required number of suitable subjects within the agreed recruitment period” (ICH-GCP [4.2.1]). As the data in the previous chapter show, however,
recruitment rates are often based on well-meaning but inaccurate assumptions,
rather than on actual data. As a consequence,
• slow recruitment is the main cause of time and cost overruns in clinical trials;
• recruitment times have been increasing, year after year, for at least the past
15 years;
• around 30% of investigators recruit one patient or no patients.
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Minimizing the uncertainty involves two activities:
• screening of patients at the site, as described here;
• agreement on and initiation of a comprehensive patient recruitment plan.
Patient screening should be carried out as soon as possible after the approved protocol synopsis, or the final protocol, is available.
Most investigators who have carried out this process are very positive about it
and recognize its value, but some may resist this process, either as an insult to their
knowledge of their patients or because they think it is a waste of time. With rare
exceptions, such as an exemplary and consistent track record, investigators who
refuse to carry out this process, or who do so badly, should not be included in the
study. This applies even if they are important and influential, unless they will not be
a limiting factor in recruitment.
What Does Patient Screening Mean?
Patient screening involves scrupulously comparing all relevant study requirements
in the protocol with actual data in the medical records of all patients being treated
for the relevant condition at the investigator’s site.
The process is time-consuming (even with electronically stored medical records),
and an appropriate fee will be paid to compensate for the time taken.
There are two categories of patients to take into account:
1. those with chronic, preexisting conditions or who are taking part in prevention
studies (these patients are immediately available);
2. those with acute conditions or acute exacerbations of a chronic condition (these
patients only become available when the relevant episode occurs). Patients with
rare chronic diseases may also trickle in, as any given investigator may not have
as many patients as needed at the start.
The Patient Screening Process
The process can be done in one of three ways: retrospectively, prospectively, or by a
combination of the two approaches.
The retrospective approach
This is especially useful in the case of chronic diseases, as real patients with the
potential to be recruited can be identified, but it is equally useful in the case of acute
conditions, as the frequency with which such patients are seen at the clinic can be
determined (though some conditions are seasonal).
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• The protocol-specific requirements are detailed in a spreadsheet, whether on
paper or electronically.
• The investigator collects the records of all patients with the relevant medical
condition.
• Patient records are checked against the criteria in the spreadsheet, optimally with
the sponsor representative and the investigator or study coordinator working
together face to face.
• The actual number of existing, eligible chronic cases is noted.
• The number of eligible acute or acute on chronic cases who have been seen at the
clinic in a given period, and the frequency with which they present, are noted.
• The records should be examined for patients currently non-eligible who could, in
principle, become eligible (e.g., by discontinuing treatment that is not allowed by
the protocol).
The prospective approach
The prospective approach may be used if current records are not specific enough for
the study population, or if more up-to-date information is needed.
•
•
•
•
The same spreadsheet is used.
The investigator site staff assess new patients as they are seen in the clinic.
The frequency with which these patients present is documented.
Patients with chronic diseases can be asked if they would be interested in taking
part in the study. At this stage, the study might not yet have been approved by the
ethics committee, in which case, it is imperative that no attempt is made to get
formal consent.
The completed spreadsheet is, in effect, the screening log for the study and may provide useful information for the design of subsequent studies.
Assessing the Results of the Screening Process
After the process is complete, the following information will be available:
• the number of actual eligible patients available at the site (chronic conditions);
• the rate at which eligible patients present to the site (acute or acute on chronic
conditions);
• the additional number of potentially eligible patients based on modifications that
can be made to their treatment or other changes that will bring them in line with
the protocol.
These data should answer the question: “Does my site have enough patients to enroll
the required number within the agreed timeline?”
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The minimum number of patients needed per site will have been determined by
the sponsor during the planning for the study. The ideal site will be one in which
the required number of patients already exists (chronic conditions) or the rate of
presentation is adequate (acute or acute on chronic conditions). In practice, however, patients may not be readily available, either because the disease is uncommon
or because of competing studies. Sometimes it may be necessary to include sites
with few patients for strategic reasons. In these cases, a realistic minimum is set as
the target, together with a comprehensive recruitment plan to get the additional
patients.
In making the decision, a number of factors need to be taken into account because
the theoretical number of patients available as revealed by screening does not reflect
the actual number who will be able to take part or complete the study:
• The appropriateness of the patient depends on many important factors other
than compliance with protocol criteria, as described in detail later in this chapter.
• Even if the patient is perfect for the study, she or he may not want to take part.
• Patients may agree to take part, but may then be ineligible due to abnormal,
pre-randomization laboratory results.
• Patients will drop out during the course of the study.
The screening target will therefore have to be several times greater (by a factor of
anywhere between 3 and 5) than the enrollment target.
Main Consequences of Failing to Carry Out the Screening Process
1. missed deadlines, as nonexistent patients have to be replaced by real ones, with
all the consequences (delayed patient access to potential healthcare benefits, loss
of competitive advantage, and loss of revenue);
2. additional costs from having to institute rescue measures for recruiting patients
and for the added monitoring and general oversight activities;
3. reduction in the power and quality of the study, usually due to the desperation
measure of including ineligible patients in order to make up the numbers or
because the shortfall in patients cannot be made up (the problem is especially
acute for small companies that may not have the money to carry out the necessary rescue activities or pay the added costs);
4. loss of credibility, loss of fees, and reduced likelihood of future participation in
studies.
Making Plans
Key Message
The activities that take place before patients are enrolled and the trial starts are
the most important in ensuring the successful conduct of the trial. Taking time,
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planning carefully, and investing money upfront will save disproportionately more
time and money later.
Introduction
Clinical trials are complex and require the concerted efforts of many people doing different jobs not only within a site, but across many organizations. In most cases, these
people will be involved in more than one trial at a time. It is impossible to coordinate
all of these activities and put contingency plans in place without careful planning.
Timelines
In a well-ordered company contemplating a study involving more than three or four
centers, the potential investigator should be contacted at lease seven months before
the intended start date. This initial contact will trigger the “should-I-take-part” questioning described above, as well as the patient identification process.
If the site meets the study-specific needs, the investigator should ideally then
have approximately six months in which to plan for and carry out the necessary pretrial activities.
Planning should be carried out to ensure adherence to the planned trial start
date; the trial start date should not be compromised.
Sponsors will have started their own activities much earlier and will have an overall plan, which should be shared with the investigator. Some activities (such as investigator meetings) may involve other sites and will need to be coordinated accordingly.
Investigator Activities To Be Included in the Plan
These are some of the relevant activities for which planning is essential:
•
•
•
•
•
•
•
•
•
Reread and understand the protocol, CRF, and study manual.
Form and prepare the site study team.
Plan for any recruitment needed.
Train the site study team on the protocol and CRF (ask the monitor for help and
do not necessarily wait for the investigator meeting).
Talk to patients identified in the patient identification process (if trial is in a
chronic condition so that patients already exist).
Look for more patients if needed.
Prepare any material needed for patient recruitment that has to be approved by
the ethics committee.
Contact any referring physicians.
If an institution is involved, help with contract negotiations to speed up the
process.
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• Know the ethics committee meeting timetable and help the sponsor prepare
the necessary documents in time for the earliest ethics committee meeting.
• Be very familiar with the requirements, processes, and quirks of the ethics
committee.
• Submit the documents to the ethics committee and follow up as needed.
• Plan for space needs.
• Plan for necessary equipment, including buying or leasing.
• Set up necessary operating procedures for handling the trial drugs, etc.
• Contact, educate, and get agreement with everyone on a site who may be involved
(pharmacy, laboratories, etc.).
• If data are to be entered electronically, ensure that all equipment is in place and
working, and that training is carried out.
• Work out a timetable for seeing patients, taking into account
o the time needed to see each patient;
o site staff availability;
o availability of others needed for special procedures or other protocol-related
activities;
o patient convenience;
o other studies being carried out by the same investigator.
• Plan for meetings with the sponsor and (if relevant) the CRO staff; the more
meetings before the study starts, the fewer needed afterward.
Main Consequences of Poor Planning
Time wasted for all concerned, especially patients, frustration, missed deadlines, and
all of the added-up effects of delay. In the worst case, conduct of the trial may become
impossible.
Knowing the Rules and Procedures
Key Messages
The messages to investigators (and to everyone in drug development) are
• know, understand, and follow the rules;
• be flexible and pragmatic;
• above all, use your common sense.
Introduction
Sensible rules that minimize risk to patients, set standards, establish where consistency is essential, and maintain overall quality make life easier for all involved in
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clinical trials. Such rules exist, and it is the responsibility of the sponsor to make sure
that the investigator and all site staff are familiar with them.
Following rules does not mean overinterpretation, however. An all too common
failing among sponsors is that the interpretation of these rules is left in the control of those who, due to poor management oversight, inexperience, or personality
issues, have obsessional risk-avoidance as their primary objective. This often results
in onerous, unnecessary, time-consuming processes based on nonexistent rules that
are quoted as being required by regulatory authorities.
Internationally Agreed Rules: Good Clinical Practice
The rules in question, good clinical practice (GCP), were formulated by the
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). ICH-GCP [1.24] states that
the purpose of GCP is to provide “A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that
the rights, integrity, and confidentiality of trial subjects are protected.”
There are 13 principles that form the philosophical basis and rationale for having
GCP standards:
2.1 Clinical trials should be conducted in accordance with the ethical principles
that have their origin in the Declaration of Helsinki, and that are consistent
with GCP and the applicable regulatory requirement(s).
2.2 Before a trial is initiated, foreseeable risks and inconveniences should be
weighed against the anticipated benefit for the individual trial subject and
society. A trial should be initiated and continued only if the anticipated benefits justify the risks.
2.3 The rights, safety, and well-being of the trial subjects are the most important
considerations and should prevail over interests of science and society.
2.4 The available nonclinical and clinical information on an investigational product
should be adequate to support the proposed clinical trial.
2.5 Clinical trials should be scientifically sound, and described in a clear, detailed
protocol.
2.6 A trial should be conducted in compliance with the protocol that has received
prior institutional review board (IRB)/independent ethics committee (IEC)
approval/favourable opinion.
2.7 The medical care given to, and medical decisions made on behalf of, subjects
should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
2.8 Each individual involved in conducting a trial should be qualified by education,
training, and experience to perform his or her respective task(s).
2.9 Freely given informed consent should be obtained from every subject prior to
clinical trial participation.
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2.10 All clinical trial information should be recorded, handled, and stored in a way
that allows its accurate reporting, interpretation, and verification.
2.11 The confidentiality of records that could identify subjects should be protected,
respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
2.12 Investigational products should be manufactured, handled, and stored in
accordance with applicable good manufacturing practice (GMP). They should
be used in accordance with the approved protocol.
2.13 Systems with procedures that assure the quality of every aspect of the trial
should be implemented.
Investigators and their staff should, at a minimum, be very familiar with all aspects
of GCP relating to their specific responsibilities, as listed in section 1 above. It is also
worth knowing the responsibilities of the sponsor, and how best the sponsor can
support investigators in the planning and day-to-day running of the trial.
The sponsor provides oversight and takes responsibility for all aspects of the concept, initiation, management, and financing of a clinical trial, including specifically
• providing an accurate, up-to-date IB with essential safety information and
instructions for proper use of the compound;
• providing a protocol;
• ensuring that the investigator receives appropriate training and access to all relevant information;
• implementing and maintaining quality assurance and quality control systems;
• ensuring that the study is reviewed by an ethics committee;
• providing a monitor to ensure that the study is run according to the protocol.
Local Rules
Sponsors will always emphasize the need to conform to the international standards
as laid down by the ICH, but it is equally important that the regulations specific to
each individual country (local regulatory requirements) also be observed. ICH-GCP
[1.4] states that local regulatory requirements are “Any law(s) and regulation(s)
addressing the conduct of clinical trials of investigational products.”
To help the investigator, who is responsible for knowing the local regulations,
the sponsor should include and explain country-specific variations and regulations
when training investigators and make sure that apparent conflicts with international
requirements are resolved.
Standard Procedures
Formal, written standard procedures are not a formal requirement for clinical trial
sites, but they are probably the best way for everyone involved to understand what
has to be done, by whom and by when.
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It is therefore important for the investigator and the site staff to
• identify all procedures that will need to be carried out;
• write them down;
• make sure they are practical and accurately reflect how trial-related activities will
be conducted in the real world;
• test them as soon as possible;
• ensure that there is consistency across different departments by ensuring, when
possible, that trial-specific standard procedures accord with those of other team
members, such as pharmacists and laboratory technicians, who may be involved
in multiple trials;
• designate someone to be responsible for implementing and checking adherence
to standard procedures, and reporting to the investigator unavoidable or medically necessary breaches of these procedures;
• provide everyone involved with a copy and make sure that they are understood.
Main Consequences of Failing to Follow Rules and Procedures
Sites can be audited for compliance with GCP by the sponsor, regulatory bodies, or
both. Noncompliance can have differing consequences, all of them serious. At best,
extensive (expensive and time-consuming) corrective activities may be needed so
that the data can be shown to be genuine and accurate. In the worst cases, the data
from a site may have to be excluded, and in extreme cases, the investigator may be
banned from conducting clinical trials.
The Study Team
Introduction
For all but the most basic studies, the investigator relies on a number of people to
carry out the day-to-day study activities. This is especially the case when the investigator is involved in several studies at once. Studies are therefore a team effort, and
it is essential that investigators understand this and manage the team accordingly.
Who Is on the Team?
• Investigator’s staff, including
o study coordinator(s);
o nurses;
o physicians;
o secretaries;
o backup staff.
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• Other staff in the clinic or hospital:
o pharmacists;
o laboratory technicians;
o personnel from other departments that might carry out special procedures or
refer patients.
• The sponsor (includes CRO staff):
o monitor;
o physician;
o others.
Managing a motivated, competent, well-aligned, and well-trained team on which
the investigator can rely is important, because the investigator always has overall
responsibility and will equally receive the blame when things go wrong as the praise
when things go right.
Managing the Team
To manage an effective team, the investigator should
•
•
•
•
•
•
•
•
•
•
schedule regular team meetings;
keep the team up to date;
make sure everyone is properly trained;
put together any standard procedures together with the team members;
ensure that all members are aware of their responsibilities, and who is responsible
for critical decisions;
document what is delegated and to whom;
make sure contact details are clearly posted;
schedule all trial-related activities at times when team members are available;
compensate team members adequately for extra work or time devoted to the study;
let everyone know when the trial is over and arrange a follow-up meeting to discuss the lessons learned. Involving the monitor in this meeting will be a useful
opportunity for mutual feedback.
Training the Team
It is expected that all those involved in a study should be fully qualified to carry out
whatever activity they are delegated. Regulatory inspectors will review the qualifications of any team members and will ask to see proof that they have been fully trained
and equipped to perform their roles and that they
•
•
•
•
are all familiar with every aspect of the trial;
know what procedures need to be performed;
understand the nonstandard aspects of the trial;
know the rules and regulations.
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The investigator and the sponsor should ensure that the necessary training is provided
as early as possible. Do not wait for the investigator meeting! The monitor should be
invited early in the process to discuss trial-specific requirements, together with more
general competence issues, especially training on the protocol, CRFs, and data cleaning.
Contingency Planning
Success is unlikely without the availability of properly qualified staff at all stages of
the trial, and this is the responsibility of the investigator, who should ensure that
there are plans for personnel cover for all members of the study team.
Simple ways for planning for expected and coping with unexpected events include
the following:
• An up-to-date unit calendar to be completed by all unit members on which
national, state, and personal holidays, as well as other planned activities, such as
conferences, are displayed.
• All team members should have current contact information for all team members.
• Formally designated backup staff who automatically step in if needed. It is
unusual for a separate team to be available, so that members of the same team
should be designated and should agree to cover for each other, and should be
trained accordingly.
• Have a recruitment agreement and policy in place to cover prolonged absences,
whether foreseen (pregnancy) or unforeseen (illness or accident), without delay.
Documents and Team Members
Filing and storage of the large quantity of documents and forms, whether paper or
electronic, is a necessary part of the clinical trial process. Therefore, a logical, accessible but secure filing system needs to be set up, and
• all team members must be familiar with the documents and the standard procedures for filing and retrieval;
• all team members should know where documents are filed;
• access to confidential information should be restricted to those who need access;
• the necessary keys or passwords need to be assigned;
• there should be an appropriate tracking system for documents, whether paper or
electronic, that are removed, borrowed, altered, or copied.
Main Consequences of Failing to Establish an Efficient Study Team
The integrity of the study is threatened for several reasons:
1. delays due to a lack of coordination because no one knows who is doing what
and when, compounded by lack of cover for absences;
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2. inefficiency due to lack of training, poor morale, and lack of collaboration;
3. poor quality, for all of the above reasons.
The Ethical Perspective: Getting Approval from an
Independent Ethics Committee (IEC) or Institutional
Review Board (IRB) †
Key Messages
No clinical trial can be carried out without approval of the relevant ethics committee.
No procedures relating to a clinical trial, including getting informed consent, can be
carried out before ethics approval is received.
What Is an Ethics Committee?
The primary role of an IEC/IRB is to protect the rights, safety, and well-being of
patients involved in clinical trials. It is
• independent;
• composed of medical, scientific, and nonscientific members who have no interest
in the trial (or who may not vote if they do have an interest).
It also
•
•
•
•
ensures protection of the rights, safety, and well-being of study patients;
provides public assurance for the conduct of clinical trials;
operates under regulatory jurisdiction;
gives the necessary approval for a trial to begin.
All trials require interaction with and approval from an IEC/IRB, and the investigator
must always plan with the IEC/IRB in mind.
General Guidelines for Communication with an IEC/IRB
It is the investigator, not the sponsor, who interacts with the IEC/IRB and understanding how to communicate is essential.
1. Know who the chairman is and members of the committee.
2. Learn their expectations, quirks, likes, and dislikes.
† The term IEC/IRB (or IRB/IEC) is the accepted way of describing an ethics committee, though the generic term “ethics committee” or EC is equally accurate. Note that it is
an ethics committee, not an ethical committee, though the honesty and integrity of the
members are not in doubt.
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3. Understand how the committee operates and which decisions, if any, can be
handled by the chair without having to wait for formal meetings.
4. Include essential information (name of principal investigator, protocol number,
protocol title, etc.) in every letter.
5. Get approval for the protocol, the consent form, payments to volunteers, and
any advertisements before carrying out any trial-related procedures.
6. Submit changes to these documents, such as protocol amendments, if needed.
7. Inform the ethics committee of any changes that may affect patients in the
study even if there is no formal requirement.
8. Inform the committee promptly of any safety issues according to GCP regulations and also according to any policies the committee may have.
9. Update the committee as and when they wish to be updated.
10. Always respond promptly to any requests from the IEC/IRB.
11. Keep and file all IEC/IRB correspondence.
Although the investigator communicates with the IEC/IRB, the sponsor should make
sure that the investigator has all the relevant information in the correct format at
the time when it is needed.
Making an IEC/IRB Submission
Collaboration and coordination between the sponsor and the investigator is the only
efficient way to approach an ethics committee submission. As always, good planning
pays dividends.
The sponsor supplies all relevant documents in the correct format. The investigator
• finds out when the IEC/IRB meets;
• finds out how long beforehand the submission should be made;
• discusses any potential problems or aspects needing explanation with the committee chairman beforehand;
• learns of any specific committee requirements and exactly what they are
looking for;
• determines how long it takes to reach and announce a decision;
• makes sure (along with the sponsor) that the documents meet ethical standards;
• knows the local, as well as the international, regulations and ethical standards.
These documents include
•
•
•
•
•
the trial protocol and amendment;
informed consent forms;
advertisements;
any written information to be provided to patients;
the investigator’s brochure;
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• information about payments and compensation available to patients;
• the investigator’s current CV and proof of any other relevant qualifications.
Points to stress:
• IEC/IRB approval can sometimes delay trial initiation. With careful planning,
submission and approval can be achieved with a minimum of problems.
• The IEC/IRB will be primarily concerned with the benefit-risk profile of the compound and the scientific and medical (not regulatory) rationale for the study as
they affect patients. These sections are often very weak, and the investigator
should be sure that the information is clearly and rationally presented.
• The list of documents above shows what an IEC/IRB reviews. Any omissions will
cause delays.
• Although it is the investigator’s responsibility to ensure that IEC/IRB approval is
obtained, the sponsor and the monitor will provide plenty of support with regard
to compiling and copying all the necessary documentation.
Receiving and Replying to IEC/IRB Decisions
According to ICH-GCP [3.1.2], the IEC/IRB should “review a proposed clinical trial
within a reasonable time and document its views in writing, clearly identifying the
trial, the documents reviewed, and the dates for the following:
•
•
•
•
approval/favorable opinion;
modifications required prior to its approval/favorable opinion;
disapproval/negative opinion;
terminations/suspension of any prior approval/favorable opinion.”
The investigator should ensure that written and dated copies of all necessary approvals are received.
Any changes to the informed consent procedure or protocol must be resubmitted
to the IEC/IRB for approval.
If any modifications are requested by the IEC/IRB, the investigator must
• understand exactly what is required;
• discuss the appropriateness of the requested changes to the protocol with the
sponsor before resubmitting;
• establish the procedure for resubmission to the IEC/IRB:
o Is it necessary to wait until the next scheduled meeting?
o Can an ad hoc meeting address the resubmission?
o Can the chairman make a decision?
• resubmit all requested information as soon as possible;
• provide the sponsor with a copy.
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Main Consequences of Failing to Plan the IEC/IRB Submission
The consequences of not getting ethics approval or of ignoring the requests of IECs/
IRBs are self-evident.
Failing to plan results in delays, with all of the resulting effects. Missing the deadline for submission can result in delays of up to a month, until the next meeting, or
even longer if holidays intervene. Submitting substandard documents results in an
endless round of submissions, questions, and resubmissions. Failure to understand
how the system works can result in simple amendments being submitted to the full
committee when a more rapid approach is available.
The Initiation Visit
In sponsored trials, the initiation visit is an integral part of the trial, and the report
produced is an essential document. The purpose is to ensure that the investigating
site is ready to start the trial.
All aspects of the trial will be discussed and reviewed with the monitor, even if
these have been discussed and reviewed before.
At a minimum, the following documents and procedures will be reviewed:
•
•
•
•
•
•
•
•
•
•
•
the protocol;
the investigator’s brochure;
the data capture process (paper or electronic);
the informed consent form and process;
the set-up and content of the investigator’s file;
the way in which site-specific processes have been defined and responsibilities
allocated;
source document requirements;
all aspects of patient recruitment;
availability of adequate trial-related supplies and equipment;
investigational product handling;
adverse event reporting.
Patients should not be randomized before the initiation visit.
Certain activities, some of which are dependent on having IEC/IRB approval, can
be carried out before the initiation visit:
•
•
•
•
patient screening;
discussion of the trial with patients;
recruitment procedures, including advertising;
obtaining consent from patients.
Randomization and treatment in the study cannot start before the initiation visit.
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Recruitment and Enrollment
Key Message
Failure to plan and adhere to a fact-based and comprehensive recruitment strategy is
the primary cause of delays in clinical trials.
Recruitment Strategies
When can activities be initiated in relation to ethics approval?
Even with the best planning, time will be a limiting factor, so that starting the
recruitment process (­figure 8.1) as early as possible is vital. Knowing what can be
done before IEC/IRB approval is therefore important.
Before IEC/IRB approval, the investigator can
• screen existing patient data to assess recruitment potential;
• discuss interest in trial participation with eligible patients (country-specific regulations permitting);
• schedule appointments after the anticipated IEC/IRB approval date to consent
patients who are interested;
• prepare a draft version and distribution plan for advertisements (where country
regulations permit advertising).
Before IEC/IRB approval, the investigator cannot
• recruit patients using any form of advertising;
• get informed consent;
• carry out any protocol-related measures on patients.
As always, country-specific regulations apply.
Document
patient
availability
Identify
potential
subjects
Obtain
informed
consent
Randomise
patients
Study start
Recruitment
Obtain
IEC/IRB
approval
Enrolment
Prerandomisation
screening
Figure 8.1 Key steps in recruitment and enrollment relative to IEC/IRB approval.
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Advance patient recruitment
The objective of the process, and the optimal outcome, is for the patients to be identified and to agree in principle to take part before the study start date and in parallel
with the time-consuming approval processes. This is especially important in countries where regulatory, contractual, and ethics processes are sequential.
The site can contact those patients with chronic, preexisting diseases identified
by the screening process and, even before ethics approval has been given, ask them
if they would, in principle, like to take part in the study. Patients who agree can then
be recruited before the start of the study, once the contractual negotiations and the
ethics approval have been completed (but not before).
This approach allows the exact number of patients needed for the study to be
ready for enrollment after the initiation visit. If more patients will be needed, the
recruitment plan can be put into action in anticipation before the start of the study,
not as a grinding, ongoing process or rescue measure.
For chronic, preexisting diseases, therefore, the actual number of patients available at the start of the study will be known. Enrollment time will now be limited by
• the resources at each site and the number of trial patients that can be enrolled
and followed up per week;
• any delays in being able to initiate sites because of delays in regulatory, contractual, or ethics approvals (most of which should have been addressed by adequate
planning);
• internal problems such as insufficient drug supply.
It may be possible for the investigator to anticipate and minimize these limitations.
For newly diagnosed acute or acute on chronic conditions, patients can only be
identified, recruited, and enrolled as they turn up, but if the screening process has
been carried out efficiently, the time needed for recruitment is predictable with
reasonable accuracy. Inevitably, recruitment time will be longer than for studies in
patients with chronic conditions.
Recruiting patients from other sources
The number of recruitment strategies and sources open to a sponsor runs into many
dozens (B. D. Harper and D. Zuckerman, 2006). Many useful strategies are best carried out by the investigator, who should be made aware of these and supported by
the sponsor. Creativity by the investigator is to be encouraged.
• Competing trials. Knowledge of competing trials is not in itself a strategy, but the
investigator may be better informed about those taking part or those referring
patients than the sponsor. This information can be used to devise appropriate
strategies.
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• Patient organizations. These can be a useful resource for disseminating information about trials. The investigator can help by answering questions and providing
reassurance for potential volunteers.
• Referrals. There are two types of referral that the investigator can initiate.
1. From other physicians, whether in hospitals or in primary care, who see similar patients. This type of referral needs careful management as physicians
are notoriously protective of their patients. The sponsor should be prepared
to support a formal agreement with a contract and payment. Other incentives include the promise of future collaboration, a reciprocal arrangement,
the potential use of data subsets, and the possibility of better care for their
patients. In many instances, there are networks of physicians who contribute to trials; investigators should try to establish networks with the necessary
support from sponsors.
2. From physicians, primarily in the same institution as the investigator but
theoretically from elsewhere, who see patients with relevant concomitant diseases. For example, patients being followed up at a diabetes clinic
might have cardiac or peripheral vascular diseases that are the subject of
the trial.
• Advertising. The investigator can facilitate the distribution of posters and leaflets
(approved by an ethics committee) at the site, and more broadly, in the hospital
or clinic in which the investigator works and among colleagues in other clinics or
in primary care.
• Consultation with more experienced colleagues. This can be especially useful in
larger academic centers, where many trials are carried out, even if the experience
is in other therapeutic areas.
• Delegation of recruitment to specialists or those with more time. Some sponsors,
CROs, and institutions carrying out many trials have or employ experienced specialist recruiters. In the absence of a specialist, the investigator can negotiate the
funding of a dedicated staff member to manage recruitment for as long as necessary. In either circumstance, the investigator remains responsible for ensuring
adequate and timely recruitment.
Patient-Related Aspects
Recruitment and the patient perspective
Successful enrollment is the culmination of a process in which finding potential
patients is only the beginning. The chances of success are significantly diminished if
the investigator does not take the patient’s perspective into account, because information that a patient thinks is important may not necessarily be considered important by the investigator. Patients decide to take part in studies for a wide variety
of reasons, including altruism, an incurable or inadequately treated condition, or
boredom; there will always be underlying concerns to address, and many patients
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may refuse to consider consenting because of concerns that can often be allayed by
the investigator.
Frequent questions that the investigator should anticipate relate to concerns
about the trial treatment and inconvenience and discomfort.
Treatment considerations:
•
•
•
•
•
•
What are the risks or side effects?
Will I be on placebo?
How does the treatment work?
How often will I have to take the study treatment?
Is it likely to make me better?
Do I have to come to the clinic for injections?
Inconvenience and discomfort:
•
•
•
•
•
•
•
•
•
•
How often do I have to come to the clinic?
At what time will I have to come?
Will I have to wait long each time?
How long is the trial?
Are there a lot of tests?
What type of test will I have to undergo?
Are they painful?
Do they take time?
Will I still be able to go to work and carry out my normal activities?
Will my expenses be paid?
Is the patient suitable for the trial?
Identifying patients who comply with the protocol requirements is only the first part
of the process for assessing patient suitability for a trial. All of the other information
needed to determine suitability should not be overlooked because of the pressure to
find the most patients as quickly as possible.
Before proceeding to informed consent and then to any pre-randomization tests,
the investigator should question the ability of the patient to take part.
Is the patient currently involved in other trials?
Patients should only be enrolled in one trial at any one time. ICH-GCP [4.3.3] recommends that a patient’s primary physician be informed, with the agreement of the
patient, of their potential participation in a trial. This may enable the investigator to
find out about any other trials in which the patient may be taking part (or considering taking part).
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Has the patient been in another trial recently?
There should be a relevant time lapse before a patient who has been in one study can
be in another, in order to ensure the safety of the patient and to prevent potential
confounding events from the interaction of two investigational products.
Is the protocol too complex for the patient?
The patient may be unable to undergo the protocol procedures, whether rigorous
investigations, complex questionnaires, or burdensome dosing schedules, due either
to the effects of illness or of age (young and old).
Does the patient have a history of compliance or noncompliance?
This need not be just compliance in a trial, but also in taking medication or in showing up for scheduled medical appointments. The primary physician of the patient
and other medical records may provide information.
Is the patient competent to use the investigational product?
Manual or physical dexterity is needed for some administration devices, such as
injectors or inhalers. A patient may not be able to cope with self-administration. In
such cases, the investigator should inquire if there is a partner, friend, or caregiver
who can help, or if it is possible to modify the mode of administration.
Will the patient be available for the duration of the study?
Consider the general health of the patient, work, family commitments, and holidays.
Are there practical limitations that the patient faces?
Distance from the clinic and inadequate means of transportation might limit attendance. Even if transportation is available, is the patient physically capable of traveling alone, or at all? Does the patient have young children who need supervision? Is
the patient’s job a limiting factor? All of these issues can potentially be addressed,
but only if the issues are known.
Does the patient have the right attitude?
This is an important assessment to make, because a patient with the wrong attitude,
for whatever reason, can disrupt the trial, waste a lot of people’s time, and ultimately
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provide no useful data. There will then be the added time and expense of recruiting
a replacement.
How is recruitment progressing? The importance of the screening log
It should be clear by now that there are many steps between the initial pretrial patient
screening and identification and the enrollment of a patient, so that many patients
initially identified as eligible will fall by the wayside. Maintaining a detailed, up-to-date
log of patients screened after study startup will allow the investigator and the sponsor
to evaluate recruitment with a view to identifying and correcting any limiting factors.
The fact that protocol feasibility has been carried out does not preclude absolutely the
necessity of making further changes to the protocol if necessary.
A screening log is a document in which details of all the patients screened for a
trial are recorded, as illustrated below. All patients, whether enrolled or not, should
be included, as well as the reasons for those excluded.
Did the patient meet the inclusion criteria?....................Yes....No........
If not, why?.........................................................................................
Did the patient meet the exclusion criteria?...............Yes....No............
If so, why?...........................................................................................
Was the patient suitable for the study?.......................Yes....No............
If not, why? (e.g., poor compliance history).....................................
Did the patient give informed consent?......................Yes....No............
If not, why? (e.g., unacceptable risks)..............................................
Was the patient enrolled?.............................................Yes....No...........
If not, why? (e.g., failed additional test)..........................................
Examining why certain patients were excluded may help to identify reasons why investigators are having difficulty in meeting recruitment targets, such as overly restrictive
eligibility criteria (despite protocol feasibility), off-putting aspects of the protocol, or
poor interview technique, so that possible corrections can be made as soon as possible.
Practical Considerations for the Investigator
Enrollment tactics
These tactics are best considered by looking at the extremes represented by the two
possible types of study population.
Patients with common chronic conditions or studies in prevention:
• known patient population;
• recruitment can be completed early;
• many patients can be enrolled at the same time.
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Patients with acute, acute on chronic, or rare chronic conditions:
• estimated patient population;
• patients can only be recruited as they present;
• inevitably, enrollment has to be staggered.
Careful planning is needed for the first category of patient, with the possibility of
very rapid enrollment (though sometimes patients with acute conditions can present very frequently). The importance of rapid enrollment needs to be balanced by
practical considerations.
The investigator should consider the following to help determine how quickly
patients can be enrolled and randomized:
• How long will it take to see each patient? Remember that some visits will take
longer than others, especially at the start of the study.
• Is there space to accommodate several patients at once?
• How many patients can the available staff manage in a day?
• Are the important supporting functions, such as the pharmacy and the laboratory, able to cope with and in agreement with the proposed rate of enrollment?
• Will there be unnecessary inconvenience to the patient (waiting time, unfavorable clinic hours)?
• Is enough study drug available?
• Will the care of the investigator’s other patients be compromised?
Why is enrollment slower than anticipated?
The most important action an investigator can take if recruitment is not proceeding as expected is to inform the monitor as early as possible. If corrective measures
are not instituted immediately and effectively, the most important response by the
monitor will be triggered: The site will be closed.
Why might enrollment lag behind expectations? Often, there is more than one
reason. Awareness by the investigator of possible reasons is essential. Many are simple and can be fixed quickly:
• competing trials by other investigators;
• competing trial at the same investigator site (which may be of greater interest or
associated with a higher fee, or both) resulting in competition for investigator
loyalty, as well as patients;
• poor protocol feasibility;
• patients are there but have not been identified due to poor patient screening and
exploration of other sources;
• original screening failures have not been rescreened;
• change in the therapeutic environment, giving patients a better alternative to the
drug being investigated;
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• information given during informed consent (practical issues such as visit frequency or travel, difficult protocol, potential safety issues) puts patients off;
• inadequate support for patients;
• seasonal medical conditions;
• the holiday season in certain countries;
• inadequate resources or facilities due to lack of planning or due to illness;
• lack of interest on the part of the investigator;
• inexperienced or inadequately trained staff;
• lack of motivation of study team;
• poor relationships and communication with patients;
• referring physicians not performing as expected;
• poor or unsuccessful recruitment plan;
• the site does not have the patients and should not have been included.
Apart from the fact that the sponsor needs to be informed about recruitment rates
frequently and continuously as a matter of course, the faster the reasons for slow
recruitment can be analyzed and discussed with the sponsor, the sooner corrective
measures can be implemented. The investigator is primarily responsible for identifying the reasons and proposing and implementing solutions, which include
• going through all the possible sources for patients again, including a thorough
review of all the clinic records;
• analyzing how best to approach eligible patients who refused to take part;
• rescreening some screening failures;
• badgering referring physicians;
• taking more notice of the patients’ reasons for not wanting to take part; asking for
more support from the sponsor (money for patient support, fees, additional staff);
• introducing potential recruits to patients already in the study, as they can answer
questions and provide reassurance based on experience;
• training staff;
• doing more to motivate staff;
• being fair with patient allocation if undertaking a competing trial;
• coming clean if the site will not meet expectations.
At worst, because of the delays, the protocol may have to be amended, but this can
only be done in the light of information recorded by the investigator.
Informed Consent
Key Message
The purpose of informed consent is to ensure that the “rights, safety, and well-being
of patients are protected.”
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Before the Informed Consent Interview
Preparation
Time taken to prepare for the informed consent interview will make it more effective
and easier for the patient, increasing the likelihood of a positive response. In preparation, the investigator should make sure that
• The IEC/IRB has approved the consent form and any other information that will
be given to the patient.
• She or he knows every detail of the purpose of the trial, the protocol, the IB, the
characteristics of the trial drug, and any other information to be given to the
patient. Patients will expect the investigator to understand and be able to justify
and explain all aspects of the trial.
• Preparation takes into account the possibility that the patient may have received
a lot of information about the investigational drug or the study from the Internet
or other sources. On the one hand, it destroys credibility if the patient knows
more than the investigator. On the other hand, the investigator should be prepared to correct any misinformation.
• The way in which the information will be presented to patients and the questions
that may need to be answered have been rehearsed, preferably with experienced
colleagues.
• All relevant patient information documents or leaflets that detail study-related
issues provided by the sponsor (and approved by the IEC/IRB) are readily available.
• Both the investigator and the patient have the time needed.
• A room that is quiet, comfortable, and free from disturbances is available.
Communication considerations
Good communication is essential if patients are to understand all the complexities
of the trial and what is expected of them. To achieve this, all of the following must
be done:
• Documents used during informed consent must be nontechnical and easily comprehended by a lay audience. This is a primary concern of the IRB/IEC.
• The investigator must not be patronizing or over-friendly. It is important that no
coercion or undue influence is brought to bear on potential trial subjects.
• Sufficient time must be allowed for patients to ask questions.
• The investigator must give honest answers. When unable to answer a question,
the investigator should find the answer and get back to the patient at a later date.
• Take-home materials should be provided for overnight review if that promotes
understanding or if the patient wants to consult with others. Follow-up meetings
may be needed.
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• Information must be provided in the language in which the patient is most fluent.
A legally acceptable translator may be needed for the interview, and the informed
consent form and any patient information sheets will need to be translated.
Translation will need IRB/IEC approval.
The Content of the Interview
Section 4.8.10 of ICH-GCP states that “both the informed consent discussion and
the written informed consent form and any other written information to be provided to subjects should include explanations of the following”:
(a) That the trial involves research.
(b) The purpose of the trial.
(c) The trial treatment(s) and the probability for random assignment to each
treatment.
(d) The trial procedures to be followed, including all invasive procedures.
(e) The subject’s responsibilities.
(f) Those aspects of the trial that are experimental.
(g) The reasonably foreseeable risks or inconveniences to the subject and, when
applicable, to an embryo, fetus, or nursing infant.
(h) The reasonably expected benefits. When there is no intended clinical benefit to
the subject, the subject should be made aware of this.
(i) The alternative procedure(s) or course(s) of treatment that may be available to
the subject, and their important potential benefits and risks.
(j) The compensation and/or treatment available to the subject in the event of
trial-related injury.
(k) The anticipated prorated payment, if any, to the subject for participating in
the trial.
(l) The anticipated expenses, if any, to the subject for participating in the trial.
(m) That the subject’s participation in the trial is voluntary and that the subject may
refuse to participate or withdraw from the trial, at any time, without penalty
or loss of benefits to which the subject is otherwise entitled.
(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory
authority(ies) will be granted direct access to the subject’s original medical records for verification of clinical trial procedures and/or data, without
violating the confidentiality of the subject, to the extent permitted by the
applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject’s legally acceptable representative is
authorizing such access.
(o) That records identifying the subject will be kept confidential and, to the extent
permitted by the applicable laws and/or regulations, will not be made publicly
available. If the results of the trial are published, the subject’s identity will
remain confidential.
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(p) That the subject or the subject’s legally acceptable representative will be
informed in a timely manner if information becomes available that may be
relevant to the subject’s willingness to continue participation in the trial.
(q) The person(s) to contact for further information regarding the trial and the
rights of trial subjects, and whom to contact in the event of trial-related injury.
(r) The foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be terminated.
(s) The expected duration of the subject’s participation in the trial.
(t) The approximate number of subjects involved in the trial.
The content of this long list can be summarized as follows:
•
•
•
•
•
all aspects of the trial, the procedures involved and the duration;
the potential clinical benefit;
the things that could go wrong;
alternative treatments available;
all their rights, including the fact that the informed consent is not a contract and
that signing it does not bind the patient in any way;
• what happens to her or his information.
This is a large amount of information (much of which may involve terms or concepts
unfamiliar to most patients) to take in at one time.
Clarity, patience, and repetition when needed are essential. This is especially true
because, all too often, consent forms are long, dense, and poorly written. If there is any
concern that the patient does not understand any part of the information, or is confused
or undecided, the process should be repeated later. Involving someone else may help.
Signing and Filing the Informed Consent Document
Who must sign and date the informed consent document?
• the person who conducted the informed consent discussion (the investigator or
delegated team member, where permitted);
• the patient (or the patient’s legally acceptable representative);
• an impartial witness when the patient is unable to read, who should be present
throughout the informed consent discussion.
Additional considerations
• Some IEC/IRBs require the principal investigator’s signature in addition to the
signature of whoever conducted the interview.
• An independent witness may also be required in some countries.
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• In some sites, the investigator is the only person allowed to obtain informed consent; in others, the investigator can delegate this responsibility. The investigator
must check their local regulations for guidelines on who may or may not obtain
consent from patients.
• Medical supervision during informed consent is essential for answering patients’
questions.
• When acute indications are being studied and rapid informed consent is needed,
it is important to determine whether the sponsor or the IEC/ IRB will allow delegation of informed consent responsibilities in the absence of the investigator.
• Written informed consent must be obtained from the patient. When this is not
possible due to age, disability, or the nature of the condition, informed consent
may be obtained from the patient’s legally acceptable representative (next of kin,
parent, or guardian).
• U.S. Food and Drug Administration (FDA) regulations stipulate that minors must
have a basic understanding of the trial.
• Before participating in a study, the patient (or the patient’s legally acceptable
representative) must receive a signed and dated copy of the form together with
a copy of any other written information provided to them during the consent
process.
• Informed consent has to be received and documented in writing before any invasive trial-related procedure can begin. A copy should be kept by the investigator
as this will be required during any audit.
• Failure to obtain or properly document informed consent is a serious offense.
Informed Consent under Special Conditions
This addresses situations when the potential trial subject is unable to give consent,
or when genetic testing is involved.
Special requirements for those who cannot give consent
The following persons are defined as unable to give consent:
•
•
•
•
a minor;
someone not legally competent;
an illiterate person;
a patient unable to give informed consent owing to the nature of the trial or their
medical condition.
The protocol or IEC/IRB may identify other cases where there are special requirements for informed consent. The investigator should be very familiar with the
relevant parts of section 4.8 of the ICH GCP guidelines concerning these special
requirements.
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If the patient is unable to provide informed consent, then consent should be
obtained from the patient’s legally acceptable representative. ICH-GCP [4.8.12]
states that, whatever the situation, the patient “should be informed about the
trial to the extent compatible with the subject’s understanding and, if capable,
the subject should sign and personally date the written informed consent.” There
is also a procedure for certain rare emergency situations [ICH-GCP 4.8.15] in
which prior consent of the suject or the subject's legal representative is not
possible.
Special requirements when genetic testing is involved
The investigator will need to discuss the following with the patient:
• the genetic component of the trial;
• potential risk and benefits;
• how any incidental findings will be handled.
The additional informed consent form will include details on the protection of the
genetic data:
•
•
•
•
access;
archiving procedures;
destruction procedures;
future use by third parties.
As always, the investigator must be aware of local regulations.
Consent Requirements Following Protocol Revision or Amendment
Informed consent is a continuing process. Changes may be made to the protocol during the course of a study, and the investigator must provide any new information to
a patient that has a potential bearing on that patient’s willingness to participate in a
trial. The patient must then consent to the changed protocol.
• Protocol revision or amendment may require appropriate revision of the
consent form.
• The amended form must be approved by the IEC/IRB.
• The patient should consent to the amended protocol once the consent form has
been approved.
• The investigator must be aware of any applicable local regulations relating to
changes in the protocol or the informed consent form.
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The Final Steps to Enrollment and Randomization
Now that the patient has given informed consent to be included in the trial, there
are usually one or more steps before the patient can be formally randomized and
considered as having entered the trial.
The Washout Period
In some trials, there may be a washout period to allow clearance of any discontinued prior medications before study initiation. This will have been explained in the
informed consent process.
The Baseline Assessment
A pre-randomization baseline assessment is usually required as part of the process
for establishing eligibility and to establish a baseline. If either clinical or laboratory
findings are outside the protocol requirements, the patient may not be randomized.
It is therefore important that patients understand that they will not necessarily be
enrolled in the trial, despite having given informed consent.
In some instances, the baseline assessment can be repeated at a later date to see
if the findings have changed and the patient may be eligible.
Assigning a Patient Number
To protect a patient’s confidentiality, the investigator will assign a number to each
patient. This number will then be used when the sponsor subsequently allocates each
patient a randomization code.
Allocating a Randomization Number
In randomized trials, the patient is allocated a number that randomly assigns the
patient to a treatment group. This number will be used as the confidential patient
identifier during the trial. The protocol will explain how and when to allocate a randomization number.
The patient is now ready to receive study medication.
Making Sure the Patient Stays in the Study
Key Message
Retaining patients after enrollment is just as important as recruiting them in the
first place.
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Introduction
There are four types of reasons why patients drop out:
• drug-related;
• protocol-related;
• emotional;
• practical.
Drug-related reasons
Withdrawal from the trial because of adverse events or poor tolerability cannot be
prevented.
Protocol-related reasons
The burden imposed by the protocol should have been explained to the patient
before obtaining consent. However, the reality may be different from the perception, despite detailed explanation, so that, apart from amending the protocol,
there is little that can be done. If the problem is widespread, the protocol will
inevitably need amending. This takes time, so the quicker the sponsor is informed,
the better.
Emotional reasons
Emotional reasons are entirely subjective, can be hard to define or understand, and
can be difficult to address. This does not make them any less valid or important
than other reasons. Sometimes the reason is unquantifiable, while at other times
there is a concrete basis. In all circumstances, it is important for the investigator
to understand the concern, to reassure, and, above all, to comply with the patient’s
wishes.
Practical reasons
The practical issues are the easiest to anticipate and deal with. Clinical trials
inevitably disrupt the lives of patients, and simple measures can minimize the
disruptions.
• Suggest any support that makes it easier for patients to take part and reimburse
all legitimate costs in full immediately. The investigator and sponsor should agree
how this can be done with the least fuss for the patient.
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• Providing a fixed maximum sum irrespective of the cost to the patient is not
acceptable.
• Legitimate costs include:
o fares, including taxi fares;
o meals;
o childcare;
o a traveling companion;
o overnight accommodation.
• Minimize the disruption caused by the trial:
o schedule clinic visits to coincide with the availability of the patient;
o provide full instructions and equipment for anything the patient has to do
at home;
o provide 24-hour telephone support;
o take the clinic to the patient when possible by having dedicated trial site staff
(who may be shared between sites) visit the patients to perform simple procedures or assessments at times convenient for the patient.
The Data
Key Messages
The collection of data drives the clinical trial process. Without accurate data, the outcome of the trial is meaningless and may be misleading. The data have no credibility
without supporting documents to demonstrate that the trial was conducted properly
and the data are accurate.
Introduction
Physicians are familiar with measuring and recording patient details accurately in
clinical practice, but clinical trials are different because
• the volume of data is considerably greater;
• recording and storage of data are more complicated.
Documents and Source Document Verification
Everything relating to clinical trials must be documented; the documents must be
accurate and up to date; they must be securely stored; and they must be readily accessible. If the relevant documents are not available at the site, or if the procedures for
handling them are not observed, the data obtained by the site may be considered
invalid.
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Essential documents and the paper trail
Certain documents are defined as “essential” by the regulations. ICH-GCP [8]‌lists
53 documents such documents that are grouped according to when during the trial
process they are generated. Of these, 20 are generated during the pretrial period, 25
during the trial, and eight as a result of post-trial procedures.
The investigator, no less than the sponsor, should be familiar with the requirements of section 8 of the regulations because copies of most of the documents must
be filed by the investigator.
The importance of the paper trail
Compliance with this regulation is essential because a paper trail is being created
from which it should be possible to reconstitute all aspects of the study. Regulatory
authorities require this paper trail, which provides the necessary information to
assess compliance with the protocol and the regulations, and provides some evidence
of the validity of the data.
What should be documented
As a general rule, the investigator should document everything, from telephone calls
and meetings with the sponsor to the more formal aspects of the trial. It is very
unlikely that too much information could ever be generated. Too little information,
however, could jeopardize the smooth running of the trial.
Maintaining documents correctly is essential not only because of the regulations
and the scrutiny they will come under during a formal audit, but because it is the
basis for the professional conduct of a credible clinical trial.
Source documents: the core of the paper trail
Source documents are the original documents in which data are recorded. They
include, for example (ICH-GCP [1.52]):
•
•
•
•
•
•
•
hospital records;
clinical and office charts;
laboratory notes;
memoranda;
pharmacy dispensing records;
microfilm or magnetic media;
x-rays.
The list is potentially endless.
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The important thing to remember is that the original document in which data are
recorded is the source. In a clinical trial, the data may be entered first in the CRF. The
CRF then becomes the source document for that information. Failure to understand this leads
to a lot of unnecessary work for the site staff (and the sponsor, though the sponsor is
often the instigator) because some sponsors will insist on copying the original data from
the CRF into another document as the “source,” from which the CRF data can then be
“verified”!
One of the responsibilities of the sponsor is to verify that data in the CRF are an
accurate reflection of the data at the source. A number of approaches are used:
1. Verification of 100% of data in 100% of patients. This is really only necessary
either when the investigator is inexperienced and has just entered the first
patients, or if there is a significant problem at the site.
2. Verification of up to 100% of data in a randomly selected subset of patients.
3. A more targeted approach, in which only specific data are verified in some or all of
the patients.
To make this process more reliable and efficient, the investigator and the sponsor
should define and document the following before the study starts:
• for which data will the CRF be the source document;
• other source documents and data;
• storage and availability of source documents.
Source documents are as important as any other trial document, whether listed as
essential in the ICH guidelines or not.
Increasingly, the source of a lot of the data is electronic (patient hospital records,
laboratory results, digital images, electronic patient diaries, etc.); the CRF into which
the data are entered is also electronic. It is important to read the FDA draft guidance
called “Electronic Source Data in Clinical Investigations” (November 2012) to learn
how these data should be handled.
From Patient to Publication: The Clinical Trial Data Flow
The high-level flowchart in fi
­ gure 8.2 shows the key stages of the trial data flow and
who is responsible. The objective is to get to the trial report and publication stages
as soon as possible.
The investigator site
1. Data required by the protocol are collected by the investigator and the site support staff. Data will be received in many formats:
• orally, by questioning the patient;
• by observation and measurement from physical examination of the patient;
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Investigator
Sponsor
Sponsor
Clinical data
Trial database
Analysis
Source
document
Checked and
cleaned
Trial report
CRF
Database
closure
Investigator & sponsor
Publication
Figure 8.2 Key stages of and primary responsibility for clinical trial data flow.
2.
3.
4.
5.
• electronically, when investigation results such as blood analyses, x-rays, or
ECGs are available on line;
• on paper or some other physical medium, where when electronic transmission
is unavailable or inappropriate.
Information received orally or from observation or measurement during physical examination is immediately recorded, either in the clinic patient records or
directly in the trial CRF, whether paper or electronic.
The first place in which data are recorded is called the “source document.”
If the source document is not the CRF, as will be the case much of the time, the
data are then transcribed from the source document into the CRF. If data are
being collected electronically, some information, such as laboratory results, medical images, or patient electronic diaries, may be transferred directly to the CRF,
without the need for transcription by hand. The original electronic source must be
maintained, be linked to the entry in the electronic CRF, and be accessible to any
reviewer.
Before sending the data to the sponsor, whether on paper or electronically, the
investigator should check periodically to ensure that there are no inconsistencies,
improbable values (wildly out of range laboratory results, dates, or ages), transcription errors, illegible entries, or missing values. In the case of paper CRFs,
the monitor also usually checks the CRF before it is returned to the sponsor.
The sponsor
1. Data received from the investigator are entered into the trial database.
2. The data are checked for the same kinds of errors and omissions as
described above.
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3. Each error or omission that needs to be addressed by the investigator results in a
query that is sent to the site for correction.
4. Once the database is as clean or complete as possible, it is locked. No further
changes can be made.
5. The data are analyzed, and a formal report of the trial results is written.
6. The results of the trial are published.
Responsibility for Complete and Accurate Data
The only purpose of a clinical trial is to collect accurate data, and it is the responsibility of the investigator to ensure “the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports”
(ICH-GCP [4.9.1]).
This means that the investigator remains responsible, even when data collection
and entry are delegated to another team member, so it is important to emphasize
to all team members the need for conscientious data handling throughout the trial
process, as would be expected during routine clinical practice.
Failure to do so can end up costing the investigator time or money or both,
because ensuring that data are free from inaccuracies and errors is not only a regulatory but also a contractual obligation. Most trial agreements will specify the proportion of the fee that will be held back until data are clean or that will not be paid if
data are inadequate.
How Dirty Data Dam the Flow
Two things interrupt the data flow: the absence of patients (already discussed) and
dirty data.
By definition, any data that cannot be used, for whatever reason, are dirty data.
By this definition, absent data count as dirty data. The term “dirty” is applied because
their consequence is to foul up both the data flow and the outcome of the study.
Dirty data are the results of errors, which can be
•
•
•
•
•
•
measurement errors, due to poor observation or faulty equipment;
recording errors, when the correct data are recorded incorrectly;
abstraction or analytical errors, when wrong conclusions are drawn;
transcription errors, when data are copied from a source document to the CRF;
entry errors, when data are transferred manually from the CRF to the database;
errors of omission, when data are not entered at all.
The increasing use of electronic data capture (EDC) systems with direct data entry
has resulted in a reduction in transcription errors when data, such as laboratory
results, can be transferred to the CRF electronically, and in entry errors because this
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step is absent. In addition, most EDC systems are programmed to recognize data
that are absent, illogical, or well beyond rational boundaries and automatically query
these so that the investigator is immediately aware of the error, eliminating a number of steps that are needed with a paper-based system.
Unfortunately, this does not mean that dirty data and their consequences are things
of the past. To begin with, comparable error rates, as assessed by the number of queries
generated, are similar for EDC and paper CRFs irrespective of where in the world the
study is conducted (P. B. Desai, C. Anderson, and W. K. Sietsema, 2012). More important, the majority of studies are still carried out using paper CRFs, and this state of
affairs will continue for many years. In some cases, EDC is not recommended for practical or cost-effectiveness reasons, as when the trial is too small, too short, or there is not
enough set-up time. In other cases, the cost, the infrastructure, or the particular likes
or abilities of the investigator (or a combination of these factors) preclude or inhibit the
use of EDC. Some studies have a mix of paper and EDC to accommodate specific sites.
The consequences of dirty data are felt before data are entered in the database,
during the data management process, and after database lock.
Consequences before data are entered in the database
At this stage, the main consequence is wasted time, for the investigator, the site
staff, and the monitor. Scouring CRFs, finding the errors, finding the correct information, making the corrections, and putting corrective measures in place takes
time, causes frustration, and gets in the way of other activities. Added time on-site
increases the monitor overhead cost. Addressed carefully, the overall timeline should
not be affected, but the potential for delay is there.
Consequences during the data management process
After the CRFs have been submitted to the sponsor for entry into the trial database,
data queries will be generated by the data management team (­figure 8.3).
The consequences now are far more significant. The cycle of generating queries, sending them to the site, waiting for the answers, and re-entering the data is
time-consuming and expensive, and can itself lead to further queries and a repeat of
the cycle if replies are inadequate. There is an enormous waste of time for the investigator and the sponsor, especially if the study is finished and database lock is delayed.
The cost at this stage is considerable for both parties. Query resolution can take
up to 50% of data review time, and it is eight times more costly to correct errors
once the data are in-house. A single data entry error can cost between $60 and $75.
At this stage, the potential for delay is very much increased, especially if, as is often
the case, response to queries is not immediate. At worst, the amount of unusable or
missing data can result in the need for additional patients to be included, with the
added time and cost. The added time that the investigator has to contribute is not
compensated.
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Fill in CRF from source doc.
Send to sponsor
Data logged onto trial database
Data checked
Data cleaned & database closed
Missing, illegible,
inaccurate or
inconsistent data
Archive data and
documents
Statistical analysis
Trial report
Regulatory dossier
Publication
Figure 8.3 The vicious circle of dirty data queries.
Consequences after database lock
This is the stage when the worst consequences are felt. Data that are not available or
are incorrect (since inaccurate data are not always evident and correctable) severely
diminish the power of a study, to the point where the result may be falsely negative
or positive. Patients, or even the data from an entire site, may have to be excluded,
with similar consequences. An entire development program may be delayed, preventing patient access to new treatments and affecting company revenues and stock
prices. For investigators, the result is loss of income in both the short term, as study
fees may be withheld, and the long term, as the opportunity to carry out further
studies is lost.
Dodging Dirty Data
There is no excuse for dirty data in a clinical trial. Although perfection is unattainable, it does not take super-human efforts to make data collection as near to perfect
as possible. What it takes is adherence to professional, commonsense practice. Both
the sponsor and the investigator have a part to play in all the relevant activities,
though for practical reasons, one or the other will have primary responsibility.
Good data collection practices that are primarily the responsibility of the sponsor
1. Making sure the CRF is well designed and usable. A well-designed CRF is the foundation for consistently accurate data entry. The minimum requirements are as
follows:
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• a collaborative effort by the sponsor involving medical, operational, data management, and statistical input, at a minimum;
• input from users (the draft CRF should be sent to a select number of experienced investigators and their staff for review and simple field testing, and the
feedback should be taken into account);
• clear instructions that are visible to the person completing the CRF (the
instructions can be on a facing page or in the body of the form itself; there is
little use, as was the case in one study, in putting the instructions on the other
side of the page that is being filled in);
• simple, with a logical flow;
• limitation of information to what is relevant to the trial (overall, the CRF
reflects the protocol, where the minimum needs should be laid out, but there is
room for some embellishment).
The most common example of collecting unnecessary data concerns concomitant
medications. For those that are not specifically of interest because of their potential
to influence the outcome (e.g., the addition of immunosuppressants in an autoimmune disease trial), all that is needed is the name of the drug and the start and stop
dates. Instead, most CRFs request the dose, frequency, and route of administration,
even though these data are never analyzed, even if they are entered in the database.
The excuse is that the data might be needed retrospectively, which opens up a whole
Pandora’s box if applied to all possible data that could ever be collected. The relevant
data will always be found when really needed, as in serious adverse event forms.
Vigilance over this type of rationalization can simplify all aspects of the trial process.
2. Making site staff familiar with the CRF and showing them how to fill it in.
3. Making sure that the CRF will only be filled in by staff members who understand
the protocol, the disease, and the relevance of the data.
4. Motivating the site staff by providing tangible recognition of their value.
Good data collection practices that are primarily the responsibility
of the investigator
1. Complete the CRF at the time of the visit or immediately after. The longer the
gap between collecting and entering the data, the greater the chances of error or
lost data.
2. Make time for the visit of the patient and all the related activities, including CRF
completion:
• time patient visits so that they do not clash with other activities;
• time patient visits so that they are not too late in the day;
• do not schedule more patients than can be managed in the time available.
3. Avoid unnecessary transcription. If the data are primarily for the clinical trial,
enter them directly in the CRF, even if the data will be recorded somewhere else
as well. The CRF is then the source document.
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4. Make sure that training is provided and that only trained staff who understand
the data are allowed to fill in CRFs.
5. Routinely check the CRFs for errors and omissions.
6. Make corrections accurately to avoid unnecessary queries.
7. Keep the site staff motivated by good management and delegation of responsibility, recognition of work well done, and compensation for any additional work.
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C h apter 9
What about the Customer? The Patient’s
Dilemma
Listen to your patients. They are telling you what you need to know.
—After Sir William Osler, founding physician at Johns Hopkins Hospital
Introduction
Apparently no one was listening to Sir William. In a study carried out 80 years after
Osler’s exhortation, physicians interrupted patients, on average, after 18 seconds
(H. Beckman and R. Frankel, 1984).
It is common to take for granted the very people who are essential for our continued paid employment and the success of our endeavors, namely our customers. For
example, some airline staff refer to passengers as “self-loading freight” or SLF (www.
pprune.org), which, though mildly amusing and certainly accurate, is hardly indicative of a warm and friendly service-focused attitude. Attitudes in the pharmaceutical
business are no different. Throughout the development and marketing cycles, the
emphasis is primarily on satisfying intermediaries such as regulators, opinion leaders, prescribers, and insurers. Important though these intermediaries may be, they
are not the customers. Patients are the sole customers. Only patients pay for their
drugs (whether directly or through insurance or taxation) and only patients consume pharmaceutical products and experience the benefits and adverse effects. Only
patients decide whether or not to continue taking a drug. Put simply, if there were no
patients, there would be no pharmaceutical industry.
Sir William Osler was talking in the context of clinical history taking and examination, but his comment applies more broadly. Over the past 10 to 15 years, there
has been slowly increasing recognition that there are virtually no aspects of development, registration, and commercialization of a drug in which listening to the patient
does not improve the outcome. Guidance issued by the FDA (Guidance for Industry,
Patient-Reported Outcome Measures: Use in Medical Product Development to
Support Labeling Claims, U.S. Department of Health and Human Services, Food and
Drug Administration, December 2009) has gone a long way in helping to redirect and
focus the industry. The implications are broad and go beyond the traditional areas
of patient input such as quality of life measures and can significantly influence trial
design, approval, labeling, and reimbursement.
Study design, conduct, and outcome are improved by considering the patient
throughout the process, with emphasis on
• making studies as acceptable to patients as possible without compromising
objectives;
• involving patients in some aspects of study feasibility;
• relying on direct, unfiltered data from the patient when only the patient can provide the data.
Of Patients and Lab Rats
The great thing about working with experimental animals is that you never have
to ask them how they feel about the study and how it is being conducted. On the
surface, it may often appear that sponsors feel the same way about patients, a phenomenon exacerbated by the absence of direct contact between the two. But, unlike
lab rats, patients have a choice.
Of the many factors that motivate patients to take the risks associated with the
trial of a new drug, the two most important are a desire to get some immediate
benefit themselves (better treatment and additional attention) and the hope that
others might benefit later. These positive factors are counterbalanced by fear: fear
of unknown effects, fear of being given a placebo, and fear of disruption and inconvenience. A lot can be done to minimize these negative factors if the patient perspective is given the same consideration, from the design phase of the protocol and
throughout the conduct of the study, as the medical and regulatory aspects.
Tailor the Protocol to the Patient
Look at the protocol from the point of view of the patient. For example:
•
•
•
•
•
Why would anyone want to take part in this study?
Are all the procedures necessary?
Is it essential to carry out the procedures so often?
Can the number of visits be reduced?
Are there too many questionnaires for the patient to complete?
Feasibility of the draft synopsis should then be tested by patients, as well as by
physicians. Disease-specific patient-support groups can provide valuable feedback,
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especially if there has been recent experience in similar studies. Broader and more
general education about study participation (for patients and clinical trialists alike)
is the specific objective of the Center for Information and Study on Clinical Research
Participation (CISCRP). The CISCRP website (ciscrp.org) contains a wealth of knowledge about patient attitudes toward clinical trials, their likes and dislikes, and pointers for good practice.
Make Sure Patients Are Properly Informed about What
They Are Getting Into
The patient will probably first hear about specific details of a trial from the investigating physician. So the first priority is to make sure that all potential investigators
(and referring physicians) are well motivated and informed and are supplied with all
the information that a patient may ask about. Often, the investigator is not the best
person to allay fears or answer the practical questions of a patient; the best person
might be another patient who is either in the same study or has been in previous
studies. Part of trial planning is to make investigators aware of this and put them in
touch with such patients or their support groups.
The next thing that usually happens is that the patient is asked to read and sign an
informed consent form. Unfortunately, all too often the result is uninformed consent
or confused consent; in an effort to provide all relevant information, the document
becomes unnecessarily long, convoluted, confusing, and ultimately uninformative
and counterproductive. Efforts over the years to introduce plain, clear language in
the writing of informed consents is beginning to bear fruit, but the ultimate test is
that it should be completely understandable to anyone who might be interested in
volunteering for a study. Testing the draft consent form on a random cross-section
of patients (not a fixed panel) is the only certain way to know what is being absorbed
and understood. Standard wording for generic or commonly used sections can be
reused, and several examples are available online.
A Pampered Patient Is a Motivated Patient
The main challenge once the patient has been enrolled is to provide all the support
needed to keep the patient in the study. In fact, far from pampering the patient, these
support measures represent nothing more than the provision of basic needs to which
the patients are entitled. These are some fundamental principles to keep in mind:
• This can only be managed through the site, so that a agreement with, and motivation of, site staff is a prerequisite.
• Participation in a study should not cost the patient any money.
• Disruption to the life of the patient should be kept to the absolute, unavoidable
minimum.
• Patients should be informed about the progress of the trial.
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All this is self-evident, but it is rare for all of these aspects to be planned in detail,
down to the needs of individual patients.
Provide the Necessary Support for the Patient
All of the means of patient support that the sponsor intends to provide (some
examples of which are given below) should be agreed to in advance with each site.
Frequently, investigators have their own ideas about how to proceed, not all of
which are helpful. An example of an unhelpful approach is the investigator who
would give patients only a fixed (low) sum to cover travel expenses, irrespective
of the actual cost to the patient. The reasoning was that patients should not be
paid for taking part in a trial. Not only did fewer patients take part as a result,
but those who did were disgruntled and blamed the sponsor. The most trivial
aspects should be covered (e.g., when patients are to be reimbursed through the
site, fundamental details about how to prove an expense (receipts are not always
available), what will be reimbursed, where the cash is kept, etc.) and be included
in the contract.
Site staff are unlikely to be a motivating and informative force unless they are
well motivated and informed themselves. The most important people are those who
have the most contact with the patients and do most of the work, not necessarily the
investigators. It is very easy to make people feel appreciated, and the key element is
to always remember to do it.
Patients Should Not Fund Studies
Patients should not have to pay to be in a study, though frequently they do, and
sponsors take it for granted. Some of the ways in which patients pay are less obvious
than others, and many costs are not reimbursed.
• Fares. This is self-evident. All fares, including taxi fares (why should a patient
waste time standing in the cold and rain or the heat and crowds waiting for public
transport, often having to change en route, in order to save money for a sponsor?)
must be reimbursed. When no receipts are available for a mode of transport, an
appropriate alternative way of making claims must be agreed on.
• Meals. Timing of clinic visits may disrupt mealtimes, so that patients may be
obliged to eat while en route or at the clinic. These are valid expenses.
• Childcare. This should be offered and paid for as a matter of course.
• Travel companion. If a patient needs someone to accompany them on clinic visits
(children, elderly, or frail patients), the expenses of the companion should also be
reimbursed. It may be necessary to pay someone to accompany a patient.
• Overnight accommodation. This may be needed for patients (and companions or
children) traveling far, especially when transportation is erratic. One example of
a pragmatic solution for a patient in India who had to travel over 200 miles each
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way once a week for a year to participate in a study was to allow her to sleep overnight in the hospital.*
Minimize Disruption
Some disruption is inevitable, especially if the clinic visits for the trial do not coincide with the visits a patient would routinely make. Most of the many types of
trial-related disruptions can be minimized with a bit of forethought.
Scheduling Clinic Visits to Coincide with the Needs of the Patient
This is not always easy, because the needs of the site staff are also important, and
clinics hate to change their routines. Not addressing the issue is a certain way not
to solve it, however. Often, it is possible to accommodate at least some patients by
scheduling visits before work, after work, during breaks, or on weekends.
Provide Full Instructions and Equipment for Anything the Patient
Has to Do at Home
That goes without saying, of course, but even experienced trialists can overlook the
obvious. In a study in which the primary endpoint depended on 24-hour urine collections to be done at home, some patients were initially provided with just one 500ml
bottle. The volumes provided were therefore remarkably consistent, though some
patients improvised and filled all manner of containers, which they carried around
as discreetly as possible to avoid embarrassment. The sponsor and the investigator
each thought the other was taking care of this, and useful data were lost before the
mistake was corrected. More important, patients were unnecessarily confused and
discomfited.
Take the Clinic to the Patient
Many visits are for routine follow-up; this can just as easily be carried out by visiting nurses at the patients’ homes as in the clinic. The added advantage is flexibility. The visit can occur at a time convenient to the patient or can be made at short
notice if information or blood needs to be collected immediately after an acute event.
Evaluation at home can prevent an unnecessary clinic visit, or it can prompt an
unscheduled visit if one is needed.
* An unexpected consequence of this, but a wonderful example of the type of convoluted
thinking that mires drug development, was the (very short-lived) decision by a safety officer to report each overnight stay as a serious adverse event.
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Keep the Study Volunteers Informed
Most people like to know what is going on, so why not tell them? In longer-term
studies, newsletters with details of how the study is progressing, stories or input
from volunteers, disease-related information, and general stories of interest contribute to a feeling of being part of something. Short-term studies may not lend
themselves to this, but at the end of any study, a general outline of the results brings
a sense of fulfillment and conclusion. It is always important to check whether or
not some of the information provided needs ethics committee approval.
Straight from the Horse’s Mouth
Getting information from the source is obviously the best way to ensure accuracy.
Despite this, the clinical trial process tends to favor filtering all information through
the investigator. This is not always the best way to get accurate data, but information
derived straight from the patient is not always accurate either. Sources and methods
of data collection need to be chosen judiciously.
Doctor Knows Best?
Though all data in clinical trials are derived from patients, if not always directly, the
emphasis tends to be on measures of objective or hard endpoints and on the opinion
of the investigator, rather than on the opinion of the patient. The argument is that
the opinion of patients is subjective and hard to quantify, while hard endpoints are
measurable and consistent, and of course, the physician knows the patients best.
In fact, the validity of most so-called hard endpoints is as subject to interpretation;
environmental, emotional, or physiological circumstances; technical ability; and
human and mechanical error as any other type of endpoint. Most notoriously inaccurate of all are physician assessments of how patients feel.
Physicians downgrade the severity of symptoms, have a low agreement rate with
patients if effects are subjective, and may even miss events altogether. This results in
the often gross underreporting (and undertreating) of, for example, adverse symptoms associated with cancer, such as pain (P. Mäntyselkä, E. Kumpusalo, R. Ahonen
et al., 2001), nausea, vomiting, and diarrhea (E. Basch, 2010).
The consequence in clinical trials is that adverse events might be seriously underestimated, leading to misleading labeling. This example illustrates the point that when
information can only be given by the patient, it is important not to filter, reinterpret,
and distort it, but to collect it in as objective and reproducible a manner as possible.
Patient Diaries: Not Worth the Paper
One aspect of patient-reported data deserves special emphasis, however, and that is
the use of diaries. When the trial’s primary endpoint depends entirely on the opinion
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of the patient (e.g., the absence or presence of pain and its severity) or can only be
realistically documented by the patient (e.g., the frequency and volume of micturition), the validity of the study rests on the reliability of the data. This in turn rests
on the method of data collection, but this aspect is frequently overlooked. In order
to be reliable, data need to be, at the very least,
•
•
•
•
legible;
accurate;
collected at the time of the event;
auditable.
Paper diaries cannot guarantee any of these, as illustrated by the development
of tolterodine for the treatment of overactive bladder in the 1990s. The studies
depended on patients recording daily frequency of micturition, number of incontinence episodes, and volume of urine per micturition on paper diary cards. One striking feature of the trials was the variability of the efficacy data in studies with similar
populations and designs, so that in some instances, significant improvements compared with placebo observed in one study were not observed in another.
At the time, no correlation was made between this observation and the condition
of the diary cards, which was disturbing from both aesthetic and content perspectives. A lot of subsequent research has identified the cause, which in retrospect is
self-evident. The most disturbing data, from a double-blind study comparing electronic with paper diaries, showed how completely unreliable paper diaries can be
(A. A. Stone, S. Shiffman, J. E. Schwartz et al., 2002).
The study lasted 21 days, during which time patients had to enter data at fixed
times (with a 30-minute window) three times a day. The reported compliance for
the paper diary was 90%, while the actual compliance was 11%. Compliance for the
electronic diary was 94%. In addition, data were “hoarded”; the paper diary was
unopened on 32% of days (reported compliance 92%), with 75% of patients hoarding for at least one day, and 50% of patients filling in their diaries in advance.
Despite being completely discredited (V. Arnera, 2009) paper diaries continue to
be used, with the subsequent loss of power and probability of a type II error. A common excuse for not using electronic diaries is that they are hard for some people
to understand and use and are therefore disliked by patients, especially the elderly.
This has been shown to be a false premise in a number of studies (B. Tiplady, G. K.
Crompton, M. H. Dewar et al., 1997; B. Tiplady, K. Kirste Goodman, G. Cummings
et al., 2010). In the study by Tiplady et al. in 1997, the majority of patients preferred the electronic diary, while nearly a quarter had no preference, and only 18%
preferred paper. Age, gender, and familiarity with technology did not influence
preference. Subsequent studies support these findings. The reason is that carefully
designed screen pages are simpler, easier to understand, and provide a more logical
flow than paper diaries.
The other common excuses are that use of electronic diaries is expensive, takes
time to set up, and is subject to programming errors. As discussed earlier, intelligent planning allows plenty of time to set up and validate the diaries, a process no
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different from setting up any form of electronic data capture. The expense relative
to paper is insignificant. The resultant increase in power means that fewer patients
are needed, and the increased reliability of the data reduces the chance of false negative or equivocal results, which could sink an entire development program. A small
investment at the beginning can bring incalculable rewards later.
Finally, only data from electronic diaries are auditable and have any scientific or
regulatory credibility; any argument for the use of paper diaries is now untenable.
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PART FIVE
And Another Thing. . .
Meetings and presentations may not seem central to the issues of drug development,
but having spent a significant portion of my academic and industry life in interminable meetings and presentations whose only purpose seemed to be to waste my time
(and during which I no doubt wasted other people’s time) when I could have been
doing something useful, I am sure that others must have endured the same experience. I eventually discovered that it need not be like that, and that meetings and
presentations could be effective in making drug development efficient, educational,
and fun. Here is what I learned.
C h apter 1 0
About Time: Making Meetings Matter
A committee is a group that keeps minutes and loses hours.
—Milton Berle, comedian and actor
Objective
The objective is to ensure that meetings are both efficient* and effective.† It is possible to be efficient without being effective and vice-versa.
Introduction
Most people acknowledge that meetings, especially formal, routine, scheduled meetings, waste more time than any other business activity. Time is wasted for two main
reasons: redundancy and inefficiency. Often, meetings substitute random motion for
useful activity, serving no more purpose than to mask indecision by deferring and
diluting the decision-making process. Even when there is a genuine need for a meeting, time during the meeting is often wasted because of poor preparation, inappropriate attendance, unprofessional meeting behavior, and lack of follow-up. Pithy sayings,
some centuries old, denigrating the value of committees and meetings, underline the
ubiquity of the problem. And yet, meetings continue to be held and probably always
will be, so it is as well to try and make them as efficient and effective as possible.
The responsibility of every attendee for making a meeting as efficient and effective as possible is rarely considered or practiced. The way in which individuals behave
in meetings is not only the major cause of time-wasting and inefficiency, but also
* Performing or functioning in the best possible manner with the least waste of time and
effort.
†
Producing the intended or expected result.
provides unexpected insights into how apparently responsible people think. So what
if I arrive late, I haven’t read the briefing material, I don’t listen attentively, I answer
my phone, I read my e-mails, and send text messages? I may join in endless discussions on subjects about which I know nothing, chat with the person seated next to
me, take too long to present my section, and leave early, but who cares? After all, isn’t
the chairperson responsible for running the meeting?
This section specifically addresses the typical, common, routine meetings related
to drug development, at whatever the hierarchical level, in which data are presented
and strategic and operational decisions are made. However, most of the principles
described apply equally to most types of meetings.
Before the Meeting
Good planning and preparation are the foundation for efficient meetings. In recognition of this, most large companies have dedicated meeting planners and managers (though sometimes, to justify the role, the result is that planning and managing
meetings becomes the end in itself), but small companies do not have this luxury,
so that extra motivation and effort on the part of already busy people are needed.
Consider the Need for a Meeting
This is deliberately ambiguous. On the one hand, the need to hold a scheduled meeting
should always be questioned. Just because it is routine and expected does not mean that
this particular meeting needs to take place. On the other hand, what if there is a need for a
meeting, but the date for the next formal meeting is days, weeks, or even months ahead?
The importance or urgency of the need for a meeting should determine the timing.
A fundamental point to remember is this: A process that is entirely dependent for a
decision on a meeting that occurs only at a fixed interval is, by definition, mindless,
inefficient, and a waste of time. The key words are entirely dependent. Many decisions
can wait; the problem arises when there is no alternative to help in making urgent or
important decisions earlier.
Schedule the Meetings Well in Advance
It is surprising that there are still people who try to organize routine meetings as
they go along, constantly proposing different dates and upsetting everyone’s schedules while expressing surprise that people are not free to attend. Optimally, all
companies, whatever their size, should have some sort of corporate calendar that is
visible to all and carefully managed, listing all the routine meetings for at least a year
in advance. This ensures that
• there are no clashes between meetings;
• everyone is informed well in advance;
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• related meetings can be arranged;
• other activities can be planned to not interfere;
• there is absolutely no excuse for not being available.
Make the Agenda Issue-Specific
The number of standing items is best kept to a minimum to avoid discussions occurring by rote. Going through a routine, tedious round of updates function by function
may give everyone an overview, but it can be incredibly time-consuming and lead to
innumerable digressions that divert from more important discussions.
The best use of time is to discuss data or issues of current importance, or
with strategic or tactical implications, affecting some or all of the functions
represented.
A well-written agenda is a template for the minutes that will follow and may
include some of these generic topics:
• review of the minutes and actions of the previous meeting, including any decisions made in the interim;
• update on continuing issues with emphasis on their consequences and resolution;
• new issues to be addressed with
o a clear description of the issue;
o the reason for bringing it to the meeting (information, resolution, etc.);
o the expected outcome;
o the person responsible for the item;
• presentation of new data;
• (very) brief update from each function;
• any other business;
• review of decisions and actions with clear indication of who is accountable and
the date of resolution.
Tailor the Length of the Meeting to the Agenda (and Not the Other
Way Around)
Since meetings are scheduled before the agenda is known, a standard, fixed amount
of time is allocated, usually in multiples of an hour. There is then a tendency to fill
that time, irrespective of whether it is needed or not. Therefore, sensibly tailoring
the length of the meeting to the agenda can not only save time but can also help
people focus on what is essential.
Allocating time limits to each topic is a common ploy to try to make sure that all
items on the agenda are addressed in the available time, but the times allocated are
necessarily arbitrary, restrictive, and usually ignored. Common sense, self-discipline,
and adequate preparation are probably better alternatives.
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If properly planned and managed, it is rarely necessary for a meeting to run over its
allotted time. Above all, flexibility and pragmatism are key because the overriding objective
is not that a meeting should finish in any given time, but that it should achieve its aims.
Who Should Be There
Company culture and resource availability play a significant role in defining committee and team membership, and in determining who else attends meetings. Most
development-related meetings are attended by a specific, delegated, multifunctional,
representative group of people with a defined function. In some instances, membership of the group is limited to a small core, to which others are invited as and when
necessary, while in others, membership is much broader and includes all functions
all the time. In small companies, there is little or no choice, and almost everyone is a
member of every team and committee.
Irrespective of culture or company size, there are some overriding factors worth
considering in determining the best attendees for an effective meeting. For brevity,
the term “team” is defined as all permanent members of a team or committee routinely attending and running a meeting.
• No one should attend unless they have
o the necessary knowledge and experience;
o something to contribute;
o full accountability;
o the motivation to prepare effectively;
o the ability to communicate.
• Equally, no one should attend unless they have the ability and authority to make
all decisions within the assigned responsibilities of the team without having to
get endorsement from higher up, and with the knowledge that they will be supported in the decisions they make. This helps to ensure that decisions are not
deferred or rediscussed.
• Seniority alone is not a valid reason for being on a team.
• Meetings are not a spectator sport (unless the meeting is called specifically to
present information and for no other reason). Those who regularly attend meetings “to keep informed” and who don’t say anything, a practice occasionally
encouraged in some companies, are often held up as being solid, dependable, and
praiseworthy. In fact, they clearly don’t have any worthwhile responsibilities and
are just wasting company time and money.
• All appointed team members should attend all meetings. Other than in an emergency, there is no excuse for nonattendance.
• Each member should have a named deputy in case of emergency. The deputy
should ideally have the same decision-making power, though it is often difficult
to find experienced backup staff in smaller companies.
• Keeping ad hoc attendees (who are invited for a specific topic) captive at meetings
while other things are discussed or insisting on the attendance of someone just to
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And Another Thing . . .
provide support (or for any other nonproductive reason) are practices as counterproductive as nonattendance of permanent team members.
• The best meeting is always one in which everyone is in the same room, especially if
there are disagreements or difficult decisions to make. Pragmatism often requires
other alternatives, such as video or teleconferencing to include participants from
other sites or countries. The latter should only be an option when there are no
video-conference facilities or in case of ad-hoc meetings, as routine meetings
should be planned well in advance precisely to ensure no double booking.
Help Attendees to Prepare for the Meeting
A lot of time at meetings is taken up by presentations, explanations, and updates
that could as well be read beforehand. On the other hand, it is rare to find anyone
who conscientiously reads material provided in preparation for meetings. Here are
some suggestions for striking the right balance:
• Keep everything short and avoid the impulse to write a thesis on every topic.
• Routine updates from each function should not need more than a sentence or
two. If things are going as planned, there is no need to say more. If there are
issues, they will be addressed specifically.
• Summaries of issues to be discussed, with possible solutions or outcomes, avoid
the need for lengthy presentations.
• The same applies to new data.
• Pre-meeting discussions between those affected by issues or data promote alignment
or allow opposing views to be formulated before, rather than during, the meeting.
Think Carefully about Having Meetings to Prepare for Meetings
There is an argument that having a pre-meeting meeting to prepare for a meeting
improves the conduct of the meeting. Although there are times when careful preparation and rehearsal are important (meetings with regulatory authorities are a good
example), the reason is usually that they are played by unfamiliar, external rules, are
far from routine, and represent one of few chances to present an argument. In most
cases, however, it is difficult to accept that having two meetings in place of one is a
more efficient use of time than careful individual preparation and ad hoc discussion
in keeping with the suggestions made above.
During the Meeting
Introduction
Meeting procedure is fairly standard, and a generic agenda could probably be used in
most companies. Unfortunately, due entirely to the vagaries of human nature, what
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actually happens often does not reflect the relative importance of the agenda topics
or the time available for each. Avoiding some common pitfalls can radically improve
agenda management.
The first prerequisite for managing the agenda effectively is an experienced and
objective person to chair the meeting.
The second prerequisite is that everybody at the meeting should be equally responsible and accountable for managing the agenda. This prerequisite is rarely fulfilled.
Do Not Rerun Previous Meeting when Reviewing Minutes and Actions
Actions either have or have not been carried out. There should be no surprise at the
meeting because, in a professional organization,
• the chairperson and relevant team members should have been notified as soon as
it was known that an agreed action would not be completed on time, with details
of the consequences and the revised timeline;
• the chairperson and relevant team members should have been notified when an
agreed-on action was completed.
Instead, what usually happens is the “let’s wait for the meeting” syndrome, with a
consequent plodding through the minutes and actions one by one and discussions
that virtually rehash the previous meeting. What should take a few minutes threatens to take over the whole meeting.
Let Presentations Run their Course without Interruption
Even with good preparatory material, the need for brief presentations of new data
or explanations of issues remains essential. One foolproof way to ensure that a presentation ceases to be brief and effective is to interrupt and ask questions before the
presentation is finished. Frequently, the presenter will even invite interruptions, in
the belief that this is more collegiate. Unless the presentation is didactic in nature,
where interaction is an important component, the two consequences of an interruption are that
1. the presenter will say “I am just coming to that” but may digress and answer the
question immediately anyway;
2. others will join in asking more and more questions, frequently leading to meandering digressions, with the presenter unable to get a word in.
The result is that a presentation that should have taken a few minutes frequently has
to be rushed at the end as time runs out.
To avoid this common occurrence, it is best if all questions are asked at the end
(unless a given slide or statement is incomprehensible, in which case clarification is
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And Another Thing . . .
important). In this way, many interim questions will have been answered, the points
to be made will have been made coherently, and the remaining time can be devoted
to questions and discussion, rather than to rushing to finish or having to truncate
the presentation.
Manage Issues, But Don’t Necessarily Try to Solve Them
Issue resolution should only take place among those who are individually and collectively qualified to resolve the issue, at times and places set aside specifically for
that purpose. The purpose of the development team or committee is to understand
the nature of an issue, to ensure that it is being resolved, and to manage the consequences, but not to resolve the issue during routine meetings.
Discussion at meetings is often more time-consuming and convoluted than
necessary because of failure to comply with some simple principles when an issue
arises:
•
•
•
•
immediately inform all who need to know;
start the resolution process;
provide a briefing summary before the meeting;
at the meeting, present the issue, the possible options and the preferred option
at the very beginning, followed by the reasoning. The alternative of going through
all the reasoning and leaving the preferred option to the end, like the dénouement
in a thriller, invites uninformed digression and defers the important discussion,
namely the merits and consequences of the preferred and the alternative options.
Progress Updates Should Not Impede the Progress of the Meeting
Going through progress reports function by function is a staple of multidisciplinary
meetings. It can take a significant amount of time without achieving any purpose
except to allow people to speak. So what is the point? Would any sensible person wait
for a meeting to inform people about something urgent? And if all is going according
to plan, why say anything?
The value of the progress update is in alerting people to potential problems (most
of which will already be resolved) and in following up on problems that are unresolved. A written briefing paragraph listing these aspects of the progress (or lack of
it) of a given function provides the necessary information and is a good basis for a
focused discussion, should any discussion be needed.
Make Sure that the Meeting Is Not Simply Displacement Activity
Unless there is formal agreement on the actions that were decided during the
meeting, and by whom and by when they will be carried out, there will almost
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certainly be no follow-up at all. Simply sending out minutes and hoping that
people will agree with the actions assigned to them represents the triumph of
fantasy over reality. A formal review of decisions and actions is therefore essential at the end of every meeting, and these need to be reflected accurately in the
minutes.
N.B.: The common practice of informing people who were not at the meeting of
actions they have been delegated only via minutes is both inefficient and ineffective. Actions should be discussed and agreed on face to face (even if often there is
no choice but to agree). The responsibility for doing this is given to someone at the
meeting, especially if they are the line manager of the person for whom the action
is intended.
“Sorry I’m late, but . . .”—Starting and Finishing on Time
Funny how it’s almost always the same people who are late, whether at the beginning
of a meeting or returning from a break. Minding time is not an obsession or a fetish
or a theoretical virtue; it is important because not paying attention to time is a pernicious form of selfishness that impinges cumulatively on the time and effectiveness of
everybody, and for which there is rarely a rational excuse.
These are just a few of the consequences of poor time management:
• the meeting finishes late, so that subsequent meetings start late and there is less
time for meeting attendees to attend to their routine activities;
• ad hoc attendees who are only invited for a specific part of the meeting sit and
wait (and wait) for their moment, which might be compressed or even canceled,
and their own schedules are always disrupted;
• the meeting is truncated in order to keep to time, so that one or more topics may
be deferred or rushed;
• deferred topics are usually added to the agenda for the next meeting, wasting
time and cluttering the new agenda;
• rushed topics may result in poor decisions or may need to be rediscussed.
Meetings run late for many reasons, not simply because a few people turn up late:
• poor preparation, so that there are unnecessary questions and digressions;
• presentations that go on and on because the presenter has not considered how
long it will take;
• possibly relevant but unnecessarily long-winded questions, answers, and
comments;
• interruptions and comments by those who have nothing to contribute to a subject (see below under “Talking”);
• attempts to resolve issues better dealt with by others outside the meeting;
• inability to conclude a topic or make a decision without endless repetitive
discussions.
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What can be done about it? These, in order, are the two most important elements:
1. Establish a culture in which meeting behavior is defined, understood, and
accepted by everybody. Peer behavior and pressure are more effective than anything else in maintaining standards.
2. The chairperson of the meeting should be experienced and professional. Any
group of people, however disciplined, needs someone to lead them, keep discussions focused, and ensure that decisions are made.
Other things that can be done:
•
•
•
•
•
•
•
plan well in advance and keep everyone informed;
prepare useful briefing documents and a sensible agenda;
ensure the right attendees;
eliminate the behaviors described below;
start the meeting at the appointed time, irrespective of who is absent;
do not repeat things for those who arrive late;
use shock tactics (judiciously) on persistent offenders. Locking the door at the
beginning of a meeting and stopping punctually at the scheduled finishing time,
whoever is speaking, are approaches that send an unambiguous message. One
very senior manager of a major pharmaceutical company allegedly walked out of
a meeting that was running late by taking the quickest available route to the door,
across the meeting room table.
“Just one last thing . . .”—Talking a Meeting to Death
Wise men talk because they have something to say; fools because they have to say something.
—Plato, Greek philosopher
Before saying anything, it is worth thinking about the consequences. Not doing so
can disrupt and prolong meetings, as the following examples illustrate.
Everyone has an opinion
People with an irresistible urge to take part in every discussion (whether they have
anything relevant to say or not) are a major reason why meetings become inefficient
and ineffective, especially when it comes to making decisions. Contributions to a
discussion need not require specialized knowledge of the subject in question; objective views can often expose inconsistencies or lead to alternative explanations or
conclusions. The problem is the difficulty in filtering out the uninformed posturing
from the well-thought-out, logical comment.
The most important meeting discipline is knowing when to say nothing, and the most
effective chairperson is one who keeps a tight rein on those who are unaware of this fact.
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“What was that question again?”
People ask questions because they want an answer. There are, broadly, two types of
questions:
• those to which the answer is “yes” or “no,” with or without qualification (“Will the
trial start on time?”);
• those that ask for information to which the answer is not “yes” or “no” (“How did
this happen?” or “What happened?”).
Answers are not always straightforward, but there are some people to whom posing
any question is a decision instantly regretted, as simple answers become convoluted;
complicated answers become incomprehensible; and whatever the answer, it takes
forever to be given. It need not be like that if some simple principles are applied.
Listen to and then answer the question
This is so blindingly obvious that it should be a waste of space to mention it. Yet
it is surprising how much analysis, paranoia, and rationalization a simple question can provoke, resulting in answers that bear no relationship to the question. At
other times, poor answers are simply a reflection of how inept some people are in
answering.
There are circumstances, as in politics or interviews with the media, when the
objectives of the questioner may have nothing to do with getting a factual response,
and the game is to deliver only your own message. Mrs. Thatcher, when prime minister, famously replied to an interviewer, “That is not the right question. The right
question is . . .” and she then proceeded to answer her own question.
In the context of the type of meeting that is the subject of this chapter, however,
the purpose of which is to make and oversee strategic and operational plans, identify
issues, and make decisions, only clear, factual answers are acceptable.
Start with the answer, not the explanation
If the answer is “yes” or “no,” say so straightaway. All too frequently, the answer to
a question is a long, rambling explanation, sometimes as a defensive measure, often
because no thought has been given to the answer, and always without consideration
for the impediment to progress and for the time wasted.
Often, answers are not clear-cut, and it is important to allow the answer to be
qualified, but by starting with either “yes” or “no,” the context and relevance of the
qualification are easier to understand. For the same reason, when there is no “yes/
no” answer, a succinct one-sentence summary of the relevant information should
precede the explanation.
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If you don’t know the answer, say so immediately
Trying to cover up only makes things worse. If an immediate answer is essential, go
and get it. If not, let everyone know how soon the answer will be available, and make
sure that it happens.
We’ll just talk among ourselves
Often a topic that arises is the concern of only two or three attendees, who then
proceed to talk about the subject at length while everyone else looks on impatiently.
These separate meetings are usually not the best use of everyone’s time, even if
the topic is important. Unless immediate resolution is essential, the most effective
course is to stop and arrange for the discussion to continue later. Unfortunately, the
participants in these breakaway meetings are rarely aware of what they are doing, so
firm chairing of the meeting is needed.
Interrupt me if you can
Most meetings have at least one circular breather who starts to talk at great and
unnecessary length and is then impossible to interrupt because he or she never
pauses for breath and is impervious to physical signs. This is the one person to whom
one never willingly addresses a question. The staggering lack of insight associated
with this behavior can only be addressed by very firm management. This is necessary because it takes only one person like this to interrupt the flow of a discussion,
introduce obfuscation, waste time, and frustrate participants.
“Can we just go back a minute?”—the never-ending discussion
The discussion has ended, a decision has been reached, relevant actions have been
allocated, and the chairperson introduces the next item on the agenda. At this point,
someone says, “Can we just go back a minute?”
This is a not-uncommon occurrence, to which the answer should always be “No.”
It is generally a ploy by those who disagree with a decision, who are uncomfortable
in making decisions, or who simply haven’t been listening. Reopening a discussion
rarely results in a better decision and always results in wasted time.
Let’s talk about this instead
Taking the line of least resistance is a normal human trait expressed in meetings
by unwittingly digressing whenever possible. More sinister is when the focus of a
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meeting is disrupted by someone who deliberately introduces an irrelevant topic.
A good illustration of this behavior occurred at a meeting that was convened to
address a very urgent issue that threatened to destroy not only a project but also
the company. The only, and clearly stated, objective of the meeting was to find
possible solutions and assign actions. Before the discussion could begin, however, a senior manager insisted that first he wanted to know why the problem
arose and who was responsible, and so he wasted precious time and resolved
nothing.
As with everything discussed in this chapter, the role of all participants in curbing
any kind of digression is the most important factor.
After the Meeting
Do Not Turn Writing the Minutes into a Literary and Bureaucratic
Marathon
The purpose of minutes is to inform people of decisions that have been made and
to list actions, with associated accountabilities and timelines. The value of meeting
minutes diminishes very rapidly in direct proportion to their length and the time
it takes to circulate them. Ideally, minutes should be issued on the same day as the
meeting, or the following morning at the latest.
Most company meeting minutes are not intended as works of literature and are
not likely to spark international incidents, as might the minutes of a U.N. meeting,
with the potential for misunderstanding, cultural insensitivity, and political machination. It is therefore remarkable how much useless detail is often included, how
many revisions minutes can go through, and the complicated hierarchical review and
signing-off procedure that is often in place.
The ideal minutes, meaning ones that will be read and acted upon, should not
be more than two or three pages in length and should list decisions and agreed-on
actions, with the names of those responsible for each action and the date of completion. Unless there is a radical change in strategy or significant budgetary implications, there is rarely a need to include details of how decisions were reached.
Courtesy and the Conference Call
The ability to include participants by telephone, though not the optimal way to conduct a meeting, has allowed for broader and more flexible participation. Remote
participation will continue to increase as working from home, or telecommuting,
becomes more widespread. However, the lack of actual participants in a room and
the lack of formal constraints experienced by a remote participant can get in the way
of effective participation in the absence of some agreed-to practices. These are often
taken for granted but rarely observed.
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Meeting Room Practices
• Make sure that the conference phone works and the microphone is positioned so
that all participants in a room are audible to those who are calling in. Use multiple
microphones if necessary. One inaudible participant in effect negates the value of
a meeting.
• Introduce everyone in the room and each of the remote participants, making sure
that everyone can hear everyone else.
• Remote participants might be in a different time zone, so arrange the agenda to
accommodate them accordingly.
• Speak only when invited to do so by the chairperson (as should be the case in any
meeting), who introduces each speaker by name. In this way, only one person
should be talking at a time, and everyone knows who it is.
• Include all remote participants, by name, in every discussion so that there is no
need for anyone to interrupt in order to say something, and no one feels left out.
• Nevertheless, listen carefully for someone trying to get a word in, as some elements of spontaneity are useful.
• Remember that foreign languages are even more difficult to understand over the
telephone.
• Describe anything not visible to remote participants, and ensure that everyone is
looking at the same slide or handout.
• Try not to forget that there are remote participants.
• Make sure that remote participants have agreed to decisions and actions arising
from the meeting.
• When closing the meeting, ensure that remote participants are aware of the fact.
Practices for Remote Participation
• Call from a room in which there are no extraneous sounds and where no one will
disturb you.
• Make sure in advance that any call-in number is correct and works.
• Call in on time.
• Call preferably from a land line; if not, be certain that the Internet signal for your
computer or the wireless signal for your mobile phone is strong.
• In the case of routine or prearranged meetings (in other words, most meetings),
do not call while doing other things such as shopping, driving, or looking after
the kids, only a few of the real examples that some have deemed appropriate for a
meeting call.
• Behave as though you are physically present in the meeting room; do not read
e-mail or the newspaper just because you are invisible and your phone is on mute.
• Make it known immediately if you can’t hear clearly.
• Speak only when invited to do so, unless an interruption is urgent or there is no
meeting management at the other end.
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• The circular breather online is the bane of teleconferences. Pause when talking to allow people to interrupt, especially if making a lengthy statement or
presentation.
• If you have to leave the teleconference at any time, make sure that everyone
knows (also when you return). If leaving the meeting early, this should be agreed
to and made known beforehand.
Decisions, Decisions
When Is a Decision Not a Decision?
A decision is not a decision when it is immediately revisited without good reason.
The practice of discussing decisions again after a meeting is over is rarely for a good
reason, but usually motivated by disagreement, politics, or fear of commitment. The
most valid reason for reviewing a decision is if relevant new information that was
not taken into account before for whatever reason (because it was unknown, suppressed, or did not exist, for example) now becomes available.
Decisions are rarely perfect, and it is unlikely that the perfect decision exists (except
retrospectively). However, the most successful organizations are those that make sensible decisions in which benefits and risks are well defined and then act on them, with
the knowledge that modifications might be needed later. Sticking to a decision does
not imply inflexibility any more than revisiting decisions is a sign of flexibility.
“So we’re all in agreement?”—Confusing Decision-Making with
Democracy
Agreement is good, provided that the agreement is to support a decision, as opposed
to compromising a decision so that everyone agrees with it.
The invitation to take part in a meeting and the freedom to comment are not indications of an equal voice in the making of all decisions. There is often an assumption that
this is the case, supported in some instances by the local culture. I have been at meetings where the decisions were agreed to or rejected by popular vote, even though each
time, most of the people voting knew absolutely nothing about the topic in question.
The whole purpose of having a multidisciplinary group is that there should be
someone experienced to represent each function. In the event that a decision needs
to be made concerning a specific function, the representative for that function
should take the lead in making the decision. While decisions should always be made
with the views and needs of others in mind, the views and needs of others do not
necessarily dictate the best course of action, which is why the discriminatory insight
of the person with the relevant experience is vital.
There are three common ways in which this aspect of decision-making is
undermined.
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The first is when the functional representative either does not have the experience or does not have the authority to make decisions.
The second is when someone (often the chairperson) pulls rank in order to impose
his or her view.
The third, more insidious, way is when everyone suddenly becomes an expert on
the subject in question, and their views are given equal weight. From my experience,
physicians in the industry are notorious for knowing all there is to know about statistics, and everybody (especially CEOs of small biotech companies) knows all about
clinical research.
Ignoring Potentially Useful Discussion Points
Common practice after a presentation or a suggestion is made is for the chairperson
to ask if there are any comments. Several hands shoot up and the chairperson invites
each person to comment in turn, whether or not each subsequent comment has anything to do with the previous one. This practice may seem to be egalitarian in giving
everyone a voice, but it is in itself of little value.
The real value happens if each of the comments is explored to the limit, when the
comment is relevant and exploration to the limit is warranted, before going on to
the next one. Failure to do this can result in important considerations being overlooked. An additional advantage of this process is that, frequently, some of those
who wished to comment will drop out, either because their points have been covered
or they realize that their points are not really relevant.
Key Points
• All attendees are responsible for the good conduct of a meeting, not just the
chairperson.
• Planning is essential:
o determine need for a meeting, whether routine or ad hoc;
o schedule routine meetings well in advance;
o make the agenda issue-specific;
o brief attendees in advance;
o tailor the duration to the needs of the meeting, not vice-versa.
• Make sure the right people are present, taking into account:
o expertise;
o authority to make decisions.
• Concentrate time on the issues and not on the standing items.
• Keep to time and eradicate time-wasting behaviors.
• Say only what needs to be said.
• Agree on sensible conference call policies.
• Make decisions on the basis of informed opinions, and stick to them.
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C h apter 1 1
The Brain-Scrambling, Fit-Inducing,
Mind-Numbing Technicolor Laser Show
Objective
The main objective is to make presentations less painful and more presentable.
Introduction
Presentations are made in order to provide information to an audience in such a way
as to achieve a desired objective, whatever that may be. The objective is unlikely to be
achieved unless the audience
•
•
•
•
wants to listen;
remains interested;
understands;
is convinced.
A natural talent for presenting material effortlessly in an informative, entertaining,
and engrossing way is shared by few, so most of us put disproportionate reliance on
props. The most commonly used props are slides and pointers. Unfortunately, the use
of slides and pointers has almost become an end in itself, often obscuring the message.
As with all the processes described in this book, the aim here is to apply a core of
common sense. This will not address every aspect of the use of slides and pointers or
result in the perfect presentation every time (something even the most comprehensive manuals and training courses rarely achieve). What should result with consistency is more clarity and comprehensibility, and less frustration and confusion, all of
which should serve to keep an audience from losing interest and fiddling with their
cell phones after five minutes.
Slides: The Good, the Bad, and the Incomprehensible
Why use slides? After all, the greatest orators of all time managed to keep audiences spellbound with long recitations (just think of Homer and the Iliad) without
using any props or prompts. Okay, so their audiences didn’t have TV or many other
alternatives for entertainment, but that does not detract from the underlying principle, namely that audiences are generally primarily interested in what the speaker has to
say, not in the props. After all, why else go to a presentation when information is so
widely available today in many forms, especially electronically? The question may be
answered by thinking about the good reasons for using slides.
Some Good (and Not So Good) Reasons for Using Slides
As an aid to memory
This is a common reason for most presenters, especially in situations when there is
new, lengthy, detailed, or complicated information.
Too much detail for audiences to assimilate just by listening
Just as presenters have difficulty remembering detailed information, so audiences
need time and different types of input (visual, as well as auditory) in order to assimilate
new details. While it is rarely acceptable for each slide to contain much detail, the overall presentation may be improved by having several slides covering the salient points.
The concept or information is complicated
This is not necessarily the same thing as being detailed. Again, the idea is not to
have complicated slides, but to use visual representations to explain something
complicated.
Language
In the absence of simultaneous translation, the use of slides is an important factor in
overcoming difficulties with language.
It is unusual for everyone in an audience to speak, as their first language, the
same language as the presenter. Even fluent speakers of a foreign language can have
difficulty understanding presentations, especially if these are riddled with idioms
and spoken quickly with background noise and poor acoustics, combinations and
permutations of which occur all too frequently. For those who are not so fluent,
understanding can be almost impossible. Clearly presented slides left in place long
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[203]
enough to be read and shown with the judicious use of a pointer go a long way to
increasing understanding.
The reverse situation, when the speaker is not fluent in the language of the presentation (usually English in the business world), is one where the use of slides is
essential, not only as an aid to memory but because reading them word for word
might be the only way the speaker can get through the presentation.
Paper copies of slides can be used as handouts
Wanting to have a handout is no reason in itself to use slides in the presentation.
Realistically, however, slides will be copied and used as handouts. Unfortunately, this
form of handout is the most common, the laziest, and the least useful imaginable, so
it is worth considering its value in the first place.
A significant proportion of the slides will be so cryptic or complicated as to be
unintelligible, especially when the presentation fades from memory. Even with copious note-taking, the context, the nuances, and the details will be lost or misinterpreted. In sum, the value of the presentation is minimized by simply using copies of
the slides as handouts.
The optimal handout is one in which the slides are annotated with the key points
or explanations the presenter wishes to make, with cross-references to other slides
if relevant or, best of all, with the slide images embedded in a coherent, flowing text.
For those who want to give handouts (whether annotated or not), positions are
polarized as to whether they should be given out before the presentation or after.
The “before” camp will emphasize
• the need for people to be able to read the slides in their own time (they may not
be clear on the screen, or may not be shown for long enough);
• the value of making notes on the actual copy of the slide;
• the overall increased understanding.
The “after” camp will point out that
• having the copy in hand distracts the audience so that they pay less attention to
the speaker, even if they are following slide by slide;
• there is a tendency to read through the whole handout and then get bored and
give up listening altogether;
• notes can be taken without having to write on the handout.
Since both camps are absolutely correct as far as the points they make go, each presenter has to consider the merits of one approach compared with the other and act
according to their own conclusion.
Once the (inevitable) decision is made to use slides, the next step is to do as little
as possible to diminish their value. In fact, “do as little as possible” is probably the
best advice to give in general.
[204]
And Another Thing . . .
Diminishing the Value of the Slides
There is considerable overlap between these categories.
Give too much information
This is a relatively common occurrence. In this example, the information may not be
particularly complicated, but there is an awful lot of it. If possible, break down information into digestible boluses; if not, ensure that the slide stays up for more than a
moment, and use a laser pointer logically, steadily, and carefully.
Make slides too complicated
This is a close relative of too much information. The same suggestions apply.
Use too many slides
If the definition of a bore is “someone who tells you everything” (apologies to
Voltaire), then there is a tendency in all of us to be a bore when it comes to presentations, when we try to cram too much into an allotted time. Also, there is no accurate
rule of thumb as to how many slides are optimal for a given length of presentation,
as speaking style and slide content will be the determining factors.
Determining the length of a presentation by the number of slides to be shown
diminishes the value of what is being said, and there is no rule about how long one
should talk for each slide. The need to change slides at frequent or predetermined
intervals, as many do in order to maintain interest, merely suggests that there is nothing of interest to hear. The only reliable way to pare the number of slides down to the
essential minimum is by extensive revision and rehearsal in front of others. If necessary, it is always possible to elaborate while presenting and when answering questions.
There are situations when the amount and type of information require numerous
or complicated slides, or both. The ways in which the resulting negative impact on
attention span and motivation can be exacerbated are described below. Suggestions
for improvement follow after.
Make the information too small to read
This phenomenon crops up frequently in presentations of scientific data. A common,
pragmatic (lazy) approach is simply to copy a table of results from a publication onto
a slide. Apart from the fact that the result is usually crooked and fuzzy (not to mention too detailed), the numbers in larger tables are so small that they are impossible to read. Preparing a table with the essential information really doesn’t take that
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long, but if the copy-the-table approach is your favorite, please consider enlarging
the relevant portions first.
Make the slides (and the presentation) in the wrong language
The international language of business is English, or so all native English (and
American) speakers will tell you to justify presenting in English wherever in the
world they may be. The objective of a presentation, however, is not to speak English
(and never mind if no one understands) but to impart information in a way that is
comprehensible, useful, and interesting.
The use of English is certainly justified for a multinational audience, but what
about an audience in which everyone speaks one language and that language is not
English? This is often the case, for example, when presenting to affiliates within a
company or when conducting investigator meetings. It is worth repeating that even
fluent speakers of English as a second language do not necessarily understand presenters whose diction may be unclear, who may speak too fast and colloquially, and
who may be in a venue with less-than-perfect acoustics.
In these situations, translating the slides into the local language and having them
presented by a native speaker (or even just presenting the English slides in the local
language) ensures comprehension, interest, a longer attention span, and an enormous amount of goodwill. It is also much cheaper than simultaneous translation.
Being there to answer questions (in English) makes up for the few drawbacks of having a surrogate speaker, which are more than offset by the advantages.
Use idioms and colloquialisms
Those who make a pig’s ear of their presentations by laying idioms on thickly and
causing audience members to have “deer-in-the-headlights” expressions should be
taken out to the woodshed and taught how to keep a straight bat.
Put another way, always make a conscious effort to use only plain, simple language in slides and when speaking. There are rare exceptions when idioms or colloquialisms can deliberately be used for effect. A colleague of mine has had great
success in encouraging audience participation at the start of a training course by
using the expression “Teach your grandmother to suck eggs” and then (after explaining what it means) asking for an equivalent expression from other countries.
Use every font, color, theme, animation, and sound effect provided by
the slide-producing software
Special effects used sparingly for the right reasons are very effective. A few too many
special effects rapidly become irritating and distracting, and may induce a desire to
cause bodily harm to the presenter.
[206]
And Another Thing . . .
Painful Presentation Perpetrators
The Laser Pointer Warrior
Along with the slide comes the overwhelming urge to point to it. The problem is that
hardly anyone uses a pointer to point; it is most commonly used to slash and parry.
Based on objective observation and analysis carried out while enduring presentations for over 40 years, I have determined the proportion of time that pointing with
lasers is useful (see ­figure 11.1).
Once a laser pointer is available, the person wielding it immediately assumes that
no one can read what is on a slide unless the laser beam is constantly pointing it
out. I sometimes wonder if these presenters are themselves unable to read anything
unless there is someone to wave a laser pointer at their book or computer screen.
Laser beam brandishers come in many shapes and sizes, from the swashbuckling
to the timid, but the following types are the most common, the most irritating, and
the least effective.
The karaoke singer
Perhaps the least offensive of the laser wielders, though nonetheless irritating, is the
karaoke singer, who bounces the laser beam from syllable to syllable while talking,
often out of sync. The hypnotic effect of this approach guarantees that no one will
remember anything when they come to.
The abstract artist or egg whisker
The most annoying and least effective laser wielder falls into this category. With his
or her back to the audience, the presenter ensures that the laser beam is never at
120
100
Time (%)
80
60
40
20
0
Useful
Mind-numbeing
Figure 11.1 Proportion of time when pointing with a laser is useful.
T h e Te c h n i c ol or La s e r S h o w
[207]
rest, covering the slide with broad, colorful sweeps to illustrate general points, then
whisking briskly several times around, over, and in the approximate vicinity of a
number or a word that is suddenly the focus of attention. This approach is a failsafe way of inducing vertigo and nausea, and the preferred approach of the academic
community.
The extrasensory perceptionist
Perhaps as annoying as anyone, but for the opposite reasons from those mentioned
above, is the extrasensory perceptionist. Imagine a complex slide, whether of an MRI
scan of the brain or a complex equation, in which the key detail or trail of logic is not
easy to spot. Just when a steady pointer would be welcome, the presenter decides
that what is obvious to her or him must be obvious to all who are listening, so obvious in fact that the slide must rapidly be replaced by a series of equally incomprehensible slides.
The Mushroom-Grower
Mushroom-growers are those who can only perform in a darkened room, “otherwise
no one can see the slides/the pointer.” This obsession with darkness is perhaps justified if the presentation consists of photographs or slides in which minute detail must
be clear, but not when the presentation is predominantly text, which is usually perfectly readable in daylight using modern projectors. This is a prime example of the
slide becoming the end in itself. The consequence of this unnecessary obsession is
that the audience falls asleep significantly earlier than it would normally have done.
The U-Turner
So keen is the perpetrator to emphasize the slide contents to the audience or, more
likely, so unfamiliar is the perpetrator with the content of the slides, that the only
recourse is to turn and stand with his or her back to the audience while reading and
pointing. U-turners include all of the categories of laser-pointing types mentioned
above, as having to point is a major cause of the condition of U-turning. One advantage of failing to make eye contact with the audience is that their irritation, boredom, and impending comas are not visible to the presenter.
The Proofreader
Once the proofreader gets into stride, not one word, number, symbol, or punctuation mark on a slide goes unmentioned. On the other hand, it is rare that additional
[208]
And Another Thing . . .
information or thoughts are revealed. The sheer agony of reading a slide in 15 seconds and then waiting an eternity for the presenter to finish epitomizes cruel and
unusual punishment.
Less Pain, More Gain
As an average presenter who has at one time or another been guilty of all the sins
listed above, I have found that my messages are more likely to be listened to and
understood if I do the following.
Keep the Slides to a Minimum
The only effective way to do this is to rehearse with critical reviewers who are not
inhibited in compelling the removal of all the wonderful but redundant slides you
have spent hours preparing. Here are some things to consider:
• Focus only on the important messages.
• If there is a mass of data or learning material to present, it may be most effective
to distribute the material in advance so that people can at least have some idea of
the content (few people read everything that is sent in advance).
• Whether or not material is distributed in advance or at the meeting itself,
breaking the presentation into small, discrete, item-related chunks, with frequent short breaks for questions and a rest, helps keep the attention focused.
• If there are is a mass of information that genuinely requires lengthy presentation,
changing speakers for the various segments reduces the monotony.
Tailor the Slides (and the Presentation Style) to the Audience
Simple language without colloquialisms provides the best basis for understanding
in an international setting. To avoid misunderstandings, consider translations and
presentation in the local language, especially if there are important or complicated
details or nuances.
Keep the Slides as Simple as Possible
Perfection is achieved, not when there is nothing more to add, but when there is nothing left
to take away.
—Antoine de Saint-Exupery, poet, writer, and aviator
One of my professors used to say that the perfect slide has only one word on it, but
perhaps that is a bit extreme. Simple slides are more likely to be read and understood,
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[209]
especially by those whose first language is different from the presentation language.
It is also worth remembering the saying about the relative values of pictures and
words. Most important, what is said is more important than what is on the slide.
Know the Topic Intimately and the Key Points by Heart
Fluency (as opposed to slickness) is an important factor in ensuring clarity, maintaining audience interest, and providing credibility. Referring to notes (or occasionally) to the slides is sometimes unavoidable or essential, and it is perfectly acceptable
as long as it doesn’t interrupt the rhythm of the presentation. Reading from a script
is not advisable, except when there is a language difficulty, because usually the result
is a poorly delivered, monotonous drone.
Face the Audience
This is probably as important an aspect of making presentations as any, but it is
frequently ignored. Nothing engages an audience more than making eye contact
with the speaker, and some simple preparation can minimize the amount of time a
speaker spends looking at the slides.
• Always arrange to have a monitor visible from wherever you are speaking. Most
professional venues have such an arrangement, and the computer from which the
slides are being projected can serve the same purpose. This will at least allow you
to know at which slide the audience is currently looking.
• Have legible copies of the slides in hand. Most speakers need to read at least some
of the slides, and often monitors or computer screens are not near enough or
large enough to read. Glancing at a copy of the slide in front of you is infinitely
better than turning to read what is on the screen.
Use a Pointer Judiciously
Some slides necessarily have a lot of information or specific sections to which the
audience’s attention needs to be drawn. Judicious use of a pointer is essential in
these circumstances, but the important word is judicious. Here are some pointers
for pointing:
• Promiscuous use of a pointer does not enhance a presentation.
• Most text does not need to be pointed at; if numbered or bulleted points are being
made, it should be obvious to which one a speaker is referring. If it is not obvious,
then either the slide needs to be recomposed, or the presentation needs to be
rephrased (or both).
[210]
And Another Thing . . .
• Point only when it is essential to focus on one part of a slide (and NOT because the
slide is badly composed or unnecessarily busy and complicated). In these cases:
o keep the pointer absolutely steady on the relevant part of the slide;
o say whatever needs to be said;
o leave the slide in place and point long enough for everyone to see what is being
pointed at and listen to what is being said.
• On more formal occasions, the most effective approach is for someone at the back
of the audience, facing the screen, to do the pointing at the right moments, leaving the speaker free to concentrate on speaking.
Don’t Keep Saying “I’ll come back to this later”
This is a personal bugbear, but one that may be shared by others: when virtually
every statement from a speaker is followed by “I’ll come back to this later,” giving the
impression that he or she will never come to the point and inducing mounting anxiety that there will not be enough time to cover everything. In my experience, many
of the deferred topics are never mentioned again. Unless used sparingly and with
intention to follow through, the phrase introduces an irritating element of incompleteness and lack of fluidity to a presentation.
Key Points
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
The focus of most presentations should be on what is being said, not the slides.
Keep slides uncluttered and contents very simple.
The fewer slides the better; what is said is usually more important than the slide.
Concentrate slides on essential information that can only be imparted visually.
Avoid turning your back to the audience.
Make sure the slides are legible and clear.
Avoid too much gratuitous artistry and animation.
Face the audience.
Be very familiar with what you are talking about and avoid reading a script.
Use monitors and copies of slides for reference so that there is no need to turn
and read the screen.
Do not read every word on every slide.
Avoid colloquialisms and idioms.
Point only when essential and at what is essential.
Keep the pointer steady.
Distribute slides after the presentation; better still, distribute annotated slides or
text in which slides are embedded so that the handout includes the actual talk.
Consider translations when relevant.
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[215]
Index
academics, 61–62
amendments, 70–71
analysis plan, 63, 91
approval process, 90
Arriaga, A. F., 18
Arrowsmith, J., 19–20
authorship, 135–136
baseline assessment, 165
benchmarking, 15–16
bias, deliberate, 11
blame culture, 12–13
bottlenecks, 24
Brown, Grahaem, 83fig, 121fig
case record forms (CRFs), 26, 63, 91,
128–129, 169, 170, 173–175
Center for Information and Study on
Clinical Research Participation
(CISCRP), 178
CenterWatch, 105, 125
Chan, Bernard, 83fig
checklist approach, 18
Checklist Manifesto, The (Gawande), 18
checks and signatures, 24
clinical development plan (CDP), 34,
58fig, 59
clinical pharmacology, 42–43
ClinicalTrials.gov, 111
CMR International, 105
collaboration, 12–13
communal accountability, 12–13
communication
informed consent and, 160
patients and, 180–181
competitive advantage, 3, 63, 106
Competitive Drug Development
International Ltd., 83fig
complexity/complication
causes of, 23–25
increases in, 21–22
reasons for, 5
unnecessary, 21–25, 21fig
Comprehensive Unit-based Safety Program
(CUSP), 18
concomitant medications, 22, 77, 82,
154, 174
confidentiality, 144
contingency planning, 134–135, 147
contracts, 49–50, 53, 120, 127
cost issues, 50, 106
country identification, 76
country selection, 69
Cramer, J. A., 117
credibility, 107
CROs, 111–112, 123–124
culture
company, 10, 17
complication and, 23
management, 97
data, dirty, 171–174, 173fig
data analysis, 82–86
data collection, 22, 81–82, 124,
167–175
data flow, 169–171, 170fig
data gap, 37, 37fig
data manipulation, 11–12
database lock, 171, 173
database setup, 63, 91
Declaration of Helsinki, 143
delays
costs of, 70–71, 119
patient recruitment and, 105–106
rates of, 105, 105fig, 106fig
reasons for, 95
delegation, 13–14
development plan, 30fig
device characteristics, 45
diaries, 181–183
dirty data, 171–174, 173fig
dishonest behavior, examples of, 11–12
disruptions, minimizing, 180
documentation, essential, 168
draft protocol synopsis, 47fig, 50–51, 57,
59–63, 90, 98, 177–178
electronic data capture (EDC), 171–172
electronic diaries, 182–183
electronic medical records (EMRs), 88
Emerson, Ralph Waldo, 18
enrollment tactics, 157–159
enrollment times, 4, 70, 153, 157–159. See
also patient enrollment
equipment requirements, 132–133
ethical issues, 118
ethics approval, 115, 152, 152fig
ethics committees (IEC/IRB), 48–49,
53, 129, 148–151, 160, 161, 162,
163, 164
excellence, 9
exclusion criteria, 65, 79, 82, 103,
112–113, 157
excuses, 86–88, 118–122
experience, lack of, 23
filing system, 147
final protocol, 52, 53, 90, 91–92
flexibility, 97–98
Food and Drug Administration, 176–177
full protocol
approval of, 99
common information in, 93
drug-related information in, 93–94
flowchart for, 96fig
reviewing and approving, 96–98
study-specific information in, 94
writing, 92–94
gap analysis, 37–42
Gawande, Atul, 18
GCP, 126
genetic testing, 164
good clinical practice (GCP), 26–27,
143–144, 145
Gorovitz, Samuel, 17
handovers, 24–25
Harris, 10
honesty, 11–12
ICH-GCP, 26, 109, 129, 143–144, 161–162,
163–164, 168
ignorance, 23
import licenses, 53, 63, 91
inaccuracies, reasons for, 95
independent ethics committees (IECs). See
ethics committees (IEC/IRB)
individual clinical trials, 30, 47–54
informed consent, 159–164, 178
infrastructure issues, 134
initiation visit, 151
[218]
Index
initiative, 13–14
institutional review boards (IRBs). See
ethics committees (IEC/IRB)
intellectual property information, 45
interdependence, 7
International Conference on
Harmonisation of Technical
Requirements for Registration of
Pharmaceuticals for Human Use (ICH)
guidelines. See ICH-GCP
Investigator Brochure, 128
investigator meeting, 125
investigators
patient perspectives and, 178
payment schedules and, 135
planning activities and, 141–142
publication policy and, 135–136
recruitment of, 127, 128–137
resources and, 129–130
responsibilities of, 127–128
role of, 61
time requirements and, 130–132
training and education and, 123,
124–125
key opinion leaders (KOLs), 107, 108
laboratory samples and tests, 133–134
Lasagna, Louis, 109
Lasagna’s Law, 109, 109fig
laser pointers, 207–208, 210–211
late-stage failure, 19–20
listening, 14–15. See also communication
local regulatory requirements, 144
MacIntyre, Alasdair, 17
management
culture of, 97
poor, 23
of team, 146
time, 194–195
manufacturing information, 44
market exclusivity, 3
marketing, 60, 108
measuring outcomes, 15–16
medical information, for target package
insert (TPI), 43–44
meetings
attendees and, 190–191
conference calls and, 198–200
decisions from, 198–201
minutes from, 194, 198
overview of, 187–188
preparation for, 188–191
questions at, 196
running of, 191–198
minimal viability requirement (MVR),
38–39, 39fig, 40, 41
minimizing disruptions, 180
monitoring, 26–27
new chemical entity (NCE), 31
new medical entities (NME), decrease in, 3
open-mindedness, 14–15
operational planning, 30fig
organizational perspective, 23
organizational structure, 10
Osler, William, 176
outcomes research, 44
PACK study, 111
package insert, 38, 39–40, 42
patient availability, 79–80
patient costs, 179–180
patient diaries, 181–183
patient enrollment, 104, 114–117, 165.
See also enrollment times
patient numbers, 165
patient perspectives, 45–46, 60–61, 78–79,
176–183
patient randomization, 48
patient recruitment, 63, 70, 85, 91, 103,
104–111, 114, 120–121, 121fig, 129,
137, 152–159, 152fig
patient retention, 165–167
patient screening, 51, 52, 63, 76, 91, 103,
112–114, 137–140
patient selection, 47fig, 94
patient support, 178–179
patients, responsibility to, 17
Patton, George, 29
perception gap, 37, 38fig
performance measurements, decline in, 4
pharmaceutical development
information, 44
pharmaceutical industry, reputation of, 10
Pharmacia, 7–8, 7fig
pharmaco-economic measures, 61
Phase II, late-stage failure and,
19–20, 19fig
Phase III
amendments and, 70–71
failure rates for, 19, 19fig
review at start of, 41
source document verification (SDV)
and, 27
planning
importance of, 29–30
inadequate, 110
overview of, 140–142
presentations
advice for, 209–211
handouts for, 204
mistakes made during, 207–209
overview of, 202
slides and, 203–206
pre-study activities, 110–111
principles, use of, 10–11
process perspective, 23
product characteristics, 45
project development plan (PDP), 34,
40fig, 58fig
proof-of-concept groups, 25
prospective approach, 113, 114, 139
protocol feasibility
changes based on, 98
compensation and, 73, 78
country-specific aspects of, 69, 76–77
description of, 69–70
draft protocol synopsis and, 51, 62–63
ethical aspects of, 77, 78, 81
excuses used for avoiding, 86–88
key points for, 88–89
mistakes made during, 72–73, 74–75
preparing for, 76–81
purpose of, 68
site-specific aspects of, 69, 77–78,
80–81
technology and, 88
timeline and, 47fig
protocol procedures, 21–22, 21fig
protocol synopsis
approval of, 98
approved, 58, 90–91
definitive, 51, 52
derivation of, 58fig
draft, 47fig, 50–51, 57, 59–63, 90, 98,
177–178
flowchart for, 96fig
vs. full protocol, 92
purpose of, 50, 57
reviewing and approving, 96–98
template for, 57, 64–67
protocol violations, 129
publication policy, 135–136
quality assurance, 23
quality control, 23
quality-of-life measures, 61
questionnaires, 120
randomization, 63, 91, 165
rate-limiting factors, 53
Recap Portfolio Index, 19
Index
[219]
recruitment rescue activity, 106, 121–122,
121fig. See also patient recruitment
regulations, 26–27
regulatory approvals, 53
regulatory authorities, 48, 63, 91
requests for proposals (RFPs), 51, 63,
76, 77, 91
research and development (R&D)
approval, 49
resource planning, 63
retrospective approach, 113–114,
138–139
risk-aversion, 23
rules and procedures, 142–145
screening log, 157
selection criteria, 82
sequential activities, 24–25
simplification, 20–26
site identification, 50, 76
site selection, 47fig, 52, 63, 69, 91,
104–111, 117–118
source document verification (SDV),
26–27, 87, 118, 167–169, 170
space requirements, 132
Spilker, B., 117
staff issues, 16, 134–135
standard procedures, 144–145
standardization, lack of, 23
standards, commitment to high, 15–16
startup activities, 47fig, 53
statistical analysis plan, 63, 91
statisticians, 60
storage space, 132
strategic planning, 30fig
study insurance, 63, 91
study manual, 63, 91
[220]
Index
study team, 145–148
synopsis, finalizing, 47fig
tactical planning, 30fig
target package insert (TPI), 40, 40fig, 42
target product profile (TPP)
characteristics of, 32
common errors involving, 32–34
content of, 34–35, 42–46
development plan and, 30, 30fig
example of, 36fig
gap analysis and, 38
minimal viability requirement (MVR)
and, 38–39, 39fig, 41
objective for, 31–32
structure of, 35–36
target package insert (TPI) and, 40,
40fig, 42
timing of, 34
team management, 146
Temple, Robert, 125
terminations, 107
time management, 194–195
time requirements, 130–132
timelines, 47–48, 47fig, 141
Tiplady, B., 182
toxicology, 42
training and education, 53, 63, 76, 77–78,
91, 123–124, 125–126, 146–147
transparency, 12
trust, 13–14
Tufts Center for the Study of Drug
Development, 21
United Kingdom, 49
washout period, 165
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