Changing Scene of Clinical
Research
Judy Stone, MD
www.conductingclinicalresearch.com
© Creative Commons AttributionNoncommercial-Share Alike
Background on Changing Scene
Globalization of Clinical Trials
Background:
What % of Sites are Outside the US?
10 %
20 %
40 %
60 %
Background:
What % of Sites are Outside the US?
10 %
20 %
40 %
60 %
Open Phase 3 Clinical Trials, 2007
56% of trials are
outside of US
1/3 of trials done
solely outside US
Open Phase 3 Clinical Trials, 2007
1995
# Countries
33
2005
70
large incr in countries
US % of trials
54
43
10% decr in trials
# Pts/trial
215
661
large incr in # trial asubjects
Glickman, Seth et al. Ethical and Scientific Implications of the Globalization of Clinical Research.
NEJM 360 (8): 816-823, 2009
Non-US Clinical Investigators Tracked by
FDA
# of investigators
16,000
14,000
12,000
10,000
8,000
6,000
4,000
2,000
00
80-84
85-89
90-94
95-99
Increase in Overseas Trials
http://www.financialexpress.com/news/huge-growth-in-clinical-trials-in-country-official/389956/,
Shift in Clinical Investigators Submitting INDs
hybrid slide of data from Centerwatch Analysis 2009 and Tufts CSDD Impact Volume 1, 2009
What is Driving the Shift Overseas?
Access to patients
# of pts needed for trials rose:
2.8 million people in 1999 to
19.8 million in 2005
only 1-2% participation rate in trials in US
http://www.boston.com/news/nation/articles/2007/12/29
Distribution of World Population
0.00
2.00
4.00
6.00
8.00
2007
# of pts needed for trials per yr-19.8 million
10.00
12.00
14.00
16.00
What is Driving the Shift Overseas?
Need for:
Large numbers with a specific condition*
Specialized centers
Phase 2 “supercenters” with up to 9000 outpt
visits/day**
Treatment naive patients
Different ethnic/racial groups
e.g., Iressa effective in Asia, not US
lg Japanese pop in Brazil; less competition
**http://www.dddmag.com/clinical-trials-on-the-move.aspx
What is Driving the Shift Overseas?
Bureaucracy
delays in protocol development
phase III ECOG trial protocols require about 800
days from conception to activation*
contracts and grants negotiation now the longest part of
starting a study
at one institution, 87 steps and 29 signatures were
required to launch a trial
*Sandler, Alan in http://www.cancernetwork.com/display/article/10165/1382200, 09
What is Driving the Shift Overseas?
Availability of patients
Slow recruitment causes 85-90% of delay in trials
80% of studies run over by 30-42%, or avg. 6 mo*
Recruitment speed may be 25 x or more higher**
Cost
Need to shorten development time…
Trials in the Fast Lane: Accelerating Clinical Trials: Budgets, Patient Recruitment, and Productivity,
Cutting Edge Information
**www.ngpsummit.com/pdf/Clinstar.pdf
Costs of Delay
direct cost of delay $37,000 per day in out-of-pocket expenses.
indirect cost for a billion dollar drug is 83 million/month or 2.8
million/day* (another estimate is $15.6 million/day**)
*Excel-China CW
**www.ngpsummit.com/pdf/Clinstar.pdf
Relative Costs of Trials
Germany
US
China
India
1.400
1.200
1.000
0.800
0.600
0.400
0.200
0.000
Fast track, 2006: Amretechpharma.com
Russia
What is Driving the Shift Overseas?
Grooming markets in developing countries
Huge population of potential buyers
Reduce regulatory barriers
Problems in US Trials
Difficulty recruiting patients in US
Low volunteer rate, <5% even for cancer trials
Liability
Mistrust of pharma
Less risk-tolerant patients
More competition for pts as more drugs in development
restrictive inclusion-exclusion req
req for larger trials
HIPAA
Unique Problems in US Trials
Costs higher
employee benefits 30%
administrative costs higher
designated person to reconcile billing, to ensure that Medicare or third
party payers are not inadvertently billed
Cost of finding pts higher
due to increased screening req
HIPAA
Cost to site of obtaining HIPAA consent $5/per subject =>10 million/yr
Goldfarb, N
Association of Academic Health Centers (AAHC), “The HIPAA Privacy Rule: Lacks Patient
Benefit, Impedes Research Growth,” Johnson, Guy GW
Unique Problems in US Trials
Fewer feel need to participate
higher standard of care
Insurance precluding participation
What is Driving Move to Conduct Clinical Trials in
Developing Countries?
Summary
Costs are 50+ % lower outside of US
More readily available “naïve” patients
More compliant patients
Less regulatory oversight
Less litigious climate
How Profitable are Clinical Trials for a Site?
a) 2 %
b) 5 %
c) 10%
d) 20 %
How Profitable are Clinical Trials for a Site?
a) 2 %
b) 5 %
c) 10%
d) 20 %
Where Does the Clinical Grant Dollar Go?
Salaries
Profit
Overhead
Operating Costs
4%
2%
6%
18%
Training
Hidden Costs
7%
63%
Hidden Costs incl managing Adv Event, Travel to req Inv Meeting, Supervision,
review of CRF, attending initiation meeting, CRA interactions-Ken Getz
Sponsor-Site Relationships
Sponsor site relationships
Less friendly; no longer personal relationships
Now computer data-base driven
Cross-indemnification clauses
CROs/CRAs:
More use of CROs rather than in-house team
High turnover in CRAs
Costly for site to train CRAs
Inconsistency in CRFs, etc.
Sponsor site relationships
New clinical trials starts—has declined by 40 % since mid-2008.
Numerous programs have also been halted and cancelled.
Investigators have to “hedge their bets”
may be left with expensive infrastructure expenses if trial is
cancelled
Decline in # PIs
New PIs declined 10% betw 2000-07, while the # of studies has incr
~15%
45% of all PIs in 2000 decided to quit after their studies ended,
compared to a 27% turnover rate during the early 1990s.
Lack of exposure in training; Enormous time commitment
Increasing difficulties recruiting pts
HIPAA, insurance restrictions, incl-excl criteria
Liability issues
Decline in # PIs
Financial incentives diminishing
2% profit now
investigator compensation per procedure has declined 3 percent
annually since 1999 while the sites’ work burden increased 10.5
percent annually.
Financial Disclosure requirements offend many
Problems with Recruitment, Retention:
Incr competition for pts
Incl-Excl criteria are more complex and rigid=>
Ave eligibility criteria have increased by 58%*
More screening
Expectation of <1 pt/mo
Smaller pool of potential volunteers
Enrollment rates dropped from 75% between 1999 - 2002 to 59%
between 2003 - 2006.
Retention rates fell by 30%.
Mistrust: increased from 28% to 75% from 1996 to 2002
Getz, Ken. Chasing Veteran US Sites Out of the Enterprise. Why investigative sites are at
financial risk and how it may effect sponsors and CROs. Applied Clinical Trials, Nov. 2010
Retention
Incr complexity and # of procedures
6.5% annual growth in # unique procedures per protocol
8.7% annual growth in the frequency of the protocol activities
(1999-2005)
Volunteer retention dropped from 69 percent to 48 percent
between 2003 and 2006
Ave number of procedures required rose from 89.8 to 150.5.
Mistrust: OIG noted a tenfold increase in complaints against sites.
Less publicized impediments:
CRF size; e-crfs (with dedicated computer/line)
 HIPAA
 Staffing at hospitals declining and rapid turnover of staff =>
inability to do trials without errors;
no longer a dedicated unit for trials
 Utilization Review
Revolving door
Insurance denials of stay/investigative Rx
 Standard order sets
e.g. Pneumonia—call Dr. Stone re drug study was not an
option

Contract Issues
Contract Issues
Grant payment schedules
Back-loaded favored by sponsor
Front-loaded advantageous for site
Contract Issues--Tips
Start-up $ when contract is finalized
rather than enrollment of 1st pt
Grant broken down by patient and
Insist that payments include a remittance advice, or detailed
breakdown of what the funds are for, to avoid a bookkeeping
nightmare.
Contract Issues--Tips
Be wary of milestones like payment after every 5th pt
might end up floating a loan to sponsor
if enrollment is slow
Contract Issues--Tips
Require the monitor to visit the site within 2 weeks of your having
enrolled your first patient.
close monitoring on complex studies ensures that
you are enrolling patients appropriately and performing all
the study evaluations correctly.
avoids costly unevaluable pts
Contract Issues--Start-ups
Complete a financial review of the sponsor or CRO, and have
clauses for:
Recovery of all attorney fees and costs, in case of nonpayment
Ability to withhold data for nonpayment
Retrieval of CRFs at specified intervals and interim $ if not
retrieved
Insurance for the sponsor-min of $5 million
Contract Issues--Warnings

Publication clauses

Patent and Inventions

Cross-indemnification clauses
insist on receiving a draft contract prior to investing a lot of time in the
protocol.

Insurance
indemnification clauses do not cover alleged physician error
most malpractice insurance policies exclude coverage for clinical trials
Be sure to limit indemnification to limits of your coverage
Conflict of Interest
Conflict of Interest
IOM definition: “…creates a risk that professional judgment or
actions regarding a primary interest will be unduly influenced
by a secondary interest.”
Conflict of Interest-History
1980s pressure to translate basic bench research into Rx for
patients =>
research collaborations between the government (NIH) and
industry became acceptable
Bayh-Dole Patent and Trademark Laws Amend. Act of 1980
academic institutions gained intellectual property rights when
carrying out government-funded research=> receiving the
patent and licensing funds and ongoing royalties
Conflict of Interest-History
NIH 1995, Dr. Harold Varmus rescinded policies prohibiting
investigators from accepting consulting fees or stock from
industry/sponsors
Annual limits on work and revenue from outside the NIH were
also removed.
Pendulum swings back:
NIH now requires reporting of salary or stocks totaling more than
$10,000 for a related company
Conflict of Interest-History
To what degree should financial interests by investigators be
disclosed to prospective research participants?
Conflict of Interest-History
5 percent of volunteers said they would not participate because of
an investigator’s equity interest
vs
investment as a plus, feeling the PI would work harder or believed
more strongly in the potential benefit of the intervention.
Conflict of Interest-Physician
Pressure re enrolling their own patients--trust, coercion
Pressure to enroll borderline patients:
financial, for overhead and salary expenses
(bonuses for goals)
site’s prospects for future trials
prestige, coauthorship on publications
rank and tenure
Conflict of Interest-Physician
Does participation in trial influence:
hospital’s formulary decisions?
alter a physician’s prescribing patterns?
Pt-Prompted Ethical Issues
Patients who lie about their medical histories or problems
to gain access to medical therapies that would not otherwise be
available to them
Make reasonable payments to cover patients’ time and trouble in
participating (e.g., gas, parking, taxi fare), rather than excessive
participation fees that might be unduly tempting or coercive.
Pt-Prompted Ethical Issues
Occur when:
the PI is also the patient’s personal physician.
Sometimes MD so intensely wants to help their pt that they bend
the enrollment criteria for a trial so a patient can have access to
a potentially lifesaving drug…
Pt-Prompted Ethical Issues
~64% of respondents thought that PIs should deviate from the
protocol to improve subjects’ care.
22% recruited an ineligible patient anyway if they believed the
trial would be beneficial to the pt
of 36% who said one of their pts had met termination criteria but
seemed to benefit medically from the trial, 9% reported that
they kept the subject in the trial.
Pt-Prompted Ethical Issues
dual role/relationship [of physician and investigator] may confuse
research with clinical care and puts the investigator in a
position to heavily influence the patient’s/subject’s decisions.
Conflict of Interest: IRBs
Commercial IRBs are paid directly by the drug company sponsor
Presumably, they don’t want to bite the hand that feeds
Other nonfinancial ethical conflicts may be due to excessive
personal involvement or prejudgment or
when there is a personal or collaborative relationship between the
investigator and the IRB member.
Increasingly, competition may exist between the PI and IRB
members.
IRB Impracticality:
Form FDA 1572 obligations place this responsibility on a PI:
“I will ensure that an IRB that complies with the requirements of
21 CFR Part 56 will be responsible for the initial and continuing
review and approval of the clinical investigation.”
2007 Guidance:
Supervisory Responsibility of Investigators
contains 2 critical points:
When tasks are delegated by the investigator, the s/he is responsible for
providing adequate supervision and is accountable for regulatory
violations from failure to do so
to be able to discuss the risks and benefits of a trial
2007 Guidance:
Supervisory Responsibility of Investigators
Inappropriate delegation includes: medical histories
screening evaluations conducted by individuals with inadequate
medical training (e.g., a medical assistant).
assessment of inclusion/exclusion criteria
informed consent obtained by individuals who lack the medical
training, knowledge of the Protocol or Inv. Product needed to be able to
discuss the risks and benefits of a trial
So, Why Do Studies?
Basic physiologic
Income
and safety needs
need for love, sense of
membership
belonging
need for esteem
publication and recognition
intellectual challenge
higher needs of self-actualization
and transcendence
altruism, wanting to develop a
medicine or device that will help others
Selected References
Cutting Edge Information Trials in the Fast Lane: Accelerating Clinical Trials: Budgets,
Patient Recruitment, and Productivity, 2004
Getz, Ken. Chasing Veteran US Sites Out of the Enterprise. Why investigative sites are
at financial risk and how it may effect sponsors and CROs. Applied Clinical Trials, Nov.
2010
Glickman, Seth et al. Ethical and Scientific Implications of the Globalization of Clinical
Research. NEJM 360 (8): 816-823, 2009
Goldfarb, Norm Clinical Research Terminology Codes: What We Do and How Much It
Costs, 2006
What is Killing Off the Investigators? A Clinical Research Mystery, 2005
Steinberg, Mindy. Association of Academic Health Centers (AAHC), “The HIPAA Privacy
Rule: Lacks Patient Benefit, Impedes Research Growth” 2009
Thank you!
Questions?
jstone@conductingclinicalresearch.com