Introduction to Clinical Trials
Chin-Fu Hsiao
Division of Biostatistics & Bioinformatics
National Health Research Institutes
chinfu@nhri.org.tw
Chapter 1
Introduction to Clinical
Trials
REFERENCES
1.Friedman, Furberg & DeMets. (3rd edition,
1998) Fundamentals of Clinical Trials.
Springer-Verlag, NY, NY.
2.Chow, S.C., and Liu, J.P. (2004). Design and
Analysis of Clinical Trials: Concepts and
Methodologies, Second Edition. November,
2003 by John Wiley and Sons, Inc., New York,
New York, U.S.A.
Clinical Trials
Natural Experiment
• General Lancaster (1600)
• East Indian Shipping Co.
– 4 ships - Lancaster’s ship fortuitously
had lemon juice on board
– Lancaster’s ship remained free of
scurvy (壞血病)
– Natural Experiment, not planned
Clinical Trials
Planned Experiment
• Smallpox (天花)Experiment (1721)
– Perhaps first planned experiment
– Lady Mary Wortley Montaque
– Six inmates of Newgate Prison
– Sentence commuted if they volunteered for inoculation (
種痘)
– All remained free  Inoculation effective
– No concurrent control group
Clinical Trials
Concurrent Control
• Scurvy Experiment - Lind (1747)
– Used control group (concurrent)
– On board Salisbury
– 12 patients with scurvy
– Evaluated 6 treatments (2 subjects/treatment)
– One treatment (oranges and lemons) had two
men recover
Clinical Trials
• Concept of Randomization in designed experiments,
introduced by Fisher into agriculture in 1926
• First randomized clinical trial 1931 by Amberson
in tuberculosis patients
12
Sano crysin
(無機金鹽硫代硫酸金鈉)
(gold compound)
12
Control saline(鹽水)
injection
randomized
blinded
Clinical Trials
Use of Randomization
• Multicenter Trials (1944) - Common Cold
– Medical Research Council
– Treatment of common cold
– Different sites all using common protocol
– Patulin(棒麴黴素) vs. Placebo
• MRC Tuberculosis Trial (1948) – “Grandfather Trial”
(Ref: British Medical Journal, 1948)
– Randomized (by random numbers)
– Streptomycin(鏈黴素) vs. Placebo
– Based on work of Bradford Hill, founder of modern day clinical
trial
• Supported Concept of Randomization
Blindness
• The principle of blindness was
introduced in the trial by Amberson et al.
• In a trial of cold vaccines in 1938, Diehl
et al. referred to the saline solution
given to the subjects in the control
group as a placebo (安慰劑)
Clinical Trials
• The clinical trials emerged as the
preferred method in the evaluation of
medical interventions only in the past
few decades
• Many of the principles have their origins
in work by Hill
What Is A Clinical Trial?
• A clinical trial is defined as a prospective
study comparing the effect and the value of
intervention(s) against a control in human
beings
• Prospective but not retrospective (casecontrol study)
• Each patient must be followed from a welldefined point, which becomes time zero or
baseline for the study
Intervention Techniques
• A clinical trial must employ one or more
interventions.
• Interventions include “prophylactic,
diagnostic or therapeutic agents,
devices, regimens, procedures, etc.”
• Follow-up of people over time without
active intervention does not constitute a
clinical trial (observational study)
Control Group
• A clinical trial must contain a control group against
which the intervention group is compared
• The control group at baseline must be sufficiently
similar in relevant respects to the intervention group
• A new intervention is compared with best current
standard therapy (active control)
• “No active intervention” means that the participant
may receive either a placebo or no intervention at all
• Participants in all groups may be on a variety of
additional therapies and regimens, so-called
concomitant interventions, which may be either selfadministered or prescribed by others
Clinical Trials
• In this class, only studies on human beings
will be considered as clinical trials
• Each trial must incorporate participant safety
considerations into its basic design
• Strategies referred to attempts at getting all
participants to comply to the best of their
ability with their originally assigned
intervention needs to be developed
Clinical trial Phases
•
•
•
•
Phase I studies
Phase II studies
Phase III studies
Phase IV studies
Phase I Studies (1)
• The first step, or phase in developing a drug
or a biologic is to understand how well it can
be tolerated in a small number of individuals
• The purpose is often to estimate how large a
dose can be given before unacceptable
toxicity is experienced by patients (maximally
tolerated dose, MTD)
• A 3-3 design is usually used
Phase I Studies (2)
• The investigator usually starts with a very low dose and
escalates the dose until a prespecified level of toxicity in
patients is obtained
• Three patients are entered sequentially at a particular dose
• If no specified level of toxicity is observed, the next predefinied
higher dose level is used
• If unacceptable toxicity is observed in any of the three patients,
additional 3 patients are treated at the same dose
• If no further toxicity is seen, the dose is escalated to the next
higher dose
• If additional unacceptable toxicity is observed, then the dose
escalation is terminated and the dose, or the previous dose, is
declared to be the MTD
Phase II Studies (1)
• The goal is to evaluate whether the drug has
any biologic activity or effect and to estimate
the rate of adverse events
• The phase II design depends on the quality
and adequacy of the Phase I study
• The successful results of the phase II trial will
be used to design the comparative phase III
trial
Phase II Studies (2)
• The most commonly used phase II
designs in cancer is Simon’s two-stage
design
• In the first stage the investigator tries to
rule out drugs that have no or little
biologic activity
Phase III Studies
• Phase III trials are generally designed to
assess the effectiveness of the new
intervention
• The focus of this class is on phase III
trials
• Many design assumptions for phase III
trials depend on a series of phase I and
II studies
Phase IV Studies
• Phase III trials of chronic conditions or diseases often
have a short follow-up period for evaluation, relative
to the time the intervention might be used in clinical
practice (hypertension drug)
• Phase III trials focus on effectiveness, but knowledge
of safety needs to evaluate fully the proper role of an
intervention
• A procedure or device may fail after a few years and
have adverse sequelae for the patient
• The long-term surveillance of an intervention, which
do not involve control groups, is referred to as phase
IV trial (postmarking trial)
Why Are Clinical Trials Needed?
(1)
• It is the clearest method of determining whether an
intervention has the postulated effect
• Given the uncertain knowledge about disease course
and the usual large variations in biologic measures, it
is often difficult to say on the basis of uncontrolled
clinical observation whether a new treatment has
made a difference to outcome, or what the magnitude
may be
• A clinical trial offers the possibility of such judgment
because there exists a control group-which, ideally, is
comparable to the intervention group in every way
Why Are Clinical Trials Needed?
(2)
• Only recently, after the drug (digitalis毛地黃,一種強心
劑) has been used for more than 200 years, has a
large clinical trial evaluating the effect of digitalis on
mortality been mounted in patients with congestive
heart failure
• High concentration of oxygen was used for therapy in
premature infants until a clinical trial demonstrated its
harm
• The Cardiac Arrhythmia Suppression Trial (心律失常
抑制試驗) documented that commonly used
antiarrhythmic drugs were harmful in patients who
had had a myocardial infarction (心肌梗塞) and
raised questions about routine use of an entire class
of antiarrhythmic agents
Why Are Clinical Trials Needed? (3)
• Most of interventions cannot be entirely free of
undesirable effects
• A clinical trial can determine the incidence of adverse
effects of complications of the intervention
• In the final evaluation, an investigator must compare
the benefit of an intervention with its other, possibly
unwanted effects to decide whether, and under what
circumstances, its use should be recommended
• The cost implications of an intervention must be
considered
Why Are Clinical Trials Needed? (4)
• Thrombolytic therapy (血栓溶解治療)
has been repeatedly shown to be beneficial
in acute myocardial infarction
• The cost of different thrombolytic agents
varies several-fold
• Are the added benefits of the most expensive
agents worth the extra cost
• Such assessments must rely on the judgment
of the investigator and the physician
Why Are Clinical Trials Needed? (5)
• It has been argued that traditional clinical trials are
not the sole legitimate way of determining whether
interventions are useful (AIDS trials)
• Sometimes, clinical trial researchers need to be
willing to modify aspects of study design or
management
• If the patient community is unwilling to participate in
clinical trials conducted along traditional lines, or in
ways that are scientifically pure, trials are not feasible
• Investigators need to involve the relevant
communities or populations at risk, even if this could
lead to some compromises in design and scientific
purity
Why Are Clinical Trials Needed? (6)
• Investigators need to decide when such
compromises so invalidate the results that the
study is not worth conducting
• Note that the rapidity with which trial results
are demanded, the extent of community
involvement, and the consequence effect on
study design can change as knowledge of the
disease increases, as at least partially
effective therapy becomes available, and as
understanding of the need for valid research
designs, including clinical trials, develops
Why Are Clinical Trials Needed? (7)
• Clinical trials are conducted because it is
expected that they will influence practice
• The influence depends on numerous factors,
including direction of the findings, means of
dissemination of the results, and existence of
evidence from other relevant research
• Well-designed clinical trials can certainly have
pronounced effects on clinical practice
Why Are Clinical Trials Needed? (8)
• Note that there is no such thing as a perfect
study
• A well thought-out, well-designed,
appropriately conducted and analyzed clinical
trial is an effective tool
• Even if well-designed clinical trials are not
infallible, they can provide a sounder
rationale for intervention than is obtainable by
other methods of investigation
Why Are Clinical Trials Needed? (9)
• Poorly designed and conducted trials
can be misleading
• Without supporting evidence, no single
study should be definitive
• Consistency with data from laboratory,
animal, epidemiologic, and other clinical
research must be considered
Problems in the Timing of a Trial
(1)
• Once drugs and procedures of unproved
clinical benefit have become part of general
medical practice, performing an adequate
clinical trial becomes difficulty ethnically and
logistically
• Some people advocate instituting clinical
trials as early as possible in the evaluation of
new therapies
• The trials must be feasible
Problems in the Timing of a Trial
(2)
• Before a trial, an investigator needs to have
the necessary knowledge and tools
• The investigator must know something about
the safety of the intervention and what
outcomes to assess and have the techniques
to do so
• Well-run clinical trials of adequate magnitude
are costly and should be done only when the
preliminary evidence of the efficacy of an
intervention looks promising enough to
warrant the effort and expenses involved
Problems in the Timing of a Trial
(3)
• Consideration of the relative stability of the
intervention is another issue
• For trials of surgical interventions, surgical
methods are constantly being improved
• Evaluating an operative technique of several
years past, when a study was initiated, may
not reflect the current status of surgery
Problems in the Timing of a Trial
(4)
• In the Veterans Administration study of coronary
artery bypass surgery(冠狀動脈繞道手術), the trial
showed that surgery was beneficial in subgroups of
patients with left main coronary artery disease and
three vessel disease, but not overall
• Critics of the trial argued that when the trial was
started, the surgical techniques were still evolving
• Surgical mortality in the study did not reflect what
occurred in actual practice at the end of the long-term
trial
• There were wide differences in surgical mortality
between the cooperating clinics, which may have
been related to the experience of the surgeons
Problems in the Timing of a Trial
(5)
• Defenders of the study maintained that the surgical mortality in
the Veterans Administration hospitals was not very different form
the national experience at the time
• In the Coronary Artery Surgery Study, surgical mortality was
lower than in the Veterans Administration trial, reflecting better
technique
• While the best approach would be to postpone a trial until a
procedure has reached a plateau and is unlikely to change
greatly, such a postponement will probably mean waiting until
the procedure has been widely accepted as efficacious for some
indication, thus making it impossible to conduct the trial
• Allowing for improvements in operative techniques in a clinical
trial is possible (Chalmers & Sacks)
When Should a Clinical Trial Be Started?
1. Intervention (knowledge about it)
– Safety
– Correct dose/duration
– Final form (TPA story)
– Defining study population (PHS)
– Obsolescence
2. Trial Design
– What outcomes to assess
– Ability to measure
– Expected effect of intervention
3. Feasible
– Resources
• Financial
• Staff
• Equipment/technology
• Time
– Availability of subjects
Ethics (1)
• The ethical problems center around the
issues of the physician’s obligation to his
patient vs. societal good, informed consent,
randomization, and the use of placebo
• Studies that require ongoing intervention or
studies that continue to enroll participants
after trends in the data have appeared have
raised some of the controversy
Ethics (2)
• Properly designed and conducted clinical
trials are ethical
• A well-designed trial can answer important
public health questions without impairing the
welfare of individuals
• There may be conflicts between a physicians
perception of what is good for his patient, and
the needs of the trial
• The needs of the participants must be
predominate
Ethics (3)
• Proper informed consent is essential
• Simply adhering to legal requirements does
not ensure informed consent
• The investigator is obligated to update he
consent form and notify current participants in
an appropriate manner due to important
information derives from either other studies
or the trial being conducted, which is relevant
to the informed consent during the trial
Ethics (4)
• A trial of antioxidants (抗氧化劑) in Finnish
male smokers indicated that beta carotene
and vitamin E may have been harmful with
respect to cancer or cardiovascular disease
• Investigators of other ongoing trials of
antioxidants informed the participants of the
results and the possible risks
• A well-informed participants is usually a better
trial participant
Ethics (5)
• Randomization has been more of a problem
for physicians than for participants
• The objection to random assignment should
only apply if the investigator believes that a
preferred therapy exists
• If the physician truly cannot say one
treatment is better than another, there should
be no ethnical problem with randomization
Ethics (6)
• The use of a placebo is acceptable if there is no
known best therapy
• All participants must be told that there is a specified
probability (50%) of their receiving placebo
• The use of a placebo does not imply that control
group participants will receive no treatment
• In many trials, the objective is to see whether a new
intervention plus standard care is better or worse
than a placebo plus standard care
• In all trials, there is the ethical obligation to allow the
best standard care to be used
Ethics (7)
• With advance understanding by both
participants and investigators that they
will not be told interim results, and that
there is a responsible data monitoring
group, ethical concerns should be
lessened, if not totally alleviated
• Confidence in the integrity of the trial
and its results is essential to every trial
醫學倫理學四大原則
Tom L. Beauchamp及James F. Childress 1979
•
尊重自主原則
(the principle of respect for autonomy)、
•
不傷害原則
(the principle of nonmaleficence)
•
行善原則
(the principle of beneficence)
•
公平正義原則
(the principle of justice)
The Principles of Biomedical Ethics
Ethical Committee (EC)
Clinical Ethical Committee
倫理委員會
Human Subject Committee
Institutional Review Board (IRB)
二次大戰後逐漸被重視
• 二次大戰時德國以真人做試驗。
– 低氧試驗：200人， 40%死亡。
– 低溫試驗：300人， 30%死亡。
– 化學戰劑試驗： 25%死亡。
• 日本細菌戰試驗：日本在中國東北的
731部隊。
• 美國的Tuskeegee Trial
Tuskegee Syphilis study
• 1932-1972美國Public Health Service主導之研究計劃
• Alabama/Macon county/Tuskegee
• 600位非裔男性
– 400位梅毒潛伏期患者
– 200位健康對照組
• 1950盤尼西林問世後，試驗仍繼續進行，且未提供應
有治療
– 至少有100人因梅毒或其併發症死亡。
– 至少有40位妻子感染梅毒。
– 至少有19位嬰兒在出生時就感染梅毒。
• 1972年被媒體舉發。1973年停止。
• 柯林頓總統於1997年5月16日代表美國政府向所有受難
者道歉
醫學研究的倫理準則
兩個重要宣言
1. 二次戰後的Nuremberg Code for Human
Experimentation (1945)
2. WMA(World Medical Association)的
Declaration of Helsinki (1964)
(中文有台北榮總江晨恩醫師翻譯，成大醫學院
創院院長黃崑巖教授修訂版)
以人為對象之
生物醫學研究的倫理規範
• 紐倫堡法典（Nuremberg Code 1949）
– 自願性原則、善意原則
• 赫爾辛基宣言（Helsinki Declaration 1964
1975 1983 1989 1996 2000）
– 區分治療性試驗與非治療性試驗
– 獨立倫理審查
– 拒絕刊登不符倫理之研究論文
• Belmont Report 1979
– 生物醫學研究之倫理三原則
– 對人之尊重、善意原則、正義原則
The Nuremberg Code (1)
Some Principles
• Voluntary consent
• Experiments yield results for good of society
• Experiments based on animal experiments and
knowledge of natural history of disease
• Avoid all unnecessary physical, mental
suffering and injury
• No experiment if a prior reason to believe that
death or disabling injury will occur
The Nuremberg Code (2)
Some Principles
• Degree of risk should never exceed humanitarian
importance of problem to be solved.
• Protect subject against remote possibility of injury.
• Experiments conducted only by scientificallyqualified persons
• Human subject should be at liberty to bring
experiment to an end.
• Scientist in charge must be prepared to terminate
experiment if probable cause that continuation of
experiment is likely to cause injury, disability or
death.
The Declaration of Helsinki
(1964,2000)
• Many of the Nuremberg Principles
became formalized in the Helsinki
Declaration in 1964
• Declaration has been modified or updated
• Most recent modification addresses use
of placebo controls when a proven
therapy exists
Belmont Report (1979)
Ethical Principles & Guidelines
Sponsored by NIH
• Respect for Persons
– Persons with diminished autonomy are entitled
to protection (e.g. children, prisoners)
• Beneficence
– Maximize possible benefits and minimize
possible harm.
• Justice
– Fairness in distribution & access to
experimental treatment
人體試驗委員會之國際規定
• 赫爾辛基宣言第13點（2000.10）
所有以人為對象之研究計畫都必須經過倫理審查委員會的審
查及批准
– The design and performance of each experimental
procedure involving human subjects should be clearly
formulated in an experimental protocol. This protocol
should be submitted for consideration, comment,
guidance, and where appropriate, approval to a specially
appointed ethical review committee, which must be
independent of the investigator, the sponsor or any other
kind of undue influence. （52nd WMA General
Assembly, Edinburgh, Scotland, October 2000 ）
人體試驗委員會
1. 醫學雜誌要求論文需有人體試驗委員會同意函
。
2. 研究資助單位要求申請之計畫書需有人體試驗
委員會同意函。
3.美國從1981年起，政府贊助的各項研究，一定
要有人體試驗委員會同意函。
4.國家衛生研究院自1999年起。
5.衛生署自2000年起。
6.國科會自2001年起。
Study Protocol (1)
• Every well-designed clinical trial requires a
protocol
• The study protocol can be viewed as a written
agreement between investigator, the
participant, and the scientific community
• The contents provide the background, specify
the objectives, and describe the design and
organization of the trial
• The protocol serves as a document to assist
communication among those working in the
trial
Study Protocol (2)
• The protocol should be developed before the
beginning of participant enrollment and should
remain essentially unchanged except for minor
updates
• Major revisions that alter the direction of the trial
should be rare. If they occur, the rationale behind
such changes needs to be clearly described
• An example is the Cardiac Arrhythmia Suppression
Trial, which, on the basis of important study findings,
changed intervention, participant eligibility criteria,
and sample size
Purposes of a Protocol
1.
2.
3.
4.
5.
6.
To assist the investigator in thinking through the research.
To insure that both patient and study management are
considered at the planning stage.
To provide a “sounding board” for external comments.
To orient the staff for the preparation of forms and data
processing procedures.
To guide the treatment of the patient on the study.
To provide a document which can be used by other
investigators who wish to “confirm” the results or use the
treatment in practice.
Reference: Dana-Farber Cancer Institute: Outline to Writing a
Protocol
Format and Contents of a Protocol (1)
1. Protocol cover sheet
2. Background
3. Objectives
Primary
Secondary
4. Study plan
Study design
Subject inclusion criteria
Subject exclusion criteria
Treatment plan
Format and Contents of a Protocol (2)
5. Study drugs
Dose and route
Method of dispensing
Method and time of administration
Description of controls
Methods of randomization and blinding
Package and labeling
Duration of treatment
Concomitant medications
Concomitant procedures
Format and Contents of a Protocol (3)
6. Measurements and observations
Efficacy endpoints
Safety endpoints
Validity of measurements
Time and events schedules
Screening, baseline, treatment periods, and post-treatment
follow-up
Format and Contents of a Protocol (4)
7. Statistical methods
Database management procedures
Methods to minimize bias
Sample size determination
Statistical general considerations
Randomization and blinding
Dropout, premature termination, and missing data
Baseline, statistical parameters, and covariates
Multicenter studies
Multiple testing
Subgroup analysis
Interim analysis
Statistical analysis of demography and baseline characteristics
Statistical analysis of efficacy data
Statistical analysis of safety data
Format and Contents of a Protocol (5)
8. Adverse events
Serious adverse events
Adverse events attributions
Adverse event intensity
Adverse event reporting
Laboratory test abnormalities
9. Warning and precautions
10. Subject withdrawal and discontinuation
Subject withdrawal
End of treatment
End of study
Format and Contents of a Protocol (6)
11.Protocol changes and protocol deviations
Protocol changes
Protocol deviation
Study termination
12.Institutional review and consent requirement
Institutional review board (IRB)
Informed consent
Format and Contents of a Protocol (7)
13. Obligations of investigations and administrative aspects
Study drug accountability
Case report forms
Laboratory and other reports
Study monitoring
Study registry
Record retention
Form FDA 1572
Signatures of investigators
Confidentiality
Publication of results
Format and Contents of a Protocol (8)
14. Flow chart of studies activities
15. References
16. Appendixes
Standard statistical skills are necessary for
many clinical statistical roles. The expected
skills coming out of school include the
ability to:
• Design clinical studies
• Calculate sample size and/or power
• Develop analysis plans
• Handle missing data problems
• Check model assumptions
• Conduct sensitivity analyses
• Make proper inference in complex settings
Specialized Statistical Skills
• Epidemiologic methods for safety surveillance
• Imaging analysis for pre-clinical and clinical
imaging
• Pharmacogenomics and statistical genetics
for genetic biomarkers
• Deterministic and stochastic models for
model-based drug development
• Proteomics, metabanomics, metabalomics
• Pharmacokinetics, pharmacodynamics
• Bayesian approaches as alternative to
current standards
The General Flow of
Statistical Inference
Patient
Population
C
Protocol
Entry
Criteria
B
Sample
Patients On
Study
A
Inference about Population
Observed
Results