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Title: Chin-Fu Hsiao


1
Introduction to Clinical Trials
  • Chin-Fu Hsiao
  • Division of Biostatistics Bioinformatics
  • National Health Research Institutes
  • chinfu_at_nhri.org.tw

2
Chapter 1
  • Introduction to Clinical Trials

3
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.

4
Clinical TrialsNatural Experiment
  • General Lancaster (1600)
  • East Indian Shipping Co.
  • 4 ships - Lancasters ship luckily had lemon
    juice on board
  • Lancasters ship remained free of scurvy (???)
  • Natural Experiment, not planned

5
Clinical TrialsPlanned Experiment
  • Smallpox (??)Experiment (1721)
  • Perhaps first planned experiment
  • Lady Mary Wortley Montaque
  • Six inmates of Newgate Prison
  • Sentence commuted if they volunteered for
    inoculation (??)
  • All remained free ? Inoculation effective
  • No concurrent control group

6
Clinical TrialsConcurrent 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
    recovered

7
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

randomized
12
12
blinded
Control saline(??) injection
Sano crysin (??????????) (gold compound)
8
Clinical TrialsUse of Randomization
  • Multicenter Trials (1944) - Common Cold
  • Medical Research Council
  • Treatment of common cold
  • Different sites all using common protocol
  • Patulin(????) vs. Placebo
  • MRC Tuberculosis Trial (1948) Grandfather
    Trial
  • (Ref British Medical Journal, 1948)
  • Randomized (by random numbers)
  • Streptomycin(???) vs. Placebo
  • Based on work of Bradford Hill, founder of modern
    day clinical trial
  • Supported Concept of Randomization

9
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 (???)

10
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

11
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 (case-control
    study)
  • Each patient must be followed from a well-defined
    point, which becomes time zero or baseline for
    the study

12
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)

13
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
    self-administered or prescribed by others

14
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

15
Clinical trial Phases
  • Phase I studies
  • Phase II studies
  • Phase III studies
  • Phase IV studies

16
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

17
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

18
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

19
Phase II Studies (2)
  • The most commonly used phase II designs in cancer
    is Simons two-stage design
  • In the first stage the investigator tries to rule
    out drugs that have no or little biologic
    activity

20
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

21
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 sequel 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)

22
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

23
Why Are Clinical Trials Needed? (2)
  • Only recently, after the drug (digitalis???,?????)
    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
    (????????) documented that commonly used
    antiarrhythmic drugs were harmful in patients who
    had had a myocardial infarction (????) and raised
    questions about routine use of an entire class of
    antiarrhythmic agents

24
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

25
Why Are Clinical Trials Needed? (4)
  • Thrombolytic therapy (??????)
  • 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

26
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

27
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

28
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

29
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

30
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

31
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

32
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

33
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

34
Problems in the Timing of a Trial (4)
  • In the Veterans Administration study of coronary
    artery bypass surgery(????????), 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

35
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)

36
When Should a Clinical Trial Be Started?
  • 1. Intervention (knowledge about it)
  • Safety
  • Correct dose/duration
  • Final form (TPA story)
  • Defining study population (PHS)
  • Shelf Life
  • 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

37
Ethics (1)
  • The issues center around the issues of the
    physicians 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

38
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

39
Ethics (3)
  • Proper informed consent is essential
  • Simply adhering to legal requirements does not
    ensure informed consent
  • The investigator is obligated to update the
    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

40
Ethics (4)
  • A trial of antioxidants (????) 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

41
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

42
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

43
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

44
Ethics (8)
  • Moral quality of a course of action
  • Rules or standards governing the conduct of a
    profession
  • Societys view of ethical behavior in the context
    of a course of action changes over time.
  • Ethical behavior may vary with individuals,
    ethnic groups and countries.

45
?????????Tom L. Beauchamp?James F. Childress 1979
  • ??????
  • (the principle of respect for autonomy)?
  • ?????
  • (the principle of nonmaleficence)
  • ????
  • (the principle of beneficence)
  • ??????
  • (the principle of justice)

The Principles of Biomedical Ethics
46
Ethical Committee (EC)

Clinical Ethical Committee
?????
Human Subject Committee
Institutional Review Board (IRB)
47
??????????
  • ??????????????
  • ????200?, 40???
  • ????300?, 30???
  • ?????? 25???
  • ???????????????
  • 731???
  • ???Tuskeegee Trial

48
Tuskegee Syphilis study
  • 1932-1972??Public Health Service???????
  • Alabama/Macon county/Tuskegee
  • 600?????
  • 400????????
  • 200??????
  • 1950???????,???????,????????
  • ???100????????????
  • ???40????????
  • ???19?????????????
  • 1972???????1973????
  • ??????1997?5?16???????????????

49
???????????????
1. ?????Nuremberg Code for Human
Experimentation (1945) 2. WMA(World Medical
Association)? Declaration of Helsinki (1964)
(??????????????,????? ????????????)
50
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

51
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 scientifically-quali
    fied 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.

52
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

53
Belmont Report (1979)Ethical Principles
GuidelinesSponsored 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

54
????????????
  • ???????13?(2000.10)
  • ??????????????????????????????
  • 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 )

55
?????????????????
  • ?????(Nuremberg Code 1949)
  • ??????????
  • ??????(Helsinki Declaration 1964 1975 1983 1989
    1996 2000)
  • ??????????????
  • ??????
  • ?????????????
  • Belmont Report 1979
  • ????????????
  • ???????????????

56
???????(IRB)
1. ????????????????????? 2. ??????????????????????
????? 3.???1981??,?????????,??????????????? 4.????
????1999??? 5.????2000??? 6.????2001???
57
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

58
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

59
Purposes of a Protocol
  • 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

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  • 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

69
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

70
The General Flow of Statistical Inference
Protocol Entry Criteria
Sample Patients On Study
Patient Population
Observed Results
B
A
C
Inference about Population
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