Chin-Fu Hsiao Division of Biostatistics & Bioinformatics National Health Research Institutes [email protected] Introduction to Clinical Trials

Chin-Fu Hsiao

Division of Biostatistics & Bioinformatics

National Health Research Institutes

[email protected]

Introduction to Clinical TrialsIntroduction to Clinical Trials

Chapter 1Chapter 1

Introduction to Clinical Trials

REFERENCESREFERENCES

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 TrialsClinical TrialsNatural ExperimentNatural 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 TrialsClinical TrialsPlanned ExperimentPlanned 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 TrialsClinical TrialsConcurrent ControlConcurrent 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 TrialsClinical Trials

• Concept of Randomization in designed experiments, introduced by Fisher into agriculture in 1926

• First randomized clinical trial 1931 by Amberson in tuberculosis patients

Sano crysin

( 無機金鹽硫代硫酸金鈉 ) (gold compound)

Control saline( 鹽水 )injection

blinded

randomized12 12

Clinical TrialsClinical TrialsUse of RandomizationUse 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

BlindnessBlindness

• 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 )


• 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?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

Intervention TechniquesIntervention 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 GroupControl 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


• 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 PhasesClinical trial Phases

• Phase I studies

• Phase II studies

• Phase III studies

• Phase IV studies

Phase I Studies (1)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)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)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)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 StudiesPhase 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 StudiesPhase 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? Why Are Clinical Trials Needed? (1)(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? Why Are Clinical Trials Needed? (2)(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)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


• 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


• 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


• 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


• 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


• 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


• 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 Problems in the Timing of a Trial (1)(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


• 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


• 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


• 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


• 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?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)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


• 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


• 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


• 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


• 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


• 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


• 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醫學倫理學四大原則Tom L. BeauchampTom L. Beauchamp 及及 James F. Childress 1979James 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

倫理委員會

Ethical Committee (EC)

Clinical Ethical Committee

Human Subject Committee

Institutional Review Board (IRB)

二次大戰後逐漸被重視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

• 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

Tuskegee Syphilis study

醫學研究的倫理準則醫學研究的倫理準則兩個重要宣言兩個重要宣言

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 )

• 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

以人為對象之生物醫學研究的倫理規範

The Nuremberg Code The Nuremberg Code (1)(1)Some PrinciplesSome 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 CodeThe Nuremberg Code (2) (2) Some Principles 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-qualified 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 HelsinkiThe Declaration of Helsinki(1964,2000)(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)Belmont Report (1979)Ethical Principles & GuidelinesEthical Principles & Guidelines

Sponsored by NIHSponsored 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

• 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 ）

人體試驗委員會之國際規定

人體試驗委員會人體試驗委員會

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)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)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 ProtocolPurposes of a Protocol

1. To assist the investigator in thinking through the research.2. To insure that both patient and study management are

considered at the planning stage.3. To provide a “sounding board” for external comments.4. To orient the staff for the preparation of forms and data

processing procedures.5. To guide the treatment of the patient on the study.6. 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


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


6. Measurements and observations

Efficacy endpoints

Safety endpoints

Validity of measurements

Time and events schedules

Screening, baseline, treatment periods, and post-treatment

follow-up


7. Statistical methodsDatabase management proceduresMethods to minimize biasSample size determinationStatistical general considerations

Randomization and blindingDropout, premature termination, and missing dataBaseline, statistical parameters, and covariatesMulticenter studiesMultiple testingSubgroup analysisInterim analysis

Statistical analysis of demography and baseline characteristicsStatistical analysis of efficacy dataStatistical analysis of safety data


8. Adverse eventsSerious adverse eventsAdverse events attributionsAdverse event intensityAdverse event reportingLaboratory test abnormalities

9. Warning and precautions10. Subject withdrawal and discontinuation

Subject withdrawalEnd of treatmentEnd of study


11.Protocol changes and protocol deviations

Protocol changes

Protocol deviation

Study termination

12.Institutional review and consent requirement

Institutional review board (IRB)

Informed consent


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


14. Flow chart of studies activities

15. References

16. Appendixes

Standard statistical skills are necessary formany clinical statistical roles. The expectedskills coming out of school include theability 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 SkillsSpecialized 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 The General Flow of Statistical InferenceStatistical Inference

Patient Population

Sample Patients On

Study

Observed Results

Inference about Population

Protocol Entry

Criteria

C B A

Documents

Chin-Fu Hsiao Division of Biostatistics & Bioinformatics National Health Research Institutes [email protected] Introduction to Clinical Trials