1. Introduction to Clinical Trials
Chin-Fu Hsiao
Division of Biostatistics & Bioinformatics
National Health Research Institutes 2

2. Introduction to Clinical Trials
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 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

5. 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

6. 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

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
Sano crysin
(無機金鹽硫代硫酸金鈉)
(gold compound)
Control saline(鹽水)
injection
blinded

8. 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

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 (安慰劑)

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 Simon’s 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 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)

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

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 (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

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(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

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)
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

37. 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

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 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

40. 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

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. 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

45. 倫理委員會 Ethical Committee (EC) Clinical Ethical Committee
Human Subject Committee
Institutional Review Board (IRB)

46. 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

47. Tuskegee Syphilis study
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

48. 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)

49. 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 ）
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

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-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.

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 & 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

54. 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 ）

55. 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。

56. 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

57. 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

58. 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

67. 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

68. 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

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