Ethical Issues in Intervention Studies

1. Ethical Issues in Intervention Studies (and any kind of research involving human subjects)

2. The Nuremberg Code (1946-47 Trials) • “Experimentation” by Nazi physicians was exposed in 1946-47 trials. Resulting code adopted 10 principles: • Study participants must give voluntary consent • There must be no reasonable alternative to conducting the experiment • Anticipated results must have a basis in biological knowledge and animal experimentation • Procedures should avoid unnecessary suffering and injury

3. The Nuremberg Code (1946-47 Trials) • No expectation for death or disability as a result of the trial • Degree of patient risk is consistent with the humanitarian importance of the study • Subjects are protected against even a remote possibility of death or injury • Study must be conducted by qualified scientists • The subject can stop participation at will • Investigator must terminate the experiment if injury seems likely

4. Declaration of Helsinki - 1964(Revised 1975) • Issued by the World Medical Association who adopted a formal code of ethics for physicians engaged in clinical research “It is the mission of the physician to safeguard the health of the people.” “Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.”

5. Other International Guidelines • 1982 - World Health Organization (WHO) and Council for International Organizations of Medical Sciences (CIOMS) Document: -- “Proposed International Guidelines for Biomedical Research Involving Human Subjects” Document: -- International Guidelines for Ethical Review of Epidemiologic Studies

6. High Profile Mistakes in U.S. • 1936 -- Tuskegee Alabama: Study of the effects of untreated syphilis which continued long after an effective treatment was known. • 1963 -- Brooklyn - Jewish Chronic Diseases Hospital: Cancer cells were injected into debilitated elderly patients to see if they would immunologically reject the cells. • 1972 - Willowbrook State Hospital in New York: Retarded children were deliberately infected with viral hepatitis to study its natural history.

7. Modern PerspectiveInstitutional Review Board (IRB) • IRBs are required for all research funded in whole or in part by the federal government. • IRB approval is required for all drugs or products regulated by FDA (regardless of the funding source).

8. Modern PerspectiveInstitutional Review Board (IRB) Composition of IRBs: --- At least 5 members with relevant expertise --- At least one scientist and one non- scientist --- At least one person not affiliated with the institution --- Diverse racial, gender, and cultural backgrounds

9. Modern PerspectiveInstitutional Review Board (IRB) • Research requirements judged by IRBs: • Risks to study participants are minimized • Risks are reasonable in relation to anticipated benefits • Selection of study participants is equitable

10. Modern PerspectiveInstitutional Review Board (IRB) • Research requirements judged by IRBs (cont.): • Informed consent is obtained and appropriately documented for each participant • Adequate provisions for monitoring data collection to ensure safety of the study participants • Participant privacy and confidentiality is protected

11. Informed Patient Consent • “…the doctor should obtain the subject’s freely-given informed consent, preferably in writing…” • “…if the doctor considers it essential not to obtain informed consent, the specific reasons for this proposal should be stated in the experimental protocol…”

12. Design & Conduct of Clinical Trials Axiom: The randomized clinical trial represents “The Gold Standard” for epidemiological research. However, other study designs can be equally valid, and a RCT does not guarantee a valid study.

13. Issues in Clinical Trials:Cost and Feasibility • Clinical trials are expensive and unwieldy to conduct (require collaboration between patients, physicians, nurses, data managers, methodologists, etc.). • Secular trends in health behavior may make some interventions difficult to test (e.g. antioxidants). • Large simple trials with streamlined protocols are being advocated by many today. • Ethical guidelines and concerns continue to evolve.

14. Issues in Clinical Trials:Statistical Power • Definition of Power: The probability of rejecting the null hypothesis of no association when a true association exists. • Clinical trials must have sufficient power to reliably detect small-to-moderate yet clinically important differences between treatment groups that are likely to occur.

15. Issues in Clinical Trials:Statistical Power • Power of a trial may be less than expected because: • The number of outcomes is less than expected • Observation bias • Loss to follow-up

16. Issues in Clinical Trials:Selection of a Study Population • Define the reference population -- to whom will the results of the study be applicable. • Experimental population -- the actual group in which the trial is conducted. Ideally, should match the reference population. • Sufficient outcomes must be expected. • Willing participants must be screened for eligibility according to pre-defined criteria. • Willing and eligible comprise the actual study population.

17. Issues in Clinical Trials:Selection of a Study Population • The actual study population is often a small fraction of the experimental population. • Be careful, the eligible and willing participants may experience less outcomes than expected (“volunteer effect”). • Try to obtain baseline data for eligible but unwilling individuals (e.g. to aid in determining generalizability of results).

18. Issues in Clinical Trials:Allocation of Study Regimens-Designs • Simple Randomization: • Participants are assigned at random to one of the treatment regimens (parallel groups). • Randomization Assignment Means: • Each individual has the same chance of receiving each of the possible treatments. • The probability that a subject receives a treatment is independent of the probability of other individuals receiving the same treatment.

19. Issues in Clinical Trials: Advantages of Random Assignment: • Potential for bias in allocation to study groups is removed (since no one involved in deciding patient eligibility or procedure allocation will know assigned treatment group). • Study groups will be comparable with respect to all variables except for the intervention being studied. • Randomization can control for known and unknown confounding!

20. Issues in Clinical Trials:Allocation of Study Regimens-Designs • 2 x 2 Factorial Design: Treatment B No Yes No Yes Treatment A

21. Issues in Clinical Trials:Allocation of Study Regimens-Designs • Strengths of the 2 x 2 Factorial Design: • In some circumstances, two treatments can be tested using the same number of subjects and minimal additional cost. • The interaction (effect modification) of the two treatments can be evaluated.

22. Issues in Clinical Trials:Allocation of Study Regimens-Designs • Limitations of the 2 x 2 Factorial Design: • The two treatments must be amenable to being administered in combination (e.g. collective side effects can not make the regimen hazardous) • Not appropriate for treatments that are believed to have the same mechanism of action

23. Issues in Clinical Trials:Allocation of Study Regimens-Designs Males Females Block # YoungOldYoungOld 1 A B B A 1 B B A B 1 B A B A 1 A A A B 2 A B A B 2 A A B B 2 B B A A 2 B A B A • Randomization in Blocks:

24. Issues in Clinical Trials:Allocation of Study Regimens-Designs • Advantages of Randomization in Blocks: • Improves the balance in the number of treatment assignments in each group. • Makes the sequence of assignments more random.

25. Issues in Clinical Trials:Allocation of Study Regimens-Designs • Crossover Design: • Each treatment is administered to each patient at different times in the study • Permits within-patient comparisons of treatment effects • Each person serves as their own “control” • May improve recruitment since subjects are offered both treatments

26. Issues in Clinical Trials:Allocation of Study Regimens-Designs • Crossover Design – Disadvantages: • Be careful -- “carry-over” effects may be present • Be careful -- There may be a treatment by period interaction • The analysis is more complex than in a parallel groups design

27. Issues in Clinical Trials:Allocation of Study Regimens-Designs • Equivalence Trials: • Research question is whether an existing/new therapy is as effective as a standard therapy. • Traditional hypothesis testing is reversed: • The “null hypothesis” is that the treatments are different. • Statistical testing is performed to test whether the treatments are sufficiently similar.

28. Issues in Clinical Trials:Allocation of Study Regimens-Designs • Equivalence Trials: Frequently used to test “bioequivalence” or compare efficacy of therapies with different costs and side effects. • Be careful, misclassification tends to cause the treatment groups to be more similar – this results in bias away from the null.

29. Issues in Clinical Trials:Characteristics of Control Groups • Spontaneous remission • Hawthorne Effect -- Subjects may change behavior because they are being observed. • Regression to the mean -- Extreme values on initial examination show improvement during subsequent exams, by chance alone. • Placebo Effect -- Tendency of individuals to report a favorable response to any therapy regardless of the physiologic efficacy of what they receive.

30. What is a placebo? • Physiologically inert substance that is identical in physical characteristics to the active drug. • Placebo effect: Persons taking a drug or undergoing a medical procedure tend to ascribe any symptom to their treatment.

31. Why use a placebo? • Ensures that all aspects of the program offered to participants are identical, except for the actual experimental treatment

32. Clinical Trials - Maintenance and Assessment of Compliance • Maintaining high compliance with the treatment protocol is a major issue. • Non-compliance is generally related to the length of time required for adherence to the study protocol and to the complexity of the protocol. • Non-compliance decreases statistical power -- by making the two treatment groups more similar. • Non-compliance is a threat to the validity of the study results (e.g. when a “null” result is observed).

33. Protocol Deviations • Methods to assess non-compliance: • Give more pills than needed and count the remaining pills during follow-up • Measure drug concentration in serum or urine • Measure drug-induced biochemical changes

34. Clinical Trials - Outcome Assessment • Goal is to obtain complete and unbiased information. • As follow-up time increases, maintaining complete • ascertainment of outcomes becomes more difficult. • When the proportion of outcomes not ascertained is large or differs among the study groups, a biased result is likely. • The potential for observation bias is related to non-use of masking (blinding) and subjectivity of the study outcomes.

35. Blinding (Masking)

36. Blinding (Masking) in Clinical Trials - to reduce observation bias • Single Blind Trials • Patients do not know their treatment assignment. • Double Blind Trials • Neither patient nor investigator responsible for assessing the outcome knows treatment assignment (especially useful for “subjective” outcomes). • Triple Blind Trial • Patients, investigators, and evaluators (e.g. Data Safety and Monitoring Committee) do not know treatment assignment.

37. Issues in Analysis • Always compare baseline characteristics of the study groups to assess the effectiveness of randomization in balancing the treatment groups. • Which subjects should be included in the analysis? • Remove non-compliers? (general rule is NO). • “Intention to Treat” (e.g. once randomized always randomized). • Keep in mind that the research question posed is whether offering of the treatment program is of benefit (not whether or not compliance is).

38. Issues in Analysis • Subgroup Analyses: • A priori versus post-hoc analyses • Problem of multiple comparisons and the role of chance • Overall balance achieved by randomization is not assured when subgroup analyses are performed

39. Early Trial Termination • Stopping Rules: • Rules to decide whether a trial should be terminated or modified before originally scheduled. • Used to assure the welfare of study participants is protected. • Interim results should be monitored by an outside (independent) entity.

40. Early Trial Termination • Reasons for Early Termination: • Data indicate a clear and extreme benefit on the primary study outcome (e.g. would be unethical to allow other continuation with the less effective treatment regimen(s)). • Treatments are found to be convincingly not different by impartial knowledgeable experts. • A treatment is observed to be clearly harmful.

41. Early Trial Termination • Reasons for Early Termination (cont.): • The data are of poor quality. • Subject accrual is too slow to complete the study in a timely fashion. • Definitive information becomes available from outside the study, making the trial unnecessary or unethical.

42. Early Trial Termination • Reasons for Early Termination (cont.): • Adherence to treatment regimens is unacceptably poor, preventing an answer to the basic research question. • Resources to perform the study are lost or no longer available. • The study integrity has been undermined by fraud or misconduct.

43. Review of Recommended ReadingDiabetes Prevention Program --- Multi-center trial of 3,234 persons at “high-risk” of developing diabetes. --- Randomly assigned to either (i) standard lifestyle + placebo; (ii) standard lifestyle + metformin; (iii) intensive lifestyle modification program. --- Adherence to assigned treatment regimens assessed quarterly. --- Goals of intensive lifestyle program were reduction of >7% of body weight and engage in moderate physical activity for >150 minutes per week. --- Primary outcome measure was incident diabetes. --- Participants followed for average of 2.8 years.

44. Discussion Question 1 In table 1, does it appear that the process of random assignment balanced the 3 study groups in terms of potential confounding variables? Source: NEJM 2002; 346:393-403.

45. Discussion Question 2 In figure 1, does it appear that the intensive lifestyle intervention program was truly implemented and maintained over the course of the study? Source: NEJM 2002; 346:393-403.

46. Discussion Question 3 Interpret the results of figure 2. (i) Was the effect of treatment assignment consistent over the course of the study? (ii) The “effect sizes” observed may be underestimates of the true effect – Why? Source: NEJM 2002; 346:393-403.

47. Discussion Question 4 • Interpret the results of table 2. • Is there evidence of effect measure • modification (i.e. the effect of treatment • assignment varied according to baseline • characteristics such as age or gender?) Source: NEJM 2002; 346:393-403.

48. Discussion Question 5 Comment on the adverse events presented in table 3. Are the results for GI symptoms surprising? Source: NEJM 2002; 346:393-403.