ethical issues in intervention studies (and any kind of research involving human subjects)
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Ethical Issues in Ethical Issues in Intervention StudiesIntervention Studies
Ethical Issues in Ethical Issues in Intervention StudiesIntervention Studies
(and any kind of research involving human subjects)
The Nuremberg Code The Nuremberg Code (1946-47 Trials)(1946-47 Trials)
The Nuremberg Code The Nuremberg Code (1946-47 Trials)(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
The Nuremberg Code The Nuremberg Code (1946-47 Trials)(1946-47 Trials)
The Nuremberg Code The Nuremberg Code (1946-47 Trials)(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
Declaration of Helsinki - 1964Declaration of Helsinki - 1964(Revised 1975)(Revised 1975)
Declaration of Helsinki - 1964Declaration of Helsinki - 1964(Revised 1975)(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.”
Other International GuidelinesOther International GuidelinesOther International GuidelinesOther 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
High Profile Mistakes in U.S.High Profile Mistakes in U.S.High Profile Mistakes in U.S.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.
Modern PerspectiveModern PerspectiveInstitutional Review Board (IRB)Institutional Review Board (IRB)
Modern PerspectiveModern PerspectiveInstitutional Review Board (IRB)Institutional 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).
Modern PerspectiveModern PerspectiveInstitutional Review Board (IRB)Institutional Review Board (IRB)
Modern PerspectiveModern PerspectiveInstitutional Review Board (IRB)Institutional 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
Modern PerspectiveModern PerspectiveInstitutional Review Board (IRB)Institutional Review Board (IRB)
Modern PerspectiveModern PerspectiveInstitutional Review Board (IRB)Institutional 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
Modern PerspectiveModern PerspectiveInstitutional Review Board (IRB)Institutional Review Board (IRB)
Modern PerspectiveModern PerspectiveInstitutional Review Board (IRB)Institutional 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
Informed Patient ConsentInformed Patient ConsentInformed Patient ConsentInformed 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…”
Design & Conduct of Design & Conduct of Clinical TrialsClinical Trials
Design & Conduct of Design & Conduct of Clinical TrialsClinical 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.
Issues in Clinical Trials:Issues in Clinical Trials:Cost and FeasibilityCost and Feasibility
Issues in Clinical Trials:Issues in Clinical Trials:Cost and FeasibilityCost 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.
Issues in Clinical Trials:Issues in Clinical Trials:
Statistical PowerStatistical Power Issues in Clinical Trials:Issues in Clinical Trials:
Statistical PowerStatistical 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.
Issues in Clinical Trials:Issues in Clinical Trials:
Statistical PowerStatistical Power Issues in Clinical Trials:Issues in Clinical Trials:
Statistical PowerStatistical 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
Issues in Clinical Trials:Issues in Clinical Trials:Selection of a Study PopulationSelection of a Study Population
Issues in Clinical Trials:Issues in Clinical Trials:Selection of a Study PopulationSelection 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.
Issues in Clinical Trials:Issues in Clinical Trials:Selection of a Study PopulationSelection of a Study Population
Issues in Clinical Trials:Issues in Clinical Trials:Selection of a Study PopulationSelection 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).
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation 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.
Issues in Clinical Trials:Issues in Clinical Trials:Issues in Clinical Trials: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!
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
2 x 2 Factorial Design:
Treatment BNo Yes
A B
C D
Tre
atm
ent
A
No
Yes
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation 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.
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation 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
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Randomization in Blocks:
Males FemalesBlock # Young Old Young Old
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
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation 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.
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation 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
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation 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
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation 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.
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation of Study Regimens-Designs
Issues in Clinical Trials:Issues in Clinical Trials:Allocation of Study Regimens-DesignsAllocation 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.
Issues in Clinical Trials:Issues in Clinical Trials:Characteristics of Control GroupsCharacteristics of Control Groups
Issues in Clinical Trials:Issues in Clinical Trials:Characteristics of Control GroupsCharacteristics 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.
What is a placebo?What is a placebo?What is a placebo?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.
Why use a placebo?Why use a placebo?Why use a placebo?Why use a placebo?
–Ensures that all aspects of the program offered to participants are identical, except for the actual experimental treatment
Clinical Trials - Maintenance and Clinical Trials - Maintenance and Assessment of ComplianceAssessment of Compliance
Clinical Trials - Maintenance and Clinical Trials - Maintenance and Assessment of ComplianceAssessment 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).
Protocol DeviationsProtocol DeviationsProtocol DeviationsProtocol 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
Clinical Trials - Outcome AssessmentClinical Trials - Outcome AssessmentClinical Trials - Outcome AssessmentClinical 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.
Blinding (Masking) in Clinical Trials - to Blinding (Masking) in Clinical Trials - to reduce observation biasreduce observation bias
Blinding (Masking) in Clinical Trials - to Blinding (Masking) in Clinical Trials - to reduce observation biasreduce 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.
Issues in AnalysisIssues in AnalysisIssues in AnalysisIssues 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).
Issues in AnalysisIssues in AnalysisIssues in AnalysisIssues 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
Early Trial TerminationEarly Trial TerminationEarly Trial TerminationEarly 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.
Early Trial TerminationEarly Trial TerminationEarly Trial TerminationEarly 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.
Early Trial TerminationEarly Trial TerminationEarly Trial TerminationEarly 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.
Early Trial TerminationEarly Trial TerminationEarly Trial TerminationEarly 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.
Review of Recommended ReadingReview of Recommended ReadingDiabetes Prevention ProgramDiabetes Prevention Program
Review of Recommended ReadingReview of Recommended ReadingDiabetes Prevention ProgramDiabetes 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.
Discussion Question 1Discussion 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.
Discussion Question 2Discussion 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.
Discussion Question 3Discussion 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.
Discussion Question 4Discussion Question 4
Interpret the results of table 2.
(i) 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.