Informed Consent, Institutional Review Boards, Data

1
Informed Consent, Institutional Review Boards,
Data Safety Monitoring Boards
Human Subjects Protection in Clinical Trials
2
Human Subjects ProtectionEthical Principles

• The Nuremberg Code (1947)
• Developed by the Nuremberg Military Tribunal as
  standards against which to judge human
  experimentation conducted by the Nazis

3
Nuremberg Code

• Freely given consent
• capacity to consent
• freedom from coercion
• comprehension of risks and benefits
• Minimization of risk from harm
• Favorable risk/benefit ratio
• Freedom to withdraw
• Qualified investigators using appropriate
  research designs

4
Human Subjects ProtectionSpecific Guidance

• Declaration of Helsinki (1964)
• Guidance for medical doctors in biomedical
  research involving human subjects (1964)
• revisions 1975, 1989, 1997
• Recommendations similar to Nuremberg Code

5
Human Subjects ProtectionLinking principles
with practice

• The Belmont Report (1979)
• Broad principles to use to generate specific
  rules and regulations to assure human
  subjects protection in the aftermath of scandals
  in which human subjects were not protected

6
Human Subjects ProtectionOperationalizing the
Ethical Principles

• The Institutional Review Board (IRB) system
• Data Safety and Monitoring Boards

7
Institutional Review BoardIRB

• An administrative body established to protect
  the rights and welfare of human research subjects
  recruited to participate in research activities
  conducted under the auspices of the institution
  with which it is affiliated

8
Institutional Review BoardIRB

• At least 5 members at least one of whom must be
  a scientist and one of whom must be a
  representative of the community who is not a
  scientist and is unaffiliated with the
  institution
• Must be free of financial and other conflicts
  to participate in review of specific projects.

9
Institutional Review BoardIRB

• A major responsibility is to assess the risks
  and benefits of the research before it begins
• The IRB judges whether the anticipated benefit,
  either to new knowledge or of improved health for
  the subjects, justifies any person to undertake
  the risk.

10
Institutional Review BoardIRB

• Determines that risks will be minimized,to the
  extent possible
• Assures subjects will be provided with an
  accurate and fair description of the risks or
  discomforts and the anticipated benefits (that
  consent is informed)

11
Institutional Review BoardIRB

• Conducts periodic review and assures, where
  appropriate, that adequate provisions are in
  place for monitoring data

12
Data Safety and Monitoring Board DSMB

• AKA Ethics Review Committee
• Ethics Committee
• Data Monitoring Committee

13
Data Safety and Monitoring Board DSMB Principles

• Independent experts
• Absence of conflict (financial and other)
• Confidential deliberations
• Masking of treatment in data review
• Predefined criteria for stopping

14
Data Safety and Monitoring BoardDSMB

• Directs or carries out data analyses for
  treatment effects
• Reviews interim reports to assess evidence for
  adverse or beneficial treatment effects
• Recommends changes in the protocol
• Terminates the study based on considerations
  related to human subjects protection (risks too
  great benefits too great risk/benefits
  unfavorable)

15

• Reports
• DSMB Local IRBs
• Risk/Benefit
• Consent Content
• Participant
• Protection

16
Seven Requirements for Ethical Clinical Trials

• Social or scientific value
• Scientific validity (equipoise)
• Fair subject selection
• Favorable risk-benefit rating
• Independent review
• Informed consent
• Respect for potential and enrolled subjects
• Emanuel JAMA 20002832701

17

• Requirement
• Social or scientific value

• Explanation
• Evaluation of a treatment, intervention, or
  theory that will improve health and well-being or
  increase knowledge

18

• Requirement
• Scientific validity

• Explanation
• Use of accepted scientific principles and
  methods, including statistical techniques, to
  produce reliable and valid data
• Equipoise.the belief, based on evidence that the
  treatments are equal

19

• Requirement
• Fair subject selection

• Explanation
• Selection of subjects so that stigmatized and
  vulnerable individuals are not targeted for risky
  research and the rich and socially powerful not
  favored for potentially beneficial research

20

• Requirement
• Favorable risk-benefit ratio

• Explanation
• Minimization of risks enhancement of potential
  benefits risks to the subject are proportionate
  to the benefits to the subject and society

21

• Requirement
• Independent review

• Explanation
• Review of the design of the research trial, its
  proposed subject population, and risk benefit
  ratio by individuals unaffiliated with the
  research

22

• Requirement
• Informed consent

• Explanation
• Provision of information to subjects about
  purpose of the research, its procedures,
  potential risks, benefits, and alternatives, so
  that the individual understands this information
  and can make a voluntary decision whether to
  enroll and continue to participate

23

• Requirement
• Respect for potential and enrolled subjects

• Explanation
• Respect for subjects by
• 1) permitting withdrawal from the research
• 2) protecting privacy through confidentiality
• 3) informing subjects of newly discovered risks
  or benefits
• 4) informing subjects of results of clinical
  research
• 5) maintaining welfare of subjects

24
Womens Health InitiativeScientific Review

• NIH
• IOM committee

25
Womens Health InitiativeHuman Subjects Review
at Initiation

• 41 local IRBs reviewed the WHI protocol and
  consent
• 41 of the reviewing IRBs approved the WHI
• no IRB reviewed the WHI and disapproved it

26
Womens Health InitiativeSafety Monitoring

• A 12 member DSMB was appointed
• It met every 6 months since 1997
• It developed a formal plan for safety monitoring
  and published information about its plan

27
Womens Health InitiativeWhat Were Women Told

• .Whether these pills protect women against
  heart disease and broken bones has been suggested
  but not proven by past studies. The WHI is
  specially designed to find out whether taking
  these hormone pills will prevent heart disease
  and fractures. The WHI will also see if there
  are other risks and benefits from taking hormone
  pills.

28
Womens Health InitiativeWhat Were Women Told

• .An independent committee of experts in medical
  research will review study results regularly to
  see if there are clear benefits or harmful side
  effects. You will be informed if definite
  benefits or harmful results are found during the
  study..

29
Womens Health InitiativeThe Safety Monitoring
Plan

• Boundaries were set for the primary beneficial
  effect (CHD) and for primary adverse effect and
  for global beneficial and adverse outcomes

30
Womens Health InitiativeWhat Were Women Told

• POSSIBLE RISKS
• (Bad Effects)
• Out of every 1,000 women taking estrogen
• and progesterone
• 4-8 more may get breast cancer
• Blood clots in the legs or lungs may increase
• Symptoms like a period may increase

31
Womens Health InitiativeSafety Monitoring
Outcome

• Stroke was not an anticipated adverse effect
• Risk of thromboembolism was greater than expected
  
• Expected increased risk of breast cancer emerged
  earlier than expected and was larger than
  expected
• CHD was not an anticipated adverse effect

32
Womens Health InitiativeSafety Monitoring
Outcome

• Global index indicated more harmful than
  beneficial outcomes in the estrogen plus
  progestin group
• If the study had found exactly the same increases
  in the risk of CHD, stroke, VTE, and breast
  cancer in the placebo group, early termination
  would not be controversial

33

• Requirement
• Favorable risk-benefit ratio

• Explanation
• Minimization of risks enhancement of potential
  benefits risks to the subject are proportionate
  to the benefits to the subject and society

34

• Requirement
• Respect for potential and enrolled subjects

• Explanation
• Respect for subjects by
• 1) permitting withdrawal from the research
• 2) protecting privacy through confidentiality
• 3) informing subjects of newly discovered risks
  or benefits
• 4) informing subjects of results of clinical
  research
• 5) maintaining welfare of subjects

35
Womens Health InitiativeThe Safety Monitoring
Plan

• Boundaries were set for the primary beneficial
  effect (CHD) and for primary adverse effect and
  for global beneficial and adverse outcomes
• These boundaries were crossed for the adverse
  event and for the global index and there were
  unanticipated adverse effects

36
Conclusion

• The WHI was conducted according to the highest
  ethical principles
• The decision to terminate the study was the
  correct decision considering human subjects
  protection
• No amount of gain in knowledge from
  continuation of a study is worth the loss to
  society when human subjects are not protected