# Presentation: 416725

## Informed Consent, Institutional Review Boards, Data & Safety Monitoring Boards 

- Human Subjects Protection in Clinical Trials

## Human Subjects Protection:Ethical Principles 

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

## 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
*** ***

## Human Subjects Protection:Specific 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

## Human Subjects Protection:Linking 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

## Human Subjects Protection:Operationalizing the Ethical Principles 

- The Institutional Review Board (IRB) system
- Data Safety and Monitoring Boards
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## Institutional Review Board:IRB 

-   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

## Institutional Review Board:IRB 

-   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.*** ***

## Institutional Review Board:IRB 

-   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.

## Institutional Review Board:IRB 

-   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)

## Institutional Review Board:IRB 

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

## Data Safety and Monitoring Board: DSMB 

-  	 AKA :	Ethics Review Committee
- 			Ethics Committee
- 			Data Monitoring Committee

## 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

## Data Safety and Monitoring Board:DSMB

- 	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)

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

## 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 2000;283:2701***

## Requirement

Social or scientific value 			

- Social or scientific value

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

## Requirement

Scientific validity			

- 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

## Requirement

Fair subject selection		

- 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

## Requirement

Favorable risk-benefit ratio			

- 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

## Requirement

Independent review			

- 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

## Requirement
Informed consent			

- 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

## Requirement
Respect for potential and enrolled subjects		

- 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

## Women’s Health Initiative:Scientific Review 

- 	NIH
- 	IOM committee

## Women’s Health Initiative:Human 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

## Women’s Health Initiative:Safety 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

## Women’s Health Initiative:What 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....”

## Women’s Health Initiative:What 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.....”

## Women’s Health Initiative:The Safety Monitoring Plan

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

## Women’s Health Initiative:What 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”

## Women’s Health Initiative:Safety 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

## Women’s Health Initiative:Safety 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

## Requirement

Favorable risk-benefit ratio			

- 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

## Requirement
Respect for potential and enrolled subjects		

- 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

## Women’s Health Initiative:The 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

## 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