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Table of Contents
                            Letter of Transmittal to the President
Letter from the President to the Commission
Members of the Commission
Commission Staff and Consultants
Executive Summary
	Improving Accountability
	Treating and Compensating for Research-Related Injury
	Creating a Culture of Responsibility: Human Research Protections as Professional Standards
	Respecting Equivalent Protections
	Promoting Community Engagement
	Justifying Site Selection
	Ensuring Ethical Study Design
	Promoting Current Federal Reform Efforts
	Following Up
Chapter 1
	The Need to Assess the Contemporary Environment
	Research Across Borders
	Contemporaneous Reviews of the Human Subjects Protection System
	About this Report
Chapter 2
	The Scope and Volume of Federal Human Subjects Research
	Current Rules
Chapter 3
Further Analysis and Recommendations
	Commission Recommendations
		1. Improving Accountability
		2. Treating and Compensating for Research-Related Injury
			Ethical Justification for Compensation
			Reparations for Unethical Research
			Designing a System of Compensation
		3. Creating a Culture of Responsibility: Human Research Protections as Professional Standards
		4. Respecting Equivalent Protections
		5. Promoting Community Engagement
		6. Justifying Site Selection
		7. Ensuring Ethical Study Design
			Towards a Middle Ground on Study Design
				(1) Treatment Standards
				(2) Methodological Constraints
				(3) Risk Minimization
		8. Promoting Current Reform Efforts
			Ensuring Risk-Based Protections
			Streamlining IRB Review of Multi-Site Studies
			Improving Informed Consent
			Clarifying and Harmonizing Regulatory Requirements and Agency Guidance
			Data Collection to Enhance Adverse Event Reporting
		9. Following Up
	Appendix I: Human Subjects Research Landscape Project: Scope and Volume of Federally Supported Human Subjects Research
	Appendix II: Human Subjects Research Landscape Project Methods
	Appendix III: U.S. Treatment/Compensation for Treatment Methods
	Appendix IV:  International and Transnational Requirements for Treatment and Compensation for Research Injuries
	Appendix V: International Research Panel
	Appendix VI: Guest Speakers
Document Text Contents
Page 1

December 2011

Protecting Participants in
Human Subjects Research

Presidential Commission
for the Study of Bioethical Issues

Page 2

Updated edition June 2012

Page 104

MOR AL SCIENCE Protecting Participants in Human Subjects Research


The standard of care available to subjects in a control group need not be
the best-proven, especially when there is uncertainty about whether such a
standard would be best for the local population under study. Thus, in spite
of the rhetorical appeal of the “no double standards” objection, it has become
increasingly evident that trial designs offering human subjects an intervention
that falls short of the best-proven approach can pass moral muster without
relying on moral relativism (which would underlie an objectionable double
standard), provided that certain rigorous conditions are met.

First, any application of clinical equipoise must carefully and scrupulously
take into account local context. This does not, however, mean that the appro-
priate measure of the standard of care for determining ethical study design
should be the level of access currently afforded to the study population. The
so-called “local de facto” standard permits the deployment of placebos in
control groups whenever the local “standard of care” is in fact no care at
all.210 But to call “no treatment” due to impoverished health care budgets
the local “standard of care” is to distort the meaning of standard of care as a
guiding medical norm.211

Recognizing that meaningful debate on this issue continues, the Commission
finds that the optimal standard lies between the “best-proven” and “local de
facto” interpretations: for example, a standard of care that would or should
be optimal for a certain population; given their health needs and the level of
available medical and logistical infrastructure, cultural practices, genetics,
and economic capacity to sustain treatment into the future.

The Commission recognizes too that a rigid insistence upon a best-proven
standard could have the unintended consequence of precluding meaningful
research and achievable health reforms in relatively poor host countries. As
Zulfiquer Bhutta, a well-known pediatrics expert, has noted, major progress in
treating newborns with suspected sepsis has recently been achieved in India,
but such progress would have been unlikely had the best-proven standard
of care, intravenous antibiotics, been ethically required of the researchers.
Instead, the researchers were able to compare an intervention against the local
standard of care and conclude that the intervention was both accessible to the
population and more effective than the local standard.212

Page 105



(2) Methodological Constraints

Second, the scientific design of a trial must be adequate to yield usable
results. Absent this, results will not be credible and human subjects would
have been exposed to risk unnecessarily. However, there is disagreement
about the level of confidence required for sound science and adequate trial
design. Some insist that a placebo-controlled, double-blinded, random-
ized trial is the gold standard for testing new interventions or treatments.
Others regard insistence upon such a design as counter-productive, and an
inappropriate dismissal of potential trial results that may be somewhat less
conclusive but obtainable without the potentially unacceptable ethical costs
of a placebo-controlled trial.213

The Commission does not need to take sides in this debate to agree that
the results of clinical trials must be amenable to definitive interpretation.
As Robert Temple and Susan Ellenberg, clinical trial experts from the FDA,
have pointed out, it is highly desirable that the meaning and significance of
studies be contained within the study itself.214 Ideally, one should not have to
rely on results outside of a trial to interpret a single trial’s results. In placebo-
controlled trials, this additional outside evidence is not required because the
study itself can show that the intervention being tested is better than no inter-
vention. But in some designs, for example “equivalency” designs (trying to
show that the intervention being studied is at least as good as an intervention
already being employed), previous studies demonstrating the effectiveness of
the intervention already being employed in a similar population are required.
Temple and Ellenberg describe this as the problem of “assay sensitivity.”
Absent a placebo control or independent evidence taken from outside the
trial that the intervention already being employed is effective, researchers will
be unable to interpret the study’s results.215 This sort of design is appealing,
however, because it does not subject trial subjects to the medical risks of a
placebo control. It is, however, logistically and economically more challenging
because it requires the recruitment of more subjects for trials of longer dura-
tion and greater expense.216

Similar worries concern equivalency trials wherein the new drug is expected
to perform less well than the established standard, as in the perinatal AZT
trials, but there are compelling policy reasons to find an alternative to the

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Presidential Commission for the Study of Bioethical Issues
1425 New York Avenue NW, Suite C-100
Washington, D.C. 20005
(202) 233-3960

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