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2012 VA IRB Chair MeetingTuesday, August 14, 2012

Remembering Ethics -- When Legal & Ethical Constraints Diverge in Human Subjects Protection

Valerie H. Bonham Senior AttorneyOffice of the General CounselU.S. Department of Health and Human Services

2Objectives

• Recognize the interplay of bioethics and law and the reasons why both need to be considered in protecting research subjects.

• Understand U.S. legal framework for protecting human research subjects – domestically and internationally.

• Discuss 3 example cases, old and new, where legal standard may be met, but ethics clearly fell short.

3Bioethics & Law – Overlap

• Bioethics principles, e.g., respect for persons and individual autonomy, are often reflected in law.– Example: Informed consent, in U.S. law:

– 21 U.S.C. 355 (requiring informed consent in certain FDA-regulated research since 1962)

– 42 U.S.C. 218 (requiring informed consent in HHS-funded research since 1974)

– 45 CFR Part 46.116 (Common Rule)– 21 CFR Part 50 (FDA equivalent)

– See, also, requirements to minimize risk & avoid unnecessary harms, e.g., in U.S. Common Rule, 45 CFR Part 46.111 (Criteria for IRB review)

4Bioethics & Law – What’s the difference?

Over-simply --• Both are concerned with distinguishing what is right from

what is wrong. – Set standards & boundaries to guide action.

• Bioethics: Arises from moral philosophy and religious traditions; violators face moral sanction.

• Law: Arises from authority of the government; violators face civil & sometimes criminal penalties.

• Sometimes divergent actions, e.g.,– Access to care & compensation for research injuries.

• Law reaches broader issues, e.g., peer review for U.S. grants.

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1. HHS Regulations (“the Common Rule”), 45 C.F.R. Part 46

-- Apply directly to international research when U.S. funded.

2. FDA Regulations, 21 CFR Parts 50, 56, 312, 812.

-- Apply to international research when FDA approval sought.

** Collectively, these extend to most, but not all research in the United States and some research internationally.

U.S. Legal Framework – Main Sources

6U.S. Legal Framework

SOURCE: U.S. PRESIDENTIAL COMMISSION FOR THE STUDY OF ETHICAL ISSUES, MORAL SCIENCE (2011)

7U.S. FUNDING –LOCATIONSOURCE: U.S. PRESIDENTIAL COMMISSION FOR THE STUDY OF ETHICAL ISSUES, MORAL SCIENCE (2011)

8Informed Consent – Bioethics & Law

• Largely overlap, but….• Sometimes law may permit what bioethics might

reject, including, case-by-case: – Residual use of “de-identified” samples

• 45 CFR 46 is limited to research use of data with “identifiable private information” or obtained through intervention or interaction with a living individual; and

• “Identifiability” of genetic samples and scope of consent presents recurring challenges.

9Compliance

• For many, complying with law is marker for satisfying ethical principles

• U.S. Government regulatory compliance efforts are broad:– OHRP, FDA: myriad guidance documents,

enforcement programs, etc.– NIH: numerous policies, grant statements,

enforcement, withhold funding, etc.

• We focus on legal compliance… some times to our detriment.

10What is Legal is Not Always Ethical

Jewish Chronic Disease Hospital (1963)• Patients injected with live cancer cells;• Patients deceived; and• No signed or documented consent.

– Lead investigators suspended following administrative review (amd law suit for records), but one elected vice-president of AACR shortly after.

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National Commission for the Protection of Human Subjects of Biomedical

and Behavioral Research• Congressional mandate to:

– Identify ethical principles underlying human subjects research

– Develop guidelines to be followed• The Belmont Report (1979)

– Enduring framework for medical research ethics today

U.S. Ethics Framework – Some Sources

12The Guatemala Experiments

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“The President reaffirmed the United States’ unwavering commitment to ensure that all human medical studies conducted today meet exacting U.S. and

international legal and ethical standards. ”October 1, 2010

National Reaction – 2010

14International Reaction – 2010

15Investigation Timeline

Timeline

• June 2003 Reverby discovers Dr. Cutler records at University of Pittsburgh.

• May 2010 Reverby notifies Dr. David Sencer, former Director of the Centers for Disease Control and Prevention.

• Summer 2010 U.S. recovers Cutler documents and undertakes preliminary review.

• October 2010 Public release; President and Secretaries, Sebelius and Clinton, apologize; Secretaries announce independent Investigation.

• November 2010 President charges Commission.

• January 2011 Commission begins investigation.

• September 2011 Commission issues historical report.

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• Reviewed over 125,000 pages of original records and 550 published documents– Over 10,000 pages from Cutler archives– Searches conducted in archives across US

• Consulted independent JHU syphilologist with 30+ years experience.

• Prepared subject database with 1,074,196 entries.

Investigation Methods

17Research Design

• Original goal: to test the orvus-mapharsen prophylaxis wash as a prophylaxis for syphilis in prisoners exposed to infected commercial sex workers.

• Intentional exposure studies conducted 1946-1948 with:– commercial sex workers – prisoners– Guatemalan soldiers, and – psychiatric hospital patients.

• Exposure methods: sexual intercourse, skin contact, direct injection, scarification/abrasion, and cisternal punctures.

18Research Design, cont’d.

• Serology studies conducted 1946-1953 with– most subjects from intentional exposure studies, – children from orphanage and school, – leprosarium patients, and – U.S. Air Force Personnel

• Serology methods: blood draws, lumbar punctures, and cisternal punctures.

19Research Design, cont’d.

• No record of any of the subjects giving consent. – Some subjects, including those with mental illness and

children, did not have the capacity to consent. – Evidence shows that researchers intentionally deceived

some subjects about the nature of the study and what was being done to them.

20Subject Specific Data

• Total Subject numbers: 5540

1. Intentional exposure: 1308

678 of whom show some record of treatment

2. Diagnostic testing: 5128

820 of whom show some record of treatment

21Subject Age Ranges

• Subject age ranges:

1. Intentional exposure: 10 to 72 years.• Mean: 25• Mode: 20• Median: 22

2. Diagnostic testing: 1 to 72 years.

22Subject & Population Summary

SOURCE: U.S. PRESIDENTIAL COMMISSION FOR THE STUDY OF ETHICAL ISSUES, ETHICALLY IMPOSSIBLE (2011)

23SUBJECT PROFILE : BERTASOURCE: U.S. PRESIDENTIAL COMMISSION FOR THE STUDY OF ETHICAL ISSUES, ETHICALLY IMPOSSIBLE (2011)

24FEMALE PSYCHIATRIC PATIENT LIST

25SYPHILIS EXPERIMENT PROTOCOL

26SUBJECT SEROLOGY RESULTS

27SUBJECT CLINICAL NOTECARD

28Institutional Support

• Public Health Service Venereal Disease Division– Funded grant, supplied staff, design, and supplies

• Now part of the CDC • NIH

– Issued 2-year grant to Pan American Sanitary Bureau (PASB)• Now the Pan American Health Organization

• PASB – Built laboratory, negotiated agreements with the Guatemalan

government giving authority to work with Guatemalan

officials and institutions, paid for staff and supplies• Government of Guatemala

– Supplied staff, facilities, and encouraged work

29Approval & Oversight

• Approved by:– NIH Syphilis Study Section (meeting one)– National Advisory Health Council– Surgeon General Thomas Parran

• Supervision and site visits from:– Dr. John Heller, Chief, Venereal Disease

Division– Dr. John Mahoney, Director, VDRL– Dr. RC Arnold, Asst. Director, VDRL– Dr. Cassius Van Slyke, Chief, Research

Grants Office– Dr. Fred Soper, Director of PASB

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• PHS/PASB Team– Dr. John Cutler, Senior Surgeon, PHS– Dr. Sasha Levitan, Senior Surgeon, PHS– Dr. Lee Harlow, Asst. Surgeon, PHS

• Guatemala Team– Dr. Luis Galich, Director, Ministry of Public Health– Dr. Juan Funes, Chief, Venereal Disease Section, Ministry of

Public Health– Dr. Hector Aragon, Director, National Orphanage of Guatemala– Dr. Roberto Robles Chincilla, Director of Medical Services,

Penitentiary– Dr. Carlos Salvado, Director, National Psychiatric Hospital– Dr. Carlos Tejeda, Chief of the Army Medical Department

In Guatemala

31PCSBI’s Ethical Analysis

• Faulty Scientific Design:– The experiments were not carefully designed by either current or

contemporaneous understandings of appropriate scientific methods: • modes of transmission were used that supervisors warned

against, • data was altered or excised before inclusion in summary

reports, and• not all of the subjects exposed to STDs were treated.

• Failure to Obtain Consent:– In 1943-1944, many of the same researchers carefully considered

and adopted strict requirements for individual consent and voluntariness in similar gonorrhea research at the federal prison in Terre Haute, Indiana. Evidence showed they ignored this standard, and in frequently sought to deceive subjects and outside observers.

32International Reaction – 2011

33What is Legal is Not Always Ethical, II

Havasupai Indians (2000s)• 1990 diabetes study collecting over

200 blood samples for “the causes of behavioral/medical disorders” [Diabetes]

• Samples used thereafter for myriad secondary uses, including evolutionary genetics challenging tribe’s cultural beliefs

• Tribe sued Arizona State University, which settled in 2010 with return of samples, apology and money damages.

34What’s wrong?

• Violation of respect for human dignity and individual ethical rights/interests

• Violation of law (sometimes)• Real and potential costs to research:

– Enrollment declines.– Public trust in the research enterprise

declines.– Funding declines.– Advance of science and treatment slows.

35Summary – what do we do now?

• Bioethics and law Remember both • In design, funding, approval and monitoring

– IRBs play a critical part.• Responsible stewardship & Public Trust

LawBioethics