Tuesday August 14 2012 Remembering Ethics When Legal amp Ethical Constraints Diverge in Human Subjects Protection Valerie H Bonham Senior Attorney Office of the General Counsel US Department of Health and Human Services ID: 269723
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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 Attorney
Office of the General Counsel
U.S. Department of Health and Human ServicesSlide2
Objectives
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.Slide3
Bioethics & 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)Slide4
Bioethics & 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.Slide5
HHS Regulations
(“the Common Rule”), 45 C.F.R. Part 46 -- Apply directly to international research when U.S. funded.
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 SourcesSlide6
U.S. Legal Framework
Source: U.S. Presidential Commission for the Study Of Ethical Issues,
Moral Science
(2011)Slide7
U.S. Funding –Location
Source: U.S. Presidential Commission for the Study Of Ethical Issues, Moral Science (2011)Slide8
Informed Consent – Bioethics & Law
Largely overlap, but….Sometimes law may permit what bioethics might reject, including, case-by-case: Residual use of “de-identified” samples45 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.Slide9
Compliance 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.Slide10
What 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.Slide11
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
SourcesSlide12
The Guatemala ExperimentsSlide13
“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 – 2010Slide14
International Reaction – 2010Slide15
Investigation 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.Slide16
Reviewed over 125,000 pages of original records and 550 published documents
Over 10,000 pages from Cutler archivesSearches conducted in archives across USConsulted independent JHU syphilologist
with 30+ years experience.
Prepared subject database with 1,074,196 entries.
Investigation MethodsSlide17
Research 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. Slide18
Research Design, cont’d.
Serology studies conducted 1946-1953 withmost 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. Slide19
Research 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.Slide20
Subject Specific Data
Total Subject numbers: 5540Intentional exposure: 1308
678 of whom show some record of treatment
Diagnostic testing
: 5128
820 of whom show some record of treatment Slide21
Subject Age RangesSubject age ranges:
Intentional exposure: 10 to 72 years.Mean: 25
Mode: 20
Median: 22
Diagnostic testing
: 1 to 72 years.Slide22
Subject & Population Summary
Source: U.S. Presidential Commission for the Study Of Ethical Issues,
Ethically Impossible
(2011
)Slide23
Subject Profile : Berta
Source: U.S. Presidential Commission for the Study Of Ethical Issues,
Ethically Impossible
(2011)Slide24
Female Psychiatric Patient listSlide25
Syphilis Experiment Protocol Slide26
Subject Serology ResultsSlide27
Subject Clinical
Notecard
Slide28
Institutional Support
Public Health Service Venereal Disease DivisionFunded grant, supplied staff, design, and suppliesNow
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 workSlide29
Approval & 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 PASBSlide30
PHS/PASB TeamDr. John Cutler, Senior Surgeon, PHSDr. Sasha Levitan, Senior Surgeon, PHSDr. Lee Harlow, Asst. Surgeon, PHS
Guatemala TeamDr. Luis Galich, Director, Ministry of Public HealthDr. 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
I
n GuatemalaSlide31
PCSBI’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.Slide32
International Reaction – 2011Slide33
What 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.Slide34
What’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.
HeaderSlide35
Summary – 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
Law
Bioethics