History, Ethics, and Regulations of Human Subjects Research

1
History, Ethics, and Regulations of Human
Subjects Research

• Michael Mahoney
• Coordinator, IRB-01
• University of Florida
• mmahoney_at_ufl.edu
• http//irb.ufl.edu/irb01/

2
Overview

• Where are we?
• Historical review
• Violations
• Guidance documents
• Regulations
• Apply regs ethics
• Where do we go from here?

3
PART I Historical Context

• Army Yellow Fever 1900
• Nazi Experiments1942-1946
• US Scandals 1960s
• Tuskegee Syphilis Study 1932-1972

4
Yellow Fever 1900

• Expose volunteers to infected mosquitos
• Consented subjects
• Warned of death
• Paid 100, 100 if infected
• 2 experimenters
• Some spanish immigrants
• Mostly soldiers
• Could contract illness anyway, would get
  immediate medical attention in research.

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Yellow Fever 1900

• The undersigned understands perfectly well that
  in case of the development of yellow fever in
  him, that he endangers his life to a certain
  extent but it being entirely impossible for him
  to avoid the infection during his stay in this
  island, he prefers to take the chance of
  contracting it intentionally in the belief that
  he will receive from the said Commission the
  greatest care and the most skillful medical
  service.
• The undersigned binds himself not to leave the
  bounds of this camp during the period of the
  experiments and will forfeit all right to the
  benefits named in this contract if he breaks this
  agreement.
• And to bind himself he signs this paper in
  duplicate, in the Experimental Camp, near
  Quemados, Cuba, on the 26th day of November
  nineteen hundred.
• The contracting party,

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Nazi Medical Experiments1942 1946

• High Altitude
• Freezing
• Malaria
• Epidemic jaundice
• Vaccination
• Sterilization

• Seawater
• LOST gas
• Sulfonamide
• Regeneration
• Poison
• Incendiary bomb

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Nuremberg Code

• Voluntary Consent of subjects.
• Subject is free to stop.
• PRIOR knowledge of disease/problem and/or animal
  experiments.
• Experiment should have scientific benefits to
  society.
• Benefits outweigh risks.

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Nuremberg Code

• Avoid all unnecessary suffering and injury
  (physical or mental).
• No intentional death or disability.
• Protect against injury, disability, and death.
• Investigator to stop if injury, disability, or
  death likely.
• Only qualified investigators.

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GuidelinesDeclaration of Helsinki1964

• 32 Principals in three parts
• Basic Principles
• Clinical Research
• Non-therapeutic Research

http//www.opt.auckland.ac.nz/public/staffpgs/myap
/helsinki.html
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GuidelinesDeclaration of Helsinki1964

• Clinical
• Can use experimental treatment in emergencies.
• Compare benefits and risks of research to best
  current standard methods.
• All subjects, even controls, get best treatment.
• The refusal of the patient to participate in a
  study must never interfere with the
  physician-patient relationship.
• Must explain waivers of consent.
• Research and medicine can be combined so long as
  there is potential benefit to the subject.

http//www.opt.auckland.ac.nz/public/staffpgs/myap
/helsinki.html
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GuidelinesDeclaration of Helsinki1964

• Non Therapeutic
• Researcher protects subjects.
• The subjects should be volunteers.
• The research should stop if continuing the
  research could be harmful to the subject.
• The interest of science and society should never
  take precedence over the well-being of the
  subject.

http//www.opt.auckland.ac.nz/public/staffpgs/myap
/helsinki.html
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U.S. First Action

• 1966 NIH creates Office for Protection of
  Research Subjects (OPRR)
• OPRR issues Policies for Protection of Human
  Subjects
• First call for ethic board review

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US Scandals 1960s

• Jewish Chronic Disease Hospital 1962
• Milgrams Obedience Study 1962
• Willowbrook 1956 -1972
• Radiation experiments
• Prisoner research

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Tuskegee Syphilis Study1932-1972

• Federally Funded
• 400 low-income African-American males
• 40 years
• Actively denied proven cure
• At least 28 died of syphilis
• 100 more suffered blindness and insanity
• Death the ultimate outcome

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U.S. Second Action

• 1974 National Research Act
• 1975 Policies for Protection of Human Subjects
  raised to regulatory status
• 45 CFR 46
• Requires IRBs

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• 1978
• National Commission for the Protection of Human
  Subjects of Biomedical and Behavioral Research

Belmont Report 1979
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Belmont Report Cornerstones

• Respect for Persons
• Informed Consent process
• Privacy and Confidentiality

http//ohrp.osophs.dhhs.gov/humansubjects/guidance
/belmont.htm
18
Belmont Report Cornerstones

• Beneficence
• Risk/Benefit Analysis
• Scientific Merit

http//ohrp.osophs.dhhs.gov/humansubjects/guidance
/belmont.htm
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Belmont Report Cornerstones

• Justice
• Review of subject selection

http//ohrp.osophs.dhhs.gov/humansubjects/guidance
/belmont.htm
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7 Ethical requirementsJAMA, Volume 283(20), May
24/31, 2000, 2701-2711

• 1. Value
• Leads to improvements
• Generate important knowledge
• Disseminated
• 2. Informed consent
• Does not ensure ethical research by itself

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Ethical Requirements

• 3. Scientific validity
• Good research questions
• Answered by good research techniques
• 4. Fair subject selection
• Scientific goals determines the subject base

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Ethical Requirements

• 5. Favorable risk/benefit ratio
• Risks identified
• Minimized by research design
• Potential benefits delineated
• No formula
• 6. Independent review
• Assures society that no misuse of humans will
  occur

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Ethical Requirements

• 7. Respect for potential and enrolled subjects
• Privacy/confidentiality
• Permitting subjects to withdraw
• New information shared with participants
• Welfare carefully monitored
• Recognize participant contribution inform them
  of what was learned

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Federal Regulations

• DHHS Regulations for the Protection of Research
  Subjects
• 45 CFR 46 (1976)
• Federal Policy adopted in 1981
• Common Rule (1991)
• FDA regulations
• 21 CFR 50, 54, 56, 312, 812 (first in 1980)
• OCR - HIPAA (2003)

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OHRP who, what?

• Office of Human Research Protections
• Department of Health and Human Services (DHHS)
• Responsible for oversight of 45 CFR 46
• 45 CFR 46 covers ALL federally funded human
  subjects research
• Assurance

http//ohrp.osophs.dhhs.gov/humansubjects/guidance
/45cfr46.htm
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Assurance what, who?

• Assurance needed to receive federal funds for
  research
• Institution assures OHRP that research will be
  conducted under 45 CFR 46
• Obligates institution, its officials, and
  researchers
• UF FWA (FWA00005790)
• Shands
• VA
• Outside locations?

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Common Rule Who is Covered?

• Dept. of Agriculture
• Dept. of Energy
• Dept. of Commerce
• Dept. of HUD
• Dept. of Justice
• Dept. of Defense
• Dept. of Education
• Dept. of Veterans Affairs

• Dept. of HHS
• Dept. of Transportation
• NSF
• NASA
• EPA
• CIA

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FDA who, what?

• Food Drug Administration
• Separate set of regulations governing human
  subjects research when research involves an
  investigational drug or device.
• The basic requirements for IRBs and for Informed
  Consent are congruent between OHRP and FDA.
• However, FDA regs have some additional
  requirements.

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FDA who, what?

• 21 CFR 50 Protect Human Subjects
• 21 CFR 54 Financial Disclosure by Investigators
• 21 CFR 56 Institutional Review Boards
• 21 CFR 312 IND
• 21 CFR 812 IDE

Plus MANY more!
30
FDA who, what?

• NOT tied to OHRPs federal assurance.
• Applicable to any food or drugs transported
  across state lines, regardless of whether or not
  federal funding is received.

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Federal Regulations vs. Guidance

• Both OHRP and FDA publish Guidance about the
  Regulations.
• Guidance ? Guidelines (Nuremberg Code, etc)
• Guidance government interpretation or
  implementation of regulations
• MUST comply with regulations.

32
OCR who, what?

• Office of Civil Rights
• Oversight of HIPAA Health Insurance Portability
  and Accountability Act of 1996
• Protect Patient Privacy
• Went into effect April 14, 2003

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Why Ethics, Guidance, and IRBs?

• Oct 30, 2003 A former cancer researcher was
  indicted by a federal grand jury on charges of
  criminally negligent homicide, manslaughter, and
  fraud for allegedly falsifying medical records
  in order to enroll patients in drug studies.

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Application to current research

• What is a human subject?
• What is human subjects research?
• Examples of research
• Examples that dont need IRB approval
• Examples of non-human research that need IRB
  approval

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What is a human subject?

• Human subject means a living individual about
  whom an investigator (whether professional or
  student) conducting research obtains
• data through intervention or interaction with the
  individual, or
• identifiable private information.
• 45 CFR 46.102.(f)

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What is human subjects research?

• Research means a systematic investigation,
  including research development, testing and
  evaluation, designed to develop or contribute to
  generalizable knowledge.
• 45 CFR 46.102.(d)

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Examples of research

• Retrospective review of medical records
• Research involving tissue
• Either with identifiable data
• Direct collection from subjects
• Therapeutic Research
• Banking of tissue or data

IRB APPROVAL REQUIRED.
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Research?

• Need IRB approval
• Anonymous tissue previously collected
• Exempt research
• Research involving decedent tissue/data (HIPAA)

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Some examples that are not research

• Do not need IRB approval
• Case reports
• Designed to contribute to generalizable
  knowledge, but NOT a systematic investigation
• Quality Assurance
• Systematic investigation, but NOT to contribute
  to generalizable knowledge
• NOTE intent to publish contribute to
  knowledge research IRB approval required!

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Quality Assurance (no publication)
Case Reports
No IRB Approval Required
IRB Approval Required
Exempt
Therapeutic / Clinical Research
Chart review
Surveys
Quality Assurance (publication)
Decedent Research (HIPAA)
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Under what authority do you have access to
these subjects and/or their information?
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IRB

• IRB bases requirements on
• Ethics
• Guidelines
• Regulations
• Federal Guidance
• Findings at other institutions
• University policies

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Other Protections

• Institution
• HURRC
• IBC
• GCRC
• VA
• SCI
• RD
• Accreditation

• Consent monitor / patient advocate
• CRO
• Research Sponsor(s)

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Where do we go from here??

• Mandatory Accreditation for HRPP
• Mandatory education for researchers
• Certification of researchers
• Conflict of Interest (COI)
• Additional protections for vulnerable populations
• More litigation

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Where do we go from here??

• Harmonization between committees
• Streamlined electronic processing
• Better Adverse Event Reporting

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Links

• Guidance, Regulations, UF Assurance, and IRB-01
  Policy and Procedureshttp//irb.ufl.edu/ethics/et
  hicsregs.pdf
• OHRP Web Site http//ohrp.osophs.dhhs.gov/
• FDA Web Site http//www.fda.gov/
• FDA Regs http//www.accessdata.fda.gov/scripts/cd
  rh/cfdocs/cfcfr/cfrsearch.cfm
• OCR Web site http//www.hhs.gov/ocr/
• IRB-01 Web Site http//irb.ufl.edu/irb01/
• UF FWA http//irb.ufl.edu/FWA.htm
• IRB-01 Policy Procedures http//irb.ufl.edu/doc
  s/irb01ppmanual20100603.doc

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Recommended Reading
Beauchamp, Tom L., and Childress, James F.
Principals of Biomedical Ethics, 3d ed. New York
Oxford University Press, 1989 Beecher, Henry K.
Ethics and Clinical Research. New England
Journal of Medicine, 274 (1966)
1354-1360 Rothman, David J. Strangers at the
Bedside A History of How Law and Bioethics
Transformed Medical Decision Making. New York
Basic Books, 1991 Rothman, David J. Ethics and
Human Experimentation Henry Beecher Revisited.
New England Journal of Medicine, 317 (No. 19,
November 5, 1987) 1195-1199. Sieber, Joan E.
Planning Ethically Responsible Research A Guide
for Students and Internal Review Boards, Applied
Social Research Methods Series, vol. 31. Newbury
Park, CA Sage Publications, 1992. U.S. National
Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research. A
complete list of the National Commissions
reports and recommendations is provided in
Appendix 1.