Use of Human Subjects in Research

1
Use of Human Subjects in Research

• Ruth A. Mulnard, RN, DNSc, FAAN
• Associate Professor of Nursing Science
• Chair, Institutional Review Board

2
Definition of Research

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

3
Definition of Human Subject

• Human subject means a living individual about
  whom an investigator (whether professional or
  student) conducting research obtains
• (1) Data through intervention or interaction with
  the individual, or(2) Identifiable private
  information.

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Definition of Human Subject

• Intervention includes both physical procedures by
  which data are gathered (for example,
  venipuncture) and manipulations of the subject or
  the subject's environment that are performed for
  research purposes.
• Interaction includes communication or
  interpersonal contact between investigator and
  subject.

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Definition of Human Subject

• Private information includes information about
  behavior that occurs in a context in which an
  individual can reasonably expect that no
  observation or recording is taking place, and
  information which has been provided for specific
  purposes by an individual and which the
  individual can reasonably expect will not be made
  public (for example, a medical record). Private
  information must be individually identifiable
  (i.e., the identity of the subject is or may
  readily be ascertained by the investigator or
  associated with the information) in order for
  obtaining the information to constitute research
  involving human subjects.

6
How Are We Regulated?

• International
• ICH Guidelines
• Federal
• OHRP (Office for Human Research Protections) has
  jurisdiction over Department of Health and Human
  Services (DHHS) via 45CFR46
• FDA (Food and Drug Administration) has
  jurisdiction over all research involving food,
  biologics, drugs and devices via 21 CFR
• State of California
• Department of Health Services (DHS)
• Local guidance and policy
• UC Office of the President (UCOP)
• Institutional Review Board (IRB)

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Department of Health and Human Services (DHHS)

• 45CFR Part 46 Common Rule (enforced by OHRP)
• The Common Rule Federal Policy for the
  Protection of Human Subjects
• Subpart A Basic HHS Policy
• Subpart B Pregnant women, Fetuses and Neonates
• Subpart C Prisoners
• Subpart D Minors

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Food and Drug Administration (FDA)

• 21CFR Parts 50 and 56 (enforced by FDA)
• IDE (Part 312) - Investigational New Device
  Exemption
• IND (Part 812) - Investigational New Drugs/
  Biologics

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State of California - CA Health and Safety Code
Section 24170-24179.5

• Protection of Human Subjects in Medical
  Experimentation Act
• Requires "experimental subject's bill of rights"
• Defines Legally Authorized Representative (use of
  surrogate)
• Specifies that children 7 years of age or older
  must also consent to research, not just their LAR

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Key Events that Influenced Policy Development

• Nazi doctors trial 1946
• The Tuskegee syphilis study 1932-1972
• Radiation exposure studies 1944-1974
• Thalidomide tragedy (Kefauver Amendment 1962)
• The Milgram obedience experiments 1972
• U. Pennsylvania gene therapy 1999

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The Tuskegee Study

• U.S. Public Health Service project
• 600 low-income African-American males, 400 of
  whom had syphilis infections, monitored for 40
  years.
• Free medical examinations were given but
  participants were not told about their disease.
• When penicillin became available in the 1950s,
  the study continued and participants were denied
  treatment. In some cases, researchers intervened
  to prevent treatment by other physicians.
• Many participants died of syphilis. The study was
  stopped in 1973 by the U.S. DHEW only after its
  existence was publicized.

12
The Development of Human Subjects Protection
Policy

• The Hippocratic Oath
• The Nuremburg Code of 1947
• Declaration of Helsinki 1964
• National Research Act of 1974
• The Belmont Report of 1979

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The Nuremburg Code

• Informed consent without coercion
• Human experiments should be based on animal
  experimentation
• Anticipated results should justify the experiment
• Only qualified scientists should conduct medical
  research
• Physical and mental suffering should be avoided
• No expectation of death or disabling injury

14
The Belmont Report Basic Ethical Principles

• Respect for persons
• Autonomy
• Protection of those with diminished autonomy
• Beneficence
• Justice

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Respect for PersonsAutonomy

• Subject must be capable of acting on personal
  goals
• Investigator must respect the considered opinions
  of the subjects
• Participation MUST be freely given. Cannot deny
  medical care for decision not to participate in
  research.

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Respect for PersonsProtections

• Those not fully capable of self determination
  must be protected, including
• The very young, the cognitively impaired, some
  physically incapacitated
• Those who are subject to coercion
• staff and students of investigator
• prisoners

17
Respect for PersonsAvailable Protections

• Exclusion from study
• Surrogate consent
• Assent of minors age 7 or older
• Prohibition on excessive inducements for
  participation

18
Beneficence

• First, do no harm.
• Maximize possible benefits and minimize possible
  harms. Risk-benefit analysis
• Unavoidable risks
• Benefits may not accrue to research subject

19
Justice

• Fair distribution of the risks and benefits of
  research
• Risks cannot be limited to one subset of possible
  beneficiaries (e.g. prisoners, the poor, one
  ethnic group)
• Benefits must be reasonably available to all who
  might benefit

20
Boundaries Between Practice and Research

• Not all experiments are research
• Not all research is experimental
• Practice seeks the best available result for the
  individual patient
• Research should be hypothesis testing, systematic
  and allow conclusions that are generalizable to a
  broader population.

21
Implementation Informed Consent

• Informed consent is a process, not a piece of
  paper.
• Consent for all full committee protocols must be
  written and for clinical studies must be
  witnessed.
• Verbal consent (with a waiver of documentation)
  may be possible for other kinds of research
  using a study information sheet
• Consent form must be understandable to the
  subject and not excessively technical.

22
Informed Consent (cont)

• Consent must identify risks, benefits, and
  possible outcomes.
• Consent must be obtained by a member of the
  investigative team.
• The subject must have an opportunity to ask
  questions and raise concerns.
• Financial interests must be disclosed.

23
Implementation The IRB (Institutional Review
Board)

• Delegated to institution
• Federal-Wide Assurance (FWA) in place with OHRP
• Reports to VC for Research
• UCI 2 medical and 1 social-behavioral
• Medical committee composed of physicians,
  scientists, other medical personnel, pharmacists,
  community representatives.
• Community member (non-scientific) must be present
  for IRB to proceed.

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IRB Responsibilities

• Safeguard rights, safety and well-being of all
  trial subjects (with special attention to
  vulnerable subjects)
• Obtain the following documents
• Trial protocol and all amendments
• Informed consent and any updates
• Subject recruitment procedures, anything written
  to subjects
• Investigators Brochure and applicable safety
  data
• Investigators qualifications

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IRB Responsibilities

• Review of the proposed research
• Approval / favorable opinion
• Minor changes required to make it approvable
• Disapproval / negative opinion
• Termination / suspension of prior approval
• Consider the qualifications of the investigator
  to conduct the research

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IRB Responsibilities

• May request additional information not supplied
  by investigator and/or sponsor
• Must conduct continuing review of protocol at
  least once a year (time interval should be
  appropriate to risk)
• Review the amount and method of payment
• No coercion, pro-rated for partial completion

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IRB Responsibilities

• Require that information given to subjects as
  part of informed consent is in accordance with
  the regulations
• Require documentation of informed consent or may
  waive documentation in accordance with the
  regulations
• Notify investigators and the institution in
  writing of its decision to approve or disapprove
  proposed research or of modifications required to
  secure IRB approval of the research activity

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IRB Responsibilities

• May observe or have a third party observe the
  consent process and the research and
• May suspend or terminate approval of research
  that is not being conducted in accordance with
  the IRB's requirements or that has been
  associated with unexpected serious harm to
  subjects.

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Authority of the IRB

• Approve or disapprove research
• Suspend or terminate approval that is not being
  done in accordance with IRB requirements, or that
  has resulted in unexpected harm to subjects

30
Investigator Responsibilities

• Obtain all required approvals prior to commencing
  the research (CRFA, DSMB, IRB, CTPRMC, GCRC)
• Obtain informed consent of all human subjects or
  their legally authorized representatives (unless
  waived) and use only the currently approved,
  stamped consent form
• Make no changes without prior review and approval
  by the IRB
• Obtain re-review at least every 365 days

31
Full Committee Review

• Full Committee Research
• Most common level of review
• Requires full committee vote (majority decides)
• 2 reviewers plus staff
• Scientific review - IRB reviews the science as it
  relates to risk/benefit ratio

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Other Levels of Review

• Expedited
• No greater than minimal risk (e.g. blood samples
  from healthy donors, hair or saliva specimens)
• Reviewed by one committee member or Chair unless
  problems identified
• No greater than minimal risk
• Means that the probability and magnitude of harm
  or discomfort anticipated in the research are not
  greater in and of themselves than those
  ordinarily encountered in daily life or during
  the performance of routine physical or
  psychological examinations or tests

33
Other Levels of Review

• Exempt registration
• Exempt from federal regulations
• Virtually no risk (e.g. retrospective data
  analysis, discarded pathology materials
  de-identified)
• Investigator cannot decide if their research is
  exempt IRB must decide
• 3 year registration required at UCI

34
Case study 1

• Investigator X wants to do a study where cadavers
  will be run through an x-ray machine to scan for
  healed fractures. No information about the
  cadavers or their living relatives is required.
• Is this research?
• Is this human subjects research?

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Case study 2

• An Instructor wants to have all students in a
  class interview each other to practice
  interviewing skills. The results will not be
  written up or distributed outside the classroom
  in any way.
• Is this research?
• Is this human subjects research?

36
Case study 3

• A physician wants to compare Tylenol with Advil
  for controlling headache. He plans to prescribe
  Tylenol on odd days and Advil on even days. Then
  compare the results. Both drugs already are
  approved by the FDA to treat headache and are
  available over the counter.
• Is this research?
• Is this human subjects research?

37
Case study 4

• A physician wants to review the medical charts of
  his patients to test the theory that women heal
  more quickly than men from a certain type of
  surgery. The only information to be recorded
  from the charts is gender and number of days in
  the hospital.
• Is this research?
• Is this human subjects research?

38
Advancement of IRB Processes

• All IRB processes are now electronic
• Reporting of adverse events, unanticipated
  problems, protocol violations, protocol
  deviations
• Modification requests (E-Mod)
• Continuing protocol applications (E-CPA)
• Initial IRB Application
• Non Human Subjects Determination form

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Take Home LessonsHuman Subject Protection Rules

• The rules are there to protect the subjects from
  excessive risk or exploitation.
• The welfare and reputation of the institution and
  the investigators are also at stake.
• The investigator is responsible for knowing the
  relevant regulations.
• When in doubt, ask the IRB staff.

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UCI IRB Accomplishment

• UCI achieved re-accreditation from AAHRPP in June
  of 2008.
• This is a three-year accreditation
• http//www.rgs.uci.edu/ora/rp/hrpp/index.htm