Use of Human Subjects in Research

1
Use of Human Subjects in Research

• Ruth A. Mulnard, RN, DNSc, FAAN
• Professor Emeritus, Nursing Science
• Member, 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.

4
Why do human subjects needs protection in
research?
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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.

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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 Dept of Health Services
  (DHS)
• Local guidance and policy
• UC Office of the President (UCOP)
• Local 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 (basic human
  subjects, IRB regulations)
• 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"
• Last page of the Informed Consent Form (ICF)
• Defines Legally Authorized Representative (use of
  proxy or surrogate)
• Specifies that children 7 years of age or older
  must also consent to research, not just their
  parent(s) (LAR)

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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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Basic Ethical Principles

• Respect for Persons
• Individuals should be treated as autonomous
  agents
• Individuals with diminished autonomy are entitled
  to protections
• Beneficence
• Do not harm
• Maximum possible benefits, and minimize potential
  harms
• Justice
• Fair distribution of burdens and benefits of
  research

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Respect for Persons

• Treat individuals as autonomous persons allow
  individuals to choose for themselves
• Persons with limited autonomy need additional
  protection, even to the point of excluding them
  from activities that may harm them. The extent of
  protection should depend upon the risk of harm,
  and the likelihood of benefit.
• The judgment that any individual lacks autonomy
  should be periodically re-evaluated, and will
  vary across situations.

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Respect for Persons Autonomy

• 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 Persons Protections

• 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

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Respect for Persons Available Protections

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

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Application of Respect for Persons

• Informed Consent Process
• Information - Does the consent form provide all
  the information necessary for the individual to
  make a reasoned decision?
• Comprehension - Is the consent form crafted in
  language understandable to the potential
  participant?
• Voluntariness - Does the consent form clearly
  indicate that participation in the research is
  voluntary?
• What additional protections can protect those
  with limited autonomy?
• How to determine whether one lacks the autonomy
  to make a reasoned decision? (per study
  assessment, not a blanket decision).

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Beneficence

• First, do no harm.
• Maximize possible benefits and minimize possible
  harms. Requires a risk-benefit analysis.
• Unavoidable risks
• Benefits may not accrue to research subject yet,
  may accrue to others or society at large.

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Beneficence

• The IRB should determine whether the risks to
  subjects are reasonable in relation to
  anticipated benefits
• Obligations of beneficence affect both the
  researcher and society
• investigators are required to give forethought on
  maximization of benefits and reduction of risk
  that may be involved in the research
• society should recognize the longer term benefits
  and risk that may result from the improvement of
  knowledge, and from the development of novel
  medical, psychological, and social processes and
  procedures

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Applications of Beneficence

• Assessment of Risks and Benefits
• Risk refers to the probability of harm when
  considering risk, one should consider both the
  probability and the severity of the envisioned
  harm while the term, benefit refers to something
  that promotes health, well-being, or welfare.
• What are the risks of harm to the participants
  (consider physical, psychological, social, and
  economic harms)? Are the risks justified? Can
  they be minimized?
• Can the research design be improved to minimize
  risk and maximize benefit?
• What are the benefits (to the participant to
  society)?

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Justice

• Treat people fairly
• Do not exploit those who are readily available or
  malleable / vulnerable
• Fair distribution of the risks and the benefits
  of research based upon the problem/issue under
  investigation

22
Applications of Justice

• Selection of Subjects
• Is the potential subject pool appropriate for the
  research?
• Is it appropriate to involve vulnerable
  populations (e.g., economically disadvantaged
  limited cognitive capacity) in the research or
  are they being enrolled because it is convenient
  or because they are easily manipulated as a
  result of their situation?
• Are the recruitment procedures fair and
  impartial?
• Are the inclusion and exclusion criteria fair and
  appropriate?

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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 (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.

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Informed Consent (cont)

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

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Applications of the General Principles

• Consideration of the three general principles in
  the conduct of research lead to the consideration
  of
• Informed Consent process
• Risk/Benefits assessment
• Selection of research participants

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Implementation The IRB (Institutional Review
Board)

• Delegated to institution
• Federal-Wide Assurance (FWA) in place with OHRP
  Reports to VC for Research
• UCI 2 biomedical, 1 social-behavioral, 1
  compliance
• Medical committee composed of physicians,
  scientists, other medical personnel, pharmacists,
  community representatives.
• Community member (non-scientist) 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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Criteria for IRB Approval

• Risks to subjects are minimized
• Risk/benefit ratio is reasonable
• Selection of subjects is equitable
• Informed consent will be sought
• Informed consent will be documented, as needed
• Safety oversight is provided
• Privacy and confidentiality are protected
• Additional safeguards for vulnerable 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
• May observe or have a third party observe the
  consent process and the research
• May apply sanctions to investigators
• No one can overturn IRB decision not even
  university administration

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Investigator Responsibilities

• For student research, this applies to you and
  your faculty sponsor
• Obtain all required approvals prior to commencing
  the research (CRFA, DSMB, IRB, CTPRMC, ICTS)
• 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

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IRB - Full Committee Review

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

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IRB - Other Levels of Review

• Expedited
• No greater than minimal risk (e.g. blood samples
  from healthy donors, hair or saliva specimens)
• 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
• Reviewed by one committee member or Chair unless
  problems identified

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IRB - 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 if the research is
  exempt
• 3 year registration required at UCI

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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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Research or Not??

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

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Case study 3

• A physician wants to compare Tylenol with Advil
  for controlling headache. He/she plans to
  prescribe Tylenol on odd days and Advil on even
  days then compare the results. Both drugs are
  already approved by the FDA to treat headache and
  are available over the counter.
• Is this research?
• Is this human subjects research?
• Does the physician automatically have access to
  his patients medical records for research
  purposes because of being the treating physician?

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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 specific 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?
• Does the physician need to get patient permission
  to extract this information from the medical
  charts for research purposes?

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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 (e-APP)
• Non Human Subjects Determination form

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Take Home Lessons

• Primary concern The rules are there to protect
  the subjects from excessive risk or exploitation.
• Secondary concern 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 Accomplishments

• UCI is part of systemwide MOU for all UC campuses
  intent to rely on one IRB
• UCI has MOU with CHOC for research
• UCI is negotiating MOU with Millers Childrens,
  Memorial Med Ctr, and CHOC
• UCI allows use of commercial IRB for review and
  approval of industry-sponsored research
• http//www.rgs.uci.edu/ora/rp/hrpp/index.htm

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NPRM New Proposed Rule Making

• Stay Tuned for Changes in Human Subjects Research
  Regulations
• e.g., shortened informed consent documents
• e.g., review by a single IRB