Research Involving Human Subjects: Ethics, Law and Regulation

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Research Involving Human Subjects Ethics, Law
and Regulation

• December 2002

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William Beaumont Alexis St. Martin

• Beaumont carried out a series of experiments on
  Alexis St. Martin over a period of many years
• Was Beaumont a pioneer in ethical research or
  someone who abused his research subject?
• Be careful of applying present-day standards to
  historical figures
• The prime value of this case lies in what it
  tells us about how to do things today, not
  whether Beaumont was a good or bad man

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Beaumont (1785-1853)

• Had a 2 year apprenticeship with a country doctor
• Enlisted as a surgeons mate in 1812. Briefly
  left the army after the War of 1812, but rejoined
  as a surgeon in 1820
• 1822 Encounters St. Martin
• 1833 Experiments and Observations on the
  Gastric Juices and the Physiology of Digestion
• produced a picture of the living stomach that
  has required only a little updating in the
  century and a half since he made his
  observations.

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St. Martin (1803?-1880)

• June 6, 1822 St. Martin, a French-Canadian
  working for the American Fur Company, was
  accidentally shot in Northern Michigan
• The result was a fistula exposing part of St.
  Martins lung and stomach
• St. Martin survived, but the fistula never closed
  fully
• After 8-10 months of attempts to close it,
  Beaumont concluded that the only means of doing
  so was to suture the sides together, an
  operation to which the patient would not submit.

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The Experiments

• First experiment in May, 1823?
• Administering a cathartic by pouring it in
• Literally hundreds between 1825 and 1833, most
  involving inserting or removing material through
  the valve in St. Martins stomach

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The Relationship

• 1825 Beaumont carried out experiments from
  May-August then St. Martin returned to Canada
  without obtaining my consent. (18)
• In correspondence, Beaumont described this as a
  faithless absconding.
• 1829 St. Martin enters Beaumonts service in
  August
• St. Martin performed all the duties of a common
  servant when experiments were not being carried
  out. (19)
• This continues until March, 1831, when Beaumont
  allows St. Martin to return home.

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The Relationship

• 1832 In October, St. Martin returns.
• The two sign a contract binding St. Martin to
  obey, suffer comply with all reasonable
  proper orders or experiments.
• In exchange, St. Martin was to receive 150 plus
  room and board.
• In 1832, St. Martin was persuaded to join the
  U.S. Army for a period of 5 years. He was
  eventually assigned to Beaumont as an assistant

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The Relationship

• 1833 A new contract is signed, for 2 years at
  200 a year
• Shortly afterward, Beaumont advances St. Martin
  some of the 200 in order for St. Martin to
  return his family to Canada.
• St. Martin never returned, although Beaumont made
  increasingly lucrative offers (500/year in 1850,
  shortly before Beaumonts death)

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Beaumont as Medical Ethics Pioneer?

• Beecher (1970) credits Beaumont with producing
  the oldest American code concerning human
  experimentation
• 5. The voluntary consent of the subject is
  necessary
• 6. The experiment is to be discontinued when it
  causes distress to the subject
• 7. The project must be abandoned when the subject
  becomes dissatisfied.
• There is, however, some dispute about whether
  this code actually existed. (Numbers, 1979)

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Some Issues

• When did Beaumont take St. Martin into his home?
• Beaumont tells us it was before he began using
  St. Martin as a research subject. Others
  (Numbers, 1979) say it was after.
• Returning to Canada without my permission?
• Some experiments clearly caused St. Martin
  discomfort
• Payment for participation in research

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Outline

• A. what is research?
• B. rationale for research ethics review
• C. ethical/legal/regulatory framework
  for human subject research in Canada
• D. some major ethical/legal issues in biomedical
  research

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What is Research?

• sometimes difficult to distinguish research from
  therapy
• often carried out simultaneously
• investigators often physicians
• terminology - therapeutic research, clinical
  research, experimental interventions
• research vs. innovative care

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Research and/or Therapy?

• Why is the distinction important?
• determines whether particular set of regulations
  or research ethics guidelines must be followed
• determines whether prior approval by a Research
  Ethics Board (REB) is required
• affects the legal standard for disclosure of
  information
• may affect ability of substitute decision-maker
  to give consent

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What is Human Subject Research?

• the generation of data about persons, through
  intervention or otherwise, that goes beyond that
  necessary for the persons immediate well-being
• 1987 MRC Guidelines
• an activity that involves a systematic
  investigation to establish facts, principles or
  generalizable knowledge
• 1998 Tri-Council Policy Statement Ethical
  Conduct of Research Involving Humans

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Rationale For Research Ethics Review

• part of crucial system of checks and balances
• safeguard rights and well-being of research
  subjects
• address actual, perceived, potential conflicts of
  interest
• reinforce and rehabilitate public trust in
  medical research

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Rationale For Research Ethics Review

• inherent tension between primary aims of research
  and treatment
• when patients participate in clinical research,
  physician-investigator may experience this
  tension
• notion of clinical equipoise
• - RCTs ethically acceptable where expert
  community in state of honest professional
  disagreement as to relative merits of two
  alternatives

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Research Codes and Guidelines

• primary purpose - to protect the physical
  well-being, dignity and integrity of individuals
  who serve as participants
• interests of investigators in pursuing their
  professions
• interests of society in increasing knowledge re
  public and individual health

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Historical Context

• will be covered in future session
• several instances of research controversies and
  atrocities in many different countries
• a number of international instruments have been
  developed to try to address ethical standards and
  regulation of human subject research

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Governance of Human Subject Research in Canada

• in Canada, no comprehensive legislation to
  regulate all research involving humans
• - biomedical research governed by law that is
  primarily directed to other purposes
• - some legislation applies almost inadvertently
  to research
• - other legislation re health care deliberately
  excludes research from its ambit
• - role of the common law- consent, negligence,
  etc.
• - Quebec - Civil Code

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Newfoundland Legislation

• some statutes in NF containing provisions
  applicable to research
• - Advance Health Care Directives Act
• - Access to Information and Protection of Privacy
  Act
• - Hospitals Act
• - Human Tissue Act

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Codes, Guidelines and Policies

• these extra-legal instruments play important
  role in regulation of research in Canada
• promulgated by governmental bodies, funding
  agencies, professional organizations and local
  institutions
• ethics codes, guidelines and policy statements
  usually lack means of direct legal enforcement
• however may be relied on by courts to indicate
  applicable standards of conduct

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Tri-Council Policy Statement on the Ethical
Conduct of Research Involving Human Subjects
(1998)

• MRC, NSERC, SSHRC
• context - the need for research, guiding ethical
  principles, subject-centered perspective
• research requiring ethics review, REBs
• consent, confidentiality, conflict of interest
• inclusion in research - women, incompetent
  individuals, aboriginal people
• clinical trials
• human genetic research, research on
  embryos/fetuses and human tissues

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CMA Code of Ethics

• duty of physicians to obtain from research ethics
  committee review and approval of research
  involving humans
• duty of physicians to obtain informed consent
  from potential research subjects
• duty to report unethical research behaviour

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Some Major Ethical/Legal Issues in Medical
Research

• 1. conflicts of interest
• 2. consent - informed, voluntary
• 3. confidentiality, access to information
• 4. scope of acceptable research
• 5. children, mentally incompetent individuals
• 6. justice in recruitment of subjects

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Conflicts of Interest

• investigators interests
• - fame, publishable results, medical
  breakthroughs to benefit society
• financial conflicts of interest
• - pharmaceutical companies
• - partnerships between academic institutions and
  corporations
• - commercial value of research results

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Conflicts of Interest and REBs

• one role of REBs is conflict of interest
  oversight
• - financial conflicts
• - impact of conflicts on informed consent
• conflicts of interest involving the REB
• - membership, operation within institution
• - collegiality, concerns about promotion,
  bringing valuable research funding into
  institution, etc.

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Consent - General Principles

• capacity
• - must be given by person legally capable of
  making decision
• voluntary
• - no coercion/undue influence
• specific
• - to procedure(s), physician(s) involved
• informed
• - disclosure/discussion required

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Consent to Research in the Courts

• two categories of research dealt with differently
  by the courts
• 1. consent to research with no intended benefit
  for participants
• 2. consent to research with intended benefit with
  participants

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Research with no Intended Benefit for Participants

• Halushka v. U. of Saskatchewan (Sask. C.A. 1965)
• - healthy university student paid 50 to
  participate in anesthetic drug trial, requiring
  cardiac catheterization
• - told test was nothing to worry about
• - suffered cardiac arrest, residual injuries
• Court held duty of disclosure of investigators
  at least as great as, if not greater than, duty
  of ordinary physician/surgeon to patient
• - full and frank disclosure
• - no therapeutic privilege, no waiver

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Research with no Intended Benefit for Participants

• Weiss v. Solomon (Que. Sup. Ct. 1989)
• - trial of ophthalmic drops in reducing post-op
  retinal edema
• - fluorescein angiography used to verify effects
  of drops
• - told risks discomfort, nausea and minor
  allergic reactions
• - patient died from severe allergic reaction
• Court held investigator and REB at fault for
  failure to warn of all the risks involved in the
  research
• - all risks must be disclosed, even if
  rare/remote, particularly if serious consequences
• - court based decision in part on Helsinki
  Declaration

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Research with Intended Benefit for Participants

• no Canadian cases involving research pursuant to
  protocol reviewed for ethical/scientific merit
• cases involving individual MDs testing
  therapeutic innovations of their own design in
  course of Dr.-pt. relationship
• courts have applied standard of disclosure
  generally applied to Dr.-pt. relationship - What
  would reasonable pt. want to know?
• fact that procedure unique or experimental
  something most people would want to know

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Confidentiality

• general obligation of confidentiality owed by
  physicians to patients extends to researchers
• embodied in research codes, guidelines
• REBs typically require policies re storage and
  destruction of data and samples, anonymization of
  data
• should also be addressed in consent forms

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Confidentiality

• tension between need to share data and privacy of
  subjects
• beware of over-promising confidentiality
• - access to data for safety and ethics
  monitoring
• - Health Protection Branch, Health Canada
• - periodic review by REBs
• - genetic research
• - right to know/right not to know?
• - duty/right to inform relatives of their risks?