Research Ethics

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• Research Ethics
• History and Ethical Principles
• Henry Silverman, MD, MA

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Outline of Presentation

• Unethical research Unethical practices in the
  history of human subjects research
• Ethics documents Key ethics documents in
  response to ethical questions raised by human
  subjects research
• Ethical principles Foundational ethical
  principles in human subjects research

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Why Research Ethics?

• To maintain respect for persons
• To protect participants in research
• To advocate for justice
• fairly distribute the burdens and benefits of
  research
• To ensure scientific merit
• research has a valid purpose
• research will enhance the health of society
• Funding requirements
• Publishing requirements

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Why Do We Have Ethical Guidelines?

• How did ethical guidelines and principles for
  human subjects research evolve?
• Ethical reasons?

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Ethical Justification

• Clinical research develops generalizable
  knowledge that improves health.
• People who participate in clinical research are a
  means to securing that generalizable knowledge.
• These people can be exploited, i.e., can be
  used as a means for the benefits of others.
• Ethical guidelines for research are meant to
  minimize the possibility of exploitation.

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Why Do We Have Ethical Guidelines?

• How did ethical guidelines and principles for
  human subjects research evolve?
• Ethical reasons?

Historical Reasons
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History of Research Ethics

• Book of Daniel
• Celsius 1st century Roman Historian
• Justified anatomical experiments on condemned
  criminalsIt is not cruel to inflict on a few
  criminals sufferings which may benefit multitudes
  of innocent people through all centuries.

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Balancing Twin Goals
Subject Welfare/Rights
Goals of Science
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Early Formulations of Research Ethics

• Moses Maimonides
• (1135 1204)
• Instructed colleagues
• always to treat patients as
• ends in themselves, not
• merely as means for
• learning new truths

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Early Formulations of Research Ethics

• Roger Bacon (1214-1294)
• The operative and practical sciences which do
  their work on insensate bodies can multiply their
  experiments until they get rid of deficiency and
  errors, but a physician cannot do this because of
  the nobility of the material in which he works
  for that body demands that no error be made in
  operating upon it, and so experience of the
  experimental method is so difficult in medicine.

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Early Clinical Trials

• Small scale and intimate/ Therapeutic in intent
• James Lind (1747) treatment for scurvy
• Edward Jenner (1749 1823) first tested small
  pox vaccines on his son and on neighborhood
  children
• Johann Jorg (1779-1856) swallowed 17 drugs in
  various doses to record their properties
• Louis Pasteur (1822-1895) tested his pioneering
  rabies treatment on man for the first time the
  young Joseph Meister was saved.

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Beaumonts Gastric Studies

• Dr. William Beaumont (1785-1853)
• Conducted experiments on the healed stomach wound
  of Alexis St. Martin.
• Agreement whereby in return for board, lodging,
  and 150/year, St. Martin allowed experiments
  made in his stomach
• Why was the stomach opening never allowed to
  close? Conflict of interest?

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Early Formulations of Research Ethics

• The first principle of medical morality
  consists in never performing on man an
  experiment which might be harmful to him to any
  extent, even though the result might be highly
  advantageous to science
• Claude Bernard (1865)
• An Introduction to the Study of Experimental
  Medicine (1865)

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Early Formulations of Research Ethics

• I have already several cases of dogs immunized
  after rabic bites. I have not yet dared to
  attempt anything on man, in spite of my
  confidence in the result I must wait first till
  I have got a whole crowd of successful results on
  animals. But, however I should multiply my cases
  of protection of dogs, I think that my hand will
  shake when I have to go on to man. Louis
  Pasteur
• He finally did so only when he was convinced the
  death of the child, the first test subject,
  appeared inevitable.

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Early Clinical Trials

• Larger Scale Clinical Trials
• 1767- Watsons study of smallpox
• 1917- Goldbergers comparative study of diet in
  two orphanages for treatment of pellagra.
• Clinical trial in a vulnerable population where
  consent was not obtained from parents.

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Historical Justification

• Arguments for the importance of consent in
  research occurred before 1900
• 1892- Dr. William Coley injected cancer patients
  with Streptococcus to induce artificial
  erysipelas.
• Consent after some deliberation he consented
  and injections began.

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Historical Justification

• 1897 Sanarelli announced he discovered the
  bacillus of yellow fever and produced yellow
  fever in 5 patients.
• 1898 Osler condemns Sanarelli
• To deliberately inject a poison of known high
  degree of virulence into a human being, unless
  you obtain that mans sanction, is not
  ridiculous, it is criminal

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Historical Justification

• 1900 Yellow Fever Experiment Board established in
  USA
• 1901 Walter Reed decides that ethics of research
  required
• self-experimentation
• Written agreements with subjects
• Payment in gold
• Restrictions to adult subjects
• In all publications, it was stated with his
  full consent

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Wartime Research

• World War II was a transforming event in the
  conduct of human subjects research
• Transition benefiting subjects to benefiting
  others
• Research agenda dictated by military need
• Develop therapeutic measures to protect health of
  soldiers
• Recruited large numbers of subjects
• Little concern for informed consent
• US malaria after Pearl Harbor researchers
  infected residents of state hospitals and prisons
• Japanese use of Chinese residents and prisoners

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Nuremberg Code (1947)

• Nazi Doctors Trial
• Nazi doctors and scientists put on trial for the
  murder of concentration camp inmates who were
  used as research subjects.
• Nuremberg Code contains certain basic principles
  that must be observed in order to satisfy
  moral, ethical and legal concepts.
• The beginning of codification of research
  regulations
• The first and longest principle is The voluntary
  consent of the human subject is absolutely
  essential.

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Nuremberg Code (1947)

• Nuremberg Code of Ethics
• Voluntary consent is absolutely essential
• Need for scientific merit
• Qualified researchers use appropriate research
  designs
• Favorable risk/benefit ratio
• Suffering by subjects should be avoided
• Subjects must be free to stop at any time

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Nuremberg Code (1947)

• Only addressed research on healthy subjects
• Did not have the strength of law
• Researchers in the US did not think the code
  applied to them, as ethical conduct was already
  implicit in their work.
• Science was pure, politics was corrupt
• The state should not oversee research
• Medical science left on its own

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Declaration of Helsinki (1964)

• World Medical Assembly
• It has 22 recommendations as a guide to every
  physicians in biomedical research involving human
  subjects.

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Declaration of Helsinki (1964)

• Went beyond Nuremberg Code to address
• Research with therapeutic intent
• Independent review of research
• Vulnerable individuals
• legal representative to provide consent for
  individuals with diminished capacity
• urged caution if subject is in dependent
  relationship with a physician- researcher

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Historical Justification

• 1966 Beechers article in The New England
  Journal of Medicine.
• Described 22 examples in which patients never
  had the risk satisfactorily explain to them, and
  it seems obvious that further hundreds have not
  known that they were the subjects of an
  experiment although grave consequences have been
  suffered.

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Historical Justification

• Beechers 22 examples included
• Withholding antibiotics from men with Rheumatic
  fever
• Purposely infecting institutionalized children
  with hepatitis (Willowbrook)
• Injecting live cancer cells into nursing home
  patients (Jewish Chronic Disease Hospital)
• Transplanting melanoma from daughter to mother
  who died about a year and half later
• Abuses and exploitations of humans in research
  continued despite codes of ethics

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Historical Justification

• Tuskegee Syphilis Study (1932 - 1972)
• Observing the natural progression of secondary
  syphilis
• 400 African-American men with syphilis and 200
  uninfected controls
• Ethical Issues
• Inadequate disclosure of information
• USPHS actively tried to prevent men from
  receiving penicillin
• 1972 press reports caused the U.S. government to
  stop the study

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Response to Ethical Lapses

• U.S. National Research Act (1974)
• National Regulations
• Independent review of research by Institutional
  Review Boards (IRBs)
• Belmont Report (1979)
• statement of ethical principles
• Autonomy, Beneficence, Justice

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The U.S. Code of Federal Regulations (1991)

• Prior approval by ethics committee
• Written informed consent and documentation
• Equitable recruitment of research participants
• Assurances of privacy and confidentiality
• Risks are reasonable in relation to benefits to
  the subjects, if any, and to society
• Special protection for vulnerable groups
• Continuing review of approved research

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Council for International Organizations of
Medical Science Guidelines (CIOMS 1993, 2002)
Nuremberg

• Informed consent
• Protection of vulnerable populations
• Distribution of burdens and benefits
• Role of ethics committees
• Research in developing countries

Helsinki
CIOMS
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Ethics Codes

• Belmont Report
• Declaration of Helsinki
• CIOMS
• National Bioethics Advisory Report (U.S)
• Nuffield Council Report on Ethics of Health
  Research in Developing Countries

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Autonomy

• Respect for Persons
• Individuals treated as autonomous agents
• Respect for personal self-determination
• Respect for privacy
• Respect for confidentiality
• Respect for persons with limited autonomy
• Vulnerable persons need special protection
• Rules
• Obtain informed consent
• Allow subjects to withdraw from the research
• Respect privacy/confidentiality

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Beneficence (Nonmaleficence)

• Hippocratic tradition first do no harm
• Protection of subjects from harm/minimize harms
• Maximize benefits when able
• Rules
• Evaluate the scientific value and validity of the
  research
• Use the best possible research design to minimize
  harms
• Prohibition of research without a favorable
  risk-benefit ratio
• Ensure that the researchers are able to perform
  the procedures and handle risks

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Justice

• Distributive Justice fairness in distribution of
  risks and benefits
• Fairness in selection of human subjects
• Fairness in outcomes

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Justice

• Rules
• Avoid choosing groups based on easy availability,
  compromised position, and manipulability.
• Avoid excluding groups without a good scientific
  reason
• Evaluate inclusion/exclusion criteria and
  recruitment methods
• Research should not unduly involve persons from
  groups unlikely to be among the beneficiaries of
  subsequent applications of the research.

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Ethical Issues in International Collaborative
Research

• International injustice Research sponsored by
  the developed world in the developing world
• Concern with exploitation of developing
  countries
• What standards should prevail?

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Ethical Issues in International Collaborative
Research

• 1998 AIDS AZT trial
• Maternal-Fetal transmission
• AZT proven in the US to reduce risk
• Could a shorter and cheaper course of AZT prevent
  perinatal transmission
• Double-blind, placebo controlled trial
• Was placebo control ethical?
• Concern that subjects in control group was not
  given the best proven therapy

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Ethical Issues in International Research

• Standard of Care Controversy
• Should there be a requirement to provide all
  participants in control group, regardless of
  location and availability of treatments, the best
  proven same standard of care?
• Responsiveness to needs of the country
• Obligation to provide post-trial proven treatment
  
• To participants? To general community? By whom?
• Informed Consent
• Illiterate and poor populations

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From Fundamental Ethical Principles to Local
Guidelines
Respect for Persons, Beneficence, Justice
International guidelines
National Regulations
Institution operational guidelines
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