Responsibilities of Investigators

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Responsibilities of Investigators

• Stan Korenman, M.D.
• Professor of Medicine and Associate Dean,
• Ethics
• David Geffen School of Medicine at UCLA

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Definition of Research Integrity

• "Research integrity may be defined as active
  adherence to the ethical principles and
  professional standards essential for the
  responsible practice of research."

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Active Adherence
By active adherence we mean adoption of the
principles and practices as a personal credo, not
simply accepting them as impositions by others.
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Principles

• By ethical principles we mean honesty, the golden
  rule, trustworthiness, and high regard for the
  scientific record.
• While we encourage vigorous defense of ones
  ideas and work, ultimately research integrity
  means examining the data with objectivity and
  being guided by the results rather than by
  preconceived notions.

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Practices

• Honesty, fairness and proficiency in
• 1. proposing, performing, and reporting research
• 2. representing contributions to research
  proposals and reports
• 3. peer review
• Collegiality in scientific interactions,
  communications and sharing of resources
• Avoidance and disclosure of conflicts of interest
• Protection of human subjects
• Humane care of animals
• Adherence to the mutual responsibilities of
  mentors and trainees

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Breaching the Public Trust

• Gelsinger case at Penn gene therapy
• Johns Hopkins case inhaled hexamethonium,
  leading to death
• Phen-fen case still paying out
• Rezulin liver failure
• Vioxx failed to recognize CV disease
• Paxil failed to acknowledge threat of suicide
  in adolescents

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Fiduciary Responsibilities

• Definition a requirement for a person to act for
  the benefit of another.
• Every member of the research team is responsible
  to the participant and to the public, to ensure
  that research integrity is sustained.

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Responsibilities of the Investigator

• 1. Judgement about whether a proposed trial is
  ethically sound and good science. Komesaroff
• 2. Management of personal conflicts of interest.
  Boyd
• 3. Ensuring adequate protections for research
  participants including uncoerced and truly
  informed consent. Bigby
• 4. Ensuring that the research staff conducts the
  study honestly and thoroughly.

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Responsibilities 2

• 5. Handling and reporting adverse events
  promptly, completely and accurately.
• 6. Taking personal responsibility for the
  veracity of all reports in which the
  investigators name is mentioned.
• 7. Objectivity and evenhandedness when reporting
  to colleagues.
• 8. Maintaining scientific detachment and caution
  when reporting to the public.
• 9. Reporting malfeasance and misconduct. Merrill

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Is A Proposed Trial Ethically Sound And Good
Science

• Will the research most probably answer the
  question? Sample? Power? Controls?
• Does the proposed protocol consider all
  predictable adverse reactions?
• Does it involve appropriate groups?
• Do you believe there is clinical equipoise?

• The Belmont Report
• Basic Principles of Research on Human Subjects
• 1. Respect for persons
• 2. Beneficence
• 3. Justice

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Equipoise In Clinical Research

• 1. The research team should have genuine
  uncertainty regarding the comparative therapeutic
  merits of each arm of the trial.
• 2. The medical community has genuine uncertainty
  regarding the comparative therapeutic merits of
  each arm of the trial.

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Conflict Over Equipoise

• Presumption of increased effectiveness or safety
  underlies the testing of new agents.
• Bayesian analysis of work leading to the clinical
  trial should generally indicate that the baseline
  probability of success is greater than random so
  that equipoise is a faulty concept.
• Recent evidence that in Phase I-II cancer trials
  benefits have gt 50 probability

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Definition

• Informed consent does not relate to what
  investigators think they need to disclose. but
  rather what the participant needs to know!

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Ensuring Protections for Research Participants

• Critical Nature of Informed Consent
• Participants trust you more than a confusing
  piece of paper. Be worthy of their trust.
• Participate in the consenting process and make
  sure they understand.

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Human Subjects Consent Form

• 10 Financial obligation
• 11. Emergency care and compensation for injury
• 12. Privacy and confidentiality
• 13. Participation and withdrawal
• 14. Consequences of withdrawal
• 15. Withdrawal of participation by the
  investigator
• 16. New findings
• 17. Identification of investigators
• 18. Rights of research subjects
• 19. Adherence to HIPAA

• 1. Purpose of the study
• 2. Procedures
• 3. Potential risks and discomforts
• 4. Anticipated benefits to subjects
• 5. Anticipated benefits to society
• 6. Alternatives to participation
• 7. Payment for participation
• 8. Possible commercial products
• 9. Sample remaining at the end of the
  study

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Therapeutic Misconception

• Participants often enter clinical trials because
  they think they will benefit from the treatment.
• Sometimes the investigator is a little misleading
  to encourage them to enter, but often, they
  refuse to hear anything but the possibility of
  treatment.
• Yet, are they wrong?

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HIPAA and The Common Rule

• HIPAA uses the same definition of research as the
  federal Common Rule (45 CFR 46), which is a
  systematic investigation designed to contribute
  to generalizeable knowledge.
• Research that creates, uses, or discloses
  personally identifiable information in the course
  of providing health care services is protected
  health information (PHI) under the HIPAA Privacy
  Rule.
• Research that records personally identifiable
  health information to characterize and better
  understand disease processes without associated
  clinical intervention, is covered by the common
  rule but is not protected health information
  under HIPAA.

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Conditions Under Which PHI May Be Released for
Research Purposes

• Authorization by subject (or legal
  representative)
• Waiver of authorization by IRB or Privacy Board
• Limited data set no identifiers
• De-identified data set identifiers removed by
  computer expert
• Disclosures related to FDA-regulated product
• Otherwise, you cant use PHI or release it
  to others!

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Ensuring That the Team Conducts the Study
Honestly and Thoroughly

• Have protocol review to make everyone on the team
  comfortable with the study.
• No pressure for admissions they might forego
  protocol criteria.
• Investigators and nurses available, especially
  for adverse events.
• Ensure Good Clinical Practices for gathering data
  and review the data themselves.
• Individual integrity will make the team better
  and more concerned about the participants.

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Adverse Events (AEs)

• An adverse event is an undesirable and
  unintended, although not necessarily unexpected
  result of therapy or other intervention.
• An SAE is an event that may result in death, a
  life-threatening experience, a required or
  prolonged hospitalization, persistent or
  significant disability, congenital anomaly/birth
  defect or required intervention to prevent the
  above.
• Document them all, report unexpected and serious.
• Dont succumb to pressure to call adverse events
  unrelated . Check on adverse event reports from
  other sites to see whether there is a pattern.

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Definitions Adverse Events

• An adverse event (AE) is an undesirable and
  unintended, although not necessarily unexpected,
  result of therapy or other intervention.
• An SAE is an event that may result in death, a
  life-threatening experience, a required or
  prolonged hospitalization, persistent or
  significant disability, congenital anomaly/birth
  defect or required intervention to prevent the
  above.

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Reporting AEs

• SAEs, unexpected AEs, that are related to the
  research activity.
• Other AEs that require an addendum to the
  protocol.
• External AEs that are serious, unexpected, and
  related to the research activity or that require
  a change in the research protocol.

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Research Monitoring

• Most clinical studies have Data and Safety
  Monitoring Boards. They are independent review
  boards that routinely break the blinding to see
  whether the study is demonstrating efficacy or
  problems with safety
• CRC studies have Research Subject Advocacy
  programs as well. We have ORPA. They watch over
  the research as it is being carried out and try
  to prevent or rapidly ameliorate trouble.
• The research team should work with them. They
  will help and support everyone to do the right
  thing.

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Taking Responsibility for the Veracity of Reports
Using Your Work

• The PI should review the data - insist on it.
• Never agree to anything if not convinced.
• Try to write up reports if possible.
• Dont let them use your name if you havent done
  the work. Sponsors love to trade on your
  reputation.
• Major changes have taken place in how things are
  done in relation to clinical trials including
  entry into a database at initiation and
  reporting all outcomes.

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Reporting

• Objectivity and evenhandedness when reporting to
  colleagues.
• Maintaining scientific detachment and caution
  when reporting to the public.
• You are encouraged to be an enthusiast by the
  media and the company. If youre complicit, you
  will get more lucrative lectures.
• Thats bad scientific reporting and bad science
  policy. The public has already begun to distrust
  us.
• The media often wish to promote a particular
  position. You have a responsibility to the public
  to explain and comment on research. What to do?