Ethics of Clinical Trials - PowerPoint PPT Presentation

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Ethics of Clinical Trials

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Director, UCLA Center for Clinical AIDS Research and Education ... Participants often enter clinical trials because they think they will benefit ... – PowerPoint PPT presentation

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Title: Ethics of Clinical Trials


1
Ethics of Clinical Trials
  • Ronald Mitsuyasu, MD
  • Professor of Medicine
  • Director, UCLA Center for Clinical AIDS Research
    and Education

2
Evolution of Research Ethics Guidelines
  • 1946 Nuremburg Doctors Trial
  • 1947 Nuremburg Code
  • 1948 UN Universal Declaration of Human Rights
  • 1964 Declaration of Helsinki
  • 1979 Belmont Report
  • 1993 CIOMS International Ethical Guidelines
    for Biomedical Research (Updated 2002)
  • 1996 US CFR
  • 1997 ICHTR for Registration of Pharmaceutical
    for Human Use

3
Summary of Nuremburg Code
  • Voluntary consent is absolutely essential
  • Scientific rigor
  • Good study design
  • Avoid unnecessary suffering
  • Death or serious injury should not be expected
    outcome
  • Risk weighted against importance of the problem
  • Facilities and means to protect subject
  • Scientific qualification of researcher
  • Subject must be free to withdraw at any time
  • Be able to stop the study at any time

4
Ethical Conduct of Research with Human
Participant The Belmont Report
  • Basic Principles for Research on Human Subjects
  • Respect for persons
  • Non-malfeasance
  • Beneficence
  • Justice

5
CIOM GuidelinesInternational Ethical Guidelines
for Biomedical Research with Human Subjects
  • Ethical justification and scientific validity of
    research
  • Ethical review committee
  • Individual informed consent
  • Providing essential information in informed
    consent
  • Obligations of sponsors and investigators
  • Inducement to participation
  • Benefits and risks to subjects
  • Vulnerable populations
  • Research in populations with limited resources

6
CIOM GuidelinesInternational Ethical Guidelines
for Biomedical Research with Human Subjects
  • Choice of controls
  • Equitable distribution of burdens and benefits
  • Research in children, and those unable to give
    consent
  • Women as research subjects
  • Pregnant women as research participants
  • Safeguarding confidentiality
  • Rights of injured subjects to treatment and
    compensation
  • Strengthening capacity for ethical and scientific
    review
  • Ethical obligation of sponsors to provide health
    care

7
The Consent Process CIOMS Guidelines
  • Process not just signing a form
  • Inform why he/she is being approached
  • Ensure consent if voluntary
  • Explain purpose of research
  • Describe the study design in lay terms
  • Explain the duration of participation required
  • Discuss any remuneration
  • Discuss mechanism to inform of study results
  • Discuss confidentiality arrangements and access
    to data
  • Confirm ethical review has been obtained

8
The Consent Process CIOMS Guidelines
  • Discuss foreseeable risks
  • Discuss possible benefits to individual and
    community
  • Will treatment be available after study
    completion?
  • Discuss alternatives to study medication or
    therapy
  • Discuss any secondary studies proposed
  • Distinctions between role of investigator and
    physician
  • Will medical services be provided for the subject
    during the study?
  • What arrangements have been made to deal with
    research-related injuries?
  • Will subject be compensated for research-related
    injuries?

9
Responsibilities of Individual Investigators
  • Research integrity demands a personal acceptance
    and active adherence to professional standards
    and ethical principles essential for the
    responsible practice of research, not just
    accepting them as impositions by others

10
Responsibilities of Individual Investigators
  • Judgement about whether a proposed trial is
    ethically sound and good science
  • Management of personal conflict of interests
  • Ensuring adequate protection of research
    participants including uncoerced and truly
    informed consent
  • Ensuring that the research staff conducts the
    study honestly and thoroughly

11
Responsibilities of Individual Investigators
  • Handling and reporting adverse events promptly,
    completely and accurately
  • Taking personal responsibility for the veracity
    of all reports in which the investigator is
    mentioned
  • Being objective and evenhanded when reporting
    results and problems to colleagues
  • Maintaining scientific detachment and caution
    when reporting to the public
  • Reporting malfeasance and misconduct

12
Equipoise in Clinical Research
  • The investigator should have a genuine
    uncertainty regarding the comparative merits of
    each arm of the trial or about the efficacy of a
    new agent
  • The medical community should have a genuine
    uncertainty regarding the comparative merits too
  • Individual practitioners have an imperative to
    offer the best treatment they have
  • Presumption of increased effectiveness or safety
    underlies the testing of new agents
  • There is also the therapeutic misconception
    argument that since it is research the
    presumption of success vs failure should be equal

13
Therapeutic Misconception
  • Participants often enter clinical trials because
    they think they will benefit from the treatment
    or intervention
  • Sometimes the investigator may be a little
    misleading to encourage them to enter a study,
    but often, they refuse to hear anything but the
    possibility of better treatment

14
Case Study 1NIMH Collaborative HIV/STD
Prevention Trial
  • Study of efficacy of community-level, social
    diffusion HIV/STD prevention on behavioral and
    biologic endpoints in 5 countries (China, India,
    Peru, Russia and Zimbabwe) from 2000-2003.
    Overall study showed variable rates of HIV from
    27 to 0.1 with variable access to ART and
    variable reporting requirements

AIDS 2007, 21 (suppl 2), S69-80.
15
Case 1
  • Established principles for conduct of study,
    identify issues and for resolving ethical
    dilemmas as they were identified
  • Each site had a local Community Advisory Board
    and NIMH established a data safety and monitoring
    board for adjudicating ethical dilemmas and
    decisions and study was approved by 9 US and 5
    in-country IRBs

16
Case 1Issues Deliberated
  • Confidentiality
  • Partner notification
  • Strategies to reduce risk (social harm,
    stigmatization)
  • Informed consent, conform to local customs
  • Improved staff training, clinical vignettes
  • Establishing acceptable standard of care
  • Some easier to established than others
  • Can you test for HIV if HIV treatment not
    available?
  • Responsibility to inform, if treatment not
    available?
  • Responsibility to provide or advocate for
    appropriate Tx?
  • e.g. antibacterial Tx, HSV Tx, HIV Tx,
    circumcision
  • Treatment after the study for participants
  • Additional responsibilities of the trial
  • Capacity building, technology transfer, future
    studies
  • Implementation and policies

17
Case 2Therapy for AIDS-Lymphoma in Africa
  • AIDS-NHL is fatal disease if not treated.
    Treatment can prolong life, but most effective
    treatment require intensive chemotherapy and many
    side effects. Treatment of side effects and
    complications require hospitals and expensive
    medications not available in many African
    countries. Proposal to conduct trial using
    somewhat effective, but less than
    standard-of-care therapy in the West. How do we
    proceed?

18
Case 2
  • Obtain input from advocacy groups, physicians,
    investigators about the current and near future
    therapy for AIDS-NHL and risk-benefit in the
    specific countries.
  • Convene panel of stakeholders, ethicists, sponsor
    and investigators to rule on scientific
    importance of question and adequacy of safeguards
  • Thorough review by national ethics committees or
    government regulatory bodies
  • Independent data safety monitoring board
  • Continuous assessment of changes in health care
    situation in-country
  • Full training of staff and investigators prior to
    initiation
  • Rapid trial completion
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