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