Ethics of Clinical Trials

Ronald Mitsuyasu, MD
Professor of Medicine
Director, UCLA Center for Clinical
AIDS Research and Education
 Evolution of Research Ethics Guidelines
• 1946 Nuremburg “Doctor’s 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
 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
Ethical Conduct of Research with Human
Participant: The Belmont Report

Basic Principles for Research on Human Subjects

Respect for persons

Non-malfeasance
Beneficence
Justice
 CIOM Guidelines:
International 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
 CIOM Guidelines:
International 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
 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
 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?
 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
 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
 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
 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
 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
 Case Study 1:
NIMH 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.
 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
 Case 1
Issues 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
 Case 2
Therapy 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?
 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