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

Evolution of Research Ethics Guidelines 1946Nuremburg “Doctor’s Trial” 1947Nuremburg Code 1948 UN Universal Declaration of Human Rights 1964Declaration of Helsinki 1979Belmont Report 1993CIOMS International Ethical Guidelines for Biomedical Research (Updated 2002) 1996US CFR 1997ICHTR 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 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