The Vaccine Research Center (VRC) Clinical Trials Core is devoted to the tenets of Good Clinical Practices (GCP) and the primary charge to the physician of doing no harm. Thus, the VRC has established multiple safeguards to protect volunteers from physical and social harm. There is a systematic commitment to the ethical principles of clinical studies. These conditions include
- Social value
- Scientific validity
- Fair subject selection
- Favorable risk-benefit ratio
- Independent review
- Informed consent
- Respect for human subjects
We have established a system that incorporates the following processes to accomplish these goals:
- Regulatory oversight
- Scientific oversight
- Public oversight
- Extensive education and informed consent process
- Personal commitment
Approaches to Assuring Volunteer Safety at the VRC
Each study is carefully developed by a protocol team with the range of clinical trials expertise needed to conduct an ethical and scientifically sound study. The team is led by an experienced principal investigator and includes a biostatistician, a protocol specialist, physicians, research nurses, laboratory scientists, pharmacists, data specialists, regulatory staff, and other support staff. All staff are trained to conduct studies ethically and with scientifically rigorous methods. Clinical trial protocol development is a stepwise process with multiple layers of reviews. The review process begins with presenting the protocol to an independent group of scientists not associated with the VRC, who provide advice and criticism to make sure the protocol is designed to answer an important question for human health.
All research sponsored by the U.S. government must be in keeping with the regulations and guidelines of the U.S. Department of Health and human Services Office for Human Research Protections (OHRP). When the research involves the administration of an investigational product, such as a vaccine, it must also be in keeping with the regulations and guidelines of the Food and Drug Administration (FDA).
When a promising vaccine is identified, the development, production, and evaluation is carefully scrutinized by the FDA in a multi-step process. An investigational new drug application (IND) must be submitted to the FDA. The FDA must review how the study vaccine was produced and tested for safety and potential for preventing a disease, as well as the protocol plan for administration and testing in humans before it can begin evaluation in human clinical trials.
In addition to oversight from the FDA, the clinical protocol must be reviewed by the NIAID Institutional Review Board (IRB). This is a diverse group of clinicians, scientists, and community members who judge the risk/benefit of the proposed study and assure that it is being conducted according to the Code of Federal Regulations and in accordance with NIH policies. The IRB also reviews the informed consent documents and make sure they are accurate and complete. If you take part in a study at NIH, you will be given information about how to contact the IRB.
While still in the planning stage, protocols are reviewed by a Community Advisory Board (CAB). The VRC is supported by the Capital Area Vaccine Effort (CAVE) which is a community-based organization that reviews the status of HIV vaccine development. They provide insight into the process of vaccine evaluation, recruitment of volunteers, and raise any concerns from the point-of-view of a trial participant. The CAB is organized locally but also interacts with the National and Global CAB. These organizations have the charge of advocating for the rights of the study participants and challenging the investigators and manufacturers on any areas of concern to the general public.
One of the key elements in the performance of a clinical trial is the informed consent process. This means that the volunteer has to be educated and informed about all the details of the study and their rights. This process is taken very seriously by the VRC staff. It is important to us that you understand exactly what we plan to do and why. You will be evaluated for your knowledge of HIV, how the vaccine works, and what the study entails prior to signing the informed consent document. Even after the study begins, the volunteer is always in control of what happens next. Each subject is free to stop the study at any time.
The regulatory and oversight functions continue during the performance of the study. Investigators are required to submit regular reports to the sponsor of the study, the FDA, and the IRB and to notify these oversight groups per the protocol guidelines if there are adverse events that occur during the study. In addition, an independent Data and Safety Monitoring Board (DSMB) of scientists, physicians, statisticians, ethicists, and community representatives evaluates the progress of studies where some subjects receive placebo rather than vaccine. The FDA, the IRB, the DSMB, or the investigators supervising the study all have the authority to stop the trial if there is evidence of concern for human subject protection.
The NIH institutional commitments to volunteer safety are recorded in the informed consent document. All the agencies, committees, and individuals involved in oversight of the studies are fully devoted to the safety of participants as their top priority. In addition, the investigators and clinical staff of the VRC have made personal commitments to the safety and well being of anyone involved in the vaccine studies.
Preventive HIV Vaccine Development
All vaccines are produced using molecular biology techniques that exclude the HIV virus from the manufacturing process. Therefore, it is not possible to be infected with HIV from a vaccine. Candidate vaccines are tested in small animals and often in nonhuman primates for signs of toxicity or any evidence of harm. In addition, the candidate vaccines are often tested in monkeys to determine whether it might have the ability to protect against infection or disease. Only if the vaccine is safe and shows evidence of benefit in animal models would it be considered for testing in humans. The concept is reviewed with other scientists, and a decision for further testing is based on its comparative value relative to other vaccine concepts being developed. Because testing will be performed in healthy, uninfected people, there is a high standard for safety that must be achieved by the candidate vaccine.
General References on the Conduct of Human Research
The principals of ethical human research are rooted in several key commissions and reports from the mid-to-late 20th century; among them are the Belmont Report, the Declaration of Helsinki, the Nuremberg Code, and the Common Rule. These were constituted to codify the principals by which human research should be conducted and to prevent any future failure to protect human subjects.
The Belmont Report, published in 1979, is especially important to the conduct of research in the United States. It was issued by the National Commission for the Protection of Human Subjects of Biomedical Research which was appointed to address the failure of human subjects protection in the Tuskegee Syphilis Study. The Report outlines the principles of Respect for Persons, Beneficence, and Justice. These principles are the basis for current regulations involving human participants, including the policies outlined in Title 45, Code of Federal Regulations, Part 46 governing all federally sponsored research.
The Belmont Report
The Belmont Report - Ethical Principles and Guidelines for the Protection of Human Subject provides the philosophical underpinnings for the current laws governing human subjects research by establishing three fundamental ethical principles relevant to all research involving human subjects: Respect for Persons, Beneficence, and Justice.
- The principle of Respect for Persons acknowledges the dignity and autonomy of individuals, and requires that people with diminished autonomy be provided special protection. This principle requires that subjects give informed consent to participation in research. Because of their potential vulnerability, certain subject populations are provided with additional protections. These include live human fetuses, children, prisoners, the mentally disabled, and people with severe illnesses.
- The principle of Beneficence requires us to protect individuals by maximizing anticipated benefits and minimizing possible harms. Therefore, it is necessary to examine carefully the design of the study and its risks and benefits including, in some cases, identifying alternative ways of obtaining the benefits sought from the research. Research risks must always be justified by the expected benefits of research.
- The principle of Justice requires that we treat subjects fairly. For example, subjects should be carefully and equitably chosen to insure that certain individuals or classes of individuals-such as prisoners, elderly people, or financially impoverished people-are not systematically selected or excluded, unless there are scientifically or ethically valid reasons for doing so. Also, unless there is careful justification for an exception, research should not involve persons from groups that are unlikely to benefit from subsequent applications of the research.
Each of these principles carries strong moral force, and difficult ethical dilemmas arise when they conflict. A careful and thoughtful application of the principles of The Belmont Report will not always achieve clear resolution of ethical problems. However, it is important to understand and apply the principles because doing so helps to assure that people who agree to be experimental subjects will be treated in a respectful and ethical manner.