VRC Home

Clinical Studies
About Clinical Studies

VACCINE SAFEGUARDS
The government has strict guidelines and safeguards to protect people who choose to participate in clinical trials. Every clinical trial in the U.S. must be approved and monitored by an Institutional Review Board (IRB) to make sure the risks are as low as possible and are worth any potential benefits.

An IRB is an independent committee of physicians, statisticians, community advocates, and others that ensures that a clinical trial is ethical and the rights of study participants are protected. All institutions that conduct or support biomedical research involving people must, by federal regulation, have an IRB that initially approves and periodically reviews the research. If you take part in a study at the NIH, you will be given information about how to contact the IRB.

Ethical Issues in Clinical Trials and Approaches to Assuring Volunteer Safety
The VRC Clinical Trials Core is devoted to the prevention of HIV infection and AIDS. We will do this both through community education on basic mechanisms of HIV transmission and prevention and through vaccine development. We are committed to these goals and will bring the most creative and experimentally sound ideas to bear on this problem. We are also committed to the tenets of good clinical practice and the primary charge to the physician of doing no harm. While the physician's oath is more than 2000 years old, the guiding principles for conducting safe and ethical clinical research can be traced to a series of documents and laws produced since the end of World War II. These are referenced below for your review. The Belmont Report is especially important because it established the importance of 1) respect for persons, 2) beneficence, and 3) justice that are principles providing the basis for any studies involving human participants. It also serves as the foundation for the policies outlined in Title 45, Code of Federal Regulations, Part 46 which govern all federally-sponsored research. The Belmont Report also directly addressed some of the wrongs done in the Tuskeegee Syphilis Study to help assure that this type of thing will never happen again.

• 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

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 by HIV from a vaccination. Candidate vaccines are tested in cell culture, in small animals, and in nonhuman primates for signs of toxicity or any evidence of harm. In addition, the candidate vaccine is tested in monkeys to determine whether it has the ability to protect against infection. Only if the vaccine is safe, and shows the ability to protect against infection in animal models will 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. All the studies performed by the VRC will be designed to obtain the most information from the fewest participants possible. Each study will be carefully evaluated by a biostatistician to determine the power to answer specific questions. In addition, all studies will be conducted using scientifically rigorous methods. This means that appropriate placebo control groups will be included in each study, the enrollment will be randomized, and the studies will be performed without the investigators or the participants knowing which study product they have received (double-blind).

When a promising vaccine is identified, the development, production, and evaluation is carefully scrutinized by the FDA in a multi-step process. The FDA is required to approve the way a vaccine is produced and tested for toxicity, as well as the way the vaccine will be administered and tested in humans. In addition to the approvals from the FDA, the clinical protocol must be reviewed by the NIH Institutional Review Board (IRB). This is a group composed of scientists, ethicists, 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 the principles of the Belmont Report. They also review the informed consent documents and make sure they are accurate and complete.

Before a study is initiated in the NIH Clinical Center, the proposed protocol is presented to a group of scientists not associated with the VRC, who provide advice and criticism to make sure the protocol will answer the questions intended. This independent review also evaluates the ethical basis for the study and comments on any safety concerns.

Each protocol is reviewed by a Community Advisory Board (CAB). The VRC is support 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. 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 tested 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 FDA and to the local IRB and to immediately notify both agencies if there are adverse events that occur during the study. In addition, an independent Data and Safety Monitoring Board (DSMB) constituted of scientists, physicians, statisticians, ethicists, and community representatives evaluates the progress of each study at regular intervals. The FDA, the IRB, the DSMB, or the investigators supervising the study all have the authority to stop the trial if there is any evidence of physical or social harm occurring.

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. We will work with volunteers to resolve any problems that may arise during the course of the study, whether they are necessarily related to vaccination or not. If there are issues that arise during the trial that require followup evaluation, the VRC staff will continue to follow the affected participant until the problems are resolved.

References

• NIH Guidelines for research involving human subjects
• The historical, ethical and legal foundations for the NIH policies and procedures involving human subjects
• Nuremberg Code (1949)
• Declaration of Helsinki (1964)
• The Belmont Report (1979)
  

  The Belmont Report—Ethical Principles and Guidelines for the Protection of Human Subjects, which was published in 1979, provides the philosophical underpinnings for the current laws governing human subjects research. Unlike the Nuremberg Code and the Helsinki Declaration, which consist of "guidances" or "rules", The Belmont Report establishes three fundamental ethical principles that are relevant to all research involving human subjects: Respect for Persons, Beneficence, and Justice. Although other important principles sometimes apply to research, these three provide a comprehensive framework for ethical decision-making in research involving human subjects.

  1. 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.
  2. 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.
  3. 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.
  

• Title 45, Code of Federal Regulations, Part 46 (45-CFR-46) - Protection of Human Subjects (The Common Rule) - (Code of Federal Regulations effective August 19, 1991
• National Bioethics Advisory Commission
• NIAID Division of AIDS references on ethics associated with HIV/AIDS
• Bioethics Resources on the web
• Tuskeegee Syphilis Study