VRC Clinical Trials
Clinical Trials and Vaccine
The 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 trials. These conditions include:
Fair subject selection
Favorable risk-benefit ratio
Respect for human subjects
We have established a system that incorporates the following
processes to accomplish these goals:
Extensive education and informed consent process
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
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 U.S.
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 group composed of 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 the 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 to 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) constituted 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
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
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.
Report, published in 1979, is especially important to
the conduct of research in the U.S. 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 Subjects,
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,
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.
Guidelines for Research Involving Human Subjects
Resources on the web