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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.
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:
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 ReportEthical
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.
- 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 individualssuch
as prisoners, elderly people, or financially impoverished
peopleare 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
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