Protecting 'Human Guinea Pigs'
By Richard C. Thompson
Contributor: John Henkel
In 1963, a New York hospital allowed some elderly ill and feeble patients to be
injected under the skin with cancer cells to study immune response. Patients were not told
what the injections were--just that their "resistance" was being measured.
Nothing came from this ill-conceived effort, which was intercepted and stopped soon after
it began, with none of the patients getting cancer.
That same year, in the classic thalidomide case, officials learned that some U.S.
physicians had obtained and were using thalidomide for what they believed was a
therapeutic use. Thalidomide was not approved in the United States then, and the
physicians' actions amounted to uncontrolled testing of the drug in pregnant women. Only a
few infants with birth defects resulting from exposure to the drug were born in this
country, compared to several thousand in Europe, because an alert FDA medical officer,
Frances O. Kelsey, M.D., Ph.D., prevented the drug from being made widely available here.
In early 1994, the federal government released documents detailing hundreds of
radiation experiments performed on thousands of civilians and military personnel decades
ago, apparently in some cases without adequate knowledge or consent. Experiments included
giving food mixed with tracer doses of radioactive substances to subjects and injecting
infants with radioactive iodine. Energy Department Secretary Hazel O'Leary has spearheaded
efforts to make the details of these experiments public.
These are worst-case examples of failure to inform and protect human subjects used
without their knowledge in drug testing and medical experimentation. They are not remote
historical events. The cancer injections were stopped more than 30 years ago. The
radiation experiments occurred in the 1940s and 1950s.
Such disregard for the rights and welfare of patients is far less likely today. Review
boards at hospitals and research institutions throughout the country make sure
participants are fully informed and willing before studies ever get under way. Known as
Institutional Review Boards, or IRBs, these committees of experts and lay persons also
review the research as it goes along. Watching these watchers are the FDA and other
federal agencies such as the National Institutes of Health, whose rules now protect those
taking part in medical research.
In 1976, the FDA issued regulations requiring IRB review of all studies using
institutionalized subjects. Regulations amended in 1981 require all studies needing an FDA
research permit to be reviewed and approved by an IRB before tests on humans can begin,
whether or not subjects are in an institution.
Edmund Pellegrino, M.D., professor of medicine at Georgetown University in Washington,
D.C., and an internationally recognized expert on medical ethics, says that using human
subjects to advance scientific knowledge is acceptable "as long as there is informed
consent and the rights of the subjects are respected."
In an instructional videotape prepared by the FDA, Pellegrino says persons entering a
study must be told they are "willing volunteers" who can stop or even leave the
study at any time if they become stressed or apprehensive, or suffer too great discomfort,
or simply wish to go no further.
The first responsibility of the physician is to "do no harm," and there are
few who set out to violate that principle. But at the extreme of those who did were
scientists convicted at the 1946 Nuremberg trials of conducting experiments on
concentration camp inmates. From those trials came the Nuremberg Code, a 1948 formal
statement on medical ethics that led to present standards in the United States and
elsewhere which protect human research subjects.
Informed consent was a requirement of the 1962 Kefauver-Harris Amendments to the
federal Food, Drug, and Cosmetic Act. A signed consent document was not required, only a
notation in the chart that verbal consent had been obtained. A 1967 FDA policy statement
outlined the consent process and required consent to be obtained in writing for early
stages of research.
The U.S. Public Health Service in 1966 defined the right of subjects to be told about
the benefits, risks and purpose of the research for which they are volunteering. It made
this "informed consent" a condition of PHS funding for research grants.
A decade later, the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research developed principles governing research involving
people and made recommendations concerning IRBs. In 1981, the FDA revised regulations,
expanding the requirement for written informed consent to all studies of products the FDA
regulates.
Before it will approve a new drug or device for marketing, the FDA requires evidence of
the product's safety and effectiveness from the manufacturer. The evidence comes first
from tests with rabbits, rats and other laboratory animals, then from "clinical
trials" in human volunteers. The process from the first tests to final approval can
take a number of years.
Persons taking part in clinical trials are not necessarily patients in hospitals and
institutions. Many are patients of private practitioners involved in clinical research.
Many are not patients at all, but are healthy individuals who have been recruited for a
study through a newspaper ad, poster, or other source. FDA's IRB and informed-consent
regulations ensure that research subjects are informed and willing participants and that
their health and safety are not unnecessarily endangered.
An IRB is composed of at least five people with varying backgrounds who are generally
knowledgeable through training or experience in the research areas likely to be
considered. Racial, ethnic and other interests must be represented, and at least one
member must come from a nonscientific discipline, such as law or the clergy, and at least
one must not be affiliated with the research institution. Maintaining a diverse membership
helps an IRB stay objective.
The IRB meets to review the protocol, or research plan, for the proposed project and
may approve or disapprove it or--as happens most frequently--make changes before granting
approval. It also must review and approve or modify and approve the informed consent form
to receive research subjects. The IRB also conducts continuing review at least annually
while research is under way.
IRB review ensures that:
- Risks to subjects are minimized. Procedures must be used that are consistent with good
research design and do not expose subjects to unnecessary risk. If the subject is a
patient, the study must be designed and conducted in a way that does not adversely affect
the patient's progress.
- Informed consent is obtained and documented from each subject or the subject's legal
representative.
- Selection of subjects is fair and equitable, and there are safeguards to protect
subjects, such as the mentally retarded, who may not be able to look out for their own
interests.
- Risks to subjects are reasonable in relation to expected benefit to those subjects and
the importance of the knowledge that may be gained.
- Provisions exist to protect the privacy of subjects and to maintain data
confidentiality.
IRBs also ensure that appropriate additional safeguards are in place to protect the
rights and welfare of vulnerable populations, such as women, children, prisoners, those
with mental disabilities, and persons who are economically or educationally disadvantaged.
Periodically, the FDA inspects IRB records and operations to certify that approvals,
human subject safeguards (including informed consent), membership, and conduct of business
are what they should be. Sometimes these inspections yield evidence of problems, such as
in 1993 when FDA imposed penalties on a large California university IRB for infractions
that included failure to report deaths.
Informed consent--the key element in protecting the rights and welfare of study
subjects--is not simply a matter of having the subject sign a piece of paper. It requires
that the researcher:
- give the subject adequate information about the study
- respond fully to the subject's questions and be certain that the subject understands all
the risks and responsibilities that participation entails
- ensure that the subject (if a patient is receiving treatment, for example) is aware of
other options, along with their advantages and disadvantages
- obtain the subject's voluntary consent to take part.
Researcher and subject should discuss the study and the subject's role in it until both
are satisfied that the subject can make an informed decision about whether to participate.
In July 1993, the FDA released new guidelines for including women and minorities in
clinical research. The guidelines promote recruitment of women and minority participants
and foster understanding of cultural nuances. In March 1994, the National Institutes of
Health published guidelines implementing a new statutory requirement that women and
minorities be adequately represented in federally funded research. IRBs, together with
investigators and institutional officials, will play important roles in ensuring
compliance with these guidelines.
How an IRB fulfills its role can be seen in a Georgetown University study into the
effects of strenuous exercise on blood clotting. The study involved healthy young female
runners recruited through the campus newspaper. Runners had blood drawn before and after
treadmill exercise, with the fibrin (blood-clotting) time recorded. Blood pressure, heart
rate, and respiration also were recorded.
Participants knew that findings might help determine whether exercise is desirable for
persons recovering from heart attacks. The study also benefited participants by allowing
them to better understand their own physiology when running, an aid when deciding whether
to stay in competition. Also, participants and their doctors were informed of any health
problems that showed up in the study.
Before approving the study, the IRB at Georgetown asked that participants be told that
the study followed earlier successful research of male athletes; that the total blood
drawn would be one-quarter that of a routine blood donation; and that, although it was a
low-risk study, emergency equipment would be on standby. The IRB found it a big plus that
the physician doing the research had gone through the blood and treadmill test herself
when the study was designed.
Pellegrino stresses that study subjects must not be coerced or misled by researchers,
who often do not realize how little the subjects understand. He says that patients
receiving treatment who are asked to join a study "can easily confuse the experiment
with their treatment." He also acknowledges that some scientists feel IRB review
"somehow interferes with that research."
The FDA does not require that subjects be compensated if there is injury or other
unfavorable result. But in any study that involves more than minimal risk, subjects must
be told before they enter the study whether compensation and medical treatment will be
provided and what that compensation will be or how to obtain information about it. The
institution or IRB must establish a compensation policy before a study is begun.
An additional layer of review sometimes used is an independent Data and Safety
Monitoring Board. At periodic intervals during clinical research, this board reviews
accumulated data and makes recommendations on continuation or modification of the study.
Present FDA policy requires that only under certain circumstances may sponsors charge
clinical investigators or research subjects for investigational drugs. A firm intending to
charge for experimental drugs must first justify the charges to the FDA. Companies
sponsoring research with investigational medical devices, however, may generally charge
the investigator for the cost of the device. The investigator in turn can pass that charge
along to the patient, but no profit is to be made from the experimental drug or device.
Patients must be told before they enter a study if they will be charged for services or
products as a result of taking part in the study, and the IRB must be aware of and approve
such proposed charges. The consent document must list all charges attributable to the
study.
Taking part in a research project does not waive any of the subject's legal rights,
including privacy rights, since study records are confidential. However, the FDA can
inspect and copy medical records as part of its approval process for drugs and devices.
Usually, the agency doesn't need the names of individual subjects--only study results.
FDA regulations permit emergency use of a test article (drug or device) without prior
IRB review, provided such use is reported to the IRB within five working days. Any
subsequent use, however, must have prior review and approval. This means that an
investigator may, in a life-threatening emergency, use a device or administer a course of
treatment to a patient without prior IRB review, but a second use must be reviewed by the
IRB at the hospital or other institution. This was done in the 1980s at the University of
Arizona Medical Center, when a Copeland artificial heart not yet approved by the FDA was
used in a patient for three days as a "bridge" until a human replacement heart
could be found.
If a project carries little or no risk, FDA regulations permit an IRB to use an
"expedited review." This means that the research can be reviewed and approved by
the chairman or senior members without convening the full IRB. Minor changes in an
existing project also can be approved through an expedited review.
Institutions engaged in research involving humans will generally have their own IRBs
that review work done on the premises or elsewhere by the staff of the institution.
However, the IRB need not be "on site" at the institution as long as it is
available to review that institution's research. An IRB in a hospital, for example, is not
required to review studies done outside the hospital's jurisdiction, but the IRB may do so
if the hospital is willing.
IRB members usually are not paid for their services, but there is nothing in the
regulations to prevent it. Any payment should be a fixed amount and not contingent upon a
favorable review. Travel and other expenses may be reimbursed.
The FDA relies upon the careful review of the responsible IRB to ensure that research
studies are not unnecessarily risky and are valid endeavors. Human subjects are informed
about the research and agree to participate voluntarily in an approved consent process.
Together, these two activities serve to protect the rights and welfare of research
participants.
Source: Food and Drug Administration (FDA)
"Protecting 'Human Guinea Pigs' " originally appeared in
the December 1986-January 1987 FDA Consumer and was substantially revised for the FDA
Consumer Special Report on New Drug Development in the United States (January 1995).
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