Date: Mon, 1 Jan 2001 01:16:43 EST

Protecting 'Human Guinea Pigs'

by Richard C. Thompson

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 just over 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 FDA and other federal agencies such as the National Institutes of Health, whose rules now protect those taking part in medical research.

In 1976, 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 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, FDA revised regulations, expanding the requirement for written informed consent to all studies of products FDA regulates.

Before it will approve a new drug or device for marketing, 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, 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, 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."

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. (Congress is currently considering legislation that would mandate compensation or require it of health insurers.)

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 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, 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 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.

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.

Richard C. Thompson is a former member of FDA's public affairs staff. John Henkel, staff writer for FDA Consumer, also contributed to this article.

"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).