25
INFORMED CONSENT FOR
STORED TISSUE SAMPLES:
THE NHANES III EXPERIENCE
 
KK STEINBERG
 
    Tissues are routinely collected as part of clinical investigations, epidemiologic studies, and in standard patient care. These tissues are often stored and used later to test new hypotheses about pathophysiology and risk factors for disease. The ethical use of stored samples has been the subject of a national debate for at least the last two years.
 
    The Centers for Disease Control and Prevention's (CDC) experience with stored tissue samples in the Third National Health and Nutrition Survey (NHANES III) is an excellent example of the ethical issues that can arise in using stored tissue samples for reasons other than those for which they were collected.
 
    NHANES is a family of surveys conducted by the National Center for Health Statistics that began in 1966, and it does several things: 1) It estimates the prevalence of common disease and risk factors for those diseases in the US population, 2) detects secular trends for diseases and risk factors, when there is a prospective component, 3) helps explain the causes and natural history of diseases, and 4) provides normal values for the US population.
 
    A sample of DNA was collected as part of NHANES III. When the informed consent was developed for this survey in the mid-1980's, we knew very little about testing for genetic risk factors for common disease. Between the time the informed consent was written and NHANES III was completed, a revolution had occurred in the field of human genetics. A publication describing the polymerase chain reaction (PCR) in the late 1980's and the creation of the National Center for Human Genome Research would revolutionize the way we think about risk factors for common disease. Genetic factors would become part of the risk equation for diseases affecting most of the population in the next several years.
 
    Unfortunately, technical advances in science and medicine occur before ethical, legal, and social issues can be resolved leaving the possibility for people to be harmed. Congress therefore mandated that 5% of the funding for the National Center for Human Genome Research (NCHGR) be devoted to the study of these issues and the Ethical, Legal, and Social Issues (ELSI) Branch of this Project was established. Largely because of this, a literature developed on ethical issues surrounding genetic testing of people.
 
    When the CDC began to develop a proposal mechanism to use the stored DNA from NHANES III, the informed consent from the mid-1980's did not address the risks that had come to light in the subsequent 10 years. CDC drew on the resources of NCHGR through its ELSI Branch to resolve this disparity.  CDC and NCHGR sponsored a meeting addressing issues surrounding informed consent for genetic testing of stored tissue samples, and invited experts in the field of medical ethics, law, and genetic research.
 
    After a year and one half of debate, a document was completed that expressed either the consensus of the group in areas where the group agreed, or the diverging opinions of the group on points of disagreement. This document was published in the December of 1995 issue of JAMA (1).

    In the summary the document states in essence:
 
        Informed consent is required for all genetic research using linkable samples unless conditions
        for limitation or waiver are met.
 
        Informed consent is not required for genetic research using anonymous samples but may be
        considered if identifiers are to be removed from currently linkable samples.
 
        IRBs could usefully review all protocols that propose to use samples for genetic research.
 
       And as can be found in almost all publications, further work is needed.
 
    The discussion of issues in this paper takes the form of a “he said-she said” debate. For example: Some have argued that anonymizing samples without a participant’s (source’s) consent is ethically acceptable. Others argued that anonymizing samples without consent is problematic because researchers had an opportunity to seek consent but did not exercise it.
 
    At the end of the article, the recommendations for existing samples simply say that:

    1) If you want to test a person’s DNA, and you know whose DNA it is, you should ask for
        consent.
    2) If you want to make the samples anonymous, you should first ask yourself some questions
        such as is it practical to do this in another way? Will you use up a specimen that the person
        may need later, for example, a surgical specimen that is needed to determine if certain
        mutations are present?
 
    Of course, the two recommendations are greatly oversimplified. The first point does not make the distinction between the complexity of asking for consent to test for relatively benign polymorphisms that have a small impact on risk for disease, with risk depending on other genes as well as environmental factors and the genetic mutations that will almost ensure that a person will develop a disease within their lifetime. The first case will entail little risk for loss of insurance, psychological distress, and social stigmatization, and the second case will require pre-test and post-test counseling because of these substantial risks. The differences in risk make blanket consents for many types of gene testing problematic.
 
    The article that appeared in JAMA did more to bring the debate to a new level of consciousness for health care professionals and the public than to resolve all of the issues. For example, one issue that has proved problematic for many is a statement on anonymous testing: “Samples are not anonymous if it is possible for any persons to link the sample with its source. Even if the researcher cannot identify the source of tissue, the samples are not anonymous if some other individual or institution has this ability.” Since the article appeared, many professional societies, advocacy groups, and government agencies have developed recommendations on use of stored tissue samples for genetic research, and members of Congress have written legislation to address these issues.
 
    The solutions that will be ultimately adopted will depend, to some degree, on who pays for genetic testing and health care. If loss of insurance is not a risk of testing, consent will require less complex counseling. However, genetic testing for single gene disorders such as cancer mutations will still require extensive pre-test and post-test counseling because of the danger of psychological distress, whether the test is positive or negative, and the risk of social stigmatization which cannot be obviated by legislation.
 

REFERENCES
 
  1. Clayton EW, Steinberg KK, Khoury MJ, Thomson E, Andrews L, Kahn MJ, Kopelman
      LM. Informed consent for genetic research on stored tissue samples. JAMA
      1995;247:1786-92.
 
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