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This paper was published with modifications in IARC Sci Publ 1997;142:313-318


Ethical and Social Issues in the Use of Biomarkers in Epidemiologic Research

by Schulte, Hunter, and Rothman


bullet Introduction
bullet Protocol development and study design
bullet Obtaining participation
bullet Interpretation and notification of test and study results
bullet Use of stored specimens in biomarker research
bullet Confidentiality of data
bullet References

Introduction

Epidemiologic research potentially raises many ethical questions and issues. The use of biomarkers in such research may raise further issues, because biomarkers are obtained from the individual person and have the potential for providing important information about exposures, biological effects of exposures, and susceptibility for disease for that individual (Grandjean, 1991; Schulte, 1992; Van Damme et al, 1995). At the same time, there is the widespread misconception that biological information is always more valid than other information such as from questionnaires, environmental monitoring or record review. Nonetheless, the potential contribution of biomarkers to enhance determination of carcinogen exposure - disease associations, to identify disease earlier, or to identify particular etiologic subgroups, makes the use of biomarkers desirable and inevitable.

There is increasing recognition that many of the issues of recruiting and informing subjects of test and study results have varied depending by study design. Consider three examples, 1) a cross-sectional study involving occupational exposure and a biomarker of early effect (e.g. cytogenetic effects), 2) a cancer case-control study evaluating the impact of common polymorphisms of metabolizing enzymes, and 3) a prospective cohort study with banked biological specimens. In general, cross-sectional studies of healthy workers are completed in a short period of time with the expectation that the biomarkers under study may provide some insight into the potential risk of an exposed group as a whole, or possibly for an individual's risk for subsequent cancer development. Notifying workers of their results of these studies is common. In contrast, the case-control study involves subjects who are already sick along with randomly selected controls who are not definable in an a priori sense, to be at risk. These subjects are generally not notified of results. Finally, in the third example, everyone is healthy. Samples are provided with the expectation that results will not be available for a relatively long time. Cohort studies in the general population usually are not in identified high-risk groups. In other cohort studies of identified high-risk individuals, such as workers, the tendency is more likely to inform subjects of results. The practice of communication of results from questionnaire data has generally paralleled these biomarker examples or has been even less oriented toward communication of results. In the following pages we will generalize about these issues but the appropriateness may vary by study design or detail and the ethical issues should be addressed on a case-by-case basis.

In this paper, we will use the steps in the research process as the organizing theme and discuss ethical and social issues for each step. Where there are issues that differ by type of marker or by use of marker, those aspects will be identified. Finally, we will discuss the use of stored specimens in biomarker research.

A premise of this paper is that ethical use of biomarkers in research involves attention to the "rights" of subjects to appropriate information before, during and after studies so that they can make informed decisions. Failure to plan or budget adequately for these efforts can lead to these rights not being met. We would note, however, that there is some difference of opinion about when and what to tell research participants and this will be discussed in later sections.

Protocol development and study design

Ethical issues come into play from the moment biomarkers are considered for a study. Why is the biomarker being considered? Biomarkers are usually more resource and labor intensive than other measures of exposure, outcome or risk. The use of scarce resources to develop, validate, or apply a biomarker can be wasteful or inefficient if there is not a good rationale. Key in the design of transitional, etiological or applied studies is the need to identify the driving scientific or public health questions and determine whether they could be answered by some other approach (Rothman, 1993). This may be less of an issue for laboratory studies where biomarker work is the defining activity. It may be more critical when considering using biomarkers as independent or dependent variables in epidemiological studies or for public health applications like screening, monitoring, or in risk assessment (Schulte and Halperin, 1987; Perera, 1987; OTA, 1990; Rüdiger, 1994).

Ethical and social problems may also arise from failure to anticipate and to plan actions required for participating in the extremes of the biomarker assay results. This may include repeat testing, counseling, or diagnostic evaluations. For transitional studies in which the characteristics of a marker are being determined and where there are clearly no associated clinical findings or prognostic significance or meaning, the needs of subjects may be different from those situations such as screening or biological monitoring where a marker can have implications for individual risk or for disease. With markers of susceptibility it may be important to consider not only the impact of the research on individual participants but also on their families.

Obtaining participation

How subjects are recruited into studies can involve serious ethical and social issues (Schulte and Sweeney, 1995). These issues hinge on what potential subjects are told about the study and whether they can truly give informed consent. If subjects are deceived or coerced into participating in a study or are given false expectations (e.g., we can tell if you are sick or well) with respect to the value of the study to the participant, ethical principles are violated. For example, a researcher could coerce a potential subject directly (e.g., you may lose your job if you don't participate) or by implication. Communicating false expectations or using pressure are patently dishonest and unethical. It is unlikely that such deception or coercion would be overt, rather it would be more subtle and difficult to detect. A broad spectrum of opinion exists about what obtaining informed consent entails and when it is achieved. Some believe that for markers whose meaning is not known at the time of the study, a subject or worker in an occupational study cannot give truly informed consent (Samuels, 1994). This implies a much higher standard of interpretation for biomarker information than for other information routinely obtained by questionnaires, environment monitoring, or record linkage. In studies to validate markers of exposure, the level of understanding of the meaning of the marker is parallel to that from classical exposure sources. Frequently airborne exposure, levels in blood, or frequency of DNA or protein adducts are part of the same exposure paradigm. Markers of effect or susceptibility are different. Until there is determination of predictive value and course in the natural history, such markers are clearly only research variables with no clinical meaning and participants should be told that. If a marker has been validated (that is, quantitatively linked to risk of disease at the group or individual level), then a clear description of it should be given to potential research participants. With regard to informing participants of risks, general practice has been to identify only medical risks; however, it has been argued that truly informed consent should include reference to nonmedical risks that might affect participants. For example, a study subject may be informed that they carry a genetic mutation that puts them at a high risk of subsequently developing cancer. In the extreme, the mere acknowledgment on an employment or insurance application that they have had a biologic or genetic test may result in denial of employment or insurability. Another variation on this scenario is that misinterpretation of a biomarker assay result could occur and have the same impact.

Participants consent to provide the specimens and corollary demographic and risk factor information, and hence, cooperate in the specified research. The subject generally does not consent or imply consent to distribution of the data in a way that identifies him or her individually to any other parties, such as employers, unions, insurers, credit agencies, lawyers, family members, public health agencies, etc.

Dissemination or revelation of results beyond the explicit purposes for which specimens were collected intrudes on subjects' privacy. Studies where biological specimens and DNA are banked for future use may require informed consent about future use. A question is whether specimens collected for one propose can be used for different research purposes and what responsibility exists for conveying results back to subjects (Schulte and Sweeney, 1995). Also, related to this is the ownership of specimens. Who owns them, the subject, the researcher, the sponsoring agency, or others? Although this has been adjudicated in the case of a clinician who profited from a hairy cell leukemia line derived from cells taken from a patient (Cooper, 1985; OTA, 1987) we have found no references (except Clayton et al, 1995, see later discussion) to the issue as it pertains to epidemiologic research with stored specimens.

Interpretation and notification of test and study results

Biomarker research yields individual test (assay) and study results (Schulte and Singal, 1989). Research participants may want or have a right to these results and an interpretation of them. Interpretation of these results is the responsibility of investigators. Some institutions require investigators to provide individual test results to subjects as well as overall study results, while others may advise them not to communicate results of assays that have no clinical relevance. Attendant to these efforts is provision of an interpretation as far as is possible. Even though participants are told that tests may be purely for research purposes and have no clinical value, they still ultimately want to know if they are "all right." Investigators and practitioners face ethical issues in interpreting tests and deciding when biomarkers indicate that early warning steps should be taken. These may range from efforts to control exposures (in occupational or environmental settings), needs for subsequent testing, ongoing monitoring, or simply and often most importantly, counseling and demonstration of caring.

Interpretation of biomarker data can be difficult. For example, in cross-sectional studies of populations with occupational or environmental exposure evaluating the relationship between exposure and markers of early biologic effect, biomarkers will not be indicators of risk per se but of exposure, susceptibility given exposure, or biological changes that could be homeostatic responses to an exposure (Ashford, 1986). The investigator needs to sort out these changes against a background of extensive intra- and inter-individual variability in biomarkers. The current technological capabilities allow investigators and practitioners the opportunity to utilize techniques with heightened sensitivity for detecting changes at the cellular and molecular level and exposures to minute amounts of a xenobiotic. At the same time, at these levels, inherited and acquired host factors and other confounding factors can strongly be the cause of wide variability in biomarker results unrelated to the exposure of interest.

The results of studies of biomarkers of susceptibility can lead to findings that can be misunderstood or abused (Lappe, 1983; Nelkin and Tancredi, 1989, Ashford, 1986). For example, some genes (such as those that are commonly occurring and that confer low relative risk, and that require a specific exposure or other genes to increase risk of disease) (see Chapter by Caporaso) do not provide unambiguous information, but various groups in society may start using such genotype information as if it were " diagnoses" rather than risk factors (Wagener, 1995).

In some studies, multiple biomarkers will be assessed and researchers have a responsibility to consider if issues of multiple comparisons can lead to inappropriate selection of significance levels. Association of biomarkers, not included in original hypotheses, should be evaluated at more rigorous levels of statistical significance and subsequent interpretations should be considered in that light.

One area of interpretation that is problematic is what is called "individual risk assessment." Generally, epidemiological studies (with or without biomarkers) yield group results. The risk pertains to the group as a whole and not necessarily to individual members of the group. It is possible to compute an individual risk using a risk function equation (Truett et al, 1969), however, if the marker being used has not been validated for disease, the calculation will be meaningless. Thus far, for the current generation of molecular biomarkers, there are practically no markers with the exception of a few genetic mutations linked to high risk of disease in cancer family syndromes, for which an individual risk can be determined based on the level of the marker.

All of these characteristics of biomarker data may lead an investigator to conclude that a particular biomarker is of uncertain meaning regarding risk. Nonetheless, the investigator has the obligation to portray accurately the degree of uncertainty in test and study results. There are a range of opinions about communicating results of biomarker tests on individuals or groups if there is no clinical meaning, such as usually occurs in transitional studies to validate markers. Some believe the autonomy of participants is not honored if they do not receive the information, others believe that the information is meaningless to participants. The latter view has the appearance of being paternalistic but may be viewed as doing no harm.

Other ethical issues in notification are the importance of communicating information in a timely fashion and evaluation of the impact of notification efforts. The timeliness of notification is most an issue when results indicate an action that could reduce exposure or risk, or effect timely treatment. Evaluating the impact of notifications may not need to be a routine matter but since the impact of notification cannot always be anticipated, it may be useful to have included in the notification an opportunity for the participant to obtain more information or provide feedback about the results.

Use of stored specimens in biomarker research

Biomarker research is qualitatively different from most other epidemiologic research because technical developments make new assays feasible on stored specimens long after the original consent is obtained. Unlike questionnaire-based research in which the response to a new hypothesis is usually to start a new study and ask the relevant questions, a new hypothesis using a biomarker can often be tested using specimens from previous studies. If it is desirable to have prospectively collected specimens, for instance if the biomarker level may be biased by disease, then available specimen banks with follow-up data will be the preferred resource for testing the new hypothesis. Otherwise, it might take many years to develop a new specimen bank with sufficient outcomes and follow-up to test a hypothesis.

Ethical issues for stored specimens relate to whether (i) consent for use of the specimens in research was originally given, whether (ii) this consent was generic or specific to the hypothesis to be tested, and whether the consent obtained when the specimens were collected still meets the standards of informed consent.

(i) Many specimens stored for research purposes were collected after informed consent to research was given, however, some types of specimens, particularly clinical specimens initially used for diagnostic or prognostic purposes, may have been stored without consent or even the patient's knowledge. Frequently in clinical settings, a wide variety of tests are ordered without any consultation with the patient, although clear exceptions such as HIV testing, for which consent is usually mandatory, exist. It has been long held as ethically acceptable practice to conduct some types of research on "discarded" blood or tissues, i.e. specimens left over after the clinical tests are performed. Access to these tissues has been critical to development of new clinical markers such as histologic or immunochemical markers of cancer prognosis, in which hundreds or thousands of uniformly collected specimens are frequently needed to establish a new test as being informative. It would seem a natural extension of this tradition that new biomarkers of genetic susceptibility or prognosis would also be evaluated in this way. However, because of the potential high predictive value of some of these tests, as well as the implications for family members, this tradition is being challenged, and a lively debate is currently underway about the ethics of using these tissues. A recent statement from a working group of the Ethical, Legal, and Social Implications of the Human Genome Project, suggested that informed consent should usually be obtained before testing for genetic susceptibility on clinical specimens (Clayton et al, 1995), although the statement acknowledged that research involving "minimal risk", and for which reconsenting subjects would be impracticable, could be exempted. The definitions of "minimal risk" and the determination of what constitutes "impracticability" are the center of much of the current uncertainty and debate.

(ii) Even in a research study, the original consent form can only be as thorough as the original aims of the study and the state of knowledge at the time permit. Samples from participants in a study of cancer risk factors, for instance, may subsequently be useful in a study of cardiovascular disease or psychiatric illness. Even the best designed and informed consent process in a study of genetic susceptibility to cancer may be outdated with the discovery of a new susceptibility gene, or a new prognostic implication of an "old" gene. A major dilemma in current biomarker research is whether a generic consent to do research on a specimen given by a participant originally, is adequate consent to conduct a specific test which may not have been even envisaged at the start of the study. The obvious strategy of obtaining fresh consent has at least three major problems: (a) subjects may be very difficult to contact if follow-up has not been maintained or they are dead, (b) a high proportion of non-consent either due to inability to recontact or to refusal may bias the study, (c) for certain especially valuable specimens such as those from cohort studies, multiple genes may be of interest and a process of very specific informed consent would generate an almost continuous stream of consent requests to the participant. Failure to obtain a new informed consent may expose the researcher to (a) allegations of unethical behavior, or (b) a difficult situation if the biomarker information may be of clinical relevance to the participant, yet the participant was not pre-test counseled about the test. The nature and force of these problems will be very different according to the predictiveness of the biomarker and its clinical implications, and the social, and cultural setting of the research.

Due to the heterogeneity of study settings, and of social norms and responses, it is likely to be impossible to draft uniform rules on what constitutes ethical behavior in every application of biomarker research and every situation. This is currently the case with research involving human subjects in which the first rule is that virtually all such research must be approved and reviewed by an appropriate ethics committee, but relatively few types of research are absolutely proscribed or highly regulated. Some have proposed that research involving genetic susceptibility is qualitatively different from other research, and that much stricter standards of informed consent should apply (Annas, 1995). While others have argued that the level of consent or notification should be commensurate to the degree of risk involved, and thus less stringent procedures may be appropriate for risk "susceptibility" genotypes than for high-risk genotypes. The possibility in the U.S. that biomarkers of susceptibility could be used to discriminate in health insurance or employment, is a major concern which may expose research participants to potential economic harm. On the other hand, epidemiology has a good track record in protecting participants from loss of confidentiality in many studies over many years, which have included highly sensitive questionnaire-based data. Although some unique issues are raised by biomarker research, most issues are similar to those encountered in other types of research, and can be overseen by appropriately constituted ethics committees who are in the best position to be aware of the local and particularistic aspects of any proposed biomarker research. Especially close scrutiny should be made of any proposal using a biomarker with likely high predictive value. Ethics committees also need to be well informed about the scope, limitations and implications of biomarker research, as the ethical climate in this field may change quite rapidly, as scientific developments occur, and society responds to them.

Confidentiality of data

Investigators need to maintain the confidentiality of biomarker data because of its potential for misuse or abuse leading to discrimination, labeling, and stigmatization. This can be increasingly difficult because ownership of stored specimens may be in question and various investigators may request use of specimens for research, litigation, or commercial enterprise. In some uses where specimens are identifiable or capable of being linked to databases where identification is possible, it may be difficult to assure confidentiality. Informatics and the ability to link disparate databases are progressing at a rapid pace. In some countries, there may be a need for further legislation to prohibit unauthorized access to or use of specimen results. The challenge will be to assure the rights of study participants while providing for a broad range of research opportunities.

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