COMMENTARY

Participation in the Cooperative Family Registry for Breast Cancer Studies: Issues of Informed Consent

Mary B. Daly, Kenneth Offit, Frederick Li, Gord Glendon, Alice Yaker, Dee West, Barbara Koenig, Margaret McCredie, Vicki Venne, Susan Nayfield, Daniela Seminara

Affiliations of authors: M. B. Daly, Fox Chase Cancer Center, Cheltenham, PA; K. Offit, Memorial Sloan-Kettering Cancer Center, New York, NY; F. Li, Dana-Farber Cancer Institute, Boston, MA; G. Glendon, Ontario Cancer Genetics Network, Cancer Care Ontario, Canada; A. Yaker, Health Consultant/Consumer Advocate; D. West, Northern California Cancer Center, Union City; B. Koenig, Center for Biomedical Ethics, Stanford University School of Medicine, CA; M. McCredie, New South Wales Cancer Council, Kings Cross, Australia; V. Venne, Huntsman Cancer Research Center, Salt Lake City, UT; S. Nayfield, D. Seminara, National Cancer Institute, Bethesda, MD.

Correspondence to: Mary B. Daly, M.D., Ph.D., Fox Chase Cancer Center, 510 Township Line Rd., Cheltenham, PA 19012 (e-mail: mb_daly{at}fccc.edu).


    INTRODUCTION
 Top
 Introduction
 The Cooperative Family Registry...
 History of the Consent...
 Content of the Proposed...
 Content Areas of Particular...
 Conclusion
 Notes
 References
 
No universal surveillance system collects information on all cases of cancer in the United States. Instead, cancer data are assembled in a variety of ways. Several very good population-based registries collect data in a fairly uniform manner, but different hospital-based registries often have different formats for data reporting, collection, coding, and analysis. Outcomes of interest include estimates of incidence, prevalence, and mortality; the identification of risk factors through epidemiologic analyses; the evaluation of patterns of care; and financial and resource planning. Few of the registries, however, have any genetic information. The recent identification of genes associated with high penetrance for breast cancer has brought a new focus to the study of cancer genetics—one that emphasizes the identification of families with heritable patterns of cancer—and has created the need for the development of registries that are defined by familial cancers.


    THE COOPERATIVE FAMILY REGISTRY FOR BREAST CANCER STUDIES
 Top
 Introduction
 The Cooperative Family Registry...
 History of the Consent...
 Content of the Proposed...
 Content Areas of Particular...
 Conclusion
 Notes
 References
 
The Cooperative Family Registry for Breast Cancer Studies (CFRBCS) is an international consortium established in 1995 as a resource for research on the epidemiologic, clinical, and genetic aspects of breast cancer. Funded by the National Cancer Institute (NCI), six sites (Northern California Cancer Center [Union City], Ontario Cancer Genetics Network, Cancer Care Ontario [Canada], University of Melbourne [Australia], Fox Chase Cancer Center [Cheltenham, PA], Metropolitan New York Registry, and Huntsman Cancer Research Center [Salt Lake City, UT]) collaborate to enroll a total of 5000 families at high risk for breast cancer into a family-based registry. The purpose of the CFRBCS is twofold: 1) to collect pedigree information, epidemiologic data, and related biologic specimens from patients with a family history of breast cancer in order to provide a registry resource for interdisciplinary studies on the etiology of and survival from breast cancer and to encourage translational research in this area and 2) to better characterize populations at high risk for breast cancer who could benefit from new preventive and therapeutic strategies.

Individuals with a personal or family history of breast cancer are identified according to a standardized set of eligibility guidelines. An attempt is made to enroll each proband, her first-degree relatives, and her affected second-degree relatives. Participants are asked to provide detailed family-history data as well as epidemiologic, medical, and lifestyle information. Blood samples are obtained from participating family members, and tumor specimens are requested from those with a cancer diagnosis. These resources are then made available to the research community for studies approved by an external advisory board of scientists and patient advocates.

The principal investigators from the participating sites and the leadership of the NCI recognized immediately the need to address the unique aspects of participation in a family-based registry with an emphasis on genetic research. The Informed Consent Working Group was created to identify issues of primary interest in the informed-consent process as it relates to involving families in an ongoing process of data collection, evaluation, and analysis and to develop a model informed-consent document. This commentary presents the results of its deliberations and discusses those issues of particular significance to registry participation.


    HISTORY OF THE CONSENT PROCESS
 Top
 Introduction
 The Cooperative Family Registry...
 History of the Consent...
 Content of the Proposed...
 Content Areas of Particular...
 Conclusion
 Notes
 References
 
Beginning with the publication of the Nuremberg Code in 1949, the realization of the need to involve research participants in voluntary consent has been a growing and evolving process. Although written consent forms for therapeutic research were introduced at the National Institutes of Health (NIH) in 1953 (1), it was not until the 1970s that the research community, in partnership with the federal government, began to develop formal guidelines for the ethical conduct of medical research. The Code of Federal Regulations published in 1975 created the system of Institutional Review Boards (IRBs) that were charged with safeguarding the rights and well-being of research subjects and guaranteeing that appropriate informed consent is obtained (2). The purpose of the consent form is to apprise the prospective research subject of the nature of the study and to disclose the potential risks and benefits associated with participation. IRBs have become an integral part of the medical research environment, and the process of obtaining informed consent has become part of the standards and guidelines in the conduct of medical research involving human subjects.

General agreement has been reached about the required content items in the standard consent form (Table 1). This model, which has been the prototype for clinical trials research for the past 20 years, is now, however, being challenged in the face of the growing genetic revolution in science. Powerful new molecular technologies are making possible the ability to map the entire human genome and to identify genes responsible for a host of human diseases. The fear that genetic information may be used to stigmatize or to discriminate against individuals or groups has led to the perception that genetic research is qualitatively different and more risky than other types of medical research and, therefore, requires an expanded process of disclosure and informed consent. Several professional and governmental agencies, including the NIH, the Centers for Disease Control and Prevention (CDC), the American Society of Human Genetics (ASHG), the American College of Epidemiology, and the American Medical Association, have recently published diverse and sometimes conflicting recommendations for obtaining appropriate informed consent for the conduct of genetic research. The members of the Informed Consent Working Group were fully cognizant of this ongoing debate when they developed the informed-consent process for the CFRBCS.


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Table 1. Components of a standard consent form

 

    CONTENT OF THE PROPOSED CONSENT FORM
 Top
 Introduction
 The Cooperative Family Registry...
 History of the Consent...
 Content of the Proposed...
 Content Areas of Particular...
 Conclusion
 Notes
 References
 
The members of the Informed Consent Working Group clearly identified the need to consider informed consent as a process that is based on a trusting relationship between study participants and investigators and reflected in both verbal and written formats. The goals of the consent process are to ensure respect for the participants, to guarantee participant autonomy, and to facilitate informed decision-making. As a first step, the group identified seven core content items necessary for inclusion in the consent form.

The Informed Consent Working Group agreed that all information should be conveyed to potential participants in language that is clear and suitable to their ages, educational levels, and cultural backgrounds. They recognized that many research subjects are interested in receiving even generalized or preliminary research project results, and another decision emerging from these discussions was the commitment to publish a regular newsletter to keep participants informed about the development of the registry, about ongoing research projects, and about general research results as they are reported.


    CONTENT AREAS OF PARTICULAR SIGNIFICANCE FOR REGISTRY PARTICIPATION
 Top
 Introduction
 The Cooperative Family Registry...
 History of the Consent...
 Content of the Proposed...
 Content Areas of Particular...
 Conclusion
 Notes
 References
 
Some aspects of consent to participate in a family-based registry for the purpose of genetic research deviate from the more traditional individual-focused clinical research protocols and require special consideration. The communication of data from multiple, international sites to a central data repository requires special safeguards. Uncertainty about the nature of the research projects that will be conducted by use of the registry's resources is common. The extent to which other family members may be affected by either registry participation or registry research findings is also unclear. And finally, the delicate distinction between research results and clinically significant findings may be especially difficult to define in the case of genetic data.

Privacy and Confidentiality

At the core of the ethical issues associated with the involvement of human subjects in medical research are the issues of privacy and confidentiality. Privacy pertains to the extent to which others can gain access to information about an individual. Privacy issues may arise in research when information is obtained about individuals without their specific consent to divulge or to disseminate that information. Of particular significance is the case of family-based studies, where one person often provides information about the medical histories of family members without their explicit consent. The creation of a family pedigree may reveal previously unknown relatives or may uncover patterns of disease of which the family was unaware.

It has been suggested that publishing family pedigrees poses the risk of invasion of privacy (3). Individuals may experience pressure from other family members to provide information so that the pedigree is complete. While recognizing that there is no clear consensus on this issue, the Office for Protection from Research Risks (OPRR) of the U.S. Department of Health and Human Services has stated that IRBs can consider the collection of pedigree information to be acceptable as long as the nature of the risks involved is defined (4).

Although the identification of the size of the family by the proband is a necessary first step in the creation of a pedigree, the subsequent recruitment of additional family members to a family cancer registry should be done without coercion and with sensitivity to the needs and concerns of each family member. The strategy taken by the Informed Consent Working Group was to request specific written permission from the proband for the registry's staff to contact each additional family member. This policy gives the proband the opportunity to consult with other family members to decide whether withholding permission to contact some family members is in their best interests. At the same time, it removes the burden of actual recruitment from the proband and allows individuals contacted by registry staff to decline to participate without fear of recriminations from family members.

In genetic research, issues of confidentiality equal privacy issues in importance. Confidentiality pertains to the handling and use of data provided by an individual for the purpose of scientific research. Appropriate mechanisms must be in place to prevent the improper disclosure of information and to limit the use of the data to the purposes prescribed in the consent process. Special confidentiality concerns arise in family studies because of the unique nature of genetic data and the implications that information about one family member may have for other family members.

The assurance of confidentiality in genetic studies has two components. First, participants in the registry should be clearly informed as to the physical security of their data and biospecimens, including methods of coding and removal of identifiers, encryption techniques, and quality-assurance policies. Second, participants should be informed about the process of releasing data to future investigators as it relates to maintaining confidentiality. To address the latter issue, the CFRBCS has been constructed as a functionally anonymous data bank that uses an informatics structure that maintains linkages to personal identifiers for the purposes of long-term follow-up but blinds individual investigators to these identifiers.

Use of Data and Biospecimens by Investigators Outside the CFRBCS

Storage of biospecimens in a tissue repository for the purpose of future research creates an archive of biologic samples. The use and reuse of archived tissues are areas of growing debate, particularly when they involve the banking of genetic material. IRB guidelines developed in 1993 by OPRR indicate that investigators should attempt to disclose plans for subsequent use or reuse of data or biospecimens at the time of consent. The dilemma is knowing how to disclose to prospective registry participants the potential risks resulting from research when the nature of future research projects is unknown, and the current pace of genetic research challenges our ability to adhere to the OPRR's recommendation.

The Informed Consent Working Group considered under what circumstances the investigator should be required to obtain a new consent for use of the specimens stored as part of registry participation, a process that may put undue burden on the research subjects or compromise the research effort. Several documents address this issue.

By federal regulation (5), research using stored tissue samples is exempt from IRB review if the tissue samples already exist when the research is proposed and the ability to identify the research subjects is not available to the research team. In cases where samples can be linked to individuals, renewal of consent may be waived when 1) it is judged that there is minimum risk to the subjects, 2) the rights or welfare of the subjects will not be jeopardized, 3) the research could not feasibly be carried out without the waiver, and 4) subjects will receive information about their role in the research when appropriate (4,6,7).

The Genetic Privacy Act, a proposal for federal legislation, recommends a stringent set of consent mechanisms for genetic research, including the restriction of access to DNA samples to persons clearly authorized by the subject at the time of consent and the requirement to destroy the sample upon completion of the specifically authorized genetic analyses unless retention is clearly authorized or the specimens are made anonymous (8). This proposal is based on the premise that genetic information is qualitatively different from other types of medical information, since it provides information about the health of the individual's family and has, historically, served as a means of discrimination.

A workshop convened by the NIH and the CDC in 1994 determined that all investigators, including those not directly involved in the participant's care, should be bound, in most cases, by the limits of the original consent and that, given the potential for risk involved in genetic research, individuals have the right to determine how their samples are used. This principle implies that renewal of consent would be necessary for research projects that are not described in the original consent form. The workshop participants made an exception for samples that were made irretrievably anonymous, since renewal of consent would be impossible (9).

The ASHG, on the other hand, takes a somewhat more flexible view regarding samples that are identifiable. Its statement maintains that subjects providing samples for prospective studies should be informed about the nature of the research proposed, its possible limitations and outcomes (including the possibility of unexpected findings), and the steps that will be taken to assure confidentiality. The ASHG supports renewing consent by subjects for new studies but offers criteria that allow recontact to be waived and that are based on the level of risk involved and the practical constraints imposed by the process of renewing consent (10).

All of the statements and guidelines published to date recognize the uncertainty of many issues pertinent to genetic research and recommend continued debate both within the scientific community and within society at large. Given these limitations, the Informed Consent Working Group recognized the need for an oversight body to monitor the use of the resources stored in the CFRBCS. With the agreement of the entire steering committee, it was decided to expand the advisory committee to include individuals with expertise in the legal and bioethical aspects of genetic research and to give the committee the responsibility to include the issue of renewing consent in their evaluation of research projects. The existence and function of this Research Ethics and Monitoring Panel (REMP) are made explicit in the consent form so that potential registry participants are made aware of the nature of the decision-making process as it relates to their biosamples.

Communication of Registry Research Results

Traditionally, data from studies in research laboratories have not been communicated to the individuals who provided samples for the project. This policy is based on the assumption that results generated in a research laboratory may be subject to less stringent reliability criteria than those originating from a clinical laboratory that is subject to the strict quality-control conditions set by the Clinical Laboratories Improvement Act. Even under the conditions set by this act, many people have questioned the clinical utility of genetic tests that predict the probability of future diseases for which there are no efficacious protective interventions. Although the specific purpose of enrolling families into the CFRBCS was not to perform genetic tests on individual family members, the Informed Consent Working Group appreciated the likelihood that many proposed research projects would include mutation analyses for the major genes associated with breast and ovarian cancers, thereby creating a dilemma regarding the communication of these test results. If results were not communicated to CFRBCS participants, they might be deprived of the potential benefits of knowing their carrier status and taking (or not taking) preventive actions indicated by the results of their tests. On the other hand, giving research results to individuals who had not specifically consented to be tested for a particular mutation—and who may not want the information—raises many other ethical problems.

After much deliberation, it was decided that the consent form would indicate that, when information of potential clinical benefit was obtained as a result of research performed with CFRBCS resources, participants would be notified collectively and offered the opportunity to seek individual genetic testing in a clinically approved laboratory. The definition of clinical benefit would be determined by the full advisory committee, including the members of the REMP, and would be based on the accuracy of the test results, the magnitude of the potential threat posed to the research subject, and the magnitude of the potential benefit to be derived from receiving the information. While this compromise was thought to be reasonable, it was appreciated that it does not address the financial barriers to genetic testing in the clinical setting.

Process Issues

In the process of developing a model consent form, the Informed Consent Working Group identified two process issues that could affect the final form and style of the consent document at each site: 1) legal and regulatory issues for multiple sites and 2) geographic and cultural issues.

Legal and regulatory issues for multiple sites. IRB approval of research protocols remains a local prerogative and is subject to the history, philosophy, and legal constraints of each board. The Informed Consent Working Group recognized the possibility that individual state laws may jeopardize the acceptance of its model consent form and would necessitate local modifications. New York State law does not, for example, allow genetic test results generated in a research setting to be used to inform individuals, because an informed-consent process specific to the exact test being performed is required, and testing must be performed in a state-approved clinical laboratory.

Geographic and cultural issues. The ability to study diverse populations in different countries served by different health care systems is a tremendous strength for the CFRBCS in terms of research opportunities. It provides some challenges, however, with regard to standardization of the informed-consent process. Although there is international agreement on the basic principles of the process, there is also a need to respect the community milieu and the cultural context in which the research is conducted. For example, scientists and identified social leaders within a Native-American tribe collaborated to develop a protocol for genetic research that relies on communal decision-making as opposed to individual determinism (11). And geneticists in China are far more supportive than scientists in the United States of enforced government-initiated genetic-screening programs (12).

With reference to CFRBCS members, one of the major differences between the U.S. sites and sites in Canada and Australia is the organization of health care. While there are millions of uninsured and underinsured individuals in the United States, where health care is a complex mixture of private and public programs, both Canada and Australia have National Health Services that guarantee basic health care to all citizens. This situation translates into major differences in the litigious climate and in individuals' perceived and real levels of vulnerability with regard to confidentiality and how it affects the availability of health care to them. In the United States, one of the major reasons cited for not participating in genetic testing research protocols is fear of discrimination by insurance companies (13). Residents of Canada and Australia, in contrast, do not share that risk and are likely to view genetic research with less concern. [Although in Canada the lack of a common law tort of discrimination precludes civil action against an insurer for discrimination, human rights legislation may provide limited protection from the use of genetic tests in underwriting insurance policies (14).]

Impact of Other Regulatory and Advisory Bodies

A growing number of academic, governmental, and political bodies are attempting to set policy with regard to genetic research and privacy, confidentiality, and discrimination issues. Their goals and agendas differ and change repeatedly to try to keep pace with the speed of genetic discovery and application. This changing environment makes it particularly difficult to address the concerns of all these organizations while developing and maintaining guidelines for informed consent for participation in the CFRBCS.


    CONCLUSION
 Top
 Introduction
 The Cooperative Family Registry...
 History of the Consent...
 Content of the Proposed...
 Content Areas of Particular...
 Conclusion
 Notes
 References
 
In order to promote and to preserve the public trust, which is essential to the success of genetics-based research, it is imperative that investigators maintain the highest ethical standards regarding informed consent and, at the same time, remain sensitive to cultural and social norms of scientific research. Genetic research in the current environment emphasizes the tension between the preservation of individual autonomy and the potential reward to the individual of contributing to genetic discovery. We recognize that the balance achieved and represented while explaining the CFRBCS to potential participants must reflect societal values and must strive to maximize benefit and minimize risk. The Informed Consent Working Group has extended the debate on informed consent by 1) considering the competing needs of the individual, the family, and the public; 2) recognizing the need for special expertise in ethics and law in the guidance of the CFRBCS; 3) anticipating the need for flexibility in the consent process as genetic knowledge moves ahead at unprecedented speed; and 4) acknowledging the responsibility of the investigators to include research participants in the dissemination of research results. It is hoped that these efforts may have relevance to others in the field of genetic research.


    NOTES
 
Supported by Public Health Service contract CA95003 with the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and through cooperative agreements with the Fox Chase Cancer Center, Huntsman Cancer Research Center, Metropolitan New York Registry, Northern California Cancer Center, Cancer Care Ontario, and the University of Melbourne.


    REFERENCES
 Top
 Introduction
 The Cooperative Family Registry...
 History of the Consent...
 Content of the Proposed...
 Content Areas of Particular...
 Conclusion
 Notes
 References
 

1 Daugherty CK. Impact of therapeutic research on informed consent and the ethics of clinical trials: a medial oncology perspective. J Clin Oncol 1999;17:1601-17.[Abstract/Free Full Text]

2 Reilly P. Rethinking risks to human subjects in genetic research. Am J Hum Genet 1998;63:682-5.[Medline]

3 Byers PH, Ashkenas J. Pedigrees—publish? Or perish the thought? Am J Hum Genet 1998;63:678-81.[Medline]

4 Office for Protection from Research Risks, U.S. Department of Health and Human Services (DHHS). Protecting human research subjects: institutional review board guidebook. Washington (DC): DHHS; 1993.

5 Code of Federal Regulations: 45 CFR §§46.101-409 (1995).

6 Merz J. Psychosocial risks of storing and using human tissues in research. Risk Health Safety & Environment 1997;8:235-48.

7 Reilly PR, Boshar MF, Holtzman SH. Ethical issues in genetic research: disclosure and informed consent. Nat Genet 1997;15:16-20.[Medline]

8 Annas GJ, Glantz LH, Roche PA. The Genetic Privacy Act. Boston (MA): Health Law Dept., Boston University School of Public Health; 1995.

9 Clayton EW, Steinberg KK, Khoury MJ, Thomson E, Andrews L, Kahn MJ, et al. Informed consent for genetic research on stored tissue samples. JAMA 1995;274:1786-92.[Abstract]

10 The American Society of Human Genetics. ASHG report. Statement on informed consent for genetic research. Am J Hum Genet 1996;59: 471-4.[Medline]

11 Foster MW, Bernsten D, Carter TH. A model agreement for genetic research in socially identifiable populations. Am J Hum Genet 1998;63:696-702.[Medline]

12 Mao X. Chinese geneticists' views of ethical issues in genetic testing and screening: evidence for eugenics in China. Am J Hum Genet 1998;63:688-95.[Medline]

13 Geller G, Bernhardt BA, Doksum T, Helzlsouer KJ, Wilcox P, Holtzman NA. Decision-making about breast cancer susceptibility testing: how similar are the attitudes of physicians, nurse practitioners, and at-risk women? J Clin Oncol 1998;16:2868-76.[Abstract]

14 Park N, Dickens B. Legal and ethical issues in genetic prediction and genetic counselling for breast, ovarian, and colon cancer susceptibility. In: Taylor K, DePetrillo D, editors. Critical choices: ethical, legal and sociobehavioral implications of heritable breast, ovarian and colon cancer. Background paper for the International Research and Policy Symposium, Toronto, Canada, April 28-30, 1995. p. 61-88.

Manuscript received November 10, 1999; accepted December 9, 1999.


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