Last updated: April 01, 2006
Acknowledgements and Executive Summary
The work of the Task Force was accomplished with the help of many others. Joshua Brown served as staff attorney for the Task Force from April 1995 to May 1996. Mr. Brown prepared very helpful briefing materials and presentations for the Task Force on laws and regulations relating to genetic testing, coordinated Task Force committee meetings, and assisted in the formulation of Task Force principles and recommendations. After Mr. Brown's departure, Emily Koscianski and Andrew Siegel continued legislative and regulatory analysis and the drafting of proposed recommendations on a part-time basis until April 1997. Dr. Siegel, a Greenwall Fellow, was particularly helpful in framing issues related to institutional review boards. Jodi Goldstein, Taria Herz, Katherine Lester, Amanda Merwin, and Michele Schoonmaker, at the time graduate students at the Johns Hopkins School of Hygiene and Public Health (Goldstein and Lester in the joint Hopkins-Georgetown University program in law, ethics, and health), also prepared very useful background papers. Jane Fullarton's familiarity with the Department of Health and Human Services proved extremely valuable in preparing the Task Force's proposed recommendations.
At the Genetics and Public Policy Studies unit at the Johns Hopkins Medical Institutions, where much of the work was done, Sharon Ennis coordinated administrative tasks and Robin Wingfield-Street maintained mailing lists and assembled briefing materials for the Task Force. Over the more than 2-year life of the Task Force, Tascon was responsible for scheduling and arranging meetings (including travel of Task Force members), final mailings, publication of the report, and overall administration. We wish to thank, particularly, Rose Salton, Cindy Elliott-Amadon, and Nancy Shapiro. The appendices to the report were edited by Alice Lium, and the main body of the report by Barbara Cobb. Cindy James, a graduate student in genetic counseling and human genetics, checked references and analyzed trends in genetic discoveries and resources. Support for the Task Force was generously provided by the National Human Genome Research Institute (NHGRI). The Task Force is grateful for the personal interest Francis Collins, Director of NHGRI, took in its work and for his very helpful input.
Finally, every voting and liaison member of the Task Force played an active role in the development of the Task Force's principles and recommendations, and the preparation of the report. Patricia Murphy generously agreed to help in the writing of Chapter 3. Carlyn Collins of the Centers for Disease Control and Prevention, Kate Kremann of the Health Care Financing Administration, and Freda Yoder of the Food and Drug Administration attended many Task Force meetings, reviewed briefing materials and drafts, and made many helpful suggestions. Voting Members: Neil A. Holtzman, M.D., M.P.H., Chair ELSI Working Group Michael S. Watson, Ph.D., FACMG, Co-Chair American College of Medical Genetics Patricia A. Barr National Breast Cancer Coalition David R. Cox, M.D., Ph.D. ELSI Working Group Jessica G. Davis, M.D. Council of Regional Networks for Genetic Services Stephen I. Goodman, M.D., M.Sc. American Society of Human Genetics Wayne W. Grody, M.D., Ph.D. College of American Pathologists Arthur L. Levin, M.D. Alliance for Managed Competition J. Alexander Lowden, M.D., Ph.D. Health Insurance Association of America Patricia D. Murphy, Ph.D., FACMG OncorMed Patricia J. Numann, M.D. American Medical Association Victoria O. Odesina, R.N., Sc.M., M.S. Alliance of Genetic Support Groups Nancy Press, Ph.D. ELSI Working Group Katherine A. Schneider, M.P.H. National Society of Genetic Counselors David B. Singer Biotechnology Industry Organization (BIO) Elliott Hillback was BIO alternate representative when Mr. Singer could not attend. Government Liaison (Non-voting) Members: Steven Gutman, M.D. Food and Drug Administration Muin J. Khoury, M.D., Ph.D. Centers for Disease Control and Prevention David Lanier, M.D. Agency for Health Care Policy and Research Peter Bouxsein, M.D. represented the Agency until September 1996. Linda R. Lebovic Health Care Financing Administration Jane S. Lin-Fu, M.D. Health Resources and Services Administration The work of the Task Force was supported by the National Institutes of Health.
The rapid pace of discovery of genetic factors in disease has improved our ability to predict risks of disease in asymptomatic individuals. We have learned how to prevent the manifestations of a few of these diseases and treat some others. Gene therapy is being actively investigated.
Despite remarkable progress much remains unknown about the risks and benefits of genetic testing:
- No effective interventions are yet available to improve the outcome of most inherited diseases.
- Negative (normal) test results might not rule out future occurrence of disease.
- Positive test results might not mean the disease will inevitably develop.
It is primarily in the context of their unknown potential risks and benefits that the Task Force considers genetic testing.
Origin and Work of the Task Force
The Task Force was created by the National Institutes of Health (NIH)-Department of Energy (DOE) Working Group on Ethical, Legal, and Social Implications (ELSI) of Human Genome Research to review genetic testing in the United States and make recommendations to ensure the development of safe and effective genetic tests. The Task Force has defined safety and effectiveness to encompass not only the validity and utility of genetic tests, but their delivery in laboratories of assured quality, and their appropriate use by health care providers and consumers.
The Working Group invited organizations with a stake in genetic testing to submit nominations from which it selected members of the Task Force. In addition, the Working Group invited five agencies in the Department of Health and Human Services (HHS) to send nonvoting liaison members to the Task Force. Principles and recommendations of the Task Force appear in bold-faced type.
Definition of Genetic Tests
Genetic test -The analysis of human DNA, RNA, chromosomes, proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes or karyotypes for clinical purposes. Such purposes include predicting risk of disease, identifying carriers and establishing prenatal and clinical diagnosis or prognosis. Prenatal, newborn and carrier screening, as well as testing in high-risk families, are included. Tests for metabolites are covered only when they are undertaken with high probability that an excess or deficiency of the metabolite indicates the presence of heritable mutations in single genes. Tests conducted purely for research are excluded from the definition, as are tests for somatic (as opposed to heritable) mutations, and testing for forensic purposes.
The Task Force is primarily concerned about predictive uses of genetic tests performed in healthy or apparently healthy people. Predictive test results do not necessarily mean that the disease will inevitably occur or remain absent; they replace the individual's prior risks based on population data or family history with risks based on genotype. Some, but not all, predictive genetic testing falls under the rubric "genetic screening," a search in a population for persons possessing certain genotypes.
The Need for Recommendations
For the most part, genetic testing in the United States has developed successfully, providing options for avoiding, preventing, and treating inherited disorders. However, problems arise as a result of current practices.
- Sometimes, genetic tests are introduced before they have been demonstrated to be safe, effective, and useful (see Chapter 2 and Appendices 5 and 6).
- There is no assurance that every laboratory performing genetic tests for clinical purposes meets high standards (see Chapter 3).
- Often, the informational materials distributed by academic and commercial genetic testing laboratories do not provide sufficient information to fill in the gaps in providers' and patients' understanding of genetic tests (see Appendix 4).
- In the next few years, a greater burden for offering genetic testing will fall on providers who have little formal training or experience in genetics.
In this report, the Task Force does not recommend policies for specific tests but suggests a framework for ensuring that new tests meet criteria for safety and effectiveness before they are unconditionally released, thereby reducing the likelihood of premature clinical use. The focus of the Task Force on potential problems in no way is intended to detract from the benefits of genetic testing. Its overriding goal is to recommend policies that will reduce the likelihood of damaging effects so the benefits of testing can be fully realized undiluted by harm.
Need for an Advisory Committee on Genetic Testing
The Task Force calls on the Secretary of Health and Human Services (HHS) to establish an advisory committee on genetic testing in the Office of the Secretary. Members of the committee should represent the stakeholders in genetic testing, including professional societies (general medicine, genetics, pathology, genetic counseling), the biotechnology industry, consumers, and insurers, as well as other interested parties. The various HHS agencies with activities related to the development and delivery of genetic tests should send nonvoting representatives to the advisory committee, which can also coordinate the relevant activities of these agencies and private organizations. The Task Force leaves it to the Secretary to determine the relationship of this advisory committee to others that may be created in the broader area of genetics and public policy, of which genetic testing is only one part.
The committee would advise the Secretary on implementation of recommendations made by the Task Force in this report to ensure that (a) the introduction of new genetic tests into clinical use is based on evidence of their analytical and clinical validity, and utility to those tested; (b) all stages of the genetic testing process in clinical laboratories meet quality standards; (c) health providers who offer and order genetic tests have sufficient competence in genetics and genetic testing to protect the well-being of their patients; and (d) there be continued and expanded availability of tests for rare genetic diseases.
The Task Force recognizes the widely inclusive nature of genetic tests. It is therefore essential that the advisory committee recommend policies for the Secretary's consideration by which agencies and organizations implementing recommendations can determine those genetic tests that need stringent scrutiny. Stringent scrutiny is indicated when a test has the ability to predict future inherited disease in healthy or apparently healthy people, is likely to be used for that purpose, and when no confirmatory test is available. The advisory committee or its designate should define additional indications.
In order to carry out its functions, the advisory committee should have its own staff and budget.
The Task Force further recommends that the Secretary review the accomplishments of the advisory committee on genetic testing after two full years of operation and determine whether it should continue to operate.
In making recommendations on safety and effectiveness, the Task Force concentrated on test validity and utility, laboratory quality, and provider competence. It recognizes, however, that other issues impinge on testing, and problems may arise from testing. Regarding these issues, the Task Force endorses the following principles.
Informed Consent. The Task Force strongly advocates written informed consent. The failure of the Task Force to comment on informed consent for other uses does not imply that it should not be obtained.
Test Development. Informed consent for any validation study must be obtained whenever the specimen can be linked to the subject from which it came.
Testing in Clinical Practice. (1) It is unacceptable to coerce or intimidate individuals or families regarding their decision about predictive genetic testing. Respect for personal autonomy is paramount. People being offered testing must understand that testing is voluntary. Their informed consent should be obtained. Whatever decision they make, their care should not be jeopardized.
(2) Prior to the initiation of predictive testing in clinical practice, health care providers must describe the features of the genetic test, including potential consequences, to potential test recipients.
Newborn Screening. (1) If informed consent is waived for a newborn screening test, the analytical and clinical validity and clinical utility of the test must be established, and parents must be provided with sufficient information to understand the reasons for screening.By clinical utility, the Task Force means that interventions to improve the outcome of the infant identified by screening have been proven to be safe and effective.
(2) For those disorders for which newborn screening is available but the tests have not been validated or shown to have clinical utility, written parental consent is required prior to testing.
Prenatal and Carrier Testing. Respect for an individual's/couples' beliefs and values concerning tests undertaken for assisting reproductive decisions is of paramount importance and can best be maintained by a nondirective stance. One way of ensuring that a non-directive stance is taken and that parents' decisions are autonomous, is through requiring informed consent.
Testing of Children. Genetic testing of children for adult onset diseases should not be undertaken unless direct medical benefit will accrue to the child and this benefit would be lost by waiting until the child has reached adulthood.
Confidentiality. Protecting the confidentiality of information is essential for all uses of genetic tests. (1) Results should be released only to those individuals for whom the test recipient has given consent for information release. Means of transmitting information should be chosen to minimize the likelihood that results will become available to unauthorized persons or organizations. Under no circumstances should results with identifiers be provided to any outside parties, including employers, insurers, or government agencies, without the test recipient's written consent. (2) Health care providers have an obligation to the person being tested not to inform other family members without the permission of the person tested, except in extreme circumstances.
Discrimination. No individual should be subjected to unfair discrimination by a third party on the basis of having had a genetic test or receiving an abnormal genetic test result. Third parties include insurers, employers, and educational and other institutions that routinely inquire about the health of applicants for services or positions.
Consumer Involvement in Policy Making. Although other stakeholders are concerned about protecting consumers, they cannot always provide the perspective brought by consumers themselves, the end users of genetic testing. Consumers should be involved in policy (but not necessarily in technical) decisions regarding the adoption, introduction, and use of new, predictive genetic tests.
Providers and consumers cannot make a fully-informed decision about whether or not to use genetic tests unless their benefits and risks have been assessed. Although extensive use has eventually proved most tests to be of benefit, a few eventually proved unhelpful and were discarded. In the meantime, people were wrongly classified as at-risk and subjected to treatments that, in their case, proved unnecessary or sometimes harmful. Others, who could have benefited from treatment were classified as "normal" and denied treatment. The Task Force strongly recommends that the following criteria be satisfied.
- The genotypes to be detected by a genetic test must be shown by scientifically valid methods to be associated with the occurrence of a disease. The observations must be independently replicated and subject to peer review.
- Analytical sensitivity and specificity of a genetic test must be determined before it is made available in clinical practice.
- Data to establish the clinical validity of genetic tests (clinical sensitivity, specificity, and predictive value) must be collected under investigative protocols. In clinical validation, the study sample must be drawn from a group of subjects representative of the population for whom the test is intended. Formal validation for each intended use of a genetic test is needed.
- Before a genetic test can be generally accepted in clinical practice, data must be collected to demonstrate the benefits and risks that accrue from both positive and negative results.
Ensuring Compliance with Criteria for Safety and Effectiveness
Because of the length of time it can take to establish the appropriateness of a test for clinical use, it is all the more important to ensure the collection of data on safety and effectiveness in the course of test development. At present, no government policy requires the collection of data on clinical validity and utility for all predictive genetic tests under development.
Considering the structures for external review of research in the U.S. today, the Task Force is of the opinion that institutional review boards (IRBs) are the most appropriate organizations to consider whether the scientific merit of protocols for the development of genetic tests warrants the risk to subjects participating in the research.
Protocols for the development of genetic tests that can be used predictively must receive the approval of an institutional review board (IRB) when subject identifiers are retained and when the intention is to make the test readily available for clinical use, i.e., to market the test. IRB review should consider the adequacy of the protocol for: (a) the protection of human subjects involved in the study, and (b) the collection of data on analytic and clinical validity, and data on the test's utility for individuals who are tested.
Tests under development must be conducted in laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) if the results will be reported to patients or their providers.
Health department laboratories or other public agencies developing new genetic tests that satisfy these conditions must also submit protocols to properly constituted IRBs.
The Task Force recommends that the Office of Protection of Human Subjects from Research Risks (OPRR) develop guidelines to assist IRBs in reviewing genetic testing protocols. The proposed Secretary's Advisory Committee should work with OPRR to accomplish this task. In developing guidelines for IRBs, OPRR should focus first on tests under development that require stringent scrutiny. The proposed Secretary's Advisory Committee or its designate, in cooperation with OPRR, should establish criteria for stringent scrutiny.
Conflict of Interest. The Task Force recommends strenuous efforts by all IRBs (commercial and academic) to avoid conflicts of interest, or the appearance of conflicts of interest, when reviewing specific protocols for genetic testing. OPRR should consider more stringent standards for all types of IRBs for avoiding conflict of interest situations.
Enforcement. Testing organizations should comply voluntarily with obtaining IRB approval of genetic test protocols. Other options the Task Force considered for enforcing the requirement for IRB approval included that: (1) the FDA use its authority to require all test developers to submit protocols to IRBs, (2) third-party payers refuse to reimburse for a genetic test unless the developer can show that it conducted validation/utility studies under an IRB-approved protocol, (3) clinical laboratory surveyors (see chapter 3) confirm that laboratories have received IRB approval of the new genetic tests that they developed, and (4) Congress enact legislation requiring submission of all research protocols, regardless of support, to an IRB.
Data Collection. To expedite data collection, collaborative efforts will often be needed. OPRR, with input from the proposed Secretary's Advisory Committee on genetic testing, should streamline the requirements for IRB review of multicenter collaborative protocols for genetic test development in order to reduce costs and get the studies quickly underway. The Task Force calls on federal agencies, particularly NIH and the Centers for Disease Control and Prevention (CDC) to support consortia and other collaborative efforts to facilitate collection of data on the safety and effectiveness of new genetic tests. CDC should play a coordinating role in data gathering and should be allocated sufficient funds for this purpose. In sharing or pooling of data, confidentiality of the subject source of the data must be strictly maintained.
The Need for Post-market Surveillance. The Task Force recognizes that assessing the validity and utility of some genetic tests will take a long time. When preliminary data indicate a test is likely to have validity and utility, the test should be approved for marketing (see below) but developers must continue to collect data until more definitive answers are obtained. Options for encouraging collection of the requisite data include the following:
- Voluntary collection of data by developers after their tests enter clinical use.
- Reimbursement for, or coverage of, tests by third party payers during investigative stages in which data are being collected.
- Conditional premarket approval by the FDA of genetic test kits. In return for conditional approval, developers could include a profit markup in the price while they continue to collect data.
Evidence-based Entry of New Genetic Tests into Clinical Practice
Test developers must submit their validation and clinical utility data to internal as well as independent external review. In addition, test developers should provide information to professional organizations in order to permit informed decisions about routine use. The Task Force recognizes that not all new genetic tests are in need of such review. The proposed Secretary's Advisory Committee should suggest criteria for external review, and recommend means of ensuring that review of tests requiring stringent scrutiny will take place. To accomplish the latter, the cooperation of various government and nongovernment groups to conduct reviews must be secured, as well as funds to support the reviews. A wide range of stakeholders should participate in reviews.
Local Review. The Task Force strongly suggests that any organization in which tests are developed conduct a structured review of the analytic and clinical validity and utility of new genetic tests before marketing them or otherwise making them available for clinical use. This structured review should be conducted by those not actually involved in developing the test and collecting the data. Some medical centers have standing committees that review tests proposed to be offered in the institution's clinical laboratories that could serve this function. For commercial organizations, a unit within the company, but independent of the laboratory that is actually developing the test, should review the data.
National Review. Current legal requirements that genetic tests be reviewed prior to their clinical use apply only to tests marketed as kits, which require premarket approval by FDA. To improve FDA perspectives on genetic testing and related issues, the Task Force recommends that FDA bring together consultants on genetic testing either from existing panels or by constructing a new panel to provide guidance to FDA on genetic testing devices with single or multiple intended uses.
Although no other legally-required mechanisms currently exist, other reviews can have a profound influence on providers' decisions to use, or not use, new medical technologies. Examples are: statements of professional societies, consensus development panels, and ratings by the U.S. Preventive Services Task Force. The decision of health insurers on whether a specific genetic test will be included in their benefits or reimbursement packages can also influence use and will be based on the insurers' own reviews or other external reviews.
Although laboratories performing chromosomal, biochemical, and/or DNA-based tests for genetic diseases must comply with general regulations under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), current requirements under CLIA are inadequate to ensure the overall quality of genetic testing because they are not specifically designed for any genetic tests except cytogenetic tests. Most laboratories performing genetic tests voluntarily participate in quality programs addressed specifically to genetic tests, but they are not required to do so. Consequently, providers and consumers have no assurance that every laboratory performs adequately.
Principles for Laboratories Adopting New Genetic Tests
No clinical laboratory should offer a genetic test whose clinical validity has not been established, unless it is collecting data on clinical validity under either an IRB-approved protocol or conditional premarket approval agreement with FDA (one of the options presented in chapter 2. The service laboratory should justify and document the basis of decisions to put new tests into service. Regardless of where the test to be adopted was developed, clinical laboratory directors are responsible for ensuring the analytic validity of each genetic test their laboratory intends to offer before they make the test available for use in clinical practice (outside of an investigative protocol).
Before routinely offering genetic tests that have been clinically validated, a laboratory must conduct a pilot phase in which it verifies that all steps in the testing process are operating appropriately. If the pilot study reveals that the laboratory is not as competent as other laboratories in performing the test, or the test does not detect as many people with the genetic alteration as anticipated, the laboratory should not proceed to report patient-specific results without attempting to rectify the problems.
Requirements Under CLIA
The stringency of CLIA requirements depends on the complexity level and specialty to which tests are assigned.
Complexity Ratings. CDC assigns a complexity level to a test according to predetermined criteria. Laboratories performing high complexity tests have more stringent personnel and quality-control requirements. Despite multiple uses, a test method gets only one rating. The Task Force recommends that tests that can be used for purposes of predicting future disease be given a rating of high complexity.
CLIA Specialties. Laboratories can perform tests only in specialties for which they are certified. Although there is a cytogenetics specialty, there is no genetics specialty. The Task Force welcomes the intention of CDC to create a genetics subcommittee of the Clinical Laboratory Improvement Advisory Committee (CLIAC), which advises on policies under CLIA. The Task Force urges this subcommittee to consider the creation of a specialty of genetics that would encompass all predictive genetic tests that satisfy criteria for stringent scrutiny. If a specialty of genetics is not feasible, the subcommittee should consider a specialty or subspecialty of molecular genetics for DNA/RNA-based tests. In the latter case, it must then address how to ensure the quality of laboratories performing nonDNA/RNA genetic tests. The subcommittee should also consider assigning tests that have widely different uses to more than one specialty.
Laboratory Personnel. Personnel requirements under CLIA, particularly at the level of laboratory director, depend on the specialty and complexity categories to which tests or analytes are assigned. Without a genetics specialty, genetic tests fall into other specialties for which requiring special training in genetics would be superfluous. The Task Force recommends that, for laboratories performing high complexity tests in the proposed specialty of molecular genetics, as well as in biochemical genetics and cytogenetics, personnel serving as directors or technical supervisors must have formal training in human and medical genetics, as documented by holding certification from an organization that assesses knowledge of human and medical genetics as part of its certification process, such as the American Board of Medical Genetics. Training programs for laboratory technicians/technologists need more human and medical genetics content than are currently available in the U.S.
Monitoring Laboratory Performance
Because laboratories provide services to providers and patients in many states it is clearly more desirable to have a rigorous Federal standard for certification or accreditation than fifty different State standards. Moreover, interstate genetic testing is unavoidable when only one or a few laboratories in the country provide tests. A national accreditation program for laboratories performing genetic tests, which includes proficiency testing and onsite inspection, is needed to promote standardization across the country. Such an accreditation program can occur more readily if a genetics specialty were established under CLIA. Until such time as a genetics specialty is established under CLIA, laboratories performing DNA/RNA-based tests for predictive purposes should choose to voluntarily participate in the College of American Pathologists' (CAP) molecular pathology program, including the CAP/American College of Medical Genetics (ACMG) molecular genetics proficiency testing program. Laboratories performing genetic tests on analytes not covered in the CAP/ACMG program, such as Tay-Sachs carrier screening and newborn screening, should participate in the available proficiency programs.
Proficiency Testing (PT). Under CLIA, every laboratory performing moderate or high complexity tests is required to enroll in PT programs recognized by HCFA. Any laboratory that fails a proficiency test must take corrective action.
So far, the Department of Health and Human Services has not approved proficiency testing programs for genetic tests because such tests do not measure regulated analytes for PT purposes. Nevertheless, under CLIA, laboratories must establish the accuracy and reliability of a test by methods of their own choosing. This can include participation in one of the voluntary PT programs. As these programs have not been approved by CLIA, no laboratory is obliged to use them and can establish accuracy and reliability by another method, although it must make the data available for onsite inspection under CLIA (see below). Participation in well-established proficiency testing programs for genetic tests must be required under CLIA once a genetics specialty is established. When no relevant proficiency testing programs exist, laboratories must, whenever possible, participate in inter-laboratory comparison programs and help develop them if none exist in their particular area of testing. Proficiency testing programs should be broadly based since the number of genetic disorders is very large and the analytical approaches to testing are numerous.
Onsite Inspection. All CLIA-certified laboratories are routinely inspected on a two-year survey cycle by (1) HCFA regional offices and State agencies, (2) private non-profit organizations to which HCFA has given "deemed" status in recognition of their ability to provide reasonable assurance that the laboratories they accredit meet the conditions required by Federal law, or (3) State-exempt licensure programs.
CAP has deemed status to conduct inspections in several specialties, but since genetics is not a specialty under CLIA, the CAP program does not have deemed status in genetics. In the CAP genetics program, laboratories who voluntarily participate in the program are inspected.
Making Laboratory Performance Assessments Public
Publishing the names of laboratories performing satisfactorily would advise users that labs not appearing on the list have either not submitted to external review or have not performed adequately. HCFA annually publishes a list ("Laboratory Registry") that identifies all poor performance laboratories. As CAP is not deemed to accredit in areas of genetics, it does not make the results of its assessments of genetic test performance public. The Task Force recommends that CAP/ACMG periodically publish, and make available to the public, a list of laboratories performing genetic tests satisfactorily under its voluntary program. Other PT programs should also publish the names of laboratories performing satisfactorily if they do not already do so. Directories of laboratories providing genetic tests should also publish information on listed laboratories' satisfactory participation in PT and other quality control programs specific to genetic tests. Managed care organizations and other third-party payers should limit reimbursement for genetic tests to the laboratories on published lists of those satisfactorily performing genetic tests.
A Central Repository of Cell Lines and DNA
Making cell lines or DNA containing disease-related mutations available to many laboratories would be useful in the validation of new tests, calibration, standardization, and quality control. To accomplish this, appropriate specimens from patients, carriers, and controls should be available through a centralized repository in order to facilitate their availability to aid in analytical validation, improving quality, and other needs.
The Importance of the Pre- and Post-analytic Phases of Testing
Educational and promotional material made available by laboratories is often used by providers and consumers who are considering testing. The completeness and accuracy of this material is, therefore, extremely important. Obtaining informed consent helps ensure that the person voluntarily agrees to testing and has some understanding of the reasons for testing. The Task Force is of the opinion that laboratories should obtain documentation of informed consent when appropriate and should not perform an analysis if documentation is lacking.
Increasingly, genetic tests will be requested by providers without much or any training in genetics. Genetic test results must be written by the laboratory in a form that is understandable to the non-geneticist health care provider.
The Task Force recommends that CAP and ACMG seek advice and input from consumer groups, such as the Alliance of Genetic Support Groups, as well as from the National Society of Genetic Counselors (NSGC), on educational, psychological, and counseling issues in pre- and post-analytic components of genetic testing that are of direct concern to consumers. CDC should consider how the pre- and post-analytic phases of predictive genetic testing can be given greater weight in CLIA standards and regulations.
Direct Marketing of Genetic Tests to the Public
Many clinical laboratories advertise the availability of tests directly to the public. Great care must be taken that information on genetic tests presented directly to the public is accurate and includes risks and limitations, as well as benefits. Consumers should discuss testing options with a health care provider competent in genetics prior to having specimens collected for analysis. The Task Force discourages advertising or marketing of predictive genetic tests to the public.
The Task Force recommends that efforts should be made to harmonize international laboratory standards to ensure the highest possible laboratory quality for genetic tests.
The rate of increase of health care professionals trained and board-certified in medical genetics or genetic counseling has not kept pace with the rate of increase of genetic discovery and of potential demand for genetic tests. Other health care professionals will have to play a role or new models of testing will have to be devised if the demands are to be met.
A Role for Non-genetic Health Care Professionals
With adequate knowledge of test validity, disease and mutation frequencies in the ethnic groups to whom they provide care, primary care providers and other non-genetic specialists can and should be the ones to offer predictive genetic tests to at-risk individuals. The role of non-genetic providers in interpreting test results is complex. The interpretation of positive results will often depend on further elicitation of risks, including family history. The options available to reduce risks must also be known. Often the results will be of importance to other relatives. A test's sensitivity and predictive value may also vary by ethnic group. Providers must be aware of these and other considerations in interpreting test results and be capable of communicating risk information and its implications to those who are tested or their parents or guardians. Consultation with geneticists and/or genetic counselors may be appropriate.
Policies for Improving the Abilities of Non-genetic Health Care Professionals
Greater Public Knowledge of Genetics. A knowledge base on genetics and genetic testing should be developed for the general public. Without a sound knowledge base, informed decisions are impossible and claims of autonomy and informed consent suspect. People who are more knowledgeable will grasp more readily the issues raised by providers when they offer tests. This could diminish the time needed for education and counseling without reducing consideration of the implications of testing. New models of providing education and counseling to patients and other consumers are needed.
Undergraduate and Graduate Medical Education. The Task Force encourages the development of genetics curricula in medical school and residency training to enable all physicians to recognize inherited risk factors in patients and families and appreciate issues in genetic testing and the use of genetic services. Those responsible for education and training have begun to recognize that most medical care is provided in ambulatory settings and that the delivery of care in those areas presents challenges for education. Genetic testing is a prime example. Moreover, teaching about genetic tests, including such issues as analytic and clinical validity, introduces students and residents to general problems of reliability and test sensitivity and specificity, which are important for a much wider range of clinical laboratory tests.
Licensure and Certification. The likelihood that genetics will be covered in curricula will improve if relevant genetics questions are included in general licensure and specialty board certification examinations, and if correctly answering a proportion of the genetics questions is needed to attain a passing score.
Continuing Medical Education. The full beneficial effects of improving medical school and residency curricula in genetics will not be felt for many years. Consequently, improving the ability of providers currently in practice to offer and interpret genetic tests correctly is of paramount importance. In addition to the basic curricula already considered, the Task Force recommends that each specialty involved with the care of patients with disorders with genetic components should design its own curriculum for continuing education in genetics.
Administrators and other nonphysician personnel who triage patients and/or make coverage or reimbursement decisions, such as those in managed care organizations, should also have knowledge of the benefits and risks of genetic testing.
The Task Force endorses the recent establishment of a National Coalition for Health Professional Education in Genetics (NCHPEG) by the American Medical Association, the American Nurses Association, and the National Human Genome Research Institute. In order to avoid duplication, the Coalition should serve as a registry and clearinghouse for, and disseminator of, information about various curricula and educational programs, grants, and training pilot programs in genetics education. It should encourage professional societies to track the effectiveness of their respective educational programs.
A major problem in all educational endeavors is finding the "teachable moment," the time at which people, including health care providers, are receptive to new information and are most likely to retain it. These moments arise when providers are asked questions about genetic tests or when charts are flagged because the patient fulfills criteria for being offered a genetic test. To make information available at the teachable moments, a 1-800 hotline that providers can call to learn more about specific genetic tests should be encouraged by NCHPEG.
Demonstrating Provider Competence. Hospitals and managed care organizations, on advice from the relevant medical specialty departments, should require evidence of competence before permitting providers to order predictive genetic tests defined as needing stringent scrutiny or to counsel about them. Periodic, systematic medical record review, with feedback to providers, should also be used to ensure appropriate use of genetic tests. In order to succeed, this policy requires, first, deciding which tests need evidence of competence, second, defining competence for those tests, and third, making educational modules readily available to enable providers to gain competence.
Medical record audits assure managed care and other organizations that providers are satisfying standards of care. The feedback given to providers also serves as a valuable reenforcement to what has previously been learned. Audits of records for frequently-ordered medical tests should be considered.
Nursing. Nurses have much to offer in helping people before, during, and after the genetic testing process. Because of their vast numbers and the wide range of health care activities they can perform, they can play an important role in providing care for those undergoing genetic testing. Nurses should be provided with additional education and training that can increase their effectiveness in providing education for people undergoing genetic testing.
Community and Public Health. Although population-wide screening can be integrated into personal health care, different models have been used. In many states, it is the responsibility of the hospital in which the baby is born to conduct newborn screening. As tests for more inherited conditions become available and the safety and effectiveness of treating them neonatally is established, newborn screening could expand markedly.
Community-centered screening presents another model. Tay-Sachs carrier screening was originally organized at the community level. Any effort to initiate community-based genetic screening must have the support and involvement of the community. Particularly when minority communities are involved, the program must be sensitive to issues of discrimination and provide sufficient resources for education and counseling.
Screening could be offered in health department clinics, mobile vans or other sites, but not all segments of the population are likely to utilize them. A greater chance of breaching confidentiality is possible at community and health department sites than in the privacy of the traditional provider-patient relationship. Traditionally, health departments have been most involved in clinical care when there were well-accepted interventions (such as immunizations or tuberculosis control) without which the health of the public would be jeopardized. It might be difficult for public health personnel to appreciate that someone who refuses genetic screening is not jeopardizing the health of the public. Before these new models are investigated, additional training of the personnel involved is necessary. Schools of nursing, public health, and social work need to strengthen their training programs in genetics.
Between 10 and 20 million Americans may suffer from one or more of the several thousand known rare diseases over their lifetimes. With the discovery of the role of inherited mutations in common diseases, such as breast and colon cancer and Alzheimer disease (albeit in a small proportion of affected people), the development and maintenance of tests for rare genetic diseases must continue to be encouraged. A comprehensive system to collect data on rare diseases must be established. Multiple sources will almost always be needed to validate tests for rare diseases. CDC and the NIH Office of Rare Diseases (ORD) should work closely to develop the appropriate data-gathering and monitoring systems to assess the validity of genetic tests for rare diseases.
Dissemination of Information About Rare Diseases
Unfortunately, the diagnosis of rare diseases is often delayed. One reason for the delay is inaccessibility of information. Physicians who encounter patients with symptoms and signs of rare genetic diseases should have access to accurate information that will enable them to include such diseases in their differential diagnosis, to know where to turn for assistance in clinical and laboratory diagnosis, and to locate laboratories that test for rare diseases.
Several private and public organizations, both professional and consumer-oriented, do provide information on rare diseases. The Task Force is concerned that there might be some unnecessary duplication of effort in compiling databases while, at the same time, some diseases or laboratories offering tests will not be included. In order to avoid redundancy and to use the expertise of these organizations more efficiently, NIH should assign its Office of Rare Diseases (ORD) the task of coordinating these efforts and provide ORD with sufficient funds to fulfill the Task Force's recommendations on rare diseases. ORD should periodically report to the proposed Secretary's Advisory Committee on the status of these activities. With CDC playing a greater role in genetics, it should be closely involved in activities in this area.
Ensuring Continuity and Quality of Tests for Rare Diseases
Because of the rarity of many diseases, only one or a few laboratories in the United States, or the world, accurately perform tests for some of them. To maintain and expand its database, ORD should identify laboratories worldwide that perform tests for rare genetic diseases, the methodology employed, and whether the tests they provide are in the investigational stage, or are being used for clinical diagnosis and decision making.
Some clinical diagnostic tests for rare diseases are performed in laboratories that are primarily engaged in research at no cost to the patient and with the primary purpose of furthering research. Such laboratories may cease performing these tests, on which clinical decisions are based, as they complete their investigations and move on to other areas of interest. The NIH Office of Rare Diseases should have the lead responsibility in ensuring the continued availability of safe and effective tests for rare diseases when it learns that a test will cease being offered. Funds to enable it to accomplish this task should be available.
Ensuring the Quality of Genetic Tests for Rare Diseases
In accordance with current law, the Task Force recommends that any laboratory performing any genetic test on which clinical diagnostic and/or management decisions are made should be certified under CLIA. Research laboratories that are not currently providing genetic test results to providers or patients but that plan to do so in the future must register under CLIA. Once a laboratory registers, it does not have to wait for a survey before performing clinical tests.
Research laboratories that provide physicians with results of genetic tests, which may be used for clinical decision making, must validate their tests and be subject to the same internal and external review as other clinical laboratories. Nevertheless, the proposed genetics subcommittee of CLIAC should consider developing regulatory language under the proposed genetics specialty that is less stringent, but does not sacrifice quality for laboratories that only occasionally and in small volume perform tests whose results are made available to health care providers or patients.
Directories of laboratories that perform tests for rare genetic diseases should indicate whether or not the laboratory is CLIA-certified and whether it has satisfied other quality assessment and proficiency assessments, such as those provided by CAP and ACMG. Directors of these laboratories are encouraged to participate in these programs or other programs of at least comparable quality that may be established.
Of great concern to the Task Force is whether certification under CLIA will ensure the quality of genetic tests, particularly those for rare genetic diseases. The creation of a subspecialty of genetics under CLIA will greatly improve the situation. Many tests for rare disorders are biochemical. The quality of performance of these tests would be ensured if they were included under a genetics specialty.
The principles and recommendations of the Task Force will help ensure that genetic testing will be provided safely and effectively and that tests for rare diseases will be more widely available but used appropriately. The Task Force concludes that with implementation of these recommendations, genetic testing will continue to flourish.