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REGULATIONS & STANDARDS
A new genetics panel for FDA
Russel K. Enns
In September, FDA announced in the Federal Register the formation of a new molecular and clinical genetics panel of its Medical Devices Advisory Committee, and issued a call for member nominations. The term of each member's service on the panel will be four years. Unfortunately, by the time this article appears, the deadline for nominating panel members will have already come and gone since the agency set October 27 as the due date. The Federal Register notice did not indicate whether FDA would accept late nominations.1
In its announcement, FDA said that nominees for membership on this newly created panel "shall have expertise in human genetics and in the clinical management of patients with genetic disorders, e.g., pediatricians, obstetricians, and neonatologists." In addition, the announcement said that FDA would consider candidates with expertise in inborn errors of metabolism, biochemical or molecular genetics, population genetics, epidemiology and related statistical training, genetic counseling, or medical ethics. The announcement also noted that the panel will include "technically qualified members who are identified with consumer interests and representatives of industry interests."
In addition to carrying out the usual review and advisory functions of a medical device panel, the new genetics panel is expected to focus on recommending "appropriate scientific criteria to diagnostically test for human genes." Other essential functions of the panel will include reviewing guidance documents issued by the agency, and recommending criteria and classification of tests for human genes.
The Need for a Panel
FDA needs the new genetics advisory panel for a number of reasons, beginning with the agency's need to keep up with rapidly advancing technologies. In the time since the enactment of the Medical Device Amendments of 1976—while the agency has been developing and refining its device regulations—the field of human genetics has achieved momentous advances. Such advances include the development of polymerase chain reaction and other amplification techniques, nucleic acid sequencing, oligonucleotide synthesis, hybridization assay formats, and cloning techniques—to name just a few of the more notable accomplishments.
The extraordinary growth of the field of molecular biology is exemplified by the huge strategic management effort of the National Human Genome Research Institute (NHGRI), led by Francis Collins. Over the past 10 years, the efforts of the NHGRI and other academic and private-sector organizations have made it possible to identify thousands of genes associated with a wide variety of human diseases. And within the next year, Collins reports, 90% of the human genome sequence will be completed, accounting for at least 100,000 more genes. Collins has frequently said that most disease, with the exception of trauma, is genetically linked in one way or another. Nevertheless, over the past decade, which has witnessed so many advances in the science of gene discovery, FDA has cleared or approved fewer than 10 human genetic tests.
In the past, the agency has considered the possibility of forming a device evaluation branch devoted to the specialty of genetics, probably within the Division of Clinical Laboratory Devices (DCLD) in the Office of Device Evaluation (ODE). Eventually this idea was rejected, leaving DCLD without specialized expertise in this field. But now, with the field of medical genetic testing seemingly on the verge of exponential expansion, FDA could not have picked a more appropriate time to establish its new panel. Formation of the new genetics advisory panel should provide DCLD a significant resource during its deliberations over the regulation of genetic tests, especially as medical interventions for genetically related diseases are also discovered.
Another major reason that FDA needs the new genetics advisory panel is to bring the agency's regulatory efforts into line with the work of other organizations in the field. Many professional organizations are developing practice guidelines or standards for medical genetic tests. Organizations that have taken a lead in such efforts include the American College of Medical Genetics, the College of American Pathology, and the National Committee for Clinical Laboratory Standards.
Government agencies have also been active in this field. The Department of Health and Human Services some years ago established a joint National Institutes of Health/Department of Energy task force on genetic testing (now defunct), whose purpose was to recommend appropriate guidance for medical genetics. In 1990, NHGRI formed the Ethical, Legal, and Social Implications Research Program (ELSI), to fund and direct studies into the ethical considerations of genetic testing. At the Centers for Disease Control and Prevention, the Clinical Laboratory Improvement Advisory Committee (CLIAC) has its own genetic testing work group, established in 1997. And most recently, in June 1999, a new group called the Secretary's Advisory Committee on Genetic Tests (SACGT) held its first meeting. Within a year, this new committee is expected to make formal recommendations to the secretary of health and human services on the best methods to regulate genetic testing.
For all the multiplicity of these professional and governmental efforts, it is still FDA that has the greatest experience in regulating IVD tests. As more and more genetic tests seek to enter the marketplace, it is critical that the agency be capable of synthesizing the recommendations of other organizations into cohesive guidance for manufacturers. David Feigal, director of FDA's Center for Devices and Radiological Health, is an ex-officio member of the SACGT. He has said that he wants to find ways to bring significant new technologies to the forefront of FDA's review process. The agency's expert panel on genetics is a means toward accomplishing this goal, complementing the agency's expertise in the regulation of IVDs and making it possible to safeguard the public's interest by clearing or approving safe and effective genetic tests.
Expectations and Challenges
The most important challenges for FDA's new genetics panel will be to offer medical perspectives and expert advice as part of the review of new genetic testing products. Members of the panel will be called upon to give advice to the agency on the appropriate use of, and safeguards related to, genetic tests. The panel will also help FDA to develop and recognize the most suitable standardization and minimum-performance specifications for new genetic tests.
Additionally, the panel will help the agency to develop guidance documents and to incorporate acceptable voluntary performance standards into its review processes. Because manufacturers will thus have clearer guidance on clinical trial design and submission requirements for new genetic test products, these panel efforts will contribute to more-uniform and consistent product reviews by the agency. Furthermore, such efforts by the panel should help the agency to better define the risks and benefits related to each product, and to classify each product accordingly.
FDA already has experience with the regulation of both traditional biochemical tests and genetic tests intended for early detection of cancer and prenatal disorders. In the future, however, increasing numbers of genetic diagnostics will probably be used predictively, enabling clinicians to select better treatment options for their patients. Such tests range from prognostic tests for somatic cell variants to the more controversial tests for detecting inheritable germline disorders. Using these tools, disease diagnoses will be made not just by phenotypic characteristics, but also by genotypic profiling of patients. FDA's new expert panel should better enable the agency to deal with the exceedingly complex scientific and medical issues related to such genetic testing.
The panel will also help FDA to meet the extraordinary challenge of establishing clinical trial standards for multiplexed genetic testing. These new tests may be formatted in microarrays in which hundreds or thousands of disease markers can be simultaneously detected from a single patient specimen. Today, the diagnostic testing community has great difficulty agreeing on the interpretive criteria for single markers of cancer. Sorting out the complexities of multiple gene and drug interaction schema will require considerable effort.
As laboratory medicine continues to move toward increased involvement in genomic disease management, FDA's new panel will play an important role in helping the agency to tackle issues related to this field. In this regard, the panel will be of service to industry by helping to develop practical guidance documents and criteria for more-uniform product reviews. Along the way, the panel will also contribute to the efforts of professional and governmental organizations to identify appropriate venues for genetic testing and establish the qualifications for laboratories conducting such testing. The panel should also help to establish guidelines that will minimize the inappropriate use of genetic testing, and to identify unsafe testing practices that should be restricted. By helping the agency to establish such standards of safety and effectiveness, the panel will help to build public awareness and confidence regarding the appropriate use of genetic tests.
A New Era
Ultimately, the work of FDA's new panel will significantly contribute to the emergence of a new era for laboratory medicine, in which clinicians will use the results of genetic tests to tailor the best therapeutic course for their patients. In place of broad diagnoses, such genetic tests will make it possible to identify and stage diseases with extraordinary specificity. Instead of dispensing one type of treatment for all cases in a given disease classification, clinicians will be able to select from a range of very precise treatments known to be effective for the case at hand.
IVD manufacturers should embrace FDA's formation of the new molecular and clinical genetics panel. This new panel should be good for medical genetics, good for FDA, good for industry, and, best of all, good for patients. Late or not, manufacturers should submit to FDA their recommendations for panel members, including the consumer and industry representatives, as soon as possible.
Reference
1. Federal Register, 64 FR:52098—52099, September 27, 1999.
Russel K. Enns, PhD, is vice president for regulatory affairs at Vysis Inc. (Downers Grove, IL).
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