Medical Device Link.

Originally Published IVD Technology November/December 2003

COMMENTARY

Emily S. Winn-Deen

Emily S. Winn-Deen, PhD, is senior director for genomics business at Roche Molecular Systems Inc. (Pleasanton, CA). She can be reached at emily.winn-deen@roche.com.

The human genome project was completed in April 2003, with a report from the National Human Genome Research Institute at the National Institutes of Health (NIH; Bethesda, MD) that the final sequence gaps had been filled. However, knowing gene sequences is only the first step in being able to use this information to improve healthcare. What will it take to be able to use this information to fulfill the promise of personalized medicine?

To reach this goal, a number of barriers need to be overcome. Convincing genotype-phenotype correlation data for each new clinical application will need to be developed. FDA will need to clarify its data requirements for studies to support clinical utility claims on such tests. Both practicing physicians and those who are still in training will need to be educated on how to use this information properly in patient management. The public will need to be educated so that people know how to deal with informed consent and how to become active participants in their own health management. In addition to education, patients will need to feel protected from any real or perceived potential for job or healthcare discrimination based on the results of genetic tests. Finally, a reimbursement system for tests that predict future health status, rather than diagnosing current conditions, will need to be developed to provide equal access to the power of personalized medicine.

Collecting Data

The first step toward the era of preventive medicine is understanding the role of genetics in disease susceptibility and the multiple pathways that can lead to the same disease. There are many hypotheses to test, and well-characterized clinical samples are needed to find these genotype-phenotype correlations. There are already some excellent sample sets available to work with. For example, after obtaining permission from the government of Iceland, deCODE Genetics (Reykjavik, Iceland) has combined many years of Icelandic genealogy records with its centralized medical records and identified families in which disease is present, as well as appropriate nonaffected controls. The company has been able to contact specific individuals and ask them to give their DNA samples, under fully informed consent, for use in deCODE's linkage studies.

The National Cancer Institute (Bethesda, MD) has also established a unique resource, the Early Detection Research Network, which is a grant-funded cancer consortium of clinical investigators. While some such investigators are focusing on collecting well-characterized and fully consented clinical samples, others are focusing on identifying new tumor markers. The consortium also provides centralized statistical resources for study design and data analysis.

While there are other clinical resources of this type available in the United States and around the world, not all diseases have freely available clinical collections for both the original research into marker discovery and validation, and final performance assessment of IVD products based on these markers. For some diseases, collecting new prospective samples for final product validation is not a major problem. This is true for common diseases in which the clinical endpoint is either immediately obvious, or there is a rapid treatment response. However, for other situations, particularly those in which the clinical endpoint takes many years to be fully reached, it is important to start collecting prospective, longitudinal study samples now.

NIH has discussed creating funding for this type of translational research. Its genomics-to-biology initiative will focus on comprehensively identifying the structural and functional components of the human genome, elucidating the organization of genetic networks and protein pathways, and establishing how they contribute to cellular and organismal phenotypes. This initiative will also explore developing a detailed understanding of the heritable variation in the human genome, understanding evolutionary variations across species and the mechanisms underlying them, and developing policy options that facilitate the widespread use of genome information in both research and clinical settings.

NIH also has another initiative, its genomics-to-health initiative, that will focus on developing robust strategies for identifying the genetic contributions to disease and drug response, as well as those gene variants that contribute to good health and resistance to disease. This initiative will also look into developing genome-based approaches to predicting disease susceptibility and drug response, developing methods for the early detection of illness and molecular taxonomy of disease states, and using the new understanding of genes and pathways to develop powerful new therapeutic approaches to disease. In addition, it will examine how genetic risk information is conveyed in clinical settings and how that information influences health strategies, behaviors, health outcomes, and costs; and developing genome-based tools that improve the health of all.

This translational research that is needed to make personalized medicine a reality will need support from the research, IVD, and pharmaceutical communities to fund the required large, population-based, longitudinal sample collections. Many of these studies are beyond the budgets of individual researchers or companies, so the government must invest in the future of healthcare by providing a central resource that will be available to everyone.

FDA Requirements

FDA has been actively working with the IVD industry to help formulate its policies on how to review and regulate genetic testing. In 2001, the Health and Human Services Secretary's Advisory Committee on Genetic Testing made specific recommendations for increased FDA oversight of both home-brew and IVD genetic tests. This report grew out of a concern that genetic tests were not always ordered when appropriate, and that results were not always correctly interpreted. In addition, there was a noticeable lack of consensus within the genetics community about exactly when a test for a new marker was sufficiently validated for it to enter into clinical service. Some labs rushed to provide testing after the first publication, while others waited until the results had been replicated in multiple studies or multiple ethnic groups.

The biggest issues have concerned those genetic tests with high predictive power, but minimal opportunity for medical intervention. FDA is continuing to discuss these issues internally, and is reviewing its statutory power to regulate home-brew test providers as manufacturers of diagnostic tests. In addition, a new concept was recently proposed for an additional IVD category, the in vitro analytical test (IVAT). The IVAT would be sold as a reagent kit with instructions for use, but would only make an analytical performance claim, and not a specific clinical utility claim. FDA is reviewing this proposal and is likely to use it as the basis for a document for formal public comment in the near future. The IVAT approach to gaining FDA approval would be ideally suited for emerging markers, such as those likely to be used for personalized medicine, in which solid claims for predictive ability might take years to develop.

In addition, FDA has also completed a public comment period on its proposed regulation of multiplex tests based on microarrays. A revision of this proposal based on this public feedback is likely. This is particularly relevant to tests for complex diseases in which many markers need to be evaluated simultaneously in order to make a good prediction of outcome. The Centers for Medicare and Medicaid Services (CMS, Baltimore) has also reviewed its regulations under the Clinical Laboratory Improvement Amendments, and has proposed upgrading the qualifications for lab directors whose labs perform genetic tests, in order to assure that they are prepared to deal with the unique issues that genetic tests present.

Other Factors

Even after a set of disease markers has been fully validated, with corresponding FDA-approved IVD assays, there is still much work to be done to assure that the medical community makes full use of this new information. Physician education will be required in the form of continuing medical education for currently practicing physicians, as well as the addition of classes on genetic concepts to the medical school curriculum for physicians in training. In 1996, the American Medical Association, the National Human Genome Research Institute, and the American Nurses Association founded the National Coalition for Health Professional Education in Genetics. With more than 120 member organizations including professional societies, biotechnology and pharmaceutical corporations, managed-care organizations, consumer advocacy groups, and government agencies, this group is focused on facilitating genetics education for all health professionals. It is working on developing curriculum and sharing success stories between institutions, as well as providing public education approaches.

The general public will also need to be educated about genetics. Most high school biology courses now include a fairly good overview of genetics, and this will prepare the younger members of society for the era of personalized medicine. But how can the people who completed their education some years ago be reached? Special issues of Time and Newsweek have focused on the promise of genetics, and numerous Web sites provide basic information about genetics. Most disease-based organizations also carry information on their Web sites about progress in research and therapy development. It is still up to those persons working in the field to use every opportunity to educate the public, whether this is a sideline discussion at a soccer game, or more-formal lectures to civic groups.

Patient protection against discrimination is also needed to overcome the public's fear of potential misuse of genetic information. Current patient protection of genetic test results is at least as good as that for any other confidential medical information. Almost all states have laws regulating the use of genetic tests by insurers and employers. For example, the Health Insurance Portability and Accountability Act regulates how group insurance can and cannot use genetic information. The Equal Employment Opportunity Commission has said that the Americans with Disabilities Act applies to the use of genetic information in employment settings. In February 2002, former President Clinton issued an executive order protecting federal workers from discrimination on the basis of genetic test results. This order prohibits federal employers from requiring or requesting genetic tests as a condition of being hired or receiving benefits. This order also prohibits federal employers from using protected genetic information to classify employees in a manner that deprives them of advancement opportunities, and provides strong privacy protections to any genetic information used for medical treatment and research. Congress has proposed various bills extending this protection to all citizens. On October 14, the U.S. Senate approved the Genetic Information Nondiscrimination Act of 2003 (S.1053). Approval by the House of Representatives is still required to enact this bill as law.

Access to genetic testing will be determined by how widespread reimbursement becomes. CMS has been an active participant in the debates on optimizing genetic testing and has shown a willingness to incorporate this new paradigm into Medicare reimbursement. However, IVD manufacturers will need to provide good health economic arguments to justify reimbursement for their genetics products. Insurers will also have to be willing to take a longer-term view, as genetic tests run today may result in better preventive medicine but may only provide long-term economic payback.

Conclusion

Change is coming, and everyone actively working to develop genetics tests believes that they will have a dramatically positive impact on medical practices. Even though many barriers need to be overcome, by taking them one hurdle at a time, the promise will begin to be fulfilled. One of the first success stories is clearly the use of a test for HER-2/neu in breast cancer tumors to determine which women should be treated with the anti-HER-2/neu antibody drug, herceptin. This is a drug that has gained rapid acceptance through the concerted work of drug manufacturers, IVD test providers, FDA, treating physicians, patient advocacy groups, and reimbursement agencies. It is only by understanding individual genetic differences that society can reap the benefits of personalized medicine.

Copyright ©2003 IVD Technology