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Which way for genetic-test regulation? Leave test interpretation to specialists
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"S everal regulatory agencies are gearing up to control at least some aspects of genetic testing. In the United States, the Food and Drug Administration (FDA) held meetings in June and July on how and what to regulate 1,2 . In Europe, regulatory authorities and industry lobbyists are pushing to remove an exemption from the European Union directive on in vitro diagnostic medical devices. This currently allows institutions to design, produce and vali- date the performance of their own tests. Some regulation is essential. Yet implement- ing appropriate constraints is a formidable challenge given the complexity of the biology and the speed at which the technology and knowledge are evolving. If the FDA follows through on the approach that it seems to be pursuing ? and regulates the interpretation of genetic tests in impractical detail ? at best, a huge amount of government time and money will be wasted. At worst, genetic diagnostics will grind to a halt. To ensure that patients are not deprived of real and potential benefits of medical advances, the agency should instead apply stringent regulation to the performance of the tests themselves and allow the interpreta- tion of the results to be carried out by board- certified practitioners. Genetic-testing services are proliferating fast. In 1993, tests were available for about 100 dis- eases. By 2009, the number was almost 1,900 (see ?Growth of genetic tests?) 3 . Some forms of testing are major advances in the diagnosis of certain conditions, such as Rett syndrome and types of brittle bone disease. The clinical utility of others ? such as the high-throughput geno- typing that is widely offered by companies that sell tests directly to consumers ? is debatable. Less than 1% of genetic testing is currently overseen by regulatory agencies, such as the the FDA and the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom. Increasingly, such agencies are responding to calls to exert greater con- trol ? from politicians, health-care adminis- trators and government advisory committees, as well as from geneticists and the public. Academic organizations in Europe and the United States are right to have recommended a ban on ?direct-to-consumer? medical genetic testing 4,5 . Direct-to-consumer tests, by defi- nition, mean that individuals are given their results without the involvement of a health- care provider. In the future, this method of delivering results could be approved for testing ancestry or determining the sex of an unborn baby. But the interpretation of findings that might warrant medical intervention requires a level of expertise that is currently beyond the capacity of even most physicians. In the clinic Turning to the kind of testing used in clinical diagnostics, recent FDA announcements 1,2 and recommendations from a US government advi- sory committee on genetics, health and society 6 suggest that the FDA is pursuing an ill-consid- ered approach. Some statements 6 imply that genetic tests should meet certain requirements for clinical sensitivity (the proportion of patients for whom the test correctly identifies or predicts a disorder), clinical specificity (the proportion of patients for whom the test correctly detects or predicts the absence of a disorder) and clinical utility (the balance between the health-related benefits and the harm, either psychological or medical, that might result from a test). Homing in on this level of detail has been appropriate in more straightforward scenarios, such as the regulation of HIV testing. But mak- ing a clinical diagnosis based on genetic test- ing often means assessing tens of thousands or even hundreds of thousands of variations in the genome ? as well as complex interactions between genetic variants and the environment. Also, one of the novelties of the genetic data currently being generated is that we know that we will be able to interpret them more accu- rately in one, five or ten years from now. Some genetic tests are fairly straightforward. For example, in Marfan syndrome and neuro- fibromatosis, a relatively simple relationship exists between each disease and a single muta- tion ? although even for these conditions, the importance of several other disease-asso- ciated mutations is uncertain. In other cases, the significance of observed genetic variation is unclear. Laboratories carrying out tests to detect the number of copies of specific DNA sequences in the genome routinely report find- ings of uncertain significance, with the expec- tation that their clinical relevance will become clear in the next few years. If regulatory agencies block testing until the clinical sensitivity, specificity and utility of all Which way for genetic-test regulation? Although largely unregulated, genetic tests are increasingly used to diagnose conditions, map ancestry or predict disease risk. In the first of two related pieces, Arthur L. Beaudet advocates the US Food and Drug Administration banning direct-to-consumer medical tests but leaving the analysis of clinical diagnostics to specialists. In the second, Gail Javitt argues that the agency should implement a regulatory framework for all health-related tests. Leave test interpretation to specialists GROWTH OF GENETIC TESTS 1,800 1,600 1,400 1,200 1,000 800 600 400 200 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Number of diseases f or which t esting is a v ailable S OUR CE: REF . 3 816 Vol 466|12 August 2010 OPINION � 20 Macmillan Publishers Limited. All rights reserved10 the genetic markers involved in any one diag- nosis have been assessed and approved, the use of genetic diagnostics will come to a standstill. In such a situation, almost all complex forms of genetic testing would become outmoded before they could be approved. To allow the science and medical practice of genetic testing to flourish, regulatory agen- cies should ensure that all genetic tests provide accurate and reliable genotype, sequence and copy-number data. They should also ensure that complete and detailed data sets are stored electronically in a way that guarantees the pri- vacy of individuals ? for example, as part of, or linked to, medical records. By contrast, the agen- cies need to understand that data interpretation must remain an integral part of the decision- making ?art? of medical practice and be held in check only by the mechanisms normally used to oversee the practice of medicine ? primarily board certification. This dual pathway would be similar to the regulatory framework used in radiology, say. For magnetic resonance imaging of a patient?s brain, for example, agencies such as the MHRA and FDA regulate the equipment used (whether the software and magnets are appropriate, for instance). The interpretation of the scans is overseen through the training programmes, examinations and licensing procedures for radiologists. Currently, the results of genetic tests are inter- preted by molecular geneticists, cyto geneticists and molecular pathologists. As more is dis- covered, perhaps more specialist ?genomicists? will be needed. These people would be trained specifically in disease pathogenesis, genetics, genomics and bioinformatics. Ultimately, separating test performance from test interpretation will make the tasks of regula- tory agencies far more achievable and keep them within the purview of their public mandate. ? Arthur L. Beaudet is in the Department of Molecular and Human Genetics at Baylor College of Medicine, Houston, Texas 77030, USA. e-mail: abeaudet@bcm.edu. 1. www.fda.gov/MedicalDevices/NewsEvents/ WorkshopsConferences/ucm214671.htm 2. www.fda.gov/MedicalDevices/NewsEvents/ WorkshopsConferences/ucm212830.htm 3. www.ncbi.nlm.nih.gov/projects/GeneTests/static/ whatsnew/labdirgrowth.shtml 4. American College of Medical Genetics Board of Directors. Genet. Med. 6, 60 (2004). 5. www.eshg.org/fileadmin/www.eshg.org/documents/ PPPC-ESHG-DTC-06122009.pdf 6. The Secretary?s Advisory Committee on Genetics, Health, and Society. U.S. System of Oversight of Genetic Testing (US Dept Health & Human Services, 2008); available at http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS_ oversight_report.pdf The author declares competing interests: details accompany the article at go.nature.com/RVnqJ8. T his summer, the US Food and Drug Administration (FDA) sent letters to several companies that offer health- related genetic testing directly to customers. These missives informed the companies that the tests are medical devices requiring FDA authorization. The agency has stopped short of threatening to block sales, but the impli- cation is clear: the FDA believes the current marketing of these tests to be unlawful. Opponents of direct-to-consumer (DTC) testing, who worry that consumers could make harmful decisions after receiving incor- rect or inadequate information about test results 1 , may be relieved by the FDA?s actions. Proponents of such testing may question whether the FDA can justify acting as gate- keeper to people?s genomes. Either way, the FDA?s letters are a stopgap measure that fails to ensure genetic testing quality in general or to position DTC tests appropriately within an overarching regulatory scheme. ?Direct to consumer? is simply a delivery method that in itself provides no information about the quality of the test offered. Instead of treating DTC genetic testing as a special case, the FDA and other agencies around the world should implement a regulatory framework that ensures the quality of all health-related genetic tests and imposes requirements com- mensurate with each test?s level of risk. Within this framework, regulators should define the contexts under which direct consumer access to health-related genetic tests is appropriate. They should also put in place requirements to ensure that customers receive adequate explanation of test results. About 30 companies worldwide now offer more than 400 tests directly to consumers. These range from the ?recreational?, such as Assign regulation appropriate to the level of risk GENETIC TESTS OFFERED BY DIRECT-TO-CONSUMER COMPANIES Type of health-related condition or trait assessed Examples Number of companies Chromosomal aberrations Recurrent pregnancy loss, deletion of a piece of chromosome 22q (DiGeorge syndrome) 2 Single-gene diseases Cystic fibrosis, haemochromatosis 7 Susceptibility to cancer High risk: variants of tumour-suppressor genes BRCA1, BRCA2, PTEN 3 Low risk: variants of genes associated with lung cancer or prostate cancer 7 Susceptibility to non-cancerous common complex diseases Cardiovascular: thrombosis 15 Digestive : Crohn?s disease, gall-bladder disease 8 Endocrine: obesity, type 2 diabetes 6 Immune: allergies, lupus 6 Nervous: amyotrophic lateral sclerosis, epilepsy 10 Reproductive: endometriosis, infertility 4 Respiratory: asthma, emphysema 4 Skeletal: arthritis, back pain 9 Skin: psoriasis 3 Urinary: kidney stones 2 Susceptibility to psychiatric conditions Depression, schizophrenia 4 Risk due to oxidative stress Coenzyme Q10 efficiency 3 Metabolism of, or response to, pharmaceuticals or other substances Caffeine metabolism, ?-blocker response 13 Substance dependence Nicotine dependence, heroin addiction 4 Risk or progression of infectious disease Norovirus resistance, HIV infection progression 3 Non-disease-related health profiles Fatigue, body composition 9 S OUR CE: REF . 5 817 NATURE|Vol 466|12 August 2010 OPINION � 20 Macmillan Publishers Limited. All rights reserved10 those for earwax type, to the serious, for the risk of developing diabetes or heart disease (see ?Genetic tests offered by direct-to-consumer companies?). In most cases, the results of tests are provided with little if any involvement of a health-care practitioner. Recent analyses have found that many of the companies? claims relating to the significance of genetic mark- ers are overblown 2,3 ? suggesting that at least some businesses will not be able to validate their tests to the FDA?s satisfaction. Yet if the agency?s endgame is to block DTC testing in the long term ? as recent statements by some FDA officials imply ? it will have to come up with a rationale beyond whether the tests are adequately validated. Some in the genetics community would like to draw a line between ?legitimate? tests offered by clinical laboratories and DTC genetic tests. But such a distinction is likely to prove illusory. Any test performed on a blood or saliva specimen could, in theory, be offered directly to consumers, and many such tests have already been well validated, including those for diagnosing classical Mendelian disorders such as sickle-cell anaemia and cystic fibrosis. For some of the emer- ging predictive genetic mark- ers, validation data are likely to surface after further research. A categorical ban on DTC testing using vali- dated tests would be difficult for the FDA to jus- tify. Certainly, in the past decade, the agency?s ability to prevent the public from gaining access to truthful, non-misleading information about prescription drugs and dietary supplements has been sharply curtailed by the judiciary 4 . In reality, the problems popularly associ- ated with genetic tests go beyond DTC testing. Insufficient oversight is in place to ensure the clinical validity of at least some of the newer, more complex tests offered by both DTC companies and clinical laboratories. Also, for many genetic tests, neither health-care prov- iders nor the public has access to enough infor- mation to properly interpret test results. Prior knowledge US regulatory agencies have many tools already at hand to ensure that all genetic testing is valid and safe, regardless of how test results are deliv- ered. They should draw on their considerable experience in dealing with other regulated products, such as pharmaceuticals. A first step should be for regulators ? in particular, the US Federal Trade Commission, which protects consumers against fraud ? to enforce existing laws against companies mak- ing false or misleading claims about their tests. Some of the more outrageous claims (for instance, accurately predicting the sex of a child five weeks into a pregnancy, which is not supported by scientific evidence) have come from DTC testing companies, so in this regard the DTC testing industry does need particular attention. Agencies should next assign regulation to each test accord- ing to its level of risk. It would be a waste of resources for the FDA to require laboratories to submit clinical validation data for certain tests. Those recommended by pro- fessional medical societies for prenatal or new- born screening, for example, are already well validated and are now part of standard medical practice. However, the FDA should ensure that tests based on novel methods, or used to make therapeutic decisions with significant clinical impact, are properly validated before they are introduced into health care. Whether a test can be delivered directly to consumers should depend on its level of risk ? as is the case for other FDA-regulated products. Some genetic tests are likely to be comparable to pregnancy tests and could be sold over the counter. Others may be similar to HIV test kits. In this case, sample collection kits may lawfully be sold directly to customers but need to be sent to a laboratory for process- ing. Manufacturers of such tests are required by the FDA to ensure that counselling is provided. Still other tests should be treated in the same way as diagnostic tests for cancer, which cur- rently can be obtained only through a health- care practitioner. A particular challenge for the regulators of genetic testing, both in the United States and elsewhere, is that geneticists? understanding of the clinical significance of markers is evolv- ing rapidly. Again, the FDA can draw on past experience to deal with this. Existing regula- tory tools ? such as those used for prescrip- tion drugs ? allow companies to make certain changes to their products, without prior FDA approval, in the light of new information. They also allow products to be marketed on the con- dition that more data will be collected. In such a fast-changing landscape, striking the right balance between protecting the pub- lic and promoting innovation is crucial. To get it right, agencies must proceed in small steps, articulate clear goals and rationales for their proposed actions, and consider input from all those affected. ? Gail Javitt is a research scholar at the Berman Institute of Bioethics, Johns Hopkins University and counsel at Sidley Austin. e-mail: gjavitt1@jhu.edu 1. Offit, K. J. Am. Med. Assoc. 299, 1353?1355 (2008). 2. Janssens, A. C. J. W. et al. Am. J. Hum. Genet. 82, 593?599 (2008). 3. Mihaescu, R. et al. Genet. Med. 11, 588?594 (2009). 4. Javitt, G. H., Stanley, E. & Hudson, K. Okla. Law Rev. 57, 251?302 (2004). 5. Lachance, C. R., Erby, L. A., Ford, B. M., Allen, V. C. Jr & Kaphingst, K. A. Genet. Med. 12, 304?312 (2010). The author declares competing interests: details accompany the article at go.nature.com/gRYQwm. See Editorial, page 797. ?A categorical ban on direct-to-consumer testing using validated tests would be difficult for the FDA to justify.? A. B R OOKES / C ORBIS 818 NATURE|Vol 466|12 August 2010OPINION � 20 Macmillan Publishers Limited. All rights reserved10 "
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