Regulation of genetic testing

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There is considerable debate over which, if any, government entity should have oversight of the testing, particularly for testing for nutritional and health applications. In the USA, diverse federal regulations provide basic oversight on genetic testing proficiencies. This oversight currently is provided by the Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments (CLIA) to ensure laboratory proficiency of genetic testing. Genetic testing laboratories applying for CLIA certification must meet standards for testing and quality control (Food and Drug Administration, 2007). The challenge for a CLIA inspector, however, is that there are many different techniques for measuring genetic variation, whether direct sequencing or various genotyping methods or platforms are used. Most laboratories develop genetic assay protocols in-house and the tests are thus true 'home brew' tests. A critical area for development of the industry is to establish coherent, cross-platform standards for validation and quality control of genetic testing, including chain of custody of individual samples. Many of the standards applied to traditional types of laboratory analyses, such as complete blood count tests, can be applied to genetic testing but, due to the variable nature of the techniques used for detection of genetic variations, the personnel charged with inspection must be able to apply standards that can be translated to the different circumstances of analysis.

Under CLIA, CMS is currently responsible only for the pre-analytic and analytic phases of genetic testing, with a particular interest in patient records and accessioning data, together with the actual laboratory results of testing. CMS is not currently charged with post-analytic evaluation, i.e. how the genetic information is translated or communicated to the end user, consumer or patient. The US Secretary's Advisory Committee on Genetics, Health and Society (SACGHS) has called for greater oversight of commercial genetic testing services, with the prospect of additional post-market monitoring by the Food and Drug Administration. SACGHS released a report in May 2008, 'US System of Oversight: A Response to the Charge of the Secretary of Health and Human Services', recommending a number of actions to strengthen CLIA oversight of genetic testing, and also recommended that the FDA address genetic testing 'in a manner that takes advantage of its current experience' (Secretary's Advisory Committee on Genetics, Health and Society, 2008). Of particular note, the SACGHS report urges that the level of FDA oversight of genetic testing be based on level of risk to the individual, thus recognizing that a 'one size fits all' regulatory approach to genetic testing would not be desirable.

Considering the broad range of genetic testing applications, from diagnostic tests for Huntington's chorea, to identification of breast and ovarian cancer risk associated with BRCA1 and BRCA2 mutations, and finally to the use of genetic testing to identify particular nutritional requirements for health, the recognition of the need for a tailored approach to the type of genetic testing appears to be a positive step in the development of a regulatory framework. This regulatory framework might support an emerging industry based on nutrigenomic applications and, at the same time, protect the interests of the consumer. The FDA released draft guidance documents in September 2006 on two specific issues relevant to genetic testing: one series addressed the use of commercially distributed analyte specific reagents (ASRs) used in developing laboratory tests, and the other series focused on a category of diagnostic genetic tests called in vitro diagnostic multivariate index assays (IVDMIA), which includes genetic tests and the algorithms used to obtain and deliver information that may lead to diagnosis or treatment of diseases (Food and Drug Administration, 2006). In response to the guidance documents, Sharon Terry from the Genetic Alliance, a group of stakeholders from industry, health care and consumers with interests in genetic testing, gave a public commentary on the SACGHS report (Terry, 2008). These comments pertained to:

  • Improvement of oversight of genetic testing through the enforcement of regulatory authority under the CLIA program
  • Registration of all genetic tests through a federal agency such as the FDA or the NIH, to include test performance and reference data, analytical and clinical validity and adverse event reporting
  • Establishment of a laboratory-oriented consortium for sharing information related to quality control, validation and performance issues
  • Creation of a public consortium of stakeholders to assess clinical utility and evidence related to genetic tests
  • Agreement with the SACGHS report's concern over potential FDA oversight of information used in clinical applications
  • Regulation of direct-to-consumer access to testing to ensure the public's safety
  • Coordination by the US federal Department of Health and Human Services of relevant Health and Human Services agencies and interested stakeholders to develop a framework for genetic testing.

To complicate matters further in the USA, each state has its own set of regulatory guidelines for genetic testing, leading to a complex and often contradictory legal landscape. New York State, for example, has several requirements for licensure that have been broadly applied to all types of genetic testing. All genetic tests must be ordered by a health care provider, the results must be reported back to the health care provider and the patient must pay the laboratory directly for the genetic testing. The health care provider cannot bill the patient for the testing services. New York State has a detailed list of health care providers who are authorized to order the tests. Currently, dietitians and chiropractors are not authorized to order genetic tests but, for reasons that are unclear, podiatrists are authorized to order these tests. The New York State Department of Health has been active in the enforcement of their regulations and has issued Cease and Desist Letters to many companies involved in genetic testing, both for nutrigenomic applications and also for diagnostic or prognostic applications. The current restrictions on the method of ordering and paying for the tests represents a significant challenge for industries entering the field of genetic testing and the broad brush application of the regulations to all genetic tests at the time of this writing warrants further debate.

Should all genetic tests be considered medical or clinical in nature? The Department of Health from the State of California has recently followed the approach of New York State, issuing Cease and Desist Letters in June 2008 to companies involved in direct-to-consumer genetic testing. According to California statutes, laboratories that conduct clinical tests must be licensed. Again, the definition of what constitutes a clinical test is a matter of some debate in the industry. Nevertheless, at the present time, according to Code BP 1206 (a) (4) 'clinical laboratory test or examination' means the detection, identification, measurement, evaluation, correlation, monitoring, and reporting of any particular analyte, entity or substance within a biological specimen for the purpose of obtaining scientific data which may be used an as aid to ascertain the presence, progress, and source of a disease or physiological condition in a human being, or used as an aid in the prevention, prognosis, monitoring, or treatment of a physiological or pathological condition in a human being, or for the performance of non diagnostic tests for assessing the health of an individual (State of California, 2006).

California state law requires licensing for any laboratory that conducts tests of moderate or high complexity under CLIA on human tissue samples originating in the state of California (BP Code 1265). Genetic testing is considered high complexity testing under CLIA. Finally, California law (BP Code 1246.5) states that tests must be ordered by a physician. The Department of Health is currently working through the responses from the affected parties and has indicated that, in addition to ensuring the accuracy and quality of testing results, the State intends to examine post-analytic reporting, i.e. the scientific substantiation of the information that is communicated following the genetic test. In both California and New York, the timeline for evaluation and the resources available to examine and grant licensure is a significant issue. For companies that wish to become licensed in the states, licensure can take months to complete, causing a significant impediment to business development in the two largest markets in the USA.

In 2003, in the UK, the Human Genetics Commission (HGC) carried out a lengthy consultation with the public and with specific stakeholders to provide recommendations to the government on the development of a clear regulatory strategy (Human Genetics Commission, 2003). Of particular relevance to the business of nutrigenomics was the conclusion of the HGC that there is a spectrum of genetic tests, so regulations should be developed that can accommodate tests with diverse purposes. A different set of criteria for a test diagnosing Huntington's chorea, for instance, would be needed in comparison with a nutrigenomic test identifying requirements for a particular nutrient. The HGC released another report in December 2007 (Human Genetics Commission, 2007). One of the recommendations included in this report was the development of a code of practice relating to genetic testing services supplied directly to the public. The HGC continues to consult with stakeholders and is exploring the adoption of voluntary regulation of direct-to-consumer (DTC) tests through a series of discussions with the goal of reaching a consensus on standards of good practice that could be adopted by companies involved in DTC tests.

In 2006, companies involved in DTC nutrigenomic testing to the public came under scrutiny by the Senate Special Committee on Aging, with the release of a report by the US Government Accountability Office (US Government Accountability Office, 2007). Representatives from industry, including the author of this chapter, were called to testify to the committee. The testimony of the participants and a rebuttal of the GAO report, written by the author of this chapter, now form part of the congressional record. Experience with the GAO investigation revealed how important open dialogue and clear understanding will be to the development of a regulatory framework for nutrigenomic applications because early and effective communication can dispel misperceptions about nutrigenomics. One of the key conclusions of the GAO report was that consumers were being misled and that genetic information was not used in preparation of consumer reports. The investigator described the use of 14 different lifestyle questionnaire answers resulting in 14 different report outcomes. In fact, the questionnaires are used to provide personalized information on dietary and lifestyle habits and this information is presented alongside genetically based information. The 14 different questionnaires should produce personalized feedback related to the questionnaires juxtaposed with genetically based goals. The GAO report does not disclose that the 14 different reports gave identical genetic information for the samples that were submitted, a result that indicates the laboratory tests conducted by different companies were providing consistent results.

Representatives from government regulatory agencies and the academic community were also asked to testify at the Senate hearing. A positive result of this debate has been greater dialogue between industry participants and regulatory representatives. A key factor in discussions with the regulators, similar to that with the HGC in the UK previously, has been the determination of perceived 'risk' to the individual. In general, there is consensus currently that the use of genetic testing to provide dietary and lifestyle advice represents a relatively low risk to the individual, but concerns remain over the development of appropriate standards for genetic analysis and communication of information.

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