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SACGHS Recommendations Aim to Close ‘Significant Gaps’ in Gene-Dx Regulation

The HHS Secretary's Advisory Committee for Genetics, Health, and Society earlier this month finalized its recommendations for regulating genetic tests, a 276-page document that urges HHS to develop a mandatory registry for laboratory tests; outlines ways for the Center of Medicare and Medicaid Services to address gaps in how it regulates labs that perform genetic testing in the absence of a genetic specialty; and asserts the US Food and Drug Administration should exercise regulatory oversight over all laboratory-developed tests.
“After extensive fact-finding, consultation, and analysis, the committee found significant gaps in the US system of oversight of genetic testing that can lead to harms,” SACGHS states in the report. “The committee also identified novel opportunities that would enhance oversight.”
SACGHS asserted that if its recommendations are “sufficiently supported,” they will “close major gaps, enhance future oversight, help ensure public safety and health, and facilitate the realization of personalized healthcare.”
The committee also stressed that the actions required by its recommendations are “extraordinarily challenging, and ... will require both swift action and sustained leadership by the HHS Secretary and coordinated efforts at the highest level within the administration of HHS.”
Many of the agency's recommendations require HHS to commit an undisclosed amount of funding for such things as additional research, forming consortia to discuss and develop guidelines and standards, and creating a lead agency to develop and maintain the mandatory registry for laboratory tests.
It is unclear how binding these recommendations are. HHS is said to be currently reviewing them. However, since HHS Secretary Michael Leavitt announced his Personalized Health Care Initiative last March, it is likely that some of the committee's recommendations may have resonance within HHS [see PGx Reporter 12-12-2007].
Mandatory Registry
As reported by Pharmacogenomics Reporter in February, the establishment of a mandatory, web-based registry for all laboratory-developed tests is one of the main vehicles the committee is proposing in order to improve how the federal government regulates genetic tests [see PGx Reporter 02-20-2008]. 
“HHS should appoint and fund a lead agency to develop and maintain the mandatory registry for laboratory tests,” SACGHS recommends in the report.
The registry would include all laboratory-developed tests, not just gene-based ones. “Since genetic tests are not different from other laboratory tests for oversight purposes, the registry should include all laboratory tests,” the report says.
This agency would work together with other government bodies to create the registry. More importantly, this agency and its sister bodies will convene a stakeholders meeting by September to establish the information regarding analytical and clinical validity, clinical utility, and accessibility that test makers would be required to submit. 
“The lead agency, through this stakeholder effort, should assess the level of effort, as well as the burden on the laboratory and the impact on other key stakeholders such as patients, physicians, and payers, necessary to obtain each data element, including linking to reliable sources of existing information,” the report says.
Noting “unresolved” practical and legal questions requiring additional analysis, SACGHS left it up to HHS to decide how to implement the registry and under which higher agency's aegis it should reside: the Center for Disease Control and Prevention, CMS, or the FDA.
While the proposed registry is in the process of being set up, SACGHS advises HHS to incentivize the voluntary registration of laboratory tests with the NIH-funded data repository GeneTests, and to encourage laboratories to make publicly available their test menus and analytical and clinical validity data for these tests.
SACGHS acknowledges that there was some question as to whether to make the test registry voluntary or mandatory. Ultimately, the committee settled on a mandatory registry on the grounds that this “would offer the best approach to addressing these information gaps in the availability of tests and their analytical and clinical validity.”
Johns Hopkins University's Genetics & Public Policy Center is one policy group that has been advocating for a mandatory registry. In comments to SACGHS' draft recommendations, it stressed that only a mandatory test registry will ensure the level of oversight necessary for genetic tests.
“The Center believes that only a mandatory test registration system will fill these gaps adequately,” GPPC said in its comments. “To be sure, GeneTests has provided an invaluable service to the genetics community, but it does not have the authority to require all laboratories to submit information. Partial participation yields only an incomplete picture of the number and types of tests being offered.”

“Although the report calls for such a registry of all [laboratory] tests, we believe it important to start narrowly to allow an evaluation of the benefits and burdens of developing and maintaining such a registry.”

In contrast, the Coalition for 21st Century Medicine would prefer that HHS pilot-test the structure of the registry before mandating registry for all laboratory tests. The group suggested the creation of a specific list of tests that would not be subject to registration, but that would be updated periodically.
“Although we support the call for a broad voluntary system of genetic test registration through public-private partnerships, we believe some types of tests may appropriately be subject to mandatory registration with government regulatory bodies,” the coalition said in comments to SACGHS' draft recommendations.
“Whether a registry is voluntary or mandatory, we would encourage pilot testing the structure of the registry, the format for submission, and the methods for submitting electronically to it to ensure that the information collected is useful and that the burdens of collection and maintenance of the registry are reasonable,” the coalition suggested.
This recommendation is similar to the “phased-in” regulatory approach the coalition has been urging FDA to adopt for genetic tests [see PGx Reporter 02-06-2008].
As part of its phase-in recommendations, the coalition suggests mandating registration of multivariate index assays with the FDA as a first phase in developing “a risk and experience-based regulatory framework.” Such a step would be an alternative to the regulatory approach proposed by the agency in its draft guidelines, in which the agency suggests that in vitro diagnostic multivariate index, a subset of laboratory-developed tests, will likely be classified as Class II or III devices, requiring 510(k) clearance or pre-market approval [see PGx Reporter 02-14-07]. 
“The coalition supports the call for a public registry of genetic tests to support the transparency of claims made about the clinical validity of these tests,” Paul Radensky, a lawyer at McDermott Will & Emery representing the coalition, told Pharmacogenomics Reporter. “Although the report calls for such a registry of all tests, we believe it [is] important to start narrowly to allow an evaluation of the benefits and burdens of developing and maintaining such a registry.”
CMS' Role
CMS' role in overseeing genetic tests, particularly how the agency should handle proficiency testing for labs, has been a point of much debate in the industry.
In 2006, GPPC, Genetic Alliance, and Public Citizen filed a Citizen Petition asking CMS to create a genetic specialty under the Clinical Laboratory Improvement Amendment, which would be a step toward making proficiency testing mandatory for all CLIA-certified labs. CMS rejected the Citizen Petition in September, explaining that mandating proficiency testing for all CLIA-certified labs would be too expensive to implement [see PGx Reporter 09-05-2007].
CMS said it was more cost-effective to establish the safety of genetic tests through partnerships between professional and public organizations to ensure stringent quality control and develop new proficiency tests. The agency has said it plans to collaborate with other federal agencies and professional associations to develop additional proficiency tests, evaluate analytical test validation of laboratory-developed tests, and ensure effective oversight of genetic tests.
SACGHS, after reviewing CMS' oversight plans and comments from groups that favor the creation of a genetic specialty, said it believes that the “identified gaps can be addressed without the creation of a genetic testing specialty.”
The committee noted that while CLIA requires all non-waived tests to undergo some form of performance assessment, there are only 83 specific analytes, not necessarily genetic tests, that are required to undergo proficiency testing — the most “rigorous” form of performance assessment.
“In principle, genetic tests and all other non-waived laboratory tests should be required to undergo PT,” SACGHS notes in the report. However, since this cannot be achieved immediately, the committee recommends CMS to require PT for all non-waived laboratory tests for which PT products are available; promote the development of new PT products; train inspectors of genetic testing labs; and use revenue generated by the CLIA program to hire sufficient staff to fulfill CLIA’s statutory responsibilities.
The CLIA program “should be exempt from any hiring constraints imposed by or on CMS,” SACGHS states.
According to the committee, laboratories that make tests for which there are no PT products must use alternative assessment methods, and HHS should fund studies to determine the effectiveness of other types of performance assessment methods and compare them to performance testing.
“Having long argued that enhanced proficiency testing is vital to ensure the safety of genetic testing, we are pleased SACGHS recommends that laboratories be required to enroll in available proficiency testing programs,” Gail Javitt, GPPC's law and policy director, said.
However, the policy group urged the committee to be more aggressive in its recommendations to CMS, suggesting that CMS “replace the antiquated list of 83 'regulated analytes' with a requirement that all laboratories engaged in non-waived testing enroll in available approved proficiency testing programs.” 
In its comments, the GPPC said it “believes that requiring enrollment in available programs would itself create incentives for the development of new PT programs, consistent with the draft report’s recommendation.”
FDA's Role
In the report, SACGHS says it is “concerned by the gap in oversight related to clinical validity and believes that it is imperative to close this gap as expeditiously as possible.”
In this regard, the committee recommends that the FDA “address all laboratory tests in a manner that takes advantage of its current experience in evaluating laboratory tests.” In order to do this, the committee recognizes that the FDA will “require the commitment of significant resources to optimize the time and cost of review without compromising the quality of assessment.”
The FDA has refrained from commenting on specific recommendations in the report directed at the agency.
As reported in Pharmacogenomics Reporter sister publication GenomeWeb Daily News, earlier this year, Steven Gutman, director of FDA's Office of In Vitro Diagnostic Device Evaluation and Safety, said that SACGHS's recommendations “will be challenging for HHS to address.” He added that it is too early to say how much more of a role the FDA will play than it currently does in the regulatory oversight of genetic tests. 
Radensky, representing the Coalition for 21st Century Medicine, noted that while the “FDA should play an important role in the oversight of genetic tests, we would urge caution in rushing to extend FDA regulation to laboratory-developed genetic tests.”
He said the SACGHS should ensure that the oversight recommendations issued to the FDA “are risk-based and least burdensome and to allow for a realistic and reasonable transition from current regulation under CLIA to dual regulation under CLIA and FDA.”
Radensky added that additional regulation should be “carefully tailored to improve patient outcomes and should avoid unnecessary increases in the cost of test development, delays in the introduction of important new tests, and limits on the usefulness of labeling claims for decision making.”
The SACGHS also recommends that HHS convene a multi-stakeholder public and private sector group to determine the criteria for a risk-based regulatory approach of oversight for genetic tests. “This group should consider new and existing regulatory models and data sources (e.g., New York State Department of Health Clinical Laboratory Evaluation Program) ... [as well as] explicitly address and eliminate duplicative oversight procedures,” the report states.
SACGHS said that data collected through the mandatory test registry would enable it to formulate these risk-based criteria.

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