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HHS Group Finds Gaps in Oversight of Genetic Tests; Suggests Public-Private Collaboration

Collaborations between federal healthcare agencies and public- and private-sector partnerships are the key to closing gaps in regulatory oversight of genetic tests, according to a draft report issued by a Department of Health and Human Services’ advisory committee last week.
According to the HHS Secretary’s Advisory Committee for Genetics, Health, and Society, “a critical theme in many of the recommendations” in the 192-page report “is that new and enhanced collaborations and public partnerships between the federal government and the private sector are needed.”
The report, called “U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of HHS,” touches on some of the concerns raised following the US Food and Drug Administration’s recent decision to regulate certain homebrew tests, called in vitro diagnostic multivariate index assays, typically overseen by the Centers for Medicare and Medicaid Services’ Clinical Laboratory Improvement Amendments.
In this regard, the SACGHS said it supports FDA’s “flexible, risk-based” approach toward regulating lab-developed tests, but recommends that the agency study some more the question whether “the appropriate weight has been apportioned to the risks associated with the novelty and complexity of” certain testing platforms and technologies.
In the SACGHS’ view, to ensure the safety of genetic tests, HHS should coordinate interagency efforts to ensure that regulatory bodies like CMS, the FDA, and the Federal Trade Commission work “synergistically with one another” and with “knowledge generation agencies” such as the Agency for Healthcare Research and Quality, the Centers for Disease Control and Prevention, and the National Institutes of Health.  
“The HHS Secretary [should] take steps to enhance interagency coordination of the activities associated with the oversight of genetic testing, including policy and resource development, education, regulation, and knowledge generation,” the SACGHS states in its report.
Steve Gutman, director of FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety, discussed the report at a personalized medicine conference this week hosted by Burrill & Company in San Francisco, While Gutman was “surprised” that the SACGHS found “huge gaps in who is in charge of ensuring the clinical validity of laboratory-developed tests,” he emphasized that the agency is in “listening mode.”
Stakeholders will discuss the report in more detail during an SACGHS public meeting later this month, he added.
Who’s the Boss?
The report, which can be found here, describes a need for increased coordination between the FDA and CMS, the agencies that provide the two pathways by which a genetic test can come to market.
Typically, the FDA looks at a test’s safety and effectiveness by reviewing its intended use, as well as the available scientific information about the link between genetic markers and clinical diagnosis. Traditionally, the agency regulates genetic tests that are for sale at multiple test sites but does not oversee laboratory-developed tests, which fall under CMS’ purview.
Meanwhile, CLIA rules enforce the analytical validity of laboratory-developed tests, or homebrew assays, by ensuring that labs have quality assurance programs in place, but CLIA-reviewed diagnostics are not required to do performance testing.
However, there is much confusion among laboratory test developers about which agency has regulatory control over a small subset of complex laboratory-developed tests, called in vitro diagnostic multivariate index assays. Recently, the FDA issued a draft guidance expressing its intent to regulate IVDMIAs, reasoning that they are more complex, difficult to interpret, and have higher risks associated with them than other laboratory-developed tests.
At a meeting hosted by the FDA last February, laboratory test developers called the guidance confusing in scope and were concerned how FDA regulation of IVDMIAs would dovetail with CLIA regulations [see PGx Reporter 02-14-2007].
Due to the overwhelming number of comments to this first draft guidance issued in September 2006, the FDA issued a second draft document in July, attempting to clarify some of the confusion. While laboratory test developers felt the second draft answered some of their questions regarding FDA/CLIA oversight, they maintained that the definition of an IVDMIA was “highly subjective” and therefore, FDA enforcement remained “unpredictable.”  [see PGx Reporter 08-01-2007]. 
At the Burrill & Company conference, Gutman suggested that perhaps test developers have misunderstood the scope of the guidance. “The FDA is only changing its regulatory oversight over IVDMIAs,” Gutman emphasized. “That’s a very small subset of laboratory-developed tests.”
The SACGHS report points out that FDA’s job of ensuring the clinical validity of tests, particularly of predictive or pre-symptomatic tests, is complicated by the fact that prospective data for such tests’ clinical validity are unavailable or incomplete for several years after a test is developed. Given the nature of the market, the FDA should convene the assistance of other agencies to provide input on the development of a risk-based framework for regulating laboratory-developed tests.
Gutman said the agency understands that prospective data for predictive tests are difficult to garner. Ensuring that the analytes are stable and sample collection has minimum bias, the agency accepts retrospective data.
“The FDA is interested in good science. But the FDA is interested in least burdensome science, as well,” Gutman noted, adding that the agency is willing to work with companies to outline the appropriate study requirements.
In order to close the gaps between analytical and clinical validity, the SACGHS recommends the HHS pay for the development of reference materials, and samples for assay validation, quality control, and performance assessment; fund the development of a laboratory-oriented consortium for sharing information about test validation and performance issues; and provide guidance to professional organizations to develop additional standards and guidelines for applying genetic tests in clinical practice.
In addition, agencies such as the NIH and CDC should work with public/private partners to improve the collection of mutation and polymorphism data from public reference databases, the report states.
For its part, the FDA is waiting for the final SACGHS report before it weighs in on the committee’s recommendations.
In an email to Pharmacogenomics Reporter, Gutman wrote that the “FDA, like other government agencies involved in this type of work, is very interested in the recommendations being developed by SACGHS. Once these recommendations have been finalized and vetted by HHS, we are looking forward to working with others in HHS to be responsive to the issues raised.”
According to Kathy Hudson, director of Johns Hopkins University’s Genetics and Public Policy Center, the FDA and CMS do work together on some fronts but they should do more in this regard.
“The real issue, I think, is leadership from the top,” Hudson told Pharmacogenomics Reporter this week. “When FDA is considering a new approach, and if consulting with sister agencies slips their mind, the Secretary [of HHS] should ask for other agencies’ input. The Secretary is the boss here and could demand better coordination.”
Leave it to Leavitt
The report also points out areas where CMS’ oversight of genetic tests can be strengthened. The committee provides some recommendations regarding how the agency should handle proficiency testing for labs, a point of much debate in the industry.
Groups like GPPC, Genetic Alliance, and Public Citizen have been pushing CMS to create a genetic specialty under CLIA, which would be a step toward making proficiency testing mandatory for all CLIA-certified laboratories. The three non-profits last year filed a Citizen Petition asking CMS to create such a program [see PGx Reporter 09-27-2006].
Although the agency had previously discussed the possibility of creating a genetic specialty, 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].
“In principle, all genetic tests and other high-complexity tests should be required to undergo” performance testing, the SACGHS report states. “Thus gaps in oversight still exist regarding the regulation, breadth, costs, and availability of testing materials for existing [performance testing] programs.”

“The big political question, then, is whether Leavitt has the mettle to make CMS do what CMS either lacks the will or the ability to do.”

However, the SACGHS report notes that the regulatory gaps in the oversight of genetic tests “can be addressed without the creation of a genetic specialty.” Although performance testing is considered “the most rigorous form of performance assessment,” given CMS’ financial limitations, HHS should fund studies to identify other equally-stringent assessment methods and spur innovation in the manner of conducting performance testing, “such as through methodology-based processes,” according to the report.
With this “alternative assessment” requirement, SACGHS is trying to “assure accuracy when a formal PT program is not available,” said GPPC’s Hudson, who was also a member of the SACGHS task force.
Under this scenario, “the regulators tell labs to ascertain the accuracy of the test periodically. If no formal [performance testing] is available, then they must use an alternative assessment,” Hudson explained. She added that the report’s recommendations mirror what the GPPC has been calling for in its petition all along and “CMS’ response was, ‘No, No, a thousand times No,’ and ‘you can’t make me.’
“The problem is that there are no ‘How To’ books or standards for ‘alternative assessment,’ or any comparisons of how it performs as compared to formal” performance testing, Hudson said. “The committee wisely recognized this and is telling HHS to fix it. The big political question then is whether Leavitt has the mettle to make CMS do what CMS either lacks the will or the ability to do.”
Currently, CLIA requires all non-waived tests to undergo some type of performance assessment, but only 83 specific analytes – none of which are genetic tests – are required to undergo proficiency testing. In this regard, the SACGHS report issued several recommendations to urge the incorporation of PT in CLIA regs.
The committee urged CMS to amend CLIA regulations to expand this list of analytes to include genetic tests for which performance-tested products are available, and restructure the PT provision under CLIA to ensure that the list can be updated quickly with relevant genetic tests. Additionally, “HHS should develop incentives for PT providers to expand PT products for those genetic tests,” the report states.
Another recommendation in the report points out the need for CMS to hire and train appropriate staff. SACGHS suggests CMS consult or contract experts to train inspectors of genetic testing laboratories and use revenues generated by the CLIA program to hire the appropriate number of staff to meet its oversight responsibilities.
According to Hudson, CMS has a cap on the number of full-time equivalent staff, or FTEs, the agency hires. “So, while they have excess cash in hand, they cannot spend it on people’s salaries,” Hudson noted. “I would point out that the same FTE restrictions apply to other agencies, and they have figured out clever ways of getting around it, namely contracting out for staff.”
Following the Money
The report also discusses measures for establishing the clinical utility of tests, since payors are increasingly requesting data showing whether genetic testing improves patient outcomes and lowers healthcare costs.
In this regard, SACGHS advises HHS to fund a public/private group of stakeholders to asses the clinical utility of genetic tests by identifying evidence requirements, establishing standards of evidence, developing research and development priorities, and achieving consensus on minimum evidence criteria.
Additionally, the SACGHS encourages payors to get involved in gauging the clinical utility of genetic tests themselves. “Public and private health payeors should develop mechanisms, such as coverage with evidence development or phased reimbursement, to facilitate the collection of clinical utility evidence,” the report states.
Some insurers, such as Kaiser Permanente, are already funding their own studies investigating the genetic underpinnings for certain diseases. Pharmacy benefit managers, Medco and PharmaCare, are conducing outcomes studies to see whether genetic tests have clinical and economic utility [see PGx Reporter 02-28-2007, 12-06-2006].
While the committee’s recommendations will likely require substantial funding for HHS and related federal agencies with regulatory oversight of genetic tests, the SACGHS has not estimated how much all this will cost.
“No budget estimates were made,” Hudson said. “On the CMS recommendation for PT, I would think the cost implications for the government would be trivial.”
However, “there would be cost implications for labs as PT programs cost money,” she noted. The report recommends HHS provide incentives for PT providers to expand PT products for genetic tests.

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