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Industry, Patient-Advocacy Groups Propose Alternatives to FDA Oversight of Gene Dxs

Calling the US Food and Drug Administration’s approach to regulating genetic tests arbitrary, unfair to test kit manufacturers, and a hindrance to innovation, coalitions of diagnostic firms, clinical labs, venture capitalists, and non-profit groups have petitioned the agency to consider alternative regulatory strategies they feel ensure the safety of tests but are more market friendly.
“We spent a substantial amount of time considering the goals and objectives that led the FDA to propose the draft guidance [on in vitro diagnostic multivariate index assays], as well as the concerns raised by our members and others from review of the draft guidance,” Paul Radensky, a lawyer representing the Coalition for 21st Century Medicine, told Pharmacogenomics Reporter in an e-mail this week.
The coalition, which comprises diagnostic companies, clinical labs, and venture capital firms, formed in the wake of FDA’s first IVDMIA draft guidance in September 2006, isn’t the only group that feels that FDA’s current approach toward genetic tests needs to be revised. Johns Hopkins University’s Genetics and Public Policy Center has authored a 35-page alternative proposal to the agency’s overall approach to genetic tests.
These alternative suggestions underscore the fact that many industry stakeholders are uncomfortable with the position the FDA is taking on regulating genetic tests.
After the FDA released the original draft guidance in 2006, the agency hosted a public meeting to discuss its intent to regulate IVDMIAs. At that meeting in February 2007, the majority of speakers said that the guidelines, by imposing costly and time-consuming regulatory hurdles, may hobble innovation and make reimbursement more difficult, particularly for diagnostics in niche markets. A minority held that patient safety would be jeopardized without FDA oversight of IVDMIAs [see PGx Reporter 02-14-07]. 
Due to the objections to the first draft guidance, the FDA issued a second version last July. However, industry stakeholders maintained that the FDA still didn’t get it right. The new definition of an IVDMIA remains “highly subjective,” and therefore FDA enforcement remains “unpredictable,” critics of the second draft said [see PGx Reporter 08-01-2007].
Traditionally, the FDA has practiced enforcement discretion over most laboratory-developed tests, which fall under the aegis of the Centers for Medicare & Medicaid Services. But according to the GPPC and others, there are gaps in this system.
While the CMS under the Clinical Laboratory Improvement Amendments certifies and inspects labs every two years, it cannot assess the clinical validity of tests, nor are CLIA-certified labs required to report testing errors to CMS.
According to GPPC, in choosing to regulate IVDMIAs, the FDA is further convoluting the regulatory system by giving an unfair advantage to laboratory test developers over manufacturers of test kits.
“The current system also is arbitrary in its disparate requirements for test manufacturers and clinical laboratories,” GPPC Law and Policy Director Gail Javitt wrote in an article published late last year in the Food and Drug Law Journal.
“Manufacturers that go through the added effort to manufacture a test kit are forced to compete with laboratories that do not have a similar regulatory burden, and are not similarly constrained in the product claims they may make,” she wrote.
In GPPC’s view the FDA’s current approach creates “an unstable business climate that may deter the development of new, clinically valid genetic tests” and discourages venture capitalists from investing in such products.
“FDA’s ‘enforcement discretion’ approach leaves open the possibility that the agency may suddenly change its stance from non-regulation to regulation at some unspecified point in the future, as it did when it issued the IVDMIA draft guidance,” Javitt writes in the article, entitled “In Search of a Coherent Framework: Options for FDA Oversight Genetic Tests.”
“An assessment of the regulatory risk is a key aspect of a venture capitalist’s decision to fund a new company or project,” she added. “Uncertainty about whether or how FDA will in the future regulate a product that it does not regulate today is a significant deterrent to investors, and also may deter companies from devoting resources to certain projects.”
According to the National Venture Capital Association — another group that takes issue with the FDA’s IVDMIA draft guidance — in 2006 VC shops invested $7.2 billion in emerging life sciences companies, representing 28 percent of all venture capital investment.
However, “FDA’s current guidance on IVDMIAs would result in a significant increase in development costs, which would discourage venture capital investment in innovative therapies without necessarily increasing the quality of tests,” the NVCA writes in comments to the draft guidance.
Coalition’s Proposals
Last November, the Coalition and the Genetic Alliance, a non-profit representing 650 patient support advocacy organizations, issued a proposal for an alternative regulatory approach to IVDMIAs. The proposal, formulated in response to the FDA’s second IVDMIA draft guidance, presents a two-phased, risk-based plan that would require the FDA and CMS to work together to ensure the safety of genetic tests.
“We believe that implementation of the IVDMIA guidance as drafted would have serious negative consequences on the availability of advanced diagnostic tests,” said Radensky, who along with representing the Coalition, is also a lawyer at McDermott Will & Emery LLP. “We crafted the proposal we submitted to the FDA to address [our] … concerns.”

“FDA’s current guidance on IVDMIAs would result in a significant increase in development costs, which would discourage venture capital investment in innovative therapies without necessarily increasing the quality of tests.”

In the Coalition’s proposal, the first phase would require laboratory test developers to submit information about their IVDMIAs – including data to support the analytical performance and clinical validity of the product – to an FDA-established registry before marketing their product. The second phase, which would begin after collecting and analyzing data about the product for three to five years, would submit tests to greater regulatory scrutiny if “the processes established in Phase 1 alone are insufficient to safeguard public health.”
In Radensky’s view, FDA’s current approach to regulating IVDMIAs would define many IVDMIAs as class III devices requiring pre-market approval. “Science and technology are changing too rapidly and we need to be flexible in incorporating new discoveries into diagnostics,” he said this week during a presentation.
According to the proposal, the FDA would review data submitted to the registry and develop with CMS, the Centers for Disease Control and Prevention, and other relevant agencies, a criteria for classifying IVDMIAs as low-, moderate-, or high-risk devices.
Low-risk tests would be listed in the FDA registry but would not be subject to FDA review. Developers of moderate-risk tests would need to submit to FDA data regarding the analytical and clinical validity of the product before marketing the test. Makers of high-risk tests would be subject to FDA clearance under the 510(k) process.
“The proposal the working group submitted to the FDA should maintain incentives to develop and offer these tests, while enhancing oversight to give treating physicians and their patients confidence that tests are accurate, reliable, meaningful, and of high quality,” Radensky added.
GPPC’s Alternatives
The Coalition’s proposal echoes another set of regulatory alternatives for all genetic tests recommended by GPPC. According to Radensky, many of the Coalition’s recommendations are consistent with the regulatory suggestions proposed in GPPC’s Food and Drug Law Journal article.
Although the GPPC suggests alternative regulatory strategies for all genetic laboratory-developed tests, and the Coalition’s ideas comprise just IVDMIAs, the two proposals similarly recommend laboratory test developers register their products with the FDA, and the agency use this data to develop a database.
Also similar to the Coalition’s proposal for IVDMIA regulation, the FDA would consider 510(k) notification or a pre-market clearance only in the instance when the safety of a test cannot be established based on data in the FDA’s registry.
According to Javitt’s article, the FDA would require 510(k) submission for new gene-based LDTs for serious conditions “where results could influence selection or dosing of therapy, or where the methodology used is not supported by adequate data.”
Additionally, the GPPC favors regulation that treats PMAs as a last resort. “The FDA could not require a laboratory to submit a PMA unless it determined that the type of data needed to establish safety and effectiveness could not be provided within 510(k) framework.”
Javitt’s article also proposes the FDA and CMS collaborate to ensure the clinical validity of genetic tests; test developers submit clinical and analytical validity data to the FDA prior to marketing their products; the FDA classify all genetic tests as Class II devices subject to special controls; mandatory adverse events reporting for all laboratory developed tests; and documentation exemptions for rare-disease tests. Additionally, GPPC proposes each laboratory establish an adverse event hotline with appropriately trained personnel for handling AE reports.
In the case of high-risk LDTs for low-volume or rare-disease tests, the agency would exempt these tests from pre-market review but these tests would have to be labeled to indicate to the public and to physicians that these products had not been reviewed by the FDA.
The FDA should also give market incentives to encourage test developers to develop rare-disease tests, the GPPC suggests. For instance, under Humanitarian Device Exemptions, the FDA would approve low volume LDTs without clinical validity data under the condition that such data were provided in a post-market setting.
“FDA would waive the requirement for documentation that devices costing more than $250 do not exceed the costs of research, development, fabrication and distribution since the cost of developing LDTs will likely be much higher,” Javitt proposes in the article.
The alternative regulatory strategies from GPPC, Genetic Alliance, and the Coalition for 21st Century Medicine would significantly increase the FDA’s oversight responsibilities of genetic tests. As a result, the agency will likely require additional resources (see below).
However, neither the GPPC, Genetic Alliance, or the Coalition could provide an estimate of the additional resources that would be required for FDA to establish and monitor a registry, enforce adverse events reporting, and coordinate reviews with CMS.
“I do not have a budgetary estimate for any of these options,” Radensky wrote in his e-mail. However, “one would expect the resources required to implement these options would be less than those required were FDA to exercise the jurisdiction the agency indicates it has over all genetic laboratory-developed tests and require laboratories to submit 510(k) clearance notices or pre-market approval applications for these tests.”

Paying for It
Some of alternative recommendations to the US Food and Drug Administration’s draft guidance for IVDMIAs would add to the agency’s responsibilities, which in turn is sure to require staffing and funding increases. However, currently there is no estimate for the level of additional resources that will be necessary in this regard.
Generally, industry observers have long complained that congressional appropriations for the agency have been inadequate.
According to the Alliance for a Stronger FDA, rapidly advancing science has increased the FDA’s regulatory responsibilities, but the funding for the agency has not been commensurate. According to the Alliance – an organization of 170 members, including patient groups; industry trade associations; and research organizations that support congressional funding increases for the FDA – in the last 14 years, funds for the agency have decreased $400 million in inflation-adjusted dollars.
In fiscal year 2009, the President is requesting for the FDA a 5.7 percent increase in its budget to $2.4 billion. The request comprises $1.77 billion in budget authority and $628 million in industry fees.
“The budget proposal includes strategic increases to strengthen food protection, modernize drug safety, speed approval of generic drugs, and improve the safety and review of medical devices,” the FDA said in a statement this week.
However, the Alliance for a Stronger FDA feels that this proposed amount, which fails to adjusts costs to inflation, would lead to staff decreases and result in the agency’s failure to fulfill its mission. According to the alliance, the agency should receive $2.1 billion in congressional appropriations.
“FDA can’t improve its science, prepare for the future, or protect American consumers without significant additional resources,” Don Kennedy, a former FDA commissioner and editor-in-chief of Science, said in a statement. “The Administration and Congress are starting now on the FDA’s FY 2009 budget and must fix this critical problem.”

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