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Draft Bill Proposes FDA Create New Division to Review 'Advanced Personalized Diagnostics'

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By Turna Ray

A draft bill making the rounds in Washington, DC, includes provisions for creating a new center under the aegis of the US Food and Drug Administration dedicated solely to the evaluation of diagnostic tests, regardless of whether they are developed as a genetic test kit or by a laboratory.

The "Better Evaluation and Treatment Through Essential Regulatory Reform for Patient Care Act," under development by Senator Orrin Hatch (R-UT), would create a so-called Center for Advanced Diagnostics Evaluation and Research that would be responsible for ensuring the safety and efficacy of a new category of tests called "advanced personalized diagnostics," comprising both test kits and laboratory-developed tests.

The bill emphasizes that diagnostics should be regulatorily distinct from devices, and thus should be reviewed by a division other than FDA's existing Center for Devices and Radiological Health.

Pharmacogenomics Reporter obtained a copy of the draft bill, which notes that "the current regulatory pathway for review and approval of diagnostic tests and the components of diagnostic test kits as 'devices,' is ill suited for assessing the scientific basis and reliability of diagnostic, prognostic, and treatment selection claims made with respect to advanced personalized diagnostics and for providing adequate directions for the use of the results of advanced diagnostics by health professionals."

The bill defines an APDx as a regulated product "distinct from a device" that provides analysis of DNA, RNA, a chromosome, a protein, or a metabolite and that is used for diagnosing or treating disease.

The Hatch bill would provide a basic level of oversight for all APDxs by requiring sponsors of such tests to register their products as part of a database managed by the new center. The test developers, whether labs or diagnostic companies, must submit their tests as falling under one of three categories, based on whether the diagnostic has a low, moderate, or high health impact. Consistent with current practices, the FDA would require premarket clearance for tests with greater impact on public health, and the Center for Advanced Diagnostics Evaluation and Research would work with the Centers for Medicare and Medicaid Services to certify laboratories where certain tests are developed.

Currently, test developers can either certify their laboratories through CMS' Clinical Laboratory Improvement Amendments, or submit their tests for FDA's clearance or approval. The FDA currently puts devices into three classes, indicating low-, medium-, and high-risk tests, but has left the majority of low-risk LDTs to be regulated by CMS.

Although the FDA has traditionally exercised "enforcement discretion" over the majority of LDTs, four years ago the agency recognized that certain LDTs were increasing in complexity. As such, the agency expressed a desire to regulate a subset of high-risk LDTs, called in vitro diagnostic multivariate index assays. This move has created confusion in the industry, and raised calls for the agency to take a more consistent approach in regulating all diagnostics regardless of where they were developed.

More recently, FDA's move to regulate genomic testing companies that market their services directly to consumers further highlighted the lack of clarity industry has with regard to the regulatory pathway for genetic tests (PGx Reporter 06/16/10). Many of the DTC genomics firms that received letters from FDA questioning why their tests hadn't been cleared or approved by the agency were operating under the impression that they were providers of laboratory-based testing services not subject to FDA oversight.

After informing many of these DTC firms that their tests were not LDTs, however, the agency announced it will hold a public meeting to discuss regulation of all LDTs and reconsider its longstanding "enforcement discretion" policy (PGx Reporter 06/16/10). In announcing the meeting, the FDA recognized that the technology, business models, and frequency of use of LDTs has evolved, raising public safety concerns. The meeting is scheduled for July, and public comments will be accepted until Aug. 15.

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Hatch's draft bill recognizes this changing diagnostics landscape in proposing a new FDA division specifically responsible for regulating advanced personalized diagnostics.

Mara Aspinall, CEO of personalized cancer diagnostics firm On-Q-ity and former president of Genzyme Genetics, has long been a proponent of creating a separate diagnostics division at the FDA. "There has been much discussion about" the need for a separate division, Aspinall told Pharmacogenomics Reporter this week. "It's very much in the spirit of what the FDA has announced, which is for them to regulate" all LDTs. Aspinall advised Hatch's legislative team in crafting the draft bill.

Despite pushback from test developers, FDA has maintained all along that it has the authority to regulate all diagnostic tests under the Food, Drug, & Cosmetics Act, whether they are test kits or LDTs. The Hatch bill, in creating a separate FDA division for regulating advanced personalized diagnostics, attempts to address the changing paradigms in diagnostics development and be more specific with regard to FDA's regulatory authority.

A spokesperson from Hatch's office told PGx Reporter this week that the draft bill is still being discussed among stakeholders on Capitol Hill, and no date has been set for the bill's introduction.

Meanwhile, at the US House of Representatives, a bill on personalized medicine has been introduced by Congressman Patrick Kennedy (D-RI) and Congresswoman Anna Eshoo (D-CA) that aims to clarify regulation, change reimbursement policies, and drive translational research to advance personalized medicine. The Genomics and Personalized Medicine Act of 2010 (HR 5440), introduced to the House Committee on Energy and Commerce, would create an Office of Personalized Healthcare within HHS that would be able to clarify regulation of personalized medicine products to reduce interagency conflicts. However, the House bill isn't specific with regard to how the regulatory framework would be structured (PGx Reporter 06/02/10).

Distinct from Devices

While Aspinall agrees that FDA should be involved in regulating all diagnostics, she emphasized the regulation need not be overly burdensome to industry and should simultaneously encourage innovation. More importantly, Aspinall's belief that FDA regulations should distinguish advanced diagnostics from the general category of devices is the main crux of the draft bill.

"What is critical is that regulation be specific and appropriate to diagnostics," she said, likening the role of the proposed center to that of the Center for Biologics Evaluation and Research.

The FDA split the National Center for Drugs and Biologics into the two separate divisions in 1988, creating CBER and the Center for Drug Evaluation and Research. CBER evaluates products developed from living sources, including blood, vaccines, allergenics, tissues, and cellular and gene therapies. CDER oversees the safety and efficacy of non-biologic over-the-counter and prescription drugs, as well as certain biologics, such as monoclonal antibodies and proteins for therapeutic use.

In creating the APDx category, the Hatch bill emphasizes the distinction between diagnostics and devices, and promotes the idea that advanced diagnostics require evaluation by an entity other than the existing Center for Devices and Radiological Health.

Under the Food, Drugs, & Cosmetics Act, the term "device" includes an "instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent," or an accessory part that is (among other criteria) intended for the diagnosis of disease.

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In the draft bill, the term APDx comprises components of a diagnostic needed to perform a test and generate test results, such as instrumentation, reagents, and the laboratory report template. However, the APDx category would not include laboratory services, test reports to individual customers, or consultations by a laboratory to treating doctors.

New Terms

The term "in vitro diagnostic multivariate index assays" created significant confusion among industry players when FDA first introduced it in draft guidelines in 2006. Now, Hatch's draft bill introduces a slew of new terms that industry and healthcare stakeholders would have to get used to under the proposed new regulatory pathway for APDxs.

For example, a laboratory developing a test is referred to in the bill as an "APDx Developer-Performer." Meanwhile, a genetic test kit would be made by an "APDx kit developer" and analyzed by an "APDx kit performer."

Furthermore, when labs and test developers submit a test to this new Center for Advanced Diagnostics Evaluation and Research, they would no longer file for 510(k) clearance or premarket approval, but would submit a "premarket claim statement" for evaluation by regulatory authorities that discusses the category and clinical features of the test.

FDA currently classifies devices as Class I, Class II, or Class III devices, reflecting the risk the tests pose to the public health. Class I devices present minimal harm to the user, and are usually exempt from good manufacturing practices and FDA notification requirements. Class II devices are tests that are deemed by the FDA to be of higher risk, and sponsors must meet special controls in order to market these tests, such as labeling requirements, performance standards, and post-market surveillance. Devices deemed by the FDA to have a Class II risk often require 510(k) clearance from the agency. Class III devices are considered by the FDA to be the highest risk tests, and as such they require premarket approval.

The Institute of Medicine is currently reviewing the strengths and weaknesses of FDA's 510(k) device clearance process. The review comes after the Government Accountability office reported last year that the FDA may be clearing too many high-risk devices through the less stringent 510(k) process (PGx Reporter 09/30/09).

The draft bill would also separate APDx into three categories, but the regulatory requirements for these tests would increase based on their impact on public health. It is currently unclear how considerations of a test's "health impact" would differ from a test's "health risk" considerations.

Under the proposed format, the first category would comprise tests that are "generally recognized as safe and effective," based on publicly available information from experts in the field. Category 2 tests, which have a moderate health impact, would include tests that are used with other health or diagnostic information and do not make "a definitive diagnosis of a serious or life-threatening disease." The third category would be for tests with a high health impact that can guide treatment with a drug, and make a definitive disease diagnosis.

Category 1 tests would not require premarket review, but the sponsor would still need to submit the test's information to an APDx databank. Category 2 and 3 tests would be subject to premarket oversight by FDA.

The proposed new division, while it would review LDTs and test kits alike, wouldn't entirely eliminate the dual regulatory pathway currently shared by FDA and CMS.

The draft bill states that the director of the new FDA center and the CMS administrator "shall share responsibility for postmarket surveillance of APDx." CMS would still enforce CLIA to certify laboratory services, operations, and test performance of LDTs. Specifically, an APDx developer-performer that markets a Category 2 or Category 3 diagnostic would need its lab to be accredited under CLIA.

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"There wouldn't be a monolithic rule for all tests, but the regulation should be appropriate for the type of impact the test would have to the patient," Aspinall said. "There are a number of different options with how the CLIA rules would be integrated [in the draft bill]. I think the biggest issue for the labs is they can't be in conflict" with FDA and CLIA rules.

Database and Advisory Committee

Under Hatch's draft bill, all APDxs would be registered in a database. This type of regulatory repository is something that currently doesn't exist in the CMS/FDA dual regulatory system. The absence of such a resource has often been identified by stakeholders as a public health risk since there is no centralized method for tracking diagnostics.

The draft bill would require sponsors to submit their tests to the new diagnostics center, specifying their tests' health impact-based category. At that point, health regulators would either agree with the sponsor's classification of the test or challenge it.

Each registered diagnostic would also be subject to an annual registration fee, though the fee would be waived for small businesses and government entities developing and registering an APDx.

The NIH is currently developing the Genetic Testing Registry, which is a voluntary public database that will house information on the availability, scientific basis, and usefulness of genetic tests, including DTC genomic tests (PGx Reporter 06/02/10). By comparison, the database proposed in Hatch's bill would be a mandatory requirement for sponsors marketing an APDx.

However, the APDx databank would be integrated and coordinated with "other databanks containing similar information," the draft bill notes. Sponsors submitting information to the APDx database will need to provide information on the test's accuracy, precision, analytical sensitivity and specificity, and clinical validity. Eventually, the APDx registry will be expanded to include clinical validity information on registered tests in a manner understandable by the general public.

The bill would also establish an advisory committee for APDx, called the Personalized Advanced Diagnostics Advisory Committee. Similar to other FDA advisory committees, this 11-member panel from a variety of genomic and diagnostic disciplines would advise the agency with regard to the categorization of a particular test, and review the clinical evidence submitted by sponsors about the efficacy and safety of a test.

The FDA's Center for Devices and Radiological Health currently has two advisory committees ─ the Device Good Manufacturing Practice Advisory Committee and the Medical Devices Advisory Committee ─ that provide the agency with recommendations about diagnostic tests submitted for clearance or approval, as well as evaluate the clinical evidence related to genetic tests accompanying drugs.

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