A citizen petition from biotech giant Genentech is adding new fire to the debate over whether FDA should regulate more laboratory-developed tests, and under what authority.

In a Dec. 5 ¹ citizen petition, posted on FDA's dockets Dec. 10, Genentech urges the agency to regulate all in vitro diagnostic tests that guide therapeutic decisions, including tests that help clinicians decide whether to give a patient a certain drug or determine an appropriate dosage.

"Given the potential risks to patient safety associated with use of diagnostic tests that make unsubstantiated claims intended to guide specific drug or biologic therapeutic decision-making, it is imperative that FDA exercise its regulatory authority consistently," the petition states.

Genentech has already garnered support from some quarters, including Johns Hopkins' Genetics and Public Policy Center, but labs and others are gearing up to oppose the effort.

As Lab Tests Evolve, FDA Must Adapt - Genentech

According to Genentech, the number and type of lab-developed tests has grown significantly in recent years. Lab tests historically have been more focused on rare diseases or conditions, but now address more common conditions, some of which are "serious and life-threatening," the firm says.

The so-called "home brew" tests also are moving into the promising yet still nascent arena of personalized medicine.

Efforts to tailor drug therapies to individual patients based on their genetic characteristics have begun to bear fruit, Genentech says, with 10% of all FDA-approved drugs containing some pharmacogenomic information in the labeling.

For example, before Genentech's breast cancer drug Herceptin (trastuzumab) can be prescribed, patients must be tested and exhibit an over-expression of the HER-2 protein. There are a number of FDA-cleared test kits and lab-developed tests used for this purpose, Genentech notes in its petition.

Traditionally, lab tests that are developed in-house are not subject to FDA regulatory review. Instead, CMS regulates lab practices and protocols under the Clinical Laboratory Improvement Amendments, including through periodic sample testing and inspections.

But for tests that help guide therapy, "it is critical that they are accurate, reliable and clinically valid," Genentech argues. Therefore, CLIA validation is not enough, according to the company.

CLIA "is intended to ensure the quality of conditions under which the tests are performed, not the safety and effectiveness of the tests themselves," Johns Hopkins University's Genetics and Public Policy Center notes in its Dec. 15 comments supporting the citizen petition.

The regulatory pathway of a test should depend on what claims are made about it, not where the test is produced, Genentech maintains.

Unvalidated Claims Are Main Target

Genentech's petition calls on FDA to establish, through rulemaking, standards for the development of diagnostic tests that guide therapeutic decisions, and to explain what information test makers must submit to FDA prior to marketing.

FDA should also take immediate action to remove from the market tests that make clinical claims without strong scientific evidence, Genentech says.

"We're not interested in [FDA] necessarily having oversight over all tests," Robert Schueren, Ph.D., senior director of companion diagnostics at Genentech, said in an interview.

"We really focused our citizen petition primarily on any lab-developed tests that make clinically unvalidated claims that would be intended to guide specific therapies."

Genentech is pursuing development of companion diagnostics, with more than 100 employees involved in the effort, Schueren says.

The firm also has five related agreements with diagnostic companies in place, including a new co-development pact to develop a test with cancer diagnostics firm Dako, he said.

Lab-Developed Tests Vs. Kits

The line between lab-developed tests used as part of a lab testing service, regulated by CMS under the CLIA program, and commercial test kits made by manufacturers and regulated by FDA, has become increasingly blurred in the past two years.

In 2006, FDA made its first attempt to regulate a certain type of lab-developed test that uses complex data analysis methods to translate multiple analyte measurements into a diagnostic or prognostic score.

But draft guidance issued in 2006 and revised in 2007 on the so-called in vitro diagnostic multivariate index assays (IVDMIAs) has drawn strong opposition from laboratory stakeholders, and has not yet been finalized (² Also see "Lab Stakeholders Still Oppose FDA’s Multivariate Assay Policy" - Medtech Insight, 3 September, 2007., p. 7).

Some labs, such as Agendia and Pathwork Diagnostics, have opted to pursue FDA clearance anyway, while others like Genomic Health, which markets the Oncotype DX breast cancer recurrence test, are awaiting final guidelines before seeking FDA approval.

Once the IVDMIA guidance is finalized, FDA will allow labs up to 18 months to come into compliance, the agency says.

Genentech feels that FDA took a step in the right direction with its proposed regulation of IVDMIAs, but should "expand and strengthen" its regulation of lab-developed tests even further.

Earlier this year, an HHS advisory committee agreed that FDA oversight of diagnostics, specifically genetic tests, should increase to some extent, with higher-risk lab tests potentially coming under FDA review. The April 2008 oversight report from the Secretary's Advisory Committee on Genetics, Health and Society is still under review by the HHS Secretary (³ Also see "Regulatory News In Brief" - Medtech Insight, 5 May, 2008., p. 20).

To an extent, FDA may already have begun doing so. In September, the agency warned Laboratory Corporation of America that its OvaSure ovarian cancer test did not fall under the "home brew" category after all, and was therefore being illegally marketed without 510(k) or PMA approval (⁴ Also see "LabCorp Pulls OvaSure, But Charges FDA With Overreaching" - Medtech Insight, 27 October, 2008., p. 10).

Lab Test Developers Caught Off-Guard

Laboratory stakeholders, many apparently caught off-guard by the drug firm's petition, urge FDA to stick to the status quo. The American Clinical Laboratory Association (ACLA) called the petition "ill-informed" in a Dec. 19 statement.

"Many, if not all, in the industry of clinical laboratory testing raised their eyebrows when they saw the request from Genentech for all laboratory tests to be regulated," said CombiMatrix Molecular Diagnostics CEO Mansoor Mohammed.

The firm makes array comparative genomic hybridization (CGH) technologies and offers molecular diagnostic testing services out of its CLIA- and College of American Pathologists-certified lab, including HerScan , which evaluates the HER-2 copy number status in breast cancer patients.

Lab-developed tests are based on "sound scientific evidence," biotech firm Clinical Data asserts in a Dec. 16 response to the Genentech petition. The firm's PGxHealth division develops PGxPredict tests designed to predict responses to a variety of drugs, such as warfarin and rituximab.

Clinical Data, along with others including CombiMatrix Molecular Diagnostics, Monogram Biosciences and Genzyme, were singled out in Genentech's petition as examples of firms that market tests with clinical claims unvetted by FDA.

In response, the companies argue that FDA review is not the only way to establish the clinical validity of a product.

"We're committed to validating all of our tests by employing the most up-to-date technology and based on verifiable scientific information," Genzyme Genetics Senior VP and General Manager Jon Hart said in a statement last week.

"HerScan is rigorously validated," Mohammed added. "In all of these labs that adhere to strict CLIA and CAP guidelines and practice sound laboratory practices, I think the safety and effectiveness is almost never a question," he said in an interview.

Both Sides Say Stifling Of Innovation Could Result

Genentech says that as development of home brews has increased over the past five years, the number of kits submitted for FDA review has dropped.

"Clinical laboratories are beginning to fill the need traditionally met by diagnostic test kit manufacturers because they have a lower regulatory burden and a more favorable reimbursement environment," the Dec. 5 petition states.

The disparate path to market for commercial test kits versus lab-developed tests creates a disincentive for FDA-regulated firms to develop diagnostic tests, the firm says, including pharmacogenomic tests.

FDA's "current failure to regulate these genetic [lab-developed tests] threatens public health, creates serious inequities in the marketplace that disincentivize innovation, and impedes the success of personalized medicine," the JHU Genetics and Public Policy Center writes in its public comments.

On the other hand, labs believe that enhanced FDA oversight of their testing services would stifle their diagnostic development programs.

Clinical Data quotes Stanford University fellow and former FDA official Henry Miller as warning: "Unnecessary regulatory oversight is not the solution and only hinders the scientific and medical innovation that drives the development and delivery of new therapies."

Lab-developed tests can be modified more quickly than approved test kits to incorporate important developments, ACLA argues. "These tests meet otherwise unmet medical needs because of the rapidity of updating testing parameters and information being provided by clinicians," ACLA maintains.

Nevertheless, some lab-developed tests may warrant additional FDA oversight, CombiMatrix's Mohammed acknowledged.

"We do believe there are more tests that should be regulated," the exec said. "We don't believe [that] just because you can make it in the lab, that it's a lab-developed test that falls into that ... home-brew allowance from FDA." The problem is: "Where does one draw the line?"

"To try to exercise a blanket statement that will fit all of these tests probably is going to be very difficult," he said.

- Jessica Bylander (j.bylander@elsevier.com)

Genentech Petition Rekindles Debate On Lab-Developed Test Regulation

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