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Genentech Petitions FDA to Regulate All Predictive LDTs, Provide Greater ‘Clarity’

Genentech last week petitioned the US Food and Drug Administration to regulate all predictive laboratory-developed tests and take a more consistent approach to regulating in vitro diagnostics.
In its Dec. 8 filing — the first Citizen Petition to request FDA expand its oversight of all predictive LDTs — the biotech company said the FDA has the legal authority, the expertise, and the resources to regulate all predictive IVD tests used to guide treatment. According to Genentech, greater consistency from the FDA in this regard will help protect the public’s health.
Genentech “believes that FDA should exercise its regulatory authority over all in vitro diagnostic tests pursuant to the risk-based classification system it uses for medical devices,” the company states in the Citizen Petition. “Based on the current classification system, Genentech anticipates that many [laboratory-developed tests] will be considered low risk and would not require significant regulatory oversight.”
The resulting regulatory landscape “would allow FDA to focus its attention on high risk LDTs,” which the company defined as those “used in clinical decision making to determine the use of a particular drug or biologic for the treatment of a patient.”
Currently, the FDA regulates test kits as medical devices and has exercised “enforcement discretion” over LDTs. The Centers for Medicare & Medicaid Services, under the Clinical Laboratory Improvement Amendment, oversees most laboratory testing services. However, confusion over the extent of FDA’s regulatory authority over in vitro diagnostics arose three years ago when the agency decided to regulate a complex subset of LDTs, called in vitro diagnostic multivariate index assays [see PGx Reporter 02-14-2006].
In its Citizen Petition, Genentech highlights the marketing claims made by several laboratory test developers to suggest that the FDA’s “inconsistent” approach to regulating LDTs has led to a steep increase in the number of tests that are not adequately validated.
“Given the recent proliferation and availability of diagnostic tests that make unsubstantiated, and therefore possibly inaccurate or misleading, claims intending to guide both the treatment and payment decisions made by healthcare providers and payors, Genentech believes it is critical for FDA to assert its jurisdiction over all such tests, and to provide much needed clarity over its ability and intention to regulate LDTs,” the drug giant states in the petition.
“The failure to apply clear and consistent standards and regulatory oversight to all LDTs could threaten the public health and serve as a disincentive for the development of diagnostic test kits through FDA’s review pathway, thereby potentially undermining the move toward more personalized approaches to healthcare treatment and delivery,” Genentech added.
The “inaccurate or misleading” tests named by Genentech in the Citizen Petition include: Monogram’s HERmark and CombiMatrix’s HerScan assays, which detect amplification of the HER-2 gene; Clinical Data’s PGxPredict: Rituximab, which predicts response to Rituximab for non-Hodgkin’s lymphoma; a test made by Rosetta Genomics to differentiate between squamous and non-squamous non-small cell lung cancer and guide treatment with Avastin; a Genzyme assay that detects KRAS mutations and guides treatment with Tarceva in NSCLC; Response Genetics’ pharmacogenomic cancer diagnostic tests; and Genomic Health’s Oncotype DX, which gauges breast-cancer recurrence and predicts chemotherapy response.
However, several companies named in the petition maintained in statements to Pharmacogenomics Reporter that their tests are adequately validated and argued that regulating all predictive LDTs, as Genentech suggest, would stifle innovation.
Some industry observers, who have requested anonymity, suggested that Genentech stands to financially gain by slowing the rapid entry of diagnostics to market. A higher regulatory bar for all predictive LDTs would, in effect, create more barriers for diagnostics that would shrink the patient population for drugs marketed by Genentech.
Genentech did not respond to questions regarding the Citizen Petition prior to deadline.
‘Well Equipped’
This is the first Citizen Petition FDA has received requesting the agency to expand its regulatory authority over all predictive LDTs.
Previously, the FDA received two Citizen Petitions, one in 1992 from the law firm Hyman, Phelps & McNamara and another in 2006 from the Washington Legal Foundation, requesting FDA not regulate LDTs as medical devices. Hyman, Phelps & McNamara in its Citizen Petition asserted that the FDA did not have the authority to regulate testing services offered by clinical laboratories, a sentiment that many laboratory test developers voiced during a contentious public meeting in February 2006 to discuss the agency’s intent to regulate IVDMIAs.

“Genentech argues … rightly so, that expanding FDA's standard risk-based classification scheme to all laboratory-developed genetic tests will permit sufficient regulatory flexibility to encourage innovation while safeguarding public health.”

The FDA denied the 1992 petition and has not responded to the 2006 Citizen Petition. In denying the first Citizen Petition, the FDA has asserted its jurisdiction over LDTs, Genentech points out in its petition.
Additionally, the FDA has blamed a lack of resources for its decision to practice enforcement discretion over most LDTs. Genentech said, however, that the Medical Devices Amendments of 2002 allowed FDA to increase its staff, and 510(k) and PMA submissions are accompanied by user fees, which would help offset the cost of conducting additional product reviews.
Furthermore, “FDA would be able to use its risk-based classification scheme to reduce or eliminate the regulatory submissions for those LDTs that the FDA determines present little or no patient safety risk,” Genentech states.
In its petition, Genentech said it believes the FDA is “well equipped” to handle the resulting increase in regulatory submissions because the agency has years of experience reviewing diagnostic submissions and has issued guidelines on pharmacogenomic test standards.
Thus, “in cases where an LDT is being offered to guide therapy without strong scientific evidence of analytical and clinical validity, FDA should take immediate enforcement action to remove the test from the market until the clinical laboratory conducts the necessary studies” recommended by the agency, Genentech said.
‘Powerful Disincentive’
Several diagnostic test developers named in Genentech’s Citizen Petition took issue with its hardline stance toward regulating LDTs. Clinical Data accused Genentech of “ignor[ing] the fact that excessive or inappropriate regulation is a powerful disincentive to the development of innovative healthcare products that improve outcomes while lowering healthcare costs.”
A representative from Clinical Data told Pharmacogenomics Reporter this week that a “universal standard for different types of diagnostic tests may negatively impact a doctor’s ability to make beneficial decisions on behalf of patients.”
Meanwhile, CombiMatrix said Genentech had mischaracterized its HerScan assay by suggesting that it is not adequately validated, and had misrepresented CombiMatrix by asserting that the company makes unsubstantiated claims about its products.
CombiMatrix CEO Amit Kumar told Pharmacogenomics Reporter this week that the company met with the FDA in 2006 to discuss the regulatory status of its comparative genomic-hybridization test to identify the genetic cause for developmental delays in children. After the meeting, the FDA sent CombiMatrix a letter informing the company that its test does not fall under the definition of an IVDMIA and could be operated as an LDT.
“While this letter discussed our first commercial test, which is the only test we had ready at the time, our discussions with the FDA indicated that as long as we ran our other tests in the same manner they could all be offered as LDTs,” Kumar said. “As such, we have launched over a dozen tests since 2006 in the same manner as our first.”
Kumar expressed “disappointment” over Genentech’s comments about CombiMatrix, saying that “our philosophy for testing and our technology all make the benefits to the patient the first priority.”
“We welcome discussions with Genentech, physician groups, patient groups, the FDA, or any other organization or individual that wants to understand out tests and technology better,” said Kumar.
Other companies named in the Citizen Petition were contacted by Pharmacogenomics Reporter, but many did not respond to requests for comment.
Meanwhile, at least one policy group said it supports Genentech’s Citizen Petition. Johns Hopkins University’s Genetics and Public Policy Center, which has long urged the FDA to take a more consistent approach toward regulation of genetic tests, said in a statement it “applaud[s] Genentech for pointing out that an even playing field for all developers of genetic tests intended for medical use based on risk is the best guarantee of a stable, equitable marketplace.
“Genentech's risk-based approach would replace the current practice of treating all laboratory-developed tests as low risk, despite lack of assurance of clinical validity or scientific evidence underlying marketing claims for the tests,” the group said. “Genentech argues, and rightly so, that expanding FDA's standard risk-based classification scheme to all laboratory-developed genetic tests will permit sufficient regulatory flexibility to encourage innovation while safeguarding public health.”
Faulty Assumptions’
Although Genentech asserts that preserving the public’s health is the main motivation behind its Citizen Petition, there might be other incentives at play. Some industry observers have suggested that the biotech could benefit from more stringent regulatory commitments that deter the launch of tests that could potentially shrink the patient population for its most profitable drugs.
Indeed, most of the LDTs Genentech names in its petition would narrow the patient population for four of its top revenue-generating drugs: Avastin, Rituxan, Herceptin, and Tarceva.
For the three months ended Sept. 30, US sales for Avastin, Rituxan, and Herceptin generated $704 million, $655 million, and $368 million, respectively. Tarceva, Genentech’s sixth-best selling drug, brought in $110 million during the quarter.
The blockbuster-hungry pharmaceutical industry still holds a bad reputation for being skeptical about investing in personalized medicine. However, in the Citizen Petition, the drug giant attempted to present itself as being supportive of pharmacogenomics.
“Genentech is applying a personalized medicine approach to nearly all of its clinical development programs and is developing diagnostic approaches with every product we believe is an appropriate candidate for such an approach,” Genentech states. “We collaborate with a variety of partners in these efforts, including traditional diagnostic test kit manufacturers as well as clinical laboratories.”
Indeed, Genentech’s collaboration with Dako to develop a companion diagnostic for Herceptin is often held up as the first successful example of Rx/Dx codevelopment.
However, in its Citizen Petition Genentech takes particular issue with the “increasing number of LDTs of unknown analytical and clinical validity” that are being marketed as an alternative method to determine whether a patient should be treated with Herceptin.
Genentech points out that Herceptin’s label does not provide information on the use of non-FDA-approved LDTs for the indication. The label does mention Dako’s FDA-cleared immunohistochemistry HercepTest, the FDA-cleared IHC tests made by Ventana, and FISH tests marketed by Dako and PathVysion.
Several test developers, including two named in Genentech’s Citizen Petition, Monogram and CombiMatrix, have launched homebrew assays for the indication, claiming their tests are better than standard IHC and FISH methods.
These claims gained particular attention after guidelines issued by the American Society of Clinical Oncology and the College of American Pathologists showed that approximately 20 percent of HER2 determinations yielded by IHC and FISH may be inaccurate. Many independent studies have also shown that IHC and FISH-based HER-2 testing yields a high false-positive rate.
In fact, Genentech submitted its Citizen Petition just before the San Antonio Breast Cancer Symposium, during which Monogram submitted new clinical data that its HERmark assay “was a better predictor of response to Herceptin than FISH testing, even when conducted in a central laboratory.”
In February, when CombiMatrix launched its homebrew HER-2 test HerScan, the company claimed that the comparative genomic hybridization array-based assay could “measure HER-2 gene copy number with simultaneous analysis of the entire tumor genome.”
In the Citizen Petition, Genentech asserts that both CombiMatrix and Monogram are making “unvalidated claims,” and said that “as a consequence, treatment and payment decisions may be made based on faulty assumptions and unvalidated claims.”

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