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Genentech Defends Citizen Petition on FDA Regulation of LDTs, Maintains Support for Diagnostics

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After issuing a Citizen Petition last month requesting the US Food and Drug Administration regulate all laboratory-developed diagnostic tests, Genentech defended its position saying it is fully behind advancing personalized medicine, but is concerned the current regulatory structure does not protect the public's health.

"Our primary focus is always going to be what is best for patients. We've got a pretty significant effort in diagnostics and tests to understand which patients are most likely to benefit from our drugs," Robert Schueren, senior director of companion diagnostics at Genentech, told Pharmacogenomics Reporter earlier this month. "Ultimately, what's good for patients will translate to what's good for business."

In its Dec. 8 Citizen Petition — the first of its kind to ask the FDA to expand its oversight over all predictive LDTs — Genentech said the agency has the legal authority, the expertise, and the resources to regulate all predictive tests used to guide treatment.

At the time, Genentech said greater consistency from the FDA in this regard will help protect the public's health [see PGx Reporter 12-17-2008].

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 said it retains the authority 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.

As a result, the Citizen Petition stirred up controversy in the diagnostics industry. Several companies, whose non-FDA-cleared tests were named in the petition as "inaccurate or misleading," maintained in statements to Pharmacogenomics Reporter previously that their tests are adequately validated and argued that regulating all predictive LDTs, as Genentech suggests, would stifle innovation.

Meantime, some industry observers, who requested anonymity, have suggested that Genentech stands to gain financially by slowing the entry of diagnostics to market, which theoretically could shrink patient populations for certain drugs.

Genentech's Schueren dismissed these accusations as unfounded. He pointed out that Genentech has a diagnostics division with more than 100 employees, has signed as many as six partnerships over the last two years to develop companion diagnostic products for its drugs, and is the developer of the genetically targeted breast cancer drug Herceptin, which is often held up as the first example of a successful drug/diagnostic combination product.

"Clearly, everyone knows the Herceptin story where we pioneered this whole concept of selecting patients for it, and I think we haven't moved away from that mission at all," Schueren said.

"Regarding the examples [of tests] we've cited [in the Citizen Petition], if those tests are good and the data are solid then having the safety and effectiveness of them reviewed shouldn't be an issue at all," he maintained.

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However, Genentech's Citizen Petition comes during a period of rapid commercialization of LDTs. Currently there are genetic tests commercially available for more than 1,500 diseases. By requesting that all LDTs be reviewed by the FDA, Genentech is essentially proposing a higher regulatory bar for products that would compete with the companion test kits the company is developing with partners.

"It will be interesting for companies that do lab-developed tests for [Genentech's] Tarceva. As we release data on over 1,000 patients [it will reveal] what the best analytical sets show," Schueren said.

Genentech's Dx Commitment

Among Genentech's recently penned deals to develop companion diagnostics is one with Ventana. The two firms announced they had entered into a non-exclusive long-term collaboration agreement to co-develop and commercialize tissue-based diagnostic assays for therapeutic candidates designated by Genentech.

In November, Genentech penned an agreement with Dako, the same company that developed the companion HercepTest for Herceptin, to develop a new test for an undisclosed "specific Genentech investigational therapeutic."

Previously, Genentech announced separate collaborations with Abbott and Dako to develop companion tests for its non-small cell lung cancer drug Tarceva (erlotinib).

"If the data support it," then Genentech will take any companion diagnostics resulting from these partnerships through the FDA regulatory process and try to get the drugs' labels updated with a recommendation for genetic testing, Schueren said.

However, the biotech giant is keeping a tight lid on the details of most of its collaborations with diagnostics firms. "We don't want to say what the targets are but we are very active in diagnostic discovery and development," Schueren said. "The only one we have specific targets for, that we've disclosed, is for Tarceva. We don't want to disclose what the other specific targets are because of our competitors."

Genentech recently announced top-line data from two Phase III Tarceva trials, in which the company had near-100-percent tissue collection and measured a number of biomarkers related to Tarceva response. Genentech will announce full clinical trial results at the American Association for Cancer Research's annual meeting in March and at the American Society of Clinical Oncology's annual meeting in early June.

"We would love to definitively answer the questions about diagnostics and drugs like that," Schueren said. "We just want to make sure that whatever is done is truly backed by good science and good data.

Dx Coalition vs. Genentech

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 Avastin treatment; 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.

In response to the Citizen Petition, the Coalition for 21st Century Medicine — a group that represents the interests of diagnostics firms, clinical laboratories, researchers, physicians, venture capitalists, and patient advocacy groups — issued a statement criticizing that Genentech's position, claiming it would delay the introduction of "critically needed" diagnostic tests and that it ignores regulatory requirements already imposed on labs under CMS' CLIA.

The coalition charges that FDA regulation of all LDTs would impose huge costs on laboratories and put significant pressure on the agency's already limited budget and personnel.

"Genentech wrongly asserts that FDA approval is a prerequisite for claims to be considered 'scientifically proven,'" the coalition said in its statement. "FDA approval is not needed for a LDT's performance to be demonstrated. There are many other methods of establishing a LDT's performance, such as the publication of reproducible research findings in peer-reviewed publications."

Furthermore, the coalition asserts that "a lack of information about some LDTs does not justify a revolutionary change in the regulatory regime for laboratories," and points out that the Federal Trade Commission already has oversight authority to ensure that claims made by diagnostics companies are truthful.

"Concerns about allegedly inaccurate statements can be readily — and efficiently — addressed within the existing regulatory framework," the coalition stated.

The group has criticized the FDA's "piecemeal approach" to regulating LDTs, and made statements opposing the agency's expressed intent to regulate IVDMIAs. Specifically, the coalition challenges whether the agency has the regulatory authority to exercise oversight over LDTs.

"As Genentech acknowledges, even if the FDA were to seek to regulate LDTs, the agency needs to proceed through notice-and-comment rulemaking," the coalition said. "Until that process is completed, FDA cannot take enforcement action against laboratories for offering LDTs. Singling out individual laboratories for ad hoc enforcement, based on unstated criteria, can only result in arbitrary and capricious decisions."

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