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FDA Delays Rx/Dx Co-Development Guidance; Agency Official Provides Insight on Submissions

SAN FRANCISCO – The US Food and Drug Administration will delay releasing its Rx/Dx co-development draft guidance to mid- to late-2008, a high-ranking agency official said here at a conference on personalized medicine earlier this month.
The official, Steven Gutman, director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety, during the Burrill and Company conference on personalized medicine also shed additional light on the best ways drug and diagnostic companies can submit Rx/Dx combination products to the agency for review.
Calling the concept paper on drug-diagnostic co-development the agency issued in April 2005 “a good start,” Gutman said an Rx/Dx draft guidance defining the topic in greater detail “is definitely overdue.”
Industry observers have been eagerly awaiting the release of this guidance, particulary since agency officials have said that Rx/Dx companion products are the best way to encourage physicians and patients to adopt pharmacogenomics-guided personalized medicine.
Felix Frueh, the head of the FDA’s Interdisciplinary Pharmacogenomics Research Group, previously told Pharmacogenomics Reporter that drug-diagnostic co-development is the best way to encourage physicians to incorporate genetic tests into their practice [see PGx Reporter 01-03-07].
FDA officials had initially projected that a draft guidance would be crafted from the concept paper and released by the end of 2007. “I wouldn’t like to promise anything,” Gutman said, adding that the timeline for this guidance will now more realistically be pushed back by six months to a year.
Ahead of a guidance laying out the regulatory framework for Rx/Dx combination products, Gutman broadly explained at the conference the current regulatory pathway for such products. He advised that companies planning to submit a companion diagnostic for marketing approval should either submit their documents to the OIVD or to the FDA’s Center for Drug Evaluation and Research.
Following the submission, if the two divisions don’t naturally coordinate their review of the Rx/Dx combo, then the company should turn to FDA’s Office of Combination Products.
The most salient example to date of a successfully coordinated FDA review of a combination product is when OIVD reviewed Dako’s HercepTest in concert with CDER’s review of Herceptin.
However, the agency’s oversight for combination products may vary depending on whether the laboratory developing the test decides to market it as a kit, subject to FDA premarket approval or a 510(k) review, or as a homebrew under the Centers for Medicare and Medicaid Services’ Clinical Laboratory Improvement Amendment.
For example, although Pfizer used Monogram’s Trofile assay in clinical trials to gauge patients’ tropism status before treating them with its CCR5 antagonist Selzentry, the company submitted information about the diagnostic as part of Selzentry’s master file to CDER. Although Monogram does not plan to submit the test separately to OIVD for FDA approval, CDER officials did review the test and discussed its utility and validity at an FDA advisory committee meeting in April for Selzentry [see PGx Reporter 05-02-2007].
However, Gutman suggested that as Rx/Dx submissions become more commonplace, the agency will likely increase its oversight on the diagnostics aspects of the combination product.

“More and more, some division at the agency will have to start taking responsibility for the diagnostic when it is part of treatment decisions connected to a drug.”

In situations where a genetic test is necessary to determine whether a drug will be efficacious or safe for a patient, “the drug is a slave to the diagnostic,” he said. “More and more, some division at the agency will have to start taking responsibility for the diagnostic when it is part of treatment decisions connected to a drug. The agency will begin to become more involved in this area.”
Separately, Gutman noted that just because the FDA has approved a test doesn’t mean that it will be well-received in the market.
“We don’t look at outcomes and medical necessity for assays,” Gutman explained. “We make the best judgments we can. If we can make a decision internally, we do. If we need a committee of experts, [we convene them].”
He cited as an example Roche’s cytochrome P450 test. Although the FDA approved the Amplichip in 2004, the test is not being covered by many large insurers like Aetna, and this has had a negative impact on physician adoption of the test. Insurers have demanded that Roche provide clinical utility data prior to coverage.
Another example is the warfarin testing market. Although the FDA approved Nanosphere’s warfarin sensitivity test in October [see PGx Reporter 10-10-2007], and updated warfarin’s label with genetic testing information in August [see PGx Reporter 09-26-2007], warfarin test developers have complained that the reimbursement environment is still spotty.
However, in this regard, pharmacy benefit managers like Medco and PharmaCare are conducting outcomes studies to gauge if warfarin sensitivity tests are clinically and economically useful [see PGx Reporter 04-25-2007].

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