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CDRH Releases PGx, Genetic Device Draft Guidance; Document May Interest Pharma Generating PGx Data

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The US Food and Drug Administration's Center for Devices and Radiological Health last week released a draft guidance advising companies how best to submit for clearance diagnostics based on pharmacogenomic and genetic markers.

The draft, Pharmacogenetic Tests and Genetic Tests for Heritable Markers, represents a substantial reworking of one of the first major pharmacogenomics-related policy documents produced by the FDA, Multiplex Tests for Heritable DNA Markers, Mutations, and Expression Patterns, released last February. But rather than signaling a marked change in thinking within the FDA and CDRH, the new document provides device manufacturers with clearer guidelines for generating data to support new tests, and what sorts of information the agency expects to review in support of a submitted device.

The document could brighten the regulatory outlook for pharmaceutical companies developing pharmacogenomic data, which could in turn spill over to vendors performing this kind of research for drug makers.

"It's not setting a whole new paradigm in the way that the pharmacogenomics data submissions guidance was, but at the same time, it's important from the point of view of defining the environment for work with genetic tests and so forth," Chris Webster, director of Regulatory Strategy and Intelligence for Millennium Pharmaceuticals, told Pharmacogenomics Reporter this week. Webster is also chair of the genomics technical group for the trade association PhRMA, and has worked with the FDA on some pharmacogenomics-related issues.

"In the previous guidance, there really hadn't been a lot of attention on the 'least burdensome approach,'" Webster said. "Now they have a whole section [soliciting comments on the issue], which is very important."


"Any pharmaceutical company that is developing pharmacogenomic data, even as part of a drug submission, will need to take notice of this."

Many comments on the original Multiplex Tests draft critiqued that document for being overly broad in scope, said Bill Pignato, whose firm, William J. Pignato & Associates, consults diagnostics companies. The new draft is focused only on pharmacogenetic and genetic tests, he said.

As might be expected from a guidance focused partly on pharmacogenomics, the FDA makes clear the link between devices that fit in this category and therapeutics. "We consider pharmacogenetic tests for clinical use to be mostly those that are intended to provide information that may aid in selection of certain therapeutics. When sufficient clinical information is available they may also aid in dosage selection of the therapeutic. Therefore, a pharmacogenetic test target population will typically be composed of candidates for a particular therapeutic," the draft said.

Hook for Pharma

But device sponsors are not the only entities for whom the draft guidance will be useful. "There is one part of [the draft guidance] that I found interesting," said Pignato. "FDA noted that while [the document] was derived from the Office of In Vitro Diagnostics, they noted that technical aspects of the guidance might be useful in applications that use these assay formats in support of product development" — that is, it could help drug developers generate data that can become part of an IND, BLA, or NDA.

"Any pharmaceutical company that is developing pharmacogenomic data, even as part of a drug submission, will need to take notice of this," said Millennium's Webster. "Even though [pharma companies] may not be planning to submit a test, as such, there will be aspects of this guidance [that] they will have to take into account, in order to make sure that the data that they submit around a pharmacogenomic marker is in good shape, as far as the agency is concerned."

Pharma will probably be interested in a section of the draft that concerns devices that have multiple intended uses, said Webster. In that section, the document encourages separate applications for each intended use, except in certain cases of pharmacogenomic tests. The example given seems to reflect the agency's experience with recent submissions: CDRH will consider the determination of CYP2D6 alleles for aiding drug selection as a single use, regardless of the fact that many drugs are metabolized by that enzyme. Pharmaceutical companies of all sizes will have drugs in their pipelines that are metabolized by CYP enzymes, and they would likely take notice of how the agency views their testing, said Webster.

Because of its ability to interrogate two genes simultaneously, Roche's AmpliChip CYP450 was disallowed the analyte-specific reagent clearance route, and instead was later submitted as a de novo 510(k) in vitro device.

The current document is almost certainly going to be more useful for device makers than its predecessor. "The previous guidance really addressed data in the context of drug development, whereas this addresses actual test development, so they're different," said Carol Reed, Clinical Data's chief medical officer. Reed was active within the Personalized Medicine Coalition, a non-profit with an interest in developing the field, when the group submitted its comments on the draft guidance for pharmacogenomic data submissions in early 2004. The new draft "does a very nice job of applying the usual FDA standards and criteria to a novel area of test development," she added.

The draft contains at least one sentence that will set many device makers at ease, said Reed. "'We expect that most of these tests will primarily be traditional 510(k) or de novo classifications,' I think that's something people always want to hear," because the alternative premarket approval process is more cumbersome, she said.

Although both 510(k) and PMA submissions contain the same general information, the agency may request different types of data and statistical analyses in PMAs, the draft said. That information depends on: a device's intended use, such as the detection of cytochrome P450 alleles; a device's indications, such as a predictive or prognostic for disease, treatment response, or drug sensitivity; a device's methodology, such as PCR; the technical interpretation of results; quality control and assay limitations; a device's performance; a device's clinical validity, such as its frequency of false positives; clinical interpretation; and claims made by the manufacturer, such as its effectiveness.

Even though the new pharmacogenomic test guidance was produced by CDRH, it is in principle a cross-center effort — the document's cover sheet lists contacts for that center, as well as the Center for Drug Evaluation and Research and the Center for Biologics and Evaluation and Research. "Sponsors that will be developing products that would go through any of those centers would have to take notice of this for the points that were relevant to their particular product," Webster said.

Since the FDA had been working with a different level of knowledge during the preparation of the original guidance, the new draft is a "much more thought-through and professional document than the first draft was," Webster said. Device manufacturers will not have as many questions about submission requirements, but "there still will be points where sponsors will have to consult with the agency," he said.

As has been the case with other pharmacogenomics draft guidances, including the guidance for voluntary pharmacogenomics data submissions, publication of the current document was delayed. According to Webster, the center had expected to release the draft as early as September.

The original document upon which this current draft is based "drew quite a bit of attention because it was one of the first of the pharamacogenomic guidances that the FDA had put out, and also because it had come after a lot of low-level contact between the agency and the industry — particularly the devices center and the industry," said Webster. Those contacts had begun in about 2000, he said.

"When the [February 2003] guidance came out — let's just say it had some very constructive, but very heavy criticism from the industry," said Webster. "I think the industry felt it certainly wasn't a mature document."

Like the document that preceded it, the current pharmacogenomic device draft is certain to provoke a number of industry comments and critiques. Those can be submitted to the FDA until May 19, with the identifying docket number 2006D-0012.

"I know that both of the industry associations are hoping to provide comments on this guidance," and PhRMA is currently developing its comments submission, Webster said.

— Chris Womack ([email protected])

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