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Is Your Shop Into Theranostics? So is The FDA. Here is How They Can Help


Molecular diagnostics companies eager to develop theranostics programs have regulatory agencies to navigate, reimbursement policies to fret over, finicky health-care providers to woo, and even ignorant drug makers to tutor.

But these companies may find help from an unlikely source: Steve Gutman, director of the US Food and Drug Administration’s Office of In Vitro Diagnostic, Device Evaluation and Safety, who has intimated that drug/diagnostic combinations — so-called Dx/Rx companions, or theranostics — have a strong future ahead of them.

He has previously said the FDA is committed to building the regulatory infrastructure that would encourage drug and diagnostic companies to work together on companion products. But in an unusual step, Gutman, keynoting at the first-annual Dx/Rx Summit in Reston, Va., earlier this week, offered sponsors some hints that he believes can help them navigate the budding framework his group is constructing.

The purported benefits of Dx/Rx companion products — believed to be a cornerstone of pharmacogenomics — are widely cited: safer and more efficacious drugs; smaller, less expensive clinical trials; and speedier regulatory reviews. But within industry and the FDA, opinions on theranostics vary from evolving to indifference.

For its part, industry hasn’t developed many of these companion products, so it has little experience on which to base decisions or strategies. Although there are many examples of molecular diagnostics that physicians make treatment options — think of HIV drug-resistance genotyping tests that help guide some antiretroviral regimens — Herceptin and its companion test are the only pair of Dx/Rx products approved for sale in the United States. In fact, Dx/Rx companion products are so new to the laboratory and the marketplace that drug makers are “substantially ignorant” to the unique needs of their diagnostics cousins, as one insider said.

“Many in pharma are naïve about the IVD world,” Thomas Soriano, president and CEO of Diagnostic Oncology CRO, said during his presentation at the meeting this week. Or, as Mohan Iyer, vice president of business development at Diadexus, put it: “Pharma looks at diagnostics as an afterthought.”

[To be sure, Iyer’s company recently won FDA clearance for its PLAC test, which was designed to identify individuals at risk for congestive heart failure. The test is now used by Quest Diagnostics, and GlaxoSmithKline is currently working with Diadexus to develop a therapeutic against the markers used by the test.]

The FDA, meantime, has quietly announced its intention to draft a regulatory guidance for these kinds of products [see 2/19/04 SNPtech Pharmacogenomics Reporter], and is currently rewriting a first version of a molecular diagnostics draft submitted for public comment last May [see 5/23/03 SNPtech Pharmacogenomics Reporter]. The agency hopes to have a second iteration of this draft — it considers the first version “too big to chew” — ready for industry comments this summer.

Before the Dx/Rx Summit meeting, Gutman conceded that diagnostics have “not been as large a priority as therapeutics” at the FDA. But that doesn’t mean the agency isn’t trying to turn the tide.

In a recent interview with SNPtech Pharmacogenomics Reporter, Gutman described the current regulatory environment as a “unique window of opportunity” for diagnostic-therapeutic companion products, and stressed that an upcoming draft guidance on these products is a “high priority” at the agency.

Gutman also said that his group, which is writing the draft with Janet Woodcock at the FDA’s Center for Drug Evaluation and Research, is “really quite willing” to work together with CDER in cases when two corporate partners wish to bring a theranostic to market. At the Dx/RxSummit, he added that his group is willing to work with the Center for Medicare and Medicaid Services to help define a reimbursement framework.

He has also taken the unusual step of offering some hints to industry that he said may help them better understand the agency’s position.

To help the regulatory review process for theranostic products, Gutman said sponsors on the drug and diagnostics side ought to “come in early” to the FDA; “submit a protocol,” such as a pre-Investigational Device Exemption or IDE; “make [it] user friendly;” and “consider narrow claims.”

And, “contrary to popular folklore,” the various agenc[y] groups within the FDA and elsewhere in the US Federal government responsible for reviewing and approving drugs and diagnostics, and setting reimbursement schedules — OIVD, CDER, CMS — will “work interactively,” Gutman said during his keynote. Researchers from throughout the government “can cross-reference studies” and “cross-schedule panels,” which can lead to “shorter mandatory timelines.”

Specifically, Gutman described as an “excellent example” of jointly developed Dx/Rx companion products one in which “the sponsor performs diagnostic and drug studies prospectively and concurrently, and links data between the two,” Gutman said. A “fair example” would be when “a sponsor coordinates diagnostic and drug studies prospectively but obtains drug outcome data only in patients treated because of identification of the biomarker of interest.”

A “bad example,” however, would be when a sponsor forgets about the value of diagnostic studies until drug studies are complete,” or when they “make an effort to retrospectively re-construct data and relate test results to patient results.”

“While FDA will work to label around design weaknesses, this is like skating on thin ice, and time consuming,” Gutman added. Plus, “you may never get the opportunity to recreate the data.”

In his presentation later in the day, DOCRO’s Soriano, responding to an attendee asking when diagnostics studies and therapeutic studies be synchronized, said: “As soon as possible.”

Soriano cited as an example Herceptin, whose launch was delayed in 1998 because the FDA disagreed with the sponsor, Genentech, that the product did not require a companion diagnostic. Diadexus learned from Herceptin’s mistake and decided first to develop a diagnostic while a pharma partner, Glaxo, developed a companion therapeutic.

The PLAC test was approved in 2003; Diadexus’ Iyer said Glaxo expects to have a therapeutic on the market in the United States in 2008. Asked to reconcile the reimbursement challenge of marketing the CHF-risk test while its therapeutic counterpart is still in the lab — the so-called ‘so-what’ effect — Iyer responded that there are “many classes” of drugs that treat atherosclerosis, the primary cause of CHF.

— KL

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