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FDA's Companion Dx Guidance Slated for Early 2011; Codevelopment Guidance out Later, Gutierrez Says

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Originally published Dec. 3.

By Turna Ray

BOSTON — As 2010 draws to a close, it is pretty much an accepted fact among drug and device manufacturers that the US Food and Drug Administration will not be able to fulfill its promise of issuing a draft guidance document on companion diagnostics development by the end of the year.

At the World Companion Diagnostics Summit this week in Boston, Alberto Gutierrez, director of the Office of In Vitro Diagnostics in FDA's Center for Devices and Radiological Health, verified industry's suspicions, noting that despite FDA Commissioner Margaret Hamburg's earlier promise that an Rx/Dx codevelopment guidance will be released by year end, "it's pretty much guaranteed that it won't be this year."

In Gutierrez's best estimation, a draft guidance on companion diagnostics will most likely be released in early 2011; and a separate co-development guidance focusing on the simultaneous, multi-FDA center review of combination products will be out by the end of next year. By Gutierrez's conservative projection, the codevelopment guidance may even take a few years to complete.

Until now, the agency has not publicly stated that it intends to issue two separate guidances on Rx/Dx development: one focusing solely on advancing so called companion diagnostics, tests which are used to make treatment decisions; and another document on how to gain regulatory approval for a drug and test at the same. The companion diagnostics guidance will most likely focus on how to take a test through CDRH, while the codevelopment guidance will include advice from the drug, biologic, and device centers at FDA.

"We've been working on the companion diagnostic guidance for four or five years now," Gutierrez acknowledged at the meeting in Boston. "But we still can't get it done."

In 2005 the FDA issued a "concept paper" outlining its thinking on Rx/Dx codevelopment, but that effort was criticized by both drug and diagnostic companies, which felt that the agency's proposed guidelines were too idealistic and failed to account for the challenges of aligning competing interests, different development timelines, and divergent regulatory pathways for therapeutics and diagnostics.

Then, in February this year, after several stalled attempts to issue a draft guidance on the topic, Hamburg committed the agency to issuing the drug/diagnostic codevelopment guidance by the end of the year (PGx Reporter 03/03/10).

Throughout the year, agency officials have expressed cautious optimism that the FDA would be able to make good on Hamburg's pledge, but have not publicly indicated that there was an effort inside the agency to split the Rx/Dx guidance into two separate documents, addressing different aspects of the development strategy.

In a paper published in the September issue of Personalized Medicine and authored by several employees in FDA's personalized medicine division, the agency provides advice on study designs for Rx/Dx development and addresses a variety of development situations. Companion diagnostics development in this paper comprises simultaneous Rx/Dx codevelopment strategies.

"The term companion diagnostic applies to several different scenarios — concurrent development of diagnostic and therapeutic, development of a diagnostic test intended to optimize treatment with a therapeutic that has already been approved, or optimizing a treatment with newly developed therapeutic with previously approved diagnostic test," state co-authors Živana Težak, Marina Kondratovich, and Elizabeth Mansfield of FDA's personalized medicine division at OIVD.

The authors note in the paper that the agency has "attempted to clarify the regulatory framework for companion diagnostics and their related therapies," and refer to the 2005 white paper. While adding that the FDA "is currently working towards issuing a guidance in this area," they do not indicate that two separate documents are in the works.

Divide and Conquer

At the meeting in Boston, Gutierrez explained to PGx Reporter that as the agency progressed in the guidance development process, it became clear that a guidance on companion diagnostics would emerge more quickly, since it mainly focuses on "process-type issues in CDRH."

"Industry clearly needs guidance on companion diagnostics and we are trying to get that out as quickly as possible," he said.

Meanwhile, a codevelopment guidance requires that three FDA centers — CDRH, the Center for Drug Evaluation and Research, and the Center for Biologics Evaluation and Research — come to an agreement on the various aspects of a combination product, which requires simultaneous regulatory review of a test and a therapeutic.

Gutierrez noted that there are complex issues that still need to be ironed out and various agency stakeholders need to be on the same page on these topics. "The fact that you haven't yet seen a codevelopment guidance is a sign that we're working hard on it, but we're not quite seeing eye-to-eye on many of the issues," he said at the meeting.

Meanwhile, from a business perspective, the advancement of personalized medicine ultimately depends on the codevelopment of drugs and diagnostics. The agency itself has said that the ideal pathway for combination products is for drug developers and test makers to start interacting early, and launch the test and drug together.

For example, the protracted nature of FDA's labeling updates for colorectal cancer drugs Vectibix and Erbitux with genetic testing information prodded many industry players to embark on Rx/Dx codevelopment much earlier in the drug development process, and to ensure that a test would be available when the therapeutic went on the market.

Learning from this example, over the past year, drug and diagnostic firms have moved ahead with inking numerous Rx/Dx codevelopment deals, most of which would require them to advance an investigational drug and a companion test through the regulatory approval process at the same time.

Most pharma companies believe that "biomarkers make it easier to make go/no-go decisions and that personalized medicine is a natural trajectory for the direction that advances in science and medicine were taking drug R&D," Christopher-Paul Milne, associate director at the Tufts Center for the Study of Drug Development, told PGx Reporter recently. Milne recently led a survey by Tufts of 21 drug firms that found that while less than 10 percent of companies have Rx/Dx products in late-stage clinical trials, the majority of pharma/biotech companies are using biomarkers to learn more about the investigational agents they are developing (PGx Reporter 11/21/2010).

However, the survey also revealed that "there is some debate as to whether personalized medicine is helping to streamline R&D because of the scientific challenges that remain in interpreting and acting upon pharmacogenetic data."

Donna Roscoe, a scientific reviewer at OIVD, recently noted that the FDA might take longer than usual to review pre-IDE applications, because "companion diagnostics have just exploded" (PGx Reporter 09/22/10). And the increasing volume of its Rx/Dx review load shows no signs of slowing down for the FDA in the next few years.

Among the companies surveyed in the Tufts study, 69 percent have so far submitted data to the FDA's Voluntary Exploratory Data Submissions program, a pathway through which industry can discuss early genomic data with FDA reviewers without regulatory repercussions. In addition, the Tufts study found that approximately 50 percent of clinical trials now involve the collection of DNA samples from study participants.

Back at the meeting, having acknowledged additional delays from the agency on the companion diagnostic and codevelopment guidances, Gutierrez assured attendees that the agency is working steadily to release these documents and has made progress.

Ultimately, however, he said that "the FDA is not the elephant in the room." Gutierrez noted that getting payors to reimburse for PGx products, as well as driving physician and payor adoption of tests to guide treatment decisions, present even bigger barriers to personalized medicine than do regulatory hurdles.


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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