By Turna Ray
This article was originally posted Nov. 18.
BOSTON — The US Food and Drug Administration is planning to release three new guidances late this year and early next year in an effort to inform the industry about using genomic strategies in drug development, according to a high-ranking agency official.
At a conference here hosted by the Partners Healthcare Center for Personalized Genetic Medicine, Lawrence Lesko, director of the Office of Clinical Pharmacology and Biopharmaceutics in FDA's Center for Drug Evaluation and Research, said that the agency is working on guidance documents for clinical pharmacogenomics, clinical trial enrichment, and internal standard operating procedures for cross-labeling efforts within FDA offices.
The guidance on clinical pharmacogenomics will discuss strategies for pre-market evaluation of genomic data in early-phase trials. Lesko projected that this guidance "may be" released next month. Guidelines discussing predictive and prognostic enrichment of trials using genomic subsets and clinical study design will likely come out in the early part of next year.
A third guidance document providing information about cross-labeling efforts between three FDA centers — CDER, the Center for Devices and Radiological Health, and the Center for Biologics Evaluation and Research — is "nearly complete," Lesko noted. FDA's drug and device centers need to coordinate regulatory reviews and labeling efforts for the development of drug/diagnostic combination products.
During the conference, attendees were surveyed on which personalized medicine efforts the FDA should back. The most common response, comprising around 37 percent of all respondents at the conference, was that the agency needs to issue guidance on the codevelopment of Rx/Dx products.
Since issuing a white paper on drug/diagnostic codevelopment five years ago, the FDA has not yet issued draft guidelines on the topic. However, FDA Commissioner Margaret Hamburg earlier this year committed the agency to completing its long-awaited drug/diagnostic codevelopment guidance by year end (PGx Reporter 3/3/10).
At the meeting, Vicki Seyfert-Margolis, FDA senior adviser, indicated that the companion diagnostics guidance is on track to be released in a couple of months. Ahead of releasing guidance on the topic, at a meeting in Arlington, Va., in September, an FDA official discussed detailed strategies for navigating the regulatory process for Rx/Dx combination products (PGx Reporter 9/22/2010), signaling the agency has made headway in its thinking on how combination products should be advanced through the regulatory process.
Back at the Partners meeting, the second most common response to the question question on what personalized medicine issue FDA should focus on, comprising around 27 percent of the audience, was that the agency should reach out to professional societies to educate them and encourage the issuance of clinical guidelines around the use of genomic strategies. Lesko agreed that the agency hasn't been doing all it can to engage professional societies and make sure they understand PGx labeling updates.
Citing the resistance among doctors to adopt PGx dosing strategies for warfarin, Lesko pointed out that although several studies show that in certain subsets of patients genetic testing can improve outcomes, many professional society guidelines are not keeping up with new evidence and continue to recommend against PGx strategies to dose the anticoagulant.
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He pointed to guidelines from the American College of Chest Physicians, the American Society of Hematology, and the Anticoagulation Forum as being out of step with the latest published evidence on warfarin PGx testing.
Two years ago, the Centers for Medicare & Medicaid Services issued a national coverage analysis to investigate whether it should pay for PGx testing to administer warfarin. In response to that review, payors and professional societies asserted that the government payor should not cover the genetic testing intervention due to lack of evidence that it improved patient outcomes (PGx Reporter 8/13/08).
For example, the American Heart Association wrote at the time that "while pharmacogenomic testing may affect the clinical efficacy and safety of warfarin, we do not yet know if pharmacogenomic testing will translate to better health care delivery or better long-term outcomes."
Last year, after reviewing the available evidence, CMS concluded that there was not enough data to support coverage for PGx testing among Medicare beneficiaries receiving warfarin. However, CMS did employ a "coverage with evidence development" plan, under which it would pay for PGx-based warfarin dosing only for Medicare beneficiaries who are part of a prospectively designed, randomized-controlled trial showing pharmacogenomics-guided dosing strategies improve health outcomes over standard dosing methods (PGx Reporter 5/6/09). So far, at least one industry-sponsored study and an academic trial focused on warfarin PGx testing have garnered funding under CMS' CED program.
At the Partners conference this week, presenters and audience members repeatedly discussed the need for clinical utility data supporting the adoption and coverage of personalized medicine products. To this, Lesko asserted that stakeholders need to "stop arguing about clinical utility" from a general population standpoint, and define exactly what evidence is required for personalized medicine products in terms of their value to specific subpopulations of patients.
In that regard, he highlighted an editorial published this week in Clinical Pharmacology and Therapeutics in which he and colleagues from FDA's Office of Clinical Pharmacology assert that "clinical utility" is in the "eyes of the beholder." As a result, the editorial states, the question of whether a test is clinically useful or not will yield a different answer, "depending on the interests and goals of the stakeholder."
In the editorial — part of a special section of the journal dedicated to clinical utility and personalized medicine — the authors suggest that having a "portfolio of acceptable approaches for evidence generation would be the most robust and efficient method for translating biomarker test information (genetic or other types) to the clinic." As such, they argue, the evidence supporting clinical utility of a genomic intervention would come from a range of study designs, not just randomized-controlled trials.
"Achieving consensus on when RCTs are not required, what constitutes overwhelming or mechanistically supportable evidence of clinical utility, and when well-designed observational trials would suffice for establishing clinical utility would advance the field of personalized medicine," the authors write.
Lastly, at the conference, Lesko noted that the agency is thinking about updating drug labeling with PGx data for the platinum-based chemotherapy cisplatin, the xanthine oxidase inhibitor allopurinol, interferon, and the antiviral ribavirin, though he noted that it is not yet certain whether the labels of these drugs would be updated with genomic data.
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