Recently, an FDA panel recommended that manufacturers of the anticlotting drug warfarin include new labeling that calls for genetic screening to assess a patient’s risk for adverse reactions to the medication. This regulatory move, in addition to the agency’s current work on new application guidelines for joint approval of a drug and related genetic test, is causing some in the clinical laboratory community to declare that the age of personalized medicine has finally begun. This issue of Strategies examines these recent developments and their impact on the future of genetic testing.
Last November, the FDA’s Clinical Pharmacology Subcommittee of the Advisory Committee on Pharmaceutical Science recommended that patients who need warfarin therapy undergo a test to identify genetic variations of the liver cytochrome enzymes CYP2C9 and VKORC1 before taking the anti-clotting drug. The recommendation, which proposed including language on the drug label, was based on the discovery that these two markers provide important dosage information for warfarin and that variations in these genes can alter how patients metabolize the anticoagulant. Produced in generic form and by Bristol-Myers Squibb (Princeton, N.J.) under the brand name Coumadin, incorrect doses of warfarin carry serious risks for patients: too high a dose can cause internal bleeding, but too low a dose can cause blood clots.
Although the labeling change is currently a recommendation, it’s likely that implementation will occur in the near future. “The committee voted 8-2 to update the label of warfarin to include new information to guide the selection of doses during the induction phase in individual patients, along with the traditional patient factors such as age, gender, co-administered drugs, etc.,” explained Lawrence Lesko, PhD, FCP, Director of FDA’s Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research. “FDA is going to move forward to implement. In doing so, there are steps that the agency must follow, including concurrence from the therapeutic area medical staff at the FDA, proposed appropriate language for the label, assurance of test availability, and discussion with sponsors who make the products. My estimated timeline [for implementation] is six months.” The agency is also look at drug-diagnostic co-development regulations. In April 2005, FDA officials released a draft guidance for industry on submitting joint drug and genetic testing applications, but it’s uncertain when the final guidance will be released, said Steven Gutman, MD, Director of FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety, Center for Devices and Radiological Health.
Shortly after this recommendation was announced, Mayo Clinic (Rochester, Minn) released their version of a similar pharmacogenomic test for the drug irinotecan that is used to treat colon and rectal cancers. This genetic test looks for variations in the enzyme UGT1A1 that increase the risk of a toxic reaction to the drug. Third Wave Technologies (Madison, Wis.) also received clearance from the FDA in August 2005 for their version of the test, which is available under a sublicense from Mayo.
While early adopters see this as the beginning of the pharmacogenomic era, most clinical lab directors may take a wait-and-see approach. “I think the clinical laboratory community is a little bit slow to adopt pharmacogenomics because of the high cost to enter the field,” said Alan H.B. Wu, PhD, Chief of Clinical Chemistry and Toxicology at San Francisco General Hospital and Professor of Laboratory Medicine, University of California, San Francisco, adding that he thought the clearance of the UGT1A1 test might have influenced the FDA subcommittee to issue the warfarin labeling recommendation. “The irinotecan drug is not as widely used as warfarin, with regards to the number of patients who would be involved. I think if that didn’t happen, then warfarin wouldn’t have happened either.”
Drug manufacturers are likely to be unhappy with the warfarin labeling recommendation, said Wu. The pharmaceutical industry seems to view any testing recommendations as an impediment to physicians who are not accustomed to testing before prescribing. In addition, the labeling might stimulate the adoption of the next generation of anticoagulant drugs. “These have never really done well,” Wu explained, adding that newer anticoagulants are more expensive, even though they are considered safer. “What I’m hoping is that this will accelerate clinical laboratories to get into the pharmacogenomic realm, not just for this drug, but for other drugs as well.”
Preparing for the Demand
These recent regulatory actions emphasize that the application of pharmacogenomic genotyping to specific therapeutics is ready to take off. “Laboratories will need to decide if they are going to perform testing in-house or send these out to more experienced labs,” explained Gregory J. Tsongalis, PhD, Director, Molecular Pathology and Associate Professor of Pathology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center (Lebanon, N.H.), adding that while there are numerous types of genotyping technologies available to labs, the challenge lies in analyzing the outcome data. “As with many types of genetic tests, the interpretation and dissemination of results as well as education of the providers will be critical.”
The FDA’s warfarin labeling recommendation should prompt lab directors to keep a close eye on the current technologies and those that may become available in the next year, advised Tsongalis. Look for companies to move to more simplified, user-friendly platforms that could make this type of genotyping easier on the technical end for many labs to run, he added. To help labs at all stages of pharmacogenomic implementation, the National Association of Clinical Biochemistry is currently working on proposed guidelines/recommendations for labs who want to get into genetic testing.
Call for CLIA Oversight
In order for pharmacogenomic testing to become widespread, regulatory reform in the area of genetic testing needs to accelerate. While these recent actions by the FDA are encouraging, Wu and many other clinical laboratorians continue to be frustrated with the sluggish rate at which the agency is embracing genetic testing.
“It’s slowing the adoption of tests,” said Wu. “Everything we do in the clinical lab is in response to something else—we don’t just create tests and hope people order them. There has to be a need and a demand and that has to come from the clinical side. I think that some of the things that have happened in the last few months will stimulate physicians to demand these tests because it’s going to be part of labeling. But other people have to get into the game, such as CMS. Certainly the in vitro diagnostic companies have to step up and start producing equipment and procedures and get them approved, so we can start using them in the laboratory.”
One proposed regulatory approach is to create a special category for genetic testing under CMS’ Clinical Laboratory Improvement Amendments (CLIA) of 1988, which govern U.S. clinical labs. In late November, the Genetics & Public Policy Center (GPPC) issued a letter to CMS Administrator Mark McClellan, asking him to assure the safety and accuracy of genetic testing by creating a subspecialty under CLIA. GPPC was established in 2002 by The Pew Charitable Trusts through the Johns Hopkins University. At press time, GPPC officials had not received any reaction from McClellan.
“For over a decade, government advisory committees have been saying that genetic testing is going to take off, and we need to make sure our oversight system is up to the challenge,” according to GPPC Policy Analyst Gail H. Javitt, J.D., M.P.H. “There’s been lots of recommendations, but nothing has happened..”
For more information:
The FDA’s Drug-Diagnostic Co-Development Concept Paper is available online: www.fda.gov/cder/genomics/pharmacoconceptfn.pdf
Julie McDowell is the Editor of Strategies. She can be reached by email.