By Turna Ray
BETHESDA, Md. — Janet Woodcock, drug division head at the US Food and Drug Administration, this week expressed cautious optimism for the future of personalized drug development, noting that "we may be out of the general skepticism phase, but we're in the long slog phase."
Speaking at a conference here this week hosted by the FDA and the Drug Information Association, Woodcock said she's hopeful that tailored therapeutics will be "a big part of the future," but demurred from speculating on whether the agency's recent approval of two drug/diagnostic combination products is a sign that genomically targeted treatments will soon be a mainstay of healthcare.
Woodcock instead focused on how the agency is addressing the challenges facing drug and diagnostic companies looking to develop personalized therapies — hurdles that include identifying valid biomarkers; developing companion tests in concert with drugs; and investigating multiple markers, tests, and combination drugs through new clinical trial approaches.
In August, the FDA approved two personalized oncology drugs — Roche/Plexxikon's melanoma drug Zelboraf and Pfizer's non-small cell lung cancer treatment Xalkori — along with companion tests intended to select their respective genomically targeted patient populations (PGx Reporter 9/7/2011). The agency approved these Rx/Dx combination products well ahead of its projected review time lines, presenting the first successful examples of personalized medicine codevelopment since the simultaneous approval in 1998 of Genentech's breast cancer drug Herceptin and the companion HER2 test developed by Dako.
Xalkori and Zelboraf "were developed and approved very rapidly, compared to most other cancer drugs that have come along in the last decade. And they really do illustrate the promise of the tailored approach to cancer interventions," Woodcock said. "Now the question before us really is, 'Are the programs before us two more isolated examples or do these represent the cutting edge of a trend?' I don't think we know yet, but we can keep our fingers crossed."
Woodcock recalled the environment a decade ago when industry wasn't too keen to embark on personalized medicine strategies, since identifying valid gene markers for drug development often meant pooling resources with others in industry and getting input from the FDA. Although arriving at valid biomarkers is still a challenging process, industry has become increasingly open to sharing what it knows and getting help when it lacks expertise.
As director of FDA's Center for Drug Evaluation and Research and previously the agency's deputy commissioner, Woodcock has led efforts to increase industry's comfort level in this regard by fostering public-private partnerships such as the International Serious Adverse Events Consortium and establishing a safe-harbor data-sharing effort called the Voluntary Exploratory Data Submissions program. These projects are steadily yielding data that may lead to new personalized medicine interventions.
For example, "much of the discussions" through the VXDS program have "moved from the voluntary discussion phase to the regulatory process," Woodcock said. "As [sponsors] understand genetic data better and are able to validate their assays, so they're moving into the regulatory process and actively pursuing targeted therapies." In 2010, the genomics group in FDA's Office of Clinical Pharmacology reviewed 18 biologics license applications, 54 new drug applications, and 138 investigational new drug applications containing genetic data.
The FDA in recent months has responded to the influx of genetic data in regulatory submissions by issuing a number of guidance documents that lay out the emerging principles that drug and diagnostic firms should follow when developing personalized treatments.
In July, the agency released a draft guidance on the development of companion diagnostics, in which it recommends that such tests have FDA approval (PGx Reporter 7/13/2011). "We'd like to see them approved," Woodcock said, acknowledging that there are exceptions, such as in the case of a life threatening disease, when the agency will allow the marketing of a laboratory-developed test while a companion test is being reviewed.
But even before drug developers can determine that their treatments need to be developed with a companion test, they need to identify validated biomarkers associated with treatment response, metabolism, or adverse reactions. Although "the heart of a tailored therapeutic" is a companion test that discerns which patients will receive the drug, the "major barrier" to personalized medicine, as Woodcock sees it, is "coming up with the right diagnostics."
The reason for this problem is the dearth of valid biomarkers linked to disease prognosis and drug response. Based on conversations Woodcock has had with genomics researchers, she estimated that as much as 75 percent of published biomarker associations are not replicable. "This poses a huge challenge for industry in biomarker identification and diagnostics development," she said.
To address this, the FDA in August issued a guidance outlining how industry can "qualify" biomarkers used in drug development clinical trials. "We have set up a process whereby any party can submit evidence on a new biomarker, a patient-reported outcome measure, or a drug development tool to the agency, and we will give advice and comment," Woodcock said, calling the guidance a "landmark" in drug regulation. "Once [the biomarker] is ready for use in prime time … we will issue a qualification letter stating that this tool will be accepted for this use."
Sponsors with companion diagnostics already under regulatory review at FDA's device division and for which the biomarkers of interest are validated as part of a drug trial may not need to qualify biomarkers, but the process may be useful if a marker is broadly used across a group of therapies, Woodcock noted.
The biomarker qualification process will also demonstrate the level of work needed to qualify drug development tools, which, according to Woodcock, is often underestimated. "I think this will also be good for folks ... to actually see what is needed to prepare a test of some kind or some other tool for actual robust use in clinical trials," Woodcock reflected. "I think it's coming as a shock, but I think it's good for everyone to realize that there is additional work besides just publishing a paper in the literature."
Another challenge for developers of targeted treatments, particularly in oncology, is that these drugs often yield a robust response initially by homing in on a particular pathway, but the disease eventually recurs via others pathways and mechanisms. To help industry with this challenge, the FDA last year released guidelines for how to simultaneously develop two or more investigational drugs as a combination regimen for a particular disease.
For example, clinical trials for Xalkori and Zelboraf showed that although patients treated with these drugs experienced several months without disease progression, many patients became treatment resistant and eventually their diseases returned. The drug developers are investigating additional biomarkers and combination strategies to tackle resistance and relapse with these personalized treatments.
"For effective therapies for many of these conditions we're going to have to have combinations intervening at the [same time] to get the whole range of pathways the disease could drive," Woodcock said.
Finally, Woodcock highlighted the value of adaptive clinical trials as a way to identify biomarker and drug candidate leads for further exploration. High-profile adaptive clinical trials investigating genomically guided treatment strategies, such as BATTLE in lung cancer and I-SPY2 in breast cancer, may not be enough in and of themselves to gain approval for a drug but they are efficient screening tools for matching drugs to companion tests, she said.
Such adaptive screening trials may provide a path toward individualized drug approval. If researchers identify a promising drug for a subgroup with the adaptive design, the next step could be to move into a larger "spin-off trial" that has already been set up. The sponsor could enroll patients in this second trial in a randomized fashion in one arm, exposing them to the new drug/test combination and pursuing the same endpoint as in the adaptive trial.
Although FDA has made some progress in addressing the industry's personalized drug development challenges, there are still plenty of issues for the agency to work out and many hurdles ahead for drug and test makers.
"We're going to go through a tough period over the next 10 years," she acknowledged. "We're going to have some brilliant successes, but probably a bunch of inexplicable failures as well."
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