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FDA Top Officials Discuss Ongoing Efforts to Bring Agency Into Genomics Era

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By Turna Ray

From the outside, it may seem that while the US Food and Drug Administration often talks about the promise of personalized medicine, the agency is slow to act when it comes to issuing regulatory policies critical to advancing the discipline. However, two FDA officials last week tried to dispel that notion by highlighting the agency's ongoing efforts to personalize healthcare by improving internal expertise in pharmacogenetics, increasing its focus on regulatory sceince, and launching a new group to coordinate its drug and diagnostics divisions’ application reviews for Rx/Dx combination products.

Issam Zineh, associate director for genomics at the Office of Clinical Pharmacology, and Elizabeth Mansfield, director of personalized medicine at the Office of In Vitro Diagnostic Evaluation, spoke at a symposium this week on the agency's personalized medicine efforts at FDA's Center for Drug Evaluation and Research and the Center for Devices and Radiological Health, respectively.

At the symposium, hosted for science writers by the FDA at its facilities in White Oak, Md., Zineh discussed CDER’s challenge to balance risk and benefit of personalized medicine against the backdrop of rapidly evolving evidentiary standards and efforts to improve the genomics knowledge within the division. Mansfield detailed efforts within OIVD's new personalized-medicine group, launched in June, to translate genomics research into clinical practice and to guide Rx/Dx product reviews between the drug and diagnostics divisions.

"The process of approving and not approving drugs is a process where we always rely on imperfect information," Zineh said at the symposium. "When people ask why it takes so long to translate some of these personalized medicine interventions into the clinic, I think part of the answer is this conundrum of evidence where people have different criteria for what is considered robust enough for a clinical update."

According to Zineh, FDA's drug division is working on advancing several new guidance documents, including regulations for adaptive design and enrichment, premarket application of pharmacogenetics research methodologies, and a biomarker qualifications process guidance that "hopefully will be up for clearance by the end of the year."

Since the FDA released a white paper on Rx/Dx co-development in 2005, the agency has discussed its intent to issue guidance on the topic but has not yet done so. In an effort to make progress on the stalled guidance, the FDA last year formed a multi-center, multi-disciplinary working group to discuss potential guidelines for Rx/Dx co-development.

Additionally, ahead of issuing the guidance, CDER Director Janet Woodcock has previously said the agency plans to issue additional white papers on Rx/Dx co-development topics to outline the most up-to-date knowledge on the subject [see PGx Reporter 04-22-2009].

FDA’s position was also underscored this week during a conference on personalized medicine in San Francisco hosted by Burrill & Co. There, FDA Commissioner Margaret Hamburg said the agency is in a period of transition and change. Although Hamburg acknowledged that she didn’t “have a comprehensive answer” for how to accelerate the agency's “path to the future,” she noted that updating the its regulatory science procedures will be priority in order to translate genomics discoveries into targeted treatments and diagnostics.

CDER's Knowledge Expansion

At the White Oak conference, Zineh described the work of CDER reviewers as a “constant struggle” of risk-benefit assessment. “As regulators we have to be conservative, on the other hand we are also scientists that are charged with really being innovative about patient care,” he said. “So, there is this constant struggle that manifests when we're talking about evidentiary standards.”

To illustrate this challenge, Zineh cited the controversy around whether genetic testing for the blood thinner Plavix should be broadly marketed, and highlighted the protracted regulatory process in the US to recommend KRAS mutation testing prior to administering certain colorectal cancer drugs.

A few months after the FDA required Bristol-Myers Squibb to change the label of its drug to include pharmacogenomic information, Quest Diagnostics began offering CYP2C19 testing at a Scripps Health hospital. Since there are pending studies that will further inform PGx-guided dosing for Plavix, some criticized Quest for prematurely marketing the test [see PGx Reporter 10-28-2009].

Supporting Quest's decision is Eric Topol, chief academic officer of Scripps Health and a prominent cardiologist, who was quoted in HeartWire as saying, “To say we need to wait for more studies is backward thinking. That kind of thinking is what holds up progress in medicine.”

Another notable FDA action that illustrated the agency’s dichotomy as a regulatory and scientific agency was when it recommended that colorectal cancer patients with KRAS mutations should not receive EGFR-inhibiting monoclonal antibodies, such as Erbitux and Vectibix.

However, while the FDA struggled with the decision to use retrospective data to update drug labeling in this instance, the agency was criticized for lagging behind advancing regulatory science, particularly since European regulators had made their recommendation and US professional organizations had updated treatment guidelines [see PGx Reporter 07-22-2009].

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“It illustrates the point about evidence, and how do we deal with making some call about risk-benefit when the evidence comes, let's say, from retrospective analysis,” Zineh noted at the conference. “How confident can we be as a public health agency in making these recommendations or updating labels? … The answer to the question depends on whether we're talking about efficacy, whether we're talking about safety, rare adverse events, or common adverse events.”

CDER has also been trying to improve its internal knowledge and comfort level with reviewing genomics data in drug applications. This is particularly necessary, as more and more new drug applications are coming in with pharmacogenetic analysis on subpopulations.

According to Zineh, since 2008 submissions to the FDA’s Voluntary Exploratory Data Submissions program has grown 250 percent. The FDA launched the program several years ago to encourage sponsors to share genomics data with the agency without any regulatory repercussions [see PGx Reporter 11-29-2006].

Zineh suggested that as a result of the VXDS program, the comfort level has grown among FDA reviewers and within industry in handling genomics analyses, as evidenced by the increasing numbers of drug applications incorporating such data. In order to handle greater numbers of drug applications with genomics underpinnings, CDER “is working on synthesizing [its] personalized medicine experience to be able to develop more infrastructure and more streamlined regulatory review processes, and be more impactful in development,” Zineh said.

Changing Attitudes at CDER

However, in order for the agency to feel comfortable reviewing personalized medicine products, it seems the FDA needs to dispel a prevailing skepticism about genomics at the agency, as well as get up to speed on the rapidly evolving science around pharmacogenomically guided treatments.

Based on internal surveys, Zineh noted that there are “a few visionaries” among the top ranking officials, such as Woodcock and CDER’s Office of Clinical Pharmacology Director Lawrence Lesko, but “most of the people at CDER are sitting on the fence, needing more experience with pharmacogenetics and regulatory review processes.”

Zineh estimates that around 5 percent of those at CDER are “functional resisters” and “devil’s advocates, who force us to articulate the value of the things that we are doing.” Then there are the 5 percent of “non-functional resisters, who are not going to buy into this stuff no matter what.”

“Remember we get paid to be pessimistic at FDA,” Zineh said. “We have to be ultra-conservative because of the ramifications of getting it wrong.”

At the Burrill conference this week, Leroy Hood, president of the Institute for Systems Biology, echoed that refrain. Hood, who last year was part of an Institutes of Medicine committee to review FDA’s functions, noted that while high-level officials at the agency are forward thinking, at the lower levels are “leftovers from drug companies who have very rigid views about drug development.”

“The way to deal with FDA is with overwhelming success,” Hood said, giving advice to conference participants who wanted to know the best way to push through more Rx/Dx combination product approvals.

According to Zineh, there is a concerted effort at the FDA to “get more people off the fence” when it comes to personalized medicine by filling in some of the “science gaps” about the discipline.

Some of these science gaps will be filled slowly as FDA researchers, who have received NIH funding to study pharmacogenetics questions, report their findings. Also, FDA is working with advisory committees and consortia, such as the International Serious Adverse Events Consortium, to learn more about the genetic underpinnings of drug response, Zineh noted.

From a regulatory standpoint, FDA is working on aligning its drug/diagnostic review infrastructure.

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“We're working very hard to build bridges between all the disciplines — clinical pharmatox, clinical pharmacology, statistics — involved in the interdisciplinary 21st Century review process and modernize it,” Zineh said. “So, if there is biomarker data or genetic or genomic data, then we can get in on it early and really provide meaningful review of the implications of those data and say something about risk-benefit."

CDRH Gets Personal

On the device side, similar efforts are being undertaken to improve internal expertise on genomics and coordinate review activities to handle Rx/Dx products.

"The process isn’t changing so much on the device side in terms of evidence and so on, but we do need to have the regulatory processes improved,” Mansfield said at the conference in Maryland last week.

In order to improve the device division‘s comfort level with genetic tests and companion diagnostics, FDA obtained funding to set up a new personalized medicine group within OIVD, which began operations in June. In addition to Mansfield, there are two associate directors in this group, Zivana Tezak and Marina Kondratovich.

Tezak, the personalized medicine group’s science and technology associate director, said she has been collaborating with the NCI through the inter-agency oncology task force to enable a process of translation of high-content proteomic markers into clinical use. The NCI/FDA effort aims to introduce NIH researchers to FDA's regulatory process and educate FDA reviewers on new genetics devices in research.

Kondratovic, a statistician, is working on analytical validation issues for complex devices that require new approaches.

The agency’s regulatory stance on certain multiplex predictive tests is currently uncertain. After issuing two draft guidelines on its intent to regulate in vitro diagnostic multivariate index assays, the FDA may be reassessing its regulatory approach toward this subset of complex laboratory-developed tests, historically overseen by the Centers of Medicare & Medicaid Services [see PGx Reporter 08-12-2009].

Additionally, there are around eight reviewers with specific expertise in personalized medicine spread throughout FDA's review divisions. These experts “provide input when required, such as Rx/Dx applications,” Mansfield said.

One of the main responsibilities for Mansfield’s group is to facilitate areas of collaboration between the agency’s drug and device divisions, which before the advent of Rx/Dx combination products worked fairly independently. Mansfield characterized it as a “learning process.”

"Where a single submission comes in for a drug, and [has] a test imbedded in it, we [at CDER and CDRH] have to learn how to work together, where my group will look at the test side, where the drug reviewers will look at the drug side and we will all come to the conclusion at the same time,” Mansfield said.

Lastly, CDRH’s personalized medicine group is also planning educational activities to communicate to the public about FDA's regulatory thinking and on personalized medicine

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