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Q&A: FDA's New Associate Director of Genomics Lays Out Pharmacogenomics Outlook For 2009

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Issam Zineh
Associate Director
of Genomics
Office of Clinical Pharmacology, FDA
The genomics group at the US Food and Drug Administration is facing a busy year of drug relabelings, guidance development, and increasing genetic data submissions with new drug applications, as personalized medicine steadily takes hold throughout the healthcare industry and the public becomes more familiar with the concept of “the right drug for the right patient.”
 
According to Issam Zineh, the new associate director of genomics at FDA’s Office of Clinical Pharmacology, on the horizon in 2009 are several new guidances that will discuss the incorporation of pharmacogenomic information in drug development, as well as strategies for conducting adaptive trials and enrichment studies.
 
After relabeling several marketed drugs, most recently the anticoagulant warfarin and the HIV drug abacavir, with genetic testing information, next year the agency is looking to add new gene-guided dosing information to warfarin’s label and update the label of the anti-platelet agent clopidogrel with genetic risk information (see article, in this issue).
 
In the coming year, the agency plans to continue to expand its interaction with industry to look at genomic data in drug development under the Voluntary Genomic Data Submissions program, which it has more recently begun calling the VXDS program in order to encompass “exploratory” data beyond geonomics. The FDA also plans to issue new educational materials in order to drive adoption of pharmacogenomics through its partnership with the C-Path Institute and the American Medical Association.
 
As the associate director of genomics, Zineh is in charge of coordinating the FDA’s initiatives and identifying the agency’s priority areas in pharmacogenomics. He joined the agency after Felix Frueh, the former associate director of genomics, left to work for Medco Health Solutions earlier this year. Zineh spoke with Pharmacogenomics Reporter about FDA’s priorities in 2009 with regard to pharmacogenomics. Below is an edited transcript of the interview.
 

 
Could you describe the scope of your role at FDA? Are any of these new responsibilities for the associate director for genomics?
 
I was brought on board toward the tail end of October to head up the Genomics Group. The group is made up of regulatory scientists that have a pretty diverse background in terms of their training. Essentially, the group’s charge is to maximize the impact or yield of pharmacogenetics throughout the whole drug development, regulatory, and utilization cycle. That’s our global mission. And we do that through various regulatory, research, educational, and policy activities. My role is to coordinate that group’s activities, as well as identify existing or emerging regulatory or scientific priority areas. Once we identify those areas we deal with those issues in terms of policy and how it relates to FDA, in particularly CDER’s, activities …
 
As far as whether these are new responsibilities, they are pretty much an extension of the responsibilities that Felix Frueh had in 2005. What is different is the landscape in which the group is operating is a lot different today than it was five years ago. So, there are a lot more opportunities for us to be impactful across that continuum.
 
What are some projects in pharmacogenomics you'll be focusing on in 2009?
 
We have a very extensive list of initiatives for 2009 that we’ve actually begun laying the groundwork on. [These initiatives are] laid out on the discovery/development, regulatory, and utilization side. In terms of discovery and development, we plan to expand our VXDS, or the Voluntary Genomic Data Submission Program, as well as the Biomarker Qualification Program. We are also planning to increase the number of end-of-Phase IIa meetings with sponsors. And the point of that is to really try to strategically identify opportunities where our group can be most impactful in terms of contributing to pharmacogenetic studies in later phase clinical trials. 
 
On the regulatory side, in 2009 we’re working with our internal colleagues to identify high-priority areas where, if we consider genomic information, will positively impact NDA approval, and of course labeling.
 
On the utilization side, we’re really actively involved in the relabeling [of marketed drugs]. We do post-marketing surveillance, analyze post-marketing data, [and] conduct critical appraisal of the literature in order to identify labels that need to be addressed in terms of genomic content.
 
So, those are the major activities that we have in mind for 2009. Of course, all of these activities fall beneath our umbrella functions of outreach, communication, education, and policy analysis and development.
 
Just to frame your future activities in terms of something that happened this week: FDA’s Oncologic Drugs Advisory Committee met to discuss clinical trial design issues related to Rx/Dx codevelopment. One of the sponsors presenting at the meeting noted that the company had submitted genomic data for the drug in question initially through the VXDS program. Although the VXDS program has no bearing on NDAs, do you expect that the VXDS program might help sponsors identify Rx/Dx opportunities?
 
I think that maybe the applications that come in through the VXDS program might inform how a company might think about Rx/Dx codevelopment. But as you correctly point out, that’s a scientific apparatus. VXDS was set up … [so] that the FDA can get a handle on the data that industry and academia are generating and analyzing. I think this will remain distinct. I don’t think there will be any regulatory impact for being involved in the VXDS program.
 
Do I think that participants are going to find it useful in terms of gauging how we are thinking about things in terms of science? I think so. But that’s disconnected from regulatory aspects and VXDS is operating under the safe harbor assumption. Now, our Biomarker Qualification Program, that does have regulatory implications. 
 
The FDA has not discussed any intent to regulate consumer genomics firms. Do you plan to engage more with consumer genomics firms in the coming year?
 
So my role, in part, is to identify new trends in the genomics field, undertake specific steps to keep not only the agency informed, but strategically identify how we might be able to generate new information to improve the risk/benefit profile of drugs. There is no question that consumer genomics represents at least a potential opportunity to study those things. It would be great if we could find a way to work with consumer genomics companies to identify genetic signals where people experience adverse events. But, I'm not really sure that is something that can be easily done. I'm not the only one wondering about the feasibility. 
 
What we’re doing now is pretty much having discussions with some of these companies to determine if that kind of collaboration in feasible and if that kind of analyses can be performed in line with the FDA’s public health mission. These companies weren’t set up to specifically look at drug data. That’s been the limitation to date. If we can figure out somehow if the infrastructure can help us ask and answer those questions, we’d certainly be interested in working with those folks.
There are several guidances that are stalled at the FDA, such as the ones
for Rx/Dx co-development and the IVDMIA final guidance. What is holding
these guidances up? Is there a timeline for when they will be released?
 
 
The only guidance I can really comment on is the Clinical Pharmacogenetics Guidance. I haven’t been directly involved with the Rx/Dx codevelopment and the IVDMIA guidance. These guidances don’t fall within the purview of the [genomics group] …
 
What our group has been involved in is the Clinical Pharmacogenetics Guidance. The specifics of that concept paper were presented at the Pharmaceutical Science Advisory Committee meeting in March. The aim of that guidance is to address some of the issues related to strategically using pharmacogenetic information for drug development, the design of clinical pharmacogenetic studies, and what the impact on the label would be. So, that guidance is in the works.
 
When could we expect to see that draft guidance?
 
That’s still in the drafting process …
 
One of the things I’ve heard Lawrence Lesko [Director of the Office of Clinical Pharmacology] speak out about at various conferences is the need for alternative trial designs, beyond the prospectively designed randomized controlled trials, in order for pharmacogenomics to advance. Will you be issuing guidances that will discuss some of the alternative strategies that companies can take?
 
There will be two different guidances, one on enrichment designs and one on enrichment strategies. There’s a working group being led by Robert O’Neill, who is the director of the Office of Biostatistics, looking at issues surrounding adaptive design. In the new year, there will be heavy work from a group involved in the guidance on enrichment designs.
 
I’m not one-hundred percent sure where we are in that process because of when I’m coming into the process. My group will continue to work with people to assess the safety and efficacy data for drugs that are already approved. So, we’re working across the whole spectrum of development and use of medications that are already out on the market.
One big challenge for laboratory developed tests is meeting the different
evidentiary requirements to garner marketing approval from the FDA and
reimbursement from the Centers of Medicare and Medicaid Services. Will there be any effort to bring the evidentiary requirements for CMS and FDA closer together?
 
Here’s the challenge I see with aligning FDA’s evidentiary standards with something like a CMS or a payor. We have different mandates. FDA’s mandate is to evaluate the science, identify the groups that are most likely to respond, pretty much maximize clinical benefit and minimize harm. Payors also have that on their minds, but the complicating factor in that equation is the dollar sign. It’s really tough to come to consensus about what CMS or a third-party payor might need in terms of them paying for a test and what we would need to consider the test useful.
 
That’s not to say that we’re not communicating. Our group is not directly in contact with CMS, although we’re trying to figure out the best ways to have those conversations. We are in conversations with our counterparts at the [Agency for Healthcare Research and Quality] in trying to identify areas for alignment. We need to identify what our evidentiary standards are and then figure out areas for alignment from there.
 
C-Path Institute in collaboration with the FDA released some educational materials for doctors on genetic testing to dose warfarin. Are you planning on issuing similar educational materials on other topics?
 
We worked with the C-Path Institute, the Arizona [Center for Education and Research on Therapeutics] and the American Medical Association to release those educational materials on the warfarin genetic testing. And we are working on additional opportunities through the same mechanism, with C-Path, AMA, Arizona CERT, and also the AHRQ. We are developing these materials not only to educate but also to facilitate pharmacogenomics in the medical community. [With regard to driving adoption] the educational effort is one piece, the relabeling effort is another piece, and then third is working with outside stakeholders to identify areas of improvement.
 
We have a contract with Medco, for instance, to study physician uptake of pharmacogenomics in the clinical setting, as well as to study what impact pharmacogenetic testing has on clinical practice. So, I would put all these under our educational/translational initiatives.
 
When are you planning on releasing this data you will generate with Medco?
 
The point of this collaboration is to disseminate the information and work collaboratively with Medco and others to identify the barrier to uptake of pharmacogenomics. If pharmacogenetic tests are impacting practice then we need to get that information out there. So, this information will come out in a series of publications in the peer-reviewed literature. Right now we’re in the process of generating that data. … I would comfortably say that within the next 12 months we would have data we could disseminate. There are dedicated individuals on Medco’s side, and there are people on our side who are making this pretty much their top priority.
Can you give us a heads up on the drugs you are looking to relabel with genetic testing information, since that’s a high priority of your group?
 
If you look back on the group over the last five years, I think one of the most impactful things the group has done has been to relabel drugs that have already been approved in terms of trying to identify genetic contribution to variability of response. The two biggies we’re looking at right now are warfarin and clopidogrel. Having relabeled warfarin in the past, we’re looking at new evidence on genotype-guided dosing and warfarin, but we haven’t really made any conclusions about that yet. But that’s ongoing. 
 
Also, there have been recent reports on certain drug interactions with clopidogrel, or [Bristol-Myers Squibb/Sanofi-Aventis’] Plavix, a commonly prescribed anti-platelet medication. Any time we see drug interactions we automatically think of the potential for polymorphisms and drug metabolizing enzymes to play a role. We’re looking at the data on whether or not certain drug metabolizing enzyme polymorphisms contribute to clopidogrel resistance.
 
Other than those two drugs, we’re always looking with colleagues in and outside of FDA to identify drugs for which a relabel could be warranted.

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