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FDA Says PGx Guidance Document Should be Released by End of Summer


By the end of the summer, drug developers and researchers will have a roadmap document with instructions on how they might voluntarily share genomic data with the US Food and Drug Administration as part of the drug approval process.

“We are currently in the final stages of revising the guidance and are looking to complete it by the end of July,” Larry Lesko, director of the office of clinical pharmacology and biopharmaceutics at the FDA’s Center for Drug Evaluation and Research, told BioArray News last week.

For the microarray industry, this guidance document, “Guidance for Industry: Pharmacogenomics Data Submissions,” will focus on getting gene-expression data considered in the drug approval process, but will not provide any sort of definitive answer to the big question about this rapidly evolving clinical research tool: How can microarray-generated data be considered accurate and reproducible enough to confidently provide answers to life-or-death questions in medicine?

“We are not telling companies how to do microarrays,” Lesko said. “We haven’t been specific because it is an evolving field. What we have basically said is that we are creating a brand new pathway for sponsors who wish to submit genomic data voluntarily to the FDA.”

The guidance does nothing to impose any kind of standards on data produced by this technology.

“Some data is routine these days — for example, the cytochrome enzyme genomics,” Lesko said. “What is a little more complicated is the microarray data where there are questions about things like the platform used, the interpretation of the data and the absence of known mechanisms, and reproducibility,” he said.

“We will work through that,” he said.

“We have no standards for this data at the current time and we actually like it that way,” he said. “The moment you put standards on something, you begin to stifle innovation and research. You don’t want to do that in a field that is in its infancy. We have kept that issue on the sidelines — for the time being.”

At some point, the FDA no doubt will have enough information and expertise to delineate exactly what genomic data it will consider and how it will be handled in the drug-approval process. This guidance provides an alternative and a carrot for companies to engage in genomic microarray analysis, Lesko said.

“What we are trying to do is encourage the companies to use the tool in drug development in an exploratory fashion, and when you get the results, discuss them with the FDA in the spirit of sharing information and identifying the issues that need to be discussed before genomics becomes a requirement in a submission,” he said.

The Guidance

The guidance document is in the final stages of revision by the agency’s genomics working group with an end-of-July target date for completion, said Lesko. After that, the document will go through a review process before it is released as an agency guidance.

‘We can’t predict that time frame because we don’t control it, but we are hoping it would be out this summer,” Lesko said.

Once released, the document is offered as a framework, but not as a mandate.

“A guidance represents the best thinking of the agency on a given topic; usually the topic is evolving, and one where there is uncertainty,” said Lesko. “The value of the guidance is that it is basically what the agency thinks is acceptable: it gives the industry some parameters in which to work, but it’s not binding.”

Those that don’t follow a guidance will have to answer to the agency’s questions of “Why not?”

“We would like to know why they went with an alternative,” Lesko said. “If a company doesn’t have a good reason, sometimes that’s not good. The guidance allows companies to do alternatives — if there is a good reason.”

But following the guidance allows the company to engage the FDA in a dialogue over the data voluntarily submitted.

“That will generally lead to a meeting with the company and the agency in which a company can discuss their technology, their applications,” he said. “It would be a time to educate the FDA and get questions on the table resolved.”

The Data

Some companies have already begun to voluntarily submit data and the agency is scheduling meetings with others to discuss this data, Lesko said.

The agency is preparing to schedule meetings with others in the next couple of months, Lesko said.

“We expect that in the early phases of this that [voluntarily submitted] data will tend to be more from early clinical development or perhaps even preclinical information,” Lesko said.

Vetting The Comments

In getting to the point of release of the document, the agency convened two workshops, starting with one in the Spring of 2002, followed by a two-day session in Washington, DC, in November (see BAN 11/19/2003) just after the guidance was released in draft form to start a 90-day comment period, which ended on Feb. 2, 2004.

In the comment period, Lesko said the FDA received 45 different sets of comments, some of which can be viewed on the FDA website. (Click here to view the documents in PDF format).

“The guidance document, in and of itself, will not address all of the questions that were raised in the public comment period,” said Lesko. “My overall sense is that we have answered the questions that industry has asked, to the extent that we can.”

The Guidance

Industry has expressed concern over whether voluntarily submitted microarray data is to be used by FDA in regulatory drug approval decisions. But Lesko said that will not happen.

“The first operating principle is going to be that the data will not be used for making regulatory decisions,” said Lesko. “The [manual] will describe how we will set up to assure that we keep the voluntary separate from the required data.”

When released, the guidance will consist of three documents, the guidance itself and two companion documents with standard operating procedures. The first manual will describe the process for voluntary submission and how the agency will handle it and review it, and the second will be the manual that describes the mission, goals, and objectives for the Interdisciplinary Pharmacogenomics Review Group, which will handle the data for the agency. The group will be led by Felix Frueh (see lab report, page 7), and two new hires, senior scientists who will onboard by the end of the summer, Lesko said.

The agency has already hired a second person for the review group, an unidentified but “extremely talented senior person from the pharmaceutical industry,” Lesko said. The agency will also hire a third person who will split his or her time between the pharmacogenomics review group and the agency’s oncology review group.

“We believe that so much of the genomic activity will be in the oncology area, so we want to have some link between [oncology and IPRG] as we review what is going on in the genomics field,” he said.

The new positions were approved by former FDA Commissioner Mark McClellan, who now leads the US Centers for Medicare and Medicaid Services, and by Janet Woodcock, who was then director of the center, and is now working as acting deputy commissioner of the agency.

Lesko said the FDA would consider adding to the group, with new hires depending on the number of submissions received.


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