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In Second Boost for PGx, FDA Plans to Print Draft Guidance for Array Data Used in INDs


In a second major milestone intended to clear a regulatory path for pharmacogenomics, the US Food and Drug Administration will publish a draft guidance in August outlining how microarray-derived data can be used in the drug approval process, according to an agency official.

The announcement, which comes seven weeks after the agency released a draft guidance for submitting gene-expression data for multi-analyte-based diagnostic products, represents the first formal step the FDA has taken to eventually instruct industry on how to submit these data for therapeutic products.

“This is about getting innovative science to the bedside,” Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, announced this week at a one-day meeting of the pharmacology and toxicology subcommittee of the advisory committee for pharmaceutical science. “We need an approach that will enable the free exchange of information, [and] help advance the science and technology and the timely development of appropriate regulatory policies.”

Though Woodcock emphasized that genomic information is only a piece of the puzzle that may lead to safer and more efficacious drugs, she stressed that those data are the bottom of the drug-development pyramid. “If we can pull this off, we will move from an empirical process to a mechanism-based process that is hypothesis-driven, and have more effective, less toxic drugs for a smaller population.

“The potential is tremendous, but the question is just how soon [this potential will be met], and how many bumps in the road will there be?” she said.

The meeting, held at CDER’s Rockville, Md., offices on June 10, served as a backgrounder for the 13-member subcommittee (see agenda here: The subcommittee, which serves in an advisory role and provides recommendations on FDA regulatory issues, is overseen by Meryl Karol, a professor of occupational and environmental health at the University of Pittsburgh, and includes John Quackenbush, a microarray data analyst at the Institute for Genomic Research; representatives from Affymetrix and Agilent; and FDA employees.

At the meeting, the committee heard three questions and discussed comments about how proactive CDER should be in enabling the submission of genomic data into nonclinical, or research, phases of drug development. The group also plans to clarify how results from microarray experiments should be submitted, and how the agency would likely use the data.

In addition, the subcommittee is expected to consider concerns about the reproducibility of gene-expression data across labs, platforms, and technologies, and the question of whether CDER should recommend a single common data-processing protocol and statistical-analysis technique for each platform.

Finally, the subcommittee will consider whether the FDA should develop an internal database to capture gene-expression and phenotypic outcome data from nonclinical studies to enhance its knowledge. The subcommittee’s responses will appear in the draft guidance due in August.

The draft, however, is itself a preliminary step that leads to a comment period, a workshop, and then, sometime in the fall, an actual guidance document. That document will detail a process wherein genomic data derived from microarray analysis can be shared with and evaluated by the agency in a track outside the traditional drug approval process, creating a “safe harbor” for this data.

This measure is meant to facilitate data collection from an industry that has adopted the tools of microarray analysis but is loathe to share the data with regulators without having some assurance that the data won’t reappear to stifle the drug-approval process.

“We need to ... get this [issue] settled,” said Woodcock, referring to the FDA’s pharmacogenomics initiative during a talk at the 6th annual Pharmacogenetics and Medicine Lectures at Yale University in late April.

Regulatory Riddles

Microarray analysis has made its way into the biopharma industry’s R&D processes, and many contend it is poised to play a significant role in pharmacogenomics. Thus far, however, the FDA has yet to formulate a conceptual formulation for the regulation of this technology.

For gene-expression researchers, the question at the center of this discussion is how the FDA will formulate a policy that guides formatting, content, and submission guidelines for microarray data generated during nonclinical pharmacology and toxicology studies.

The FDA currently requires that any research done under an Investigational New Drug application be reported to the agency. So far, agency officials say very little data derived from microarray analysis have been submitted through this channel. Moreover, agency officials said that it is impossible to make comparisons among the data that have been submitted due to the multiplicity of platforms being used and the methodologies of statistical analysis across the discipline.

Confounding this agenda is the fact that pharma has traditionally been leery about showing the FDA its early-stage array-based data. In large part, drug makers fret that showing the FDA exploratory genotyping or gene-expression data will spur the agency to demand additional costly trials — which is anathema to pharmacogenomics.

“Industry is afraid we will over-interpret these data in a way that will be harmful for drug development or it will slow down their drug development,” Woodcock said at Yale (see SNPtech Reporter, May 2, 2003).

Some large drug makers have expressed these concerns. For example, Pfizer, which commands 11 percent of the world’s market for prescription drugs and will spend close to $7 billion on R&D this year, said it opts out of submitting certain early-stage data. Bruce Littman, executive director of clinical sciences at Pfizer’s global R&D unit, admitted at the Yale conference that Pfizer actively shies away from submitting early-stage toxicology data for fear that some of the data, like those that depict activated proto-oncogenes, may be used against it down the road.

Woodcock stressed that this concern is unfounded, and said she hopes the impending guidance will adjust pharma’s perception: Early-stage gene-expression studies in many drugs will activate proto-oncogenes, she explained.

“We need to reassure the industry and make them feel very comfortable that we’re not going to therefore use that information in our decisionmaking about their product,” Woodcock said. “We’re on the horns of a dilemma here, and there will be some degree of trust established,” she added. “It seems that the time is right now.”

Pharma insiders remain optimistic that the meeting will have brought the agency and industry closer to reconciling their pharmacogenomics issues. Mark Fuller, executive director of the Biotechnology Medical Management Association, a health-care consulting firm based in Wexford, Penn., sees the meeting as the latest example of an agency-wide “turnaround” within the FDA.

“I hope it’s a great first step in developing better relationships between regulatory agencies of the FDA and manufacturers and other researchers that are involved in this area,” said Fuller, who did not attend the subcommittee meeting. “I’m very excited about what I see as a turnaround at the FDA in just the last six to eight months, and very hopeful that this meeting will be a real positive one. … “

Greg Glover, an attorney for Ropes & Gray who deals with FDA regulations, said many of his clients hope that “this meeting will get the FDA thinking where this may be able to go, to hear about the various issues — basically, to start a dialogue.” Glover, who has represented the pharmaceutical industry at Congressional hearings, also did not attend the meeting.

“Ultimately, for the FDA to adopt to the standard, there’s going to need to be some consensus that this is scientifically sound, that it is reproducible, and it has some clinical significance,” he said.

— MOK and KL


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