The US Food and Drug Administration has released its pharmacogenomic data submissions guidance -- finally. Now what?
The long-awaited guidance, along with supplementary materials, was developed to inform drug makers on how to submit pharmacogenomic data for drug discovery and development, for agency insight and edification, and, in the case of instruction on voluntarily submitting pharmacogenomics data, to allay industry concerns that the agency will not use these data to make regulatory decisions.
But for all the fanfare surrounding the release -- the agency has set up a special web site devoted to the guidance and its ancillary components -- the document is only one of several steps the agency will take toward promulgating "personalized medicine."
At the core of this goal are biomarkers.
In order to comprehend the FDA's long-term biomarker strategies, it is necessary to understand the pharmacogenomics guidance. The guidance "should be thought of in context of an entire framework of guidances that we hope will lay the foundation for pharmacogenomics in the future," Larry Lesko, the director of the office of clinical pharmacology and biopharmaceutics at the FDA's Center for Drug Evaluation and Research, said during a March 22 conference call with reporters.
The Pharmacogenomic Data Submissions guidance and its companion documents are the product of the FDA's Critical Path initiative to streamline the development of medical products, and represent the agency's current thinking on the field. Using these documents to light the way, the FDA will work toward identifying and classifying genomic biomarkers, and it may use the new setup to inform its decisions regarding other kinds of biomarkers in the future -- perhaps even rearranging itself a little more in the process.
"There are really four [pharmacogenomics-related] guidances that are currently in place with FDA," said Lesko: the guidance for accelerated approval of drug-metabolizing enzyme-genotyping systems; the current Pharmacogenomic Data Submissions guidance; the therapeutic-diagnostic companion product guidance; and a general microarray-genotyping guidance. Two of these, including the recent drug-metabolizing enzymeguidance, have been released, while the drug-diagnostic co-development guidance and the microarray genotyping guidance are still under development.
The Final Product
Based on 35 sets of comments on the November 2003 draft guidance submitted by industry, government, and "groups interested in personalized medicine," CDER clarified "vague or uncertain areas" to produce the final documents, said Lesko. "Many comments had to do with submission of information, and what the FDA would do with the data -- those questions are mostly answered in the [two Manuals of Policies and Procedures]," he said. "The guidance itself hasn't changed in any major ways" from its draft form, he said.
This week's release includes: the Pharmacogenomic Data Submissions guidance itself; an attachment containing examples of voluntary and required submissions; a Manual of Policies and Procedures explaining how voluntary genomic data submissions will be received, reviewed, and maintained; and a Manual of Policies and Procedures describing the function, structure, and composition of the FDA's Interdisciplinary Pharmacogenomics Review Group, which will handle voluntary data submissions.
Carol Reed, vice president of medical affairs at Genaissance Pharmaceuticals, said the manner in which the FDA handled voluntary data -- an important component that was designed to help the FDA keep abreast of new and emerging technologies, among other things -- was one of the company's major concerns about the draft. She said the final guidance seems to have addressed it. "I'm just reading this right now, but it appears to be everything we hoped for," she said.
Reed was active within the Personalized Medicine Coalition, a non-profit with an interest in developing the field, when the group submitted its comments on the draft guidance. It wasn't immediately clear whether Genaissance submitted its own comments during the 90-day comment period last, which closed February 2004.
The IPRG is designed to advise drug makers on what to do with submitted genomic data; to keep that information separate from eventual drug evaluations; and to educate scientists within the agency on the state of the art. But it may also play a role in allowing the agency to incorporate future technologies into the pharmacogenomics rubric, Chris Webster, chair of the genomics group at the Pharmaceutical Research and Manufacturers of America, told Pharmacogenomics Reporter this week.
The IPRG will work partly to build a model for the incorporation of other "translational medicine" technologies, he said, adding that IPRG "is the sort of group that would perhaps lead that within FDA. Webster drew up a consensus comment for the draft guidance on behalf of PhRMA and its members. He also wrote comments on behalf of Millennium Pharmaceuticals, where he is director of regulatory strategy and intelligence. "
Indeed, there is "sort-of corridor chatter" within the FDA about organizing a new office for translational medicine, Webster said. A dedicated office within the agency could become a "fully fledged home for pharmacogenomics," as well as other technologies on the horizon, including protein and metabolic biomarkers, new imaging technologies, and "nanotechnology, perhaps in the future," he added.
If the new system under the Pharmacogenomics Data Submissions guidance will serve as a model for incorporating these technologies in drug discovery and development, then the biomarker classifications it outlines are of special note. "Really for the first time, the agency has attempted to classify biomarkers," said Lesko. Genomic technologies have spawned a wide variety of biomarkers, which the guidance classifies into exploratory, probable valid, and known valid, said Lesko. Classifying biomarkers in this way will help pharmas and the FDA to better understand the role they play in the regulatory decision-making process.
To the FDA, a known valid biomarker is one "that is measured in an analytical test system with well-established performance characteristics and for which there is widespread agreement in the medical or scientific community about the physiologic, toxicologic, pharmacologic, or clinical significance of the results." The widespread agreement in medicine or science would likely stem from expert advisory committees or public scientific organizations, Federico Goodsaid, a staff fellow in the office of clinical pharmacology and biopharmaceutics, said at the Society of Toxicology meeting in New Orleans earlier this month.
In contrast, a probable valid biomarker may not be available for public scrutiny, may lack conclusive evidence, or may not have yet undergone independent verification, the guidance said. All other biomarkers are exploratory.
To be sure, the FDA has yet to work out exact biomarker definitions, said Webster. "We wouldn't expect that there would now be [definitions] in the new guidance. It's a much bigger discussion, and nobody, including FDA, has really got there yet. It will be something that we'll just have to work on," he said.
In the event an exploratory biomarker submitted to the IPRG appears to be a probable or known biomarker, the group will form an advisory subcommittee for public assessment of the "related issues" surrounding that biomarker, according to the IPRG's MaPP.
In any case, the search for biomarkers is nearly universal, said Ed Abrahams, executive director of the Personalized Medicine Coalition. "Many companies are developing biomarkers for every compound in the pipeline. That's happening -- eventually this is going to reach the bedside," he said.