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FDA Issues PGX Guidance

By Malorye A. Branca

April 15, 2005 | After many months of delay, some false starts, and considerable wrangling, the FDA has launched its final Guidance for Industry on pharmacogenomic data submissions ( Not surprisingly, industry’s reaction was subdued.

“It’s just nice to have it as a milestone,” says Chris Webster, director of regulatory intelligence and strategy at Millennium Pharmaceuticals.

This event has still elicited a huge sigh of relief from anxious proponents of the field.  “This will make people more comfortable,” says Richard Judson, senior vice president and chief scientific officer at Genaissance, a pharmacogenomic pioneer long involved in the guidance process. “There is clearly commitment,” says Webster, whose company is another founder of this struggling, emerging field.

Originally scheduled to post last summer, the document has missed several purported launch dates (see Genomic Medicine, March 2004, Complications, such as former FDA Commissioner Mark McClellan’s speed-of-light exit and the recent explosion of drug safety concerns, have clearly distracted the agency.

Desperately Seeking Guidance
The document lays out “the agency’s best thinking [on pharmacogenomics],” says Larry Lesko, FDA’s director of the Office of Clinical Pharmacology and Biopharmaceutics. Given the profound complexity of this field and the widespread confusion about its role in drug approvals, the document is sorely needed.  

Many drug makers and vendors of pharmacogenomic tools and services have worked closely with the FDA on the guidance since the process began about three years ago (see “FDA Fosters Pharmacogenomics,” Bio•IT World, June 2002). Iconix, for example, has “worked with FDA to help them understand what [gene] expression means in the context of toxicity,” says Don Halbert, Iconix’s executive vice president of research and development. The company’s software is installed at the FDA, and Iconix submitted a mock investigational new drug (IND) application containing pharmacogenomic data.

The final guidance says almost exactly what the earlier draft version did, but its release marks a new phase in drug discovery.

FDA’s action is mainly a response to industry fears about how investigative genomic research might be interpreted by the agency (see Genomic Medicine, Nov. 2003, Such research may generate new, and sometimes conflicting, evidence. Without diving deep into pharmacogenomics, researchers will never be able to reap its full potential value. But as long as they are fearful of repercussions regarding early, uncertain results, companies cannot risk fully embracing the field.

The agency hopes the guidance will “improve public health through the development of targeted therapies,” says Lesko. The agency is working on several documents related to this goal, including guidances on: genotyping tests for drug metabolizing enzymes (
cdrh/oivd/guidance/1551.html); instrumentation for clinical multiplex tests (; and the co-development of drugs and diagnostics. The agency says it will publish a “concept paper” on this last topic within a couple of weeks. “This [pharmacogenomics] guidance should be thought of in the context of an entire framework of guidances,” says Lesko.

Terms Defined
Pharmacogenomics is defined by FDA as “the use of a pharmacogenomic or pharmacogenetics test ... in conjunction with drug therapy.” The final guidance indicates when pharmacogenomic data must be submitted to the agency, what type of information is required, and how that data will be interpreted. It also describes the type of genomic data the agency is hoping to receive through voluntary submissions. The latter are meant to help better educate FDA staff about this young, fast-moving field.
The most closely scrutinized information in the entire document is probably the section defining biomarkers, which are classified as “known and valid,” “probably valid,” or “exploratory.” While the agency is eager to see exploratory data, and learn from it, according to the guidance such data will not be used for regulatory decision-making, which was industry’s biggest concern.
Faced with a growing number of products showing either efficacy or serious side effects in only subsets of patients, drug developers increasingly seek to identify biological markers that can sort individuals into groups of “responders/non-responders” or identify those at greatest or least risk of side effects. It’s a straightforward concept that, as often happens in drug discovery, has turned out to have unanticipated challenges. The pharmacogenomic technology boom generated a slew of questionable reports about putative genomic biomarkers. When any marker is linked to toxicity, it becomes a red flag to companies wary of raising the slightest fears among FDA reviewers.

As a result, most companies have either avoided genomic biomarker research entirely or made every effort to keep such data out of the FDA’s sight. Now, they have a document to point to if their pharmacogenomic data raises problems with a drug approval.

Pharmacogenomic data could be useful for drugs addressing any disease, but oncology is clearly going to be the first major area where biomarkers will be used. The classic example of a targeted therapy is Genentech/Roche’s Herceptin (trastuzumab), which is prescribed to women whose tumors show elevated levels of the HER2 protein. “Most of the activity around biomarkers today is in oncology,” agrees Lesko. “We are also beginning to see it in cardiovascular and neuro-pharmacology.”
The agency has received so many INDs with genomic data (more than 100) that they’ve stopped counting, according to Lesko. FDA expects pharmacogenomic markers to be important not only for drugs in development, but for marketed products as well.
Industry was also concerned about who will be reviewing the genomic data submissions. An Interdisciplinary Pharmacogenomics Review Group (IPRG) ( comprised of staff from across the agency will examine the voluntary submissions, and will also be consulting with FDA staff on regular submissions.

Along with the guidance, the agency posted a new “Genomics at FDA” Web page (
default.htm). The site provides much detailed information about pharmacogenomic data submissions, including a handy “Quick Reference” guide.  l

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