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12/2/2003

FDA Seeks Pharmacogenomic Data

Kate Traynor

The Food and Drug Administration (FDA) last month took steps to clarify the circumstances under which the agency expects to use pharmacogenomic data as part of the drug approval process.

"We are very interested in driving more efficient development of medicines through pharmacogenomics," FDA Commissioner Mark B. McClellan said at a Nov. 13 conference in Washington, D.C., sponsored by the Drug Information Association. McClellan encouraged drug makers to share pharmacogenomics data with FDA so that the agency can "develop real knowledge" out of the growing body of information emerging from the field of pharmacogenomics.

FDA made its first major foray into pharmacogenomics in 1998 with the licensing of Genentech Inc.'s trastuzumab, or Herceptin, for the treatment of HER2-positive metastatic breast cancer. An FDA-approved diagnostic kit for the detection of HER-2 overexpression was approved at the same time and was instrumental to the agency's decision to allow trastuzumab on the market.

The availability of pharmacogenomic data has increased since the decoding of the human genome in 2000, but the data are not rapidly becoming incorporated into the drug development process. In an attempt to remedy this situation, FDA on Nov. 3 issued a draft guidance document on pharmacogenomic data submission by drug manufacturers.

According to the document, manufacturers would be required to submit pharmacogenomic data if it is used to drive the course of clinical studies.

"We're proposing that you submit pharmacogenomic data...if the test results would be used for decision making in clinical trials or in animal safety studies," said Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER).

For example, Jerry M. Collins, director of pharmacology at CDER, described to conference attendees a hypothetical clinical trial in which patients with a genetic marker for increased creatine phosphokinase production were excluded from the high-dose part of the study involving a hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibitor, or statin. Patients with this marker are at increased risk of rhabdomyolysis. Most attendees at this session indicated to Collins, by a show of hands, that this case should require a full submission of the pharmacogenomic data to FDA.

Another theoretical case illustrating the need for full submission of pharmacogenomic data involved a clinical trial in which a sponsor used such data in a preliminary trial to establish a single effective dosage for patients of common genotypes but did not perform genotyping in later trials.

In addition to describing situations calling for full pharmacogenomic data submissions, the guidance describes a process dubbed the voluntary genomic data submission, or VGDS. Voluntary data submission would be welcomed for research data that could add to FDA's pharmacogenomics knowledge base. Such research data might be exploratory data from the analysis of a panel of expressed genes to see whether any correlate with the efficacy of a drug.

Woodcock and other FDA officials attempted to quell concerns from the pharmaceutical industry that the submission of pharmacogenomic data to FDA would increase regulatory scrutiny of the data and complicate the drug-review process.

"Right now, the barrier and the onerous nature of the regulatory interaction is so intense that we are receiving feedback that says experiments are not being done," said Jerry M. Collins, director of pharmacology at CDER. "We're certainly aware that there are experiments that management—rather than the scientists—have decided can't be done, because they're viewed as a potential liability" to drug approval.

"Our job," Collins said, "is to make sure that innovation can proceed, and that investigators dealing with the FDA are not at a disadvantage, within the limits of our requirements to work on safety and efficacy."

"The guidance attempts to take a middle path between two things—between encouraging and facilitating the adoption of the therapies and then providing oversight," Woodcock said.

"My belief is that much of the [pharmacogenomic] data currently available is not well enough established scientifically to be suitable for regulatory decision making," Woodcock added. She noted that "almost no pharmacogenomic tests approved by FDA" are currently on the market, which limits the agency's current ability to incorporate such testing into the product-approval process.

Of note, a commercial microarray test for mutations in the cytochrome P-450 gene was pulled from the market in October by FDA's Office of In Vitro Diagnostic Devices, because the manufacturer, Roche Molecular Diagnostics, did not obtain the necessary FDA approval to sell the product.