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FDA Plans to Use PGx Tools to Improve Drug-Safety System

The US Food and Drug Administration last week issued a new safety initiative that outlines how it can use pharmacogenomics data to “strengthen the science” that supports the drug-safety system.
“Pharmacogenomics can help improve the safety (and effectiveness) of drugs on an individualized basis. Many adverse events are due to individual overdosing because of drug metabolism differences,” the agency states in The Future of Drug Safety — Promoting and Protecting the Health of the Public, FDA's Response to the Institute of Medicine's 2006 Report. “FDA is working on several projects to better characterize these differences and reduce the frequency of such adverse events.”
Although this acknowledgement signals that “FDA scientists recognize the potential for PGx,” the agency needs to be cautious in its communication to the public about such a new and evolving science, a Critical Path Institute official said.
The FDA issued its plan for improving the safety of marketed therapeutics and medical devices last week in response to the Institute of Medicine’s assessment of the US drug-safety system, which the institute conducted at the request of the FDA.
One of the recommendations in the IoM’s September 2006 report said that in order to “facilitate formulation and testing of drug safety hypotheses, [the Center for Drug Evaluation and Research] should increase intramural and extramural programs that access study data from large automated healthcare databases, include these program studies on drug utilization patterns and background incidence rates for adverse events of interest, and develop and implement active surveillance of specific drugs and diseases as needed in a variety of settings.”
In its response, the FDA said it would test drug-safety hypotheses by using pharmacogenomic data, predictive toxicology techniques, and by improving the long-term safety of gene therapy.
The fact that the agency’s initiatives mention PGx as a component of its overall safety strategy signals that “FDA’s scientists recognize the potential of PGx,” the C-Path Institute’s Chief Scientific Officer Jeffrey Cossman told Pharmacogenomics Reporter this week. “FDA has shown a willingness, and taken leadership, in how the science of PGx could be prepared for submission for FDA review. Examples include workshops, white papers, and the beginnings of standardization of data.”
In its report, the FDA mentions several PGx-related drug-safety initiatives including the March 2006 launch of the Predictive Safety Testing Consortium forged between the C-Path Institute and 15 drug companies to validate preclinical genomic biomarkers of toxicity.
FDA also mentioned gene-based warfarin-dosing studies, one with the C-Path Institute and the University of Utah on the Cardiovascular Drug Safety and Biomarker Research Program, and another with the National Heart, Lung, and Blood Institute.
According to Cossman, the warfarin dosing project with the C-Path Institute “has progressed smoothly and patient enrollment remains strong.” The clinical study is nearly complete and data should be available publicly by May, Cossman said.
Additionally, the FDA notes in the document that it intends to enhance the long-term safety of gene therapy through its recent collaboration with the National Toxicology Program of the National Institute of Environmental Health Sciences. The alliance calls for the groups to develop and validate an animal model to evaluate the increased risk of cancer associated with some gene therapies.
“The model can be used by sponsors to test modifications to gene therapy vectors to mitigate cancer risk while preserving effectiveness,” FDA said in its document.
Also, under the Prescription Drug User Fee Act IV, the agency proposed it would develop a guidance on enriched trial designs. The guidance would “make recommendations on ways to enrich the clinical trial population to better define the efficacy and safety of the drug under development.”
Pharmaceutical companies are becoming increasingly open to using pharmacogenomic markers to select groups of patients with a strong predisposition to a disease, who would also be highly responsive to treatment. This type of enrichment can lead to faster, less expensive, and safer clinical trials, industry observers have said.

“The application of genomics to personalized medicine is in its infancy. The technology is very powerful but we are only in the early stages of learning how to channel it.”

One recent project reflecting this belief is a deal between Pfizer and Monogram to co-develop Pfizer’s investigational HIV drug Maraviroc with Monogram’s CCR-5 tropism assay. According to Pfizer, about 80 percent to 85 percent of treatment-naive HIV patients and about half of the treatment-experienced population may be eligible for Maraviroc treatment. Pfizer used Monogram’s assay in the clinical development of its drug [see PGx Reporter 12-06-06].
Another part of FDA’s safety initiatives involves improving the way it communicates drug-safety information to the public. To this end the FDA plans to establish an advisory committee to review and provide input on the agency’s risk-communication policies.
This follows plans within the FDA to try to communicate internally about PGx more effectively. According to Felix Frueh, associate director of genomics at the FDA, the agency began developing internal continuing education courses on PGx after an internal assessment revealed its staff had limited knowledge about the discipline [see PGx Reporter 01-03-07].
C-Path’s Cossman viewed the agency’s current ability to communicate PGx-related data to the public with “cautious optimism.” 
“The application of genomics to personalized medicine is in its infancy,” Cossman said. “The technology is very powerful but we are only in the early stages of learning how to channel it.”
According to Cossman, the learning process with regard to PGx will be most effective if it is a transparent sharing of strategy and knowledge among the stakeholders, including the pharmaceutical industry, diagnostic companies, academia, regulatory agencies, payors, providers and patients.

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