The U.S. Food and Drug Administration (FDA) issued three final guidance documents this month relating to drug safety and risk management. The three guidances, entitled "Premarketing Risk Assessment," "Development and Use of Risk Minimization Action Plans," and "Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment," address various stages of product development from early clinical development stages to post approval, all with recommendations for preventative measures to reduce the chance of an unforeseen risk making its way to the public.
"These are complementary documents that have been carefully crafted and extensively vetted in the public," said Paul Seligman, MD, MPH, director, Office of Pharmacoepidemiology and Statistical Science, Center for Drug Evaluation and Research, FDA, in a press conference. "They are based on years of FDA experience and provide recommendations to the industry to optimize the very important safety information coming out of late-stage drug development, as well as the safety information gathered once a product is marketed."

When asked about what specific effects the documents will have on the drug approval process and if having these guidances in place at the time of the Vioxx approval would have resulted in a different outcome, Seligman offered a general response. "Many of the principles that are articulated in terms of the size of a safety study, and the pre-market safety evaluation testing that should be done, are very much drug-specific, as well as whether or not a risk management plan should be applied, and the need for additional scrutiny in the post-marketing environment."
"We do believe very strongly that improving risk and safety assessment will improve our collective ability to assess and anticipate safety concerns. We also recognize that improving this assessment is not a guarantee that we will be able to completely avoid problems in the future," he said. In the case of Vioxx, it was not a question of the detection of cardiovascular risks; it was really a question of how the data should be interpreted, how to weigh evolving information on the benefits and risks in determining whether or how widespread a product should be made available."
The development and use of risk minimization action plans or RiskMAPs is an approach that has never been previously defined or articulated by the FDA, Seligman said. The term RiskMAP is defined in the guidance as meaning, "a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits. A RiskMAP targets one or more safety-related health outcomes or goals and uses one or more tools to achieve those goals."

An example of a stated goal, as stated in the guidance, could be "…patients on X drug should not also be prescribed Y drug" or "fetal exposures to Z drug should not occur." Then the guidance says that such goals, "be translated into pragmatic, specific, and measurable program objectives that result in processes or behaviors leading to achievement of the RiskMAP goals." It then states: "The objectives could include lowering physician co-prescribing rates and/or pharmacist co-dispensing rates."

Will such proposed self-supervising by drug makers slow the approval process? "The development of a RiskMAP is not a condition of approval and does not change the criteria on which we base approval decisions," Seligman said.
What the real-world implications of the recommendations made in the new guidances will be is difficult to determine, but the goal, Seligman said, is to get the industry to more thoroughly scrutinize the safety of its products. "What we are really trying to do in these documents is make sure that people think about, anticipate, and try to deal with as many of these safety concerns as early in the product development as possible so that there aren't surprises toward the end of development that could potentially delay a product's approval."