FDA is trying to provide clarity on its risk management plan program by creating a Web site that will serve as a central source of risk management plan information.

The agency would like to "get a Web site up that explains risk management programs and what those programs are," Office of Surveillance and Epidemiology Director Gerald Dal Pan said at a June 25-26 public workshop addressing opportunities and challenges of the programs.

Due to misperceptions about RiskMAPs on the part of stakeholders, FDA needs to improve the program's transparency, agency officials noted.

Risk Minimization Action Plans are a mystery to many stakeholders, Office of New Drugs Deputy Director Sandra Kweder said. Rather than a single entity, RiskMAPs are a collection of risk management tools. Therefore, FDA needs to develop a consistent framework through which the program will be better understood, she suggested.

For the Web site, the agency needs to create a template for presenting the plans, Kweder proposed. "What are its components, what are the measurements that are part of it, what are its goals?" Information about RiskMAPs "should be transparent, [and] it should be publicly available. Everyone ought to be able to understand what it is and why it is there."

The Web site is part of FDA's efforts to promote a more systematic approach to risk management programs both within and beyond the agency.

One way FDA is seeking to improve its own processes is by determining criteria that would indicate whether a drug requires a risk management plan that can be consistently applied to all drug applications. "It's time for the agency to be very systematic in thinking about what the criteria are to have a RiskMAP and what are the kinds of things that would lead one to need a RiskMAP," Kweder said.

By December 2006, 130 risk management plans had been submitted to FDA for review since the program began in 2002. As of February 2007, 30 products had RiskMAPs, nine of which were developed post-approval.

"We're in the process of implementing some significant changes in how we go about the process of reviewing NDAs and BLAs ... and focused attention on whether a product is going to need a RiskMAP will come very early in the development process as part of this. Hopefully that will help us avoid some of the crunch time that leads to suboptimal programs," she added.

Within FDA, however, the RiskMAP program is currently fragmented and the agency is understaffed for making efficient decisions. "We don't have a central location for RiskMAPs. We have a very, very small staff that weighs in on them ... and that's just not enough people," Kweder said.

"People who are involved in the business of reviewing drugs [have] a completely different mindset than people who are actually using the drugs and having to think about how to interface safety and efficacy data with standard clinical practice. We need to get better at that, and we need to put resources and processes [in place] and have ... a go-to place that oversees this."

In addition to standardizing a regulatory approach for requiring risk management plans, the agency is grappling with the correlated question of when it would be appropriate to remove the RiskMAP restrictions from a product. "We have to start thinking about RiskMAPs with the end in mind," Kweder said.

FDA does not want RiskMAPs to stop physicians from thinking, she maintained. "Heaven forbid I don't want a RiskMAP to be my doctor. I want doctors to be able to have tools that help them take care of patients. I want my doctor to have everything he or she needs to help me use a medicine wisely."

"When are we done? When have we established a sound practice that is part of expectations in the community of practitioners such that we don't need hard key entries to keep people in line?"

Answers to those questions may be illuminated by work on another of the agency's top priorities - improving the way it evaluates the impact RiskMAPs have on issues such as patient care.

There is some evidence that some risk management programs are effective - like those for clozapine and thalidomide - "but for the most part programs have been relatively small so it has been difficult to evaluate the effectiveness of these programs," OSE Senior Risk Management Analyst Mary Willy said.

"Like any intervention, RiskMAPs need to be evaluated for their safety and effectiveness," Brian Strom, University of Pennsylvania, said. "Like drugs they require evaluation. We need to know what their benefit is as well as their harm."

FDA is looking to develop methods of evaluation to determine the impact of a RiskMAP as a whole, as well as the impact of its component tools on the plan's goals. The agency is also interested in ascertaining the general effectiveness of risk management tools that are used in multiple plans.

"We're just beginning along this road. And we have some tools that have been started to be employed in a lot of these programs, but are they doing what we really want them to do? And how ... we test that is still a big question for us," Kweder said.

Only when those assessments of risk management plans and tools are possible "can we start making the kind of rational, intelligent and evidence-based decisions [about] how to build RiskMAPs and how to evaluate them," Dal Pan stated.

However, the agency currently lacks experience and manpower in its search for methods of evaluation.

"I suspect we need a lot of methods development here. ... The systems here are so complex that I don't think this is a single discipline issue, and we're going to have to expand beyond our traditional medical epidemiology," Dal Pan said. "This is clearly an area we have to grow."

"There is no question that we can't do this all alone," Kweder said. "The tools that are needed to do a lot of these systematic evaluations - we're not experts on those. And we need agencies like AHRQ and other experts in the community to help us with that."

FDA is also relying upon better compliance with risk management guidances by sponsors that have been submitting insufficient or inadequate RiskMAP proposals (¹ Also see "Risk Management Submissions Need To Be Better Organized, FDA Says" - Pink Sheet, 5 March, 2007., p. 9).

"In the submitted RiskMAP proposal, an evaluation plan should be included and it should include a timeline," Willy noted. "It is always wise to discuss the components of the evaluation plan with the agency since the process can be very complicated," she added.

Developing risk management plans could become a routine part of the application process for sponsors if the Prescription Drug User Fee Act is reauthorized with language requiring a Risk Evaluation and Mitigation Strategy for many new drugs (² Also see "PDUFA Draft Bill Adds $70 Mil. For Rx Safety To User Fee Totals; Mark-Up Looms" - Pink Sheet, 16 April, 2007., p. 14).

- Brian Marson (b.marson@elsevier.com)

FDA Putting System In Place For RiskMAP Evaluation And Management

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