FDA Contract Explores Quantified Risk/Benefit Approach

FDA is exploring the idea of a more formal, quantitative system for assessing the risk/benefit of drugs.

A recently closed request for proposals signals a potential shift in the agency's approach to risk/benefit analysis and its views on outcome measures, which some see as bringing more transparency while also shielding the agency from criticism.

The RFP sought "an independent consultant with the clinical, epidemiology, decision science and other analytic expertise" to conduct a comprehensive risk/benefit assessment on two agency-provided case studies. Bids were closed in late August.

The planned study will examine how results of a more formalized risk/benefit analysis might compare to human judgments - the less formal analyses that are made in the FDA review - and determine whether and where the new approach would yield the greatest potential value to decision making (see chart: " ¹ A More Formal Approach to Risk/Benefit Analysis ").

The contractor is to consider whether different kinds of data, such as patient-reported outcomes or comparative data, could assist in these approaches.

The agency will provide information on two cases in which FDA approved a drug despite safety concerns and two cases in which FDA did not approve the drug due to safety concerns. The contractor is to present results from the analysis to FDA 28 weeks after the contract is awarded.

Although the findings would travel a long road before becoming FDA's governing principle, a quantitative system could help address concerns - internal and external - about how FDA makes safety decisions.

Critics of the agency have long said that FDA often fails to adequately consider safety issues in product review, either because of industry pressure or simply because of organizational structure at the agency.

Having an independently developed process to rely on when making those decisions could help quell such concerns. It might also clarify for sponsors what is required to get products to market.

However, as FDA notes, the process would also involve the "loss of the unquantifiable judgments based on experience and even intuition."

A Long Road To The Proposal

The idea of a quantified risk/benefit evaluation was proposed during development of the Institute of Medicine's report on the country's drug safety system. It was suggested that standardized, quantitative methods would provide FDA a stronger defense against critiques of regulatory decisions, alleviate anxiety over assessment criteria and promote innovation (² (Also see "Sweeping Changes At CDER Recommended In IoM Drug Safety Report" - Pink Sheet, 25 Sep, 2006.), p. 4).

FDA embraced the recommendation and its proposal for renewal of the user fee program noted that funds would be used to explore new models of risk/benefit analysis and assess whether pilots could be conducted.

In March, FDA's Joyce Korvick, Director of the Gastroenterology Products Division, told a group at the Drug Information Association EuroMeeting that better measurement of safety issues during clinical trials would aid regulators in evaluating the trade-offs between a drug's benefits and risks.

Participants at the DIA meeting called for more transparency and new approaches to obtaining information and reviewing risks and benefits, particularly on the quantitative side.

FDA has heard similar advice through more formal feedback channels as well. During an Endocrinologic and Metabolic Drugs Advisory Committee meeting at the beginning of July, the panel embraced the need for additional safety data to make informed risk/benefit decisions on type 2 diabetes drugs.

Is FDA The Appropriate Arbiter?

In an interview, Cleveland Clinic's Steven Nissen said the RFP solves the problem of "internal structural difficulties that the agency has in dealing with drug safety."

"There's been a lot of concern about whether a group that had been responsible for approving a drug is the best group to monitor the safety of a drug. Ultimately, once they've approved it, they've invested a certain amount of energy in the belief that the drug's benefits exceed its risks."

A memorandum of agreement was recently signed by the directors of the Office of New Drugs and Office of Surveillance and Epidemiology, allowing each office to share equal responsibility on significant safety issues for pending and approved products (³ (Also see "FDA Drug Review, Surveillance Offices To Share Authority Over Safety" - Pink Sheet, 7 Jul, 2008.), p. 12).

Nissen said industry might take issue with a more formal quantitative model, but "I actually think in the long run, really good vigilant monitoring of risk/benefit ultimately does protect industry."

FDA should "be very careful who they award this kind of contract to. There have to be strong firewalls around conflict of interest because this has a lot of commercial implications," Nissen said.

A "Culture Of Secrecy"

There have been efforts in academia to develop formal models of risk/benefit assessment, including consideration of the value of larger clinical trials. But Nissen said a lack of transparency at the agency is hindering progress.

"I think the big change we need is to make what FDA knows about drugs publicly available," he said. "Ninety-plus percent of what FDA knows about drugs' benefits and risks is not in the public domain."

"Good government and good science can't operate in a culture of secrecy. They have to operate in a culture of openness."

"I believe that we must, through legislative action and through policy within the agency itself, increase the amount of transparency so we in academia get to see more of what FDA knows."

[Editor's note: This story was contributed by " ⁴ The Pink Sheet ," your weekly source for prescription pharmaceutical news. For more information call 1-800-332-2181.]

- Becky Jungbauer ([email protected])