A Better Way to do Risk/Benefit? (Part 1)

Our sharp-eyed colleagues at “The Pink Sheet” spotted an interesting document last week: a request for proposals issued by the Food & Drug Administration seeking a contractor to explore development of “a more formalized and comprehensive approach to the benefit/risk assessment” for new drugs.

In other words, the agency wants someone to help it create a quantitative tool to use in making the toughest of regulatory judgments: when, exactly, do the risks of a product outweigh its benefits?

It is easy to see the appeal of having such a tool. Among sponsors, there is a desire for a more predictable, rational climate for discussing post-marketing safety surveillance signals and pre-market risk versus benefit decisions. Put another way, many in industry believe a risk/benefit model will do more to capture the benefit side, which sponsors never believe gets enough weight—especially in a “Safety First” regulatory climate.

FDA likes the idea too. The agency wants to respond to concerns about the quality of drug safety oversight and to develop a common framework for weighing risks versus benefits in regulatory decisions.

On both sides, there is the hope that by developing better tools to analyze the risk-benefit ratio, it will be easier to explain to the public why, for example, a small risk of potentially fatal pancreatitis is offset by the broader benefits of blood glucose control in type 2 diabetics. (If you don’t think this matters much, look at what happened to Amylin and Byetta.)

And there is the unspoken desire to take some of the guesswork out of one of the toughest decisions an executive or a regulator in the drug industry will ever face: when is a drug too dangerous to stay on the market?

This is not a new idea. When the number of safety-related drug withdrawals began to creep up in the late 1990s—climaxing with the Vioxx removal in 2004—industry CEOs began to talk about the need for a more quantitative approach to judging risks versus benefits.

FDA also embraced the idea, and it was formally endorsed by the Institute of Medicine in its 2006 report on the drug safety system. FDA and industry even agreed as part of the latest Prescription Drug User Fee program to allow FDA to devote some of the fees to developing a model.

Hence the RFP. The agency is asking a contractor to study how a "more formalized risk/benefit analysis might compare to the human judgments, using less formal analyses, that were made in the FDA review." The contractor will test the model in four different cases--two drugs approved by the agency, and two that were not. If all goes well, FDA will have a report on the results six months after the contract is awarded. And, of course, that is still a long way away from having a useable tool to support regulatory decisions.

But let’s dare to dream. Imagine a world in which everyone—regulators, industry, and society at large—agrees on how to judge whether a relatively rare but serious risk does or does not outweigh a broad but milder benefit. In other words, a world in which there are reports of severe, potentially fatal pancreatitis with a new type 2 diabetes agent like Byetta, and everyone can immediately see whether that information fundamentally changes the rationale for using the drug (or even allowing it to remain on the market.)

Such a tool could revolutionize everything. Post-marketing surveillance would be less chaotic. The drug approval process would be much more predictable. Drug development would be more efficient, as sponsors apply the same methodology as regulators in making go/no go decisions on experimental compounds.

Here’s the thing: we don't think its going to work out that way. Tomorrow, we'll tell you why...