FDA's Qnexa Decision and the Value of Benefit/Risk Analysis
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In a surprise move, the Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee on Wednesday voted 20 to 2 in favor of recommending approval of the obesity drug Qnexa. If the agency accepts that recommendation and ultimately approves Qnexa, it would become the first new obesity treatment in over a decade. Just a year and a half ago, however, the same committee (though with a slightly different composition) voted 10 to 6 against approving the same drug.

What changed their minds? A couple of things, including a labeling change recommending that lower doses be used in most cases and a proposed distribution program that will make it more difficult for pregnant women to be prescribed the drug. But, according to The New York Times, arguably the biggest change was the realization by Advisory Committee members "that obesity itself causes health problems and that there is a pressing need for treatments."

They've just now realized that obesity causes health problems? Where have these people been for the last twenty years? Apparently, they haven't been paying attention to the almost daily warnings in major and minor newspapers, on television news programs, in announcements from the Surgeon General, the Centers for Disease Control, and the First Lady that America is in the midst of an obesity epidemic that prematurely kills hundreds of thousands of us every year. Is it really too much to ask that the people we put in charge of recommending new medicines for approval or rejection would take seriously the negative consequences of the conditions those products are intended to treat?

To be sure, that's more than a little hyperbolic on my part. The Advisory Committee that recommended against approving Qnexa in 2010 did, in fact, acknowledge that obesity itself poses significant health risks. "We know that obesity is a major health problem, and all efforts to address this issue should be lauded," said the acting chairman of that committee, Dr. Kenneth Burman of the Washington Hospital Center here in DC.

Still, it seems curious, to say the least, that relatively minor proposed labeling and distribution changes for Qnexa would have such a dramatic impact on the Advisory Committee's vote -- from strong opposition to overwhelming support. This time, it does seem as though the committee took the risks of obesity far more seriously. Or was it just that new members of the Advisory Committee brought with them an entirely different perspective? Perhaps it's something else entirely. The point is, we really don't know what caused this dramatic change of heart or what weight the committee assigned to the drug's known risks or those of the underlying condition. Nor, perhaps more importantly, do we know what weight FDA will assign them when the agency makes its decision.

The entire affair seems to underscore just how important it is for FDA to make its decision-making more open and transparent. At a 2006 conference, the Institute of Medicine faulted the FDA for a "lack of a systematic, consistent, and transparent approach" for assessing the benefits and risks of new medicines. In a report published the following year, the IOM concluded that FDA's current process for assessing and balancing the benefits and risks of medicines is largely ad hoc, informal, and qualitative, relying primarily on the intuitive judgment of the agency's medical review staff and expert advisory committees. The report recommended that the agency "develop and continually improve a systematic approach to risk-benefit analysis for use throughout the FDA in the pre-approval and post-approval settings."

To some degree at least, the agency took that recommendation to heart. By 2010, it had already begun to design a qualitative "grid" of factors -- including the "severity of a medical condition and the need for a new treatment" -- for FDA personnel to consider in approval decisions. Still, by the agency's own admission, this benefit/risk grid served primarily as a tool for explaining approval and rejection decisions, rather than for guiding them.

That all may change, however, if a proposal for a more formal, quantitative, and transparent benefit-risk assessment methodology is adopted when Congress reauthorizes the Prescription Drug User Fee Act (PDUFA) later this year.

After lengthy discussions with drug and biotech firms, patient organizations, health professionals, and other stakeholders during the past two years, FDA heard overwhelming support for improving on its grid system. So, in its proposed recommendations for PDUFA reauthorization, the agency included a request that Congress give it greater authority to "develop an enhanced structured approach to benefit-risk assessments." Patient groups in particular were adamant that "[p]atients who live with a disease have a direct stake in the outcome of the drug review process." They insisted that FDA should place more weight on their views, and think more comprehensively "about the context of the decision, including gaining a strong understanding of the condition treated and the nature and extent of the unmet medical need."

The FDA's adoption of the risk-benefit grid was an important first step forward. But implementing a more formalized and comprehensive benefit-risk framework, as the agency now proposes, would do far more to promote overall patient health and well-being. Because no medicines are perfectly "safe," insisting on no adverse side effects would mean no medicines at all. What matters to patients is that the expected benefits outweigh the expected harms. Taking greater account of both sides of the benefit-risk equation is essential in making medical products approval decisions.

More formalized benefit-risk analysis is not a panacea, of course. Testing a drug in a few thousand -- or even tens of thousands of patients -- will rarely be sufficient to reveal all its risks and benefits. And some effects, such as such as pain, quality of life, and cognitive or motor skills impairment, defy easy measurement, making quantification and cross-comparison difficult if not impossible. But implementing improved analytical processes would help manufacturers better understand the kinds of data that must be generated during pre-clinical and clinical testing, help FDA product reviewers better systematize their decision-making, and help patients and medical clinicians better assess the utility of new products when prescribing treatment regimens. In cases that involve complex inter-related factors, such as drug approval and prescribing decisions, benefit-risk analysis can help decision makers better understand the likely consequences of their actions.

In the end, benefit-risk assessment is not a dispositive tool that can make choices for agencies. It merely provides a framework for agency decision makers to "organize available information" by forcing them "to state their assumptions clearly, exposing possible biases to criticism and correction." That, in my opinion, is the most valuable aspect of benefit-risk analysis: it forces decision makers to put their value judgments on record and gives the public the information it needs to evaluate the performance of the government agencies we trust with protecting public health.

There are plenty of problems with the FDA's decision making process, and benefit-risk assessment won't solve them all. But it can go a long way toward making that process more predictable and understandable, and toward helping the public hold agency decision makers more accountable.

2 Comments

Absolutely agree with the discussion here regarding benefit-risk assessment in FDA review. This was, and continues to be, a very serious concern during the recent Energy and Commerce hearings on BUFA and MDUFA III. What is perhaps the central theme underlying the re-evaluation of benefit-risk assessment is a framework between doctors and patients as well as the FDA, which might allow certain patients access to medical devices and new medications that haven't been approved but the proposed benefits outweigh the potential risks.

As this article suggests, the risk-benefit assessment needs to involve more parties than FDA officials in order to improve it.
For a look at the recent House hearings on MDUFA and BUFA check out the links below:

http://bit.ly/xpJgh6
http://bit.ly/AvTbaP

My 2cents in this is that Qnexa may be a good medication for someone who is disabled or has some rare medical condition. But the rest of society probably doesn't really need it. Rather education on what proper foods and amounts to eat. It is rather concerning that everyone who has a few extra pounds may soon think they need Qnexa and not a proper diet/exercise.


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