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In my last post, I discussed what I believed would be the basis for debate and concern among the panelists at Wednesday’s FDA DMEDP Advisory Committee–the benefit to risk balance of the drug in light of modest efficacy and risk of suicidality.

This was indeed the topic of much of the committee’s deliberations. As you now know, the committee voted unanimously (14-0) against approval of rimonabant due to a perceived unfavorable benefit to risk balance. They also voted unanimously that Sanofi-Aventis hadn’t sufficiently characterized the safety profile of the drug.

What does this mean? It means that this FDA division and its outside advisers, and probably much of CDER along with them, is taking the position that they want real, sustained evidence of benefits when risks during chronic use of a drug are small in number but potentially fatal. Stated differently, risk tolerance is low among this regulatory body, and it wants to see relatively more evidence of benefit to counterweigh a risk of a serious adverse event than in the past (I’m thinking two to three years ago). With rimonabant, they looked at a drug intended for chronic use that was associated with modest, reversible benefits on weight and markers of cardiovascular disease; no long-term cardiovascular outcome evidence; tolerance issues that promoted drug discontinuation, and an uncommon but potentially fatal adverse effect. In the current regulatory climate, rimonabant never stood a chance.

Perhaps DMEDP and its advisers would have thought differently had rimonabant been a drug developed to treat a disease without the social baggage of obesity. In this country, many people, including many health professionals, still consider obesity a condition caused solely by sloth and overindulgence that should be treated by willpower alone. But I don’t think so. Rather, I believe that this division and its advisory committee members are simply willing to be more paternalistic than in recent history, in light of missteps made by prescribers, pharmacists, sponsors and others that have led to a series of recent, high-profile drug recalls and new prescribing warnings for marketed drugs. In essence they’re saying: “The American public is either unable or unwilling to responsibly manage its use of new drugs. Until that situation changes, we must intervene by taking away the tough decisions…by limiting the choices that are available to it.”

I haven’t seen FDA place a lot of the blame on itself for the inability or unwillingness of prescribers and users of new drugs to manage their use responsibly, but most senior folks at FDA must know that through their inability to demand creation and dissemination of effective prescribing information, and through their inability to demand creation of and to enforce effective new-drug risk management plans, and through their unwillingness to require the types of large trials needed to define risk before marketing that they shoulder part, perhaps most, of the blame. None of this has to do with the needed resources for postmarketing surveillance being requested in the new PDUFA negotiations; I’m only speaking of what needs to happen before a drug reaches the market. For that, FDA has said it has the resources it needs to do the job well. So, why hasn’t it?

Sponsors, for their part, also shoulder significant blame for the rise of paternalism at FDA. Perhaps they just missed seeing the writing that has been on FDA’s wall for the past few years, but I think they saw it quite clearly and chose in some cases to ignore it, hoping it would go away, and in others to address it weakly, with a wink to their investors. Now they must overcome this guilty-until-proven-innocent mentality to market new drugs for chronic disease states, not to mention the formulary and insurance coverage hurdles awaiting new drugs once approved for marketing. The regulatory landscape won’t change for quite a while. If anything, we haven’t seen the top of this wave.

Sponsors, if you hadn’t heeded prior warnings, you’ve now been clearly warned: It’s up to you and you alone to demonstrate that your new chronic-use drugs work as intended, using highly relevant and generally accepted measures of effectiveness; that they can be used safely, where safely means that the risk of use is very clearly outweighed by the benefit, even if that means you must find ways to limit risk by restricting the user base and creating redundant methods of safeguarding their proper use. New chronic-use drugs must also be priced so as to be fiscally viable to large purchasers, and their value must not be a matter of faith but rather of overwhelming evidence. Which other companies are in late stages of development with CB1 antagonists? That would be Pfizer Inc. (NYSE:PFE), Merck & Co., Inc. (NYSE:MRK), and Solvay /Bristol Myers Squibb Co. (NYSE:BMY). We’ll see soon if they have been paying attention.

Sanofi-Aventis (NYSE:SNY) made many of the right moves with rimonabant. They misstepped by not gathering safety information in a way that could be used to create a sound risk-management strategy. There is time for them to make amends, in part, by gathering more evidence of both efficacy and safety.

Should S-A be able to generate evidence from the CRESCENDO outcomes study already in progress that very obese users (i.e. BMI >40) experience a meaningful reduction in their risk of cardiovascular events while using rimonabant, they will go a long way towards tipping the scales in favor of benefits. In the meantime, S-A must collect more evidence from Europe that shows the drug can be used safely in the “real world.” This, combined with some way of predicting suicidality through the use of simple baseline measures, other than or in addition to weight and history of depression, should suffice to create a viable risk management strategy. Whether S-A would want to launch in the U.S. with a restrictive prescribing strategy and its attendant black-box warnings is another question.

Source: Chronic Use of Rimonabant: Risk-Benefit Analysis Underway