Is There Any Path For Approval of Antiobesity Drugs?Tuesday, September 6, 2011
Regular readers will be aware that we currently have virtually no effective drugs for the treatment of obesity (which, interestingly, leaves the field wide open for the snake oil pedlars, who, in addition, enjoy an apparently ‘free-for-all’ unregulated scam-artist utopia).
That said, one can only wonder why, despite billion dollar investments, the pharma industry has not been able to bring a single new anti-obesity drug to market in North America since 1999. Is perhaps the regulatory bar simply too high?
This issue is the subject of a discussion paper by Morgan Downey (author of the Downey Obesity Report), Christopher Still (Geisinger Obesity Institute) and myself, published in the latest issue of Current Opinions in Endocrinology, Diabetes & Obesity.
As we point out, since July 2010, the FDA’s Endocrine and Metabolic Advisory Committee has reviewed three new drug applications and one previously approved drug for the treatment of obesity – all three new drug applications were declined while the one existing drug (sibutramine) was ‘voluntarily’ pulled from the market despite a split vote by the Advisory Committee.
In this paper we examine in detail the Advisory Committee’s consideration of the risk–benefit equation of the four drugs, especially in light of its decision on sibutramine and the results of the SCOUT study.
Currently, the FDA’s criteria for effectiveness for anti-obesity drugs has two alternatives: The first is a mean efficacy defined as medication-associated weight reduction of 5%. The alternative criteria is a categorical efficacy endpoint defined as a significantly greater proportion (at least 35%) of those individuals receiving the medication, compared with controls, maintaining a 5% weight loss from their initial weight. Demonstrating the resolution of any obesity associated comorbidities is not a requirement (although, it perhaps should be – see below).
These effectiveness criteria are certainly not the rate limiting step – at least one of these effectiveness criteria was met by all of the existing or newer medications.
The problem appears to lie rather in the FDA’s apparent ‘zero-tolerance’ for adverse effects, clearly holding anti-obesity drugs to far higher standards than any other prescription medications currently on the market.
Curiously enough, while the components in two of the combination medications (Qnexa and Contrave), have been around for decades and are widely used for depression or smoking cessation (bupropion), seizures or migraines (topiramate), narcotic and alcohol dependency (naltrexone), or short-term weight loss (phentermine), these drugs were deemed too ‘dangerous’ for the treatment of obesity.
Unless, the Advisory Committee (which notably lacked any members with clinical expertise in obesity management), does indeed believe that obesity in itself is not a condition worthy of pharmacological treatment, one can only speculate whether the FDA and its advisors believe that both health professionals and obese patients are largely incompetent when it comes to ascertaining risk/benefit rations for themselves or in following prescription information.
Thus, as we point out:
“…panelists expressed doubts as to the reliability of physicians to prescribe an antiobesity drug appropriately, the reliability of patients to take the drug as prescribed, the limited value of the label information, the limited value of primary care providers to work with patients on complex problems like obesity, the lack of predictability that a REMS program, or a program of limited distribution would be successful and whether insurance companies would reimburse for the drug.”
This, attitude unfortunately reeks of bias and discrimination against both health professionals who treat obesity, as well as people who have this problem.
After all, for every other indications, the FDA appears perfectly happy with approvals that include all kind of warnings and caveats – apparently these ‘warnings’ work fine for other indications like high blood pressure, diabetes, or heart failure – it is only when used for obesity treatment that suddenly all these regulatory measures are ineffective.
“One can ask, therefore, whether this skepticism extends to other areas of medical practice or are these concerns sui generis to obesity. If so, are they based on evidence or assumptions about the behavior of patients with obesity and the doctors who treat them?”
On the other hand, it may simply be that the FDA
“…currently does not view obesity as a serious disease and so any risk is too great.”
If this is indeed the case, our recent publication of the Edmonton Obesity Staging System may provide a ready solutions – as our studies show, while for some individuals carrying a few (or even substantially more) extra pounds may have little or no health risk, for others obesity related health problems pose very severe risks, shortening 20 year survival by 10 years!
So while ‘no-risk’ is acceptable for using drugs to treat obesity in ‘healthy’ overweight or obese individuals, considerable risk (as long as it is less than the natural risk of this condition) may well be acceptable for patients with higher Stage obesity.
In addition, as pointed out before, much needs to be done to prospectively define specific target populations based on an etiological framework rather than simply on the presence of excess body fat.
Will the FDA and other regulators change their views on this?
I don’t know. What I do know is that until that happens, few pharma companies will dedicate the necessary resources or invest in the large and extensive trials needed to bring new anti-obesity drugs to market.
In the meantime the beneficiaries of this lack of insight will be the snake oil pedlars on the one hand and bariatric surgeons on the other. The clear losers will be the millions of people struggling with obesity and its consequences.
Disclaimer: I have received speaking and consulting honoraria from makers of anti-obesity drugs.
Downey M, Still C, & Sharma AM (2011). Is there a path for approval of an antiobesity drug: what did the Sibutramine Cardiovascular Outcomes Trial find? Current opinion in endocrinology, diabetes, and obesity, 18 (5), 321-7 PMID: 21878755