Pharma’s Cutting Edge

Here’s a story from the AP describing in very little detail a collaboration between FDA and MIT to monitor provider databases for adverse event signals. I know nothing about how the collaboration came about or which group at MIT will be leading the data mining efforts. When I find out, I’ll post a blurb. In any case, this is an important step in the development of an active safety surveillance system monitored by FDA. Industry should applaud and support this and related efforts, as faster, more accurate safety signals and estimates of incidence will hasten detection (and response) to adverse events and help to distinguish drug-related adverse reactions from unrelated adverse events. In short, this is ostensibly an important publicly funded risk management tool that will augment industry’s own active-surveillance risk management tools. Ultimately, these tools should markedly reduce the safety liability associated with new-drug launches.

I recommend to you the editorial by Jane Henney (former FDA Commissioner) and the article which prompted it. As you’ll read, the original article is an exposition of marketing practices used in the promotion of Gabapentin (Neurontin) by Pfizer. The authors used publicly available documents obtained from Pfizer during a federal lawsuit that was settled in 2004, with Pfizer admitting that it violated federal law by promoting the drug for unapproved uses. I especially appreciate the editorial, because Dr. Henney understands that industry is always going to be under pressure from its investors to seek maximum profits from each drug it sells and that maximum profits come only with effective promotion. Thus, there will always be pressure on sales and marketing personnel to push the envelope of allowable promotional practices. This means that the targets of these promotional efforts–primarily physicians–must actively guard against illegal or unethical promotional activities. In particular, so-called key opinion leaders must be very careful to monitor their own behavior during sanctioned and informal educational activities. The guidelines for such activities are already written, but they must be followed consistently. As Henney clearly understands, the prescribing physician is ultimately responsible for shielding patients from harm. As such, physicians must not allow themselves to become compromised by financial or ego-boosting inducements from industry.

This press release from FDA cracking down on compounding practices got some broad coverage this past week. Compounding, the selective creation of new drugs using bulk drug substance or drug products by pharmacists, is a legal activity when done for an individual patient with special drug needs, in response to a valid prescription. FDA maintains a web site that describes what pharmacists may and may not do to be in compliance with compounding rules and regulations. FDA has long been wary of “compounding” activities that resemble large-scale manufacturing and distribution of drug products, as are alleged for the three pharmacies given warning letters. In response to the FDA warning, RoTech announced it would cease production of the compounded products and would switch 30,000 patients to brand-name drugs. Look for more FDA warnings in the weeks ahead, with “biodentical” hormone compounders probably the next to be targeted.

Will post some stories that happened while I was away from the office. This first one is from Randall Willis at DDN, who reports that the EMEA and FDA will jointly review and comment upon Voluntary Genomic Data Submissions (VGDS). This is fairly big news that received virtually no media attention, perhaps because observers have become accustomed to collaboration between FDA and EMEA via the ICH process. But this is different. ICH provides a framework for submission of regulatory documents. It does not provide for joint agency review and commentary, as does this VGDS initiative. Willis raises the issue of creation of a superagency, with VGDS as a first step. I don’t see broader review and commentary collaboration becoming the norm anytime soon, given legislative inertia on both sides. But I like this relatively innocuous collaboration as a test of how collaboration might look sometime in the distant future.

At first, I was very perplexed by today’s FDA decision on Sparlon, which, according to what I’m reading on the web (reported largely from the perspective of Cephalon and its CEO), was related to FDA’s concerns surrounding a single case of Steven Johnson Sydrome (SJS) purportedly associated with Sparlon during clinical studies of the drug in children with ADHD (see FDA’s March Advisory Committee briefing doc for details of this case).

The active ingredient in Sparlon, modafinil, is widely sold as Provigil for use in adults with sleep disorders. The proposed usage of modafinil for ADHD would be primarily in children. As described in a prior news story, at least four cases of SJS in adults taking modafinil had been reported to FDA’s AERS database at the time an advisory committee recommended non-approval for ADHD in April of this year, whereas no cases had been reported in children, although an estimated 36,000 children had been prescribed the drug (27,000 patient-years exposure as of August 2005, according to FDA). SJS is serious enough, and often enough associated with use of a newly started drug (~50% of cases) that it’s reasonable to expect that had there been several cases of SJS in children taking Provigil, at least one would have been reported to FDA or another drug agency. That none were reported does not mean that modafinil does not increase the risk of SJS in children. Indeed, as the incidence of SJS is reported to be 1-3/million/year, even a ca. 100-fold increase in risk of SJS due to a drug could be missed in a population the size of the reported pediatric population using Provigil off-label.

So why was I perplexed at first by the non-approval of Sparlon? Well, I hadn’t yet read FDA’s advisory committee transcript or its briefing document when I read the news this morning. So I was left with just my logical reasoning, which went something like this: The drug is sold as Provigil to adults with narcolepsy and excessive daytime sleepiness and is widely used off-label for a variety of reasons, but mostly to keep people awake when they’re sleepy. If modafinil is believed to cause SJS in kids there should also be a concern about its use in adults with sleep disorders (since the mechanism of SJS wouldn’t be expected to differ dramatically between children and adults nor between ADHD and sleep disorders). So, the issue of approvability is likely not really just an issue of an overwhelming concern over patient safety (i.e. risk) based on a single observed adverse event–as reported today–but rather an issue of relative safety given the target effects of the drug (i.e. its benefit to risk balance) in children versus adults. To my reckoning, then, FDA must have determined that the benefit to risk equation was imbalanced in kids towards the risk side but not so in adults. If I make the assumption that FDA considered the drug’s risks in kids and adults to be roughly equivalent (and what evidence would FDA have to make an alternative assumption?) then I would have to conclude that the relative benefits to kids with ADHD were judged by FDA to be not as profound as the benefits to adults with narcolepsy/excessive sleepiness.

Now, forget about my logical inferences above and look again at the briefing document and at the transcript of the advisory committee meeting in March. Unfortunately for Cephalon, what actually appears to have happened with this drug today is that FDA somehow concluded in concordance with the committee’s majority opinion that the risk of modafinil is either too great or too uncertain to approve it for ADHD. However, FDA also appears to have concluded that the risks are reasonably well known and acceptable for modafinil’s use by adults for sleep disorders. I was confused no more. Cephalon told it like it really is today. FDA appears to have reversed its course after climbing out on an unstable branch of its decision tree and falling into a pit of rotting logic. I feel Cephalon’s pain. Every company struggling to get drugs approved in the U.S. deserves to deal with a regulator that fosters a transparent, predictable and rational approval process. It sure seems like Cephalon didn’t get that opportunity with Sparlon.