Pharma’s Cutting Edge

Well, as you now know, Revlimid was recommended for approval. This is great news for patients who suffer from transfusion-dependent MDS and for related hematological conditions, for which the drug will be quickly adopted off-label (e.g. AML resistant to first-line and second-line treatment). I believe the drug to be effective for these conditions. I mentioned that I held a position in CELG prior to the ODAC meeting and so refused to provide my assessment of Celgene’s NDA package prior to the meeting. As it happens, I liquidated my position prior to the meeting, because I reasoned that a negative vote would be disastrous for the stock and was not sure that a close vote would not also result in a sell-off. My assessment of the NDA package as reflected in the briefing document was that a close or negative vote was a distinct possibility, given the totality of the data and FDA’s interpretation of it. The vote for approval was split, but the stock reacted in a mildly favorable way. In any case, this gives you an idea how I weigh benefits and risks when I hold positions I don’t mind liquidating. I could have also written a covered call option on the CELG position as a way to hedge if I had wanted to avoid liquidation (e.g. if I believed the upside to be large; if I held a large position; if I held a large position in a taxable account that was about to become long-term and thus receive favorable capital gains treatment).

This is something you rarely see–Pfizer (or any major) getting a non-approvable letter. I’m particularly surprised to see it tagged to the lasofoxifene submission, because this is a drug that has been in clinical development for many years and is operating in a space that contains a precedent (raloxifene, Evista) for regulatory considerations. Without further details from Pfizer I can’t comment on the possible reasons for the non-approval decision. It might have nothing to do with the clinical program. Whatever the reason, it’s a bad sign for Pfizer and further unwelcome news for Ligand investors (Ligand will receive a royalty on lasofoxifene sales), who received word last night that a formal SEC inquiry has become an investogation into Ligand’s accounting.

I have to admit that I was very surprised when Abbott announced that they would pursue an NDA based on the results of a single Phase 3 study that failed to meet its primary endpoint. My surprise came despite a “heads up” from a hedge fund manager who told me that word on the Street was that an NDA would be filed. In the intervening months I had forgotten the many reasons for my surprise. They came rushing back to me as I reviewed FDA’s medical review of the NDA. Let’s recount some of them: A single Phase 3 study was performed to serve as the basis for approval without supporting evidence from another study or an internal substudy. In the Phase 3 study the primary endpoint was time to disease progression, a common endpoint for prostate cancer trials. The primary endpoint was not met with statistical significance, not even close. Four of the five pre-defined secondary endpoints also were not met. Abbott decided to rely on the “per-protocol” population for evidence of efficacy when they filed the NDA (they later changed their minds and decided that a different subset of subjects would constitute the efficacy population). This population excluded the 17% of major protocol violators; 17% major violators is a red flag. Finally, the improvement in time to progression for the per-protocol population was minimally better in the treated versus placebo group. It was small enough, in fact, that it was less than the number of days between measurements to confirm disease progression, raising the possibility that it was a spurious outcome biased by differential measurements between groups. The above concerns and others have led the FDA’s medical reviewer to comment that: “The results and conduct of phase III study do not provide convincing evidence of efficacy….There are some serious cardiovascular safety issues observed in both major randomized trials. Atrasentan does not demonstrate any clear evidence of clinical efficacy in men with hormone refractory prostate cancer in the only major trial of design adequate for a registration study.”

I couldn’t have said it better. I would be very surprised if ODAC concludes differently tomorrow. But then I’ve already been surprised once by this drug.

“I mean there is something so fundamentally unethical about tying profit into educating doctors and helping patients.” No doubt that phrase, spoken by the lead character in Side Effects from writer/director Kathleen Slattery-Moschaku, was included in the trailer because it sums up the film’s main theme in a nutshell. Of course, I take the diametrically opposed view. There is absolutely nothing unethical about mixing profits with physician education and patient care. In fact, it’s essential if we wish these noble pursuits to be of enviable quality and continuously available on demand. There is simply no mechanism other than profit motive that is known to drive and to sustain innovation and quality performance.

Kathleen Slattery-Moschaku was a pharma sales rep for 10 years. That’s a long time to be in a sales job of any type but especially long for a pharma rep, who must endure the same performance metrics of other sales jobs in the face of ever-increasing pressures that severely limit quality face-time with their customers. The job becomes even tougher when the sales rep is a non-specialist with no formal medical or science training, as was the case for this auteur. Time pressure is nothing compared with the pressure of knowing that your customers have the upper hand in nearly every technical discussion about your products. It’s easy to see why non-specialist reps burn out quickly. Those who last ten years, like Ms. Slattery-Moschaku, have developed defense mechanisms to help them cope with these stresses. Apparently, if the trailer is representative of the film, Ms. Slattery-Moschaku’s chief defense mechanism was unusual candor regarding her products’ “real” effects, which in turn brought her unusual sales success. No surprise there. If docs think they’re getting the unfiltered truth, they’ll trust it and the rep it came from. It doesn’t matter if the truth suggests a flawed product; doctors know that all drugs have flaws. When faced with a choice between two or more flawed products, they will be more likely to choose the one in which the flaws were made known to them from the outset, the less sugar-coating the better.

What doesn’t necessarily come across in the trailer for the film is an admission from Ms. Slattery-Moschaku that the position of the non-specialist rep within the universe of the pharma industry is an isolated one, despite its place on the front lines, as it were. They are the industry’s ambassadors, asked to show a good face and remain loyal and optimistic but not expected to participate in the long, painful processes leading to the pharmacy shelves. Inevitably, relegation to such a role leads to a one-sided, cynical view of the industry. Only the marketing angle is seen; greed appears to be the motive for all actions. Doctors appear to be little more than dupes, buffoons swayed to participate in the deceit by little more than a well-timed laugh and a fancy lunch. Industry executives become uncaring suits whose only goal is to keep their stock options above water. The researchers who actually discover and develop the drugs are seen as profoundly naive, unaware that they are simply being used to power the corporate engines.

It’s not a surprising world view. The industry must accept blame for creating and fostering it and should change its methods to finally stop it from proliferating. Ms. Slattery-Moschaku, for her part, should admit that what drives her view is cynicism, born of a difficult, one-sided experience within industry, and not from a duty to disclose “the truth” for the good of society. The truth, it turns out, is far more complex than the industry’s critics would lead the general public to believe.

I have to apologize for not summarizing the key issues that the EMDAC will face during today’s discussions of Pargluva (muraglitazar) last night, but I was consumed by other matters yesterday. Suffice to say that FDA has had an opportunity to amass a very large volume of preclinical and clinical data on PPAR modulators, including PPAR alpha/gamma dual agonists (Pargluva’s mechanism). They know very well the issues of potential clinical concern. What they need from this committee is an outside view of potential concerns that have not been discussed in public forums like this previously. The cardiovascular issues, for instance (PPAR gamma-mediated phenomena), were publicly discussed during the approvals of troglitazone, rosiglitazone, and pioglitazone. Likewise, certain malignancy risks and the hepatotoxicity potential, have received public scrutiny. FDA will surely want to differentiate preclinical malignancy signals seen with the alpha/gamma agonists from those seen with the TZDs mentioned above and others that have not been approved to determine whether risk management should be different for this class. Although I haven’t read through the briefing docs yet, my personal experience with these classes of drugs makes me think that the advisory committee will endorse approval with currently available data and suggest (if not already suggested by BMS/Merck) that the sponsors perform active surveillance for malignancy in the postmarketing phase. They will also want to see a cardiovascular safety/efficacy study with hard outcomes performed (akin to what is curently being done for rosi- and pioglitazone).