Pharma’s Cutting Edge

Pfizer is slashing its salesforce by 20%, a move that will come as no surprise to anyone familiar with the industry. 

This inevitable decision reflects the changing pricing and customer-access dynamics of the industry.  For the past year or so, company after company has admitted that its ROI on multiplexed sales calls (multiple calls to the same practice) has eroded, and company after company has quietly reacted to this erosion with measured, targeted reductions in the number of calls per physician.

Everyone was waiting for one company, Pfizer in particular, to come out publicly and admit that it wasn’t changing its sales practices fast enough to protect profit growth.   No company wanted to be first to blink, as a unilateral move was viewed as risky.  Now that Pfizer has blinked, does this mean others will follow?

While I suspect that some execs will seriously consider using Pfizer’s move to try to gain a competitive sales edge, most majors are likely instead to use the move as an opportunity to do the same.  GSK, which has made numerous overtures in this regard (search this blog to read some), is likely to be up next, followed by many others.

Pharma…new world.  New world…pharma.  I hope you two enjoy a productive relationship.

In his Nov. 17th editorial “ADAPT: The Wrong Way to Stop a Clinical Trial” Steve Nissen of the Cleveland Clinic blasts the NIH and PI of the ADAPT trial (a comparison of celocoxib, naproxen and placebo in Alzheimer’s disease) for terminating the trial unnecessarily.  Kudos to Dr. Nissen for his bold public statements.

The actions to stop the ADAPT trial are clearly antithetical to widely accepted prinicples for conducting interim safety analyses, as I have described in a previous blog post and recently published white paper.  It’s shocking that the U.S.’s leading health-research authority would be responsible for such blatant scientific misconduct.  It’s the type of action that should result in a GAO investigation and in the loss of job for those found to be chiefly responsible.

As you’ll read in Therapeutics Daily and elsewhere, Novartis reported the delay of FDA’s review of Galvus, its answer to Merck’s recently approved Januvia, by three months.  Novartis said it submitted additional clinical data, triggering the FDA to add time to its review-cycle clock. 

What interests me about the story is the reasoning behind Novartis’ move.  Apparently, in  one or more monkey tox studies there was evidence of “skin lesions” that were of some concern.  Presumably, Novartis was trying to head off a dreaded approvable decision or maybe a nasty label warning with the additional clinical-data submission.  The nature of the skin lesions wasn’t elaborated by Novartis, although I read somewhere that blisters were involved. 

It’s hard to deduce too much from this limited information, but what I can tell you is that monkey studies aren’t run to look for skin toxicity specifically, so if a skin finding was made in monkeys, it was made during the course of a general toxicology or safety pharmacology study (more likely the former).  Also, Novartis wouldn’t have run a dermatotoxicity study (where the drug is applied to the skin) for an oral medicine like Galvus, so these skin lesions, whatever they are, were seen after oral administration.

Skin toxicity after oral drug administration is no rarity.  All sorts of skin reactions can occur with systemically administered drugs.  Usually such reactions are immune-mediated and most commonly are allergic reactions, including systemic contact dermatitis.  What is quite unusual about this case, though, is that drug-related skin reactions occurring after systemic administration, immune-mediated or otherwise, are not usually not picked up during preclinical testing at all.  They are usually first reported during clinical trials as human adverse reactions, sometimes not seen until after approval.

I couldn’t think of another example of a drug-related skin lesion following oral administration to monkeys, or any other non-human species, that was first seen during preclinical studies to compare with this case.  If you know of one, please enlighten us.

For their part, Merck reportedly denied the existence of any skin tox findings with Januvia.  Assuming that’s true, the Galvus monkey finding would appear to be specific to the drug and not an effect related to inhibition of DPP-IV per se.  GSK, whose DPP-IV Redona (denagliptin) was recently put on hold in Phase 3 for undisclosed toxicity issues, didn’t comment on the Novartis news.  Stay tuned for more from me on this story.

It was hard to miss last week’s News Release  and related press regarding the recent mouse study of resveratrol in Nature (sub. req.).  In a nutshell, resveratrol appeared able to prevent many of the deleterious effects of over-eating/obesity and extended the lives of obese mice.  The study’s senior author (David Sinclair, from Harvard) is co-founder of Sirtris Pharmaceuticals, a start-up that hopes to profit from the research.  The WSJ did a nice piece on resveratrol and related research just before the study’s announcement (sub req).

Why am I writing on the topic?  First of all, I don’t think any line of research today interests me more.  For as long as I’ve been in the biz, I’ve thought that the holy grail of obesity research is a therapeutic that ameliorates the effects of fat accumulation on cardiovascular risk.  The resveratrol researchers appear to share my belief.  But besides that I wanted to echo some of the cautious remarks being made in response to it.  It’s not that I think the research is invalid; it’s that I think it’s too early to risk taking high doses of resveratrol until more is known about it from human studies, which are recently underway in cancer patients and diabetics.

Some expert commentary made in response to the publication mentions having to drink hundreds of bottles of red wine daily to get the same levels of resveratrol given to the mice.  These comments are clearly intended as some sort of pseudo-warning to those who would consider boosting their intake of wine.  They’re not going to deter anyone with half a brain who is interested in applying this research directly to look for a way to do so.  The way, of course, is to take supplements.  Dr. Sincair himself proudly admits to doing so for several years, implying that it’s okay for others to do so.  It’s not.

As much as I’d like to believe that resveratrol or its cogeners will be life-extending to people, I’ve learned not to let my hopes serve as a substitute for evidence.  It’s one thing to consider using a supplement that has been extensively tested in people (think vitamin C, E, etc); it’s quite another to consider taking a supplement like resveratrol, for which clinical experience is scant.  The risk of harm is high and the risk of benefit is speculative at best. 

There’s no more reason to think resveratrol is safe to experiment with than there is reason to think that a synthetic new molecular entity in Phase 1 clinical trials is safe to experiment with.  Indeed, because resveratrol is not synthetic and not regulated by FDA it faces unregulated hurdles to its use prior to clinical testing.  That means no requirements for toxicology studies conducted under Good Laboratory Practices (GLP) and no required standards for drug-substance or drug-product quality under Good Manufacturing Practices (GMP).  There are also no standards for commercially available resveratrol supplements that may be used to compare the quality of the supplements from lot to lot or between manufacturers.  None of the manufacturers’ websites I visited disclosed the methods they used to isolate resveratrol nor data on intra- or inter-lot variability of resveratrol quantity (by HPLC or another reliable method).  None of the supplements I saw were certified by the USP or another third-party quality assurance laboratory.  Couple this lack of product-quality data with the reportedly markedly low systemic oral bioavailability when resveratrol is used alone (NB for this reason resveratrol supplements often include other natural compounds, such as quercetin, intended to, but not proven to, increase its systemic bioavailabilty in humans) and the lack of information on drug-food and drug-drug interactions, and you have a perfect storm–a medical disaster waiting to happen.

In other words, buyer beware and buyer, please be careful.  If you are going to experiment with resveratrol despite my admonitions, find a manufacturer of some repute and have yourself checked out by a doctor soon after starting.  I wish I could advise you well on the appropriate starting dose.  I’ll do the best I can.  In the Nature study, the mice had the observed benefits while eating a diet containing resveratrol at a dose of 0.04% (wt/wt).  This was reportedly roughly equivalent to 24 mg/kg/day.  Assuming that this dose really was non-toxic, and assuming the supplement you choose provides systemic bioavailability similar to what was provided by the dietary resveratrol, and further assuming that interspecies toxic effects scale on a mg/kg basis, you can use a scaling factor of 0.08 to find the human equivalent dose that will provide a safe starting dose.  In other words multiply 24 by 0.08, and that gives you the human equivalent dose in mg/kg.  So, a dose of 2 mg/kg/day might be considered a maximally recommended starting dose, given the myriad assumptions.  I’d suggest adding additional safety margins if the chosen supplement contains high levels of other substances intended to decrease the metabolism of resveratrol.

We now know how much it costs to fire your CEO–minimum–if you’re the Board of a major Pharma company: roughly a year’s salary. That’s how much Peter Dolan will receive from BMS in cash severance. He’ll also take away another $9M in pension benefits for his 18 years of service with the company. During his tenure as CEO of BMS, Dolan took home a total of $26M in salary and bonus COMP (excluding options exercised). At the same time, BMS’ market value fell by 55%, with most of the decline coming during the first 6 months of Dolan’s tenure.