Pharma’s Cutting Edge

In his broad, rambling essay (don’t they use editors in peer-reviewed journals anymore?) in Wednesday’s JCI, “Drug discovery in jeopardy“, Pedro Cuatrecasas, former head of R&D at Warner Lambert, tackles the problem of lagging Pharma innovation productivity.   

I find myself in disagreement more often that not with Dr. Cuatrecasas, who paints his argument with such broad, sweeping generalizations based almost entirely on anecdote that he loses me in the resulting morass.  Fundamentally, although we disagree on the specifics, Dr. Cuatrecasas and I do find important common ground in his thesis–that mismanagement of innovation is restraining improvements in Pharma R&D productivity.  I have argued this point several times in past articles in this blog and in the white paper I recently published (Strategy from Science: Evidence-based Scientific Management Principles for Pharmaceutical and Biotechnology R&D Strategists”).

Our disagreement on the specifics of the argument is important, because the devil is in the details, as they say.  Here’s are some quotes from Dr. Cuatrecasas that sum up many of his reasons for the failures of Pharma R&D management:

Most corporations’ top management does not understand the complexities of science, its mode of conduct or objectives, and runs the companies in ways that stifle creativity and innovation….With such restructuring [led by management-consulting firms], drug companies now felt more confident that they could manage and mandate results with discipline, order, formality, and efficiency. Unfortunately, many of these qualities are ones that suffocate creativity and innovation…..While in charge of R&D at Burroughs Wellcome Co. from 1975 to 1985, I witnessed many startling examples of the folly of rendering early marketing (or technical) predictions when dealing with novel compounds or diseases….Clearly, it is exceedingly difficult to predict the technical or commercial outcomes of novel compounds. One needs to focus instead on the novelty and relevance of the science, the technical rationale, basic pathophysiology, predictability of animal models, availability of human disease models, feasibility of development, and the future potential medical need as perceived through knowledge, experience, and instinct of scientists and physician-scientists. One must proceed with conviction that some of the novel compounds in the portfolio, all of which should have sound inherent scientific merit, will overcome the obstacles in development and provide real value, despite perceptions of potentially limited sales.

First, here’s where I agree:  leaders of technical or science-based companies should themselves ideally be scientists or have unusual empathy for scientists and strong fundamental scientific training.  Again, I’ve argued this point many times, although admittedly without hard data to support my contention.  Let’s leave it at that for today.

We also agree that organizational changes are instituted frequently in keeping with the latest management thinking (have you been “BCG’d” this year?), and that some, perhaps most, of these changes undoubtedly do not aid the advancement of innovation.  That said, I believe that most organizational changes have no deleterious effects on creativity at all, nor is creativity ever in short supply in Pharma.  It takes much more than organizational changes of the kinds witnessed by Pharma since the mid-80’s to squelch individuals’ creativity to a meaningful extent (I know…it sure seems like someone was trying hard to squelch it).  Rather, organizational changes will have strong effects on which ideas are “bubbled up” to become projects and which projects are supported to become products.  To the extent that organizational changes have failed to deliver in their promises of improved decision-making around such ideas, I vote guilty as charged.  In general, Pharma instituted and continues to institute organizational changes without sufficient data and evidence pre- and post-implementation.

The idea that commercial forecasts are as wrong as they are right today is becoming cliche.  Like most cliches it’s grounded in truth.  But let’s not toss out the baby with the diaper!  Managing innovation with constrained resources demands rational prioritization of projects (and proto-projects).  Indeed, such prioritization will necessarily occur even if it is not formalized by management or made explicit to researchers.  The answer to the poor predictive ability of commercial forecasts, therefore, is not to depend on management without formalized forecasts or explicit priorities and to instead depend only on the wisdom of well-meaning scientists but rather to develop improved methods of forecasting and project prioritization.  And, just as with organizational issues, I believe the answer to better forecasts (and better portfolio management generally) is better data and evidence pre- and post-implementation.  Sound familiar?

Read the white paper.  Think about it.  Call me.

So, I guess it’s clearer now why Pfizer recently chose to provide guidance that torcetrapib,–Pfizer’s best hope for replacing Lipitor sales when Lipitor goes off patent and loses its pediatric exclusivity in late March 2010–will likely face higher regulatory hurdles than they had earlier let on. Pfizer on Oct 31st (see Therapeutics Daily) announced that results of a Phase 3 clinical trial demonstrated increases of 3 to 4 mm Hg systolic BP. 

Pfizer had previously indicated that FDA would finish its review of the pivotal intravascular ultrasonography (IVUS) trial, in which Pfizer hopes to demonstrate plaque diameter reduction with the drug, by end 2008.  It warned, though, that a clinical outcomes study could be required before FDA approval.  Such a study is underway, but results won’t be available until 2010 at the earliest.

Does this blood pressure finding, 1-2 mm higher than what was seen in Phase 2, really change the outlook for approval?  Yes and no.  I think what it does is cement the need for an outcomes study pre-approval, but I also think this was likely to be required anyway, and Pfizer was simply being overly optimistic to the public after Phase 2.  Perhaps the recent change of management at Pfizer has caused them to take a more realistic public stance, or maybe they were just waiting to see the BP results from Phase 3 before urging caution, but I’m just speculating.

Assuming the drug actually does improve cardiac morbidity/mortality, Pfizer investors might actually be better off taking a hit from an approval delay.  I say this, because I think the drug’s sales are going to suffer mightily without an outcomes trial.  Again, I’m speculating, but I make this point because the stock’s value pre-launch reflects technical/regulatory uncertainties as well as sales expectations of torcetrapib, whereas the post-launch value is going to reflect sales expectations primarily. 

Look for Pfizer to downplay the relative importance of torcetrapib to Pfizer’s long-term growth prospects, as would be wise.

Finally, I wouldn’t try to transfer the experience of torcetrapib to therpies aimed at increasing HDL-C through mechanisms other than CETP inhibition.  The only relevant lesson is that sponsors must expect and plan for an outcomes study pre-approval for virtually any chronic-use cardiovascular drug with a new mechanism of action.  Plaque reduction studies are nice but aren’t going to cut it for most new drugs.