Sunday, February 17, 2008

Big Pharma's Big Problem contd. - a theory on dry pipelines

Daniel Silverstein has a theory about why Big Pharma is drying up, which may shed some light on what is really going on.

First, the absolute size and complexity of these organizations is so vast as to require highly sophisticated and elaborate management procedures to keep track of exactly what is going on. At the individual level, compliance with both the day-to-day reporting requirements, justification of projects and the periodic planning cycle consumes time, energy and resources that would be better spent on science. On the management level, the cost of infrastructure, control systems, real estate and staffing places an enormous cost burden that each drug candidate must bear, whether successful or not.

Second, the Blockbuster hurdle is too high a standard against which to measure the potential worth and value of every new product candidate. The conundrum though, is that the high cost structure of developing drugs in the typical Big Pharma setting requires that kind of financial outcome before full support is forthcoming. Since unreliable filters are set in place to assist in these judgments, not near enough candidates are launched on the perilous journey of development for an adequate number to survive the trip. I offer this comment by way of opining that predictions of final market potential cannot, by their very methodology, take cognizance of serendipitous medical insights that only occur when a drug is broadly used by physicians. Additional indications, more efficacious dosing levels, new regimens all represent value building opportunities that can be difficult to foresee.

Third, the portfolios of undeveloped compounds residing on the books of every Big Pharma represent valuable intellectual property that the owners are both reluctant, if not downright fearful, to see commercialized. The reasons for this are obvious – nobody is strongly incentivized to do deals; if, God forbid, one of these sleeping beauties turns into an actual blockbuster in the hands of another, the shame and humiliation would be matched only by the swiftness of termination of the offending deal maker; in Big Pharma not making decisions is often as well rewarded as making them (without the attendant risk).
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1 comment:

Anonymous said...

Maybe another reason for this debacle is that drug research today is increasingly led by findings from animal models of disease that have no real similarity with the human form of the disease.

In the 'old days' people first tried to understand the human form of the condition (as best as they could) and then searched for animal models that were very similar.

Nowadays the usual pattern goes somewhat like this- Some ambitious academic/ industry scientist selects a pet hobby horse (target) and makes some mutations in some animal (or selects some very defective inbred strain) that produces the desired results. They then try to 'sell' that as a good model of the disease.

In such a scenario the best salesmen (often the worst scientist) can best promote their model. Consequently any drug developed to treat the condition in that animal might cure that animal but have no or suboptimal therapeutic activity in humans.

A related situation is encountered when animal studies do not clearly show potential but foreseeable problems in human beings.

If you do not believe this, think of the real reasons drugs fail in phase III or beyond. A few examples include- torcetrapib (cetp inhibitor), ezetimibe (NPC1-L1 inhibitor), rofecoxib (cox-2 inhibitor), rimonabant (cannabinoid antagonist), varencline (partial nicotinergic antagonism)to name a few.

In each case there was either

a] less than satisfactory evidence for involvement of the proposed target in the disease (are LDL or HDL cholesterol levels/ ratios a proxy for increased risk to CVD or the cause in most humans?).

or b] poor understanding of the other roles of the receptor in normal human physiology (cox-2 inhibition, cannabinoid antagonism, partial nicotinergic antagonism).