Drug Baron

Incremental innovation lives on


In 2010, DrugBaron declared the death of incremental innovation and wrote the obituary.  It didnt seem a very bold statement at the time – increasing payor pressure was beginning to bite, and it seemed obvious that the entrenched practice of paying a premium for small (often imperceptible) improvements was passing.

If payors, whether governments, private insurers or even patients, were unwilling to pay for incremental innovation, then the inescapable logic seemed to be that the industry would have to stop developing such products, and instead seek bigger improvements in clinical performance.

But three years later, the market for late-stage products that show little, if any, differentiation remains as frothy as it has ever been.  As if to prove the point, Astrazeneca invested a little over a billion dollars in two such products in one month: another LABA combination from Pearl, and another prescription fish oil capsule from Omthera.

Global pharma companies are using their vast balance sheets to warp reality

With deals like this on the table, why not develop another me-too product against a well-validated human target?  After all, the technical risk is very low.  So as long as you as are confident someone will acquire the product, it looks like an excellent investment.

In common with Mark Twain, then, reports of the death of incremental innovation were clearly exaggerated.

How then can you square the circle?  If payors increasingly refuse to pay for incremental innovation (even before ‘pay for performance’ really takes off, as it surely will), yet pharma companies are paying big bucks for poorly differentiated products then someone has to be making a costly error.

The answer according to DrugBaron, is that pharma companies (or some of them at least) are using their gargantuan balance sheets to absorb the pressure from payors, rather than transmitting it to the early stage discovery efforts (whether internally or externally).  While they continue to buy poorly differentiated late-stage products, the drive to discover and develop really risky assets that might deliver a step change in outcomes remains impotent.

The big question has to be why do they do it?

After all, it is a strategy that is likely to end badly.  If you fill a pipeline with products displaying little real innovation or improvement in outcomes against a landscape where increasingly no-one will pay for such products then you are setting yourself up for catastrophic failure.  You can only ignore the demands of your customers for so long, even in the Alice in Wonderland world of pharmaceuticals.  A big balance sheet only provides so much insulation.

But that failure is a long time coming.  And if you are very big, it could be a decade or more away.  It seems that there are much more short term concerns that demand action – and lead to behaviours that are ultimately close to suicidal.

Elias Zahouni, the eloquent R&D chief at Sanofi recently hinted at the underlying cause of these conflicting behaviours: large pharma companies are principally motivated by fear, and expend 90% of their effort on defending existing revenues rather than on generating new sources of income.  Such defence is prudent and necessary, but the balance is wrong, he says – maybe half and half between defence and innovation would be a healthier mix, with maybe 10% on the really wild-eyed vision.

This defensive attitude causes pharma to acquire products that are less risky (and hence less innovative) than their customers are demanding.  That is a very dangerous mis-match – and one that becomes more severe the emptier the pipeline is perceived to be.

For a publicly-traded company, the spotlight falls heavily on the late-stage pipeline.  And bad news translates quickly into a falling market cap.  Faced with a choice of two kinds of bad news – a Ph3 clinical trial failure or the failure of a product to win a substantial market (products that DrugBaron has previously called ‘busters’, as opposed to ‘blockbusters’), then the defensive executive will always chose the latter.  After all, market failure will only be obvious nearly a decade down the line.  A phase 3 failure could hit the value of the company tomorrow.

Far better then to acquire a product with so little innovation that it can hardly fail to be approved – and then sweat about whether payors will actually pay for it in any kind of volume – than it is to acquire a genuinely innovative, first-in-class product and then discover it has feet of clay.

And the more your innovative bets tumble (as Lilly as experienced recently), the greater the pressure on the executives to flex the balance sheet and acquire “safe” bets.

The result will surely be a viscous downwards circle, where acquisitions of undifferentiated products that cannot fail in the clinic leads to too few sales to justify the purchase price.

There has to be a very real risk that some large pharma are already uncomfortably close to this ‘death spiral’

Avoiding this fate isnt just about taking more risk, even if the public market investors would tolerate it.  The industry has to get smarter at taking these risks.  Right now, too many innovative first-in-class programmes are failing in Phase 3.

The problem is not that real innovation is risky – of course it is.  But a way has to be found to fail these programmes much earlier.  DrugBaron has already examined the factors that several pharma companies to progress anti-amyloid drug candidates into Phase 3 (and indeed to keep on trying) when all the data (even from Phase 2) suggested this class of agents was doomed to fail.  The same story applied to Merck with the CETP inhibitor anacetrapib, and most recently to Astrazeneca with fostamatinib.  To his credit, at least Pascal Soriot and his team accepted the failure, took the painful medicine, killed the fostamatinib programme and moved on.  Anti-amyloids and CETP inhibitors, though, continue to consume vast resources with little hope of eventual success.

Taking the risks necessary to deliver real advances in patient care are only economic if the discovery and development costs can be shrunk – not just 20-30% as has been widely accepted across the industry but by two-fold or even more.

That kind of cost reduction cannot be achieved by evolving the old model – a model that in any case grew in a very different world: a world of ‘gold rush economics’ where any approved drug automatically garnered sufficient sales to justify discovering a new drug at any price.  Discovery was optimised for success not productivity.

Survival isnt just about taking more risk; instead the industry has to get smarter at taking these risks

A change in the way we design and interpret Phase 2a studies, the key gatekeeper in the drug development process, lying between relatively low cost early development and the mega-bucks of late stage, is the most pressing need.  Studies must be able to distinguish those products that will succeed, not just in later development but also in the marketplace, from those that are doomed to fail sooner or later.

Yet again, though, the conservative mindset in large companies makes such changes difficult.  If a study is borderline, or yields a grey result, its better to keep the pipeline full and delay the bad news for another day.  After all, it might work.

And its not just large companies.  The defensive mindset can permeate even the smallest operations if the management feel that their jobs, or even their careers, are in peril should the product they are developing fail.  The incentive to delay failure, until later in development, or even into the marketplace, are very strong indeed – even while repeating the ‘fail early, fail cheap’ mantra, executives in drug companies large and small are, it seems, still behaving in exactly the opposite fashion.

So incremental innovation is alive and well.  Even as its starved of oxygen by the tightening purse strings of the eventual customers, it is being sustained by the stronger imperative to avoid clinical failures, or any kind of imminent bad news, by pharma companies who failed to grasp the need to change to a leaner discovery and development model a decade ago.  For those that did start that process earlier, and whose late stage pipeline looks healthier as a result, they need to stick with it – and cut costs even more aggressively, allowing them to keep up the level of risk they can take to deliver real innovation.

 If you fill a pipeline with products displaying little innovation against a landscape where no-one will pay for such products then you are setting yourself up for catastrophic failure

Only they will survive.  Any that are caught in the trap of doing low-risk incremental innovation when the customer demands a step-change in outcomes, defying logic through the sheer power of their balance sheets built up on historical successes, will end up completely drained.

For early stage investors, then, there is a real conundrum – should they back poorly differentiated products because they offer good returns at lower risk as long as pharma keep buying?  That depends on how long the largest companies continue to use their financial muscle to warp reality.  DrugBaron was three years too early calling the death of incremental innovation – and he is not about to repeat that mistake.  Incremental innovation ought to be dead, but it looks like it will be around for a while yet.




  • Pingback: Incremental innovation lives on

  • Dani Bach

    It makes sense, doesn’t it ?
    Pharma have demonstrated to be very good at marketing and less good at doing R&D, and logically they keep focusing on what they do better, and probably so they should. Acquiring low risk , incremental innovation products, is part of their marketing efforts. They know the drug will reach the market, and will compete with other similar drugs for a piece of the cake, but do they have the choice to do otherwise ?

    Pharma marketing expenses has always been the paradigmatic example of the dilemma prisoner. Say that two pharmas have two identical drugs in the market for the same indication. They can chose not to invest a single $ in marketing and share the market 50/50, or they can chose to invest the same insane amount in marketing costs and still get the same 50/50 market share at the end, but with less net profits. And this is what actually happens, because if one of them decides not to invest in marketing, the other, investing a little bit, takes it all.

    Acquiring incremental innovation products (or even null innovation products) obeys to this same logic. Of course it would be better that nobody in the industry wastes their time on it, that all companies focus on developing the real innovation patients need, but the reality is that this is a race for market share with WHATEVER PRODUCT AVAILABLE, and if you don’t run this race, or you lose too much time focused elsewhere, the incumbents take it all.

  • AJ Aralihalli

    Dear Drug Baron,

    I enjoyed your blog on incremental innovation. Unfortunately, a number of the incredulous decisions that you write about are driven by “normal” human behavior.

    Take for example the following quote which is really a composite of quotes that you often see in press releases that try to put a positive spin on a clinical trial failure:

    “We plan on continuing to invest in Drug X, we are confident that it will ultimately show a treatment effect; while it did not show significance in this trial, there was a clear trend in favor…”

    This simple line incorporates several often seen and extensively-researched biases (some of which you have written about in previous blogs):

    Loss Aversion/Risk-Seeking/Sunk Cost – Gambling on eventual success rather than take the sure loss early.

    Overconfidence Bias/Endowment Effect – People in general do not like admitting failure too quickly and will often fail to see flaws in “their” molecules that they would normally point out in others.

    Confirmation Bias – The tendency for people to favor any information that confirms their hypothesis and discount information that does not.

    Perhaps we can change how such decisions are made by properly incentivizing people and making them aware how biases such as these affect their behavior?

  • Kelvin

    David, I love this article: you sum up very well the fundamental problem of short-sighted risk aversion in big pharma, copying existing innovations with the ultimate effect of pushing more and more risk later into development and beyond into the market (out of sight and out of mind), rather than developing new breakthrough innovations with an entrepreneurial mindset: think big and different, start small, fail fast and often, learn as you go.

    In fact, I wish you would join and contribute some of your thoughts to our linkedin group, which I have established to identify and address some of the fundamental, underlying causes of declining innovation and R&D productivity in big pharma: