Rewarding risk

December 01, 2014 by AUTHOR_NAME in Sullivan's Blog

When you start talking about rewarding pharmaceutical firms for taking risks you know this is going to get into hot water rather quickly! No one is going to take kindly to this sort of talk, and it’s a little too close to bankers bonuses for comfort. But the major firms do well by any ones standards and employees are well remunerated. Despite this commercial success there is a growing chorus of voices articulating the same mantra; that pharma are taking on too much of the risk in cancer drug development for too little. So is this hand wringing justified or is it just another political ploy to leverage position and benefit?

By any account cancer drug development is a success story. From some 65 new molecular entities in development in the late 1980’s to nearly a thousand now not including the work on companion diagnostics or other ancillary drug related technologies things don’t appear too bad on the face of it. The problem, however, is not the lack of targets or drugs to hit those targets. The problem relates to the intersection between the rapidly increasing costs of taking a drug to market and the rapidly reducing marginal benefit of each new addition to the therapeutic armoury. There are some exceptions – imatinib in CML and recently crizotinib for breast cancer – but these are small populations and no ‘blockbusters’ have really emerged. There is growing realisation that as Bill Sellers from the Novartis Institute for Biomedical Research puts it, ‘cancer is a lot more complex than we thought’. So evermore creative solutions need to found. And of course creativity, as Kay Redfield explains in Touched with Fire is intimately linked with our ability to take risks. And lets be clear this is about creativity not innovation. Innovation is an engineering term designed for linear thinking or business guru’s who believe that to get from ‘A’ to ‘E’ you need to go through ‘B, C, and D’. Creativity is about missing out these steps, it’s about the need for non-linear emergent thinking to overcome some of the most complicated issues in biology and chemistry.

So how are we to get more risk taking into cancer drug development? The popular business mantra is all about public-private partnerships. To hear the talk today you’d think some stratospheric insight had been achieved. Sadly nothing could be further from the truth. The stark reality is that public private partnership has been around for a very long time in different guises. Externalizing more R&D to increase the number of drug projects and thus the chances of getting a major new product to market isn’t new. This externalization has occurred, for the most part, through fairly traditional models—such as product licensing, program partnerships, or company acquisitions—which favor majority control of assets and put primary responsibility for product development and commercialization in the hands of pharmaceutical companies. The public sector has contributed through both federal and not-for profit routes with little change over the last forty years in their relative proportional contributions (about a third each). The only difference is by country level where either federal or philanthropic partners dominate from the public side. Where there has been a strong public sector drive in cancer drug development, e.g. the UK, the conversation rates in development (phase I to II, II to III, etc) haven’t altered much either. Don’t believe me? Then read this wonderful paper in memory of Tom Connors, one of the greats in cancer drug development.
So if this isn’t the solution what is?

It may seem rather paradoxical asking pharma to take more risk. But this isn’t about being ‘unsafe’, it’s about being creative. Most members of industry are no more enthused about making mistakes than they are about truly being creative, because those things can be terribly costly and time consuming. Better to take the safe approach and churn out your own version of that hot new product everyone else is also churning out. It’s got a lot less downside to it. The trick is understand how to promote and manage risk taking in individuals and organisations. And our evolved psychology has alot to tell us here. New research shows that not all risk is created equal and people show a mixture of both risky and non-risky behaviors. We take risks when in competition with other individuals; competition with other groups; when allocating resources for mate attraction or fertility (probably not particularly relevant to cancer drug development!); or when presented with a certain type of environment. What comes out clearly in the risk / creativity space is that to get the best out you need to promote risk not reward it. At the individual level in and out group competition appears to the best motivating factor. In spite of the new trendiness towards a commune like approach to scientific collaboration it appears that the knowledge of someone breathing down your neck is still the best way to push risk and ultimately creativity. But what about the environment? Here things have become a lot more challenging.

Considerable empirical effort in human decision-making has been devoted to the question of how individuals judge the value associated with a risky prospect. A large body of studies has demonstrated that we systematically violate the predictions of expected-utility theory in response to framing effects. In the common vernacular that means people are risk-averse when dealing with gains, but risk-seeking when the same problem was presented to emphasize losses. This reflection effect has been observed in important real-world market anomalies, even when financial stakes are high. Most notably, stockmarket investors have a tendency to hold assets that have declined in value and sell assets that have appreciated. Additionally, house sellers have been shown to leave their houses on sale longer when market prices are currently below their buying price. This asymmetric risk-preference over gains and losses does not disappear as stakes increase. The problem is that in cancer drug development, indeed in the pharmaceutical industry the whole socio-cultural space inhabited by organisations and individuals is occupied by a ‘gain’ culture; put another way, “We/I have too much to loose”. And this is the problem. If the meta-culture of drug development exists in this space the psychological framing is one of risk aversion. It’s not easy to see how you can change the direction of such a super-tanker. Thank goodness then for emerging economies. The last time I was in India chatting to a terrific young researcher working on a particularly ‘high risk’ biological I asked him whether he was worried it might not pan out. His answer was direct, “I’ve got nothing to loose”. We in high-income countries have created a system of federal, philanthropic and commercial players that may have too much to loose.