Raymond G Hill
Department of Medicine Imperial College London, UK

https://doi.org/10.36866/pn.92.27

Over the last 50 years many models have been proposed as the ideal way to discover drugs, but there is now general cynicism about the possibility of there being an optimal approach (Douglas et al. 2010; DiMassi & Foden, 2011). The cyclical nature of drug discovery caused by the time lag in incorporation of new academic basic science discoveries into drug discovery paradigms is as likely to have been the reason for swings from success to failure as is an inappropriate approach taken by the industry. Those who have worked in the pharmaceutical industry for any length of time will be aware that one constant factor for the sector is change. A continual process of internal reorganisation is a feature of the R&D organisations of most major companies. They seem to oscillate between a benevolent autocracy where a strong individual as R&D Director makes most of the key decisions swiftly (right or wrong) and governance by committee where decisions are delayed or not made at all. Surprisingly, both systems have been successful in the past and both have been shown to fail! In the golden years for the industry (probably dating from the mid-1980s to the mid-1990s) drug discovery seemed relatively simple, regulatory hurdles were easily jumped and governments and insurers were prepared to pay a premium for new and effective medicines. This resulted in large profits, some of which were reinvested in new research institutes and expansion of existing facilities. For example, over this period staff numbers in Merck/MSD R&D increased from 1500 to 10,000. There was confidence that application of modern automated technology such as robotic high-throughput screening would lead to yet more and better drugs. In the early years of this century it became obvious that just doing more of what had been successful in the past was not working and that a new approach was needed. Much more money was being spent on R&D without any obvious increase in productivity and this clearly could not continue (Munos, 2009). It was not immediately obvious what the new approach needed to be. Although an increase in collaborative research through links with academic laboratories and small companies was tried by all of the major companies, it did not seem to make an immediate difference to the number of new products reaching the market (Arrowsmith, 2011). However, a number of factors have become apparent in the recent past that will change our world in ways which we probably could not have guessed at 10 years ago. The belief that drug discovery could be industrialised is clearly mistaken. Access to larger numbers of molecular targets, larger numbers of drug-like compounds and faster screening technology has not led to proportionally more registered drugs (Munos, 2009; Abbott, 2010). Similarly our knowledge of the human genome has not yet paid off in full, although the large amount of genomic information now available and the falling cost of obtaining this have increased the power of molecular diagnostics and our ability to choose validated drug discovery targets (Plenge et al. 2013). The consequences of this have already been seen in oncology where understanding the genetic basis of survival and proliferation of particular tumour types has led to design of targeted therapies and the move toward use of these new drugs only in those patients most likely to benefit. We are thus learning more about disease processes day by day, but much of this knowledge is difficult and slow to translate into drug discovery. The regulatory environment has also become stricter with greater demands for patient safety leading to ever larger clinical trials of increased duration and cost. This has led to the industry abandoning areas of research that were seen as too difficult (CNS – see Abbott, 2010) or where prospects for return on investment were poor (antibiotics – see Coates 2012; Torjesen, 2013). The rise of governmental bodies concerned with cost effectiveness of new treatments (e.g. NICE) has also put constraints on the potential profits that can be made from new agents at a time when development costs are higher than ever before (Eichler et al. 2010). The medical need for new treatments has never been higher yet constraints on the drug discovery and development process are making the pharmaceutical sector less attractive as an investment.

Senior figures in the pharmaceutical industry are now saying in print that we need to reinvent the discovery process (Paul et al. 2010; Bennani, 2011). If we cannot close the gap between drugs losing patent protection and new product introductions then the industry will shrink. For the first time in living memory a reduction in the R&D spending of the industry has been driven by the incontrovertible fact that spending more on R&D year on year did not work (Carroll, 2010; Hirschler 2011; Piomelli et al. 2011). The realisation that ‘doing more’ was not the answer to increasing R&D productivity was slow to come. But once it was accepted that ‘quality not quantity’ was what was needed, then most – if not all – of the major companies proceeded to reduce the size of their internal research operations. Outsourcing, especially chemistry to India and China, and development to international CROs, closure of ex-US research institutes and increased reliance on academic collaboration were all expedients used across the industry (see McKernan, 2013). The driver now is to reduce costs where possible, get the investment right and only invest where probability of success is high (Kola & Landis 2004; Paul et al. 2010). Major reorganisation of R&D departments has included creation of virtual departments tasked with doing all or most research in a particular therapeutic area outside the company (e.g. CNS research at AstraZeneca – see Mullard, 2013a) and the setting up of internal business units that had to compete for funding as though they were biotechs (GlaxoSmithKline). This is coupled with a need to streamline development (FDA, 2011) and kill drugs that are not clearly an improvement over what we already have as early as feasible (Paul et al. 2010). It is perhaps necessary to admit the need to empower creative talent and admit that drug discovery is as much an art as a science (Douglas et al. 2010; Paul et al. 2010; Bennani, 2011). The crucial reorganisation may already be in progress with much of the creative part of drug discovery moving over to the biotech sector or to academic centres for drug discovery(Kotz, 2011; Stevens et al. 2011). Academic collaboration and recruitment of staff at the cutting edge of their fields facilitated by relocating research operations to academic centres of excellence is also a move being followed by most of the major companies. This phenomenon was first seen en masse in Cambridge, MA, USA, but the setting up of a substantial Pfizer research unit (Neusentis – see McKernan, 2013) and the recent decision of AstraZeneca to move their research headquarters to Cambridge,
UK may herald the start of a similar consolidation of industrial research around what is seen as the academic community most likely to be supportive of innovative drug discovery. In this context it is also interesting to note that the academic contribution to drug discovery may have been underestimated in the past (Stevens et al. 2011). Not all academics wish to work with or in the pharmaceutical industry, but for those who do, or are prepared to give it a try, the next decade will be a time of unique opportunity (Kotz, 2011; McCall, 2013; Mullard 2013b).

Investment in new R&D facilities is being made in those countries which are seen as major future markets for drugs. It is already evident that cuts in R&D spending in the UK and US have been paralleled by an increase in spending in Asia, especially in China (Zhang, 2011). One reason for the failure of the industry to sustain its productivity has been the patent expiry of the blockbusters discovered during the 1980s so that they became generics. Subsequent new drugs have had to compete with them both on efficacy and on price. In the future it may be necessary to perform an ongoing assessment of a drug’s effectiveness and safety such that the benefit–risk profile is recalibrated during the whole life cycle of the drug in question (Breckenridge et al. 2012). These factors are driving a shift from proprietary medicines to generics and by 2015 it is likely that generics will account for 39% of the total drug spend compared with 27% in 2010 (IMS, 2011). We are thus victims of our own success as the blockbusters of 2005 become the generics of 2015. Repurposing of drugs is now a major topic of research for industry–academic cooperation to jump-start new therapeutic approaches by shortening the development pathway (Corbett et al. 2012). New drugs are continuing to be discovered, many of them coming from the biotech sector (Kneller, 2010) and there is an increasing using of proteins rather than small molecule agents. Around 50% of the new drugs that will drive profitability in 2015 will be biologicals and the majority of these will be monoclonal antibodies (Nelson et al. 2010; IMS, 2011). Spin-out companies are arising from the large companies as a result of downsizing and these are starting to be productive, although there is still a funding gap for new companies that can make this process difficult to initiate. There is evidence that the new model of R&D will be a triangular association of large pharmaceutical companies, small specialist companies and academic groups working very closely together. Open access initiatives where a common precompetitive objective is worked on cooperatively without intellectual property constraints are starting to take effect (Hunter & Stephens, 2010; Hunter & Wilson, 2011) and are a logical way to achieve regulatory approval for a biomarker as a surrogate endpoint for clinical trials. It has also been suggested that a systems biology approach will lead to better predictive modelling of clinical outcomes with novel approaches and that the lead in this will come from academic laboratories (see Abbott, 2008).

There is some evidence from recent observations on failure rates in clinical trials in 2011 and 2012 that we may be turning the corner and that more drugs are failing in phase II and fewer in Phase III, suggesting that the industry is now designing better trials that allow early termination of failing hypotheses (Arrowsmith & Miller, 2013). It has also been suggested that the innovation drought in the pharmaceutical industry is a myth and that current incentives do not reward true innovation, but reward companies for producing large numbers of new drugs with few clinical advantages over existing ones (Light & Lexchin, 2012). It is certainly true that incentives offered by regulatory authorities have resulted in a big increase in drugs targeting rare and orphan diseases and in both 2011 and 2012 a record number of orphan drugs were approved (Geilinger et al. 2013). Our world will look very different 10 years from now with an increasingly complex social, legal, scientific and political environment, but we should not lose sight of the fact that virtually all major advances in drug therapy have come from large companies and have been funded out of profits rather than philanthropy. Any remodelling of the drug discovery process needs to be in the context of a business model that allows recovery of costs and ensures that a fair reward for innovation is still achievable for those companies involved in this endeavour.

Acknowledgements

I am greatly indebted to all my colleagues during my 25 stimulating and enjoyable years in the pharmaceutical industry. Many of the views expressed in this article are attributable to conversations with them but any mistakes are entirely mine!

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