Business

Collaboration for innovation is the new mantra for the

In order to maintain a flow of innovative medicines there is a growing realisation that companies cannot allow the status quo to remain as it is and the need to identify sources of appropriate knowledge and expertise outside of their own organisations is paramount. This article discusses some of the challenges in arranging collaborative arrangements with each other and academia.

uch has been talked about the crisis in try and not adopted or supported by academia By Professor new drug development and the lack of and research funders? Jackie Hunter Mproductivity in the Pharmaceutical Pre-competitive research has been recently industry1. However, the crisis is also true for the defined by Janet Woodcock as “science participated biotechnology firms which the large pharmaceuti- in collaboratively by those who ordinarily are com- cal companies have come to rely on as a source of mercial competitors”4. Open innovation, on the pipeline sustainability2. other hand, although defined in many different This has prompted an examination of all ways, is basically the proactive use of a company’s aspects of the biomedical research and develop- intellectual property (IP) and resources to create ment (R&D) process in recent years to try to cut new innovations and generate new products and costs and improve efficiency and productivity. accompanying IP. It promotes both external and Although this has led to mergers, reorganisations internal sources of innovation and thrives in an and tens of thousands of job losses in the industry, environment where ideas are spun in and out of a so far it does not seem to have created the radical company in a very dynamic way. To create this shift required. If a radically different model is environment needs strong senior management sup- needed for companies to survive and thrive, what port as it requires a culture very different from the might that look like? Some authors have proposed more controlling, hierarchical R&D culture that abandoning the current system of patented medi- still existed in many companies at the turn of the cines altogether and introducing the funding of century. By definition, it also requires much more pharmaceutical R&D through taxation or prize- proactive management of, and communication based funding systems3. Another approach that about, a company’s unused IP. Many companies has been adopted by other industries to solve sim- have begun to explore what this means in a phar- ilar problems in terms of lack of productivity and maceutical context but it is clear that such a radical innovation is to build strategies around pre-com- new approach will require more time, effort and petitive collaboration and open innovation4. resources. However, the benefits of adopting these Many large pharmaceutical companies are now different ways of collaborating could be extensive espousing the virtue of these approaches but will in both tangible and intangible ways – reducing cost they work if adopted inconsistently by the indus- of failure through predictive biomarkers, leveraging

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of unused IP and external funding mechanisms, failure are lack of efficacy in man and unexpected access to networks of talent and innovation and toxicity either in animals or man. Therefore it is increased trust and transparency with patients and not surprising that the major areas of collaboration other stakeholders. These benefits will be realised have been in the development of tools and tech- not only for pharmaceutical companies but also for nologies for target validation and the discovery academics and other collaborators. and validation of biomarkers for efficacy and tox- icity. Many large public private consortia have Internal innovation been formed, eg the Innovative Medicines Initiative One way of experimenting with these new concepts (IMI) and the Serious Adverse Events Consortium, is to trial relevant tools and technologies internally but there is a need to co-ordinate and integrate to drive cultural change within a company before these multiple efforts within companies so that the ‘going external’. It is always a challenge for large maximum possible benefits are obtained. organisations to be able to harness the knowledge In the future, the effective pharmaceutical com- of their employees and bring people together to panies will find themselves as hubs at the centre of share insights and information, breaking down bar- a network of collaborators and suppliers, focusing riers and challenging silo mentalities. The advent of internally on their core competencies which might computing platforms such as Microsoft’s Share include medicinal chemistry, clinical trial execution Point have facilitated data sharing and exchange and sales and marketing. They will facilitate inter- and pharmaceutical companies would do well to actions across their network to stimulate the devel- emulate companies from other sectors such as opment of innovation ecosystems. The opportuni- Arup, which has developed excellent systems for ties that this will bring to expand beyond tradi- accessing knowledge across an organisation. tional products and markets will enable pharma- Companies such as Lilly and Pfizer have put in ceutical companies to evolve into companies that place internal systems for seeking solutions to offer a range of healthcare solutions. These will problems across their organisations and these have include not only prescription medicines but also demonstrated the power of this approach. diagnostics, branded generics and technologies However, many companies struggle when reorgan- that support personalised medicine as well as isations occur to retain the links and knowledge potentially nutraceuticals and other ‘wellness that has been built internally. Robust systems need options’. Although the internal size of many R&D to be put in place to maintain this knowledge base organisations will inevitably decrease, the com- but these are also important for optimising and plexities of managing and maximising the impact managing links between the internal and external of this external web of relationships will demand environment. Companies such as Procter and new skills and capabilities over and above those of Gamble have an excellent track record in doing excellent science – developing and rewarding this and their approach may also be applicable to employees who possess such skills will be an addi- large pharmaceutical companies. tional challenge. One important question is what is the optimal size of internal R&D activities given Why should companies collaborate this new environment – there is a certainly a criti- with each other and academia? cal mass of expertise required to both attract new At first sight it seems counter intuitive that compa- collaborators and be sufficiently knowledgeable to nies would want to share data and potentially give identify and interrogate new opportunities. away competitive advantage. However, this Furthermore, those companies that excel in the assumes two things: firstly that the possession of development of these new collaborative models such data does indeed give a competitive advantage will have a significant competitive advantage in and, second, that such a closed operating model is being able to work across sectors to deliver more financially sustainable. The drugs that do make it innovative healthcare solutions. to market have to fund the cost of failure of those So what current collaborative models are being compounds that did not make it. As a recent explored by pharmaceutical companies and how Morgan Stanley report pointed out6, the current successful have they been? success rates of the pharmaceutical industry are not sufficient to sustain large internal R&D organ- Collaborations based on sharing of isations and the current operating model is not expertise and resource financially viable. Thus it is essential that compa- One of the companies that has used resource shar- nies either improve success rates or decrease the ing as a way of driving their open innovation strat- cost of failure. The two major causes of compound egy is Lilly. In 2009 Lilly launched PD2, a portal

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Table 1: Open innovation assays at Lilly

DISCOVERY ENDOCRINE/CARD ONCOLOGY NEUROSCIENCE TUBERCULOSIS APPROACH IOVASCULAR

Phenotypic drug discovery Insulin secretion Anti-angiogenesis TB screening module Wnt pathway activator (IDRI) GLP-1 secretion

Target drug discovery GPR119 agonist HK2 inhibitor mGluR2 allosteric agonist APJ agonist CGRP antagonist NTP inhibitor

Details available online: https://openinnovation.lilly.com/dd/science-of-open-innovation/strategic-areas-of-interest.html

which allowed scientists to have their compounds cent to GSK’s UK Pharma R&D site. A more tan- screened against phenotypic, disease-relevant gible example of resource sharing by GSK is the assays that were already established within Lilly. In Open Innovation Labs at Tres Cantos in Spain. addition for interesting compounds relevant sec- Here the focus is on neglected diseases and the labs ondary assays can also be made available to pro- are run by a non-profit foundation. Investigators vide additional biological characterisation. Lilly from around the world can come and work in the provides all the data free of charge and with no labs and gain access to GSK’s expertise, processes, obligation to the investigator and the investigator facilities and infrastructure, including an ultra- retains the IP rights to the chemical entity tested. high-throughput screening facility and Biosafety Within a couple of years it had allowed Lilly to cre- Level 3 in vitro and in vivo laboratories. GSK has ate a network of 70 small biotechnology compa- put £10 million to date into the organisation and nies and 174 academic institutions. Data presented other funders have also provided financial support by Lilly showed that the compounds submitted (https://www.openlabfoundation.org). There are were structurally diverse from the Lilly compound three disease areas that have been prioritised and collection and a reasonable percentage had biolog- investigators have to undertake research projects ical activity in one or more assays7. The initiative that are in line with the foundation’s mission. It has already led to the establishment of new collab- will be interesting to see if there are any insights orations with academia. from this open innovation activity that could be In 2011 Lilly also introduced the TargetD2 ini- more widely applied in other areas of drug discov- tiative. In this programme, Lilly will give external ery and development. access to a panel of well-validated target-based Takeda has announced that it is providing incu- assays across five targets of interest. Importantly, bation facilities for academics and biotech compa- they say that they will also provide access to rele- nies in its Shonan research Centre in Japan, where vant computational methods to let investigators external investigators will be able to work side by carry out structure-based research on the initial side with Takeda investigators. UCB has also results (see https://openinnovation.lilly.com/dd/). announced that it will make some of the new mam- Therefore this model of sharing appears to be malian cell culture bio-pilot plant available to delivering value for Lilly. potential partners together with some in-house Another example of resource sharing is where expertise. These examples show how companies collaborators can access expertise and know-how. are seeking to leverage their in-house expertise and Glaxosmithkline (GSK) has established a group resources to expand their collaborative networks. called Scinovo (http://www.scinovogsk.com). This These companies will evaluate the success of the group sits within the R&D organisation of GSK resource sharing efforts in terms of access to new with access to GSK experts across the whole R&D partners and technologies. continuum. The terms under which this advice is Companies are also engaging more strategically provided are flexible and allow GSK to build in large networks of academic collaborators. For strong links with collaborative partners. The unit example, in 2010 Pfizer announced plans to estab- has been operating for several years and has strong lish Centres for Therapeutic Innovation (CTIs) links with Stevenage Bioscience Catalyst, the which had the remit to build open innovation part- recently-established open innovation campus adja- nerships with academic medical centres globally.

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Table 2: Rational for academics to be involved in Pfizer’s centres for therapeutic innovation Some resource-sharing collaborations have already been established for a while. For example, Acceleration of scientific progress GSK announced in 2008 a five-year, $25 million • Unprecedented access to Pfizer’s world-class antibody libraries and technologies collaboration with the Harvard stem cell institute in Dedicated support and expertise in drug development and protein sciences • Boston where participants would spend time in • Potential use of Pfizer assays and high-throughput screening, biophysical and/or animal modelling, cell-line development, protein/mAb engineering and humanisation or other each other’s laboratories and resources as well as technologies cash be made available to Harvard by GSK. • Intellectual property ownership and license rights to support continued Unfortunately, internal research priorities changed experimentation and exploration within GSK and many of the key personnel, and areas of research, involved in establishing the col- Career enhancement • Reasonable publication rights laboration changed. Whether this led to a reduction • Association with a highly competitive, well-resourced programme of the benefits for both parties is unknown • Diverse training experiences for PIs and postdocs although it must have had some impact. Indeed, feedback from academia groups involved in such Financial incentives collaborations suggests that industry participants • Well-funded fellowships for PIs and their teams • Flexible funds to support the preclinical and clinical advancement of promising can change rather frequently and when they do this, projects it can have major changes on the dynamics of the • Milestone payments and royalties, as appropriate, upon the advancement of collaboration as well as affecting the deliverables. programmes Using compounds to drive Source: http://www.pfizer.com/sites/default/files/research/partnering/cti_brochure_9x12_v12single.pdf collaboration While Pfizer is clearly making its antibody tools and technologies available, including their phage The academic partners would have access to anti- libraries, as part of the CTIs, other companies have body tools and technologies and to work alongside made their chemical compound collections avail- Pfizer staff in dedicated laboratories. The advan- able to biotechnology companies and academic tages for academics in working with the CTIs are collaborators for preclinical screening. For exam- shown in Table 2. To date Pfizer has established 20 ple, Merck Serono is providing a Mini Library, collaborations with major academic medical cen- comprising former Merck Serono development or tres in the USA and has four dedicated CTI labs in research compounds and derivatives, free of charge Boston, New York, San Francisco and San Diego. to investigators for use in their assay systems. Eisai They have received more than 300 research pro- has established a strategic collaboration with the posals and from these 20 projects were selected for John Hopkins Brain Science Institute (JHBSi). In support. Although the academic retains the right to this collaboration researchers at JHBSi build assays patent and ownership of the patent, Pfizer has first against neuroscience targets of agreed interest. rights to license any clinical probes that arise from These are then transferred to Eisai for high the collaboration, although if they decline to throughput screening. JHBSi may then carry out license the academics are free to progress the probe further hit-to-lead work with milestone payments themselves or via further partnerships. If Pfizer for successful projects9. really is making resources and tools available in Previously JHBSi had signed a deal with Biogen- this way, rather than solely providing cash, then Idec which included research support for proposals this does represent a change in the collaborative chosen on a competitive basis by a joint Biogen model between Pharma R&D and academia which Idec-BSi steering committee. The agreement was it hopefully will accelerate progress. streamlined intellectual property and reduced reg- More recently in 2013 the Karolinska Institute ulatory barriers. The first two awards were and AstraZeneca have established a joint venture announced in 2007 and a third project award was called the Karolinska Institutet/AstraZeneca announced in 2009. Target research areas included Integrated Cardio metabolic Centre. This centre Multiple Sclerosis, Alzheimer’s disease and pain. will conduct both clinical and preclinical studies Astra-Zeneca has worked with the MRC to give for AstraZeneca’s two biotech units – AstraZeneca access to 22 clinical and preclinical compounds to Innovative Medicines and MedImmune. In the cen- UK-based researchers. Although only brief details tre scientists from the company will work side by of the compounds are available on the MRC web- side with those from academia and they will be site, more details will be given under confidentiali- able to access all the facilities of the university. The ty if a proposal is of interest. This has some paral- cost to AstraZeneca is up to $20 million per year8. lels with the much larger NCATS initiative in the

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USA where a number of compounds are providing powerful force for driving collaboration. There are more than 50 clinical compounds (http://www. also examples of companies sharing compounds ncats.nih.gov/research/reengineering/rescue-repur- with each other such as AstraZeneca and Bayer, pose/therapeutic-uses/directory.html). allowing companies to greatly expand the range of Companies are also starting to provide a selec- compounds they can screen their targets against. tion of their compounds directly to academic However, this only makes sense when there is little organisations. AstraZeneca has added 250,000 redundancy between the collections, as was the high-quality compounds to the Lead Discovery case with AstraZeneca and Bayer10. Center based in Germany (LDC) to enhance its More recently in 2013, the Innovative Medicines compound collection. The LDC will then identify Initiative launched a project called the European compounds from the combined collection that Lead Factory (http://www.europeanleadfactory.eu). show activity against a portfolio of targets. These The aim is to build a Joint European Compound will be selected by the LDC from its range of aca- Library which can be accessed by both private and demic partner institutions which includes members publically funded institutions. It has 30 public and of the Max Planck Society, Germany’s leading private partners, including seven pharmaceutical basic research organisation. AstraZeneca will have companies and will establish a European Screening a preferred right to obtain a licence for pre-clinical Centre. It is hoped that this will act as a catalyst for and clinical development and commercialisation further drug discovery in Europe. with terms agreed individually for each project. Although in the above examples the pharmaceu- Precompetitive activities tical companies still retain rights and some controls The European Lead factory is an unusual form of on the use of their compounds via joint steering collaborative activity as it involves compound gen- committees, making compounds available can be a eration and sharing. Most precompetitive activities

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have been focused on areas that are traditionally also a good way to allow Neusentis to identify seen as being safer areas for collaboration, eg bio- potential collaboration partners (https://www.inno- marker identification and validation, preclinical centive.com/ar/challenge/9933445 via @innocen- safety and toxicology, method development and tive). GSK has canvassed for new therapeutic con- the design and validation of patient reported out- cepts as well – ideas are submitted to a panel of comes. Such activities certainly form the bulk of judges and 10 from Europe and 10 from the USA precompetitive collaboration today – some would will be selected to ‘win’ a collaboration with GSK. even call this ‘non-competitive’ rather than ‘pre- The winners will work with GSK scientists to competitive’. However, the boundaries for such advances their ideas, eg by screening against the collaborations do appear to be shifting. Within the GSK compound library (www.gsk.com/discovery- umbrella of the IMI, for example, the NEWMEDS fasttrack). project in schizophrenia has pooled data from clin- Experience with the use of these types of chal- ical trials and this data has enabled a better and lenges both within and without the pharmaceutical shorter trial design thus saving time and costs. industry has shown that the more specific the ques- Data from genetic studies has also been pooled to tion, the more likely that a good response will be allow correlations of genotype with phenotype forthcoming. Poorly articulated or very broad which will be important for target validation. To challenges frequently do not produce good solu- date more than 4,500 researchers are involved in tions because it is not clear what is required. IMI projects from private and public organisa- Other companies are using the web for soliciting tions, including SMEs and patient groups. This in collaborative proposals, although the way the col- itself is a considerable achievement and the advent laborations are executed seems to be along tradi- of projects such as the European Lead Factory will tional lines in most cases, ie the company solely pro- continue to expand the impact on the whole R&D vides money rather than expertise or other in-kind continuum (see http://www.imi.europa.eu). IMI is contributions. Academia is also using crowd science already providing a valuable template for public- to progress drug discovery projects, eg the India- private partnerships in biomedical science11 and based consortium Open Source Drug Discovery learnings from the consortia will be important to (http://www.OSDD.net). The Medicines for Malaria incorporate in future initiatives. Venture (MMV) and the EBI have created resources and easy-to-use data repositories for groups work- The rise of crowd sourcing ing on malaria to speed up the drug discovery Crowd sourcing approaches have been used inter- process (http://www.ebi.ac.uk/chembl/malaria). nally by a number of companies such as Roche and Preliminary data suggests that an open source, Pfizer (https://www.innocentive.com/files/node/cas- crowd-based approach can certainly increase effi- estudy/roche-experience-open-innovation.pdf). ciency and reduce costs to milestones. The best prac- Roche Diagnostics actually compared the effective- tices and lessons learned from these endeavours will ness of internal and external crowd sourcing using be valuable if made public and certainly the MMV the same problem. Internally they took six prob- is beginning to do this12. It has six key laws to abide lems out to more than 2,400 people and, although by for these open source projects:- less than 20% of those contacted actually engaged with it, they received nearly 50 proposals, one of l First Law: All data are open and all ideas are which was “truly exciting”. They then took one of shared. the six problems externally working with l Second Law: Anyone can take part at any level Innocentive, an open innovation intermediary. of the project. Within 60 days they had 113 detailed proposals l Third Law: There will be no patents. with a solution to a problem the company had been l Fourth Law: Suggestions are the best form of wrestling with for 15 years. criticism. Other companies have also used this approach – l Fifth Law: Public discussion is much more valu- Pfizer’s Neusentis business unit posed a recent chal- able than private email. lenge on the Nature/Innocentive Open innovation l Sixth Law: The project is bigger than, and is not platform. They were looking for novel means of owned by, any given laboratory. measuring the interaction between a drug and its targeted ion channel. Although they were looking Clearly these laws are not all applicable for pre- for a solution which would be applicable across all competitive collaborations or other forms of open ion channels, they would also consider proposals innovation, but other lessons learned from the specific to voltage-gated channels. Obviously this is MMV studies may be applicable, eg ways of

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tracking contributions, the optimum use of col- tion, eg the IMI, but whether these are really pro- References laborative tools and management methods. ducing a radical change in the way companies do 1 Pammolli, F et al (2011). The the business of R&D and how academics interact productivity crisis in pharmaceutical R&D. Nat. Rev. Conclusions with industry is still open to debate. DDW Drug Discov. 10, The boundaries for collaboration between compa- 428-438. nies and academia are being expanded and new 2 Pisano, G. Can Science Be A models are being explored. For example, it is Business? Harvard Business becoming possible to develop collaborations Review, Oct 2006. 3 Herper, M. Biology Goes around compounds and other IP sensitive areas in Open Source. Forbes ways that would have been unthinkable a decade Magazine. February 12, 2007. ago. There is still some way to go – many compa- 4 Hunter, AJ and Stephens, S nies close down areas of research and terminate (2010). Is Open Innovation the compounds for a particular indication, but do not way forward for big Pharma? Nature Drug Discovery 9, spin-out these assets or make the associated 87-88. reagents (antibodies, cell lines, etc) available. The 5 Woodcock, JA (2010). reasons for this are many, but the main one is that Precompetitive research: A companies have a ‘fear of success’ – that the assets new prescription for drug will make a lot of money and therefore a lot of development? Clin. Pharmacol. Therap. 87 (5) 521-523. attention is required to ensure that no ‘crown jew- 6 Morgan Stanley report els’ are given away too cheaply. However, as stated ‘Pharmaceuticals: Exist at the beginning of this article, most compounds do research and create value’. not make it! Jan 2010. The IMI and other public-private collaborations 7 Lee, JA et al (2011). Open Innovation for Phenotypic are beginning to build trust and understanding Drug Discovery: The PD2 between the various stakeholders as well as deliv- Assay Panel J. Biomol ering some real tangible benefits. There are still Screening, Volume 16 (6) challenges: 588-602. 8 Bouchie, AJ (2014). Seizing opportunities in cardiovascular l Lack of standardisation in terms of data collec- disease. Nature Rev Drug tion, storage and annotation will hamper data Disc.13(3)B7. sharing and collaboration, but again some steps 9 Simpson, PB and Reichman, are being taken to address this, eg the formation of M (2014). Opening the lead TranscelerateBiopharma as a not-for-profit organi- generation tool box Nature Rev Drug Disc. 13 3-4. sation to address standards in a range of areas 10 Kogej, T et al (2013). Big including clinical trials (http://transceleratebio- pharma screening collections: pharmainc.com/). Likewise, the Pistoia Alliance is More of the same or unique trying to do the same in the preclinical arena libraries? The AstraZeneca- http://www.pistoiaalliance.org/. Bayer Pharma case Drug Discov. Today 18: 1014-1024. l Logistics – including everything from how best 11 Papadaki, M (2012). to track compounds, contributions to who should Assessing the boundaries of be the medical sponsor for collaborative clinical precompetitive collaboration trials. TranscelerateBiopharma will address some Professor Jackie Hunter FBPharmacolS CBE has initiatives in biomedical of the issues, but this is much wider than clinical worked in the pharmaceutical industry for more research using the Innovative Medicines Initiative as an trials and the acquisition of clinical data. than 25 years where she was involved in the dis- exemplar. MPhil Thesis, l Assessing the value in the short term of collabo- covery and development of new therapeutic agents Cambridge University. ration. The R&D process is a long one and it will for dementia and other neurological disorders. She 12 Robertson, MN et al be important for the IMI and other large scale col- has also served on numerous industry committees (2013). Open source drug laborations to devise short to mid-term metrics or and academic boards including the Neuroscience discovery – a limited tutorial. Parasitology FirstView Article key performance indicators to show how valuable and Mental Health Board for the Medical Research pp 1-10. they can be. Council. She holds a personal chair at St George’s l Aligning internal and external objectives – in Hospital Medical School and is a recognised expert many companies employee bonuses and promo- in open innovation and industry-academia partner- tions for example are more dependent on internal ships. She is currently the Chief Executive of the objectives than externally focused ones. Biotechnology and Biological Sciences Research Certainly there are some new models of interac- Council in the UK.

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