Industrial drug discovery and development activities play an important role in the economy of Europe. The pharmaceutical sector is responsible for the direct employment of some 640,000 people, of which some 115,000 are directly involved in research and development (R&D). It is estimated that for each direct job in an R&D function, some 3 to 4 additional jobs are supported in services and associated roles [1]. While major pharmaceutical companies typically operate on a global basis, with research activities occurring within Asia, Europe, and North America, European-based companies still made up 6 of the top 15 positions in terms of revenues in 2010, with Novartis (2), Sanofi (4), GlaxoSmithKline (5), AstraZeneca (6), Bayer Schering (13) and Boehringer Ingelheim (14) represented. The trade body representing industrial pharmaceutical research is the European Federation of Pharmaceutical Industries and Associations (EFPIA) drawn from across the 30 members of the European Free Trade Area. Collectively, members of EFPIA invested some €27 billion into R&D in 2010 compared with €37 billion in the United States. These R&D investments are broadly in line with the size of the respective markets, with the European market representing some 29.2% of the world total, compared with 42% within the United States. However, the market for new products (launched between 2005 and 2009) in Europe falls to 22% of worldwide sales, compared with 61% in the United States, indicating a greater barrier within Europe to the acceptance of the products of innovation, namely new medicines [1].

Regardless of the huge investment in R&D, a recurring theme in recent presentations from members of the scientific, medical, and financial communities has been disappointment over the lack of the new treatment options capable of addressing patients’ unmet needs [2]. This situation has arisen despite the year-on-year increases in expenditure on pharmaceutical R&D and the opportunities presented by the increased application of genomics and other “omics-based” sciences within the drug discovery paradigm. Nevertheless, the rate of successful submissions of new molecular entities to the U.S. Food and Drug Administration (FDA) and the European Medical Agency has remained essentially stagnant [3]. To address this situation, new strategies are being developed in the pharmaceutical industry with the objective of overcoming the limitations of the current R&D process, which historically was based on an integrated operating model [4]. In the integrated model, core competencies were developed and kept in-house to prevent the distribution of knowledge and intellectual property (IP) and thus assure a competitive advantage. Gradually, the pharmaceutical industry has seen increased outsourcing of what are considered as the more routine tasks, such as liability profiling of compounds and conduct of clinical trials [5]. Although outsourcing can lead to efficiency gains, its impact on the rate of delivery of successful new molecular entities appears to be limited. Improved outsourcing strategies, although necessary, do not address issues associated with, for example, selection of the optimal disease-relevant therapeutic targets for “difficult” indications such as Alzheimer’s disease.

European Pharmaceutical Industry Response

The pharmaceutical industry has reached the conclusion that it needs to transform its R&D operation and find more efficient ways to innovate. At the same time academic biomedical research institutions are recognizing the benefits of forming deeper partnerships with the pharmaceutical industry: there are tools, technologies, experience, and financial resources within pharmaceutical companies that can help academic researchers to translate their ideas and research into drugs [6]. This understanding is leading to an opening of organizational structures leading to the formation of strong cross-links between academia and pharmaceutical industry. The umbrella term for this new R&D model is “open innovation.” Academic institutions and bridging organizations are looking to identify new ways to partner in a more collaborative manner [7]. Almost by definition, the strategies pursued by the various organizations to achieve this goal are diverse, as are their expectations and concerns. One significant outcome has been the initiation of academic small molecule drug discovery groups based around university core facilities, cross-institutional bridging organizations, and public–private partnerships [8]. This new breed includes structural biology-based drug discovery organizations, molecular screening facilities, and medicinal chemistry-focused research centers [9]. All had the remit of developing academic disease biology projects beyond the traditional end-point stage of target validation, in order to create high quality preclinical assets that would be of interest to the pharmaceutical industry. The activities of these academic-based organizations are still dependent on the interest and in some cases, financial support of the pharmaceutical industry, not only for the clinical stages of drug development but also as active partners in, for example, the counter-financing of earlier stage hit finding projects [10].

Research Charities and Drug Discovery: Examples from the United Kingdom

In the United Kingdom, research charities, both disease focused (e.g., Cancer Research U.K., British Heart Foundation) and more general in outlook (e.g., Wellcome Trust) are important sources of support for academic based drug discovery [11, 12]. In 2010, research charities made up a significant proportion of the total U.K. R&D funding contribution at higher education institutions (15%). Cancer Research U.K. has in excess of 70 projects in its drug discovery portfolio, of which over 50 involve small molecule approaches. Several Cancer Research U.K. projects are partnered with pharma, most notably a recent three-year alliance set up with AstraZeneca to develop targets related to cancer metabolism [13]. The Wellcome Trust has a number of programs that involve the development of therapeutics, including the Translation Awards, for development of new biomedical products that are close to market. The Trust’s Strategic Translation Awards fund the commercialization of novel therapeutics, vaccines, diagnostics, as well as platform or regenerative medicine technologies and associated topics that align with its scientific strategy [14]. The most relevant Wellcome funding scheme in terms of small molecule therapeutics is the Seeding Drug Discovery Initiative. The project-based program is accessed via a competitive, biannual peer review process. Academics with novel target biology insights or preexisting chemical starting points are provided with funds to enable them to progress through screening, medicinal chemistry, and pharmacological profiling. The aim is to develop projects to the lead candidate point, after which third-party funding is secured and the project advanced through preclinical and clinical stages [15]. Compared with the full costs of an internal pharmaceutical industrial project, the Seeding Drug Discovery funding rates are modest (1–3 million GBP per project over 2 to 3 years). However, outsourcing of activities such as screening, medical chemistry, and liability profiling is encouraged, allowing grant holders to use low-cost suppliers of these services. Project teams are expected to use expert professional advisors, typically with a background in the pharmaceutical industry, to guide the projects and ensure optimal alignment of outcomes with the requirements of eventual pharmaceutical industry development partners. As would be anticipated with the Wellcome Trust, diseases of the developing world are well represented within the existing portfolio, with projects addressing dengue fever, malaria and visceral leishmaniasis. However, funding of other more “mainstream” indications, which nevertheless represent clear unmet needs, is within scope. Examples include projects addressing Alzheimer’s, glioblastoma, and hepatitis C infection. In these cases, the Wellcome Trust is able fund research into unusual or novel mechanisms that may not be under active consideration by the pharmaceutical industry. The recipients of funding are predominantly drawn from the U.K. academic sector, with Universities of London, Manchester, and Cardiff well represented. However, biotechnology and pharmaceutical industry–funded projects include work at GlaxoSmithKline on hospital-acquired infections, and the Genomic Institute of the Novartis Foundation on diseases of the developing world.

Existing European-Wide Infrastructures and Public–Private Partnerships

There are relatively few operational European-wide academic infrastructures in the area of chemical biology and screening, although several initiatives are in the pipeline to remedy this deficit. The most notable existing infrastructure is that organized through the ChemBioNet network of European academic institutions, which provide an open-access distributed chemical biology platform to academic and industrial organizations [16]. The group is based in Germany (Leibnitz-Institut für Molekulare Pharmakologie, Max-Delbrück-Center for Molecular Medicine, Helmholtz-Centre for Infection Research, University of Konstanz) and Norway (University of Oslo) with associate partners drawn from across Europe. The aim of the organization is to provide biologists and chemists access to tools, including compound libraries and a range of high-throughput screening technologies. The organization has access to a compound library of >20,000 small molecules, which is distributed across the members institutions [17]. In one sense, the ChemBioNet represents a pilot project for larger scale projects planned within Europe, such as EU-OPENSCREEN, which will be discussed later.

Europe’s centerpiece public–private program focused on drug discovery is the Innovative Medicines Initiative (IMI) which brings together the pharmaceutical industry (through EFPIA), European academia, small-to-medium enterprises (SMEs), patient groups, regulatory agencies, and hospitals, with the aim of increasing the competitiveness of the European Union (EU) pharma sector through the creation of new precompetitive research tools [18]. Originally envisioned in 2004, the IMI concept passed through an extended period of development before the first call for proposals in 2008. The budget for the final program was in excess of €2 billion, dwarfing other ongoing projects. Half of funding is provided by the European Commission under the Framework 7 Health umbrella, with the balance provided by members of the EFPIA group of pharmaceutical companies, mainly in the form of in-kind contributions. The rationale behind setting up IMI aligns with the requirement to raise European R&D productivity, and the strategic approach is to initiate very large-scale projects to help increase understanding of disease and improve the selection of targets in the discovery phase and patients during the clinical phases [19]. All IMI projects cover precompetitive topics, which by definition exclude activities that will lead to the direct approval of a medicine or vaccines; instead, the projects look to improve the overall efficiency of the drug discovery process. The original IMI areas of interest in 2008 dealt with efficacy, safety, knowledge management, and education and training. These were then broken down into themes such as “predictive pharmacology,” and “validation of biomarkers,” around which specific call topics for research proposals were then published. In contrast to regular EU Framework programs, following peer review of the submitted grant proposal only a single consortium would be selected per topic. Consortia of academics would be paired with a collection of between 4 and 15 pharmaceutical companies to create integrated academia–industry teams. In 2011, there were 23 running IMI projects representing some €190 million of funding, with around 15% of the participants coming from the SME category and the rest a mixture of academia and patient groups. Although at the time of writing, the projects have been running for a relatively short time, some early success stories have been highlighted. For example, in schizophrenia, the identified bottlenecks are the lack of relevant animal models, insufficient tools to determine treatment efficacy, and widespread use of outdated clinical trial methodology. To address these deficiencies, the IMI NEWMEDS consortium has amalgamated data from 67 trials representing 11 compounds and in excess of 23,000 patients from 25 countries to create the world’s largest single repository of (anonymized) patient data in schizophrenia [20]. One of their approaches will be to develop improved clinical imaging approaches using functional MRI and PET in combination with machine learning methods in order to better define and quantify patient responses to drug treatment and allow more efficient design of clinical trials. The critical link between in-vivo models and the clinic is tackled through the development of new animal models involving quantify responses using brain recording and improved standardized behavioral tests. In the area of drug safety, a second consortium “Safe-T” has been formed to address the problem of drug-induced toxicities in the kidney, liver, and vascular tissues [21]. The Safe-T consortium is aiming very high with the expectation that their identified safety biomarkers will be suitable for use in medical product development and will gain associated European Medicine Agency and FDA approvals. An important component of IMI has been the emphasis on training and knowledge management, with four projects in this area receiving funding to date. Education and training projects cover the entire lifecycle of drug discovery and development, from basic science to pharmaco-vigilance and health economics. In the PharmaTrain consortium, the 15 pharmaceutical industry partners work with a group of 22 academic partners and 14 learned societies, as well as 3 regulatory authorities [22]. A PharmaTrain devised syllabus for postgraduate studies in drug discovery and medicine development has now been implemented at 15 universities in Europe. Direct teaching is supported by an e-campus facility and standardized syllabus. A completely new master’s degree in medicines development has been created as part of the proposal.

The IMI research priorities were updated in 2011 in response to the significant changes in pharmaceutical industry priorities in the four years since the first call [23]. The new priorities are very extensive and include pharmacogenetics, rare disease, systems approaches, active pharmaceutical ingredient development, formulations, stem cells, and imaging techniques. Of particular interest to early stage discovery is the new priority, “Beyond high throughput screening—pharmacological interactions at the molecular level.” Although the content of an associated call has yet to be fully elucidated, there is some early indication that this topic could lead to the creation of a centralized European compound collection and associated screening center. Proposals also include a chemical library drawn from a group of pharma companies (e.g., six companies each contributing 50 k compounds). This would then be augmented by a similarly sized collection (200–300 k) of newly synthesized compounds, and screens would be run for targets derived from both academic and pharmaceutical companies. At first glance, initiating compound screening–related projects would appear to go against the spirit of the original IMI mission to work exclusively on precompetitive projects. However, it is likely that such a center would address the issues that current screening technologies are finding difficult to tackle, such as defining appropriate screening platforms to identify small molecule modulators of protein : protein interactions or identifying novel targets related to protein ubiquitantion and assessing their intrinsic “druggability.”

The IMI initiative has not been without criticism from certain sectors of the academic community, particularly in relation to a perceived imbalance in the favor of the industrial partners in the eventual ownership of intellectual property derived during IMI projects [24]. As the program has developed though, it is clear from the degree of involvement from academics across Europe that most of the initial misgivings have been allayed and open questions around the IP accounted for. The current position is summarized in the statement “In the course of an IMI project, partners who generate results are the owners of corresponding information and IP rights” while any IP that is bought into a project by a partner remains under their exclusive ownership. This represents a position on IP that is similar to the bulk of European-funded public–private cooperations. Dealing with IP issues from the outset is critical to the success of IMI, as with any other public private partnership [25].

Future European Drug Discovery Research Infrastructures

Private sector drug discovery requires extensive infrastructures, such as compound libraries, screening facilities, protein and chemical analytical instrumentation, biobanks, in-vivo facilities, and imaging facilities. Although similar capabilities are required in academia and the public sector, very few publically funded organizations possess the deep pockets required either to initiate such facilities or cover ongoing running costs. The European Strategy Forum on Research Infrastructures (ESFRI) plays an important coordinating role in the development of large-scale research infrastructures within Europe [26]. The mission of ESFRI is primarily to support policy making and facilitate international cooperation with respect to existing infrastructure such as synchrotrons, biobanks, libraries, and telescopes. The Forum also provides preparatory funding for the development of new infrastructures to address Europe’s future scientific and economic needs. Within the Biological and Medical Sciences field, there are a number of planned Research Infrastructures that may impact upon European academic drug discovery either directly or indirectly toward the end of this decade [27].

European Advanced Translational Research Infrastructure in Medicine

The most advanced at the point of writing is the European Advanced Translational Research Infrastructure in Medicine (EATRIS). The aim of EATRIS will be to provide academic and industrial partners access to high-technology infrastructure, services, and training to progress projects from the discovery through the clinical stages [28]. In common with similar initiatives planned in the United States (e.g., National Center for Advancing Translational Sciences), projects entering EATRIS will be selected on the basis of their innovativeness, clinical relevance, and capacity to impact medical needs. The anticipated EATRIS Centers will address specific indication areas, including cancer, infectious diseases, neurological diseases, cardiovascular diseases, and metabolic diseases. Multiple infrastructural elements are envisioned within EATRIS to support all the main therapeutic mechanisms, including cell and gene therapies, small molecule drug discovery, vaccine development, molecular imaging (SPECT and PET), and biomarker discovery. In the area of small molecules the intention is for EATRIS to establish lead discovery and optimization facilities to identify small molecules for specific targets and then progress through a classical drug discovery process, including medicinal chemistry optimization, biophysical characterization, and structural determination. The timescale for EATRIS to become operational is strongly dependent on obtaining governmental support from member states to finance the build and operational phases of the project. Current estimates show initial operations commencing in 2012 with full implementation in 2013 onwards.

EU-OPENSCREEN

Stay updated, free articles. Join our Telegram channel

Join