Background
Open source and crowdsourcing to access knowledge of the masses
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In 1974, the Special Program for Research and Training in Tropical Diseases (TDR, http://www.who.int/tdr/en/) was initiated by the World Health Organization (WHO) as a global programme of scientific collaboration to combat neglected diseases [18]. The programme is hosted at the WHO and funded by co-sponsors, governments, foundations and agencies, such as the World Bank, the European Commission, or the Bill and Melinda Gates Foundation [19]. The African Network for Drugs and Diagnostics Innovation (ANDI) is a programme of the TDR that started in 2008 under the governance of the United Nations Economic Commission for Africa (UNECA). It focuses on the specific health needs in Africa and aims at promoting and supporting pharmaceutical R&D for neglected diseases led by African institutions to develop capacities and centres of research excellence there [20].
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The Medicines for Malaria Venture (MMV, https://www.mmv.org) was established in 1999 by a few European governments together with the World Bank to reduce the disease burden of Malaria infections [21]. Since then, the programme has gained more facilitators and received total funding of roughly USD 1 billion by 2016. The main sponsor is the Bill and Melinda Gates Foundation, with a 54.7% share. Partners form the industry include Novartis, Sanofi, Merck Serono and Takeda. The achievements are enormous. Several hundred million treatments were provided to children; 18,000 healthcare workers were trained to administer malaria medication; and 19 drug candidates have been nominated for clinical development since 1999. Since 2010, the MMV moved 17 candidates into preclinical development, of which 13 are still active [74].
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The Global Alliance for Tuberculosis Drug Development (TB Alliance, https://www.tballiance.org) is an initiative of governmental and non-governmental organizations. It was started in 2000 to discover and develop tuberculosis drugs. Today, the TB Alliance manages the largest pipeline of new TB drugs, including six new products that are in clinical development phases. Several pharmaceutical companies, such as Sanofi, Bayer or GSK have entered into collaborations with TB alliance in the past, whereas more recently Novartis transferred an entire R&D program to the TB alliance [71].
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A further open source example is the Drugs for Neglected Diseases Initiative (DNDi, https://www.dndi.org) that is supported and sponsored by numerous universities, research centres, governmental organizations, biotech companies, and several pharmaceutical companies, such as AstraZeneca, Bayer Healthcare, Bristol-Meyers Squibb (BMS), Genomics Institute of the Novartis Research Foundation, GSK, Pfizer, Sanofi and Takeda. It provides platforms for collaborative non-for-profit drug discoveries and developments for diseases such as Leishmaniasis, Sleeping Sickness, Chagas disease and paediatric HIV. Since 2003, DNDi developed four new drugs for the treatment of neglected diseases and plans to deliver 16-18 total new treatments with a total budget of EUR 650 million by 2023.
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Open source drug discovery (OSDD) was initiated by the Indian government in 2008 as a translational platform for drug discovery [22]. The hybrid model of open source and public private partnership brought together companies, organizations and scientists from different industries (such as TCG Lifesciences, Sun Microsystems, the Institute of Genomics and the Integrative Biology or Sky Quest Labs) in order to establish high-quality research on neglected diseases (such as tuberculosis) at low costs [69]. In its Connect to Decode initiative, the 4000 genes of Mycobacterium tuberculosis were annotated, and a metabolome and a protein–protein functional network of this germ were delivered [69]. OSDD also provides data on promising exploratory tuberculosis drugs via its website (http://www.osdd.net/home) and supports the progress of drug discovery projects [70].
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Finally, the Pool for Open Innovation started in 2009 as a partnership of GSK, Alnylam Pharmaceuticals and the Massachusetts Institute of Technology (MIT). It provides free access to 2300 tropical disease patents and ensures that these intellectual property (IP) rights do not hinder drug discoveries on neglected diseases.
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The integration of external knowledge,
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The access to new technologies,
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The solving of problems that could not have been solved by internal experts, and
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A reduction of overhead costs.
Type of crowdsourcing | Example | Owner | Topics |
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Mining crowd data | Open FDA | FDA | Access to publicly available FDA data |
Web search logs | Google trends | Google | Statistical analyses on health topics |
Smart phone applications | Flumoji | GSK | Track flu outbreaks |
Active crowdsourcing (pharma-specific platform) | Grants4Apps | Bayer | Electronic health |
Grants4Leads | Bayer | Drug discovery in animal health | |
Grants4Targets | Bayer | Target proposals | |
Open innovation drug discovery | Eli Lilly | Drug discovery Molecular modelling In vitro screening Drug discovery in animal health Compound proposals and synthesis NTD research | |
Open innovation platform | AstraZeneca | Drug discovery Target proposals Data mining Chemoinformatics Preclinical and clinical translational research |
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Eli Lilly left an early mark with Innocentive (2001), YourEncore (2003), and Open Innovation Drug Discovery (https://openinnovation.lilly.com/dd/) [32].
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AstraZeneca runs an open innovation platform (https://openinnovation.astrazeneca.com) that provides access to innovative discovery technologies.
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And Bayer HealthCare initiated Grants4Targets (G4T) (2009) [33, 34], Grants4Leads (2014; http://www.grants4leads.com), and Grants4Apps (2013, https://www.grants4apps.com). G4T is an open innovation platform to access new drug discovery ideas to fill Bayer Healthcare’s R&D pipeline. The process is simple and fast. External scientists are invited twice a year to propose their ideas for targets and an animal model. The administrative hurdles are low since the IP stays with the inventor. The proposals are evaluated by Bayer scientists, and if a proposal is accepted, the proposer receives a financial reward. If a proposal results in a project that finds its way officially into Bayer’s drug pipeline, then both parties can negotiate a collaborative agreement. So far, G4T has been very successful, as indicated by more than 1100 applications and inputs into 10 drug discovery projects that have led to 6 lead generations, 1 lead optimization and 2 drug development projects [34].
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Novartis partnered with PatientsLikeMe (http://www.patientslikeme.com) [35], a digital health learning system comprising more than 600,000 participants’ health conditions.
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Novartis also uses the digital trial technology of Science 37 to allow patients an easy participation in clinical trials and to move more and more to a site-less trial model.
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A recent new partnership of Novartis is the one with Pear Therapeutics on a digital therapeutic called THRIVE [72].
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Merck & Co. collaborated with Kaggle (http://www.kaggle.com) [36] to identify statistical techniques for predicting the biological activities of different molecules.
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Sanofi has applied a more focused approach around Diabetes using the Data Design Diabetes Innovation Challenge to seek service solutions for diabetes patients.
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GSK uses crowd sourced data and its Flumoji app to identify the fluctuations of flu infections [37].
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And BioMedX (https://bio.mx/) is an example of a new open innovation model at the interface of crowdsourcing and innovation centres that includes pharma companies, such AbbVie, Boehringer Ingelheim, Johnson & Johnson (J&J) or Merck and academia. Physically based on the campus of Heidelberg University, experts from universities and pharma partners support the interdisciplinary projects of teams of young scientists. Anyone (the crowd of scientists) can apply via the internet and can ask for financial and scientific support to study new drug discovery ideas in the biomedical field (oncology, respiratory diseases, neuroscience, diagnostics and consumer care) with the purpose of translating the research activities into drug development projects of the respective pharma partner.
Public private partnerships to improve competitiveness
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The Biomarker Consortium (source: http://www.biomarkerconsortium.org),
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The Critical Path Institute Consortia (www.c-path.org/consortia.cfm),
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The Innovative Medicine Initiative (www.imi.europe.eu),
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The Serious Adverse Events Consortium (http://www.saeconsortium.org),
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The National Center for Advanced Translational Sciences (https://ncats.nih.gov),
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Bristol–Myers Squibb’s International Immuno-Oncology Network (http://www.immunooncologyhcp.bmsinformation.com),
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The Global Alliance for Vaccines and Immunizations (http://www.gavi.org),
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The Global Fund to Fight AIDS, Tuberculosis and Malaria (http://www.theglobalfund.org/),
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The Stop TB Partnership (http://www.stoptb.org),
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Roll Back Malaria (http://www.rollbackmalaria.org), and
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The FDA initiated the Critical Path Initiative [41].
Topic | Number of projects | Ratio (%) |
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Biomarkers | 9 | 10 |
Cancer | 4 | 5 |
CNS disorders | 11 | 13 |
Diabetes | 3 | 3 |
Infectious diseases | 12 | 14 |
Medical research and clinical development | 6 | 7 |
NTDs | 6 | 7 |
Others | 17 | 20 |
Pain | 4 | 5 |
Toxicology and drug safety | 5 | 6 |
Medical training | 4 | 5 |
Vaccines | 5 | 6 |
Total | 86 |
Total number of teams active in IMI projects | |
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Sanofi | 51 |
GlaxoSmithKline | 47 |
Johnson & Johnson | 46 |
AstraZeneca | 44 |
Novartis | 36 |
Pfizer | 34 |
Eli Lilly | 32 |
Roche | 31 |
Bayer | 29 |
Boehringer Ingelheim | 28 |
UCB | 25 |
Novo Nordisk | 21 |
Merck | 20 |
Amgen | 16 |
AbbVie | 13 |
Merck & Co. | 10 |
Takeda | 7 |
BristolMyersSquibb | 5 |
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The SAFE-T consortium (http://www.imi-safe-t.eu) has been initiated to identify biomarkers for the early detection of drug-related safety issues related to the kidney, liver and vascular systems [46].
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The U-BIOPRED (http://www.europeanlung.org/en/projects-and-research/projects/u-biopred/home) and the PRECISESADS (http://www.precisesads.eu) consortia are both active in the field of personalized medicine in order to address the need for the characterization and classification of severe refractory asthma and autoimmune diseases [47, 48].
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The Open Pharmacological Concepts Triple Store (Open PHACTS, http://www.imi.europa.eu/content/open-phacts) is another PPP with AstraZeneca, Eli Lilly, GSK, Merck, Novartis and Pfizer that complements the 31 consortia members of universities, research organizations, public bodies and governmental organizations. It aims at delivering an open pharmacological space and linking diverse and complementary drug discovery databases to support drug research [49].
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Most likely, the most prominent example of an IMI projects is the European Lead Factory (ELF) that aims at providing new drug targets for all kinds of disease areas [50]. Any scientist from a European academic institution or small- to medium-sized entity (SME) can present a target proposal for High-Throughput-Screening (HTS) or ideas for a compound library. The ELF currently brings together 30 internal partners from private and public organizations, including AstraZeneca, Bayer, and Sanofi (https://www.europeanleadfactory.eu/about/partners/). Starting in 2013, IMI’s goal is to identify high quality small molecule drug candidates. By 2017, the ELF had delivered 300,000 new chemical compounds that were combined with the 300,000 compounds that have been provided by the EFPIA collection to a Joint European Compound Library of more than 500,000 chemical compounds for HTS screening. In addition, by end of 2015, 60 drug target proposals had been evaluated positively and accepted, and more than 500 hits had been handed over to academic institutions and SMEs for further drug development.
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To increase scale,
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To strengthen research networks,
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To share risk with industry partners,
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To integrate external (university) know-how,
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To access public financial resources,
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To accelerate the exploitation of innovation,
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To serve society and increase reputation, and
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To improve R&D productivity [51].
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Pool and share the right data that are relevant for the PPPs,
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Manage the alliances professionally,
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Exclude the IP relevant (competitive) topics,
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Manage the IP rights if such rights result from a PPP,
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Manage the cultural conflicts of partners, and
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Align the diverse interests of partners that are coming from academia and industry.
Pharma innovation centres and research alliances to leverage synergies from open innovation
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Pfizer started in 2010 their Global Centers for Therapeutic Innovation (CTIs), a USD 85 million partnership with the University of California at San Francisco (UCSF). This one example out of eight planned CTIs shall become part of Pfizer’s BioTherapeutics Research Group and it is Pfizer’s way to leverage synergies from open innovation at the interface of translational research between Pfizer and academic medical centres (http://www.pfizercti.com). The idea is that Pfizer adds its developmental knowledge, financial resources and human resources to the collaboration. Meanwhile, it expects to benefit from the research expertise in disease areas, target biology and patient populations from their academic partners. Partners in the CTI network include 25 academic institutions, four patient foundations, the National Institute of Health (NIH) and large hospitals such as the Medical Center at Columbia University, the Tufts Medical Center or Mount Sinai Hospital. Together with the NIH, Pfizer plans to identify new drugs that serve both partners’ strategic interests. NIH scientists provide more of the research aspects in the collaboration (such as disease-related pathways or mechanisms as potential drug targets), while Pfizer enables the NIH to move new drug projects into therapeutic development using industry-standard translational tools and Pfizer’s developmental expertise.
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Bayer HealthCare, the German Cancer Research Center (DKFZ) and the National Center for Tumor Diseases (NCT) initiated a drug discovery alliance in 2009 where DKFZ and NCT provide their expertise in cancer research and tumour biology, and Bayer brings in its know-how in drug R&D. The goal of this strategic partnership is technology transfer from the DKFZ to Bayer [52].
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Bayer HealthCare recently opened a centre in San Francisco to identify and manage partnerships with academic and biotech researchers in the USA [53].
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The German company Merck established a new innovation centre located at their headquarters to open Merck’s R&D towards innovation from the outside and to provide a platform for external innovation to translate their ideas into real business cases [54].
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J&J started its Life Science Innovation centre in San Diego with a Concept Lab that provides a platform for start-up companies in the earliest phase and with the Open Collaboration Space that gives the start-up companies desk space later in their development. With both programmes, J&J enables innovators to get an early proof-of-concept for their ideas by offering infrastructure, equipment and resources [55].
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GSK experimented much earlier in the field of open innovation with the Center of Excellence for External Drug Discovery (CEEDD). At its start in 2005, CEEDD’s goal was to better access external technologies using a small team of approximately 20 GSK scientists to work across all therapeutic areas and facilitate partnerships from drug discovery to PoC. Until its closure in 2012, CEEDD managed a total of 16 partnerships. One example for collaboration under this umbrella is the GSK alliance with ChemoCentryx, which was established in 2011 to access the technology of chemokine-based therapeutics. After one of the trials failed and the chemokine receptor 9-inhibitor did not achieve its primary endpoint for the treatment of Crohn’s disease, the programme was discontinued. Despite such drawbacks, CEEDD was successful in establishing both the internal and the external paths to access drug candidates at GSK and it helped to fill GSK’s early stage pipeline currently covers nearly half of its projects that are externally sourced [56].
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Since more than a decade Novartis and the MIT are collaborating on continuous manufacturing (https://novartis-mit.mit.edu/). In 2018 they added a partnership with MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) on patient real-time motion monitoring [73].
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Novartis has also successfully collaborated with selected institutions such as the Dana–Farber Cancer Institute on cancer alliances or the University of Pennsylvania on the chimeric antigen receptor (CAR) T cell [57]. In a recent interview, Novartis Institutes for BioMedical Research’s (NIBR) president Jay Bradner announced a division-wide programme to enhance the external focus and foster external collaborations in several ways [58]. A faculty of scholars will be invited to join NIBR to lead their own projects that “would not be accessible in their home institutions” [58]. This could be access to technologies but also libraries of molecules to test new concepts. The programme is special and different from other open innovation models since it focuses on sourcing new ideas into a company and provides leading academic scientists and innovators the opportunity to benefit from pharma’s strengths. Thus, this turns the effort into a collaborative partnership to the benefit of science and patients.
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In addition Novartis has started “Genesis labs” to offer employees the opportunity to suggest high-risk, high-reward transformational projects and apply for resources, funding and lab space.
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Another example of a pharma innovation centre is Takeda’s Center for IPS Cell Research Application (CiRA) at Kyoto University (TCiRA). Launched in 2015, its goal is to investigate cell therapies for the treatment of cardiovascular, metabolic, neural and cancer diseases. While Takeda provides 10 years of funding of approximately US$ 177 million, research management expertise, Takeda researchers, access to its compound library and access to the research facilities at its Shonan Research Center in Japan, it can benefit from the world-class science of the CiRA team that is headed by director Shinya Yamanaka, the 2012 Nobel Prize winner on induced pluripotent stem (iPS) cells.
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Takeda is one of the global players that has reduced its internal R&D over the past years and that increasingly uses the potential of external R&D [59, 60]. It recently announced a collaboration with the Tri-Institutional Therapeutics Discovery Institute (TDI) in New York, which is a consortium of three institutions (Cornell University, Rockefeller University, and Memorial Sloan Kettering Cancer Center), to support target research [61]. It also collaborates with J&J and OrbiMed Advisors LLC by co-investing in the Israeli biotech accelerator FutuRx with the purpose to fund medical breakthrough innovations that can be spun off in the form of new, independent companies [62].
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They bypass tedious long-lasting licensee-licensor negotiations in subsequent drug licensing;
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They allow access to internal scientific resources within the remit of the arrangement, which is an important flexibility given the risks of pharmaceutical R&D;
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They allow R&D to familiarize themselves with new technologies or therapeutic indications without the need to make significant investments upfront; and
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They give access to potential new drug candidates.
Virtualization of R&D to increase efficiency
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A reduction of internal complexity due to concentration,
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A focus of resources on core technologies that may provide a competitive edge,
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A mitigation of investment risks to partner companies, and
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A reduction of external interfaces, since the task is now shared with the partner companies.
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Projects have dedicated project-budgets,
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The focus is on phase I and clinical PoC studies,
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Projects are managed with small expert teams, and
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The main tasks are run by intensive outsourcing.
Company | Type | Founded | Number of employees | Average 10 years (2006–2016) revenue (M$) | Revenue per employee ($) |
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Helsinn | NRDO | 1976 | 680 | 320 | 470,588 |
Jazz Pharma | NRDO | 2003 | 1040 | 615 | 591,346 |
Tesaro+ | NRDO | 2010 | 446 | 0.45 | 1010 |
Puma Biotech++ | NRDO | 2010 | 183 | 0 | 0 |
Clovis | NRDO | 2009 | 278 | 0.14 | 504 |
Vanda Pharma | NRDO | 2002 | 148 | 38 | 256,756 |
Debiopharm | NRDO | 1979 | 150 | 345 | 2,300,000 |
Astra Zeneca | Large Pharma | 1999 | 59,700 | 23,000 | 385,260 |
Novartis | Large Pharma | 1996 | 12,3000 | 47,000 | 382,114 |
Sanofi | Large Pharma | 2004 | 110,000 | 32,500 | 295,454 |
Eli Lilly | Large Pharma | 1876 | 42,000 | 21,500 | 511,905 |
Bayer | Large Pharma | 1863 | 115,000 | 43,000 | 373,913 |
Pfizer | Large Pharma | 1849 | 96,500 | 51,000 | 528,497 |
GSK | Large Pharma | 2000 | 99,300 | 26,400 | 345,619 |
Amgen | Large Biotech | 1980 | 19,200 | 20,000 | 1,041,667 |
Advantages of a virtual R&D organization | Essential elements to operate a virtual R&D organization |
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Instant access to new technologies and external resources on demand | Excellent industry and academic networks |
Reduced capital requirements (overhead and infrastructure) | Professional, project, portfolio and alliance management skills |
Simple governance structure | Simple governance structure |
Reduced bureaucracy and faster decision making | Collaborative scientific and medical support from those who understand drug development |
Flexibility in selecting optimal services providers | Excellent expertise in risk management and financial valuation |
Mitigated financial risk | Outperforming licensing and acquisition strategies and skills |
Reduced time to market | Admirable outsourcing skills |
Excellent communication and motivation skills to manage external project teams |
Why is the potential of open innovation not fully utilized in the pharmaceutical industry yet?
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Company’s R&D processes need to be extroverted to implement external solutions,
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R&D employees need to be open to ideas coming from the outside,
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The R&D organization needs to have sufficient resources to access external innovation,
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Internal champions need to be able to take the lead on external proposals,
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An environment needs to exist that enables bilateral agreements,
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Concepts need to be in place regarding how to financially reimburse solvers properly and
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Clear IP regulations need to be implemented that consider the needs of both parties.
Legacy
Risk
Control
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Challenging the automatic distrust towards external partners who are motivated differently,
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Questioning the over-identification with internal capabilities and thereby overcoming the “not-invented-here syndrome”,
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Letting go of the limiting competitive reactiveness that sees everyone outside of the organization as a potential threat, and
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Reducing the influence of control in decision making.
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Incubate a new project that is geographically and structurally separate and protect it from the rest of the organization. If the project grows and succeeds, gradually redirect investment funds towards it and away from traditional operations.
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Recruit an elite team from within the old organization and from outside along with the downsizing or closure of the existing operations.
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Establish a company-based R&D-independent fund that supports new innovative ideas from employees. These can be projects that either do not have a home in a functional line or therapeutic area or that are (currently) regarded as out of scope.