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Integrated Partnerships and the Transformation of Pharmaceutical Research and Development

      From where will the life-saving and life-improving medicines of tomorrow come? It is a fair question. There is ample evidence to suggest that the extant model of drug development is yielding too few products, at too high a cost, to sustain the growth of the research-based pharmaceutical industry, long the dominant source of these medicines.
      • Munos B.
      A forensic analysis of drug targets from 2000-2012.
      Moreover, intense global price pressure, competition from generics, increasing regulatory demands, and expiring patents on many top-selling drugs have created a stifling environment for drug developers. Many observers have proclaimed that the industry’s business model is broken, and that unless companies transform the way they discover and develop new drugs, there will be a paucity of important new medicines introduced to the market in the future.
      • Pammolli F.
      • Magazzini L.
      • Riccaboni M.
      The productivity crisis in pharmaceutical R&D.
      • Sams-Dodd F.
      Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift.
      The inability of industry to translate some of the breathtaking advances in our understanding of the pathophysiology of many diseases into new medical treatments has been the subject of a large and growing body of literature. Recently in the United States, the president’s Council of Advisors on Science and Technology (PCAST) issued a report titled “Propelling Innovation in Drug Discovery, Development, and Evaluation,”

      Executive Office of the President, President’s Council of Advisors on Science and Technology. Propelling innovation in drug discovery, development and evaluation http://whitehouse.gov/sites/default/files/microsites/ostp/pcast-fda-final.pdf. Accessed August 4, 2014.

      which assessed the current innovation landscape and offered 8 specific recommendations intended to “double the output of innovative new medicines for patients with important unmet medical needs, while increasing drug efficacy and safety, through industry, academia and government working together to decrease clinical failure, clinical trial costs, time to market and regulatory uncertainty,” (p. 15). At its core, the PCAST report promotes the concept that a healthy and vibrant innovation ecosystem is necessary to ensure the development of breakthrough therapies—and that pharmaceutical companies, universities, and government are all crucial elements of that ecosystem.
      • Woodcock J.
      The PCAST report on pharmaceutical innovation: implications for the FDA.
      • Morris S.A.
      • Rosenblatt M.
      • Orloff J.J.
      • Lewis-Hall F.
      • Waldstreicher J.
      The PCAST report: impact and implications for the pharmaceutical industry.
      In response to growing pressure to change its product development model and to improve the efficiency of research and development (R&D), the pharmaceutical sector is embracing new innovation paradigms.
      • Getz K.A.
      • Kaitin K.I.
      Open innovation: the new face of pharmaceutical research and development.
      Most notable is the transformation from a fully integrated pharmaceutical company model, in which a sponsor “owns” the entire drug-development process from synthesis to marketing, to a network model of bioinnovation that encompasses all of the major stakeholders in the R&D process.
      • Kaitin K.I.
      Deconstructing the drug development process: the new face of innovation.
      Stakeholders can include large and small pharmaceutical and biotechnology companies, academic institutions, patient groups, contract research organizations, public–private partnerships, foundations, and venture capital firms. In the network model of innovation, stakeholders create strategic alliances and collaborative relationships, with the goal of improving R&D efficiency and productivity by sharing precompetitive knowledge, optimizing resources, and leveraging capabilities among the various members of the alliance.
      The core challenge for drug sponsors is managing an unwieldy drug-development process that has remained basically unchanged since the passage in 1962 of the Kefauver-Harris Amendments to the Food, Drug and Cosmetic Act—a period of >50 years. Despite decades of effort by industry to improve R&D performance, the drug-development process remains exceedingly time-consuming, risky, and expensive.
      • Kaitin K.I.
      • DiMasi J.A.
      Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000-2009.
      Recent estimates by the Tufts Center for the Study of Drug Development (Boston, Massachusetts) suggest that average cycle times—from investigational new drug (IND) application filing to new drug or biologic application (NDA and BLA, respectively) submission—are 7.5 years, followed by another 1.5 years of regulatory review and approval.

      Tufts Center for the Study of Drug Development. Analysis based on CSDD’s proprietary Approved Products Database. 2014.

      Cycle times vary across different therapeutic areas; the average time from investigational new drug application filing to NDA/BLA approval ranges from 6 years for anesthetic and analgesic drugs to 11 years for CNS drugs (medicines that treat neurodegenerative and psychiatric disorders).
      Approval clinical success rates (ie, the likelihood that a drug candidate that undergoes clinical testing will eventually be approved for marketing) have remained stubbornly low, at ~16%, ranging from a high of 24% for systemic anti-infective drugs to a low of 8% for CNS drugs.
      • DiMasi J.A.
      • Feldman L.
      • Seckler A.
      • Wilson A.
      Trends in risks associated with new drug development: success rates for investigational drugs.
      Making matters worse for developers of CNS medicines is the point in the development process at which these candidates fail; the development of 54% of CNS drugs entering Phase 3 clinical testing is terminated before NDA/BLA submission (ie, less than half [46%] proceed to submission). To fail so late in clinical testing, after such a sizeable investment of time, money, and resources, represents a “worst-case scenario” for drug developers. In light of the enormous technical risk involved in developing these drugs, several major pharmaceutical companies have substantially reduced or even eliminated their investment in the development of CNS medicines,

      R&D Cuts Curb Brain-Drug Pipeline. The Wall Street Journal. (au: Sten Stovall) March 27, 2011. http://online.wsj.com/news/articles/SB10001424052748704474804576222463927753954. Accessed August 1, 2014.

      leading to significant concern about a potential drought in the introduction of new medicines to treat CNS indications for which few or no effective medicines currently exist.
      • Kaitin K.I.
      • Milne C.P.
      A dearth of new meds: drugs to treat neuropsychiatric disorders have become too risky for big pharma.
      Long development times for new drug candidates, combined with low overall success rates, translate into exceedingly high development costs. The total long-term investment necessary to develop a single successful drug currently exceeds US $1.3 billion.
      • DiMasi J.A.
      • Grabowski H.G.
      The cost of biopharmaceutical R&D: is biotech different?.
      This figure includes direct costs (30% of the total), as well as costs associated with failed and terminated candidates (70%). Once the drug reaches the market, there is considerable pressure to generate sufficient revenue to recoup investment costs as well as to subsidize future R&D activity.
      Integrated partnerships and strategic alliances represent a dramatic shift in operating strategy for many companies that only a decade ago took great pride in being able to manage the entire drug-development process by themselves, with little or no external involvement or support. In today’s environment, companies are sharing resources, talent, and knowledge in an effort to speed development times, reduce technical risk, and contain soaring R&D costs. In this model, all stakeholders have a place at the table and are able to share in both the risks and rewards of bioinnovation.
      The articles included in this special section of Clinical Therapeutics explore various aspects of this new collaborative environment. Koski et al,
      • Koski G.
      • Tobin M.
      • Whalen M.
      “The synergy of the whole”: applying systems thinking to accelerate medicines development.
      for example, discuss a novel multicompany nonprofit organization called the Alliance for Clinical Research Excellence and Safety, the goal of which is to create a global network for the creation of clinical study standards, enabling companies to implement a “global systems approach” to new product development. Getz et al
      • Getz K.A.
      • Lamberti M.J.
      • Kaitin K.I.
      Taking the pulse of strategic outsourcing relationships.
      report on a study of outsourcing relationships between pharmaceutical companies and contract resource organizations and conclude that sponsor companies’ mixing and matching of sometimes competing strategic outsourcing models may contribute to inefficiency and less-than-peak performance. Clearly, more work needs to be done within companies to identify which types of outsourcing relationships work best and will meet the needs of the sponsor.

      References

        • Munos B.
        A forensic analysis of drug targets from 2000-2012.
        Clin Pharmacol Ther. 2013; 94: 407-411
        • Pammolli F.
        • Magazzini L.
        • Riccaboni M.
        The productivity crisis in pharmaceutical R&D.
        Nat Rev Drug Discov. 2011; 10: 428-438
        • Sams-Dodd F.
        Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift.
        Drug Disc. 2013; 18 (Today): 211-217
      1. Executive Office of the President, President’s Council of Advisors on Science and Technology. Propelling innovation in drug discovery, development and evaluation http://whitehouse.gov/sites/default/files/microsites/ostp/pcast-fda-final.pdf. Accessed August 4, 2014.

        • Woodcock J.
        The PCAST report on pharmaceutical innovation: implications for the FDA.
        Clin Pharmacol Ther. 2013; 94: 297-300
        • Morris S.A.
        • Rosenblatt M.
        • Orloff J.J.
        • Lewis-Hall F.
        • Waldstreicher J.
        The PCAST report: impact and implications for the pharmaceutical industry.
        Clin Pharmacol Ther. 2013; 94: 300-302
        • Getz K.A.
        • Kaitin K.I.
        Open innovation: the new face of pharmaceutical research and development.
        Expert Rev Clin Pharmacol. 2012; 5: 481-483
        • Kaitin K.I.
        Deconstructing the drug development process: the new face of innovation.
        Clin Pharmacol Ther. 2009; 87: 356-361
        • Kaitin K.I.
        • DiMasi J.A.
        Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000-2009.
        Clin Pharmacol Ther. 2011; 89: 183-188
      2. Tufts Center for the Study of Drug Development. Analysis based on CSDD’s proprietary Approved Products Database. 2014.

        • DiMasi J.A.
        • Feldman L.
        • Seckler A.
        • Wilson A.
        Trends in risks associated with new drug development: success rates for investigational drugs.
        Clin Pharmacol Ther. 2010; 87: 272-277
      3. R&D Cuts Curb Brain-Drug Pipeline. The Wall Street Journal. (au: Sten Stovall) March 27, 2011. http://online.wsj.com/news/articles/SB10001424052748704474804576222463927753954. Accessed August 1, 2014.

        • Kaitin K.I.
        • Milne C.P.
        A dearth of new meds: drugs to treat neuropsychiatric disorders have become too risky for big pharma.
        Scientific American. 2011; 305: 16
        • DiMasi J.A.
        • Grabowski H.G.
        The cost of biopharmaceutical R&D: is biotech different?.
        Manage Decis Econ. 2007; 28: 469-479
        • Koski G.
        • Tobin M.
        • Whalen M.
        “The synergy of the whole”: applying systems thinking to accelerate medicines development.
        Clin Ther. 2014; 36: 1355-1369
        • Getz K.A.
        • Lamberti M.J.
        • Kaitin K.I.
        Taking the pulse of strategic outsourcing relationships.
        Clin Ther. 2014; 36: 1348-1354