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Progress in Drug Discovery in Academia and Persistent Challenges of “the Valley of Death”

      At its core, Mayo Clinic works as a team. Teamwork to enhance patient care was championed by the Mayo brothers from the outset. With the astounding advances in the biomedical sciences, the concepts of teamwork are of even greater importance as we have entered a new era of team science in research.
      • Wuchty S.
      • Jones B.
      • Uzzi B.
      The increasing dominance of teams in production of knowledge.
      • Stokols D.
      • Hall K.L.
      • Taylor B.K.
      • Moser R.P.
      The science of team science: overview of the field and Introduction to the supplement.
      • Baker B.
      The science of team science: an emerging field delves into the complexities of effective collaboration.
      Anderson and his colleagues
      • Anderson J.R.
      • Chung T.D.Y.
      • Clark L.
      • et al.
      Translation to practice: accelerating the cycle of innovation to impact.
      from Mayo Clinic provide a clear outline of new components of the team science enterprise as it relates to drug and device development. The early infrastructure for various components in this new discovery pipeline stems from the clinical translational science award that Mayo Clinic successfully competed for in 2006. With support from this large federal grant, the Mayo Clinic Center for Clinical and Translational Science was born. At Mayo Clinic, and at approximately 60 other academic institutions around the country that have obtained National Center for Advancing Translational Science, National Institutes of Health, and Center for Translational Science Award funding, these awards have been transformational in how health care research is carried out.
      • Zerhouni E.A.
      Translational and clinical science—time for a new vision.
      • Barohn R.J.
      • Herbelin L.
      • Aaronson L.S.
      Clinical research: new frontiers.
      A key aspect of this new era of clinical and translational research is discovering new interventions that can be brought from bench to bedside. The process by which this occurs is difficult and requires new team partnerships among a number of entities. The Office of Translation to Practice (OTP) at Mayo Clinic, a branch of the Mayo Clinic Center for Clinical and Translational Science, was created to accommodate this new enterprise. But the investigators at Mayo Clinic found quickly that they could not move forward without a partnership with the Sanford Burnham Prebys Medical Discovery Institute (SBP). The SBP had established the chemistry, biology, and pharmacology expertise necessary to develop assays and conduct high-throughput screening of libraries of compounds. Mayo Clinic investigators compete for the funds that allow them to access SBP infrastructure not only to identify tools to further advance biology but also to discover and develop novel drugs that can ultimately be tested in the clinical arena. This venture has created a new culture of discovery among Mayo investigators. Dozens of proposals have been submitted; 22 projects have been accepted in the program; and 5 have completed high-throughput screening, and 4 “hits” have been identified. This is impressive, as the OTP has only been in existence for 3 years.
      The state of Minnesota, Mayo Clinic, and the University of Minnesota have contributed generous proof-of-concept funding for investigators who want to take advantage of this new discovery pathway. The OTP has also created translation boards that advise investigators and their teams as they learn to navigate the process of drug discovery. Project-specific management teams are formed that assist the researchers in developing milestone-based goals. This process of project management with milestones leading to go/no-go decisions is commonly used in industry.
      Academic health care systems are beginning to adopt project management teams as an important component of the discovery process for drug and device development. Startup companies can be formed by investigators at an early stage in the process, and intellectual property claims are preserved through the technology transfer office. The next steps include, among others, regulatory processes; the completion of studies necessary for Food and Drug Administration clearance such that the novel drug may be studied in humans for the first time; and the accrual of external funding that enables the clinical trial phase. The authors and Mayo Clinic should be applauded for diving into this new world of discovery and entrepreneurship with creative infrastructure tools and a deep institutional support system for investigators.
      Although this process appears rational and seamless and could potentially lead to new therapies for patients—our ultimate goal—there are pitfalls. The authors point out a few of these challenges: poor pharmacokinetic/pharmacodynamic properties of the drug, poor clinical trial design, inappropriate patient population selection, and wrong end points. Ultimately, the candidates succeed or fail according to their therapeutic index and suitable business plan. These pitfalls, the authors contend, can be overcome by expertise of the investigators working in a team environment, and that is probably accurate. These challenges and other pitfalls contribute to what is often referred to as “the valley of death” in moving academic discoveries from bench to bedside.
      • Gamo N.J.
      • Birknow M.R.
      • Sullivan D.
      • et al.
      Valley of death: a proposal to build a “translational bridge” for the next generation.
      • Parrish M.C.
      • Tan Y.J.
      • Grimes K.V.
      • Mochly-Rosen D.
      Surviving in the valley of death: opportunities and challenges in translating academic drug discoveries.
      The valley of death typically spans target validation through clinical proof of concept. This stage is expensive, and because of the lack of adequate funding, projects can die in the valley of death. Finding adequate funding is a significant challenge for investigators and one which they do not necessarily contemplate at the outset of the discovery process.
      Anderson and colleagues allude to this challenge when they discuss the need for external funding, stakeholders, and licensure of the product. But raising the capital needed to get through the valley of death should not be underestimated. And it is a challenge for universities to succeed at this, especially when compared with pharmaceutical companies that possess multiple resources to fund projects from beginning to end. Indeed, it has been argued that drug development is really not the purview of universities and academic institutions that are amateurs in some ways at these ventures and should only be done in the business/pharmaceutical company sector. Nevertheless, most academic health centers have taken the plunge into the drug/device discovery business. Some in industry see this as a positive move, as the early stages of discovery can be “de-risked” at the university level and then industry can enter the process at a later stage. However, often private sector partners require academic projects be de-risked well beyond the early stages of discovery. To do so requires funding beyond that found at the local level. Startup companies in partnership with the university inventors can apply for Small Business Innovation Research/Small Business Technology Transfer National Institutes of Health grants to begin to move through the valley of death process. But additional funding on the order of $10 million is required to advance projects to first-in-human phase 1 and clinical proof-of-concept trials. This is where venture capital and other resources such as nonprofit organizations can enter the picture. It is often difficult for inventors and technology transfer offices to locate the optimal partner for moving a project forward.
      We at the University of Kansas Medical Center have also developed a drug discovery and development program as a result of our National Center for Advancing Translational Science and Center for Translational Science Award grant Frontiers: University of Kansas Clinical and Translational Science Institute.
      • Barohn R.J.
      • Herbelin L.
      • Aaronson L.S.
      Clinical research: new frontiers.
      One if its components, the Institute for Advancing Medical Innovation (IAMI), works with academic investigators to conduct product development–focused translational research. By bringing industry-experienced drug discovery and development veterans to the university and establishing innovative public-private partnerships, IAMI has enabled projects traversing the valley of death through a few different resources.
      • Weir S.J.
      • DeGennaro L.J.
      • Austin C.P.
      Repurposing approved and abandoned drugs for the treatment and prevention of cancer through public-private partnership.
      We were fortunate to have one of the top schools of pharmacy in the United States, with renown medicinal and pharmaceutical chemistry expertise contributing to the development and commercialization of several drug products. This rich history enabled the creation of a research infrastructure throughout the University of Kansas system that is heavily leveraged. The Institute for Advancing Medical Innovation was created by the university in partnership with the Kaufman Foundation, which provided funds to get some of our early projects started. A successful partnership with the Leukemia and Lymphoma Society and National Center for Advancing Translational Science called “The Learning Collaborative” received national visibility by repurposing the rheumatoid arthritis treatment agent auranofin for chronic lymphocytic leukemia. Today, IAMI has partnered with a Kansas City area investment group, BioNovus INNOVATIONS LLC, that together are developing the University of Kansas-invented Ciclopirox Prodrug for the treatment of bladder cancer. Like Mayo Clinic, the University of Kansas Medical Center has assessed the local resources to build a unique public-private partnership to advance projects at speeds common to the private sector while creating opportunities for academic investigators to directly participate in development activities.
      The nation looks to Mayo Clinic as it has for generations to provide cutting-edge treatments for patients with severe medical disorders. Adapting the Mayo Clinic Model of Care to embrace the new age of clinical and translational science is the next step in the evolution of Mayo Clinic as the nation’s health care center.

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      Linked Article

      • Translation to Practice: Accelerating the Cycle of Innovation to Impact
        Mayo Clinic ProceedingsVol. 94Issue 3
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          The Office of Translation to Practice (OTP) is housed in the Center for Clinical and Translational Sciences at Mayo Clinic. Established in 2015, the office was tasked with developing and managing novel tools, mechanisms, and processes to facilitate and accelerate the translation of products, such as drugs, biological agents, and medical devices, into practice. Since its inception, the OTP is credited with creating valuable services through several strategic alliances and active scientific and project management involvement.
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