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Roundtable on Translating Genomic-Based Research for Health; Board on Health Sciences Policy; Institute of Medicine. Drug Repurposing and Repositioning: Workshop Summary. Washington (DC): National Academies Press (US); 2014 Aug 8.

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Drug Repurposing and Repositioning: Workshop Summary.

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5Policy Approaches and Legal Framework

Important Points Highlighted by Individual Speakers

  • A trusted intermediary is often useful to initiate collaborations and provide the infrastructure and resources for academia and industry to work together.
  • Crowdsourcing of candidate compounds for repurposing can generate ideas about new mechanisms of action and potential applications.
  • Template collaborative research agreements can be beneficial for initiating a partnership and providing a catalyst to help projects move forward quickly.
  • The release of information about potential compounds for repurposing has to strike a balance between confidentiality and providing sufficient information to attract the best research scientist and proposals.
  • A less formal program for investigators who could use a small amount of a compound for a cell culture or animal experiment may also have a significant impact on assisting in the identification of new uses for existing drugs.

The success of repurposing and repositioning depends on the participating academic research and industry partners as well as on the contractual agreements and strategies enlisted by the programs. However, the biotechnology and pharmaceutical industries have been resistant to collaborative research because intellectual property is so important in this sector, said Arti Rai, Elvin R. Latty Professor at Duke University. The expense of clinical trials changes the business model for the biopharmaceutical industry, creating a need for more procedural and legal formalities involving patents, trade secrecy, and contractual mechanisms.

Academic and industry researchers have different research focuses, expectations regarding publication, and styles of negotiation, Rai said. For this reason, a trusted intermediary is often needed to spur collaboration, fund projects, and provide the infrastructure needed for working together, such as template agreements.

Programs undertaken by NIH in the United States and the MRC in the United Kingdom have been developed to foster innovation in drug repurposing and to increase the understanding of disease mechanisms by promoting collaborations between pharmaceutical companies and academic researchers, Rai said.


The mission of NCATS is “to catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions,”1 said Christine Colvis, director of extramural therapeutics discovery at NCATS. As part of that mission, NCATS has launched a Therapeutic Discovery Pilot program with the goal of identifying “new therapeutic uses of proprietary compounds and biologics across a broad range of human diseases in areas of medical need,” Colvis said.

Eight pharmaceutical company partners—AbbVie (formerly Abbot), AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, and Sanofi—have collectively made 58 compounds available, Colvis said. All are in early stages of development and are not approved drugs, and in most cases academic researchers would typically have been unaware of the existence of these compounds. NCATS listed the compounds with their known mechanisms of action, original indications, route of administration, penetration into the central nervous system, safety and tolerability data, and clinical trial information. The intention was to provide enough information for a researcher to determine whether a drug might be appropriate for a disease of interest.

In order to be included in the program, a company needed to have at least three compounds it could offer, and each company had different philosophies and strategies for selecting compounds, Colvis said. In sending compounds to NCATS, BMS chose only compounds that were safe because it felt uncomfortable putting compounds with significant concerns about safety into the hands of people outside the company, given that BMS would have no control over how the drugs would be used, said Taylor. The company also chose compounds with enough patent life that if a positive study occurred, BMS would have the financial incentive to continue study of that compound, which would be needed for the compound to be manufactured and distributed. Only three compounds met these criteria, Taylor said, although the company has had far more than three failures in drug development.

The intent of the NCATS program was to match candidate agents from the pharmaceutical partners with members of the research community who have innovative ideas for using shelved compounds for new indications. Each match represents a three-part interaction among NIH, industry, and academic researchers. NIH provides template collaborative research agreements, confidential disclosure agreements, mechanisms for peer review, funding, and oversight of the program. The pharmaceutical partners provide therapeutic compounds and relevant drug data along with in-kind support. Academic research partners provide disease biology knowledge, new ideas for different drug indications, and access to patients. The program is designed to be a collaborative process that should ultimately benefit patients, Colvis emphasized, and it does not involve simply handing over compounds for study.

Crowdsourcing Ideas

The program's goal in making the drug information publicly available, Colvis said, was to crowdsource the compounds in order to generate ideas about potential targets and indications for use. Within about 60 days NCATS received almost 160 pre-applications for potential new uses, many of which were for different indications using the same compound. For instance, a single compound might generate interest from various academic researchers as a treatment for arthritis, cancer, kidney failure, Alzheimer's disease, and the management of pain.

At NCATS the review was remarkably fast, even with managing the conflicts that arose. Only 7 weeks passed between the application due date and the completion of the reviews, Colvis said. About 1,000 reviewers were pre-recruited, and they were given 1 week to conduct their reviews. Each application was seen by reviewers with clinical expertise, knowledge of the mechanism of action, and drug development experience. The applications were short—just six pages—so the primary consideration was whether the scientific rationale was sound. Reviewers also were asked whether this was the right team for the project and whether the team members had the expertise to start work immediately.

After peer review, the top-rated applicants were put in contact with the company for the first time. At this point the partners could make a joint decision about whether or not to go forward and execute collaborative research agreements and confidential disclosure agreements. These agreements would enable the exchange of data, after which an investigator could decide whether to submit a full application for a research project. The agreements between companies and researchers were critical in enabling projects to proceed, Colvis said. The first agreements were hardest to negotiate, while subsequent agreements were much easier to arrange. Furthermore, Colvis said, having a template for the agreements made it possible to move quickly, which would not have been the case if each agreement had to be negotiated de novo.

In June 2013, nine awards were announced, which totaled $12.7 million in funding for the first year. Eight diseases were covered: alcoholism, Alzheimer's disease, calcific aortic valve stenosis, Duchenne muscular dystrophy, lymphangioleiomyomatosis, peripheral artery disease, schizophrenia (two applications), and smoking cessation.

Signs of Success

The receipt of 160 applications within 2 months was a very positive sign, Colvis said. The willingness of eight potential competitors to participate in a single program was also a sign of success. Although a handful of awards will make only a small difference to the overall problem, demonstrating that a strategy can work—even if just a few compounds make it as far as Phase II trials—could lead to a much broader application of that strategy.

NCATS was also collecting feedback from the community so that it could consider converting the pilot program into a full program. Several other parties should be involved in future efforts, including FDA and patient advocacy groups, Colvis said. One complication with repurposing, she pointed out, is that a new indication may move a compound from one part of FDA to another, with different people and requirements becoming involved, though working with FDA could help smooth any such transitions.


The MRC is the United Kingdom's largest public funder of medical research both in universities and hospitals and in the MRC's own intramural program, said Christopher Watkins, director of translational research and industry at the MRC. One of seven research councils in the United Kingdom, the MRC is funded by the UK government but is free to support whichever science it chooses, with the exception that it cannot directly support R&D for companies. As part of its translational strategy, it focuses on research performed in humans for identifying mechanisms of disease and demonstrating proof-of-concept evidence of the validity and importance of new discoveries or treatments. The overall strategy is to ensure that the science it supports is of relevance to human health.

Under the Mechanisms of Disease Initiative, the MRC has been working with AstraZeneca to provide academic researchers access to compounds that AstraZeneca has deprioritized and is therefore no longer developing (Wadman, 2012). The goals of the program are to gain a better understanding of human disease mechanisms, to develop potential therapeutic interventions, and to stimulate relationships between academia and industry. The molecules were chosen so as not to duplicate active company research, ensuring that the MRC was supporting research that would not otherwise have been done, Watkins said. Relatively well developed toxicological information was available for the molecules, but some of the deprioritized compounds were cancer drugs for which the toxicology profile may not have been appropriate for chronic administration in other patient groups.

The call for proposals generated more than 100 applications, Watkins said. The proposals were assessed on the basis of the scientific rationale for using the compound, the availability and supply of the compound, the novelty of the study, clinical trial design, and the risks and benefits for patients. Out of 25 applicants invited to submit full proposals, 15 projects were funded at the end of 2012, 8 of which were clinical projects and 7 pre-clinical. Research areas ranged from common illnesses to orphan diseases, including an investigation of whether a compound originally designed for prostate cancer could delay Alzheimer's disease progression, a heartburn medication reused for chronic cough treatment, and the repurposing of a lung disease drug to treat muscular dystrophies, Watkins said.

The MRC specified that scientific excellence was the most important consideration, and the peer review was international, Watkins explained. As part of the agreement with AstraZeneca, none of the reviewers were industry scientists. The review mechanism was designed appropriately for its intention, with the goal of having the right experts asking the right questions in order to aid in the selection of successful research, Watkins said.

Repurposing compounds from AstraZeneca is not the explicit objective of the initiative, Watkins said. Rather, the compounds have been used as probes to investigate disease mechanisms, validate targets, and reveal new therapeutic opportunities. The program does not involve the screening of a compound library. Rather, researchers use compounds to test hypotheses. All the projects took the form of collaborative efforts between AstraZeneca scientists and academic scientists.

Similarities and Differences Between NCATS and MRC Programs

The NCATS and MRC programs have many similarities. They both have used template agreements and have served as trusted intermediaries, Rai said. The agencies also both use a two-stage process, with relatively open crowdsourcing followed by a more closed second stage that is governed by cooperative agreements. NCATS and MRC both have detailed provisions for publication, and both draw a distinction between background, including existing intellectual property protections, and the research results that could emerge from the collaboration.

The programs being conducted by the two agencies differ in several key ways, however, said Rai. The cooperative research agreements used by NIH are formally bipartite between the researcher and company, although modifications to the agreement necessitate the approval of NIH, and the agreements cannot supersede the terms and conditions of NIH grants. By contrast the MRC grant is a contract between the university and the MRC, with separate project agreements between the university and AstraZeneca. The MRC approach allows for greater confidentiality of applicant information in the first stage.

A larger difference, Rai said, is that the MRC collaboration aims to validate targets and increase the understanding of disease biology using humans as an experimental model, whereas NCATS is more focused specifically on repurposing. With NCATS, the model templates are directed to situations where molecules are repurposed and become commercially valuable as a consequence. Also, licensing provisions for the intellectual property in the results are specified in detail in advance, while AstraZeneca has the right to negotiate either exclusive or nonexclusive rights to the intellectual property retained by the academic organization.

Lessons Learned

Including industry and academic researchers as full co-applicants on all the proposals created true collaborations in which each party benefited from the study, Watkins said. AstraZeneca benefited by revisiting compounds that would not have otherwise been explored further. The researchers benefited by gaining access to the compounds as well as the related toxicology and safety data. By working together, academic researchers and industry capitalized on their unique strengths to improve their understanding of the underlying basis of human disease and aided in the development of potential therapeutic interventions.

As was the case with the NCATS programs, confidentiality template agreements were extremely beneficial for beginning collaborations, Watkins said. The agreements sped up the process well beyond what is usual for industry–academia collaboration. In particular, the use of a template known as the Model Industry Collaborative Research Agreement, which has been approved by a wide range of stakeholders, made it possible for the research agreements to be signed within 4 months of the announcement of funding decisions.


A smaller and less formal program for investigators who need a small amount of a compound to do a quick cell culture or animal experiment would be very helpful, Dietz said. Such a program could leverage the infrastructure, trust, and connections built by NCATS and the MRC. Discussions are being held with other companies concerning the creation of such a program, although the mechanisms for such a program would have to be established, Watkins said. He noted that AstraZeneca put significant time and effort into establishing the program with the MRC, and future programs should try to reduce the amount of bureaucracy necessary. The idea would be to have the best scientists in academia working with the best scientists in industry, and the program would not be “just a reagent catalog,” Watkins said.


Collaborative research agreements usually include provisions on how to deal with existing technologies—that is, what the parties had developed prior to the collaboration—along with provisions on the technology developments or results from the collaboration and the intellectual property rights associated with those developments or results, Rai said.

The release of information about the deprioritized drugs had to strike a balance between the need to provide confidentiality and the need to disclose sufficient information to attract the best research proposals, Watkins said. This information included data about the nature of the target, specificity, selectivity, and toxicology. The information did not, however, include details about whether the drug crossed the blood–brain barrier, which in retrospect was an oversight, he said.

An important issue was protecting the intellectual property of potential applications so that investigators would not be worried that companies would infringe upon their ideas. Confidentiality agreements were necessary among all partners in order to allow for the protection of some of the more detailed information, the sharing of information necessary for choosing the right molecules, the protection of the intellectual property of potential applicants, and the assuring of confidentiality from the peer reviewers, Watkins said.

AstraZeneca retains the intellectual property on its molecules, Watkins said, while any intellectual property resulting from the research is to be retained by the research organizations. AstraZeneca will be able to negotiate intellectual property protections once the studies are complete. The partners also agreed to publish the study results within 6 months so that information from the initiative enters into the public domain.

Method-of-Use Patents

Some molecules may serve simply as “parent” molecules, with patents filed on compounds derived from them, Rai said. If the compounds do not have much patent life left, it may be possible to acquire some protection through process or method-of-use patents.

One question, Rai said, is whether method patents provide sufficient incentives to complete the testing that would be necessary for FDA approval of a new use. If the molecule is already being marketed for another use, which in this case is unlikely, then the compound could simply be used off-label. If the compound is not being marketed, a method-of-use patent provides more exclusivity, though the level of exclusivity depends on the strength of the method-of-use patent.

An alternative intellectual property approach may be needed, given that the patent system is not now working optimally for the biopharmaceutical industry, Rai said. In the future, compounds may need a “therapeutic only” exclusivity comparable to the data exclusivity that biologics have. For example, the proposed Modernizing Our Drug and Diagnostic Evaluation and Regulatory Network (MODDERN) Cures Act of 20112 would have allowed the Secretary of Health and Human Services to designate a particular therapy or potential therapy as addressing an unmet medical need and thereby provide 15 years of exclusivity.



NCATS Mission Statement, http://www​.ncats.nih​.gov/about/mission.html (accessed February 26, 2014).


MODDERN Cures Act of 2011, H.R. 3497, 112th Congress, 1st session (November 18, 2011). The bill was re-introduced in 2013 as MODDERN Cures Act of 2013, H.R. 3116, 113th Congress, 1st session (September 17, 2013).

Copyright 2014 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK235864


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