MID-COURSE REVIEW MEETING, DECEMBER 20–21, 2006 – EXECUTIVE SUMMARY
The Molecular Libraries and Imaging Roadmap Initiative (MLI) is an integrated set of initiatives aimed at developing selective and potent chemical probes for basic research, with three main components: (1) Technology development, (2) screening/data production, and (3) data analysis and dissemination. Major MLI accomplishments to date include establishing 10 screening centers that form the Molecular Libraries Screening Centers Network (MLSCN), adding 111,479 compounds to the Molecular Libraries Small Molecule Repository (MLSMR), developing a number of new chemical probes, and creating and populating the PubChem database with over 12 million chemical structures and 300 assays, thus producing a rich public database of compounds and their biological activities linked to all other National Library of Medicine (NLM) databases. Reviewers considered the MLI to be an extraordinarily important initiative that should be continued with the highest priority. They also expressed enthusiasm for the remarkable progress made in a short period of time. As one reviewer observed, significant progress has been made in some areas and a transformative effect of the MLI is occurring as well—virtually every medical center is building a screening center, and the MLI appears to have accelerated this process. Projects have been funded in assay development (111); chemical diversity (22); screening/imaging instrumentation (8), predictive absorption, distribution, metabolism, excretion, and toxicological (ADMET) profiles (10), and cheminformatics research centers (CRC) (6).
The MLI officially started in September 2003, but most grants were not awarded until the summer of 2005; some initiatives have been operating in pilot phase mode since then. The NIH convened a MLI Mid-Course Review Meeting on December 20–21, 2006, to evaluate the implementation and progress of the MLI to date, to determine if any mid-course corrections are needed, and to obtain recommendations on how to move forward to fully realize the potential of this initiative. MLI mid-course reviewers were selected to provide objective, expert advice from diverse perspectives. Some were involved in the early MLI planning stages, some participated in an earlier formal feasibility study on developing metrics, and some are new to the MLI but are knowledgeable in the areas of science under consideration. Of the participating reviewers, seven were from the pharmaceutical industry (four of whom were present at the December 20-21meeting), two from academia, one from a venture capital firm, and one from a biotechnology and pharmaceutical consulting firm. None have active projects funded by Roadmap initiatives. Reviewers examined the whole spectrum of activities within he MLI with an eye toward progress to date, possible course corrections, and the future trajectory of the initiative. One decision that needed to be made in the spring of 2007 was whether to scale up the MLSCN from pilot phase to a full-scale enterprise; reviewers examined the timing and goal of such a scale-up. The major outcome of the review was a set of recommendations for the overall MLI and for specific initiatives within the MLI. Note that consensus was not sought at the meeting for the recommendations proposed by individual reviewers. However, reviewers were asked to comment on an earlier draft of this report to ensure that the panel recommendations, as presented in this report, reflect the views of the panel as a whole, with differences of opinion noted.
Proposed General MLI Recommendations
The formal phase effort needs more scientific focus to drive excellence and uniqueness from what is being done in pharmaceutical and/or academic communities. Initiatives within the MLI do not have the sense that they are working together to solve something bigger than each of them could solve individually, which lowers overall integration and collaboration. The visibility and perceived value of the MLI needs to be higher within the biological sciences research community to increase the number of new assays submitted for screening.
- Focus the MLI on difficult or unique problems as an organizing theme to drive innovation and differentiation from drug discovery screening efforts in industry.
- Concentrate efforts in difficult research areas where the academic community can make a significant contribution.
- Pursue goals and projects not being taken up by pharmaceutical or biotechnology firms to differentiate the effort and provide novel resources to the research investigator unencumbered by proprietary considerations of industry.
- Manage the MLI as a diversified portfolio of initiatives.
Estimate and monitor the probability of success associated with each “project” in order to ensure a balanced mix of low- and high-risk technologies—use this information to determine when to halt a project and to evaluate whether the original risk assessment was correct.
- Reassess the MLI and chart the overall direction at the 5-year point.
Some of the initiatives in the MLI have been operating in pilot phase for less than 2 years. At this time, it is difficult to assess their progress, future promise, or integration into the larger MLI. While one reviewer recommended adding 2 more years to the pilot phase, there did not appear to be consensus about this recommendation at the meeting.