Translational Research - NINDS Cooperative Program

Milestone-Driven Research
The guiding principle of milestone-driven research is to remain focused on a well-defined goal, thus achieving that goal with greatest efficiency. In the NINDS Translational Research Program, the use of milestones translates into accelerated progress of therapeutic candidates toward Investigational New Drug (IND) or Investigational Device Exemption (IDE) applications to the FDA. In addition, as translational research is inherently high-risk, the use of milestones provides clear indicators of a project's continued success or emergent difficulties. The milestones weigh heavily in the peer review process and poorly-constructed milestones negatively impact scores. After award, NINDS establishes a Funding Plan with go/no go milestones and reviews these milestones at the beginning of each funding year to determine whether a project should be continued.

Preclinical therapeutic development projects aimed at IND or IDE submission should have defined interim goals, achievement of which can indicate the likelihood of eventual success. Thus, milestones are very different from the specific aims of a traditional NIH grant application. Although milestones may be appropriate at any point in a project year, they are typically evaluated at the end of annual funding periods to accommodate NIH practices in issuing awards. Cooperative agreements must have milestones at the end of each year of funding. If a particular phase of a project occurs over more than a year, quantifiable interim goals must be identified that allow evaluation of the successful advancement. This document is intended to provide guidance in crafting milestones that describe an aggressive but realistic research plan and provide reliable indicators of a project's successful progress.

Describe precise study outcomes, not simply completion
The milestones should describe the goal of the work and not just a statement that the work will be completed. Given the high-risk and progressive nature of therapeutics discovery and development, results at any stage of a project might indicate a dead end, for example a toxicology study may reveal that a molecule is unsuitable for human use. Thus, the milestone should indicate the desired outcome of a study and not simply that the study was conducted, e.g., '28-day toxicology studies in two species with no observed adverse events at drug levels at least 5-fold above the therapeutic dose,' and NOT 'completion of 28-day toxicology studies in two species.' The milestones must provide objective and quantitative outcomes by which to justify advancing the project.

Provide quantifiable measures of success
The criteria for success of the studies conducted within a given funding year should be objective measures. These should be measures that would be recognizable by reviewers knowledgeable in the specific disease area as appropriate endpoints. These should also have clear success criteria that can be used for evaluation of funding continuation by NINDS. Thus, milestones should indicate specific, quantifiable measures of success, e.g., 'Medicinal chemistry optimization will produce a compound analog with EC50 < 10 nM and LD50 > 5-fold above EC50', and NOT 'Medicinal chemistry optimization will produce compound analogs with improved potency and reduced toxicity.'

Include the rationale for your choices of in vitro or in vivo models, parameters tested, and quantitative values for the go/no go outcomes
If the animal model and test parameter has been validated by successful human clinical trials, provide this information as rationale for the choices of model, parameter, and quantitative go/no go. Note that such information may not available for many neurological disorders, since often no therapeutic has yet proven successful in the clinic. In these cases, develop a strong rationale for your choices of models, parameters, and quantitative go/no go's, based upon accepted practices in the specific field. If there is a specific consensus guidance document for best preclinical testing practices in a field, cite it. While gene transcription, translation, or biochemical parameters are often useful at early stages of product development, particularly during optimization portions of the program, use of functional parameters for efficacy are often viewed as essential by reviewers for later stage milestones.

Be aggressive yet realistic
Milestones should reflect an aggressive and efficient effort toward an IND application at every stage of the project. Peer reviewers evaluate the stringency of the criteria for success of each milestone, and the timeline for achieving these milestones. Once an application is funded, the milestones will be used by NINDS to evaluate progress and to make yearly funding decisions. Therefore, the milestones should be both appropriately aggressive and realistically attainable. The quantitation of success should reflect goals that would justify continuing with the project, and not necessarily what seems attainable at the outset. For example, the goal of a medicinal chemistry effort may be to produce compounds with <10 nM potency. However, if the potency of a compound series does not improve beyond 50 nM, but the compound has other favorable properties that balance potency, such as high metabolic stability or low toxicity, then lower potency may still justify continuing the project. Thus, milestones should be developed with an eye toward justifying continuation of the project and not describing the best possible outcomes.

Define milestones for each year of funding
In the Translational Research Program, milestones are reviewed on a yearly basis, preceding the release of funding for a particular year. At a minimum, a milestone must be proposed for each year of funding requested. In general, milestones are evaluated at the end of a year. However, in some cases, particularly with very costly projects, reviewers may prefer to see a milestone part way through a funding year. There should also be a terminal milestone for the eventual goal of the project, e.g., filing an IND application with the FDA. Defining the final goal is important to reviewers and NINDS to allow assessment of the feasibility of the milestones and interim progress toward that goal.

Clearly identify the milestones in the grant application
Because the evaluation of milestones is a critical part of the peer review, milestones should be clearly identified in the application. The timeline and clear quantitative success criteria should be clearly defined. If it is left to the reviewers to derive the milestones from the specific aims of the application, the score suffers. Clear delineation of milestones, and input from expert reviewers on those milestones, is also important for NINDS in establishing the Funding Plan before the award is made.

Include FDA interactions in the milestones
As the ultimate goal of these translational projects is an IND application to the FDA, the milestones should encompass meetings with the FDA that are critical to achieving this goal. FDA/CBER strongly recommends a pre-IND meeting at least one year in advance of anticipated IND submission, therefore, a pre-IND meeting with the FDA should appear as a milestone in the appropriate year. Even earlier in the project, pre-pre-IND meetings are also strongly encouraged to determine the most efficient route to IND. For projects funded via NINDS cooperative agreements, NINDS staff must be notified of and included in meetings with the FDA pertaining to the project.

Milestone Development
Milestones are not either-this-direction /or-that-direction decision points; instead they are used to determine whether a study continues or stops. The adequacy of the proposed project milestones, and the feasibility of achieving them, is considered by peer reviewers in determining the scientific merit and score for the application. Thus, it is very important that applicants convey the rationale underlying milestone design.

Each milestone should be constructed to include: (a) the goals and timeline for completion (setting milestones at the end of each funding year), (b) the criteria for success, and (c) the rationale for the choices of in vitro or in vivo models, parameters tested, and quantitative values for the go/no go's. Note that not all of your activities generate milestones. The rationale section should be used to clearly state the logic behind your choices and make it clear why each is a go/no go milestone. If consensus guidelines have been established for therapeutic testing within a research field, citing these guidelines is helpful in establishing the rationale behind your milestones.

Points of Contact:

Thomas M. Miller, Ph.D., M.B.A.
Program Director, ERP
National Institutes of Health, NINDS
6001 Executive Blvd.
NSC, Room 2139, MSC 9527
Bethesda, MD  20892-9527
Phone: 301-496-1779
tm208y@nih.gov

Lydia Munger-Little
Program Analyst
National Institute of Health, NINDS
6001 Executive Blvd.
NSC, Room 2180, MSC 9527
Bethesda, MD  20892-9527
Phone: 301-496-1779
mungerl@ninds.nih.gov