|David A. Jett, Ph.D.
Purpose and Rationale
The CounterACT program can only be used to support research that is product-oriented with clear deliverables (e.g. validated model or therapeutic target, IND, NDA, FDA-approved new drug). Milestone-driven research is used to ensure research is focused on a well-defined goal, thus achieving that goal with greatest efficiency. 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.
Describe precise study outcomes, not simply study 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 as appropriate endpoints by reviewers knowledgeable in the specific scientific area. They should also have clear success criteria that can be used for evaluation by NIH. 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 success
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 success criteria. It is acknowledged that such information may not be available for the effects of many chemical agents, but a strong rationale for your choices of models, parameters, and quantitative success criteria should still be provided. Keep in mind that ultimately for FDA approval, endpoints should be relevant to human health and represent serious morbidity and/or mortality caused by the chemical agent. This section should be brief (3-4 sentences) and serve only as a reminder of rationale provided in the main body of the Research Plan.
Define milestones for each year of funding
Milestones are reviewed on a yearly basis, preceding the release of funding for a particular year. At a minimum, one 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 NIH 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 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 NIH in pre-award negotiations of these milestones if needed.
*Failure to meet milestones could result in discontinuation of a project. If a milestone is not met, the NIH and project PI will evaluate whether a redirection of the project is a possible alternative to project discontinuation, as long as the new direction remains within scope of the original approved project, including the original overall goals of that project.
Each milestone should be constructed to include: (a) the goals and timeline for completion (usually at the end of each funding year), (b) the criteria for success, and (c) brief rationale. Note that not all of your activities generate milestones. Milestones are NOT a list of tasks to be completed; they are goals to be achieved.
Disclaime r : The fictitious examples below are for illustrative purposes only. NIH is not endorsing particular development plans or models, parameters, or cut-off values.
Example A. Hypothetical small molecule drug development program for a nerve agent anticonvulsant.
01 Milestone #1: Identify at least three compounds with requisite biological activity (“hits”). 12 months.
Criteria for success: Requisite biological activity is: (a) EC50 in the in vitro GABA receptor binding assay of <10 nm, and (b) LC50 cytotoxicity in the CACT-293 cell line at no less than 5-fold above EC50.
Rationale: The GABA receptor binding assay used here has been validated as having predictive value for human clinical trials of anticonvulsants. Based upon discussions with our clinical collaborators of patient dosing requirements, we established a threshold potency (EC50 < 10nm) suitable for this stage of therapeutic development, and a therapeutic window of 5-fold above presumptive clinical dose provides sufficient safety for the targeted patient population.
Years 2-5 similar and stepwise leading to the ultimate goal of identifying a lead compound ready for advanced development
Example B. Hypothetical advanced development of lead compound to be used as a cyanide antidote.
01 Milestone #1: Demonstrate efficacy in reducing lethality when administered at 20 minutes after cyanide challenge. 12 months.
Criteria for success: Reduction in lethality in mice by 50% when the candidate is administered (IM) 20 minutes following an acute LCt50 dose of HCN via inhalation.
Rationale: Lethality is an acceptable endpoint for cyanide toxicity. A reduction in lethality 50% is a threshold effect that represents a starting point for subsequent studies with higher doses of the candidate compound to increase efficacy.
Years 2-4 stepwise leading to ultimate goal in Year 5:
05 Milestone #1: To be completed at CounterACT Preclinical Development Facility(CPDF) - Completion of GLP safety and toxicology testing of development candidate in two species according to plan acceptable to the FDA. 12 months.
Criteria for success: No toxicity that would preclude FDA approval for the clinical trial.
Rationale: Only studies required for IND submission to be performed; success criteria set by FDA.
05 Milestone #2: Submission of an IND application to the FDA. 12 months.
Criteria for success: Submission of an IND application to the FDA.
Last updated July 23, 2015