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Developing Milestones for NINDS Translational Research Cooperative Agreement Applications

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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.

Sample Milestones.
Disclaimer: The stepwise approaches and in vitro and in vivo models, parameters, and quantitative values for the go/no go milestones shown below are for illustrative purposes only. NINDS is not endorsing particular development plans or models, parameters, or cut-off values for a disease. Investigators should make these selections based upon the stage of their therapy development project and the appropriateness of testing paradigms and quantitative cut-off values for each therapeutic development effort.

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.

Example A. Hypothetical small molecule drug development program for an inherited demyelinating neuropathy.

Year 1

Goals and timeline: Optimize chemical scaffolds for potency and toxicity. 12 months.
Criteria for success: Two lead scaffolds selected based upon the following traits: (a) EC50 in the Pmp22 gene in vitro reporter assay of < 10 nm, (b) activity on the Pmp22 gene promoter in a human Schwann cell line, defined as a minimum of 50% increase in luciferease fluorescence, and (c) cytotoxicity in the HEK-293 cell line at no less than 5-fold above EC50.
Rationale: The Pmp22 reporter assay used here has been validated as having predictive value for human clinical trials of NeuroRegeneration Pharma's NewMyelin drug. 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 with anticipation that further optimization will improve potency to the necessary clinically feasible level. A therapeutic window of 5-fold above presumptive clinical dose provides sufficient safety for the targeted patient population. An increase of 50% or more in the Pmp22 promoter activity has been published by the Myelin Study Group as appropriate for medium-throughput screening efforts in drug development for demyelinating neuropathies.

Year 2

Goals and timeline: Synthesize analogs for each lead scaffold and select lead compounds for each of the two scaffolds based upon in vivo target modulation in the myelinless mouse. 12 months.
Criteria for success: Lead compounds for each of the two scaffolds meet minimum acceptable standard of (a) 50% increase in Pmp22 protein expression at a dose of < 100 nm, as measured by immunoblot in the myelinless mouse model, (b) 2-fold increase in the number of axonal profiles in skin biopsies from forepaw, and (c) a minimum of 2.5-fold increase in tibial nerve conduction velocity.
Rationale: The myelinless mouse is a widely accepted model of demyelinating neuropathy. Although its predictive value has yet to be established in human studies, measurements of conduction velocity and nerve ending density in skin biopsies of myelinless mice have been shown to be responsive to both pharmaceutical and gene therapy agents. Measurement of protein levels by immunoblot will confirm the targeting of the promoter by the lead compounds; a 50% improvement in protein levels has been shown to correlate with improved nerve function.
Goals and timeline: Demonstrate synthetic scale-up potential for the selected lead compound. 12 months.
Criteria for success: Show scale-up of production the lead compound up to a 10-gram scale.
Rationale: The go/no go value was selected for lead compound synthesis based upon the required dosage and cohort size to be used for the subsequent in vivo efficacy testing.

Year 3

Goals and timeline: Identify a development candidate compound from one of the scaffolds to undergo IND-enabling testing for clinical development. 12 months.
Criteria for success: The development candidate has the following characteristics: (a) oral availability in rodent as measured by favorable pharmacokinetic properties, t1/2 > 6 hours after oral administration in rodent, (b) therapeutic index of 10-fold in rodent, and (c) demonstrated efficacy in the myelinless mouse as demonstrated by a 25% improvement in rotorod performance.
Rationale: For the targeted patient population, oral dosing is essential. Milestone parameters were selected to achieve availability and pharmacokinetic properties in support of twice daily dosing. As we optimize lead compounds, a higher stringency is being applied for therapeutic index-this will increase our flexibility in dosing in the subsequent clinical trial and may allow use of the therapeutic in more severe neuropathies. A 25% improvement in rotorod performance has been accepted as adequate efficacy to move a candidate forward by the Myelin Study Group.
Goals and timeline: Pre-IND meeting. 12 months.
Criteria for success: Hold pre-IND meeting with FDA.
Rationale: Meeting necessary to define acceptable parameters for the IND-enabling toxicology and biodistribution testing.
Goals and timeline: Demonstrate synthetic scale-up potential for the development candidate. 12 months.
Criteria for success: Show scale-up production for development candidate to scale sufficient to comply with FDA response to plans for IND-enabling non-clinical studies.

Year 4

Goals and timeline: Completion of GLP safety and toxicology testing of development candidate in two species according to plan acceptable to the Division of Drug Evaluation and Research, 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.
Goals and timeline: Submission of IND. 12 months.
Criteria for success: Submission of an IND application to the FDA.

Example B. Hypothetical gene therapy development program for progressive thalamic neurodegenerative disorder.

Year 1

Goals and timeline: Produce rAAV8.CMV.GDGF vector for intracranial delivery to the thalamic ventroposteriolateral nucleus (VPL) of the allodynic mouse. 12 months.
Criteria for success: rAAV8.CMV.GDGF vector produced at a yield of 5 x l012 vg.
Rationale: 5 x l012 vg provides sufficient vector for completion of mouse efficacy studies, with cohort size based upon power analysis and our prior use of the allodynic mouse model.
Goals and timeline: Determine transfection efficiency and efficacy in the allodynic mouse model of rAAV8.CMV.GDGF delivered through an intracranial catheter. 12 months.
Criteria for success: > 35% transfection of VPL neurons as measured by cell counts of sections stained with GDGF antibody and 30% improvement in tactile allodynia in the allodynic mouse model as determined by the Warburg light touch/pressure sensitivity test applied to the hindpaw, as compared to allodynic mice treated with saline control.
Rationale: Mouse testing is designed to work out the vector delivery parameters as well as to develop better information on efficacy potential for this therapeutic strategy. The Warburg light touch/pressure sensitivity test has been shown to activate identical neurophysiologic pathways in mouse and human and thus is considered by the field to be an appropriate efficacy measure for VPL function. 30% improvement in the value obtained with this test has been associated with reduced hindlimb ulceration and thus is a valid marker of somatosensory function and quality of life in mice.

Year 2

Goals and timeline: Produce rAAV8.CMV.eGFP for intracranial delivery to the VPL of the rhesus macaque monkey. 12 months.
Criteria for success: rAAV8.CMV.eGFP vector produced at a yield of 2 x l014 vg.
Rationale: 2 x l014 vg provides sufficient vector for scale-up of evaluation of transfection efficiency testing in a non-human primate. Such testing is viewed by the FDA as essential non-clinical information before progressing to the clinical trial.
Goals and timeline: Demonstrate transfection of the VPL of the rhesus macaque with rAAV8.CMV.eGFP following intracranial delivery. 12 months.
Criteria for success: Treated monkeys show an average transfection, via eGFP fluorescence, of at least 35% of neurons within the cytoarchitectural boundaries of the VPL.
Rationale: Monkey testing is viewed as essential proof of concept for the scale up of the vector delivery system to a large mammalian brain. Delivery of eGFP in the initial monkey studies is viewed as essential to optimizing the delivery parameters prior to testing the vector construct intended for therapeutic use. The 35% threshold for transfection efficiency is derived from the allodynic mouse studies cited above.

Year 3

Goals and timeline: Demonstrate persistence of expression of GDGF protein in the VPL of rhesus macaques treated with a transient immunosuppression regimen. 12 months.
Criteria for success: Treated monkey VPL nuclei show 40% of neurons expressing GDGF protein, as measured by immunocytochemistry at 6 months following intracranial injections.
Rationale: Based upon preclinical efforts in other neurodegenerative diseases, immunoresponse to the vector capsid has been a rate-limiting factor in the efficiency of gene therapy. The approach used here is to ensure persistence of therapeutically significant level of GDGF at a time point when the transient response to vector capsid is no longer operative.
Goals and timeline: Pre-IND meeting. 12 months.
Criteria for success: Hold pre-IND meeting with FDA.
Rationale: Meeting necessary to define acceptable parameters for the IND-enabling toxicology and biodistribution testing.

Year 4

Goals and timeline: Completion of GLP safety and toxicology testing according to plan acceptable to the Center of Biologics Evaluation and Research, 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.
Goals and timeline: Submission of IND. 12 months.
Criteria for success: Submission of an IND application to the FDA.

Last updated July 08, 2008