Milestones for Translational Device Cooperative Agreements:

Milestones for Translational Device Cooperative Agreements:

Milestones are not decision points to continue in either “this-direction” or “that-direction”; they are metric driven, quantifiable and verifiable, minimum-success criteria for each year of the project.   If these minimum criteria are not met by the end of the year, completion of the overall project goals by the end of the project term will be in doubt.  Consequently, these milestones are used to determine whether support for a study will continue after the end of the year, or if funding will be substantially reduced or discontinued (i.e., go/no go decision metrics).  Applicants are strongly encouraged to consult with the approriate NIH program staff  early in the application preparation phase. The initial contact with NIH program staff should happen at least 12 weeks before the application due date. 

Each milestone should be constructed to succinctly include: (a) the goals and timeline for completion, (b) the criteria for success, including the quantitative values and scales that will be used to asses success, and (c) the rationale for the choices of in vitro or in vivo models, parameters to be tested, and quantitative values that will drive the go/no go decisions. Note that not all planned activities necessitate milestones; general progress will be documented in progress reports, and should not be the basis for a go/no go milestone. The rationale section should be used to clearly state the logic behind your choices and make it clear why success (or failure) of each milestone indicates that further support for the program is justified (or not).  If consensus guidelines have been established for device testing within a research field, citing these guidelines or standards is helpful in establishing the rationale behind your milestones.

The adequacy of the proposed project milestones and the feasibility of achieving them are considered by peer reviewers in determining the scientific merit and score for the application. Final project milestones will be negotiated with NIH program staff prior to funding the application and may be changed based on suggestions from reviewers or NIH program staff. The final agreed upon and approved milestones will be specified in the Notice of Award (NoA).


Examples:

Disclaimer: The milestones below are presented in the format preferred. 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, and are not intended to be prescriptive nor exhaustive. NINDS is not endorsing particular device development plans or models, parameters, or cut-off values. ISO and MIL standards, along with FDA regulations, specified herein are illustrative examples and may be out of date; the investigator is responsible for citing current regulations and associated standards.  Investigators should make these selections based upon their experience level, the stage of their project, and the appropriateness of testing paradigms, timing, and quantitative cut-off values for each device development effort.

Milestone X.X Quality Systems Verification
Success Criteria: External audit of Quality Systems indicating that control processes and documentations conform to laws and regulations applicable to medical devices, including FDA quality system regulation 21 CFR Part 820.
Rationale: IDE approval from the FDA is contingent upon meeting all current good manufacturing practice (CGMP) requirements as outlined in 21 CFR Part 820, barring exemptions or variances.  According to 21 CFR Part 820.1(a),  “These requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use.  The requirements in this part are intended to ensure that finished devices will be safe and effective and otherwise in compliance with Federal Food, Drug, and Cosmetics Act.”    
Milestone X.X Benchtop Device Verification
Success Criteria: Summary report of verification test results for device master file demonstrating necessary system capabilities, including:Demonstrated hermeticity of Implantable Pulse Generator (IPG) as validated by helium leak test under MIL Standard 750
  1. Stimulus pulse duration of 5-1000 microseconds with a minimum resolution of 5 microseconds
  2. Current controlled stimulus pulse amplitude of 0 – 20 mA with a minimum resolution of 2 mA
  3. Minimum implantable pulse generator lifetime at maximum stimulus settings of 1 year, given an impedance load of 1 kohm as measured using a 10 mA, 500 microsecond pulse.
Rationale: Benchtop testing will verify the minimum basic functionality required for performance of the in vivo neuromodulation system to achieve clinical goals.  NIH Note: Including such criteria indicates that failure to meet any one of them would significantly jeopardize success of the program and should result in discontinuation of support.   
Milestone X.X Software Verification
Success Criteria: External audit report on software verification, indicating that documentation is appropriate for a feasibility IDE.
Rationale: FDA Requirement.    
Milestone X.X Biocompatibility and Sterilization Testing of the Composite Implanted Device
Success Criteria: Summary report verifying the device is compliant with ISO 10993 standard for FDA implant device category Tissue/Bone contact for over 30 days, including report from an independent laboratory summarizing cytotoxicity study results.  All testing will be performed in compliance with Good Laboratory Practices (GLP) testing.
Rationale: Requirement for FDA approval of a chronically implanted device.
Milestone X.X Chronic In Vivo Efficacy Testing of the Final Device
Success Criteria: A statistically significant improvement of at least xx (units) in physiological metric ?? with respect to baseline at the one week, one month, and three month post-implantation times points in xx percent of the implanted animals.
Rationale: Minimum efficacy requirement needed to offset the risks inherent with a Class III medical device.
Milestone X.X Hold a pre-submission meeting with the FDA for feedback on pre-clinical (or clinical) studies
Success Criteria: (1) Documented feedback from FDA regarding the appropriateness and adequacy of the proposed protocol, or details as to how to modify the proposed plan. (2) All correspondence between the investigator and the FDA is shared with NIH program staff, including pre-submission documents, at least two weeks prior to submission to the FDA. (3) Invitation extended to NIH program staff to all pre-submission meetings.
Rationale: To ensure the planned clinical studies satisfy FDA expections and will likely lead to IDE approval. Further, to inform the FDA of the pre-clinical and clinical studies. Additionaal follow-up pre-sbumission meetings, or other actions may be necessary if the NIH program staff feel the feedback suggests the proposed protocol is not acceptable. Sharing documents and including NIH program staff in meetings is a requirement of the cooperative agreement and is critical to maintaining open communication and collaboration between investigators and program staff
Milestone X.X Obtain IDE Approval from FDA
Success Criteria: (1) A notification letter from the FDA approving the final protocol, with no major study design concerns or considerations. (2) All correspondence between the investigator and the FDA is shared with NIH program staff, including the submission material, at least two weeks prior to submission to the FDA, and the initial decision letter(s), within 30 days of receipt.
Rationals: IDE approval is required to start the clinical study. Any major study design considerations will be considered and resolved to maximize the probability that a future pivotal study can proceed with the data collected in this feasibility study.
Milestone X.X Hold a Scientific Steering Group (SSG) meeting
Success Criteria: (1) Invitation to meeting sent to NIH program staff at least two weeks prior to the meeting. (2) Meeting report, including participants, proceedings and decision(s) made.
Rationale: This is a requirement of the RFA and will help to ensure continued progress and success of the project.
Milestone X.X Hold a Study Monitoring Committee (SMC) meeting
Success Criteria: (1) Recommendation to continue enrollment by the SMC after reviewing the incidence andand nature of any adverse events. (2) Meeting proceedings and decision will be communicated to the NIH porgram staff within two weeks.
Rationale: This is a requirement of the RFA and will help to ensure ongoing safety of the study.
Milestone X.X Obtain IRB approval for protocol, as approved by FDA
Success Criteria IRB approval letter and informed consent documents provided to NIH program staff.
Rationale: Obtaining and maintaining IRB approval is a requirement for a clinical study
Milestone X.X Register the study on www.clinicaltrials.gov
Success Criteria: Confirmation of registration provided to NIH program staff
Rationale: Registering the study on www.clinicaltrials.gov is a requirement for all clinical studies.
Milestone X.X Implant at least 2 subjects (4 of 10 subjects implanted, total)
Success Criteria: Surgical implantation record shared with NINDS program staff
Rationale: At least 2 subjects need to be implanted to meet total participation goals of the project.
Milestone X.X Short-term Efficacy
Success Criteria: At least a X% improvement in clinical efficacy, measured compared to baseline measurements, on the ABC scale.
Rationale: The ABC scale is a widely used and accepted clinical rating scale. An improvement of X% is considered the minimum improvement needed for clinical benefit and is necessary to justify continued implantation and testing.