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Advanced Neural Prosthetics Research and Development


Example Milestones for Cooperative Agreement Mechanism

The goal of the Advanced Neural Prosthetics PARs is to enable investigators to pursue translational and pilot clinical studies for neural prosthetic devices.  For projects pursuing clinical demonstration or studies, the U.S. Food and Drug Administration (FDA) requires use of the Design Control process. Pre-IDE (Investigational Device Exemption) meetings with the FDA, intermediate steps in the Design Control process (design reviews, design verification, and design validation), and IDE submission should be represented in the annual milestones.  Note:  Budgeting for consultants with expertise in the Design Control process and/or regulatory submission is permissible.

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 (i.e., go/no go decision metrics).  Milestones should be developed with input from NIH Program staff, as they are not only a planning tool for the investigator, but serve as evaluation criteria to protect tax-payer investment.  Applicants are strongly encouraged to consult with NIH staff as plans for an application are being developed.  Early contact provides an opportunity for Program staff to discuss the program scope and goals, and to provide information and guidance on how to develop an appropriate milestone plan.  Other aspects of an application that are unique to this program are also discussed.  Consultations may include both an introductory call and a conference call with NIH staff.  The introductory call should be completed at least 10 weeks before a receipt date and the conference call at least 8 weeks before a receipt date.  Initiating interactions with Program staff even earlier are recommended, as they allow for applicants to receive input and assurance that an application will be accepted for review. 

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. Thus, it is very important that applicants convey the rationale underlying their 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 to be tested, and quantitative values that will drive the go/no go decisions. Note that not all of your activities generate 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 is helpful in establishing the rationale behind your 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, 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.


Example: Milestones for hypothetical Class III implantable neuromodulation device, including IDE submission and “proof-of-concept” human clinical study.

Note:  The milestones below are presented in the format preferred by NIH Program staff for discussion and finalization of the milestone plan, and are not intended to encompass all of the required standards or design criteria.  Investigators will have to revise this framework for brevity, consistent with the page-length restrictions for applications.  To save space, the most typical format is to include the milestones and minimum success criteria in table format, with a few paragraphs justifying each class/category of milestone (ISO standard, patient recruitment/IRB approval, etc).  

 

  Year 1 Milestones
Milestone #1: Quality Systems Verification
Criteria for success: 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 #2: Benchtop Device Verification
Criteria for success: Summary report of verification test results for device master file demonstrating necessary system capabilities, including:
  1. Demonstrated hermeticity of Implantable Pulse Generator (IPG) as validated by helium leak test under MIL Standard 750
  2. Stimulus pulse duration of 5-1000 microseconds with a minimum resolution of 5 microseconds
  3. Current controlled stimulus pulse amplitude of 0 – 20 mA with a minimum resolution of 2 mA
  4. 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 #3: First Pre-IDE Meeting with FDA
Criteria for success: Non-binding FDA feedback indicating that planned and completed benchtop testing, along with proposed animal safety and efficacy studies to be performed in year two, are sufficient for a successful IDE submission. NIH staff will attend this Pre-IDE meeting.
Rationale: Two Pre-IDE meetings are becoming increasingly common, one to discuss the sufficiency of benchtop and animal testing (known in industry as a “pre-pre IDE meeting”), and a second later Pre-IDE meeting to discuss the clinical protocol. This strategy is often necessary to ensure the planned testing satisfies FDA requirements, minimizing the expenditure of resources on performing additional testing to comply with FDA feedback. NIH Note: For investigators familiar with the regulatory pathway, this milestone also serves as a minimum success criterion for evaluation for NIH Program staff. We highly recommend beginning discussions with FDA staff as early in the process as possible.
  Year 2 Milestones
Milestone #4: Software Verification
Criteria for success: External audit report on software verification, indicating that documentation is appropriate for a feasibility IDE.
Rationale: FDA Requirement.    
Milestone #5: Biocompatibility and Sterilization Testing of the Composite Implanted Device
Criteria for success: 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 #6: Chronic In Vivo Efficacy Testing of the Final Device
Criteria for success: 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 #7: Second Pre-IDE Meeting with FDA
Criteria for success: Non-binding FDA feedback indicating that planned clinical protocol is sufficient for a successful IDE submission. NIH staff will attend this Pre-IDE Meeting.
Rationale: The second Pre-IDE meeting is intended to discuss the clinical trial design, see Milestone #3 for details.
  Year 3 Milestones
Milestone #8: Finalize Case Report Forms for IDE, Submit Feasibility IDE to FDA, and Successfully Respond to All IDE Issues from FDA
Criteria for success: Documentation of FDA IDE approval.
Rationale: FDA Requirement   
Milestone #9: Obtain IRB (Institutional Review Board) for Approval of Clinical Studies
Criteria for success: Documentation of IRB approval, pending IDE to be reviewed in Year 4.
Rationale: Requirement for clinical study.   
Milestone #10: Subject Recruitment
Criteria for success: Consent at least six subjects for baseline assessments.
Rationale: Although only four subjects will be implanted in the proof-of-concept clinical trial, it is expected from prior experience that at least twelve total subjects will need to be consented to reach this goal, given exclusion requirements and expected drop-out rate.  Six consents in Year 3 will be necessary to meet the implantation goals for the end of Year 4.
Milestone #11: Complete Baseline Assessment in at Least Four Subjects
Criteria for success: Documentation of Case Report Forms of baseline data collection. At least four subjects have completed all pre-implantation testing and are ready for surgery at the beginning of Year 4.
Rationale: Minimum requirement to reach target of first implant in Q1 (Quarter 1) of Year 4, and two implants by the end of Year 4.
  Year 4 Milestones
Milestone #12: Subject Recruitment
Criteria for success: Consent at least six additional subjects for baseline assessments.
Rationale: Although only four subjects will be implanted in the proof-of-concept clinical trial, it is expected from prior experience that at least twelve total subjects will need to be consented to reach this goal, given exclusion requirements and expected drop-out rate. Six additional consents in Year 4 will be necessary to meet the schedule for baseline assessment and surgical implantation by the end of Year 5.
Milestone #13: Complete Baseline Assessment in at Least Four Additional Subjects
Criteria for success: Documentation of Case Report Forms of baseline data collection. At least four additional subjects have completed all pre-implantation testing and are ready for surgery at the beginning of Year 5.
Rationale: Minimum requirement to reach target of 3rd and 4th implants by Q2 of Year 5.
Milestone #14: Implant Neuromodulation System in at Least Two Subjects
Criteria for success: Implantation is documented through the Surgical Implantation Document Form and Implant System Test Documentation.
Rationale: Minimum requirement to reach target of evaluation at three month time point in four patients at the end of Year 5.
Milestone #15: Short-Term Efficacy of Neuromodulation System
Criteria for success: Effectiveness measures at 1 week and 1 month, as outlined in Milestone #6, met for at least one of the two implanted patient. No system related adverse events noted in this period.
Rationale: If this short-term efficacy milestone is not met in at least one of the two patients by the end of Year 4, successful study outcome is in doubt. Minimum success criteria to support implanting the final two patients in Year 5.
  Year 5 Milestones
Milestone #16: Implant Neuromodulation System in at Least Two Additional Subjects
Criteria for success: Implantation is documented through the Surgical Implantation Document Form and Implant System Test Documentation.
Rationale: Minimum requirement to reach target of evaluation at three month time point in four patients at the end of Year 5.  Enables long-term follow up outside of the scope of the award.    
Milestone #17: Chronic Efficacy of Neuromodulation System
Criteria for success: Effectiveness measures at the 3 month time point, as outlined in Milestone #6, in at least three of the four patients.
Rationale: Minimum efficacy criteria to entice venture capital investors for expanding clinical work into a full trial.   
Milestone #18: Submission of Peer-Reviewed Manuscript – Case Study
Criteria for success: Journal receipt notice.
Rationale: Dissemination of key learning to the community for future iteration.  Undergo peer review of initial clinical data to lend credibility to findings for potential future clinical support of technology.

(See http://www.ninds.nih.gov/research/npp/resources/regulatory_guidance_resources.htm for more information regarding resources for regulatory guidance)

Last updated May 8, 2012