Phase 3 submissions are evaluated based upon the following judging criteria. When evaluating submissions, judges assign each submission 1 to 5 (5 being the highest; 1 being the lowest) points for each of the judging criteria.
Phase 3 interim criteria
Interim Targeting Performance
Extent to which the data and results demonstrate the necessary requirements for selectively modulating at least one autonomic function with a high degree of tunability, accuracy, and precision while concurrently mitigating off-target effects. Methods used to demonstrate selective modulation of the target function should be appropriate, well described, and justified. Data should be presented as rigorously as possible, even in the case of small sample sizes.
Interim Off-Target Mitigation
Extent to which the data and results demonstrate the potential to mitigate all relevant off-target effects concurrently while selectively modulating at least one intended autonomic function. Methods used to demonstrate mitigation of off-target effects should be appropriate, well described, and justified. If applicable, the rationale for not mitigating any off-target effects should be well described. Data should be presented as rigorously as possible, even in the case of small sample sizes.
Clinical Relevance
Appropriateness and feasibility of addressing the chosen clinical indication(s) with the proposed neuromodulation technique. Extent to which input from relevant clinicians and potential users support the future clinical use of the proposed technique.
Phase 3 final criteria
Final Targeting Performance
Extent to which the data and results demonstrate the ability to selectively modulate two or more autonomic functions each with a high degree of tunability, accuracy, and precision. Methods used to demonstrate selective modulation of the target function should be appropriate, well described, and justified. Controls and statistical analysis of autonomic function modulation should be appropriate and sufficient for determining effect.
Final Off-Target Mitigation
Extent to which the data and results demonstrate the ability to mitigate all relevant off-target effects concurrently while selectively modulating multiple intended autonomic functions. Methods used to demonstrate mitigation of off-target effects should be appropriate, well described, and justified. If applicable, the rationale for not mitigating any off-target effects should be well described. Mitigation of off-target effects should include appropriate and sufficient controls and statistical analyses.
Clinical Relevance
Extent to which the data and results have demonstrated clinically relevant improvement in all target functions (not just statistical significance) as well as potential comparisons to currently available prescribed treatment for the target clinical indication(s) if applicable.
Technology Readiness
Degree to which the technology demonstrates high safety and efficacy as required for an IDE and/or a clinical trial and is likely to mature along the commercial pathway for clinical use. Pre-IDE submission concerns of FDA should be resolved, if applicable.
Phase 3 judging considerations
Judges will be asked to consider the following in their evaluations of the above criteria:
Neuro-modulation Control
Demonstrated ability to control each autonomic function independently. For any and all target functions identified, the approach must result in:
- Precision of stimulation outcomes within a generally accepted range of variability. A given neuromodulation parameter consistently results in similar change in the intended autonomic function (as indicated by biomarker measurement).
- Accuracy of stimulation outcomes to a generally accepted standard of error for the target function(s). The measured result is not significantly greater than the intended change in autonomic function (as indicated by biomarker measurement).
- Tunability of both the stimulation parameters (e.g., amplitude, pulse width) and resultant change in autonomic function. The functional response can be finely tuned (as indicated by biomarker measurement) in regard to a change in the stimulation parameter.
Off-Target Effect Mitigation
Demonstrated ability to mitigate unwanted effects of modulating the target function(s). All unwanted off-target effects should be mitigated to support future clinical use, and the following features should be addressed.
- All potential relevant off-target effects of the neuromodulation approach must be described and addressed. Relevance of an off-target effect is judged by its relationship to the anatomy and functional connectivity of the nerve target and surrounding neuromodulation site, and its potential clinical impact.
- Mitigation of off-target effects must be demonstrated across all off-target effects concurrently during modulation of each target function.
- If any off-target effects are intentionally not mitigated, an evaluation of their impact on neuromodulation control and the rationale for allowing them to occur should be well described.
Biomarker Characteriza-tion
A quantitative assessment of both on-target and off- target events that occur in response to neuromodulation. Identified biomarkers must include those which are regulated by the same nerve being modulated and be correlated with outcome.
A biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions. Biomarkers may include molecular, histologic, radiographic, or physiologic characteristics. Source: FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK326791/ Co-published by National Institutes of Health (US), Bethesda (MD).