Insufficient Clinical Efficacy Evidence and Trial Design Deficiencies
Severity: criticalThe Russian clinical data were not generalizable to the US population. The US data did not provide sufficient evaluable cycles (<5,000 requested) for safety and efficacy analysis. The efficacy analysis failed to meet the prespecified non-inferiority criterion. Concerns were raised regarding the definition of on-treatment pregnancies, computation of 'compressed cycles', inclusion of varying cycle durations, and lack of specified acceptable dosing times prior to intercourse. Sensitivity analysis on 'dosing deviations' did not address the request for efficacy data stratified by the interval between gel application and intercourse.
Recommended response: Conduct a new non-inferiority trial with a US-centric population, a pre-specified statistical analysis plan, clear definitions for evaluable and ovulatory cycles, and detailed data collection (e.g., electronic diary) to ensure generalizability and sufficient data for analysis.
Inadequate Adverse Event Reporting for Genitourinary Symptoms
Severity: majorThe decision to avoid classifying mild genitourinary symptoms lasting no more than one hour after product use as adverse events limits the conclusions that can be drawn about expected side effects with Amphora gel.
Recommended response: Revise adverse event reporting criteria to include all relevant genitourinary symptoms, regardless of duration, to provide a comprehensive and accurate safety profile for the product.
Inconsistent Material Statements for Pre-filled Applicator
Severity: majorThe materials of the pre-filled applicator are not consistently stated throughout the submission, with discrepancies noted between the NDA and the Drug Master File.
Recommended response: Provide consistent and reconciled documentation for all materials used in the pre-filled applicator, ensuring alignment between the NDA and the Drug Master File.
Insufficient Biocompatibility Testing for Applicators
Severity: criticalThere is no biocompatibility testing on the final, finished pre-filled device. The material safety information for the disposable applicator is limited to a statement of conformity to FDA food contact requirements, which is insufficient. Discrepancies in material suppliers between the NDA and DMF for the disposable applicator were also noted.
Recommended response: Conduct biocompatibility testing in accordance with ISO 10993 for both pre-filled and disposable applicators. Commercial use data may be leveraged if sufficient and verifiable.
Cited: ISO 10993
Inadequate Bench Testing Specifications for Applicators
Severity: majorBench testing revealed a wide range of separation forces for both applicators. The minimum force necessary to ensure proper and accurate filling of the disposable applicator was not identified, nor was the maximum acceptable force for gel delivery for either applicator.
Recommended response: Identify and incorporate specific minimum and maximum force specifications for applicator filling and gel delivery into the design specifications for both applicator types.
Incomplete Condom Compatibility Testing
Severity: majorCondom samples used in compatibility testing were not conditioned at 40°C for 60 minutes prior to testing, as required by ASTM D7661 and previous FDA requests.
Recommended response: Repeat condom compatibility testing, ensuring that samples are properly conditioned according to ASTM D7661 and prior FDA requests.
Cited: ASTM D7661
Insufficient Stability Testing for Applicator Performance
Severity: majorStability testing for the pre-filled applicator did not include assessments of key performance specifications, such as frictional force between barrel/plunger and barrel/plunger separation force, over the intended shelf life.
Recommended response: Conduct comprehensive stability testing to evaluate and demonstrate that the key performance specifications of the pre-filled applicator are not adversely affected over its intended shelf life.
