Insufficient Biocompatibility Data for Permanent Contact Duration
Severity: criticalThe combination drug-device product (progesterone vaginal ring) contacts skin/mucosal surface for >30 days, but insufficient biocompatibility data (cytotoxicity, sensitization, genotoxicity, sub-acute toxicity) was provided. The agency requires testing on the final combination product, not just the progesterone-free ring, due to potential interactions and altered surface properties. Specific testing paradigms are recommended, including chemical characterization and toxicological risk assessment for leachables. The preliminary 14-day IP study for sub-chronic toxicity is not acceptable; 28-day IV and/or 90-day IP study is needed. Justification for the 14-day duration, dosage volume, and frequency is required. Exposure dosing should be based on the overall leachability profile of the final product, not just drug potency.
Recommended response: Conduct comprehensive biocompatibility testing on the final combination product, including cytotoxicity, sensitization, genotoxicity, and sub-acute toxicity, following the recommended testing paradigm (chemical characterization, toxicological risk assessment for leachables). Ensure sub-chronic toxicity studies meet duration and exposure requirements, basing dosing on the leachability profile.
Inadequate Clinical Safety Bridge for New Progesterone Vaginal Ring
Severity: majorAn adequate clinical safety bridge between the legacy progesterone vaginal ring used in Phase 3 trials and the new product has not been established. A study is recommended to evaluate the clinical safety of the new ring in women undergoing ART procedures, covering the entire treatment duration (up to 10 weeks post-embryo transfer) and collecting data on adverse events (pain, vaginal bleeding, vaginal irritation, vaginal infection, pregnancy outcomes like miscarriage/ectopic pregnancy) and discontinuations.
Recommended response: Design and conduct a new clinical study to evaluate the safety and tolerability of the new progesterone vaginal ring in the intended ART population, collecting comprehensive adverse event data and data on discontinuations.
Insufficient Evidence of Efficacy in Women 35-42 Years of Age
Severity: majorThere is still insufficient evidence of efficacy for the progesterone vaginal ring in women aged 35-42, a deficiency previously noted in a February 28, 2011, Complete Response letter. The agency recommends conducting a randomized, active-controlled clinical trial, adequately powered, to demonstrate efficacy in this subgroup. An alternative approach of appropriate labeling with a limitation of use and a post-marketing commitment for such a trial was also mentioned previously.
Recommended response: Conduct a randomized, active-controlled clinical trial to evaluate efficacy in women aged 35-42, or propose labeling with a limitation of use and a post-marketing commitment for such a trial, with prior agency agreement on the trial design.
Labeling Comments Reserved; Update Required
Severity: minorThe agency reserves comments on the proposed labeling until the application is otherwise adequate. Applicants are encouraged to review PLR Requirements, Pregnancy and Lactation Labeling Final Rule, and the Selected Requirements for Prescribing Information (SRPI) checklist. An updated content of labeling in structured product labeling (SPL) format is required with the response.
Recommended response: Review and update labeling according to PLR requirements, Pregnancy and Lactation Labeling Final Rule, and SRPI checklist once clinical and nonclinical deficiencies are addressed. Submit updated content in SPL format.
Cited: 21 CFR: 314.50(l)(1)(i)
Proprietary Name Acceptable Pending Approval, Resubmission Required
Severity: infoThe proposed proprietary name, MILPROSA, was found acceptable pending approval of the application in the current review cycle. It needs to be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name (MILPROSA) with the complete response to the application deficiencies.
Comprehensive Safety Update Required with Complete Response
Severity: minorA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included with the complete response. This update should detail significant changes in the safety profile, present new safety data combined with original data, compare frequencies of adverse events, provide case reports for deaths/serious AEs, describe changes in common AEs, provide updated exposure information, summarize worldwide experience, and include English translations of foreign labeling.
Recommended response: Prepare a comprehensive safety update according to 21 CFR 314.50(d)(5)(vi)(b) for inclusion with the complete response.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
