Lack of Long-Term Endometrial Safety Data
Severity: criticalYour application does not provide long-term endometrial safety data for the 4, 10, mcg estradiol vaginal inserts. Sufficient assessment of endometrial histology to support chronic use is critical to the safety evaluation of unopposed estrogen and to ensure adequate labeling for the safe use of your product. The 12-week safety data from Trial TXV14-01 are inadequate. Long-term data are needed to clarify if the product could be used without an opposing progestin and to guide prescribers on endometrial surveillance and the need for progestin therapy.
Recommended response: Conduct and provide data from a long-term endometrial trial of sufficient size and duration to adequately characterize endometrial safety and the long-term general safety profile of the product. Request a meeting to discuss trial details.
Inadequate Prescribing Information Content and Format
Severity: minorComments on proposed labeling are reserved until the application is otherwise adequate. However, any revised labeling must include updated content of labeling in structured product labeling (SPL) format and conform to 21 CFR 314.50(l)(1)(i).
Recommended response: Review labeling review resources, regulations, and guidance documents. Use the SRPI checklist to ensure conformity with format items. Update content of labeling in SPL format.
Cited: 21 CFR 314.50(l)(1)(i)
Incomplete Safety Update
Severity: majorWhen responding to deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). This includes describing significant changes in safety profile, incorporating new safety data from studies/trials, presenting tabulations of new and combined data, comparing frequencies of adverse events, providing separate tables for other indications, retabulating reasons for premature trial discontinuation, providing case report forms and narrative summaries for deaths/discontinuations due to AE and serious AEs, describing changes in common AEs, providing updated exposure information, and summarizing worldwide safety experience.
Recommended response: Provide a comprehensive safety update following 21 CFR 314.50(d)(5)(vi)(b), including all specified data and summaries.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Deviation from USP Monograph Requirements
Severity: majorThe current USP includes a monograph for Estradiol Vaginal Inserts, but the product may not conform to its requirements. Deviations should be identified on product labels. Recommend petitioning the USP with proposed revisions to the monograph.
Recommended response: Identify deviations from the USP monograph on product labels. Petition the USP for revisions to the monograph to accommodate the new drug product.
Inadequate Analytical Test Methods
Severity: majorDifferences noted in assay test method and acceptance criteria, dissolution test method and acceptance criteria, and procedure for determining related substances. The proposed HPLC-MS method for estradiol-related compounds and degradation impurities is unacceptable for regulatory purposes as it does not work in two different locations. Propose methods suitable for regulatory purposes. Perform dissolution method validation in accordance with US<1092> and adopt appropriate acceptance criteria.
Recommended response: Propose analytical methods suitable for regulatory purposes. Validate the dissolution method per US<1092> and establish appropriate acceptance criteria.
Insufficient Strength Differentiation on Carton Labeling
Severity: majorInsufficient differentiation between strengths due to primary colors (green, pink, purple) used for proprietary name and logo, which are also used for specific strengths. This increases the risk for strength selection errors. Colors chosen should be unique to each strength and avoid overlap or similarity with trade dress.
Recommended response: Revise carton labeling to ensure unique color differentiation for each strength, avoiding overlap or similarity with trade dress colors.
Incorrect Dosage Form Description
Severity: minorThe dosage form is described as '...'. This is not the appropriate dosage form. Revise the dosage form to read 'vaginal insert' on all labels and labeling.
Recommended response: Correct the dosage form description to 'vaginal insert' on all labels and labeling.
Lack of Prominence for Established Name
Severity: minorThe established name lacks prominence commensurate with the proprietary name. Increase prominence taking into account typography, layout, contrast, and other printing features in accordance with 21 CFR 201.10(g)(2).
Recommended response: Increase the prominence of the established name on labeling per 21 CFR 201.10(g)(2).
Cited: 21 CFR 201.10(g)(2)
Misplaced Statement of Strength
Severity: majorThe statement of strength is located away from the dosage form, which may lead to medication dispensing errors. Relocate the statement of strength to immediately follow the dosage form.
Recommended response: Relocate the statement of strength to immediately follow the dosage form on labeling.
Incomplete Blister Label Information
Severity: majorLack of drug-identifying information on the blister label in accordance with 21 CFR 201.10(i)(1) and 21 CFR 201.17. Specifically, missing proprietary and established name, product strength, lot or control number, expiration date (per USP), and name of manufacturer/packer/distributor. Recommend using MMMYYYY or MMMDDYYYY format for expiration date.
Recommended response: Add all required drug-identifying information (proprietary/established name, strength, lot/control number, expiration date, manufacturer) to the blister label, following 21 CFR 201.10(i)(1) and 201.17. Use recommended expiration date format.
Cited: 21 CFR 201.10(i)(1), 21 CFR 201.17
Proprietary Name Review Terminated
Severity: infoThe review of your proposed proprietary name has been terminated due to the deficiencies with the application. Resubmit the proposed proprietary name when you respond to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name with the complete response to application deficiencies.
