US FDA•United StatesAL•Approval Letter

Approval Letter Other 204017 (Jan 1, 2020)

Issued January 1, 2020

Issued

January 1, 2020

Application

Other • 204017

Review center

Other

Stage

Late Cycle

Letter type

Approval Letter

Response due March 1, 2020Product may be marketed.

Summary

The FDA issued a Complete Response Letter for Agile Therapeutics, Inc.'s New Drug Application (NDA 204017) for a levonorgestrel/ethinyl estradiol transdermal contraceptive delivery system. The application cannot be approved in its current form due to significant product quality issues related to the adhesion performance of the transdermal system, deficiencies in manufacturing facility observations, and clinical concerns regarding efficacy, high Pearl Index, and high subject discontinuation rates, which may be linked to the adhesion problems. The letter outlines specific deficiencies and provides recommendations for addressing them across product quality, facility inspections, clinical data, PREA requirements, prescribing information, proprietary name, and safety updates.

Key points

Demonstrate that in-process adhesion and tack tests are suitable for ensuring the quality and in vivo adhesion of the commercial-scale product.
Ensure the finished drug product specification is adequate for quality, tack, and adhesion at release and on stability, and that the current in vitro adhesion test ensures adequate in vivo adhesion properties.
Achieve satisfactory resolution of objectionable conditions observed at the manufacturing facility (Corium International Inc., FEI 3003693015).
Assess whether unacceptable in vivo adhesion properties are due to the current design and formulation of the drug product or other factors, and how this impacts efficacy, cycle control, and safety.
Address the implications of delays in applying the patch and high withdrawal/dropout rates observed in clinical trials.
If unacceptable adhesion is due to design/formulation, design a new transdermal system and conduct another clinical trial with the new system in the US population.
Submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End-of-Phase-2 (EOP2) meeting, or as per draft guidance, outlining pediatric studies and any waiver/deferral requests.
Revise proposed labeling to conform with format items in regulations and guidances, using the SRPI checklist, and include updated content of labeling in Structured Product Labeling (SPL) format.

Cited reasons

Inadequate In-Process Adhesion and Tack Tests
Inadequate Finished Drug Product Specification for Adhesion
Manufacturing Facility Inspection Findings
Clinical Efficacy and Adhesion Performance
Initial Pediatric Study Plan (iPSP) Submission
Updated Content of Labeling (SPL Format)
Proprietary Name Resubmission
Comprehensive Safety Update

Recommended actions

Demonstrate that in-process adhesion and tack tests are suitable for ensuring the quality and in vivo adhesion of the commercial-scale product.
Ensure the finished drug product specification is adequate for quality, tack, and adhesion at release and on stability, and that the current in vitro adhesion test ensures adequate in vivo adhesion properties.
Achieve satisfactory resolution of objectionable conditions observed at the manufacturing facility (Corium International Inc., FEI 3003693015).
Assess whether unacceptable in vivo adhesion properties are due to the current design and formulation of the drug product or other factors, and how this impacts efficacy, cycle control, and safety.
Address the implications of delays in applying the patch and high withdrawal/dropout rates observed in clinical trials.
If unacceptable adhesion is due to design/formulation, design a new transdermal system and conduct another clinical trial with the new system in the US population.
Submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End-of-Phase-2 (EOP2) meeting, or as per draft guidance, outlining pediatric studies and any waiver/deferral requests.
Revise proposed labeling to conform with format items in regulations and guidances, using the SRPI checklist, and include updated content of labeling in Structured Product Labeling (SPL) format.

Deficiency summary

The application cannot be approved in its present form due to significant product quality issues related to the transdermal system's adhesion performance, which directly impacted clinical efficacy and safety findings. Additionally, objectionable conditions were observed at the manufacturing facility, and several administrative and safety update requirements need to be addressed.

Findings

Inadequate In-Process Adhesion and Tack Tests

Severity: major

The in-process adhesion and tack tests have not been demonstrated to be suitable for ensuring the quality and in vivo adhesion of the commercial-scale product. There was a high frequency of invalid results and non-comparable profiles between batches.

Recommended response: Develop and validate in-process tests for tack and adhesion, justifying acceptable ranges using results obtained during the manufacture of drug product batches with acceptable in vivo adhesion properties.

Inadequate Finished Drug Product Specification for Adhesion

Severity: critical

The proposed finished product specification lacks a validated test and appropriate acceptance criteria for Part Tack. The current adhesion test (TP074) is highly variable, subjective, and does not ensure adequate in vivo adhesion properties requisite for safe and efficacious use.

Recommended response: Develop and validate tests for part tack and adhesion for release and stability on the finished drug product, justifying acceptable ranges using results obtained from finished drug product batches with acceptable in vivo adhesion properties.

Manufacturing Facility Inspection Findings

Severity: critical

During a recent inspection of the Corium International Inc. (FEI 3003693015) manufacturing facility, objectionable conditions were observed by the field investigator.

Recommended response: Satisfactorily resolve the objectionable conditions observed at the manufacturing facility (FEI 3003693015).

Clinical Efficacy and Adhesion Performance

Severity: critical

Clinical trial (ATI-CL23) showed 11.3% of patches with less than 75% adherence and over half of subjects reported complete patch detachment. The Pearl Index was higher than expected (5.83), with significant on-treatment pregnancies, high withdrawal/dropout rates (>50%), and unscheduled bleeding (>40%). The extent to which adhesion issues affected efficacy, bleeding, and discontinuation is unclear, and the reduced efficacy is not deemed to outweigh risks and uncertainties.

Recommended response: Assess whether unacceptable in vivo adhesion properties are due to product design/formulation or other factors, and how this impacts efficacy, cycle control, and safety. Address implications of delayed patch application, high withdrawal, and dropout rates. If due to design/formulation, design a new transdermal system and conduct a new clinical trial in the US population.

Initial Pediatric Study Plan (iPSP) Submission

Severity: minor

An Initial Pediatric Study Plan (iPSP) must be submitted within 60 days of an End-of-Phase-2 (EOP2) meeting, or as per guidance, outlining planned pediatric studies or requesting waivers/deferrals. Failure to include an Agreed iPSP with a marketing application could result in a refuse to file action.

Recommended response: Submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End-of-Phase-2 (EOP2) meeting, or as per guidance, in PDF and Word format, outlining planned pediatric studies or requesting waivers/deferrals.

Cited: 21 U.S.C. 355c

Updated Content of Labeling (SPL Format)

Severity: minor

The response must include updated content of labeling in structured product labeling (SPL) format.

Recommended response: Include updated content of labeling in Structured Product Labeling (SPL) format with the response to deficiencies.

Cited: 21 CFR 314.50(l)(1)(i)

Proprietary Name Resubmission

Severity: info

The proposed proprietary name, Twirla, was found acceptable pending approval of the application. It needs to be resubmitted when responding to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name, Twirla, with the response to application deficiencies.

Comprehensive Safety Update

Severity: major

A comprehensive safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b), including all new nonclinical and clinical safety data, detailed changes in safety profile, comparative tabulations of adverse events, reasons for discontinuations, case report forms for deaths/serious adverse events, and updated exposure information.

Recommended response: Provide a comprehensive safety update as per 21 CFR 314.50(d)(5)(vi)(b), including all new nonclinical and clinical safety data, detailed changes in safety profile, comparative tabulations of adverse events, reasons for discontinuations, case report forms for deaths/serious adverse events, and updated exposure information.

Cited: 21 CFR 314.50(d)(5)(vi)(b)

Regulatory context

Submission stage: late cycle
Regulatory pathway: 505(b)(2)

Impact

Impact score: 0.95
Estimated delay: 540 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The primary theme is the critical failure to demonstrate adequate and consistent in vivo adhesion of the transdermal delivery system, which undermines both the product's quality and its clinical efficacy and safety profile. This is compounded by manufacturing facility deficiencies and the need for comprehensive data updates and procedural compliance for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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