Assyro AI
US FDA•United StatesAL•Approval Letter

Approval Letter Other 209354 (Jan 1, 2019)

Issued January 1, 2019

Issued

January 1, 2019

Application

Other • 209354

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2020Product may be marketed.

Summary

The FDA issued a Complete Response Letter for NDA 209354, informing Dow Pharmaceutical Sciences, Inc. that their New Drug Application for halobetasol propionate and tazarotene lotion, 0.01%/0.045%, cannot be approved in its current form. The primary reason cited is insufficient nonclinical toxicology data, specifically a lack of an adequate bridge to listed drugs, and higher relative bioavailability of the proposed combination product. The letter outlines specific deficiencies and provides recommendations for resolution, including additional nonclinical studies and a comprehensive safety update.

Key points

  • Provide adequate data from a complete battery of genetic toxicology studies for both monads.
  • Provide adequate data from systemic embryofetal development studies in a rodent and a nonrodent species for both monads, ensuring adequate exposure to the drug substances.
  • Provide adequate data from a study or studies in male and female rodents for effects upon fertility, reproductive function, or early embryonic development for both monads.
  • Provide adequate data from a study in rodents for effects on pre- and postnatal development for both monads.
  • Evaluate the potential of the drug product or drug substances to induce carcinogenicity in two species for both monads, with one study using a systemic route and the other a dermal route of administration.
  • Submit protocols for carcinogenicity studies to the Division for evaluation by the Executive Carcinogenicity Assessment Committee of CDER.
  • Review labeling review resources on PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites if revising labeling.
  • Use the SRPI checklist to ensure prescribing information conforms with format items if revising labeling.

Cited reasons

  • Insufficient Nonclinical Toxicology Data and Inadequate Bridge to Listed Drugs
  • Prescribing Information Inadequacies
  • Proprietary Name Resubmission Required
  • Comprehensive Safety Update Required
  • The application cannot be approved in its present form primarily due to insufficient nonclinical toxicology data and an inadequate bridge to listed drugs, specifically regarding bioavailability. Additional deficiencies include requirements for updated prescribing information, resubmission of the proprietary name, and a comprehensive safety update.

Recommended actions

  • Provide adequate data from a complete battery of genetic toxicology studies for both monads.
  • Provide adequate data from systemic embryofetal development studies in a rodent and a nonrodent species for both monads, ensuring adequate exposure to the drug substances.
  • Provide adequate data from a study or studies in male and female rodents for effects upon fertility, reproductive function, or early embryonic development for both monads.
  • Provide adequate data from a study in rodents for effects on pre- and postnatal development for both monads.
  • Evaluate the potential of the drug product or drug substances to induce carcinogenicity in two species for both monads, with one study using a systemic route and the other a dermal route of administration.
  • Submit protocols for carcinogenicity studies to the Division for evaluation by the Executive Carcinogenicity Assessment Committee of CDER.
  • Review labeling review resources on PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites if revising labeling.
  • Use the SRPI checklist to ensure prescribing information conforms with format items if revising labeling.

Deficiency summary

The application cannot be approved in its present form primarily due to insufficient nonclinical toxicology data and an inadequate bridge to listed drugs, specifically regarding bioavailability. Additional deficiencies include requirements for updated prescribing information, resubmission of the proprietary name, and a comprehensive safety update.

Findings

Insufficient Nonclinical Toxicology Data and Inadequate Bridge to Listed Drugs

Severity: critical

Sufficient nonclinical toxicology data was not provided to support NDA approval, as an adequate bridge to the listed drugs (Ultravate and Tazorac) was not established. The relative bioavailability assessment showed the proposed combination product's bioavailability was higher than each of the listed drugs for the individual monads.

Recommended response: Conduct a complete battery of genetic toxicology studies, systemic embryofetal development studies (rodent and non-rodent), fertility/reproductive function studies, pre- and postnatal development studies, and carcinogenicity studies for both monads. Submit protocols for carcinogenicity studies to the Division for evaluation.

Cited: 21 CFR 314.125(b)(4)

Prescribing Information Inadequacies

Severity: major

Comment on proposed labeling is reserved until the application is otherwise adequate. Updated content of labeling in structured product labeling (SPL) format is required.

Recommended response: Review labeling review resources (PLR Requirements, Pregnancy and Lactation Labeling Final Rule, SRPI checklist) and submit updated content of labeling in SPL format.

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

Proprietary Name Resubmission Required

Severity: minor

The proposed proprietary name, Duobrii, was found acceptable pending approval of the application in the current review cycle. It must be resubmitted when responding to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name 'Duobrii' with the complete response to the application deficiencies.

Comprehensive Safety Update Required

Severity: major

A comprehensive safety update is required, including data from all nonclinical and clinical studies/trials. This includes describing significant changes in the safety profile, presenting new safety data (tabulated and combined with original data), providing case report forms and narrative summaries for deaths/serious adverse events, describing changes in common AEs, providing updated exposure information, summarizing worldwide experience, and providing English translations of foreign labeling.

Recommended response: Provide a detailed safety update incorporating all new nonclinical and clinical data, including updated adverse event tabulations, case report forms/narratives for deaths and serious AEs, updated exposure data, a summary of worldwide experience, and English translations of foreign labeling.

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

Regulatory context

Submission stage
final decision
Regulatory pathway
505(b)(2) New Drug Application

Impact

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

Strategic insights

The primary reason for the Complete Response is the inadequacy of nonclinical toxicology data and the failure to establish an adequate 505(b)(2) bridge to listed drugs, particularly concerning bioavailability. This necessitates extensive additional nonclinical studies. Furthermore, standard requirements for labeling updates and a comprehensive safety update are also cited.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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