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US FDA•United StatesAL•Approval Letter

Approval Letter Other 215559 (Jan 1, 2023)

Issued January 1, 2023

Issued

January 1, 2023

Application

Other • 215559

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2024Product may be marketed.

Summary

The FDA issued a Complete Response letter for NDA 215559 for palovarotene capsules, indicating that the application cannot be approved in its current form due to inadequate support for efficacy. The letter outlines major unresolved review issues, primarily concerning the efficacy data and analysis methods, and provides detailed recommendations for additional data and analyses required for resubmission.

Key points

  • Provide adequate support for the efficacy of palovarotene to prevent the formation of new heterotopic ossification (HO) in pediatric and adult patients with fibrodysplasia ossificans progressiva (FOP).
  • Address the appropriateness of reliance on post-hoc analyses to support efficacy.
  • Address the acceptability of the external control group (Natural History Study, NHS) for evaluating the efficacy of the chronic/flare-up dosing regimen.
  • Clarify the implications of the observed negative new HO volume data.
  • Demonstrate the efficacy of flare-up-only dosing from phase 2 studies and resolve inconsistencies in efficacy data between phase 2 and phase 3 for chronic/flare-up dosing.
  • Address the imbalance in flare-ups between palovarotene-treated and non-treated patients, considering the potential for increased incidence with palovarotene.
  • Provide a clear plan for demonstrating substantial evidence of effectiveness, including confirmatory evidence if relying on a single adequate and well-controlled trial.
  • Submit additional data and data analyses, including all data out to clinical study close-out, to support palovarotene's efficacy.

Cited reasons

  • Reliance on post-hoc analyses for efficacy
  • Unacceptable external control group
  • Uncertain implications of negative new HO volume data
  • Inconsistent efficacy data and lack of demonstration for flare-up-only dosing
  • Imbalance in flare-ups and safety concern
  • Unclear plan for substantial evidence of effectiveness
  • The application cannot be approved in its present form due to inadequate support for the efficacy of palovarotene. The anticipated clinical benefit in preventing new heterotopic ossification (HO) has not been established, stemming from issues with clinical trial design, data analysis, and inconsistent efficacy findings.

Recommended actions

  • Provide adequate support for the efficacy of palovarotene to prevent the formation of new heterotopic ossification (HO) in pediatric and adult patients with fibrodysplasia ossificans progressiva (FOP).
  • Address the appropriateness of reliance on post-hoc analyses to support efficacy.
  • Address the acceptability of the external control group (Natural History Study, NHS) for evaluating the efficacy of the chronic/flare-up dosing regimen.
  • Clarify the implications of the observed negative new HO volume data.
  • Demonstrate the efficacy of flare-up-only dosing from phase 2 studies and resolve inconsistencies in efficacy data between phase 2 and phase 3 for chronic/flare-up dosing.
  • Address the imbalance in flare-ups between palovarotene-treated and non-treated patients, considering the potential for increased incidence with palovarotene.
  • Provide a clear plan for demonstrating substantial evidence of effectiveness, including confirmatory evidence if relying on a single adequate and well-controlled trial.
  • Submit additional data and data analyses, including all data out to clinical study close-out, to support palovarotene's efficacy.

Deficiency summary

The application cannot be approved in its present form due to inadequate support for the efficacy of palovarotene. The anticipated clinical benefit in preventing new heterotopic ossification (HO) has not been established, stemming from issues with clinical trial design, data analysis, and inconsistent efficacy findings.

Findings

Reliance on post-hoc analyses for efficacy

Severity: major

The appropriateness of relying on post-hoc analyses to support the efficacy of palovarotene is a major unresolved issue.

Recommended response: Submit additional data and data analyses, including all data out to clinical study close-out, to support the efficacy of palovarotene. This includes detailed analyses of new HO sites, annualized new HO summary statistics, comparisons with the NHS using various statistical methods, within-subject analyses, exploration of differences between studies, and assessment of self-selection bias.

Unacceptable external control group

Severity: major

The external control group (Natural History Study, NHS) used for efficacy evaluation of the chronic/flare-up dosing regimen is not acceptable.

Recommended response: Submit additional data and data analyses, including all data out to clinical study close-out, to support the efficacy of palovarotene. This includes detailed analyses of new HO sites, annualized new HO summary statistics, comparisons with the NHS using various statistical methods, within-subject analyses, exploration of differences between studies, and assessment of self-selection bias.

Uncertain implications of negative new HO volume data

Severity: major

The implications of the observed negative new heterotopic ossification (HO) volume data are unclear and require further clarification.

Recommended response: Submit additional data and data analyses, including all data out to clinical study close-out, to support the efficacy of palovarotene. This includes detailed analyses of new HO sites, annualized new HO summary statistics, comparisons with the NHS using various statistical methods, within-subject analyses, exploration of differences between studies, and assessment of self-selection bias.

Inconsistent efficacy data and lack of demonstration for flare-up-only dosing

Severity: major

Efficacy of flare-up-only dosing was not demonstrated in phase 2 studies, and there is inconsistency in efficacy data for chronic/flare-up dosing between phase 2 and phase 3 data.

Recommended response: Submit additional data and data analyses, including all data out to clinical study close-out, to support the efficacy of palovarotene. This includes detailed analyses of new HO sites, annualized new HO summary statistics, comparisons with the NHS using various statistical methods, within-subject analyses, exploration of differences between studies, and assessment of self-selection bias.

Imbalance in flare-ups and safety concern

Severity: major

An imbalance in flare-ups between treated and non-treated patients, and the potential for increased incidence of flare-ups with palovarotene treatment, raises concerns regarding both efficacy and safety.

Recommended response: Submit additional data and data analyses, including all data out to clinical study close-out, to support the efficacy of palovarotene. This includes detailed analyses of new HO sites, annualized new HO summary statistics, comparisons with the NHS using various statistical methods, within-subject analyses, exploration of differences between studies, and assessment of self-selection bias.

Unclear plan for substantial evidence of effectiveness

Severity: major

The plan for demonstrating substantial evidence of effectiveness, especially regarding reliance on a single adequate and well-controlled trial, is unclear and requires confirmatory evidence.

Recommended response: Submit additional data and data analyses, including all data out to clinical study close-out, to support the efficacy of palovarotene. This includes detailed analyses of new HO sites, annualized new HO summary statistics, comparisons with the NHS using various statistical methods, within-subject analyses, exploration of differences between studies, and assessment of self-selection bias.

Regulatory context

Submission stage
final decision
Regulatory pathway
NDA 505(b)

Impact

Impact score
0.75
Estimated delay
365 days
Estimated rework cost
$0
Subsequent action
resubmission

Strategic insights

The primary theme is the failure to establish substantial evidence of efficacy for palovarotene due to significant deficiencies in clinical trial design, statistical analysis, and data interpretation, particularly concerning the use of post-hoc analyses, external control groups, and inconsistent results across studies.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%

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