US FDA•United StatesAL•Approval Letter

Approval Letter Other 210730 (Jan 1, 2020)

Issued January 1, 2020

Issued

January 1, 2020

Application

Other • 210730

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Product may be marketed.

Summary

This is a Complete Response letter from the FDA to Trevena, Inc. regarding their New Drug Application (NDA) for Oliceridine injection. The FDA has determined that the application cannot be approved in its present form due to several deficiencies identified in clinical, nonclinical, product quality, and labeling aspects.

Key points

Provide data from a randomized active-controlled study including 24-hour Holter monitoring and replicate QT measurements extracted every hour, compared to the control group, of adequate duration and sample size to evaluate oliceridine’s QT prolongation effects.
Provide an exposure database of adequate size to evaluate and support the safety of oliceridine for the proposed labeling, specifically including at least 350 patients exposed to the highest dose proposed for the longest duration of use indicated in the labeling.
Either conduct a dedicated embryo-fetal development study in either the rat or rabbit with TRV0109662, OR provide validated, reproducible pharmacokinetic data to support the conclusion that existing rat or rabbit embryo-fetal development study resulted in exposures to TRV0109662 that were at least 50% of human levels at the proposed maximum recommended human dose of 40 mg/day.
Validate newly developed analytical methods for leachables as per ICH Q2 recommendation and provide validation reports to the Agency.
Provide data for leachables found in stability samples analyzed by newly developed methods.
Review labeling review resources on PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites.
Use the SRPI checklist to ensure prescribing information conforms with format items in regulations and guidances if revising labeling.
Include updated content of labeling in structured product labeling (SPL) format.

Cited reasons

Inadequate data to support safety due to QT prolongation concerns
Inadequate exposure database for highest doses and longest duration of use
Inadequate characterization of major human metabolite (TRV0109662) for embryo-fetal effects
Unvalidated analytical methods for controlling identified leachables
Unacceptable proprietary name 'OLINVO' on labeling
Incorrect NDC format for carton labeling
Placement of 'Discard unused portion' statement
Negative warning statement format

Recommended actions

Provide data from a randomized active-controlled study including 24-hour Holter monitoring and replicate QT measurements extracted every hour, compared to the control group, of adequate duration and sample size to evaluate oliceridine’s QT prolongation effects.
Provide an exposure database of adequate size to evaluate and support the safety of oliceridine for the proposed labeling, specifically including at least 350 patients exposed to the highest dose proposed for the longest duration of use indicated in the labeling.
Either conduct a dedicated embryo-fetal development study in either the rat or rabbit with TRV0109662, OR provide validated, reproducible pharmacokinetic data to support the conclusion that existing rat or rabbit embryo-fetal development study resulted in exposures to TRV0109662 that were at least 50% of human levels at the proposed maximum recommended human dose of 40 mg/day.
Validate newly developed analytical methods for leachables as per ICH Q2 recommendation and provide validation reports to the Agency.
Provide data for leachables found in stability samples analyzed by newly developed methods.
Review labeling review resources on PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites.
Use the SRPI checklist to ensure prescribing information conforms with format items in regulations and guidances if revising labeling.
Include updated content of labeling in structured product labeling (SPL) format.

Deficiency summary

The application cannot be approved due to significant clinical safety concerns regarding QT prolongation and an inadequate exposure database, uncharacterized nonclinical embryo-fetal effects of a major metabolite, unvalidated analytical methods for leachables, and multiple labeling and administrative issues.

Findings

Inadequate data to support safety due to QT prolongation concerns

Severity: critical

The submitted data does not adequately support the safety of oliceridine for moderate-to-severe acute pain due to concerns related to QT prolongation. The thorough QT (tQT) study showed dose-dependent QTcF prolongation with delayed onset, and Phase 3 studies had limited ECG monitoring. Data to mitigate QT prolonging effects via labeling or monitoring were not provided. A randomized active-controlled study with 24-hour Holter monitoring and replicate QT measurements is needed.

Recommended response: Conduct a randomized active-controlled study with 24-hour Holter monitoring and replicate QT measurements extracted hourly, compared to a control group, to address QT prolongation at the maximum proposed daily dose.

Inadequate exposure database for highest doses and longest duration of use

Severity: major

The submitted exposure database is not of adequate size to evaluate and support the safety of patients exposed to the highest doses for the longest duration of use as proposed in the labeling. Specifically, the database lacks at least 350 patients exposed to the highest dose for the longest duration.

Recommended response: Provide an exposure database that includes at least 350 patients exposed to the highest dose proposed for the longest duration of use indicated in the labeling.

Inadequate characterization of major human metabolite (TRV0109662) for embryo-fetal effects

Severity: major

Adequate data has not been provided to confirm that levels of TRV0109662, a major human metabolite, have been characterized for potential embryo-fetal effects in either rat or rabbit embryo-fetal development studies. Data on metabolite formation in rabbits is lacking, and rat exposure levels are inadequate compared to humans, with assay reproducibility issues.

Recommended response: Either conduct a dedicated embryo-fetal development study in rats or rabbits with TRV0109662, or provide validated, reproducible pharmacokinetic data to support adequate exposure in existing studies.

Unvalidated analytical methods for controlling identified leachables

Severity: major

Validation reports for the analytical methods used in the leachables study have not been provided to the Agency.

Recommended response: Validate newly developed analytical methods for leachables as per ICH Q2 recommendations and provide the validation reports, along with data for leachables found in stability samples.

Unacceptable proprietary name 'OLINVO' on labeling

Severity: minor

The proprietary name 'OLINVO' was previously found unacceptable but is included on container labels and carton labeling.

Recommended response: Remove all references to 'OLINVO' and resubmit the proposed proprietary name 'OLINVYK'.

Incorrect NDC format for carton labeling

Severity: minor

The package code portion of the National Drug Code (NDC) is the same for the container label and carton labeling for all product strengths, which is inconsistent when the carton contains more than one unit.

Recommended response: Revise the NDCs for carton labeling for each strength so that the package code is different from its corresponding container label.

Placement of 'Discard unused portion' statement

Severity: minor

The statement 'Discard unused portion' is not directly after the fill volume statement, which poses a risk of overdose if the entire vial contents are administered.

Recommended response: Revise container and carton labeling so that 'Discard unused portion' appears directly after the fill volume statement.

Negative warning statement format

Severity: minor

Warning statements are written in negative language (e.g., 'Do not freeze'), which can be misinterpreted. Affirmative language is preferred.

Recommended response: Revise negative warning statements to affirmative language, such as 'Protect from freezing'.

Undefined expiration date format

Severity: minor

The format of the expiration date has not been defined on the container labels or carton labeling, leading to potential misinterpretation and medication errors.

Recommended response: Identify and use a clearly defined expiration date format (e.g., DDMMMYYYY, MMMYYYY, YYYY-MM-DD).

Inconsistent product strength statement on 30mg/30mL container label

Severity: info

The 30 mg/30 mL container label contains an unnecessary statement not present on the 1 mg/1 mL and 2 mg/2 mL container labels, leading to inconsistency.

Recommended response: Consider removing the inconsistent statement from the 30 mg/30 mL container label to maintain consistency with other strengths.

Incomplete or unclear route of administration statement

Severity: minor

The route of administration statement needs to be revised to 'FOR INTRAVENOUS USE ONLY' or 'FOR INTRAVENOUS USE'.

Recommended response: Revise the statement to 'FOR INTRAVENOUS USE ONLY' or 'FOR INTRAVENOUS USE', potentially relocating other statements.

Regulatory context

Submission stage: final decision
Regulatory pathway: NDA 505(b)

Impact

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

Strategic insights

The application received a Complete Response due to critical clinical safety concerns related to cardiac effects and insufficient patient exposure data, significant nonclinical gaps in metabolite safety characterization, and unresolved product quality issues concerning leachables. Numerous labeling and administrative deficiencies also require attention.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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