Issued January 1, 2022
Issued
January 1, 2022
Application
Other • 212304
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This letter from the FDA's Center for Drug Evaluation and Research outlines deficiencies found in New Drug Application (NDA) 212304. It provides specific instructions for revisions to labeling, packaging, and submission content, including a comprehensive safety update, to address these deficiencies.
The FDA issued a Complete Response Letter for ADLARITY, citing numerous deficiencies primarily related to product labeling and the need for a comprehensive safety update. Key labeling issues include missing NDC numbers, inconsistent strength expression, undefined expiration date format, absence of a usual dosage statement, lack of heat exposure warnings, inconsistent storage statements, and a potentially misleading IFU illustration. A detailed safety update is required, encompassing all nonclinical and clinical data, including specific analyses of adverse events, discontinuations, exposure, and worldwide experience.
The NDC numbers are denoted by a placeholder, preventing assessment from a medication safety perspective. Proposed NDC numbers should be added to labels and labeling for review.
Recommended response: Provide the proposed NDC numbers on all relevant labels and labeling for agency review.
Product strength is not consistently expressed on labels and labeling, potentially leading to misinterpretation. Strength should be consistently expressed as 'xx mg/day' wherever it appears.
Recommended response: Revise all labels and labeling to consistently express product strength as 'xx mg/day'.
The expiration date format is not defined on the container label and carton labeling, increasing the risk of deteriorated product medication errors. The Agency recommends YYYY-MM-DD or YYYY-MMM-DD format.
Recommended response: Define and implement a clear, human-readable expiration date format (e.g., YYYY-MM-DD) on all labels and labeling.
The usual dosage statement is not present on the labels and labeling, as required by 21 CFR 201.55. It is recommended to revise the container labels and carton labeling to read: 'Recommended dosage: See prescribing information and Instructions for Use for dosing and application instructions.'
Recommended response: Add the recommended dosage statement to container labels and carton labeling, referencing prescribing information and IFU.
Cited: 21 CFR 201.55
The Prescribing Information (Section 2.4 and Section 17) states heat exposure limitations, but container labels and carton labeling do not contain this warning. A statement such as 'Avoid applying heat' should be added to the principal display panel.
Recommended response: Incorporate a prominent heat exposure warning on the principal display panel of all labels and labeling.
The storage statement on container labels and carton labeling is inconsistent with that presented in the Prescribing Information. It should be revised for increased comprehension by lay users.
Recommended response: Harmonize and clarify the storage statement across all labeling components for lay user understanding.
Consider revising the carton labeling to state 'Dispense in this sealed carton' on the principal display panel, or address this concern by other means.
Recommended response: Add 'Dispense in this sealed carton' to the principal display panel or provide an alternative solution for dispensing clarity.
The readability of the net quantity statement can be improved. Consider revising it to read 'Contains sample packs. Each sample pack contains one system.'
Recommended response: Revise the net quantity statement for improved readability, using the suggested phrasing or similar.
The illustration in Step 1 of the Instructions for Use (IFU) may be misinterpreted to mean that a patch should be applied to more than one site, potentially leading to an overdose. Review labeling of other transdermal systems for guidance.
Recommended response: Revise the IFU illustration to clearly depict acceptable single patch application sites, consulting examples from other transdermal systems.
The proposed proprietary name, ADLARITY, was found acceptable pending approval but must be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proprietary name ADLARITY with the complete response to deficiencies.
A safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b), including data from all nonclinical and clinical studies/trials of the drug/product under consideration, regardless of indication, dosage form, or dose level.
Recommended response: Provide a detailed safety update covering all nonclinical and clinical data, addressing significant changes, adverse events, discontinuations, exposure, and worldwide experience.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Describe in detail any significant changes or findings in the safety profile.
Recommended response: Analyze and report any significant changes or new findings in the safety profile.
The FDA's Complete Response Letter highlights critical deficiencies in product labeling, particularly concerning medication safety and clarity for users, alongside a demand for a comprehensive and meticulously detailed safety update covering all clinical and nonclinical data. The need for consistent information across all submission components and a thorough re-evaluation of safety data are central themes.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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