US FDA•United StatesAL•Approval Letter

Approval Letter Other 205920 (Jan 1, 2018)

Issued January 1, 2018

Issued

January 1, 2018

Application

Other • 205920

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2019Product may be marketed.

Summary

This is a Complete Response letter from the FDA to Armstrong Pharmaceuticals, Inc. regarding their New Drug Application (NDA) 205920 for Primatene Mist (epinephrine inhalation aerosol). The FDA has determined that the application cannot be approved in its present form, primarily due to deficiencies in the human factors (HF) study which failed to demonstrate safe and effective use of the product for proposed over-the-counter (OTC) use. The letter outlines specific reasons for non-approval and provides detailed recommendations for addressing these issues, including further HF studies, labeling revisions, and a safety update.

Key points

Re-evaluate primary task failures and difficulties from the human factors (HF) study and their associated root causes.
Update the risk analysis based on re-evaluation of HF data.
Implement additional risk mitigation strategies as needed.
Conduct another HF validation study after implementing all changes.
Design the HF validation study protocol to include retesting subjects several weeks after the initial test session to simulate intermittent use.
Assess consumers’ ability to use the epinephrine HFA inhalation aerosol in the HF validation study, including initial priming, cleaning, and routine use (re-priming).
Ensure HF validation testing includes at least 15 participants from each distinct user group, with adequate representation of subjects with low literacy, adolescents, subjects with asthma, and subjects with previous inhaler experience.
Ensure no prompting or cues by study moderators during the HF validation study.

Cited reasons

Inadequate Human Factors Study for OTC Use
Labeling Deficiencies - Mouthpiece Instructions
Carton and Container Labeling - General Requirements
Drug Facts Labeling (DFL) Formatting and Content
Immediate Container Label Deficiencies
Website Content Inconsistencies and Deficiencies
Safety Update Requirement
The application cannot be approved in its present form primarily due to inadequate human factors data to support safe and effective over-the-counter (OTC) use, particularly concerning the user interface and critical use tasks. Additionally, there are several deficiencies in carton, container, and consumer labeling, as well as inconsistencies in website content.

Recommended actions

Re-evaluate primary task failures and difficulties from the human factors (HF) study and their associated root causes.
Update the risk analysis based on re-evaluation of HF data.
Implement additional risk mitigation strategies as needed.
Conduct another HF validation study after implementing all changes.
Design the HF validation study protocol to include retesting subjects several weeks after the initial test session to simulate intermittent use.
Assess consumers’ ability to use the epinephrine HFA inhalation aerosol in the HF validation study, including initial priming, cleaning, and routine use (re-priming).
Ensure HF validation testing includes at least 15 participants from each distinct user group, with adequate representation of subjects with low literacy, adolescents, subjects with asthma, and subjects with previous inhaler experience.
Ensure no prompting or cues by study moderators during the HF validation study.

Deficiency summary

The application cannot be approved in its present form primarily due to inadequate human factors data to support safe and effective over-the-counter (OTC) use, particularly concerning the user interface and critical use tasks. Additionally, there are several deficiencies in carton, container, and consumer labeling, as well as inconsistencies in website content.

Findings

Inadequate Human Factors Study for OTC Use

Severity: critical

The human factors (HF) study (G3) failed to demonstrate that the user interface supports safe and effective use of the product by intended users for the proposed OTC setting. The agency's mitigation analysis concluded that approximately 30% of participants failed at least one of the three primary critical use tasks (initial priming, cleaning, routine re-priming), leading to potential under or supra-therapeutic dosing. The sponsor's analysis of 'completed with issues' participants was not accepted.

Recommended response: Consider developing an alternative inhalation device and testing it anew, or further optimize labeling to improve consumer understanding and ability to complete use tasks. Re-evaluate primary task failures, update risk analysis, implement additional risk mitigation strategies, and conduct another HF validation study. Submit the HF validation study protocol for review and comment prior to conducting the study. Ensure the study assesses consumers' ability to use the device, includes critical tasks, and has adequate representation of user groups (low literacy, adolescents, asthma patients, previous inhaler users) without moderator prompting. Address device disassembly issues in the protocol and report.

Labeling Deficiencies - Mouthpiece Instructions

Severity: major

Recommended changes to mouthpiece instructions include making embossed instructions more legible (e.g., increased contrast), aligning instructional language on the actuator with the revised DFL and CIL, and adding pictograms for key steps to provide an additional prompt for correct use.

Recommended response: Implement recommended changes to mouthpiece instructions to improve legibility and consistency with other labeling.

Carton and Container Labeling - General Requirements

Severity: major

The lot number and expiration date must be visible on the immediate and outer containers. The statement of identity needs revision to 'Epinephrine Inhalation Aerosol 0.125 mg per spray Bronchodilator' using bold type and white font for readability on the Principal Display Panel (PDP). The 'Shake Spray into the air before each inhalation' statement on the PDP also requires revision.

Recommended response: Submit draft carton and container labeling revised according to the specified visibility, font, and content requirements.

Cited: 21CFR201.17, 201.18

Drug Facts Labeling (DFL) Formatting and Content

Severity: major

The Drug Facts labeling did not include the barlines and hairlines required by 21 CFR 201.66(d)(8). Complete Drug Facts font specifications are required per 21 CFR 201.66(d). The bullet in front of the asthma alert statement 'These may be signs that your asthma is getting worse' should be removed, and a period added at the end, as per 21CFR341.76(c)(6)(F). An instruction for washing the mouthpiece needs to be included under 'Directions'.

Recommended response: Revise the DFL to comply with formatting requirements for barlines, hairlines, font specifications, and specific content changes for the asthma alert and mouthpiece washing instructions.

Cited: 21 CFR 201.66(d)(8), 21 CFR 201.66(d), 21CFR341.76(c)(6)(F)

Immediate Container Label Deficiencies

Severity: minor

The statement of identity on the immediate container label needs to be revised to 'Epinephrine Inhalation Aerosol 0.125 mg per spray Bronchodilator' using black and bolded font. The Active Ingredient heading should be revised to state 'in each spray.' Specific instructions under 'Directions' are also required.

Recommended response: Implement the specified revisions to the immediate container label for clarity and consistency.

Website Content Inconsistencies and Deficiencies

Severity: major

Videos on the website must be revised to be consistent with the DFL/CIL. The statement 'see www.primatene.com' should be added to the CIL. Extra text needs to be deleted from the statement of identity on the first webpage. The bullet from the asthma alert statement on the DFL page should be removed, and a period added. A mouthpiece washing instruction must be included under 'Directions' on the DFL page. All website text must be consistent with the PDP, outer container DFL, and CIL.

Recommended response: Revise all website content, including videos and text, to ensure complete consistency and accuracy with the approved DFL, CIL, and PDP.

Safety Update Requirement

Severity: info

A comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included with the response to the deficiencies. This update should incorporate new safety data from all nonclinical and clinical studies/trials of the drug/product under consideration, regardless of indication, dosage form, or dose level, and describe any significant changes or findings in the safety profile.

Recommended response: Prepare and submit a comprehensive safety update, including all new safety data, as part of the complete response.

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

Regulatory context

Submission stage: final decision
Regulatory pathway: 505(b)(2)

Impact

Impact score: 0.95
Estimated delay: 365 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The primary theme is the inadequacy of human factors data to demonstrate safe and effective OTC use of the epinephrine inhaler, coupled with numerous labeling and instructional deficiencies that could lead to medication errors or ineffective use. Significant revisions to the device, human factors studies, and all forms of labeling (carton, container, consumer leaflet, and website) are required.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

Document viewer

Read the FDA letter and send context to the co-pilot at any time.

Loading document viewer…