Armstrong PharmaceuticalsEpinephrine HFA Inhalation Aerosol 125 mceg/actuation

NDA 205920 COMPLETE RESPONSE

Armstrong Pharmaceuticals Attention: Stephen A. Campbell, Esq. Sr. Vice President, Regulatory Affairs 25 John Road

Canton, MA 02021

Dear Mr. Campbell:

Please refer to your New Drug Application (NDA) dated July 20, 2013, received July 22, 2013, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Epinephrine HFA Inhalation Aerosol 125 mceg/actuation.

We also acknowledge receipt of your amendments dated: September 10, 16, and 19, November 5 (three), December 4 (three), 11, 20, and 23, 2013, January 14 (two), 27 (three), and 30, February 5, 6, 21, 22 and 28, March 18, 19, 24, and 26, April 2, 7, 9, 13, 16, 18 and 21, and May 12, 2014.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

PRODUCT QUALITY

During a recent inspection of the manufacturing facility for this application, our field investigator conveyed current Good Manufacturing Practices (cGMP) deficiencies to the representative of the facility.

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Information needed to address deficiency Satisfactory resolution of these cGMP deficiencies is required before this application may be approved.

NONCLINICAL

The proposed epinephrine HFA inhalation aerosol includes thymol, which is not a qualified excipient for oral inhalation products intended for chronic use.

Information needed to address deficiency Provide information supporting the safety of chronic inhalation of thymol. If such information is not currently available, conduct a repeated dose inhalation toxicity study of 6 months duration in

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an appropriate species that shows no adverse findings to support the use of thymol in your product.

CLINICAL

The submitted data do not support the proposed over-the-counter (OTC) use of epinephrine HFA inhalation aerosol for the temporary relief of mild symptoms of intermittent asthma in adults and adolescents 12 years of age and older.

The data from patient diaries and assessment of device and dose indicator performance in your clinical trials indicate that consumers may have difficulty using the proposed product correctly. Specifically, patients reported a high number of device malfunctions in your phase 3 clinical trials. One third of the reports (clogging and not dispensing properly) raise concerns regarding potential clogging. Your analysis identified user error as the potential cause for the reports of malfunction. User error with the dose indicator also appears to have contributed to patients’ perception of device malfunction. Usability issues are a significant concern for an OTC inhaler product used to treat acute asthma symptoms.

The data from your behavioral study do not provide assurance that consumers clearly understand how to use epinephrine HFA inhalation aerosol. Your behavioral study did not assess whether consumers understood the need to initially prime and clean the product without prompting. It was difficult to assess whether cleaning of the device was performed appropriately as some subjects had difficulty demonstrating the cleaning steps without a sink. Some consumers had difficulty removing the canister to clean the product, and the study did not assess whether consumers correctly reassembled the product after cleaning. In addition, your behavioral study did not adequately assess consumers with low literacy.

Your label comprehension studies identified limitations in consumers’ understanding of the following critical information: relying on the indicator if dropped, the need to prime the inhaler before using the first time, the need to clean the product daily after use, and the need to reprime when wet.

We note the complexity of the steps required for shaking, priming, actuation, and cleaning in order to ensure adequate product performance. The issues described above raise concerns about consumers’ ability to use your epinephrine HFA inhalation aerosol product for the acute treatment of asthma in the OTC setting. This usability issue is concerning for an OTC product because consumers will be using the device without the oversight of a health care professional (who the user might call if there is a problem).

Information needed to address deficiency

To support approval of epinephrine HFA inhalation aerosol, you must provide data to support consumers’ ability to use epinephrine HFA inhalation aerosol in the OTC setting, including the aspects of such use discussed above. To accomplish this you will need to do the following:

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1. Revise the labeling to optimize comprehension and assess the revised label in a label comprehension study. Optimize the labeling to improve comprehension of the following critical information: prime before first use of the product, clean the product on each day of use, reprime the inhaler when wet, do not rely on the dose indicator if dropped, instructions on removing the canister for cleaning and proper reassembly, press on the center of the dose indicator, and orientation of product during use and storage.

2. Conduct a behavioral (human factors) study with the revised label using the actual product (not a dummy product) to assess consumers’ ability to use epinephrine HFA inhalation aerosol. Include sufficient numbers of consumers with low literacy in your population assessed against target thresholds; ideally this population should be representative of the proportion of adults in the United States with basic literacy skills based on available national data. Include a sink so consumers have to demonstrate appropriate cleaning steps. Consumers should not be prompted on specific steps. Based upon the findings of the behavioral study, further changes to the label or the device may be necessary and additional behavioral (human factor) study(ies) may be necessary.

3. After conducting smaller behavioral (human factor) study(ies) to refine the labeling and potentially the device, conduct a randomized, actual use study with the revised labeling and proposed epinephrine HFA inhalation aerosol to rigorously quantify and evaluate complaints or problems associated with use of the product and characterize sources of user error. Assessment of patient complaints or problems with the dose indicator should be included in this study. We strongly recommend that you include a marketed bronchodilator product as a benchmark comparison in the study.

Depending on the results of the above iterative evaluations, modification of the product and product labeling may be necessary to minimize potential user error, e.g., revised patient instructions for use, replacement of the current dose indicator with an integrated dose counter, product reformulation and product change to simplify the steps required for adequate product performance, etc. Changes to the product may necessitate additional in vitro or clinical data for support.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21CFR314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

1. Describe in detail any significant changes or findings in the safety profile.

2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

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e Present new safety data from the studies/clinical trials for the proposed indication using the same format as the original NDA submission.

e Present tabulations of the new safety data combined with the original NDA data.

e Include tables that compare frequencies of adverse events in the original NDA with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

4. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

5. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original NDA data.

6. Provide updated exposure information for the clinical studies/trials (e.g., number of

subjects, person time).

ADDITIONAL COMMENTS We have the following comments/recommendations that are not approvability issues:

1. We recommend that you incorporate acceptance criteria for accuracy into the dose indicator specification. Propose a sampling plan and acceptance quality limit (AQL), for example, PO for regular inspection, for dose counter accuracy testing.

2. We recommend that you revise the Directions section of the Drug Facts Label to state “Children under 12 years of age: Do not use; it is not known if the drug works or is safe in children under 12.”

3. Members of the Advisory Committee raised the issue of whether this product will be misused in consumers with asthma resulting in adverse asthma outcomes. Consider whether elements of your product or labeling could be modified to address this issue. If modifications are made, include these as test elements in label comprehension and actual use studies.

OTHER Within one year after the date of this letter, you are required to resubmit or take other actions

available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under 21 CFR 314.65. You may also

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request an extension of time in which to resubmit the application. A resubmission must fully address all the deficiencies listed. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM153222.pdf. We also encourage you to request FDA advice regarding protocol designs prior to embarking on consumer studies.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, call Daniel Reed, Regulatory Project Manager, at (301) 796- 2220. Sincerely, {See appended electronic signature page} Theresa Michele, M.D. Director Division of Nonprescription Clinical Evaluation

Office of Drug Evaluation IV Center for Drug Evaluation and Research

ENCLOSURE: None

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

THERESA M MICHELE 05/22/2014

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