Fera Pharmaceuticals, LLCAvaclyr (acyclovir ophthalmic ointment)

NDA 202408 COMPLETE RESPONSE

Fera Pharmaceuticals, LLC Attention: John D’ Angelo, M.S., R.Ph. Vice President, Regulatory Affairs 134 Birch Hill Road Locust Valley, NY 11560

Dear Mr. D’ Angelo: Please refer to your New Drug Application (NDA) dated May 31, 2013, received May 31, 2013, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for

Avaclyr (acyclovir ophthalmic ointment) 3.0%.

We acknowledge receipt of your amendments dated:

June 7, 2013 (2) September 19, 2013 February 26, 2014 June 13, 2013 November 27, 2013 March 10, 2014 July 2, 2013 December 31, 2013 March 12, 2014 July 24, 2013 January 27, 2014 March 18, 2014 August 27, 2013 February 13, 2014 March 19, 2014 August 30, 2013 February 20, 2014 March 25, 2014 (2)

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 reason for this action below and, where possible, our recommendations to address this issue.

An application submitted under 505(b)(2) needs to provide a scientific “bridge” between the proposed product and the product used in the clinical studies submitted to the application. The information submitted to your application on July 24, 2013, March 12 and 25, 2014, is insufficient to establish a scientific “bridge” between the proposed product and the product used in the published clinical trials which are needed for the determination of the safety and efficacy of acyclovir ophthalmic ointment in the proposed indication of acute herpetic keratitis (dendritic ulcers).

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To address this deficiency:

We recommend that the characterization of the 3 lots of Fera’s acyclovir ophthalmic ointment 3% be compared with 3 lots (if available) of the Zovirax acyclovir ophthalmic ointment 3% product that may serve as the nominal RLD, and that the variation for measured product quality attributes fall within the variability observed for the nominal RLD.

Petrolatum

1. Petrolatum is a heterogeneous mixture of hydrocarbons that may contain varied amounts of saturated alkanes and cycloalkanes as well as unsaturated compounds, individual species of which may be liquid or solid in their purified forms. The unique heterogeneous mixture of these compounds can influence the properties of the resultant material and the performance of the dosage form. This compositional heterogeneity may be indirectly characterized as qualities of the drug product such as melting point, viscosity profile, specific gravity, etc. The specifications constrained by the tests for White Petrolatum, USP provide minimum criteria for inclusion within a grade, and are not sufficient to support a scientific bridge for product quality and performance. Further characterization of the petrolatum by the comparison of specific quality and performance attributes of the nominal RLD with Fera’s acyclovir ophthalmic ointment 3% are required.

Viscosity

2. It is known that formulations of White Petrolatum, USP can exhibit non-Newtonian (shear-thinning) behavior (e.g., see Park & Song (2010) Rheological evaluation of petroleum jelly as a base material in ointment and cream formulations with respect to rubbing onto the human body, Korea-Australia Rheology Journal 22(4) 279-289). As such, to support a scientific bridge, we recommend that comparative viscosity profile measurements be made not only to determine the linear viscoelastic response but also to investigate the nonlinear viscosity behavior over a range of shear rates.

Quality and Performance Tests

3. We recommend that the scientific bridge be supported by the collective weight of evidence from tests representing the physical qualities as well as the performance behavior of the ophthalmic ointment. These tests of the drug product are recommended to include relevant USP methods for Melting Temperature (Class II]) <741>, pH <791>, Specific Gravity <841>, Ophthalmic Ointments <771>, and Drug Release <1724>. The In Vitro Release Test (IVRT) test method for measuring drug release, performed as described in <1724>, should be validated to demonstrate the reproducibility and discrimination sensitivity of the IVRT method. Discrimination sensitivity may be demonstrated by testing of the 3% ophthalmic ointment, compared with altered (e.g., 2% and 4%) ophthalmic ointments of otherwise comparable composition, to demonstrate the sensitivity of the [VRT method to monitoring the proportionality of the release rates as a function of drug concentration, and to demonstrate the ability of the [VRT method to

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detect inequivalence of the altered formulations’ drug release rates to that measured for the 3% ophthalmic ointment, using the statistical methodology described in <1724>. The receptor solution may be composed of a buffer representing artificial tears, provided that adequate solubility for acyclovir exists so as not to compromise the linearity of the IVRT method, and that the method is appropriately discriminating.

Acyclovir Particle Size

5. The description of acyclovir particle size is inadequate. Because ophthalmic ointments are intended for application to the eye, special precautions must be taken in their preparation, to be free of large particles. As such, the drug substance is ideally added to the ointment base either as a solution or as a micronized powder. To support a scientific bridge, we recommend that the comparative particle size analysis be performed as a 3-tier analysis, reporting the D10, D50 and D90 particle sizes, compared for the nominal RLD and Fera’s acyclovir ophthalmic ointment 3%.

Acyclovir Polymorphisms

6. We recommend that Fera characterize the polymorphic form(s) of acyclovir in the nominal RLD, and demonstrate that Fera’s manufacturing process has consistently produced a drug product with a comparable polymorphic composition of acyclovir in Fera’s acyclovir ophthalmic ointment 3%.

To address this deficiency, you may also propose other options, such as conducting a controlled clinical trial using your acyclovir ophthalmic ointment 3%. If you would like to discuss this or other proposed options, you may request a meeting with the Division.

LABELING

We reserve comment on the proposed labeling until the application is otherwise adequate. If you revise labeling, your response must include updated content of labeling [21 CFR 314.50()(1)()] in structured product labeling (SPL) format as described at

http://www. fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at

21 CFR 314.50(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, ut 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).

7. Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

8. Provide English translations of current approved foreign labeling not previously submitted.

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 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.

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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 Lois Almoza, MS, Regulatory Project Manager, at (301) 796-1600.

Sincerely, {See appended electronic signature page}

Renata Albrecht, M.D.

Director

Division of Transplant and Ophthalmology Products

Office of Antimicrobial Products

Office of New Drugs

Center for Drug Evaluation and Research

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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.

RENATA ALBRECHT 03/31/2014

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