Mylan GmbHinsulin glargine injection 100 units/mL

NDA 210605 COMPLETE RESPONSE

Mylan GmbH

Attention: Suzanne Kiani

Senior Director, Regulatory Science, Biologics 781 Chestnut Ridge Road

P.O. Box 4310

Morgantown, WV 26504-4310

Dear Ms. Kiani:

Please refer to your new drug application (NDA) dated and received April 27, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for insulin glargine injection 100 units/mL.

We acknowledge receipt of your amendment dated February 28, 2019, which constituted a complete response to our May 17, 2018, action letter.

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.

FACILITY INSPECTIONS MAJOR DEFICIENCIES

During a recent inspection of Biocon Sdn. Bhd. FEI#3011248248, a manufacturing facility for this NDA, our field investigator observed objectionable conditions at the facility and conveyed that information to the representative of the facility at the close of the inspection. Satisfactory resolution of the observations is required before this NDA may be approved.

We note that this is the second Complete Response letter for this NDA that has identified inspectional observations at this manufacturing facility as a deficiency. We recommend that you work with this manufacturing facility for your insulin glargine product and apply the necessary resources to address these inspectional observations in a timely manner.

PRESCRIBING INFORMATION Your proposed Prescribing Information (PI) must conform to the content and format

regulations found at 21 CFR 201.56(a) and (d) and 201.57. As you develop your proposed PI, we encourage you to review the labeling review resources on the PLR

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Requirements for Prescribing Information’ and Pregnancy and Lactation Labeling Final

Rule? websites, which include:

e The Final Rule (Physician Labeling Rule) on the content and format of the PI for human drug and biological products

e The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of information in the Pl on pregnancy, lactation, and females and males of reproductive potential

e Regulations and related guidance documents

e Asample tool illustrating the format for Highlights and Contents, and

e The Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

FDA's established pharmacologic class (EPC) text phrases for inclusion in the Highlights Indications and Usage heading.

During our review of your submitted labeling, we identified the following labeling issues that should be addressed in your resubmission:

In the Instructions for Use (IFU) labeling for the pen injector presentations submitted on August 28, 2019, you added the word “Needle” to the Step 8 title as follows “Step 8 Needle disposal.” Please update the language in other places of the IFU that reference step 8. For example, the required supplies section states ® at the end of these Instructions for Use”. Please revise to “See Step 8 Needle disposal” in all such instances where it is appropriate to do so.

In addition, the pen IFUs use ™® to indicate sub-bullets under each step (i.e., Step 1, Step 2, etc.). Please note that we consider this to be a major change to the IFU, which was validated by the Human Factors study. Therefore, please revert to the prior sub-bullet letter designations (A, B, C, etc.) under each numbered step that were used in the Human Factors study.

Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to ensure conformance with the format items in regulations and guidances. In addition, submit updated content of labeling [21 CFR 314.50(I)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.?

http:/;www.fda.gov/Drugs/GuidanceComplianceRegulatory|nformation/LawsActsandRules/ucm08415 9.htm

2 http://www. fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 7.htm

3 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Word version. The marked-up copy should include annotations that support any proposed changes.

CARTON AND CONTAINER LABELING

Submit draft carton and container labeling that is identical to the carton and container labels submitted on August 28, 2019.

PROPRIETARY NAME

Please refer to correspondence dated May 1, 2019, which addresses the proposed proprietary name, Semglee. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

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 product 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:

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

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

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

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

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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(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 application 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 product. Include an updated estimate of use for product 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. Furthermore, as explained in FDA’s final guidance on Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009,4 “an original 505(b)(2) application (including a resubmission) for a biological product that relies, at least in part, on FDA’s finding of safety and/or effectiveness for a listed drug that is a biological product will receive a complete response if the application is pending at the end of the day (11:59 pm Eastern Daylight Time (EDT)) on Friday, March 20, 2020, because the NDA for the listed drug relied upon will no longer exist at midnight on Monday, March 23, 2020.”

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

4 Available at https://www.fda.gov/media/119590/download

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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You may request a meeting or teleconference 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 draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.>

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 Michael G. White, Ph.D., Senior Regulatory Project Manager, at (240) 402-6149.

Sincerely, {See appended electronic signature page}

Lisa B. Yanoff, M.D.

Deputy Director (Acting)

Division of Metabolism and Endocrinology Products Office of Drug Evaluation II

Center for Drug Evaluation and Research

5 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance Documents Database https://www.fda.gov/Regulatorylnformation/Guidances/default.htm.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

LISA B YANOFF 08/28/2019 02:50:21 PM

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