Mallinckrodt Hospital Products IP LimitedTerlivaz (terlipressin) 1 mg injection

NDA 22231 COMPLETE RESPONSE

Mallinckrodt Hospital Products IP Limited Attention: James Burgess

Associate Director, Regulatory Affairs 1425 US Route 206

Bedminster, NJ 07921

Dear Mr. Burgess:

Please refer to your new drug application (NDA) originally submitted May 1, 2009, received May 4, 2009, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Terlivaz (terlipressin) 1 mg injection.

We acknowledge receipt of your resubmission dated March 12, 2020, which constituted a complete response to our November 4, 2009, action letter.

We have completed our review of this application, as amended, and have determined hat 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 hese issues.

CLINICAL In our 2009 Complete Response letter, we stated that “[y]ou will need to conduct at

least one additional adequate and well-controlled study to demonstrate the efficacy and safety of intravenous terlipressin for the treatment of HRS type I. This study will need to be successful, using pre-specified endpoint(s) and analytic plan, at p<0.05.”

To address this requirement and support a claim for the treatment of adults with hepatorenal syndrome (HRS) type 1, you submitted the results of a randomized, double-blind, placebo-controlled trial comparing intravenous (IV) terlipressin to placebo in adult patients with HRS type | (CONFIRM). The prespecified primary endpoint in CONFIRM was the incidence of verified HRS reversal, defined as 2 consecutive serum creatinine values <1.5 mg/dL at least 2 hours apart, while on treatment, by Day 14 or discharge (on treatment defined as up to 24 hours after the final dose of study drug). In order to be counted in the primary endpoint, patients also needed to be alive without renal replacement therapy for at least 10 days after achieving verified HRS reversal.

We agree that CONFIRM met its primary endpoint; however, safety findings in CONFIRM, and in particular, the greater incidence of serious adverse events of respiratory failure in the terlipressin (14%) as compared to the placebo arm (5%) raise concern that the risks of terlipressin may outweigh its benefits, particularly given

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unresolved questions about the clinical significance of the primary endpoint. We acknowledge your proposed risk mitigation strategy; however, the strategy has not been prospectively tested, and it is unclear whether its implementation would adversely impact terlipressin’s efficacy for its proposed use.

To address this issue, you will need to conduct an adequate and well-controlled study that demonstrates an acceptable risk-benefit profile, perhaps utilizing the proposed risk mitigation strategy. The primary endpoint and analytic plan should be discussed with and agreed upon by the FDA prior to initiation. Given the data proffered thus far, we believe a two-sided p-value of 0.1 could provide sufficient reassurance that the risk mitigation strategy does not adversely impact the product's efficacy.

PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information’ and Pregnancy and Lactation Labeling Final Rule? websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

PROPRIETARY NAME

Please refer to correspondence dated, April 28, 2020 which addresses the proposed proprietary name, Terlivaz. 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 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:

1 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm08415 9.htm

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

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

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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 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 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 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. You may also request an extension of time in which to resubmit the application.

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

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

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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.

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, please call Anna Park, Regulatory Project Manager, at (301)796-1129.

Sincerely, {See appended electronic signature page}

Ellis Unger, M.D.

Director

Office of Cardiology, Hematology, Endocrinology, and Nephrology

Center for Drug Evaluation and Research

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.

ELLIS F UNGER 09/11/2020 05:07:53 PM

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