United Therapeutics CorporationRemodulin (treprostinil) Implantable System

NDA 208276 COMPLETE RESPONSE

United Therapeutics Corporation

Attention: Rex Mauthe, MBA

Associate Vice President, Regulatory Affairs 55 T. W. Alexander Drive

P.O. Box 14186

Research Triangle Park, NC 27709

Dear Mr. Mauthe:

Please refer to your New Drug Application (NDA) dated December 16, 2015, received December 16, 2015, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for the Remodulin (treprostinil) Implantable System.

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.

CLINICAL

1. The proposed device in this drug-device combination product was submitted to FDA under a Premarket Approval Application (PMA). On March 11, 2016, FDA issued a Not Approvable letter on the PMA. Until such time as the device is determined to be approvable for use in combination with your proposed drug under this NDA, your NDA for the drug-device combination product cannot be approved.

PRODUCT QUALITY

2. There are insufficient data to evaluate the risk of potential patient exposure to microbial contaminants when the Remodulin drug product is used in the proposed implantable pump system. Reference is made to the 24 May 2016 Medtronic response to the 08 May 2016 FDA information request regarding the low concentration of m-Cresol in the drug product following delivery by Medtronic PAH1 System. We note the response states in part, “The loss of m-Cresol from the sterile drug product solution during the infusion process would not impact the microbial quality since the high levels of preservative in the pump reservoir would be expected to control any potential microbial contamination and the implanted pump and catheter is a closed system”. However, the application does not contain data demonstrating that the catheter is a “closed system” from the standpoint of microbial ingress. Consequently, it is not clear as to whether insertion of the device into a patient may result in microbiological contamination of the tip of the catheter which may not be killed by the low concentration of the antimicrobial preservative once the drug

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traverses from the pump reservoir to the end of the catheter. Provide data demonstrating that the device is a closed system with regard to microbial ingress at the tip of the

catheter.

PRESCRIBING INFORMATION

3. We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the _PLeguirementsorR rescribingRnformationRndR regnancyRkindRactationRabeling HK inalk_uleRvebsites,

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.

If you revise labeling, use the SRPI checklist to ensure that the prescribing information

conforms with format items in regulations and guidances.

Your response must include

updated content of labeling [21 CFR 314.50(1)(1)(i)] in structured product labeling (SPL)

format as described at http://www.fda.gov/ForIndustry/DataStandards/Structure

ProductLabeling/default.htm

PROPRIETARY NAME

4. The review of your proposed proprietary name has been terminated due to the deficiencies

with the application as described in this letter. Please resul name when you respond to the application deficiencies.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety up

mit the proposed proprietary

ate 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 Remodulin Implantable System 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 the frequencies of adverse events occurring in clinical trials.

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NDA 208276 Page 3

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 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 the Remodulin Implantable System. Include an updated estimate of use for Remodulin 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 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.

‘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 FDA Guidance for Industry, “Formal Meetings Between FDA and Sponsors or Applicants,” May 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM153222.pdf.

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

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If you have any questions, call Wayne Amchin, RAC, Regulatory Project Manager, at (301) 796- 0421.

Sincerely,

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Norman Stockbridge, M.D., Ph.D. Director

Division of Cardiovascular and Renal Products Office of Drug Evaluation I

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.

WAYNE S AMCHIN 10/07/2016

NORMAN L STOCKBRIDGE 10/08/2016

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