DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
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`Food and Drug Administration
`Rockville MD 20857
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`NDA 21-272
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`United Therapeutics Corporation
`Attention: Mr. Dean Bunce
`68 T.W. Alexander Drive
`Research Triangle Park, N.C. 27709
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`Dear Mr. Bunce:
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`Please refer to your new drug application (NDA) dated October 16, 2000, withdrawn July 5, 2001 and
`resubmitted on August 9, 2001. This application was submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act for Remodulin (treprostinil sodium) Injection, 1.0, 2.5, 5.0, and
`10.0 mg/ml.
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`We acknowledge receipt of your submissions dated February 12, 13, 20 (two), 25, and 28, March 14 and
`20 (two), April 1 and 2, and May 8, 2002. Your submission of April 1, 2002 constituted a complete
`response to our February 8, 2002 approvable letter.
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`This new drug application provides for the use of Remodulin (treprostinil sodium) Injection 1.0, 2.5,
`5.0, and 10.0 mg/ml for the treatment of pulmonary arterial hypertension (PAH).
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`We have completed the review of this application, as amended, according to the regulations for
`accelerated approval, and have concluded that adequate information has been presented to approve
`Remodulin (treprostinil sodium) Injection 1.0, 2.5, 5.0, and 10.0 mg/ml for use as recommended in the
`final printed labeling (package insert and immediate container and carton labels included in your
`submission of March 21, 2002). Accordingly, the application is approved under Subpart H of the Code
`of Federal Regulations (21 CFR 314.510). Approval is effective on the date of this letter. Marketing of
`this drug product and related activities are to be in accordance with the substance and procedures of the
`referenced accelerated approval regulations.
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`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled studies to verify and describe clinical benefit. We remind you of your
`post marketing study (Subpart H post marketing commitments) specified in your submission dated
`April 1, 2002. These commitments, along with any completion dates agreed upon, are listed below.
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`We note your submission of April 1, 2002, in which you committed to the performance of a clinical
`study, P01:13 as outlined in your amendment dated April 1, 2002. This study is titled “A multicenter,
`randomized, parallel placebo-controlled study of the safety and efficacy of subcutaneous Remodulin™
`therapy after transition from Flolan® in patients with pulmonary arterial hypertension.” In this study
`a total of approximately 100 patients who are clinically stable on regimens for their pulmonary
`hypertension are to be withdrawn from Flolan and randomized to receive either placebo or Remodulin.
`The primary endpoint of the study is the time to clinical deterioration defined as the time from
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`by June 2, 2003
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`50% of Planned Enrollment:
`by December 2, 2003
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`Full (100%) Enrollment:
`Submission of Complete Study Report: by June 2, 2004
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`NDA 21-272
`Page 2
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`initiation of study drug to earliest incidence of clinical worsening of PAH symptoms requiring
`reinstitution of Flolan therapy, to rehospitalization, or to death. As patients will be closely monitored,
`deaths are not expected. The study is powered based on the expected occurrence of at least 50 events.
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`The time-lines for completion of P01:13 (and affirmed in your April 2, 2002 submission) are as
`follows:
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`Please note that failure to adhere to these time lines may be considered a failure to show due diligence
`(21 CFR 314.510) and may trigger Agency action to withdraw marketing approval under
`21 CFR 314.530.
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`The final study report should be submitted to this NDA as part of a supplemental application. For
`administrative purposes, all submissions relating to this post marketing commitment must be clearly
`designated "Subpart H Post Marketing Commitments."
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`We also remind you that, under 21 CFR 314.550, after the initial 120 day period following this
`approval, you must submit all promotional materials, including promotional labeling as well as
`advertisements, at least 30 days prior to the intended time of initial dissemination of the labeling or
`initial publication of the advertisement.
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`Validation of the regulatory methods has not been completed. At the present time, it is the policy of
`the Center not to withhold approval because the methods are being validated. Nevertheless, we expect
`your continued cooperation to resolve any problems that may be identified.
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`Please be note that, as of April 1, 1999, all applications for new active ingredients, new dosage forms,
`new indications, new routes of administration, and new dosing regimens are required to contain an
`assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is
`waived or deferred as described in the Federal Register notice of December 2, 1998 (63 FR 66632).
`We acknowledge your request of October 16, 2000 asking for a waiver of the pediatric study
`requirement for this action on this application. In accordance with 21 CFR 314.55(d), we agree to
`waive that requirement for this application for all pediatric study groups covered by the Pediatric Rule.
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`In a telephone conversation with Mr. Edward Fromm, Division of Cardio-Renal Drug Products, on
`May 14, 2002, you agreed to make the following changes to the package insert at the time of your next
`printing:
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`1) Under PRECAUTIONS, Hepatic and Renal Impairment, the phrase “SPECIAL
`POPULATIONS” should not be capitalized and should be changed to “Special Populations”.
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`2) Under HOW SUPPLIED, the sentence that reads “Unopened vials of Remodulin are stable
`until the date indicated when stored at 15 to 25°C (59 to 77°F)” should be deleted.
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`NDA 21-272
`Page 3
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`Please report these changes in your first annual report.
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`In addition, under Clinical Trials in Pulmonary Arterial Hypertension and Adverse Reactions,
`please add a discussion of whether differences were seen in demographic subgroups. This information
`should be submitted as a prior approval supplemental application.
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`We also note that there were minor editorial changes made throughout the package insert.
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`Please submit one market package of the drug product when it is available.
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`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
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`If you have any questions, please contact:
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` Mr. Edward Fromm
` Regulatory Health Project Manager
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`(301) 594-5313
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`Sincerely,
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`{See appended electronic signature page}
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`Robert Temple, M.D.
`Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`Enclosure
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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.
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` /s/
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`Robert Temple
`5/21/02 06:01:00 PM
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