CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-2 72
`
`APPROVAL LETTER
`
`

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`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockviile MD 20857
`
`NDA 21-272
`
`United Therapeutics Corporation
`Attention: Mr. Dean Bunce
`
`68 T.W. Alexander Drive
`
`Research TrianglePark, N.C. 27709
`
`Dear Mr. Bunce:
`
`Please refer to your new drug application (NDA) dated October 16, 2000, withdrawn July 5, 2001 and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.
`
`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.
`
`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).
`
`We have completed the review of this application, as amended, according to the regulations for
`accelerated approval, and have concluded that adequate infomation 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 1:1 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.
`
`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 1-1 post marketing commitments) specified in your submission dated
`April 1, 2002. These commitments, along with any completion dates agreed upon, are listed below.
`
`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 ofthe safety and efi‘icacy ofsubcutaneous RemodulinTM
`therapy afler transitionfrom 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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`NDA 21-272
`
`Page 2
`
`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.
`
`The time-lines for completion of P01 :13 (and affirmed in your April 2, 2002 submission) are as
`follows:
`
`by June 2, 2003
`50% of Planned Enrollment:
`by December 2, 2003
`Full (100%) Enrollment:
`Submission of Complete Study Report: by June 2, 2004
`
`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.
`
`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 l-l Post Marketing Commitments."
`
`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.
`
`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.
`
`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.
`
`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:
`
`1) Under PRECAUTIONS, Hepatic and Renal Impairment, the phrase “SPECIAL
`POPULATIONS” should not be capitalized and should be changed to “Special Populations”.
`
`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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`

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`NDA 21-272
`
`Page 3
`
`Please report these changes in your first annual report.
`
`In addition, under Clinical Trials in Pulmonary Arterial Hypertension and Adverse Reactions,
`please add a discussion of whether difiemnces were seen in demographic subgroups. This information
`should be submitted as a prior approval supplemental application.
`
`We also note that there were minor editorial changes made throughout the package insert.
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an'approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`If you have any questions, please contact:
`
`Mr. Edward Fromm
`
`Regulatory Health Project Manager
`(301) 594-5313
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, MD.
`Director
`
`Office of Drug Evaluation 1
`Center for Drug Evaluation and Research
`
`Enclosure
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-2 72
`
`APPROVABLE LETTER
`
`

`

`
`
` -/é DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealthService
`
`Food and Drug Administration
`Roekvllle MD 20857
`
`NDA 21-272
`
`United Therapeutics Corporation
`Attention: Mr. Dean Bunce
`
`68 T.W. Alexander Drive
`
`Research Triangle Park, N.C. 27709
`
`Dear Mr. Bunce:
`
`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.
`
`We acknowledge receipt of your pre-submissions dated August 1 1, September 18, and 22, 2000 and
`your submissions dated October 16, November 3, 10 (two), 13, and 16, December 1, 4, 14, and 22
`(two), 2000, and January 5 (two), 10, 11, 23, and 25, February 15 (three), 19, 23, 26, and 28 (two),
`March 1, April 4, 9, and 12, May 14, and June 5, 14 (two), 25, and 27, August 16, October 2, and
`November 1, 2001.
`
`This new' drug application provides for the use of Remodulin (treprostinil sodium) Injection for the
`treatment of pulmonary arterial hypertension.
`
`We have completed the review of this application, as amended, and have considered the discussions at
`the Cardiovascular and Renal Drugs Advisory Committee meeting of August 9, 2001. The application
`is approvable under 21 CFR 314 subpart H (314500-560), based on the statistically strong results of
`the combined exercise/Borg score analysis, an end point that is reasonably likely to predict clinical
`benefit (21 CFR 314.510), but is not as well—established as a clear efi‘ect on exercise alone. The effect
`of Remodulin on exercise was statistically marginal. Remodulin is used to treat a life-threatening
`illness, and for at least some patients, it has potential safety advantages compared to alternative
`available therapy. Approval is contingent upon your demonstrated commitment to conduct a post-
`approval, controlled clinical trial to test the effects of Remodulin on end points that are clearly
`clinically relevant. In addition, before this application may be approved, it will be necessary for you to
`submit final printed labeling (FPL) for Remodulin. The labeling should be identical in content to the
`enclosed marked-up drafi labeling. Please also submit carton and container labeling that reflect the
`new established name for the product.
`
`There are several acceptable designs for the post-marketing clinical trial. Two possibilities are outlined
`below. Your study must obtain placebo-controlled data unambiguously demonstrating clinical benefit
`or approval of Remodulin may be withdrawn as specified under 21 CFR 314.530.
`
`

`

`Double-blind, placebo-controlled withdrawal study
`
`Patients with pulmonary hypertension who have been receiving treprostinil for at least 2 months and are
`clinically stable could be randomized to continued treatment or withdrawal to placebo or to tapering
`doses of treprostinil. The primary end point would be time to the first occurrence of death,
`hospitalization for complications of pulmonary hypertension, or wellvdefined clinical deterioration
`requiring reinstitution of treatment. We note that with careful monitoring, few or no fatal outcomes
`would be expected. Changes in exercise tolerance (6 minute walk) and Borg score should be secondary
`end points.
`
`Double-blind, placebo~controlled study on a backgggund of therapy with bosentan or gpgprostenol
`
`A more attractive study, because it would improve on available treatment, would be to randomize
`patients with pulmonary hypertension, who are receiving stable doses of bosentan or epoprostenol but
`remain significantly symptomatic, to additional treatment with placebo or treprostinil. The principal
`end point in this study would be time to the first occurrence of death, hospitalization for complications
`of pulmonary hypertension, need for epoprostenol, or other clear evidence of deterioration. It may be
`possible to develop a persuasive symptomatic end point as an alternative or secondary end point.
`
`Final approval is contingent upon an agreement between United Therapeutics Corporation and the
`Division of Cardio-Renal Drug Products regarding the final protocol for the post-marketing study,
`including the choice of primary end point and the identification of investigators.
`
`From the date of marketing approval, 50% of planned enrollment for the study should be accomplished
`within 12 months, with full enrollment by 18 months, and a complete study report should be submitted
`within 24 months. 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
`3 14.530.
`
`Promotional Materials: As required by 21 CFR 314.550, you must submit for consideration during
`the preapproval review period, three copies of all promotional materials, including promotional
`labeling as well as advertisements, intended for dissemination or publication within 120 days following
`marketing approval. All proposed materials should be submitted in draft or mock-up form, not final
`print. Please submit one copy to the Division of Cardio-Renal Drug Products and two copies of both
`the promotional material and the package insert directly to:
`
`Food and Drug Administration
`Division of Drug Marketing, Advertising and Communications, HFD-240
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`After 120 days following marketing approval you must submit promotional materials at least 30 days
`prior to the intended time of initial dissemination of the labeling or initial publication of the
`advertisement.
`
`Within 10 days afier the date of this letter, you are required to amend the application, notify us of your
`intent to file an amendment, or follow one of your other options under 21CFR 314.1 10. In the absence
`of such action FDA may take action to withdraw the application.
`
`

`

`The drug may not be legally marketed until you have been notified in writing that the application is
`approved.
`
`If you have any questions, please contact:
`
`Mr. Edward Fromm
`
`Regulatory Health Project Manager
`(301) 594-5313
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, MD.
`Director
`
`Oflice 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.
`
`Robert Temple
`2/8/02 05:45:09 PM
`
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`é 8 page(s) 0f
`revised draft labeling
`has been redacted ‘
`I
`from this portion of
`the review.
`
`
`
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