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

`

`ORlelNAL
`
`‘—
`
`U nited .
`
`General Correspondence
`
`New Drug Application -
`
`April 2, 2002
`
`Douglas Throckmorton, M.D., Acting Director
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products, HFD-l 10
`1451 Rockville Pike
`
`Rockville, Maryland 20852
`
`Dear Dr. Throckmorton:
`
`88 T.W. Alexander Drive
`PD. Box l4lBE
`Research Triangle Park. NC 27709
`tel BIS-1.4858350
`fax 919.485.8352
`
`NEW CORRESPONDENCE
`IV- 661“.- 1’,
`
`Re: NBA 21-272
`
`Remodulin‘“ Injection
`
`Reference is made to a telephone conversation today with Ed Fromm of your Division
`concerning our April 1, 2002, complete response letter.
`
`United Therapeutics herewith commits to the timelines in the February 8, 2002, approvable letter
`for Protocol P01 :13 (“From the date of marketing approval, 50% of planned enrollment for the
`5’5
`:3 f study should be accomplished within 12 months, with full enrollment by 18 months, and a
`'-
`complete study report should be submitted within 24 months”).
`
`‘ Should you have any questions concerning this amendment, please do not hesitate to
`, icontact me by phone at 91 9-485-8350, ext. 192, by facsimile at 919-485-8352, or by email
`at dbunce@unithercom.
`
`
`
`.4
`
`:S' cerely,
`
`MW
`'3 can Bunce
`- enior Director, Regulatory Affairs
`l
`""
`
`c: Robert Temple, M.D., ODE!
`
`i —«- fi,‘ w
`
`

`

`Electronic Mail Message
`
`Date:
`From:
`To:
`Cc:
`Subject:
`
`4/13/01 7:44:03 AM
`Edward Fromm
`Dariush Farahifar *
`Natalia Morgenstern
`NDA 21-272, Remodulin Injection
`
`( FROMME )
`( FARAHIFARD )
`( MORGENSTERN )
`
`Dariush,
`
`Per instructions from Dr. Temple, please classify United Therapeutic's
`submission dated April 12, 2001 as a Major Multi—discipline Amendment
`(AZ) .
`
`This should extend the review clock by 3 months;
`should be July 16, 2001.
`
`the new goal date
`
`Thank you.
`
`Ed
`
`

`

`
`
` @ DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealthService
`
`Food and Drug Administration
`Rockville MD 20857
`
`NDA 21-272
`
`United Therapeutics Corporation
`Attention: Mr. Dean Bunce
`
`PO. Box 14186
`68 T.W. Alexander Drive
`
`Research Triangle Park, NC 27709
`
`Dear Mr. Bunce:
`
`We acknowledge receipt of your July 3, 2001 correspondence notifying us that you are withdrawing
`your October 16, 2000 new drug application (NDA) for Remodulin (treprostinil sodium) Injection.
`
`Therefore, in accordance with 21 CFR 314.65, this application is withdrawn as of the date of our
`receipt of your notification, July 5, 2001. This withdrawal does not prejudice any future filing of the
`application. You may request that the information contained in this withdrawn application be
`considered in conjunction with any future submission.
`
`If you have any questions, please call:
`
`Mr. Edward Fromm
`
`Regulatory Health Project Manager
`(301) 594-5313.
`
`Sincerely, _
`0"
`{See appended electronimalure page}
`
`Natalia A. Morgenstem
`Chief, Project Management Staff
`Division of Cardio-Renal Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Natalia Morgenstern
`7/5/01 03:23:03 PM
`
`ig
`ll
`ix
`!
`
`
`
`
`
`

`

`3V
`
`Public Health Service
`5 / DEPARTMENT or HEALTH & HUMAN SERVICES
`, C
`it...“
`.
`Food and Dmg Administration
`Rockville MD 20857
`
`NDA 21-272
`
`United Therapeutics Corp.
`Attention: Mr. Dean Bunce
`68 T.W. Alexander Drive
`
`~
`
`Research Triangle Park, NC 27709
`
`Dear Mr. Bunce:
`
`We acknowledge receipt of your resubmitted new drug application (NDA) for the following:
`
`Name of Drug Product:
`
`Remodulin (treprostinil sodium) Injection
`
`Review Priority Classification:
`
`Priority (P)
`
`Date of Resubmitted NDA:
`
`August 9, 2001
`
`Date of Receipt:
`
`August 9, 2001
`
`Unless we notify you within 60 days of our receipt date that the application is not sufficiently complete to permit
`a substantive review, this application will be filed under section 505(1)) of the Act on
`October 8, 2001 in accordance with 21 CPR 314.101(a). If the application is filed, the user fee goal date will be
`February 9, 2002.
`
`All communications concerning this NDA should be addressed as follows:
`
`US. Postal Service:
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products, HFD-l 10
`Attention: Division Document Room
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`Courier/Overnight Mail:
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products, HFD-l )0
`Attention: Division Document Room
`1451 Rockville Pike
`
`Rockville, Maryland 20852-1420
`
`If you have any questions, please call:
`
`

`

`NDA 21—272
`
`Page 2
`
`Mr. Edward Fromm
`
`Regulatory Project Manager
`(301) 594-5313
`
`Sincerely,
`
`__
`
`{See appended elemvmt‘ signature page}
`
`Natalia A. Morgenstem
`Chief, Project Management Staff
`Division of Cardio-Renal Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`This'1s a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Natalia Morgenstern
`8/15/01 05:14:26 PM
`
`

`

`‘--.--————-—-
`United
`IIIIII""
`.
`-.— -Therapelfllcs
`c o a
`P
`o
`a A ‘r
`I o N
`
`‘
`New Drug Application —
`Amendment to a Pending Application
`
`April 12, 2001
`
`Raymond J. Lipicky, M.D., Director
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products, HFD-l 10
`1451 Rockville Pike
`
`Rockville, Maryland 20852
`
`58 T.W.AlexanderDrt\/e
`RELBoxHIBE
`ResearmTfianglePaI-k.NCE7709
`telQlQABSBBSU
`fax 99485535?
`
`
`
`Re:
`
`NBA 21-272
`
`RernodulinTM (treprostinol sodium) Injection
`
`Dear Dr. Lipicky:
`
`Reference is made to our meeting on April ll, 2001 , with Dr. Temple, yourself and
`
`representatives of your Division. As discussed at the meeting, we are submitting herewith
`
`additional statistical analyses correlating the primary endpoint of exercise tolerance and Borg
`
`Dyspnea score in our pivotal studies, P01 :04 and P01 :05.
`
`Please note that we intend to submit additional analyses in the next few weeks, including
`
`analyses to further support the correlation of exercise tolerance and Borg Dyspnea scores, to
`
`support the robustness of the principal reinforcing and secondary endpoints in respect to the
`
`FDA’s concern on the potential for unblinding bias, and clarification on the use of opioids.
`
`Should you have any questions concerning this package, please do not hesitate to contact me by
`
`phone at 919—485-8350, ext. 192, by facsimile at 919-485-8352, or by email at
`
`dbunce@unither.com.
`
`S' cerely,
`
`@mé/
`
`Director Regulatory Affairs
`
`cc: Dr. Robert Temple, HFD-lOl
`
`Hand Delivered
`
`Medicines
`
`for Life"
`
`
`
`

`

`United
`llll'ln.Mill!" .4
`, - herapeutics
`c o
`v o a
`A 'r
`l o N
`
`.
`
`‘
`
`EB T.W. Nexamermve
`zit-33:19.55
`tel91343553550park.NC
`fax 919.485.8352
`
`27709
`
`New Drug Application - General Correspondence
`
`December 14, 2000
`
`Raymond J. Lipicky, MD. Director
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products, HFD-110
`1451 Rockville Pike
`Rockville, Maryland 20852
`
`Dear Dr. Lipicky:
`
`Re: NBA 21-272
`
`UT—‘lS Injection
`
`Reference is made to the December 8, 2000, meeting between yourself and
`representatives of your Division and representatives of United Therapeutics to discuss
`NDA 21-272. Reference is also made to a teleconference with Dr. Throckmorton and
`Mr. Fromm of your Division on December 12, 2000.
`
`Based on these discussions, we agree with the FDA that NDA 21—272 will not be
`presented to the Cardiovascular and Renal Drugs Advisory Committee. We welcome
`the continued opportunity to work in cooperation with representatives of your Division in
`the review of NBA 21-272.
`
`Should you have any questions concerning this submission, please do not
`hesitate to contact me at by phone at 919485-8350, ext. 192, by facsimile at
`9194858352, or by email at dbunce@unither.com.
`
`}
`
`' cerely,
`
`ll"b
`
`Dean Bunce
`
`Director, Regulatory Affairs
`
`“-
`
`MEfllcln'i-a:
`
`fur
`
`llru~
`
`TUTRL P . 82
`
`

`

`
`
` DEPARTMENT OF HEALTH & HUMAN SERVICES 5 . F KO H M
`
`\
`
`\ ‘3 kb ‘
`
`FOod and Drug Adm'nistr t'
`
`Rockville MD 202357I
`
`a m
`
`9 w
`
`U); tQCD'L/M
`4/5!0 I
`
`/
`
`J
`
`'
`
`OCT 1 9 2000
`
`NDA 21-272
`
`' UnitedTherapeuticsCorp
`
`Attention: Mr. Dean Bunce
`68 T.W. Alexander Drive
`
`Research Triangle Park, NC 27709
`
`Dear Mr. Bunce:
`
`We have received your new drug application (NDA) submitted under section 505(b) of
`the Federal Food, Drug, and Cosmetic Act for the following:
`
`Name of Drug Product: Uniprost (treprostinol sodium) Injection 1.0, 2.5, 5.0,
`10.0 mglmL
`
`Review Priority Classification: Priority (P)
`
`Date of Application: October 16, 2000
`
`Date of Receipt: October 16,, 2000
`
`Our Reference Number. NDA 21-272
`
`Unless we notify you within 60 days of the receipt date that the application is not
`sufficiently complete to permit a substantive review, this application will be filed under
`section 505(b) of the Act on December 15, 2000 in accordance with 21 CFR 314.101(a).
`If the application is filed, the user fee goal date will be April 16, 2001.
`
`Please cite the NDA number listed above at the top of the first page of any
`communications concerning this application. All communications concerning this NDA
`should be addressed as follows:
`‘
`
`US. Postal Service:
`
`Coum‘rlOvemight Mail:
`
`Food and Drug AdminiStratiori
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products,
`HF0-1 10
`Attention: Division Document Room
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`-
`»
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Cardio-Renal Drug Products,
`HFD-t 10
`Attention: Division Document Room '
`1451 Rockville Pike
`Rockville, Maryland 20852-1420
`
`

`

`NDA 21-272
`
`Page 2
`
`If you have any questions, please call:
`
`Mr. Edward Fromm
`
`Regulatory Project Manager
`(301) 594-5313
`
`Sincerely yours,
`\ '~
`(I)
`\
`Natalia A. Morgenstem
`Division of Cardio—Renal Drug Products
`Office of Drug Evaluation l
`Center for Drug Evaluation and Research
`
`

`

`NDA 21-272
`
`Page 3
`
`cc:
`
`Archival NDA 21-272
`HFD—110/division file
`um»
`HFD—110/Team Leaders and reviewers
`DISTRICT OFFICE
`
`Drafted by: ef/10/1 8/00
`lnitialed by:
`Final: asbl10l18/00
`
`Filename: 21-272(ac).doc
`
`ACKNOWLEDGMENT(AC)
`
`

`

`U l1 i ted
`.
`E1: 5.. Th
`efapelfllcs
`-.."-‘ “=3
`c o n
`p o
`I o N
`n
`A r
`
`-
`
`EB T.w. Alexander Drive
`PD. Box 14135
`Research Triangle Park. NC 27709
`telQlQ.4BS.BBSD
`fax 919.485.8352 -
`
`L/
`
`New Drug Application
`
`October 16, 2000
`
`Food and Drug Administration
`Central Document Room
`
`12229 Wilkins Avenue
`
`Rockville, MD 20852
`
`Dear Sir/Madam:
`
`Re: NDA 21-272
`
`UT-15 Injection
`
`Reference is made to our August 11, 2000'presubmission of Item 4 - Chemistry Section
`(Volumes 1.1 — 1.9) andltem 5 - Nonclinical Pharmacology and Toxicology Section
`(Volumes 1.10 - 1.35) of NDA 21—272.
`
`We are submitting herewith the remainder of NDA 21-272 for review by the Division of
`Cardio-Renal Drug Products.
`
`UT-15 Injection is submitted for the indication of Pulmonary Arterial Hypertension (PAH).
`United Therapeutics was granted Orphan designation for the indication Pulmonary
`Arterial Hypertension November 2, 1999. A copy of the letter is attached.
`
`We are requesting priority review classification for UT-15 Injection. UT-1 5 Injection is
`indicated for the treatment of PAH, a life-threatening disease for which the life expectancy
`is less than 2.5 years from diagnosis. UT-15 Injection is also more stable and thus is able
`to be delivered via subcutaneous infusion as compared to the central intravenous infusion
`of the current approved therapy. This mode of therapy provides for increased
`convenience and compliance, primarily due to the lack of serious complications with the
`delivery of the curren th ..
`
`
`
`By this letter, we are requesting, in accordance with 21 CFR 314.55(d), an exemption for
`. diatric use information for UT-15 Injection.
`
`By this letter, in accordance with 21 CFR 314.108(b)(2), we also hereby request a five-
`year period of exclusivity for UT-15. We hereby certify that UT-15 has never been
`approved either as a single entity or as part of a combination product.
`
`We are also attaching the April 11, 2000, letter granting UT-15 Injection an exemption
`from conducting carcinogenicity studies.
`
`.
`
`..
`
`.
`
`\ .
`
`Medicines
`.1___.._._._.-...
`
`for Life"
`
`

`

`éméglreigpguflcs
`
`COIDOIA‘I’IDN
`
`~
`
`: “
`
`r
`
`UT—lS Injection
`NDA 21-272
`
`'
`
`'
`
`Page 2 of 2
`
`United Therapeutics certifies, by this letter, that we did not and will not use in any capacity
`the services of any person debarred as defined in the Food, Drug and Cosmetic Act
`Section 306.
`
`Should you have any questions concerning the enclosed application, please do
`not hesitate to contact me at 919/485-8350, ext. 192.
`
`Sincerely,
`
`0mm
`
`Dean Bunce
`
`Associate Director, Regulatory Affairs
`
`

`

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`
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`
`DIVISION OF CARDIO-RENAL DRUG PRODUCTS
`
`FOOD AND DRUG ADMINISTRATION
`
`”WWW
`3'
`5
`“e,
`a...“
`
`U8 Mel address:
`FONglaERIHEEJI 1O
`5600
`ere
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`RockaIIe. MD 20857
`
`Woodmont u
`1451 Rookviue Pike
`Rockvitle. MD 20852
`
`
`This document to Intended only for the use of the party to whom it is addressed and may contain
`
`information that is prlvtteoed. eonfldenttet. and protected from disclosure under applicabte tow.
`It you are
`
`not the eddressee. or e person authorized to deliver the document to the addressee. you are hereby notified that
`any review. disclosure. diseeminottm. copying. or other action based on the content of this communication to not
`authorized. If you have received this document in error. pteeee immediately notify us by tetepnone end return It to:
`
`CDER DCRDP HFD-HD ' 5600 Fishers Lane; Rockville. MD 20857
`
`
`
`
`Transmitted to FAX Number:
`
`(919) 485-8352
`
`Attention:
`
`Mr. Dean Bunce
`
`Company Name:
`
`United Therapeutics Corporation
`
`Phone:
`
`(919) 485-8350
`
`Subject:
`
`Approveble Letter tor Remodelin (treprostinil sodium)
`Injection, NBA 21-272
`
`' Date:
`
`February 8, 2002
`
`Pages including this sheet:
`From:
`
`2)
`Edward Fromm
`
`Phone:
`
`301-594-5313
`Q“ -0. CIA-
`
`

`

`MEssnaE CUNFIRMQTIUN'
`
`’
`
`18: 36
`83/26/01
`ID=FDR CDER DCRDP
`
`DiVlSlON or CARING-RENAL DRUG Paoeucrs
`FOOD AND Dnue ADMINISTRATION
`
`_.~*""'""~a.‘
`3'
`g
`g
`“he.
`
`N
`
`US Men address:
`FDNCOER/l-lFD-t 10
`5600 Fishers Lane
`Flockviile. MD 20857
`
`.
`
`Woodmont u
`1451 Rockville Pike
`Rockvilie, MD 20852
`
`'
`
`CDER DCHDP HFD-t 10 ' 5600 Fishers Lane: Rockville MD 20857
`
`not the addressee. or a person authorized to deiiver the document to the addressee, you are hereby notified that
`any review. disclosure. dissemination, copying. or other action based on the cement at this communication is not
`authorized.
`it you have received this document in error, please immediately notily us by telephone and return it to:
`
`Transmitted to FAX Number:
`
`(919) 485-8352
`
`Attention:
`
`Mr. Dean Bunce
`
`Company Name:
`
`United Therapeutics
`
`Phone:
`
`(919) 485—8350
`
`Subject:
`
`Minutes or Telecast. March 12,2001
`
`Date:
`
`03/26/01
`
`Pages including this sheet:
`
`4
`
`From:
`mar“:
`
`Edward Fromm
`fih’ 17"" "f'
`
`’f—q
`
`
`
`

`

`DIVISION OF CARDIO-RENAL DRUG PRODUCTS
`
`FOOD AND DRUG ADMINISTRATION
`
`'
`
`c\.>"“”"“‘-¢a,
`:‘
`5
`a
`2%
`40'”
`
`US Mail address:
`FDA/CDERIHFD-110
`5600 Fishers Lane
`Rockville, MD 20857
`
`Woodmont ll
`1451 Rockville Pike
`Rockville, MD 20852
`i
`t
`I
`
`
`
`This document is intended only for the use of the party to whom it is addressed and m y contain
`information that is privileged, confidential, and protected from disclosure under applicable law if you are
`
`not the addressee, or a person authorized to deliver the document to the addressee, you are hereby otified that
`
`
`any review, disclosure, dissemination, copying, or other action based on the content of this communication is not
`
`
`authorized.
`if you have received this document in error, please immediately notify us by telephone and return it to:
`
`CDER, DCRDP HFD-110 ; 5600 Fishers Lane; Rockville, MD 20857
`
`
`
`
`
`Transmitted to FAX Number:
`
`(919) 485-8352
`
`Attention:
`
`Mr. Dean Bunce
`
`Company Name:
`
`United Therpeutics
`
`Phone:
`
`(919) 485-8350
`
`Subject:
`
`Confirmation of meeting with FDA, March 28, 2002
`Remodulin (treprotinil sodium) Injection
`NDA 21-272
`
`Date:
`
`March 14, 2002
`
`Pages including this sheet:
`
`2
`
`From:
`
`Phone:
`Fax:
`
`Edward Fromm
`
`301-594-5313
`301 -594-5494
`
`