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

`

`Time Sensitive Patent Information
`
`Pursuant to 21 CPR. 314.53
`
`for
`
`NDA #21-272
`
`
`
`The following is provided in accordance with the Drug Price Competition and Patent
`Term Restoration Act of 1984:
`
`Trade Name: UniprostTM
`Active Ingredient(s): treprostinol sodium (Applied for)
`Strength(s): 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL, 10.0 mg/mL
`Dosage Form: Injection
`~
`Approval Date: NDA submitted October 16, 2000
`
`
`
`A. This information should be provided for each
`individual patent submitted.
`
`US. Patent Number: 5,153,222
`
`Expiration Date: October 6, 2009
`
`Type of Patent--Indicate all that apply:
`
`1. Drug Substance (Active Ingredient) _Y [N
`2. Drug Product (Composition/Formulation) ____Y LN
`3. Method of Use LY ____N
`
`a; If patent claims method(s) of use, please specify approved method(s)of use or
`method(s) of use for which approval is being sought that are covered by patent:
`Treatment of pulmonary hypertension with UT-15.
`
`Name of Patent Owner: United Therapeutics Corp.
`
`US. Agent (if patent owner or applicant does not reside or have place of
`business in the US): Not Applicable
`
`

`

`The undersigned declares that the above stated United States Patent Number 5,153,222
`covers the composition, formulation and/or method of use of Uniprost. This product is:
`
`0' __currently approved under section 505 of the Federal Food, Drug, and
`Cosmetic Act)
`
`
`
`

`

`EXCLUSIVITY SUMMARY FOR NDA # 21-272
`
`
`SUPPL #
`
`Trade Name: Remodulin
`
`Generic Name: Treprostinil Sodium Injection
`
`Applicant Name: United Therapeutics Co.
`
`HFD # l 10
`
`Approval Date If Known:
`
`PART I IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1. An exclusivity determination will be made for all original applications, but only for certain
`supplements. Complete PARTS II and III of this Exclusivity Summary only if you answer "yes" to one or
`more of the following question about the submission.
`
`a) Is it an original NDA?
`YES
`
`/
`/_X__/ NO/
`
`/
`
`b) Is it an effectiveness supplement?
`
`YES I
`
`/ N0/_x_/
`
`If yes, what type? (SE1, SE2, etc.)
`
`c) Did it require the review of clinical data other than to support a safety claim or change in labeling
`related to safety? (If it required review only of bioavailability or bioequivalence data, answer "no.")
`
`YES /.x_/ NO /
`
`/
`
`If your answer is "no" because you believe the study is a bioavailability study and, therefore, not eligible
`for exclusivity, EXPLAIN why it is a bioavailability study, including your reasons for disagreeing with
`any arguments made by the applicant that the study was not simply a bioavailability study.
`
`If it is a supplement requiring the review of clinical data but it is not an effectiveness supplement,
`describe the change or claim that is supported by the clinical data:
`
`d) Did the applicant request exclusivity?
`
`YES/
`
`/
`
`NO /_x_/
`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`
`

`

`e) Has pediatric exclusivity been granted for this Active Moiety?
`
`NO
`
`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO
`THE SIGNATURE BLOCKS ON PAGE 8.
`
`2. Has a product with the same active ingredient(s), dosage form, strength, route of administration, and
`dosing schedule, previously been approved by FDA for the same use? (Rx to OTC switches should be
`answered NO-please indicate as such)
`
`YES/
`
`/ NO /_x__/
`
`If yes, NDA #
`
`.
`
`Drug Name
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS ON
`PAGE 8.
`
`3. Is this drug product or indication a DESI upgrade?
`
`YES /
`
`/ NO /_X__/
`
`IF THE ANSWER TO QUESTION 3 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS ON
`PAGE 8 (even if a study was required for the upgrade).
`
`PART II HAY-ESEVEN-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`
`(NOTE: Remodulin (treprostinol) has been granted an orphan designation for pulmonag’ arterial
`hvpertcnsion)
`(Answer either #1 or #2 as appropriate)
`
`1. Single active ingredient product.
`
`Has FDA previously approved under section 505 of the Act any drug product containing the same active
`moiety as the drug under consideration? Answer "yes" if the active moiety (including other esten'fied
`forms, salts, complexes, chelates or clathrates) has been previously approved, but this particular form of
`the active moiety, e.g., this particular ester or salt (including salts with hydrogen or coordination bonding)
`or other non-covalent derivative (such as a complex, chelate, or clathrate) has not been approved. Answer
`"no" if the compound requires metabolic conversion (other than deesterification of an esten'fied form of
`the drug) to produce an already approved active moiety.
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA #(s).
`
`YES/
`
`/
`
`NO /_x__/
`
`NDA#
`
`NDA#
`
`

`

`2. Combination product.
`
`If the product contains more than one active moiety (as defined in Part II, #1), has FDA previously
`approved an application under section 505 containing any m of the active moieties in the drug product?
`If, for example, the combination contains one never-before-approved active moiety and one previously
`approved active moiety, answer ”yes." (An active moiety that is marketed under an OTC monograph, but
`that was never approved under an NBA, is considered not previously approved.)
`
`YES /
`
`/ NO /__X_/
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA #(s).
`
`NDA#
`
`NDA#
`
`NDA#
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART I] IS "NO," GO DIRECTLY TO THE
`SIGNATURE BLOCKS ON PAGE 8. IF "YES” GO TO PART III.
`
`PART III THREE-YEAR EXCLUSIVITY FOR NDA'S AND SUPPLEMENTS
`
`To qualify for three years of exclusivity, an application or supplement must contain "reports of new
`clinical investigations (other than bioavailability studies) essential to the approval of the application and
`conducted or sponsored by the applicant." This section should be completed only if the answer to PART
`II, Question 1 or 2 was "yes."
`
`(The Agency interprets "clinical
`1. Does the application contain reports of clinical investigations?
`investigations" to mean investigations conducted on humans other than bioavailability studies.) If the
`application contains clinical investigations only by virtue of a right of reference to clinical investigations
`in another application, answer "yes," then skip to question 3(a). If the answer to 3(a) is "yes" for any
`investigation referred to in another application, do not complete remainder of summary for that
`investigation.
`
`YES/lNO/l
`
`.IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`2. A clinical investigation is "essential to the approval" if the Agency could not have approved the
`application or supplement without relying on that investigation. Thus, the investigation is not
`essential to the approval if 1) no clinical investigation is necessary to support the supplement or
`application in light of previously approved applications (i.e., information other than clinical trials,
`such as bioavailability data, would be sufficient to provide a basis for approval as an ANDA or
`505(b)(2) application because of what is already known about a previously approved product), or 2)
`there are published reports of studies (other than those conducted or sponsored by the applicant) or
`
`

`

`other publicly available data that independently would have been sufficient to support approval of the
`application, without reference to the clinical investigation submitted in the application.
`
`(a) In light of previously approved applications, is a clinical investigation (either conducted by the
`applicant or available fi'om some other source, including the published literature) necessary to support
`approval of the application or supplement?
`
`YES/
`
`/
`
`NO/
`
`/
`
`If "no," state the basis for your conclusion that a clinical trial is not necessary for approval AND GO
`DIRECTLY TO SIGNATURE BLOCK ON PAGE 8:
`
`(b) Did the applicant submit a list of published studies relevant to the safety and effectiveness of this drug
`product and a statement that the publicly available data would not independently support approval of the
`application?
`
`YES/ INOI/
`
`(1) If the answer to 2(b) is "yes," do you personally know of any reason to disagree with the applicant's
`conclusion? If not applicable, answer NO.
`
`<9
`
`Atii1i
`
`
`
`YES/
`
`/
`
`NO/
`
`/
`
`If yes, explain:
`
`(2) If the answer to 2(b) is "no," are you aware of published studies not conducted or sponsored by the
`applicant or other publicly available data that could independently demonstrate the safety and
`effectiveness of this drug product?
`
`YES/
`
`/
`
`N0/
`
`/
`
`If yes, explain:
`
`(c) If the answers to (b)(l) and (bXZ) were both "no," identify the clinical investigations submitted in the
`application that are essential to the approval:
`
`

`

`Studies comparing two products with the same ingredient(s) are considered to be bioavailability studies
`for the purpose of this section.
`
`In addition to being essential, investigations must be "new” to support exclusivity. The agency
`3.
`interprets "new clinical investigation" to mean an investigation that 1) has not been relied'on by the
`agency to demonstrate the effectiveness of a previously approved drug for any indication and 2) does not
`duplicate the results of another investigation that was relied on by the agency to demonstrate the
`effectiveness of a previously approved drug product, i.e., does not redemonstrate something the agency
`considers to have been demonstrated in an already approved application.
`
`a) For each investigation identified as "essential to the approval," has the investigation been relied on by
`the agency to demonstrate the efl‘ectiveness of a previously approved drug product? (If the investigation
`was relied on only to support the safety of a previously approved drug, answer "no.")
`
`Investigation in
`
`YES/
`
`/
`
`NO/
`
`/
`
`Investigation #2
`
`YES /____/
`
`NO /____I
`
`If you have answered "yes" for one or more investigations, identify each such investigation and the NBA
`in which each was relied upon:
`
`b) For each investigation identified as "essential to the approval", does the investigation duplicate the
`results of another investigation that was relied on by the agency to support the effectiveness of a
`previously approved drug product? _
`
`Investigation #1
`
`YES/
`
`Investigation #2
`
`YES/
`
`/
`
`/
`
`NO/
`
`.
`
`NO/
`
`/
`
`/
`
`If you have answered "yes" for one or more investigation, identify the NDA in which a similar
`investigation was relied on:
`
`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application or
`supplement that is essential to the approval (i.e., the investigations listed in #2(c), less any that are not
`"new"):
`
`

`

`4. To be eligible for exclusivity, a new investigation that is essential to approval must also have been
`conducted or sponsored by the applicant. An investigation was "conducted or sponsored by" the applicant
`if, before or during the conduct of the investigation, 1) the applicant was the sponsor of the IND named in
`the form FDA 1571 filed with the Agency, or 2) the applicant (or its predecessor in interest) provided
`substantial support for the study. Ordinarily, substantial support will mean providing 50 percent or more
`of the cost of the study.
`
`a) For each investigation identified in response to question 3(c): if the investigation was carried out under
`an IND, was the applicant identified on the FDA 157] as the sponsor?
`
`Investigation #l
`
`IND #
`
`YES /___/
`
`N0 /_/ Explain:
`
`Investigation #2
`
`IND #
`
`YES /___/
`
`NO /___/ Explain:
`
`(b) For each investigation not carried out under an IND or for which the applicant was not identified as
`the sponsor, did the applicant certify that it or the applicant's predecessor in interest provided substantial
`support for the study?
`
`Investigation #1
`
`——
`YES/
`/ Explain
`
`——
`NO/
`lExplain
`
`Investigation #2
`
`YES/
`
`/Explain
`
`NO/
`
`/ Explain
`
`

`

`(c) Notwithstanding an answer of "yes" to (a) or (b), are there other reasons to believe that the
`applicant should not be credited with having "conducted or sponsored" the study? (Purchased
`studies may not be used as the basis for exclusivity. However, if all rights to the drug are
`purchased (not just studies on the drug), the applicant may be considered to have sponsored or
`conducted the studies sponsored or conducted by its predecessor in interest.)
`
`YES /__/
`
`NO /_____/
`
`If yes, explain:
`
`Signature
`Title:
`
`Date
`
`Signature of Oflice/
`Division Director
`
`Date
`
`cc: Original NDA
`
`Division File
`
`RFD-93 Mary Ann Holovac
`
`

`

`
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`-—--——---~--—---—----
`
`Raymond Lipicky
`1/24/02 10:17:36 AM
`
`

`

`(Complete for all APPROVED original applications and efficacy supplements)
`
`PEDIATRIC PAGE
`
`'DA/BLA # : NDA 21-272
`
`Supplement Type (e.g. SE5):
`
`Supplement Number:
`
`\ Stamp Date: August 09, 2001 (resubmissionz
`
`Action Date:
`
`Februapy 9, 2002
`
`RED -1 10
`
`Trade and generic names/dosage form:
`
`Remodulin (treprostinil sodium) Injection
`
`Applicant:
`
`Upited Theragutics Co.
`
`Therapeutic Class: 1PV (ogphan)
`
`lndication(s) previously approved:
`
`none
`
`Each approved indication must have pediatric studies: Completed, Deferred, and/or Waived.
`
`Number of indications for this application(s):
`
`1
`
`Indication #1:
`
`Pulmonggy Arterial Hmrtension (Pg)
`
`‘
`
`Is there a full waiver for this indication (check one)?
`
`X Yes: Please proceed to Section A.
`
`Partial Waiver
`D No: Please check all that apply:
`NOTE: More than one may apply
`Please proceed to Section B, Section C, and/or Section D and complete as necessary.
`
`Deferred
`
`Completed
`
`ction A: Fully Waived Studies
`
`Reason(s) for full waiver:
`
`I
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`[J Disease/condition does not exist in children
`0 Too few children with disease to study
`Cl There are safety concerns
`X Other: United Thezapgutics rggugted a waiver frpm pgdiatu'c use information, in accordange with
`21 CRF 314.§5 ML 11:3; rguirement for pfiiatric use information has mn wgived because the drug has
`been granted ogphap status.
`
`Ifstudies arefully waived, then pediatric infimnation is completefor this indication. Ifthere is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`Section B: Partially Waived Studies
`
`Age/weight range being partially waived:
`
`Min
`Max
`
`kg
`kg
`
`mo.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for partial waiver:
`
`DDDDU
`
`Products in this class for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`
`Too few children with disease to study
`There are safety concerns
`Adult studies ready for annroval
`
`

`

`NDA 21-272
`
`Page 2
`
`D Other:
`
`Ifstudies are deferred, proceed to Section C. Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is
`complete and should be entered into DFS.
`'
`
`Section C: Deferred Studies
`
`Age/weight range being deferred:
`
`I
`
`Min
`Max
`
`kg
`kg
`
`mo.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for deferral:
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`D Disease/condition does not exist in children
`D Too few children with disease to study
`U There are safety concerns
`0 Adult studies ready for approval
`[3 Formulation needed
`Other:
`
`Date studies are due (mm/dd/yy):
`
`l i E
`
`3
`I
`'
`E
`
`!l
`
`i E
`
`E 4/"’studies are completed, proceed to Section D. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`i
`.
`
`fSection D: Completed Studies
`
`Age/weight range of completed studies:
`
`Min
`Max
`
`Comments:
`
`kg
`kg
`
`mo.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`E E
`
`i1
`
`Ifthere are additional indications, please proceed to Attachment A. Otherwise, this Pediatric Page is complete and should be entered
`into DFS.
`
`This page was completed by:
`
`fl
`
`IS,
`
`[,3‘fl0 b
`
`fiegulatory Project Manager
`
`cc: NDA
`111713.960] Terrie Crescenzi
`
`(revised 1-18-02)
`
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT, PEDIATRIC TEAM, RFD-960
`301-594.7337
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`
`raved: OMB No. 0910-0338
`Form
`my; om.- MW, 3,, 2003
`See OMB smament on page 2.
`
`
`
`APPLICATION TO MARKET A NEW DRUG, BIOLOGIC,
`OR AN ANTIBIOTIC DRUG FOR HUMAN USE
`
`FOR FDA USE ONLY
`APPLICATION NUMBER
`
`(Title 21. Code of Federal Regulations, Paris 314 & 601)
`
`APPLICANT INFORMATION
`NAME OF APPLICANT
`
`.
`
`United Therapeutics Inc.
`TELEPHONE No. ndude Area Code
`
`APPLICANT ADDRESS (Number. Street. City, State. Country. 2P code or Mai Code,
`and us. License mater Upreviwsor Issued):
`
`DATE OF SUBMISSION
`
`April 12, 2001
`ncIudeAm Code
`FACSIMILE
`Numbe
`'0
`I
`919434332
`AUTHOFJZED us. AGENT NAME A ADDRESS (Nunber. Sm, Olly, Slate,
`ZP Code, telephone a FAXlumber) IF APPLICABLE
`
`Research Triangle Park, North Carolina 27709
`
`68 T.W. Alexander Drive
`
`N/A
`
`
`
`
`
`PRODUCT DESCRIPTION
`
`NEw DRUG ORANIIEIOTIC APPLICATION NUMBER. CR BIOLOGICS UCENSE APPLICATION NUMBER (Ilpnviamly ma) 21-272
`ESTABLISHED NAME (.47.. Pm ,
`,
`v USP/USMImme)
`PROPRIETARY NAME (and. name) IF ANY
`.
`.msunoxsodium auedfor
`
`RM:
`
`_
`£5553
`0’ FEMININE WIS
`
`STR
`THS:
`13:35, 5.0, 10.0 mg/mL
`
`I
`I
`ms‘fifcfiéfi‘e’gu': suB’é’é'tlgfi'
`
`:
`
`'
`
`IPPLICATION INFORMATION
`‘ APPIJCATION TYPE
`(check one)
`
`B ABBREVIATED NEW DRUG APPLICATION (ANDA. 21 CFR 314.94)
`ENEW DRUG APPLICATION (21 CFR 314.50)
`BIOLOGICS LICENSE APPLICATION (21 CPR PM 601)
`
`
`
`IF AN NDA. IDENTIFY THE APPROPRIATE TYPE
`".711 505 (hXI)
`L! 505 (b)(2)
`IF AN ANDA. OR 505mm). IDENTIFY THE REFERENC LISTED CRUD PRODUCT THAT IS THE BASIS FOR THE SUBMISSION
`Name DI Drug
`Holds CI Apptoved AppIICEIIon
`
` TYPE OF SUBMISSION (clack one)
`PRESUSMISSION
`
`
`
`ORIGINAL APPUCATICN
`ANNUALREPORT
`
`
`E AMENDMENT To APENDING APPLICATION
`ESTAauSHMENT DESCRIPTION SUPPLEMENT
`if EFFICACY SUPPLaIENT
`
`OTHER
`
`.
`
`_
`E
`.CI-IEIASTRYMANUPACIURINSANDCCNTRDLSSUPPLEMENT
`QueuNCSUPPLEMENr
`
`
`
`IPA SUBMISSION or PARTIAL APPLICATION. PROVIDE LETTER DATE or ACREEMENTTO PARTIAL SUBMISSION:
`
`II= ASUPPLEMENT. IDENTIFY THE APPROPRIATE CATEGORY
`REASON FOR SUBMISSION
`
`PROPOSED MARKETING STATUS Mona
`LS WWW)
`.OVERTI-IEOOINTERPWDTC)
`
`.CSE
`
`@caE-ao EN» Approval (PA)
`
`
`
`PAPER AND ELECTRONIC a ELECTRONIC
`EPAPER
`THIS APPLICATION IS
`NUMBER OF VOLUMES SUBMITTED
`ESTABLISHMENT INFORMATION (Full mblhbr'nem Information ehould be provIded In the body CI The Appllceuon.)
`PIDvIde mmuummm. pedaglngwcomml mwmmmmumm (0mm sheets maybeueed Necessary). Include name.
`mmmiephonemnben WMmITIDeHc
`.DManber.eIId
`SI
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`608890 msubmtymflno)
`
`,.
`
`Cross References (Ilet related Lleenee AppllceIIons, lNDe. NDAS. PAIAS, 51000:, IDES, BMFe, and IMF: referenced In the canon! nppIIcetIon)
`
`——————-—
`
`FOFIM FDA 356h (4/00)
`
`Dun-“y Man-moonM 5?
`PAGE 1
`
`_._,_ .
`
`,-..,._ V. . in.-.“ ...:
`
`,,__,,_.,. A. _...... q - ”...... ...-_... _-..—m-.- _......
`
`.H ..
`
`.,
`
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`
`.,
`
`A
`
`

`

`This application contains the following items: (Check all that apply) .
`
`
`
`2. Labeling (check one)
`3. S
`»
`.
`21 CPR 314.50 c
`
`D Draft Labelmg
`
`D Final Printed Labeling
`
`4 Chemistry section
`
`‘
`
`~
`
`-'
`
`A. Chemistry manufacturing, andcontrols information (0.9.. 21 CPR 314.50(d)(1); 21 CPR 601.2)
`
`B. Samples (21 CPR 314.50 (e)(1); 21 CPR 6012 (11)) (Submit only upon PDA’s request)
`
`C Methods validation package (e.g.. 21 CPR 314.50(e)(2)(l): 21 CPR 601.2)
`
`.
`
`5 Noncimicai phamiacology and toxicology section (e.g.. 21 CPR 314.50(d)(2); 21 CPR 601.2)
`
`EDUEE
`
`
`
`14. A patent certification wrth respectto any patent whichclaims the drug (21 U S C 355 (b)(2) or 0)(2)(A))
`
`15 Establishment description (21 CPR Part 600 it applicable)
`
`16 Debarrnent certification (PD&C Act 306 mu»
`
`17 Field copy cerblication (21 CPR 314.50 (k)(3))
`
`18. User Fee Cover Sheet (Pon'n FDA 3397)
`
`
`
`DEEEEEEE
`
`
`
`News?»
`
`
`
`19. Financial lnfonnahon (21 CFR Part 54)
`Ii] 20. OTHER (epecm
`CERTIFICATION
`
`
`
`i agree to update this application with new safety Information about the product that may reasonably affect the statement of contraindications.
`warnings. precautions. oradversereactionslnthedrattlabeling.legreetoslbmitsafetyupdatereportsaspmvldediorbyregulaflonoras
`
`requested by FDA itthis appliationlsapproved. l agreetooomplywithali applicable lamand regulationsthatapplytoapproved applications.
`
`including. butnotlimitedtothetotlowing:
`
`1. Good manufacturing practice regulations ln21 CPR Parts 210. 211 or applicable regulations. Parts 606. and/or 820.
`
`Biological establishment standardsin 21 CPR Part 600.
`
`Labeling regulations in 21 CPR Parts 201. 606. 610. 660. and/or 809.
`
`lnthecase otaprescriptiondrugorbioicgicalproduct. prescriptiondrugadvertising regulations in21 CFR Part 202.
`
`Regulations on making cinema: in application in PD&C Act Section 506A. 21 CPR 314.71, 314.72. 314.97, 314.99. and 601.12.
`
`Regulations on Reports in 21 CPR 314.80. 314.81. 600.80. and 600.81.
`
`. Local. state and Federal environmental impact laws.
`lithisapplicafion appriestoadrugproductthetFDAhaspropoeediorscheduiingmdertheConboiledSubstancesAct.lagree nottomarketme
`
`productuntii the Drug EntorcementAdministration makesafinai scheduling decision.
`Thedataandiniormalionhthlssubrrissionhavebeenrevleweddeothebestotrnyknovdedgearecertiliedtobetrueandecwrate..
`Warning: A willfully false statement is acrbninal ofiense, U.S. Code. title 18. section 1001.
`-
`
`.
`TYPED NAMEANon'rLE
`DcanBunce,DxrectorRegulatoryAfi‘mrs
`Telephone Number
`( 919
`485-8350
`
`
`
`
`
`
`a.
`A
`'5 one “ONSIBLE OFPI ORAGENT
`m a i
`.0
`ADDRESS (Sheet. cry, sate, andZP Code)
`68 T.W. Alexander Drive, Research Triangle Park. NC. 27709
`
`
`DATE
`April 12, 2001
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Public reporting burden for this collection at information is estimated to average 24 hours per response. including the time for reviewing
`
`
`instmcllons.searchhge)dsting«www.mmwmgmmmwmmmmmmwcdmd
`Won. Sendcornments regardngthisburden estirnatecranyotheraspectoffl'iiscoilectionofinlorn'ation, lnoludingsuggestionsiorreducing
`burdento:
`
`
`Depamnenloil-laalthandflumanServices
`FoodandDmgAdministratlcn
`FoodandDrugAdminlstration
`CDER,HFD-94
`Anagencymaynotconductoreponsor.anda
`
`
`person is not required to respond to. aooiiection
`case. was
`12420 Penman Room3048
`
`
`1401RodwiliePllre
`Rockvlile.MD20852
`ofhbmmflonmflmitdisplaysawmnflyvafid
`
`murmur) 20852-1448
`OMBeomolrumber.
`
`
`
`FORM FDA 3561: (4100)
`
`PAGE 2
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Pub'i‘i "93"“ Service
`Food and Drug Administration
`
`CERTIFICATION: FINANCIAL INTERESTS AND
`
`ARRANGEMENTS OF CLINICAL INVESTIGATORS
`
`TO BE COMPLETED B YAPPLICANT
`
`Form Approved: OMB No. 0910-0396
`Expiration Date: 3/31/02
`
`
`
`\Mth respect to all covered clinical studies (or specific clinical studies listed below (if appropriate» submitted in
`support of this application,
`I certify to one of the statements below as appropriate.
`l understand that this
`certification is made in compliance with 21 CFR part 54 and that for the purposes of this statement, a clinical
`investigator includes the spouse and each dependent child of the investigator as defined in 21 CFR 54.2(d).
`
`Please mark the applicable checkbax.
`
`(1) As the sponsor of the submitted studies, I certify that l have not entered into any financial arrangement
`with the listed clinical investigators (enter names of clinical investigators below or attach list of names
`to this form) whereby the value of compensation to the investigator could be affected by the outcome
`of the study as defined in 21 CFR 54.2(a). i also certify that each listed clinical investigator required to
`disclose to the sponsor whether the investigator had a proprietary interest in this product or a
`significant equity in the sponsor as defined in 21 CFR 54.2(b) did not disclose any such interests. I
`further certify that no listed investigator was the recipient of significant payments of other sorts as
`defined in 21 CFR 54.2(f).
`
`8310 g
`
`E .
`
`3..5
`U
`
`(2) As the applicant who is submitting a study or studies sponsored by a firm or party other than the
`applicant.
`I certify that based on information obtained from the sponsor or from participating clinical
`investigators. the listed clinical investigators (attach list of names to this form) did not participate in any
`financial arrangement with the sponsor of a covered study whereby the value of compensation to the
`investigator for conducting the study could be affected by the outcome of the study (as defined in 21
`CFR 542(3)): had no proprietary interest in this product or significant equity interest in the sponsor of
`the covered study (as defined in 21 CFR 54.2(b)); and was not the recipient of significant payments of
`other sorts (as defined in 21 CF R 542(0).
`
`(3) As the applicant who is submitting a study or studies sponsored by a firm or party other than the
`applicant, l certify that l have acted with due diligence to obtain from the listed clinical investigators
`(attach list of names) or from the sponsor the information required under 54.4 and it was not possible
`to do so. The reason why this information could not be obtained is attached.
`
`NAME
`
`‘
`
`James Crow, PhD.
`
`FIRM]ORGANIZATION
`
`'
`
`TITLE
`
`President
`
`.
`
`United Therapeutics Corp, 68 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709
`
`SIGNA ‘llii
`
`’
`
`DATE
`
`Paperwork Reduction Act Statement
`
`, agency may not conduct or sponsor, and a person is not required to respond to, a collection of
`‘
`info I
`,
`'on unless it displays a currently valid OMB control number. Public reporting burden for
`this collection of information is estimated to average I hour per response, including time for
`rcvrewtng instructions, searching existing data sources, gathering and maintaining the necessary
`data, and completing and reviewing the collection of information: Send comments regarding this
`burden estimate or any other aspect of this collection of information to the address to the right:
`
`Department ofHealth and Human Services
`Food and Drug Administration
`5600 Fishers Lane, Room I460}
`Rockville, MD 20857
`
`

`

`CONSULTATION RESPONSE
`
`Office of Post-Marketing Drug Risk Assessment
`(OPDRA; HEB-400)
`
`DATE RECEIVED:
`
`October 17, 2000
`
`DUE DATE:
`
`OPDRA CONSULT #:
`
`January 22, 2001
`
`00-0283
`
`Raymond Lipicky, MD.
`Director, Division of Cardio-Renal Drug Products
`HFD-l 10
`
`THROUGH: Edward Fromm, Project Manager
`HFD-l 10
`
`1 mg/mL, 2.5 mg/mL, 5 mg/mL and 10 mg/mL
`
`PRODUCT NAME:
`UNIPROST (Primary)
`and REMODULIN (Alternate)
`
`(Treprostinol Sodium Injection)
`
`NDA #: 21-272
`
`MANUFACTURER: United Therapeutics Corp.
`
`SAFETY EVALUATOR: Carol Holquist, R.Ph.
`
`SUMMARY: In response to'a consult from the Division of Cardio-Renal Drug Products (HFD-l 10), OPDRA
`nducted a review of the proposed proprietary names “Uniprost” and “Remodulin” to determine the potential for
`infusion with a troved nuroric .
`and _eneric names as well as endin ; names.
`
`OPDRA RECOMMENDATION: OPDRA does not recommend the use of the proprietary name “Uniprost”.
`However, OPDRA has no objection to the use of the proprietary name “Remodulin”. In addition, OPDRA recommends
`implementation of the enclosed labeling revisions in order to minimize the potential for medication errors. See the
`checked box below.
`0W
`This name must be re-evaluated approximately 90 days prior to the expected approval of the NDA. A re-review ofthe name prior to
`NDA approval will rule out any objections based upon approvals of other proprietary names/NDAs from the signature date of this
`document. A re-review request of the name should be submitted via e-mail to “OPDRAREQUEST’ with the NDA number, the proprietary name, and the goal
`date. OPDRA will respond back via e-mail with the final recommendation.
`W
`V W
`E OPDRA considers this a final review. However, ifthe approval ofthe NDA is delayed beyond 90 days from the date ofthis review, the name must be
`reevaluated. A re-review of the name prior to NDA approval will rule out any objections based upon approvals of other proprietary names/NDA's from this date
`forward.
`
`W O
`
`PDRA will monitor this name until approximately 30 days before the approval of the NDA. The reviewing division need not submit a second consult for name
`review. OPDRA will notify the reviewing division of any changes in our recommendation ofthe name based upon the approvals of other proprietary
`names/NDAs from this date forward.
`
`__§°\____
`
`Jerry Phillips, R.Ph.
`Associate Director for Medication Error Prevention
`Office of Post-Marketing Drug Risk Assessment
`Phone: (301) 827-3242
`‘x:
`(301) 480-8173
`
`I
`
`__X’\__
`
`Martin Himmel, MD.
`Deputy Director
`Office of Post-Marketing Drug Risk Assessment
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`

`

`Office of Post-Marketing Drug Risk Assessment
`RFD-400; Rm. 15B03
`Center for Drug Evaluation and Research
`
`PROPRIETARY NAME REVIEW
`
`DATE OF REVIEW:
`
`January 9, 2001
`
`NBA NUMBER:
`
`21-272
`
`NAME OF DRUG:
`
`.
`
`UNIPROST (Primary) and REMODULIN (Alternate)
`(Treprostinol Sodium Injection)
`1 mg/mL, 2.5 mg/mL, 5 mg/mL and 10 mg/mL
`
`NDA HOLDER:
`
`United Therapeutics Corp.
`
`1.
`
`INTRODUCTION
`
`This consult was written in response to a October 16, 2000, request from the Division of Cardio-
`Renal Drug Products (HFD-l 10), for assessment of the proposed proprietary drug name, Uniprost
`and alternate name, Remodulin, regarding potential name confusion with other proprietary/generic
`drug names.
`
`PRODUCT INFORMATION
`
`Uniprost/Remodulin contains the active ingredient tresprotinol sodium. Tresprotinol is a tricyclic
`benzidene analogue of prostacyclin (PGIZ) with potent pulmonary and systemic vasodilatory activity. It
`is also a potent inhibitor ofplatelet aggregation. The vasodilatory effects reduce right and lefi
`ventricular aflerload and increase cardiac output and stroke volume. Uniprost/Remodulin is indicated
`for the
`long—term subcutaneous treatment of Pulmonary Arterial Hypertension in New York Heart
`Association (NYHA) Class II, III, and IV patients. Uniprost/Remodulin is administered by subcutaneous
`infiision, via a self-inserted subcutaneous catheter, using an infusion pump designed for subcutaneous
`dmg delivery. (The dosage is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated, the
`dosage should be reduced to 0.625 ng/kg/min. The infusion rate is calculated using the following
`formula:
`
`Infusion rate (ml/hr) = Dose (ng/kg/min) x Weight (kg) x [0.00006/Uniprost concentration (mg/mL]
`
`The infusion rate is adjusted based on Pulmonary Arterial Hypertension (PAH) signs and symptoms and
`drug side effects. The product will be supplied in 20 mL vials with the following concentrations:
`1 mg/mL, 2.5 mg/mL, 5 mg/mL, and 10 mg/mL.
`
`

`

`II.
`
`RISK ASSESSMENT
`
`The medication error staff of OPDRA conducted a search of several standard published drug product
`reference texts""""
`as well as several FDA databases” for existing drug names which sound alike or
`look alike to Uniprost and Remodulin to a degree where potential confusion between drug names
`could occur under the usual clinical practice settings. A search of the electronic online version of the
`US. Patent and Trademark Office’s Text and Image Database was also conducted”. An Expert Panel
`discussion was conducted to review all findings from the searches. In addition, OPDRA conducted
`six prescription analysis studies, to simulate the prescription ordering process.
`
`A'. EXPERT PANEL DISCUSSION
`
`An Expert Panel discussion was held by OPDRA to gather professional opinions on the safety of
`the proprietary names Uniprost and Remodulin. Potential concerns regarding drug marketing and
`promotion related to the proposed name were also discussed. This group is composed of OPDRA
`Medication Errors Prevention Staff and representation fi'om the Division of Drug Marketing and
`Advertising Communications (DDMAC). The group relies on their clinical and other
`professional experiences and a number of standard references when making a decision on the
`acceptability of a proprietary name.
`
`Several products were identified in the Expert Panel Discussion that was thought to have
`potential for confusion with Uniprost and/or Remodulin. These products are listed in Table 1,
`along with the dosage forms available and usual FDA-approved dosage. The panel also
`expressed their preference for Remodulin due to the numerous products currently marketed with
`the prefix “Uni”.
`
`DDMAC did not have any concerns with regard to promotional claims for either name.
`
`APPEARS THIS WAY
`0N ORiGlNAL
`
`iMICROMEDEX Healthcare Intranet Series, 2000, MICROMEDEX, Inc., 6200 South Syracuse Way, Suite 300, Englewood,
`Colorado 80111-4740, which includes the following published texts: DrugDex, Poisindex, Martindale (Parfitt K (Ed),
`Martindale: The Complete Drug Reference. London: Pharmaceutical Pr