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` CENTER FOR DRUG EVALUATION AND
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` RESEARCH
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` APPLICATION NUMBER:
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`208276Orig1s000
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` SUMMARY REVIEW
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`DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS
`Divisional Memo
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`208276 Remodulin (treprostinil) Implantable System
`for PAH.
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`United Therapeutics
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`Sponsor:
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`NDA:
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`Review date: 8 October 2016
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`Reviewer:
`N. Stockbridge, M.D., Ph.D., HFD-110
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`This memo conveys the Division’s decision not to approve this application.
`This application has been the subject of reviews of CMC (Wong, Metcalfe, Williams,
`Zhao, McMichael, 27 July 2016), pharmacology/toxicology (Tesfamarian; 4 August
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`2016), clinical pharmacology (Lai; 21 September 2016), clinical (Gordon, Garnett; 3
`August 2016), and statistics (Kong, 7 July 2016). There is no CDTL memo.
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`The system is a drug-device combination. The drug product is the same as was
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`approved for infusion in 2002. The device is a central venous catheter and battery-
` weeks by syringe needle.
`operated implanted pump that is filled every
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`The original application was submitted in 2015, and the Division refused to file it (26
`March 2015) because of problems with the reviewability of study data and identified
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`device issues. The PMA was updated on 14 December 2015 and the NDA was
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`resubmitted on 16 December 2015.
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`A multi-center study was conducted in 60 subjects to assess catheter-related
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`complications. All were users of Remodulin with an external pump and a central
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`catheter. The primary hypothesis being tested was whether the catheter-related
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`complication rate was less than 2.5 per 1000 patient-days, a number derived from a
`review of the literature with use of the external pump.
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`These 60 subjects accumulated 44000 days of exposure, involving 1700 refills. During
`this period, there were 7 catheter-related complications in 4 subjects, ruling out (95%
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`CI) a rate as high as 0.6 per 1000 days. These events were a procedure-related
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`pneumothorax in one subject, two device dislocations in a second subject, one
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`dislocation and two catheter punctures in a third subject, and venous stasis in a fourth
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`subject.
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`There were 9 deaths during follow-up; all appeared to have been disease-related.
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`Three subjects had device-related infections (two sepsis, one local).
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`Ninety percent of subjects reported either site pain or site reactions.
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`Subjects had plasma levels of treprostinil obtained at baseline (on previous infusion
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`modality) and then at 1 week. The mean change was 2.3%, with about 25% within-
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`subject variability, which is similar to what is observed during oral treprostinil
`administration.
`Pump accuracy decreases about 5% per year; most subjects had their doses increase
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`during the study, but whether this represents compensation for pump performance or
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`disease worsening is not clear.
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`6MWT was performed at baseline and 6 weeks, as were several patient-reported
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`outcome measures, all of which seemed fairly stable.
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`\\fda.gov\wodc\CDER\Users01\STOCKBRIDGEN\Docs-backup\NDA\N208276 Remodulin
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`implantable\RemodulinImplantableDivMemo.docLast saved
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`07:12 Saturday, October 08, 2016
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`Reference ID: 3996990
`Reference ID: 4409052
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`(b) (4)
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`Divisional memo
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`Remodulin (treprostinil) implantable system
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`NDA 208276
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`Pulmonary arterial hypertension
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`The observed performance of the Remodulin Implanted System seems compatible with
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`approval. The product quality team recommends against approval pending
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`demonstration that m-creosol levels are adequate to control the risk of infection
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`through refills. I concur.
`In addition, the drug-device combination cannot be approved until the device is
`approvable. The PMA holder was notified of deficiencies, and the PMA was not approved
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`by CDRH on 11 March 2016.
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`\\fda.gov\wodc\CDER\Users01\STOCKBRIDGEN\Docs-backup\NDA\N208276 Remodulin
`implantable\RemodulinImplantableDivMemo.docLast saved
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`07:12 Saturday, October 08, 2016
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`Reference ID: 3996990
`Reference ID: 4409052
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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.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`NORMAN L STOCKBRIDGE
`10/08/2016
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`Reference ID: 3996990
`Reference ID: 4409052
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