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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`
`
` CLINICAL PHARMACOLOGY AND
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` BIOPHARMACEUTICS REVIEW(S)
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`

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`Office of Clinical Pharmacology
`
`Integrated Review
`
`
`NDA or BLA Number
`Link to EDR
`Submission Date
`Submission Type
`Brand Name
`Generic Name
`Dosage Form and Strength
`Route of Administration
`
`Proposed Indication
`Applicant
`Associated IND
`OCP Review Team
`
`208276
`//Cdsesub1/evsprod/NDA208276/208276.enx
`16th December 2015
`Standard
`Remodulin Implantable System (RIS)
`Treprostinil
`1, 2.5, 5, and 10 mg/mL (approved formulations)
`Programmable pump delivering continuous intravenous
`infusion (iv) infusion
`Pulmonary Arterial Hypertension (PAH)
`United Therapeutics Corporation
`None
`Ju-Ping Lai, Ph.D.; Sudharshan Hariharan, Ph.D.
`
`
`Reference ID: 3988934
`Reference ID: 4409052
`
`1
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`

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`Table of Contents
`1. EXECUTIVE SUMMARY..............................................................................................................................3
`
`1.1 Recommendations..............................................................................................................................3
`
`1.2 Post-Marketing Requirements and Commitments.............................................................................4
`
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT.........................................................................4
`
`2.1 Pharmacology and Clinical Pharmacokinetics ....................................................................................4
`
`2.2 Dosing and Therapeutic Individualization ..........................................................................................4
`
`2.3 Outstanding Issues..............................................................................................................................4
`
`2.4 Summary of Labeling Recommendations ...........................................................................................4
`
`3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW............................................................................4
`
`3.1 Overview of the Product and Regulatory Background .......................................................................4
`
`3.2 General Pharmacological and Pharmacokinetic Characteristics.........................................................4
`
`3.3 Clinical Pharmacology Questions........................................................................................................5
`
`3.3.1 Evaluation of PK data pre- and post-device implantation ...........................................................5
`
`3.3.2 Is the proposed general dosing regimen appropriate? ...............................................................6
`
`3.3.3 Is an alternative dosing regimen and management strategy required for subpopulations based
`
`on intrinsic factors? ..............................................................................................................................6
`
`3.3.4 Are there clinically relevant food-drug or drug-drug interactions and what is the appropriate
`
`management strategy?.........................................................................................................................6
`
`3.3.5 Is the to-be-marketed formulation the same as the clinical trial formulation, and if not, are
`
`there bioequivalence data to support the to-be-marketed formulation? ...........................................6
`
`4. Appendices ...............................................................................................................................................6
`
`4.1 Summary of Bioanalytical Method Validation ....................................................................................6
`
`
`Reference ID: 3988934
`Reference ID: 4409052
`
`2
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`

`

`1. EXECUTIVE SUMMARY
`
`Remodulin (treprostinil) Injection was approved on May 21, 2002 for the treatment of pulmonary
`arterial hypertension (PAH). It is a sterile sodium salt formulated for continuous subcutaneous or
`intravenous (IV) administration. Remodulin Injection is administered via an external infusion
`pump and surgically placed central venous catheter.
`
`The applicant submitted NDA 208276 on December 16, 2015 and is seeking approval of
`Remodulin Implantable System (RIS), which consists of an approved drug (treprostinil) with its
`approved formulation (1, 2.5, 5, and 10 mg/mL) through an approved dosing route (IV infusion),
`for the same PAH indication in the same patient population, yet delivered by a new
`programmable and implantable drug delivery system.
`
`
`The submission includes a multi-center, prospective, single arm, non-randomized, open label
`study designed to evaluate the safety of RIS in the treatment of PAH. From the clinical
`pharmacology perspective, two plasma samples were collected in each patient, one at baseline
`and the other at one week post-implant to assess maintenance of treprostinil steady state after
`switching of delivery system. For the safety evaluation, please refer to the clinical review by Drs.
`Gordon and Garnett (DARRTS date: 8/3/2016).
`
`The use of Remodulin in the RIS does not change the drug’s indication, subject population, drug
`dosage, formulation or route of administration for which the drug has already received FDA
`approval. However, a non-approvable letter was issued by Center for Devices and Radiological
`Health (CDRH) on March, 11, 2016 for the implantable device. A comprehensive summary of
`the issues pertaining to non-approvability of the device is summarized that letter.
`
`The key review question focuses on evaluation of pharmacokinetic (PK) data collected pre- and
`post-implantation of RIS.
`
`1.1 Recommendations
`The Office of Clinical Pharmacology, Division of Clinical Pharmacology I has reviewed the
`information contained in NDA 208-276. This NDA is considered approvable from a clinical
`
`pharmacology perspective pending approval of the device by CDRH. The key review issue with
`
`specific recommendations/comments is summarized below:
`Review Issue
`Recommendations and Comments
`Evaluation of treprostinil
`trial
`The plasma samples collected from
`the
`plasma concentration
`
`provides evidence that the drug was delivered using
`collected pre- (baseline)
`the proposed RIS. The intra-subject variability
`
`and post-implantation (1-
`estimate is within the past clinical experience with
`week) of RIS
`the oral product of treprostinil. The utility of PK
`data collected 1-week post-device implantation
`may be limited at least in terms of predicting the
`long term performance of the device.
`
`Reference ID: 3988934
`Reference ID: 4409052
`
`3
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`1.2 Post-Marketing Requirements and Commitments
`None (for the infused drug, Remodulin).
`
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT
`
`2.1 Pharmacology and Clinical Pharmacokinetics
`Treprostinil acts by direct vasodilation of pulmonary and systemic arterial vascular beds. The
`current submission does not contain any new clinical pharmacology information and would not
`lead to any changes in the label of Remodulin. Therefore no additional clinical pharmacology
`information is summarized in this review. Please refer to the USPI and the clinical pharmacology
`review (DARRTS date: 3/12/2001) of Remodulin for the ADME information.
`
`2.2 Dosing and Therapeutic Individualization
`Not applicable for the infused drug, Remodulin. The studied dose in the clinical trial followed
`the USPI of Remodulin and dose titrations were within what is prescribed in the USPI. There is
`no proposal to change the doses or dose titration steps. Therefore, no additional evaluation was
`
`performed to assess dosing from the submitted study report.
`
`2.3 Outstanding Issues
`None for the infused drug, Remodulin. For the implantable device, the CDRH issued a non­
`approvable letter on March 11, 2016. A comprehensive summary of the issues pertaining to non­
`approvability of the device is summarized that letter.
`
`2.4 Summary of Labeling Recommendations
`Not applicable for the infused drug, Remodulin.
`
`3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW
`
`3.1 Overview of the Product and Regulatory Background
`This is a drug-device combination product. The original NDA was submitted to CDER
`and Premarket Approval Application (PMA) to CDRH on January 26, 2015 but was issued a
`refusal to file letter on March 26, 2015 by CDER. The resubmission was sent in on December
`16, 2015. A non-approvable letter was issued by CDRH on March, 11, 2016 for the implantable
`device while the review clock within CDER for the infused drug has continued.
`3.2 General Pharmacological and Pharmacokinetic Characteristics
`Please refer to the USPI and clinical pharmacology review of Remodulin as there is no new
`clinical pharmacology information from this submission.
`
`Reference ID: 3988934
`Reference ID: 4409052
`
`4
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`3.3 Clinical Pharmacology Questions
`
`3.3.1 Evaluation of PK data pre- and post-implantation of Remodulin Implantable System
`Study G100017 enrolled subjects who were receiving IV Remodulin via an external infusion
`pump. Patients need to be on stable dose of Remodulin for at least 4 weeks to enroll. The
`delivery system delivered drug at the subject’s prescribed infusion rate, and the subject was
`transitioned off the external delivery system to the RIS when the implantation procedure was
`completed.
`
`Plasma treprostinil concentrations were measured to ensure the RIS maintained the steady state
`levels of treprostinil that the patient was previously stabilized on. The time points were at
`baseline (where patients were on stable dose of Remodulin) and at one week post-implant of the
`proposed delivery system. The infusion rate of the drug was kept constant until the one-week PK
`sample was obtained. Drug plasma concentrations were available in 58 patients. The mean
`change (± standard deviation) in the drug concentration between two delivery systems is 2.3 %
`(± 41%), however the drug concentration between the two occasions on a patient level were
`more variable ranging from -60.5% to 235.5%. Eight out of 58 patients (~14%) exhibited
`concentration change of greater than –25% or +50% (Table 1).
`
`Table 1: Subjects with concentration change of greater than –25% or +50%.
`No
`Patients
`Plasma concentration (ng/ml)
`% change
`1 week post
`implantation
`
`
`
`
`
`Baseline
`
`
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`3.01
`
`6.35
`
`1.47
`
`9.74
`
`13.2
`
`4.95
`
`1.92
`
`11.5
`
`10.1
`
`2.51
`
`2.57
`
`5.37
`
`8.67
`
`2.69
`
`3.81
`
`5.65
`
`235.5
`
`-60.5
`
`74.8
`
`-44.9
`
`-34.3
`
`-45.7
`
`98.4
`
`-50.9
`
`The within-subject variability estimate from this study is ~25%. This variability is within the
`past clinical experience with the oral formulation of treprostinil (Orenitram®) where the
`estimated within-subject variability were 31% and 25% for Cmax and AUC, respectively. There
`are a few patients with greater plasma concentration changes than expected in this study (as
`shown in Table 1), however, in the absence of a control arm it is not known if similar extent of
`variability would have been observed following Remodulin external infusion pump at two
`
`5
`
`
`Reference ID: 3988934
`Reference ID: 4409052
`
`(b) (6)
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`

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`different occasions within the same individual. Nevertheless, PAH symptoms in these patients
`did not deteriorate significantly over time. Treprostinil infusion rates increased over time in this
`study, but it may be more reflective of the clinical practice with prostacyclins. Therefore,
`evaluation of PK data following one-week post implantation is not really indicative of device
`performance over the long-term. Instead, device accuracy ratio and long-term clinical
`experience, which are discussed in detail in the clinical review, are more reflective of the long­
`term performance of the device.
`
`3.3.2 Is the proposed general dosing regimen appropriate?
`Not applicable for the infused drug, Remodulin.
`
`3.3.3 Is an alternative dosing regimen and management strategy required for subpopulations
`based on intrinsic factors?
`Not applicable for the infused drug, Remodulin.
`
`3.3.4 Are there clinically relevant food-drug or drug-drug interactions and what is the
`appropriate management strategy?
`Not applicable for the infused drug, Remodulin.
`
`3.3.5 Is the to-be-marketed formulation the same as the clinical trial formulation, and if not,
`are there bioequivalence data to support the to-be-marketed formulation?
`Not applicable for the infused drug, Remodulin.
`
`4. Appendices
`
`4.1 Summary of Bioanalytical Method Validation
`The assay validation for treprostinil is within the specifications and acceptable. Concentrations
`of treprostinil in plasma were determined using validated liquid chromatography tandem mass
`spectrometry (LC-MS/MS) method. The lower limit of quantitation (LLOQ) for treprostinil in
`the plasma was 0.01 ng/mL. Accuracy and precision for the Quality Control (QC) samples are <
`7.7 % and < 14%, respectively, and is acceptable according to the specification listed in
`‘Guidance for Industry: Bioanalytical Method Validation’.
`
`Reference ID: 3988934
`Reference ID: 4409052
`
`6
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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/
`----------------------------------------------------
`JU PING LAI
`09/21/2016
`
`SUDHARSHAN HARIHARAN
`09/21/2016
`
`Reference ID: 3988934
`Reference ID: 4409052
`
`