CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
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`
`
`
` APPLICATION NUMBER:
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` 208276Orig1s000
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`
`
`
` OTHER ACTION LETTERS
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`
`
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`
`
`
`
`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 208276
`
`United Therapeutics Corporation
`
`Attention: Rex Mauthe, MBA
`
`Associate Vice President, Regulatory Affairs
`
`55 T. W. Alexander Drive
`
`P.O. Box 14186
`
`Research Triangle Park, NC 27709
`
`
`Dear Mr. Mauthe:
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`COMPLETE RESPONSE
`
`
`Please refer to your New Drug Application (NDA) originally submitted December 26, 2015,
`received December 26, 2015, and your amendments, submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act, for Implantable System for Remodulin (treprostinil)
`solution for injection.
`
`We acknowledge receipt of your amendment dated December 15, 2016, which constituted a
`complete response to our October 8, 2016, action letter.
`
`We have completed our review of this application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this
`action below and, where possible, our recommendations to address these issues.
`
`CLINICAL
`
`1. As noted in our October 8, 2016, Complete Response letter, the device component of this
`combination product received a Not Approvable letter on the PMA on March 11, 2016.
`As stated in our October 8, 2016, letter, until such time as the device is determined to be
`approvable for use in combination with your proposed drug under this NDA, your NDA
`for the drug-device combination product cannot be approved.
`
`2. Sufficient human factors (HF) data has not been provided to demonstrate that the
`Implantable System for Remodulin (ISR) user interface supports safe and effective use
`for the intended users, uses and use environments. Therefore, the original HF deficiencies
`included in the Not Approvable letter issued by FDA’s Center for Devices and
`Radiological Health (CDRH) on March 11, 2016 and the HF deficiencies identified by
`CDRH on February 9, 2017, with respect to the PMA resubmission to CDRH, remain
`outstanding. In addition, pursuant to 21 CFR 820.30, the ISR user interface, including the
`training plan, should be optimized and validated prior to approval to ensure the ISR can
`be used safely and effectively by the intended users, for the intended use, and in the
`intended use environment. We recommend that the device component of this combination
`
`Reference ID: 4106543
`Reference ID: 4409052
`
`

`

`NDA 208276
`
`Page 2
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`product undergo a re-evaluation of the HF validation study results, implementation of
`additional mitigations, finalize the intended training program, and supply additional HF
`validation data to demonstrate that representative users can use the product safely and
`effectively before the product is approved. Submit the HF validation study protocol for
`Agency review and feedback before commencing the study to ensure that the
`methodology is acceptable.
`
`PRESCRIBING INFORMATION
`
`3. We reserve final comment on the proposed labeling until the application is otherwise
`adequate. We have, however, decided to incorporate the use of the Implantable System
`for Remodulin into the existing Remodulin label.
`
`When you resubmit your application, please propose a unified Prescribing Information
`incorporating use of the Implantable System for Remodulin in the existing label for
`Remodulin.
`
`We encourage you to review the labeling review resources on the PLR Requirements for
`Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites,
`
`
`
`including regulations and related guidance documents and the Selected Requirements for
`Prescribing Information (SRPI) − a checklist of important format items from labeling
`regulations and guidances.
`
`If you revise labeling, use the SRPI checklist to ensure that the prescribing information
`conforms with format items in regulations and guidances. Your response must include
`in structured product labeling
`updated content of labeling [21 CFR 314.50(l)(1)(i)]
`
`(SPL) format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`
`To facilitate review of your submission, provide a highlighted or marked-up copy that
`shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should include annotations that support any proposed changes.
`
`PROPRIETARY NAME
`
`4. Please refer to correspondence dated, April 7, 2017 which addresses the proposed
`proprietary name, Implantable System for Remodulin. This name was found acceptable
`pending approval of the application in the current review cycle. Please resubmit the
`proposed proprietary name when you respond to the application deficiencies.
`
`SAFETY UPDATE
`
`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
`clinical studies/trials of the drug/product under consideration regardless of indication, dosage
`form, or dose level.
`
`Reference ID: 4106543
`Reference ID: 4409052
`
`

`

`NDA 208276
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`Page 3
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`1. Describe in detail any significant changes or findings in the safety profile.
`
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`• Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as in the original submission.
`• Present tabulations of the new safety data combined with the original/supplemental
`application data.
`Include tables that compare frequencies of adverse events in the original
`/supplemental application with the retabulated frequencies described in the bullet
`above.
`• For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
`•
`
`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original/supplemental
`application data.
`
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`7. Provide a summary of worldwide experience on the safety of this drug/product. Include
`an updated estimate of use for drug/product marketed in other countries.
`
`8. Provide English translations of current approved foreign labeling not previously
`
`submitted.
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the application.
`
`Reference ID: 4106543
`Reference ID: 4409052
`
`

`

`NDA 208276
`Page 4
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`A resubmission must fully address all the deficiencies listed in this letter and should be clearly
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`marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter
`
`of the submission. The cover letter should clearly state that you consider this resubmission a
`
`complete response to the deficiencies outlined in this letter. A partial response to this letter will
`
`not be processed as a resubmission and will not start a new review cycle.
`
`
`You may request a meeting or teleconference with us to discuss what steps you need to take
`
`before the application may be approved. If you wish to have such a meeting, submit your
`
`meeting request as described in the draft FDA Guidance for Industry, “Formal Meetings
`
`Between the FDA and Sponsors or Applicants of PDUFA Products,” March 2015 at
`
`http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
`
`437431.pdf.
`
`The drug product may not be legally marketed until you have been notified in writing that this
`
`application is approved.
`
`
`If you have any questions, call Wayne Amchin, RAC, Regulatory Project Manager, at (301) 796-
`0421.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Reference ID: 4106543
`Reference ID: 4409052
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`WAYNE S AMCHIN
`06/02/2017
`
`NORMAN L STOCKBRIDGE
`06/02/2017
`
`Reference ID: 4106543
`Reference ID: 4409052
`
`

`

`
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 208276
`
`United Therapeutics Corporation
`
`Attention: Rex Mauthe, MBA
`
`Associate Vice President, Regulatory Affairs
`
`55 T. W. Alexander Drive
`
`P.O. Box 14186
`
`Research Triangle Park, NC 27709
`
`
`Dear Mr. Mauthe:
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`COMPLETE RESPONSE
`
`
`Please refer to your New Drug Application (NDA) dated December 16, 2015, received
`December 16, 2015, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act for the Remodulin (treprostinil) Implantable System.
`
`We have completed our review of this application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this
`
`action below and, where possible, our recommendations to address these issues.
`
`CLINICAL
`
`1. The proposed device in this drug-device combination product was submitted to FDA
`under a Premarket Approval Application (PMA). On March 11, 2016, FDA issued a Not
`Approvable letter on the PMA. Until such time as the device is determined to be
`approvable for use in combination with your proposed drug under this NDA, your NDA
`for the drug-device combination product cannot be approved.
`
`PRODUCT QUALITY
`
`2. There are insufficient data to evaluate the risk of potential patient exposure to microbial
`contaminants when the Remodulin drug product is used in the proposed implantable
`pump system. Reference is made to the 24 May 2016 Medtronic response to the 08 May
`2016 FDA information request regarding the low concentration of m-Cresol in the drug
`product following delivery by Medtronic PAH1 System. We note the response states in
`
`part, “The loss of m-Cresol from the sterile drug product solution during the infusion
`process would not impact the microbial quality since the high levels of preservative in the
`pump reservoir would be expected to control any potential microbial contamination and
`the implanted pump and catheter is a closed system”. However, the application does not
`contain data demonstrating that the catheter is a “closed system” from the standpoint of
`microbial ingress. Consequently, it is not clear as to whether insertion of the device into a
`patient may result in microbiological contamination of the tip of the catheter which may
`not be killed by the low concentration of the antimicrobial preservative once the drug
`
`Reference ID: 3996381
`Reference ID: 4409052
`
`

`

`NDA 208276
`Page 2
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`traverses from the pump reservoir to the end of the catheter. Provide data demonstrating
`that the device is a closed system with regard to microbial ingress at the tip of the
`catheter.
`
`PRESCRIBING INFORMATION
`
`3. We reserve comment on the proposed labeling until the application is otherwise adequate.
`We encourage you to review the labeling review resources on the PLRLequirementsRforR
` rescribingRInformationRandR regnancyRandRPactationRPabelingRFinalRLuleRwebsites,
`including regulations and related guidance documents and the Selected Requirements for
`
`Prescribing Information (SRPI) − a checklist of important format items from labeling
`regulations and guidances.
`
`
`If you revise labeling, use the SRPI checklist to ensure that the prescribing information
`conforms with format items in regulations and guidances. Your response must include
`updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL)
`format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`
`PROPRIETARY NAME
`
`4. The review of your proposed proprietary name has been terminated due to the deficiencies
`with the application as described in this letter. Please resubmit the proposed proprietary
`name when you respond to the application deficiencies.
`
`SAFETY UPDATE
`
`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
`
`clinical studies/trials of the Remodulin Implantable System under consideration regardless of
`indication, dosage form, or dose level.
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`
`• Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as in the original submission.
`• Present tabulations of the new safety data combined with the original application
`data.
`Include tables that compare frequencies of adverse events in the original application
`with the retabulated frequencies described in the bullet above.
`• For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
`•
`
`Reference ID: 3996381
`Reference ID: 4409052
`
`

`

`NDA 208276
`Page 3
`
`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
`
` the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original application data.
`
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`7. Provide a summary of worldwide experience on the safety of the Remodulin Implantable
`System. Include an updated estimate of use for Remodulin marketed in other countries.
`
`8. Provide English translations of current approved foreign labeling not previously
`
`submitted.
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`
`request an extension of time in which to resubmit the application.
`
`A resubmission must fully address all the deficiencies listed in this letter and should be clearly
`marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter
`of the submission. The cover letter should clearly state that you consider this resubmission a
`complete response to the deficiencies outlined in this letter. A partial response to this letter will
`not be processed as a resubmission and will not start a new review cycle.
`
`You may request a meeting or teleconference with us to discuss what steps you need to take
`before the application may be approved. If you wish to have such a meeting, submit your
`meeting request as described in the FDA Guidance for Industry, “Formal Meetings Between
`FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
`
`Reference ID: 3996381
`Reference ID: 4409052
`
`

`

`NDA 208276
`Page 4
`
`If you have any questions, call Wayne Amchin, RAC, Regulatory Project Manager, at (301) 796-
`0421.
`
`Sincerely,
`
`{SeeRappendedRelectronicRsignatureRpage}
`
`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Reference ID: 3996381
`Reference ID: 4409052
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`WAYNE S AMCHIN
`10/07/2016
`
`NORMAN L STOCKBRIDGE
`10/08/2016
`
`Reference ID: 3996381
`Reference ID: 4409052
`
`(
`
`
`
`