CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`214324Orig1s000
`
`OTHER ACTION LETTERS
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`

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`NDA 214324
`
`United Therapeutics Corp.
`Attention: Sarah Gemberling, PhD, RAC
`Manager, Regulatory Affairs
`55 TW Alexander Drive, PO Box 14186
`Research Triangle Park, NC 27709
`
`Dear Dr. Gemberling:
`
`COMPLETE RESPONSE
`
`Please refer to your new drug application (NDA) dated April 16, 2021, received April 16,
`2021, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act for treprostinil inhalation powder.
`
`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.
`
`FACILITY INSPECTIONS
`
` for
`During a recent inspection of the
`this application, our field investigator conveyed deficiencies to the representative of the
`facility. As a result of this inspection, FDA has classified this facility as Official Action
`Indicated (OAI) on
` for drug CGMP. Satisfactory resolution of these
`deficiencies is required before this application may be approved.
`
`PRESCRIBING INFORMATION
`
`We acknowledge your email dated October 8, 2021 containing revised labeling. We
`reserve further comment on the proposed labeling until the application is otherwise
`adequate. We encourage you to review the labeling review resources on the
`Prescription Drug Labeling Resources1 and Pregnancy and Lactation Labeling Final
`Rule2 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
`
`1 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources
`2 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs-
`final-rule
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`Reference ID: 4873490
`
`(b) (4)
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`(b) (4)
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`NDA 214324
`Page 2
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`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)].
`
`CARTON AND CONTAINER LABELING
`
`We reserve further comment on the proposed labeling until the application is otherwise
`adequate.
`
`PROPRIETARY NAME
`
`Please refer to correspondence dated, June 17, 2021 which addresses the proposed
`proprietary name, Tyvaso DPI. 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 product 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.
`
`(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.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4873490
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`NDA 214324
`Page 3
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`(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).
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`(7) Provide a summary of worldwide experience on the safety of this product. Include
`an updated estimate of use for product marketed in other countries.
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`(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 draft guidance for industry Formal
`Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.
`
`The drug product may not be legally marketed until you have been notified in writing
`that this application is approved.
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`ADDITIONAL COMMENT
`
`On July 8, 2021, Lassman Law + Policy submitted a citizen petition to FDA (Docket No.
`FDA-2021-P-0714) regarding the approvability of NDA 214324 for Tyvaso DPI. The
`issues raised by this petition are currently under review by the Agency, and FDA has
`not made a final decision on the issues the petition raises. The deficiency comments
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4873490
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`

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`NDA 214324
`Page 4
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`included in this communication reflect only our current thinking, and this communication
`does not represent a final decision by the Agency on the issues raised in the pending
`citizen petition.
`
`If you have any questions, please call Brian Cooney, Regulatory Project Manager, at
`(301) 796-0886.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, MD, PhD
`Director
`Division of Cardiology and Nephrology
`Office of Cardiology, Hematology, Endocrinology,
`and Nephrology
`Office of New Drugs
`Center for Drug Evaluation and Research
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4873490
`
`

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`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
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`NORMAN L STOCKBRIDGE
`10/15/2021 05:02:13 PM
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`Reference ID: 4873490
`
`