CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205103Orig1s000
`
`OTHER ACTION LETTERS
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 205103
`
`POZEN Inc.
`Attention: Paul Ossi
`Senior Vice President, Regulatory Affairs
`1414 Raleigh Road, Suite 400
`Chapel Hill, NC 27517
`
`Dear Mr. Ossi:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`COMPLETE RESPONSE
`
`Please refer to your New Drug Application (NDA) dated and received March 25, 2013,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA),
`for Yosprala (aspirin and omeprazole) delayed-release tablets, 81 mg/40 mg and 325 mg/40 mg.
`
`We acknowledge receipt of your amendments dated March 27, 2013, April 30, 2013, May 21,
`2013, June 5, 2013, June 13, 2013, June 14, 2013, June 18, 2013, July 16, 2013, July 17, 2013,
`July 24, 2013, July 29, 2013, July 31, 2013, August 1, 2013, September 4, 2013, September 20,
`2013, October 4, 2013, October 21, 2013, November 1, 2013, November 6, 2013, November 14,
`2013, November 25, 2013, November 26, 2013, November 27, 2013, December 11, 2013,
`December 18, 2013, January 8, 2014, January 23, 2014, February 12, 2014, February 28, 2014,
`March 24, 2014, March 26, 2014, April 3, 2014, April 4, 2014, April 16, 2014, June 30, 2014,
`July 21, 2014, July 28, 2014, October 17, 2014, October 31, 2014 and December 3, 2014.
`
`The June 30, 2014, submission constituted a complete response to our April 25, 2014, 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.
`
`FACILITY INSPECTIONS
`
`manufacturing facility for this
`1. During a recent inspection of the
`application, our field investigator conveyed deficiencies to the representative of the
`facility. Satisfactory resolution of these deficiencies is required before this application
`may be approved.
`
`PRESCRIBING INFORMATION
`
`2. We reserve comment on the proposed labeling until the application is otherwise adequate.
`We encourage you to review the labeling review resources on the PLR Requirements for
`
`Reference ID: 3673471
`
`(b) (4)
`
`

`

`NDA 205103
`Page 2
`
`Prescribing Information website, including regulations and related guidance documents
`and the Selected Requirements for Prescribing Information (SRPI) − a checklist of 42
`important format items from labeling regulations and guidances.
`
`If you revise labeling, use the SRPI checklist to ensure that the PI 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
`
`Please refer to correspondence dated, October 3, 2014, which addresses the proposed proprietary
`name, Yosprala. 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 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 the original NDA submission.
` Present tabulations of the new safety data combined with the original NDA data.
`Include tables that compare frequencies of adverse events in the original NDA 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.
`
`Reference ID: 3673471
`
`

`

`NDA 205103
`Page 3
`
`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 NDA 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. Include an
`updated estimate of use for drug 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. A partial response to this letter will not be processed as a
`resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference 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 the 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.
`
`If you have any questions, call CDR Stacy Barley, Senior Regulatory Project Manager, at (301)
`796-2137.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Donna Griebel, M.D.
`Director
`Division of Gastroenterology and Inborn Errors
`Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`Reference ID: 3673471
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DONNA J GRIEBEL
`12/16/2014
`
`Reference ID: 3673471
`
`

`

`
`
`
`
`NDA 205103
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`COMPLETE RESPONSE
`
`
`POZEN Inc.
`Attention: Paul Ossi
`Senior Vice President, Regulatory Affairs
`1414 Raleigh Road, Suite 400
`Chapel Hill, NC 27517
`
`Dear Mr. Ossi:
`
`Please refer to your New Drug Application (NDA) dated and received March 25, 2013,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Yosprala (aspirin and omeprazole) delayed-release tablets, 81 mg/40 mg and 325 mg/40 mg.
`
`We acknowledge receipt of your amendment(s) dated March 27, 2013, April 30, 2013, May 21,
`2013, June 5, 2013, June 13, 2013, June 14, 2013, June 18, 2013, July 16, 2013, July 17, 2013,
`July 24, 2013, July 29, 2013, July 31, 2013, August 1, 2013, September 4, 2013, September 20,
`2013, October 4, 2013, October 21, 2013, November 1, 2013, November 6, 2013, November 14,
`2013, November 25, 2013, November 27, 2013, December 11, 2013, December 18, 2013,
`January 8, 2014, January 23, 2014, February 12, 2014, February 28, 2014, March 24, 2014,
`March 26, 2014, April 3, 2014, April 4, 2014, and April 16, 2014.
`
`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
`
`
` manufacturing facility for this
`1. During a recent inspection of the
`application, the field investigator conveyed deficiencies to the representative of the
`facility. Satisfactory resolution of these deficiencies is required before this application
`may be approved.
`
`
`LABELING
`
`
`2. At the time of completion of this review, agreement had not been reached on final
`labeling. To address this deficiency, submit draft labeling that incorporates revisions in
`the attached labeling. In addition, submit 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.
`
`
`Reference ID: 3496230
`
`(b) (4)
`
`

`

`NDA 205103
`Page 2
`
`
`
`Please note that additional labeling revisions may become necessary after the resubmitted
`label has been reviewed. 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.
`
`Please submit draft carton and container labeling. Add the following bolded statement or
`appropriate alternative to the carton and container labels per 21 CFR 208.24(d):
`"ATTENTION PHARMACIST: Each patient is required to receive the enclosed
`Medication Guide."
`
`
`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 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 the original NDA submission.
`• Present tabulations of the new safety data combined with the original NDA data.
`Include tables that compare frequencies of adverse events in the original NDA 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 NDA data.
`
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3496230
`
`

`

`NDA 205103
`Page 3
`
`
`
`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug 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. A partial response to this letter will not be processed as a
`resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference 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 the 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.
`
`If you have any questions, call CDR Stacy Barley, Senior Regulatory Project Manager, at (301)
`796-2137.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Donna Griebel, M.D.
`Director
`Division of Gastroenterology and Inborn Errors
`Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`Labeling
`
`
`
`Reference ID: 3496230
`
`46 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DONNA J GRIEBEL
`04/25/2014
`
`Reference ID: 3496230
`
`