CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`200533Orig1s000
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`OTHER ACTION LETTER(s)
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring, MD 20993
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`NDA 200533
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`COMPLETE RESPONSE
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`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`c/o Johnson & Johnson Pharmaceutical
` Research & Development, L.L.C.
`1125 Trenton-Harbourton Road, P.O. Box 200
`Titusville, NJ 08560
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`Attention: Kathleen F. Dusek, R.Ph., RAC
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`Associate Director, Regulatory Affairs
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`Dear Ms. Dusek:
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`Please refer to your New Drug Application (NDA) dated November 30, 2009, received
`December 1, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`for Nucynta ER (tapentadol) Extended-Release Tablets 50, 100, 150, 200, and 250 mg.
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`We acknowledge receipt of your amendments dated December 11, 2009, and March 11, 12, 25,
`and 30, April 2, 21, 26(2), and 30, May 13 and 21, June 4 and 21, July 23, and August 5 and 19,
`2010.
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`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.
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`PRODUCT QUALITY/BIOPHARMACEUTICS
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`1. Your proposed in vitro in vivo correlation (IVIVC) models do not support the bridging of
`the clinical study batches (PR2) to the to-be-marketed tamper resistant formulation (TBM
`TRF).
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`2. The re-constructed IVIVC models using individual plasma concentrations are not
`acceptable for the following reasons:
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`• The models submitted on July 23, 2010, still include a mathematical term that has no
`mechanistic foundation and, therefore, are not acceptable.
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` The models using the individual subject concentrations failed the external validation,
`indicating a lack of robustness.
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` •
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`NDA 200533
`Page 2
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`3. The proposed dissolution acceptance criteria for TBM TRF tapentadol ER tablets were
`based on the proposed IVIVC models. Because these models were not accepted, these
`dissolution acceptance criteria will need to be revised. You may refer to our advice letter
`dated August 12, 2010, for additional guidance concerning these acceptance criteria.
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`4. Given that your proposed IVIVC models do not support the bridging of the clinical study
`batches to the TBM TRF, bioequivalence has not been demonstrated. Provide in vivo
`bioequivalence (BE) data comparing the PR2 and TBM TRF formulations. Because the
`compositions of your formulations are not proportional, you should provide
`bioequivalence (BE) data for the lowest, 50 mg, and highest, 250 mg, strengths. You
`may request a biowaiver for the intermediate strengths. The biowaiver request should be
`supported with: 1) acceptable in vivo BE data for the lowest and highest strengths and 2)
`in vitro comparative dissolution profile data and similar f2 values (using the highest and
`lowest strengths as references).
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`CLINICAL
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`5. For Protocols KF5503/23 and KF5503/36, data pertaining to subject eligibility, primary
`endpoint, and rescue medication use were directly submitted by subjects via eDiaries to
`eTrials, the contract research organization (CRO) responsible for this electronic data
`capture. Because the clinical investigator sites did not maintain independent source
`documentation of the data that were transmitted directly to eTrials via eDiaries,
`verification of source data at the CRO, in conjunction with evaluation of findings from
`other completed inspections, is required before this application may be approved.
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`LABELING
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`6. We reserve comment on the proposed labeling until the application is otherwise adequate.
`If you revise labeling, 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.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`As described in our letter dated April 22, 2010, in accordance with section 505-1 of the FDCA,
`we have determined that a risk evaluation and mitigation strategy (REMS) is necessary for
`Nucynta ER to ensure that the benefits of the drug outweigh the risks of abuse, misuse, and
`overdose.
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`We acknowledge the submission of your proposed REMS on November 30, 2009, and revised
`proposed REMS on June 21, 2010, which contains a Medication Guide, elements to assure safe
`use, and a timetable for submission of assessments of the REMS.
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`We have determined that your proposed REMS does not adequately communicate the risks of
`abuse, misuse, and overdose. Because your application cannot be approved without an approved
`REMS, you must revise your proposed REMS and submit it as part of your response to the
`deficiencies cited in this letter and in our September 21, 2010 information request letter
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`NDA 200533
`Page 3
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`concerning your REMS. We will continue review and discussion of your proposed REMS after
`your complete response to this action letter has been submitted.
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`SAFETY UPDATE
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`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.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`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.
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`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.
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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.
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`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.
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`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 drug. Include an
`updated estimate of use for drug marketed in other countries.
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`8. Provide English translations of current approved foreign labeling not previously
`submitted.
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`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
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`NDA 200533
`Page 4
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`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.
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`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’s “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.
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`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
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`If you have any questions, call Dominic Chiapperino, Regulatory Project Manager, at (301) 796-
`1183.
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`Sincerely,
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`{See appended electronic signature page}
`
`Rigoberto Roca, M.D.
`Deputy Director
`Division of Anesthesia and Analgesia Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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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/
`----------------------------------------------------
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`RIGOBERTO A ROCA
`10/01/2010
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`Reference ID: 2844428
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