CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`203794Orig1s000
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`MEDICAL REVIEW(S)
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`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
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`Office of Clinical Pharmacology
`New Drug Application Filing and Review Form
`General Information About the Submission
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`NDA/BLA Number
`OCP Division (I, II, III, IV, V)
`Medical Division
`OCP Reviewer
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`Information
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`203794
`II
`DAAAP
`David Lee, Ph.D.
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`Brand Name
`Generic Name
`Drug Class
`Indication(s)
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`OCP Team Leader
`Pharmacometrics Reviewer
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`Yun Xu, Ph.D.
`-
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`Dosage Form
`Dosing Regimen
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`Date of Submission
`Estimated Due Date of OCP Review
`Medical Division Due Date
`PDUFA Due Date
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`Dec 15, 2011
`Sept 15, 2012
`Sept 15, 2012
`Oct 15, 2012
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`Route of Administration
`Sponsor
`Priority Classification
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`
`Information
`Nucynta Oral Solution
`Tapentadol Oral Solution
`Pain
`For the management of
`moderate to severe acute
`pain in patients 18 years
`of age or older
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`Solution 20 mg/mL
`50 mg, 75 mg, or 100 mg
`Q4 - 6 h depending upon
`pain intensity. On the first
`day of dosing, the second
`dose may be administered
`as soon as one hour after
`the first dose, if adequate
`pain relief is not attained
`with the first dose.
`Subsequent dosing is 50
`mg, 75 mg, or 100 mg Q 4
`- 6 h and should be
`adjusted to maintain
`adequate analgesia with
`acceptable tolerability.
`Daily doses greater than
`700 mg on the first day of
`therapy and 600 mg on
`subsequent days have not
`been studied and are,
`therefore, not
`recommended.
`Oral
`Janssen
`Standard
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`Clin. Pharm. and Biopharm. Information
`“X” if included
`Number of
`Number of
`at filing
`studies
`studies
`submitted
`reviewed
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`Critical Comments If any
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`STUDY TYPE
`Table of Contents present and sufficient to
`locate reports, tables, data, etc.
`Tabular Listing of All Human Studies
`HPK Summary
`Labeling
`Reference Bioanalytical and Analytical
`Methods
`I. Clinical Pharmacology
` Mass balance:
` Isozyme characterization:
` Blood/plasma ratio:
` Plasma protein binding:
` Pharmacokinetics (e.g., Phase I) -
`Healthy Volunteers-
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`Patients-
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`single dose:
`multiple dose:
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`single dose:
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`Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for NDA_BLA or Supplement
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`Reference ID: 3093044
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`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
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`Comment
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`Biowaiver is granted for this product.
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`multiple dose:
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` Dose proportionality -
`fasting / non-fasting single dose:
`fasting / non-fasting multiple dose:
` Drug-drug interaction studies -
`In-vivo effects on primary drug:
`In-vivo effects of primary drug:
`In-vitro:
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` Subpopulation studies -
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`ethnicity:
`gender:
`pediatrics:
`geriatrics:
`renal impairment:
`hepatic impairment:
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`Phase 2:
`Phase 3:
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` PD -
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` PK/PD -
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`Phase 1 and/or 2, proof of concept:
`Phase 3 clinical trial:
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` Population Analyses -
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`Data rich:
`Data sparse:
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`II. Biopharmaceutics
` Absolute bioavailability
` Relative bioavailability -
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`solution as reference:
`alternate formulation as reference:
` Bioequivalence studies -
`traditional design; single / multi dose:
`replicate design; single / multi dose:
` Food-drug interaction studies
` Bio-waiver request based on BCS
` BCS class
` Dissolution study to evaluate alcohol induced
` dose-dumping
`III. Other CPB Studies
` Genotype/phenotype studies
` Chronopharmacokinetics
` Pediatric development plan
` Literature References
`Total Number of Studies
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`On initial review of the NDA/BLA application for filing:
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`Content Parameter
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`Criteria for Refusal to File (RTF)
`1 Has the applicant submitted bioequivalence
`data comparing to-be-marketed product(s)
`and those used in the pivotal clinical trials?
`2 Has the applicant provided metabolism and
`drug-drug interaction information?
`3 Has the sponsor submitted bioavailability
`data satisfying the CFR requirements?
`4 Did the sponsor submit data to allow the
`evaluation of the validity of the analytical
`assay?
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`Yes No N/A
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`x
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`Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for NDA_BLA or Supplement
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`Reference ID: 3093044
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`

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`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
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`6
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`5 Has a rationale for dose selection been
`submitted?
`Is the clinical pharmacology and
`biopharmaceutics section of the NDA
`organized, indexed and paginated in a
`manner to allow substantive review to
`begin?
`Is the clinical pharmacology and
`biopharmaceutics section of the NDA
`legible so that a substantive review can
`begin?
`Is the electronic submission searchable,
`does it have appropriate hyperlinks and do
`the hyperlinks work?
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`Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality)
` Data
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`9 Are the data sets, as requested during pre-
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`submission discussions, submitted in the
`appropriate format (e.g., CDISC)?
`If applicable, are the pharmacogenomic data
`sets submitted in the appropriate format?
` Studies and Analyses
`11
`Is the appropriate pharmacokinetic
`information submitted?
`12 Has the applicant made an appropriate
`attempt to determine reasonable dose
`individualization strategies for this product
`(i.e., appropriately designed and analyzed
`dose-ranging or pivotal studies)?
`13 Are the appropriate exposure-response (for
`desired and undesired effects) analyses
`conducted and submitted as described in the
`Exposure-Response guidance?
`Is there an adequate attempt by the applicant
`to use exposure-response relationships in
`order to assess the need for dose
`adjustments for intrinsic/extrinsic factors
`that might affect the pharmacokinetic or
`pharmacodynamics?
`15 Are the pediatric exclusivity studies
`adequately designed to demonstrate
`effectiveness, if the drug is indeed
`effective?
`16 Did the applicant submit all the pediatric
`exclusivity data, as described in the WR?
`Is there adequate information on the
`pharmacokinetics and exposure-response in
`the clinical pharmacology section of the
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`Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for NDA_BLA or Supplement
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`Reference ID: 3093044
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`

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`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
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`x
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`label?
` General
`18 Are the clinical pharmacology and
`biopharmaceutics studies of appropriate
`design and breadth of investigation to meet
`basic requirements for approvability of this
`product?
`19 Was the translation (of study reports or
`other study information) from another
`language needed and provided in this
`submission?
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`IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION FILEABLE?
`_____yes___
`
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`If the NDA/BLA is not fileable from the clinical pharmacology perspective, state the reasons and
`provide comments to be sent to the Applicant.
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`
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`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter.
`
`Reviewing Clinical Pharmacologist
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`Team Leader/Supervisor
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`Janssen Research & Development, LLC, submitted a New Drug Application (NDA) for
`Nucynta® (tapentadol) Oral Solution, on behalf of Janssen Pharmaceuticals, Inc., in accordance
`with Section 505(b) of the Federal Food, Drugs, and Cosmetic Act. The indication for this
`NDA is for the management of moderate to severe acute pain, as in the approved NDA 22304 for
`Nucynta® (tapentadol) immediate-release tablets by the same Sponsor. A reference is made to
`NDA 22304 for Clinical, Nonclinical, Toxicology, and Pharmacology information.
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`No clinical studies were provided with this Application, due to the fact that a biowaiver was
`requested and granted by the Agency on 6/29/09. In spite the fact that biowaiver being granted the
`Applicant has submitted Study HP5503/59, titled, “A relative bioavailability trial to compare a new
`tapentadol oral solution 100 mg with the tapentadol immediate release 100 mg tablet,” on 2/7/12.
`According to the Applicant, Study 5503/59 utilized the same tapentadol solution formulation that is
`the subject to this NDA approval.
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`In the memo dated February 24, 2012 by Dr. Christine Moore, Acting Office Director of ONDQA,
`the suitability of a biowaiver for NDA 203794 Nucynta Oral Solution relative to the immediate
`release tablet is discussed. It is stated that “Based on the information reviewed, I deem that the
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`Date
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`Date
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`Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for NDA_BLA or Supplement
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`Reference ID: 3093044
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`

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`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
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`biowaiver granted by ONDQA for IND 61,345 on 6/29/09 is valid for NDA 203794”. Since the
`Agency granted the biowaiver of the proposed tapentadol solution and it is deemed valid, this
`application may be approved based on the biowaiver grant without additional clinical or clinical
`pharmacology studies. Therefore, the submitted study report HP5503/59 will be considered as non-
`pivotal information and no OSI inspection will be requested for this study.
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`From a clinical pharmacology perspective, the application is recommended for filing. We will
`request the Sponsor to submit the following information for completeness of the submission:
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`1. Regarding study HP5503/59, confirm that:
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`a. Tapentadol oral solution used in the study is the to-be-marketed formulation; and
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`b. FDA-approved Nucynta (tapentadol) immediate-release tablet was the
`immediate-release tablet formulation used as reference.
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`2. In addition to submitted Bioanalytical Analyses Study SBA_S_09040 (i.e., study
`PK1210A), and in order to have complete information concerning bioanalytical
`analyses, submit the following reports:
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`a. PK1134, “Complete Validation of an LC-MS/MS method for the determination
`of R331333 and R403347 in human serum,” December 2007, including also
`Amendment 1 to study report PK1134, January 2009, containing long-term (24
`months) stability data at -25°C
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`b. PK1070 (SBA_S_07093), “Partial validation of a method for the determination
`of CG5503 free base and its metabolite CG5503 glucuronide (GRTE1472) in
`human serum by LC-MS/MS,” including also Amendment 1 to report
`SBA_S_07093, 2008, containing freeze/thaw stability data (-25°C/room
`temperature) and short-term (72 hours) stability data at room temperature
` respectively); and
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`c. PK711 (SBA_S_04004), “Stability of CG5503, CG5503 glucuronide
`(GRTE1472), and CG5503 sulfate (GRT3793H) in human blood and human
`serum - investigation by LC-MS/MS,” October 2007, containing post-preparative
`stability data, 192 hours at 8°C (conditions during autosampling)
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`Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for NDA_BLA or Supplement
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`Reference ID: 3093044
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`(b) (4)
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`(b) (4)
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`(b) (4)
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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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`DAVID J LEE
`02/27/2012
`
`YUN XU
`02/27/2012
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`Reference ID: 3093044
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`