CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-3 04
`
`MEDICAL REVIEW! S)
`
`

`

`h FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANALGESIA, ANESTHESIA, AND RHEUMATOLOGY PRODUCTS
`10903 NEW HAMPSHIRE AVENUE, BLDG 22, SILVER SPRING, MARYLAND 20993
`
`
`Memorandum: Labeling Addendum
`
`
`DATE:
`
`RE:
`
`November 20, 2008
`
`Labeling addendum
`
`NDA:
`
`22-3 04
`
`Tapentadol
`THROUGH: Sharon Hertz, M.D., Deputy Directory, DAARP
`
`FROMi
`
`Robert Shibuya, M.D., Medical Team Leader, DAARP
`Ellen Fields, M.D., MPH, Medical Team Leader, DAARP
`
`This memorandum will summarize the resolution of three labeling issues for NDA 22-
`304, tapentadol tablets.
`
`l. Serotonin syndrome
`The clinical trial database was searched for the term “serotonin syndrome” and
`sign/symptom complexes suspicious for serotonin syndrome, and no cases were
`identified. The pharmacology of tapentadol reflects primarily selective
`norephinephrine reuptake inhibition and mu opioid agonism, however there is
`serotonin reuptake inhibition as well, albeit to a lesser extent. Taken in concert
`with the potential level of morbidity and mortality associated with serotonin
`syndrome, we felt that appropriate language regarding serotonin syndrome should
`be placed into the Warnings and Precautions section of the labeling.
`
`Contraindication for concomitant use of monoamine oxidase inhibitors
`
`Although patients receiving MAOIs were not included in the clinical trials of
`tapentadol, because of the pharmacology of tapentadol and the applicant’s
`concerns about this risk, this contraindication was included in the product
`labeling.
`'
`'
`
`

`

`3. Medication Guide
`
`»
`
`In their review of the abuse liability data, the Controlled Substance Staff noted
`that studies with tapentadol had findings consistent with a very high abuse
`liability (similar to hydromorphone). Despite the fact that tapentadol is likely to
`be classified in Schedule II by the Drug Enforcement Administration, additional
`patient education is considered prudent and necessary to mitigate abuse. Hence, a
`Medication Guide (and subsequently a REMS) has been added to the labeling for
`tapentadol.
`.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`
`
`
`
`his is a representation of an electronic record that was signed electronically and.
`this page is the manifestation of the electronic signature.
`
`
`
`
`Robert Shibuya
`11/20/2008 01:36:24 PM
`MEDICAL OFFICER
`
`Ellen Fields
`11/20/2008 05:25:20 PM
`MEDICAL OFFICER
`
`Ellen Fields
`11/20/2008 05:25:47 PM
`MEDICAL OFFICER
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`‘
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Anesthesia, Analgesia and Rheumatology
`Products, HFD-170
`10903 New Hampshire Avenue, Silver spring, MD 20993
`
`Medical Officer Review
`
`Date of Submission:
`Type of Submission:
`
`Product:
`
`Sponsor:
`
`Review Date:
`
`PDUFA Date:
`
`Reviewer:
`
`January 23, 2008
`New Drug Application
`
`Tapentadol TM
`
`Johnson & Johnson
`
`September 18, 2008
`
`November 23, 2008
`
`Ellen W. Fields, M.D., M.P.H.
`Clinical Team Leader
`
`Project Manager:
`
`Matthew Sullivan
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Table of Contents
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`-
`
`4
`............................
`................
`1. RECOMMENDATIONS/RISK BENEFIT ANALYSIS
`l
`1 .1
`RECOMMENDATION ON REGULATORY ACTION ............................................................................ 4
`RISK BENEFIT ANALYSIS..................................................................................... 4
`1.2
`
`RECOMMENDATIONS FOR POSTMARKETING RISK MANAGEMENT ACTIVITIES
`1.3
`.. .. 5
`1.4
`RECOMMENDATION FOR OTHER POSTMARKETING STUDY COMMITMENTS .................................. 6
`2. INTRODUCTION AND REGULATORY BACKGROUND ..........
`.............................................. 6
`2.]
`PRODUCT INFORMATION .............................................................................................................. 6
`2.2
`TABLE(S) 0F CURRENTLY AVAILABLE TREATMENT(S) FOR PROPOSED INDICATION(S) ............... 7
`2.3
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ................................. 7
`IMPORTANT ISSUES WITH CONSIDERATION To RELATED DRUGS ......................................
`... 7
`2.4
`
`
`2.5
`SUMMARY OF PRESUBMISSION REGULATORY ACTIVITY RELATED To THIS SUBMISSION ..
`3
`OTHER RELEVANT BACKGROUND INFORMATION.................................................................... 10
`2.6
`
`............................
`3. ETHICS AND GOOD CLINICAL PRACTICES ..............
`10
`3 .1
`SUBMISSION QUALITY AND INTEGRITY ....................................................................................... 10
`3.2
`COMPLIANCE WITH GOOD CLINICAL PRACTICES ...................................... 10
`3.3
`FINANCIAL DISCLOSURES .......................................................................................................... 12
`4 SIGNIFICANT EFFICACY OR SAFETY FINDINGS RELATED TO OTHER REVIEW
`DISCIPLINES
`.............
`.......................
`......
`.......................................................
`................ 12
`4.1 CHEMISTRY MANUFACTURING AND CONTROLS ................................................................................. 12
`4.2 CLINICAL MICROBIOLOGY (IF APPLICABLE) ..................................... 13
`
`4.3 PRECLINICAL PHARMACOLOGY/TOXICOLOGY ............................................... 13
`
`
`4.4 CLINICAL PHARMACOLOGY .........................................
`13
`4.4.] Mechanism of Action .....
`13
`
`.....................
`4.4.2
`Pharmacodynamics
`13
`
`
`Pharmacokinetics ........................................................................................................... 14
`4.4.3
`SOURCES OF CLINICAL DATA AND REVIEW STRATEGY...”
`..........................
`15
`
`5.1
`TABLES OF CLINICAL STUDIES ................................................................................. 15
`
`
`5.2
`REVIEW STRATEGY .......................
`17
`5.3 DISCUSSION OF INDIVIDUAL STUDIES ................................................................................................. 17
`INTEGRATED REVIEW OF EFFICACY ..........................
`........................ 68
`SUMMARY OF EFFICACY RESULTS AND CONCLUSIONS ............................................................................ 68
`6.1 PROPOSED INDICATION ................................................
`‘
`......................... 72
`
`6.2 METHODS/STUDY DESIGN
`............................................................ 72
`
`
`6.3 DEMOGRAPHICS .............................................................. 73
`
`6.4 PATIENT DISPOSITION ....................................
`73
`....................
`6.5 ANALYSIS OF THE PRIMARY ENDPOINT(s).....
`73
`
`6.6 SECONDARY ENDPOINT(S) .....................................................................~...... 76
`6.7 SUBPOFULATIONS ..........................................................,.................................................. 77
`6.8 ANALYSIS OF CLINICAL INFORMATION RELEVANT To DOSING RECOMMENDATIONS ......................... 78
`6.9 DISCUSSION OF PERSISTENCE OF EFFICACY AND/OR TOLERANCE EFFECTS .......................... 79
`
`6.10 ADDITIONAL EFFICACYISSUES/ANALYSES
`.................. 82
`7 INTEGRATED REVIEW OF SAFETY
`....................................................................... 83
`SUMMARY OF SAFETY RESULTS AND CONCLUSIONS ................................................................................ 83
`METHODS ................................................................................. 88
`7.1
`
`............................................. 88
`7.1.1 Discussion of Clinical Studies Used to Evaluate Safety
`7.l.2
`Adequacy of Data ................................................................................................................. 91
`7.1.3 Pooling Data Across Studies to Estimate and Compare Incidence. ........................................... 91
`
`5
`
`6.
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`'
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`7.2
`7.2.1
`
`............................... 91
`ADEQUACY OF SAFETY ASSESSMENTS
`Overall Exposure at Appropriate Doses/Durations‘ and Demographics of Target Populations
`91
`
`Explorations for Dose Response........................................................................................... 97
`7.2.2
`
`Special Animal and/or In Vitro Testing...
`..... 97
`7.2.3
`Routine Clinical Testing ........................................................................... 97
`7.2.4
`7.2.5 Metabolic, Clearance, and Interaction Workup
`.................................................. 97
`
`7.2.6
`Evaluation for Potential Adverse Events for Similar Drugs in Drug Class
`..... 97
`MAJOR SAFETY RESULTS AND DISCUSSION ......-....................................................... 98
`
`Deaths ...............................................................'. ............................ 98
`
`Nonfatal Serious Adverse Events .................................................. 99
`Significant Adverse Events..............................
`1 14
`
`7.4
`............................... I 14
`SUPPORTIVE SAFETY RESULTS AND DISCUSSION ..
`
`7.4.1
`Common Adverse Events ............................................................... 114
`
`7.4.2
`Laboratory Findings ................................ 123
`
`7.4.4
`...... 132
`Electrocardiograms (ECGs)....
`
`7.4.5
`Special Safety Studies ............................................................. 136
`
`7.4.6 Immunogenicity ............................................................................ 137
`
`OTHER SAFETY EXPLORATIONS .....................
`137
`
`Dose Dependency for Adverse Findings .................................. 137
`
`Drug-Demographic Interactions (gender, race) ........................... 138
`
`Drug Disease Interactions ....................................
`'
`140
`
`Drug-Drug Interactions .......
`144
`
`SMQs ..................................................................................................... 147
`
`ADDITIONAL SAFETY EVALUATIONS .......................................................................... 15 l
`Human Reproduction and Pregnancy Data ........................... 151
`
`Pediatrics and Assessment and/or Effects on Growth ................. 152
`
`Overdose, Drug Abuse Potential/ Withdrawal and Rebound...
`...... 152
`
`ADDITIONAL SUBMISSIONS .........
`155
`
`....................
`........................................ 155
`
`7.3
`
`7.3.1
`7.3.2
`7.3.4
`
`7.5
`
`7.5.1
`7.5.2
`7.5.3
`7.5.4
`7.5.5
`
`7.6
`7.6.1
`7.6.2
`7.6.3
`
`7.7
`
`8.
`
`9..
`
`POSTMARKETING EXPERIENCE.........
`
`APPENDICES ......
`
`...............................................
`
`..................................................... 155
`
`9.1 LITERATURE REVIEW AND OTHER IMPORTANT RELEVANT MATERIALS/REFERENCES ...................... 155
`
`LABELING RECOMMENDATIONS ............................................................
`.
`...... 155
`9.2
`
`9.3
`ADVISORY COMMITTEE MEETING ............................................
`156
`9.4 ADDITIONAL TABLES ........................................................................................................................ 156
`
`

`

`:
`Nfi‘A 22-364
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`‘
`
`1. RECOMMENDATIONS/RISK BENEFIT ANALYSIS
`
`Recommendation on Regulatory Action
`1.1
`I recommend approval for tapentadol HCL IR for the management of acute moderate-to-
`severe pain in adults. Efficacy was demonstrated at doses of 50mg, 75mg, and 100mg,
`using a dosing interval of every 4 to 6 hours in two adequate and well-controlled clinical
`trials.
`_ These trials examined subjects with moderate-to-severe pain following a
`bunionectomy or due to end-stage degenerative joint disease. Efficacy was supported by
`the improvement of pain compared to placebo across several standard pain assessments
`and by using different imputation methods.
`
`The safety profile oftapentadol HCL IR was demonstrated in over 3500 treated subjects.
`The adverse event profile appeared acceptable across the intended marketed dosage range
`in both inpatients and outpatients. The profile of adverse events is consistent with a
`centrally acting compound with mu-opioid agonist activity.
`
`The dosing recommendations are acceptable based on data from Phase 2 and 3 studies.
`No dosing adjustments are recommended for the elderly, or patients with hepatic or renal
`impairment; however tapentadol IR is not recommended for patients with severe renal or
`hepatic impairment. Details regarding dosing are located in Section 4.4.
`
`F
`
`l3(4)
`
`,J
`
`1.2
`Risk Benefit Analysis
`The efficacy of tapentadol IR was demonstrated at doses of 50mg, 75mg, and 100mg,
`using a dosing interval of every 4 to 6 hours in two adequate and well-controlled clinical
`trials. These trials were carried out in two distinct patient populations; an inpatient post-
`operative population who experienced moderate-to-severe acute pain following
`bunionectomy procedures, and an outpatient population with end-stage osteoarthritis of
`the hip or knee (awaiting joint replacement) who also had moderate-to severe pain,
`although chronic in nature.
`
`The endpoints for both studies were based on the summed pain intensity difference
`'(SPID) from baseline to endpoint, 48 hours in the bunionectomy study and .5 days in the
`OA study. SPIDs are used frequently and are acceptable for the analysis of analgesic
`efficacy for acute pain. The analyses showed significance at the p<.0.001 level for the
`two studies using imputation methods that included last observation carried forward
`(LOCF), baseline observation carried forward (BOCF), and worst observation carried
`forward (WOCF).
`
`there was a trend of increasing efficacy with increasing
`In the bunionectomy study,
`tapentadol dose (50mg, 75mg, 100mg).
`In addition, between 65% and 79% of the
`
`

`

`_ NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`september 18, 2009
`
`‘
`
`tapentadol-treated subjects experienCed at least a 30%improvement in pain intensity at
`48 hours compared to 40% of the placebo treated patients, which further supports the
`finding of efficacy.
`In the 0A study, there was not a dose related increase in efficacy
`fiom 50mg to 75mg. The proportion of subjects who showed at least 30% improvement
`in pain intensity at Day 5 was 30% in the placebo group, and 43% and 41% in the
`tapentadol IR 50 mg and 75 mg groups, respectively. The subjects in the 0A study had a
`high rate of concomitant non-opioid analgesic use, which may have affected the results of
`the study and the less impressive treatment effect. Nonetheless, tapentadol was found to
`be efficacious in both populations.
`
`In terms of safety, the premarketing exposure to tapentadol IR (>3500 subjects) appears
`adequate. There were no deaths attributable to tapentadol IR, and no unexpected or
`unusual adverse events of interest.
`
`Tapentadol IR was found to have a safety profile very similar to that of other immediate-
`release opioid analgesics and tramadol to which it tapentadol
`is structually related.
`Common adverse events included nausea, dizziness, vomiting, sorrmolence, headache,
`constipation, pruritis, and asthenic conditions. As expected, the incidence of treatment
`emergent adverse events appeared to be dose-related.
`There were no important
`laboratory or ECG related adverse events, and the only vital sign seemingly affected by
`tapentadol was oxygen saturation as measured by pulse oximetry. A thorough QT study
`was negative.
`
`In a Phase 1 study, tapentadol IR was found to have an abuse liability similar to
`hydromorphone.
`In addition, when subjects in a Phase 3 study abruptly discontinued
`treatment with tapentadol IR, 17% experienced at least onewithdrawal symptom, and 1%
`experienced a withdrawal syndrome. There were no reports of overdose during the
`development program.
`'
`
`The risk/benefit analysis for tapentadol IR is similar to that ofother opioid analgesics and
`Tramadol. Tapentadol IR appears to be effective in the treatment of acute moderate-to—
`severe pain as studied in two distinct populations. Given its safety profile, the risks of
`tapentadol IR appear manageable by standard pharmacovigilance approaches and the
`proposed DEA Schedule II status.
`
`As there were no issues identified related to CMC, Pharmacology/toxicology, or
`Biopharmaceutics that would affect the approvability of tapentadol, and given the clinical
`risk/benefit analysis, I recommend approval for tapentadol
`IR for the treatment of
`moderate-to-severe acute pain.
`
`Recommendations for Postmarketing Risk Management Activities
`1.3
`A “Tapentadol IR Safety Surveillance Plan” was submitted by the Applicant with this
`NDA, which was reviewed by the Division of Drug Risk Management (DRISK, June 26,
`2008).
`‘
`
`-
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review _
`The Applicant identified important and potential risks associated with tapentadol IR as
`follows:
`'
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`‘
`
`'
`
`Table 1: Summary of Safety Concerns
`Safety Concerns
`Important identified risks:
`. Potential for abuse
`Seizure
`Important potential risks:
`Overdose
`,
`Off-label use, incl. pediatric patients ‘
`Potential for medication errors (inappropriate
`prescribing, inappropriate dosing, inappropriate
`use) and patient misuse
`Accidental exposure
`Diversion
`Important missing information:
`Use in pediatrics
`Source: Tapentadol IR Safety Surveillance Plan
`
`A plan was proposed that will include routine and product specific pharmacovigilance.
`
`The Division agrees with DRISK’s review of the plan. The risks associated with the use
`of tapentadol HCL IR are similar to the risks of other immediate-release opiate products
`indicated for the treatment of pain with potency similar to morphine IR and oxycodone
`IR. It is appropriate to manage the risks of tapentadol HCL IR with labeling and routine
`pharmacovigilance. At this time, the establishment of a risk evaluation and mitigation
`strategy (REMS) for this product is not recommended.
`
`1.4
`
`Recommendation for other Postmarketing Study Commitments
`
`In order to comply with Pediatric Research Equity Act of 2007 (PREA), the Applicant
`submitted a Pediatric Plan and staged deferral request with this NDA. They propose to
`begin clinical studies in the oldest age group C
`’
`jyears of age)
`approximatelyC
`jollowing approval of the adult indications in acute pain, to take
`advantage of available safety information from both the preclinical juvenile program and
`the adult postmarketing database. Trials will be conducted in a step-wise manner to
`gather adequate pharmacokinetic, safety and efficacy information in the older children
`before exposing younger age groups. This staged deferral proposal will expose the
`minimum number of children and will allow the ability to perform the necessary clinical
`studies that will support information on closing tapentadol in the pediatric population.
`
`The Pediatric Plan and deferral request will be reviewed by PERC on October 8, 2008.
`
`No additional postmarketing study commitments are recommended at this time.
`
`2. INTRODUCTION AND REGULATORY BACKGROUND
`
`2.1
`
`Product Information
`
`Tapentadol HCl is a novel centrally-active antinociceptive agent being developed in an
`immediate-release (IR) tablet formulation for the relief of moderate-to-severe acute pain.
`
`hi4)
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`.
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`It appears to have a dual mode of action, being both a u—opioid receptor (MOR) agonist
`and an inhibitor of norepinephrine (NE) (re)uptake. Both mechanisms are likely to
`contribute to'the analgesic effects of the compound.
`
`0 Description of the product:
`Immediate—release oral tablet; 50, 75, and 100mg
`doses
`'
`-
`0 Established name and proposed trade name: Tapentadol HCL (no proposed
`tradename at this writing)
`0 Chemical class: New molecular entity
`0 Pharmacological class: Centrally acting analgesic (opioid plus SNRI)
`o Applicant's proposed indications, dosing regimens, age groups: Relief of
`moderate-to-severe acute pain in adults; 50mg, 75mg, or 100mg every 4 to 6
`hours as needed
`
`Table(s) of Currently Available Treatment(s) for Proposed
`2.2
`Indication(s)
`'
`Multiple products are available for the treatment of moderate-to-severe acute pain,
`including immediate-release opioids, prescription strength NSAIDs, and tramadol.
`
`Availability of Proposed Active Ingredient in the United States
`2.3
`This product is not marketed in or outside the United States.
`
`Important Issues with Consideration to Related Drugs
`2.4
`Tapentadol is a centrally-acting synthetic analgesic combining opioid and non—opioid
`activity, similar to Tramadol. Both drugs appear to have mu-receptor agonist activity
`combined with inhibition of norepinephrine reuptake. Consequently, both drugs have
`adverse events common to other mu—receptor agonists and SNRIs.
`
`A serious risk associated with Tramadol is the occurrence of seizures, which have been
`reported in patients receiving Tramadol within the recommended dosage range.
`Spontaneous post-marketing reports indicate that seizure risk is increased with doses of
`Tramadol HCL above the recommended range, and the risk of seizure is increased in
`patients taking SSRIs, tricyclyic antidepressants, or other opioids. Administration of
`tramadol may enhance the seizure risk in patients taking MAO inhibitors, neuroleptics, or
`other drugs that reduce the seizure threshold.
`
`Concomitant use of Tramadol with MAO inhibitors and SSRIs also may increase the risk
`of serotonin syndrome.
`
`Tramadol and other opioid analgesics are associated with known and potentially serious
`adverse events of respiratory depression, withdrawal, physical dependence and abuse,
`and the risk of overdosage. Labels include warnings regarding concomitant use with"
`CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines,
`tranquilizers or sedative hypnotics.
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H._
`September 18, 2009
`
`The common adverse event (2 5% incidence) profile for Tramadol includes dizziness,
`nausea, constipation, headache, somnolence, vomiting, pruritus, CNS stimulation,
`asthenia, sweating dyspepsia, dry mouth and diarrhea. These are also seen commonly
`with other opioid analgesics.
`
`Drug abuse, dependence, overdosage and withdrawal are important safety concerns
`associated with Tramadol and other Schedule II opioid analgesics.
`
`Summary of Presubmission Regulatory Activity Related to this
`2.5
`Submission
`
`Important aspects of the presubmission regulatory activity for this NDA are described
`below.
`
`Pre-IND Meeting, November 17, 2000
`0 Efficacy must be addressed in multiple-dose studies.
`0 CMC requirements outlined
`o Pharmacokinetic study requirements outlined
`0 CSS requirement outlined, including binding studies to identify site of action in
`the brain, effect of route of administration of product on behavior and
`bioavailability, assessment of abusability offormulation, studies in subjects with a
`history of drug abuse to assess drug discrimination, self-administration, and drug
`abuse liability.
`
`Response to Applicant’s Questions in Writing, March 28, 2005
`o The highest and lowest doses to be marketed, as well as dosing regimen, must be
`demonstrated to be safe and effective in a clinical'trial. Modeling and simulation
`may suffice for intermediate doses.
`
`Type C Meeting, December 16, 2005
`0 Division agreed that a bioequivalence study bridging the capsule and tablet
`formulation to be used in the Phase 3 program is adequate.
`- The information provided to the Division suggested that 46mg CG5503 IR could
`be the minimum target dose for Phase 3, as it was approximately the minimal
`efficacious dose found in bunionectomy patients.
`'
`0 The choice of 93mg of CGSSO3 IR appeared reasonable as a maximum target
`dose for Phase 3; however the Applicant could consider exploring a slightly
`higher dose.
`0 Division agreed that a flexible dosing interval of Q4 to '6 hours would be
`acceptable in a Phase 3 study as long as the timing of doses was carefillly
`captured and analyzed.
`0 Labeling instructions to patients to take a second “reloading” dose as soon as one
`hour after initiating treatment (for insufficient analgesia) is acceptable as long as
`it was studied in that manner and the data support the benefit and safety of such
`use.
`
`0
`
`In general the use of rescue medication in analgesic trials is encouraged, and
`when used should be accounted for in the efficacy analysis.
`
`

`

`NDA 22-304
`Ellen Fields, M.D., M.P.H;
`Tapentadol HCL
`September 18, 2009
`Clinical Review
`,
`A minimum of three to five days of treatment is recommended to support a
`finding of efficacy.
`‘
`Onset of action should be defined using the double stopwatch method
`To support proposed dosing interval, median time to remedication should be
`determined
`'
`.
`More than one patient population should be studied to support a finding of
`efficacy for acute pain since this product is an NME.
`_
`The proposed endpoint for the pivotal Phase 3 trials, SPl-12, is not acceptable.
`The endpoint should be modified to address the effect of study drug on pain
`intensity over three to five days (e.g., SPID48).
`-
`LOCF is not adequate as the method for imputing missing data in the primary
`efficacy analysis. The method of imputation should assign a bad score to patients
`who drop out of the study early regardless of reason, such as BOCF. Another
`approach is use of a continuous responder analysis.
`
`Pre—NDA Meeting, June 5, 2007
`The Sponsor’s non-clinical package appears adequate for the NDA submission
`The types of clinical pharmacology studies conducted appear adequate.
`The Division agreed with the Applicant’s proposed PK/PD/AE analysis.
`F
`
`A,
`
`h(4)
`
`Study population and primary endpoint for study KF5503/33 are acceptable.
`Studies KF5503/32 and KF5503/33 appear to be sufficient to support filing an
`application for treatment of moderate to severe acute pain.
`Regarding the SAP, as stated during the December 16, 2005 meeting, LOCF is
`not adequate as the method for imputing missing data in the primary efficacy
`analysis. A conservative strategy should be used, such as BOCF. The Applicant
`stated they wished to retain LOCF as the primary analysis, but would conduct
`BOCF as a sensitivity analysis. The Division stated that a positive study using
`LOCF that fails more conservative imputation methods will not be considered
`adequate demonstration of efficacy and will not support approval.
`(7
`
`F
`
`b(4)
`
`A summary of safety from studies ofthe ER formulation must be provided.
`
`J
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M_.D., M.P.H.
`September 18, 2009
`
`0 A proposal for scheduling must be provided with justification.
`0 All information and data related to abuse liability must be provided.
`0 A formal RiskMAP is not required for tapentadol
`IR, however a careful
`pharmacovigilance program should be formulated.
`
`2.6 Other Relevant Background Information
`This product is not approved or marketed outside the United States.
`
`3. ETHICS AND Goon CLINICAL PRACTICES
`
`Submission Quality and Integrity
`3.1
`It was Well organized and easily
`This submission appeared to be of good quality.
`navigated. A number of information requests were sent to the Applicant for tables and
`clarifications; however no additional datasets were requested.
`
`3.2
`Compliance with Good Clinical Practices
`The Division of Scientific Investigations (DSI) conducted routine inspections of 4 study
`sites involved in studies KF55'03/32, KF5503/33, and KF5503/34. The study sites were
`selected based on the number of enrolled study subjects. DSI inspected the following
`investigators:
`
`
`Table 2
`Inspection
`Name ofCl, IRB, or
`
`Dates
`Sponsor
`
`site # and location
`
`
`Richard A. Pollak
`
`MD.
`
`San Antonio, TX
`
`lra J. Gottlieb, MD.
`
`il
`l Pasadena, MD
`
` James P. Beretta,
`
`
`
`: M.D.
`_ Bimiingham, AL
`
`i .
`
`Marc Alilalo, MD.
`a Montreal, QC H3Tl
`E7
`Canada
`
`
`
`
`
`5/l3-l9/08
`
`'
`
`Krssos/
`32
`
`KF5503/
`32
`
`5/27-29/08
`
`KF5503/
`34
`
`6/3-5/08
`'
`
`KF5503/
`33
`
`7/ 14- ] 7/08
`
`
`
`Final
`Classification)
`
`NAI
`'
`
`VA]
`
`NM
`
`-
`
`
`
`
`
`
`
`
`Source: Evaluation of Clinical Inspections, DSI, September ID, 2008
`
`According to the D31 review, the data from all
`support of the pending application.
`
`inspected sites appear acceptable in
`
`All studies performed in support of this application included adequate informed consent.
`There were no protocol violations that affected the integrity or results of the studies. Dr.
`Jonathan Norton, (the statistical reviewer) assessed the impact of two irregularities
`discovered for Study KF5503/32 during the D31 inspection (failure to file documents
`associated with monitoring visits in a timely'manner and failure to fully report all
`information relevant to safety and efficacy data in the clinical study report). These issues
`
`10
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`,
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`were satisfactorily resolved by the Applicant as reported by DSI. Dr. Norton reanalyzed
`the primary endpoint omitting relevant subjects from the analysis, and the results were
`consistent with the results obtained when these subjects were, included. See Dr. Norton’s
`statistical review for details of this analysis.
`I
`
`Study KF5503/31, site 01l006
`The Applicant conducted an investigation of the clinical investigator site of Dr. Jonathan
`Hummel on 02-04 October 2007. The purpose of the investigation was to verify concerns
`regarding duplicate ECG tracing across multiple subjects. As a result of this
`investigation, potential non-compliance with the good clinical
`trial practices was
`identified.
`
`Dr. Hummel’s site conducted two phase 3 clinical trials, R331333-PAI-3001 (Total Hip
`Replacement Surgery Pain) and R33l333-PAI-3004 (Safety), associated with the Acute
`Pain Indication
`
`. The results of the investigation were as follows:
`
`The fdlowing Critical observations were-noted:
`
`ECG Tracings:
`
`i
`
`Identical ECG tracings were transmitted toC
`subjects and visits.
`
`jfor multiple
`'
`
`o The ECG acquisition times were after 5:00 pm, When the study
`coordinator stated that no procedures were performed after this time.
`Lab Reports:
`
`0 There were at least two instances where the screening laboratory data
`(clinical chemistry, hematology, urinalysis) for two subjects were
`identical with each other.
`
`The following Major observations were noted:
`
`0 The Pain Scales to be completed by the subjects only, were noted to
`have similar handwriting and marks from one subject to another.
`
`0 There was an inconsistency in source data regarding the screening
`ECG for subjects. For example:
`
`— The source notes stated that the ECG was unable to be acquired,
`which was entered into the Electronic Case Report Form (eCRF) as,
`"UNABLE TO OBTAIN". However, an ECG tracing fromC
`3
`clearly labeled for the subject and visit was available and this ECG
`tracing was duplicate of the qualifying visit ECG.
`
`Study KF5503/3l was ongoing at the time of the cutoff date of 3 October 2007 for the
`NDA submission, and because this study was not a pivotal study it was not included in
`the NDA. The safety data from this study was described in the 4-Month Safety Update,
`with the data from site 011006 described separately. The efficacy data from the study
`
`11
`
`”(4)
`
`

`

`11(6)
`
`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`KF5503/31 was not provided because the clinical study report was in progress when the
`4-Month Safety Update was submitted. In the efficacy analysis of KF5503/31 that is part
`of the clinical study report, the ITT analysis set excluded the subjects from site 011006.
`
`DSI was consulted on July 2, 2008, to perform a “for cause” inspection of Dr. Hummel,
`however since this study site is outside of the United States this inspection could not be
`carried out. The data obtained did not contribute to findings of efficacy for tapentadol IR,
`this investigator is not involved any other INDs.
`
`3.3
`
`Financial Discldsures
`
`The Applicant adequately disclosed financial arrangements with clinical investigators as
`recommended in the FDA guidance for industry on Financial Disclosure by Clinical
`Investigators. These arrangements do not raise questions about the integrity ofthe data.
`
`37MD, a sub-investigator who participated
`One clinical investigator, C:
`in study KF5503/33 reported equity interest inwthe sponsor of the covered study: stock in
`excess of $50,000. The study site enrolled and randomized C, ”Ia total of 674 subjects.
`The Applicant stated that steps taken to minimize bias included the fact that the study
`was a double-blind, placebo-controlled trial consisting of multiple sites fi‘om' which the
`data was pooled. This appears to be acceptable especially given the small proportion of
`patients enrolled by this investigator.
`
`4 SIGNIFICANT EFFICACY 0R SAFETY FINDINGS RELATED TO OTHER REVIEW DISCIPLINES
`
`4.] Chemistry Manufacturing and C