CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`200533Orig1s000
`
`MEDICAL REVIEW(S)
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`
`

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 200-533
`Priority or Standard Resubmission (Complete Response)
`
`Submit Date(s) February 28, 2011
`Received Date(s) February 28, 2011
`PDUFA Goal Date August 28, 2011
`Division / Office DAAAP/OND
`
`Reviewer Name(s) Elizabeth Kilgore, M.D.
`Review Completion Date
`July 29, 2011
`
`Established Name Tapentadol Extended-Release (ER)
`(Proposed) Trade Name Nucynta ER
`Therapeutic Class Opioid analgesic
`Applicant
`Johnson and Johnson
`
`Formulation(s) Oral tablets
`Dosing Regimen 50, 100, 150, 200 and 250 mg
`Indication(s) Management of moderate to severe
`chronic pain in patients 18 years of age
`or older when a continuous, around-the-
`clock opioid analgesic is needed for an
`extended period of time
`Adult, chronic pain
`
`Intended Population(s)
`
`
`
`
`Template Version: March 6, 2009
`
`Reference ID: 2981497
`
`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6
`1.1 Recommendation on Regulatory Action ............................................................. 6
`1.2 Risk Benefit Assessment.................................................................................... 7
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 8
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 11
`2.1 Product Information .......................................................................................... 11
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 12
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 13
`2.4
`Important Safety Issues with Consideration to Related Drugs.......................... 13
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 14
`2.6 Other Relevant Background Information .......................................................... 15
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 15
`3.1 Submission Quality and Integrity ...................................................................... 15
`3.2 Compliance with Good Clinical Practices ......................................................... 15
`3.3 Financial Disclosures........................................................................................ 17
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 17
`4.1 Chemistry Manufacturing and Controls ............................................................ 17
`4.4 Clinical Pharmacology...................................................................................... 18
`4.4.1 Mechanism of Action.................................................................................. 19
`4.4.2 Pharmacodynamics.................................................................................... 19
`4.4.3 Pharmacokinetics....................................................................................... 19
`5 SOURCES OF CLINICAL DATA............................................................................ 20
`5.1 Tables of Studies/Clinical Trials ....................................................................... 20
`5.2 Review Strategy ............................................................................................... 26
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 26
`6 REVIEW OF EFFICACY......................................................................................... 26
`Efficacy Summary...................................................................................................... 26
`7 REVIEW OF SAFETY............................................................................................. 26
`7.1 Methods............................................................................................................ 27
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 29
`7.1.2 Categorization of Adverse Events.............................................................. 30
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 30
`
`Reference ID: 2981497
`
`2
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`
`7.2 Adequacy of Safety Assessment...................................................................... 30
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 30
`7.3 Major Safety Results ........................................................................................ 31
`7.3.1 Deaths........................................................................................................ 31
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 32
`7.3.4 Significant Adverse Events ........................................................................ 35
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 35
`7.4 Supportive Safety Results ................................................................................ 44
`7.4.1 Common Adverse Events .......................................................................... 44
`7.4.2 Laboratory Findings ................................................................................... 46
`7.4.3 Vital Signs .................................................................................................. 46
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 47
`7.5 Other Safety Explorations................................................................................. 48
`7.5.3 Drug-Demographic Interactions ................................................................. 48
`7.6 Additional Safety Evaluations ........................................................................... 49
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 49
`7.7 Additional Submissions / Safety Issues............................................................ 50
`8 POSTMARKET EXPERIENCE............................................................................... 51
`
`9 APPENDICES ........................................................................................................ 53
`9.1 Literature Review/References .......................................................................... 53
`9.2 Labeling Recommendations ............................................................................. 53
`9.3 Advisory Committee Meeting............................................................................ 53
`
`
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`Reference ID: 2981497
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`3
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`
`Table of Tables
`
`Table 1. Timeline for Proposed Pediatric Study with Tapentadol ER .......................... 10
`Table 2. Approved Long-Acting Opioid Products for the Treatment of Chronic Pain.... 12
`Table 3. U.S. Sites Audited in Studies 11 and 151 ....................................................... 16
`Table 4. Description of Phase 1 Single-Dose Tapentadol ER Completed Studies...... 23
`Table 5. Description of Phase 2 and 3 Tapentadol ER Completed Studies ................. 24
`Table 6. Description of Phase 2 and 3 Tapentadol ER Ongoing Studies ..................... 25
`Table 7. Safety Data by Tapentadol Formulation: Completed Studies........................ 28
`Table 8. Safety Data by Tapentadol Formulation: Ongoing Studies............................ 28
`Table 9. Summary of Deaths in Ongoing Tapentadol ER Studies................................ 32
`Table 10. Summary of SAEs in Completed Studies in CR Safety Update................... 34
`Table 11. Phase 1 Pivotal Bioequivalence Studies which Compared Tapentadol
`Formulations PR2 to TRF (Dose Range 50-250mg)...................................... 36
`Table 12. Studies Supporting Tapentadol 50mg TRF .................................................. 37
`Table 13. TEAE Phase 1 Study HP5503/82 – Tapentadol 50mg TRF vs 50mg PR2... 38
`Table 14. AEs ≥10% Study KF36 (50mg PR2) and KF56 (50mg TRF)........................ 39
`Table 15. Incidence of TEAEs in at Least 5% of Subjects in Any Treatment Group
`(TRF or Oxycodone CR) ................................................................................ 40
`Table 16. Doses and Tablets Strengths for a Single Intake for the Open-Label Period
`(Study KF56).................................................................................................. 41
`Table 17. Common AEs Tapentadol ER First Cycle Review........................................ 45
`Table 18. Phase 1 Studies: Gender Differences in TEAEs (Tapentadol TRF and PR2)
`....................................................................................................................... 48
`
`
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`Reference ID: 2981497
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`4
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`
`Table of Figures
`
`Figure 1. Tapentadol ER Structural Formula................................................................ 18
`Figure 2. Complete Response Safety Update Tapentadol ER Studies ....................... 29
`
`
`Reference ID: 2981497
`
`5
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
` 1
`
` Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`Original NDA 200-533, Nucynta ER (Tapentadol extended-release) was submitted by
`the Applicant on December 1, 2009 under section 505(b)(1). The Agency could not
`approve the product, with the primary deficiency being that the Applicant’s proposed in
`vitro in vivo correlation (IVIVC) models did not support the bridging of the clinical study
`batches (PR2) to the to-be-marketed tamper resistant formulation (TRF). The Agency
`issued a Complete Response on October 1, 2010. The Applicant submitted the
`response to the Complete Response which serves as the basis for this review.
`
`
`Approval is recommended for Nucynta ER, 50, 100, 150, 200 and 250mg oral tablets for
`the indication of management of moderate to severe chronic pain in patients 18 years of
`age or older when a continuous, around-the-clock opioid analgesic is needed for an
`extended period of time. The Applicant’s response to the Agency’s Complete Response
`is acceptable to support approvability based upon the following determinants:
`
`Efficacy: Efficacy was established in the original NDA review cycle and no new efficacy
`studies were submitted in the Applicant’s Complete Response (CR) resubmission.
`Based upon the Clinical Review of Dr. Eric Brodsky, dated 8/19/10, the efficacy of
`Tapentadol ER in the treatment of chronic pain was established from two positive
`adequate and well-controlled trials (Studies 11 and 15) with supportive evidence from
`Study 8. The two positive trials had different designs (i.e., induction and an enriched
`randomized withdrawal design), different populations (low back pain [LBP] and painful
`diabetic peripheral neuropathy [DPN]), and different types of pain (nociceptive and
`neuropathic), thereby providing heterogeneous designs and populations for study of
`Tapentadol ER. The number and type of positive trials to support an efficacy claim for a
`long-acting opioid for chronic pain is consistent with the review division’s statements to
`the sponsor during pre-NDA meetings.
`
`There were no new findings in the CR resubmission which changed the Division’s prior
`efficacy determination.
`
`Safety: The Applicant’s safety data in the CR resubmission were, overall, consistent
`with the safety findings identified in the first cycle review.
`
`As determined in the first review cycle, the safety profile of Tapentadol ER in the
`treatment of chronic pain appears to be consistent with the safety profile of approved
`long-acting opioid products. The Tapentadol ER labeling should be consistent with
`current labeling of approved long-acting opioids and contain Contraindications (in
`
`Reference ID: 2981497
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`6
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`unmonitored patients with severely impaired pulmonary function and in patients
`receiving MAO inhibitors), Boxed Warnings (in patients at increased risk of abuse or
`diversion); Warnings and Precautions (respiratory and CNS depression, increased
`intracranial pressure, driving and operating machinery, and drug withdrawal). Consistent
`with the Tapentadol IR label, the Tapentadol ER label should contain additional
`Warnings and Precautions for seizures and serotonin syndrome given the biologic
`plausibility and the post-marketing cases of these events in patients who received
`Tapentadol IR.
`
`The dosing recommendations are acceptable based upon the data from the first cycle.
`
`Risk Mitigation: The Applicant’s CR resubmission included an updated Risk Evaluation
`and Mitigation Strategy (REMS) to manage the risks (including overdose, misuse and
`abuse) associated with this drug. The REMS is currently under review by the Agency.
`Ultimately this product will be part of the class-wide, long-acting opioid REMS.
`
`1.2 Risk Benefit Assessment
`
`Tapentadol ER is a Controlled Substance Act (CSA) Schedule II drug, with risk of abuse
`and misuse.
`
`All opioids carry the risk of abuse and misuse. Based upon the first cycle review by Dr.
`Brodsky, “overall, the results support an adequately favorable risk-benefit profile for
`Tapentadol ER within the proposed therapeutic range (100 to 250 mg BID) for the
`proposed indication of treatment of chronic pain”.
`
`The reader is referred to the review of Dr. Alicja Lerner of the Agency’s Controlled
`Substance Staff (CSS) for further discussion regarding abuse and misuse potential of
`this product. Dr. Lerner’s conclusions and recommendations are discussed below:
`
`CSS Conclusions:
`• The controlled release properties of the TRF formulation can be readily
`overcome by multiple simple physiochemical manipulations.
`• The TRF formulation, in particular the dose of >150 mg, appears to exhibit an
`increased frequency of adverse events (e.g. euphoria) signaling abuse potential.
`• A high incidence of euphoria and feeling drunk occurred in Phase 1 studies in
`subjects who received tapentadol TRF as compared to those who received “all
`tapentadol ER formulations.” Euphoria was reported in 50% of subjects who
`received tapentadol TRF 250 mg with water in Study R331333-PAI-1028
`(HP5503/44).
`• Review of the current post-CR bioequivalence studies with the TRF formulation
`indicates a possible gender effect, in that the majority of AEs were reported to
`occur in females, in particular for nervous, gastrointestinal disorders, and
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`Reference ID: 2981497
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`7
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`
`psychiatric AEs, such as euphoria. They occurred in females in the ratio of
`8F:1M. Additionally, almost all discontinuations which were caused by vomiting
`occurred again mainly in females, 12:5.
`• Withdrawal symptoms, including insomnia, depressed mood, depression, suicidal
`ideation, disturbance in attention and restless leg syndrome, occurred after
`Nucynta ER administration was stopped. The occurrence of withdrawal
`symptoms indicates development of dependency and a need to slowly taper
`discontinuation of drug.
`
`
`CSS Recommendations
`•
`Include appropriate warning language in the label about susceptibility of
`females to develop majority of AEs, sometimes of a severity that leads to
`discontinuation of the drug. The extent of the relation of gender differences to
`safe use of the drug should be further examined. One of possibilities would be
`to provide the data on withdrawal, and discontinuation due to AEs with
`respect to gender, and relationship to the dose.
`• All planned clinical trials and all ongoing clinical trials (where possible) should
`include prospective assessment of suicidality, due to appearance of
`suicidality in the post-marketing phase of Nucynta.
`
`The CSS recommendations are under further discussion within the Agency at the time
`of this review.
`
`The risks associated with this extended-release opioid appear similar to other opioids in
`this class. These risks, however, appear to be manageable with appropriate risk-
`management strategies, including a REMS, and should not preclude approval.
`
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`The Applicant’s Risk Evaluation and Mitigation Strategy (REMS) proposal is under
`review by the Agency’s Division of Risk Management (DRISK).
`
`It is expected that the approved REMS for Nucynta ER will be consistent with the
`interim REMS already approved for other long-acting opioids. This product will adopt
`the class-wide, long-acting opioid REMS when it is ready for approval.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`There are two Postmarketing Requirements for this product as follows:
`
`
`Reference ID: 2981497
`
`8
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`1) Pediatric Research Equity Act (PREA): In order to comply with the Pediatric
`Research Equity Act, the Applicant submitted a pediatric plan.
`
`In the pediatric plan, the Applicant requested and was granted a waiver in the pediatric
`age group birth to <7 years of age due to the fact that chronic pain studies are
`impossible or highly impractical in this age group due to the small number of pediatric
`patients in this category.
`
`Pediatric study requirements for Tapentadol ER include pharmacokinetics, safety and
`efficacy in pediatric patients ages 7 to <17 years.
`
`As per the current Division policy, efficacy findings from adults may be extrapolated to
`pediatric patients over the age of two years for the opioid drug class, as the mechanism
`of action is well understood and is similar in both adults and pediatric patients.
`Tapentadol is a drug product whose mechanism of action includes both a mu-opioid
`receptor agonism and an inhibition of norepinephrine uptake, and is not as clearly
`understood, even in adults. Therefore, the efficacy of this drug cannot be extrapolated
`from adults to the pediatric population.
`
` A
`
` deferral for the conduct of pediatric studies was granted for pediatric patients aged 7
`to <17 years, as the Applicant is awaiting pharmacokinetic results in pediatric patients
`for immediate-release Tapentadol (Tapentadol IR) in order to better determine dosing of
`the ER formulation.
`
`The Applicant’s proposed pediatric plan is shown below in Table 1.
`
`Reference ID: 2981497
`
`9
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`
`Table 1. Timeline for Proposed Pediatric Study with Tapentadol ER
`
`(Source: Applicant’s submission, p. 1, Pediatric Correspondence, Response to 6/11/11
`Request for Information)
`
`The proposed pediatric plan was presented to the Agency’s Pediatric Review
`Committee (PeRC) on 7/6/11 and was found to be acceptable.
`
`2) Enhanced Pharmacovigilance for AEs of Interest: Although no specific safety signal
`was identified in the Applicant’s clinical trials for the AEs of interest that include choking,
`sticking, or GI obstruction, the Agency had concerns for the potential risk of such events
`with the Tapentadol ER tamper resistant formulation (TRF) because the product
`contains
` polyethylene oxide, which has been associated with
`stickiness of other drug products and subsequent adverse events such as choking and
`GI obstruction in patients with abnormal GI tracts. As such, the Applicant will be
`required to perform postmarketing enhanced pharmacovigilance for the detection of
`these adverse events of interest. The Applicant’s CR resubmission included a revised
`Safety Surveillance Plan (SSP) to reflect this requirement. The details of the SSP
`relevant to the choking, sticking and GI obstruction are discussed in Section 7.3.5 of this
`review (Submission Specific Primary Safety Concerns).
`
`Reference ID: 2981497
`
`10
`
`(b) (4)
`
`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
` 2
`
` Introduction and Regulatory Background
`
`2.1 Product Information
`
`•
`
`The active ingredient of this product, Tapentadol, is a centrally acting analgesic with a
`dual mode of action being both a mu-opioid receptor agonist and an inhibitor of
`norepinephrine uptake. The Applicant purports that preclinical data suggest that both
`mechanisms are likely to contribute to the analgesic effects. Tapentadol is a pure
`enantiomer that acts directly on the central nervous system (CNS).
`
`The Nucynta ER product characteristics are summarized as follows:
`• Trade Name (established name): NUCYNTA™ ER (tapentadol extended-
`release) oral tablets
`Indication: For “the management of moderate to severe chronic pain in patients
`18 years of age or older when a continuous, around-the-clock opioid analgesic is
`needed for an extended period of time.”
`• Age Group: Adult patients 18 years or older
`• Dose Regimen: The recommended oral daily dose is 100 to 250 mg BID.
`o For patients currently not taking opioid analgesics, begin with 50 mg BID
`and then titrate to an optimal dose within 100 to 250 mg BID range.
`o For patients switching from Tapentadol IR to Tapentadol ER, the total
`daily dose of Tapentadol IR (given 4 to 6 times per day) can be converted
`to the equivalent total daily dose of Tapentadol ER (given twice a day).
`The maximum total daily dose of Tapentadol ER is 500 mg per day.
`
`o The dosing regimen should be individualized according to the severity of
`pain, supplemental opioid utilization, previous experience with opioid
`analgesics, the patient’s ability to tolerate Tapentadol ER, the ability for
`patients to follow-up, and the ability of providers to provide oversight of
`treatment. Total daily doses greater than 500 mg of Tapentadol ER have
`not been studied and, therefore, are not recommended.
`• Pharmacologic Class: Opioid analgesic
`• How supplied: 50, 100, 150, 200, and 250 mg extended-release tablets
`
`Reference ID: 2981497
`
`11
`
`(b) (4)
`
`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Multiple products are available for the treatment of moderate-to-severe pain, including
`immediate and extended-release opioids, prescription strength NSAIDs, Tramadol and
`immediate-release Tapentadol.
`
`The proposed indication is the “management of moderate to severe chronic pain in
`patients 18 years of age or older when a continuous, around-the-clock opioid analgesic
`is needed for an extended period of time.”
`
`Table 2 below summarizes the long-acting opioid products that are approved for the
`treatment of moderate to severe chronic pain in opioid tolerant and/or opioid-naive
`patients in the United States.
`
`Table 2. Approved Long-Acting Opioid Products for the Treatment of Chronic
`Pain
`
`(Source: Dr. Eric Brodsky’s Nucynta ER Clinical Review, p. 11)
`
`
`
`Reference ID: 2981497
`
`12
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`An immediate-release (IR) formulation of Tapentadol (Nucynta) was approved in the
`United States under NDA 22-304 in November, 2008 “for the relief of moderate to
`severe acute pain in patients 18 years of age or older”. Since Tapentadol IR was not
`scheduled under the Controlled Substance Act at the time of its approval, it was not
`allowed to be marketed in the United States. On June 22, 2009, Tapentadol IR was
`scheduled as a Schedule II drug. The Tapentadol IR label was updated to include the
`scheduling information, and Tapentadol IR was initially marketed in the United States at
`that time.
`
`2.4 Important Safety Issues with Consideration to Related Drugs
`
`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, tricyclic 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.
`
`The common adverse event (≥ 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. Post-Marketing
`Reports associated with Tapentadol IR from the first review cycle identified the AEs of
`
`Reference ID: 2981497
`
`13
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`hallucination, seizures, serotonin syndrome and suicide as safety issues of interest.
`The Agency has subsequently conducted an internal review of these safety events. The
`reader is referred to Section 8 of this review, Postmarketing Experience, for further
`discussion.
`
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`Throughout the original NDA submission review cycle, post-action period for 1st cycle,
`and CR resubmission there were face-to-face meetings, teleconferences and email
`exchanges between the Applicant and the Agency. The key correspondences related to
`regulatory activity are summarized below:
`
`
`• 11/30/09:
`o NDA 200533 for Nucynta ER (Tapentadol) Extended-Release Tablets 50,
`100, 150, 200 and 250mg initially submitted to the Agency by J&J
`• 12/1/09:
`o
` Agency received the submission
`• 10/1/10:
`o The Agency issued a Complete Response Letter, on the basis of the
`following key deficiency:
`(cid:131)
`In vitro in vivo correlation (IVIVC) was not supportive of the bridging
`of the clinical study batches of the Prolonged-Release 2 (PR2)
`clinical formulation to the to- be-marketed tamper resistant
`formulation (TRF)
`
`• 11/9/10:
`o Type A Meeting between Agency and Applicant to discuss the results of
`the 5 Phase 1 pivotal bioequivalence (BE) studies comparing the
`Tapentadol TRF with the PR2 clinical formulation used in the Phase 3
`clinical studies, the proposed content and format of the submission in
`response to the CR letter, and agreement upon a path forward for
`regulatory requirements for a complete submission. The Agency required
`the Applicant to submit the following in the response to Complete
`Response:
`(cid:131) Data to support the bioequivalence (BE) of the TRF to PR2
`formulation
`(cid:131) Data to support the interchangeability (switchability) of Tapentadol
`ER tablets of different dosage strengths to achieve a particular total
`dose
`(cid:131) Safety data concerning the question of whether TRF tablets
`become sticky and expand upon getting moist and the related
`potential to cause difficulty swallowing and becoming a potential
`choking hazard
`
`Reference ID: 2981497
`
`14
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`

`

`Clinical Review
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`
`
`(cid:131) Division of Scientific Investigations (DSI) Inspection summaries
`from selected sites
`(cid:131) Safety update and a revised proposed Risk Evaluation and
`Mitigation Strategy (REMS)
`
`2.6 Other Relevant Background Information
`
`Tapentadol HCl was developed in an extended release (ER) tablet formulation for the
`indication of ‘management of moderate to severe chronic pain’. Prior to this formulation,
`two ER formulations, referred to as “PR1” and “PR2” were investigated in Phase 1, 2,
`and 3 studies during the course of Applicant’s clinical development. The PR2
`formulation replaced the earlier PR1 formulation that had a similar composition but
`could not accommodate the higher drug load required for the higher doses being
`studied. The Phase 3 safety and efficacy studies employed the PR2 formulation only.
`
`Another extended release oral tablet formulation, described as a “tamper resistant
`formulation” (TRF), was developed primarily for the US market. Throughout this review,
`the formulation used in the studies is so designated when appropriate.
`
`3 Ethics and Good Clinical Practices
`
`3.1 Submission Quality and Integrity
`
`The electronic submission appeared to be of good quality, was well organized and
`easily navigated. The Applicant responded in a timely manner and complied with all
`information requests with no substantive outstanding requests at the time of this review.
`
`3.2 Compliance with Good Clinical Practices
`
`As per the Applicant, all studies in the Tapentadol clinical development program were
`performed according to the principles of Good Clinical Practices.
`
`Division of Scientific Investigation (DSI) inspections were ongoing at four clinical sites
`(shown below in Table 3) at the time of the 1st cycle review and results of the DSI
`findings could not be included in that review.
`
`Reference ID: 2981497
`
`15
`
`

`

`Clinical Review
`
`Elizabeth Kilgore, M.D.
`NDA 200-533 Resubmission (Complete Response)
`Nucynta ER (Tapentadol ER)
`
`Table 3. US. Sites Audited in Studies 11 and 151
`
`Site #
`
`Principle Imestigatm Contact Infounation
`
`
`_umbeIof Patients
`2
`Treated “'“h
`1'93“"
`Tapgktadol
`with
`Placebo
`
`Randomized
`
`
`
`Bret \"ittmer. MD.
`Commonwealth Biomedical Research LLC
`
`240 East Ayr Parkway. Madisom'llle. KY 42431. l'SA
`Allan Soo, .\l.D.
`Premiere Pharmaceutical Research. LLC.
`3316 S. McClintocl-z DriI'e. Tem -e. AZ 85282. l'SA
`
`Pamela Amador. M.D.. Gables Research
`85 Grand Canal Drive. £1 400. Miami. FL 33144. USA
`1 Studtes 11 and 15 are Studtes M31333—PAI—3011 (10550323) and 11331333—PA1—3015 (KFSSOB 36). respccnvely.
`l Randmmzed patients Included panents treated with tapentadol ER placebo. or the acm'e control (11.. oxycodone CR) and
`patxents not treated Wlih study medication.
`3 Thu sxte was selected after J & .T Informed the Agency that there may have been potential nnsconduct In Study 1 1.
`
`(Dr. Brodksy's Nucynta ER Clinical Review, p. 18)
`
`The DSI inspections have now been completed. As taken from the DSI Summary
`Review and Review addendum by Dr. Susan Leibenhaut, primary DSI reviewer, the
`final recommendations and conclusions of the DSI inspections are as follow:
`0 Verification of electronically captured pri