CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`200533Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
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`

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`Cross Discipline Team Leader Review
`NDA 200533 Nucynta ER
`August 11. 2011
`
`Ellen Fields. M.D.. M.P.H.
`
`Cross-Discipline Team Leader Review
`
`
`Date
`August 11, 2011
`From
`Ellen Fields, M.D., M.P.H.
`m_ Cross-Disci line Team Leader Review
`200533 Class 2 Resubmission
`
`Johnson & Johnson Pharmaceutical
`
`Date of Submission
`February 28, 2011
`
`PDUFA Goal Date
`August 28, 2011
`
`time.
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Dosa_e forms / Stren_ h
`Proposed Indication(s)
`
`Nucynta ER/ tapentadol extended release tablets
`
`Tablets 50, 100, 150, 200, and 250m
`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
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`Page 1 of 19
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`Reference ID: 2999214
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`1. Introduction
`Tapentadol is a centrally-acting analgesic compound that has been developed in an extended-
`release tablet formulation for the management of moderate-to-severe chronic pain in adults
`when an around-the-clock opioid analgesic is needed for an extended period of time. It is
`believed to have a dual mechanism of action, involving both mu-opioid agonism and
`norepinephrine reuptake inhibition. Tapentadol immediate-release (IR) tablets received FDA
`approval for the relief of moderate-to-severe acute pain in adults (NDA 22-304, approved 20
`November 2008). Of the long-acting opioids that have been approved, tapentadol is most
`similar to tramadol, which also has agonist activity on the mu opioid receptor and inhibits the
`reuptake of norepinephrine and serotonin.
`
`Johnson & Johnson has submitted this NDA as a response to the Complete Response (CR)
`action issued by the Division on October 1, 2010. The major reason for the CR action was the
`lack of adequate bridging between the formulation studied in the Phase 3 trials and the to-be-
`marketed formulation.
`2. Background
`The original NDA for tapentadol extended-release tablets was submitted on December 1, 2009.
`The basis for the NDA was four randomized, controlled Phase 3 trials, two in patients with
`chronic pain due to osteoarthritis of the knee, and one each in patients with chronic low back
`pain and painful diabetic peripheral neuropathy. Additional open-label safety data was
`submitted from a one-year study in patients with chronic pain, and results of multiple Phase 1
`and 2 studies were also included in the NDA. All four Phase 3 trials were considered by the
`first cycle review team to be adequate and well-controlled. Two trials successfully
`demonstrated the efficacy of tapentadol ER; Study 3011 in patients with chronic low back
`pain, and Study 3015 in patients with painful DPN. Neither of the two OA trials demonstrated
`efficacy. The safety of tapentadol ER was found to be similar to that of other extended-release
`opioids and IR tapentadol. Details regarding the safety and efficacy reviews are available in
`the clinical review from the first cycle.
`
`The primary issue that precluded the approval of tapentadol ER was the lack of adequate
`bridging of the Phase 3 clinical formulation (PR2) and the to-be-marketed formulation (TBM).
`In the original NDA, the Sponsor proposed a bridging strategy illustrated in the figure below
`taken from Dr. Sarah Okada’s CDTL memo from the first cycle. The strategy included the use
`of two In-Vivo-In-Vitro Correlation (IVIVC) models and bioavailability (BA) studies to
`bridge the pilot batches and the clinical batches to the to-be-marketed formulation.
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`Reference ID: 2999214
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`Figure X: Bridging
`Strategy
`
`
`However, during the review of the submission the ONDQA biopharmaceutics team found the
`proposed IVIVC models unacceptable. This was communicated to the Applicant during the
`review cycle at which time the Agency recommended that the Applicant reconstruct the model.
`In a later submission the Applicant conveyed to the Agency that they did not intend to
`reconstruct the IVIVC models; instead they proposed to perform additional fasted
`bioequivalence studies between the Phase 3 PR2 tablets and the TBM TRF (tamper-resistant
`formulation) tablets to support the bridging of the strengths originally proposed to be covered
`by the high-strength IVIVC (i.e., 150 mg and 200 mg doses). The Applicant proposed to
`submit the reports of these studies prior to the end of the original 10-month review cycle,
`however, since the composition of the 50 mg tablet was found not proportional to the 100 mg
`strength and these two strengths are not proportionally similar to the higher strengths, the
`biopharmaceutics team advised the Applicant to conduct BE studies with the highest (250 mg)
`and lowest (50 mg) strengths instead.
`
`Although the biopharmaceutics team found the proposed dissolution method acceptable, the
`proposed dissolution specifications were not acceptable because these were based on the
`IVIVC models that were determined to be unacceptable. Therefore, the acceptance criteria also
`needed to be finalized once the results of the proposed BE studies bridging the to-be marketed
`formulation with the clinical trial formulation, and the dissolution profile comparisons data are
`submitted.
`
`Based on the above issues, a Complete Response action was taken for NDA 200533. The
`following is an excerpt from the Action Letter dated October 1, 2010 listing the deficiencies
`that resulted in the CR action. An additional deficiency is related to verification of clinical
`trial source data at the Contract Research Organization (CRO).
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`Page 3 of 19
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`Reference ID: 2999214
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`
`
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`
`
`A post-action Type A meeting was conducted between the Applicant and the Division on
`November 9, 2010. The discussion focused on the Applicant’s pending resubmission of the
`NDA. The Division was in agreement with the Applicant that they had demonstrated
`bioequivalence for all strengths of tapentadol TRF except for the 50mg strength, and that a
`biowaiver for the intermediate strengths would no longer be needed as long as the BE studies
`were found acceptable by the review team, and that the 50mg tablet could potentially be
`approved after review of the Applicant’s rationale, pharmacokinetic, and safety data in the
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`NDA resubmission. The Division also requested that the Applicant submit information to
`support the interchangeability of multiple 50mg tablets with one tablet of a higher dose, given
`the lack of bioequivalence of the 50mg tablets with the PR2 formulation. The approvability
`and safety of the 50mg tablets will be discussed in detail in this review.
`
`Another issue that arose during the November meeting was that the tapentadol TRF tablets
`contain polyethylene oxide, an excipient that has been associated with swelling and stickiness
`of tablets for other drug products that contain it, and resulting adverse events of the tablet
`sticking in the throat and the patient experiencing choking episodes. The Applicant was asked
`to submit safety data to inform whether the TRF formulation represents a choking hazard.
`
`Because tapentadol is an extended-release opioid, it will be required to adopt the class wide
`Risk Evaluation and Mitigation Strategy (REMS) for long-acting opioids. Until the class-wide
`REMS is finalized, an interim REMS for this will be part of this approval, and will be closely
`modeled on the recently approved interim REMS for Embeda and OxyContin.
`3. CMC/Device
`Dr. Craig Bertha completed the CMC reviews during the first cycle of this NDA. No
`additional CMC information was included in this submission. From the CMC perspective
`there were no issues precluding approval other than the unacceptable IVIVC modeling as
`stated in the Complete Response.
`4. Nonclinical Pharmacology/Toxicology
`The Pharmacology/Toxicology team completed their reviews during the first cycle of this
`NDA. No additional pharmacology/toxicology information was included in this submission.
`According to the review team, there are no issues that preclude approval.
`5. Clinical Pharmacology/Biopharmaceutics
`Clinical Pharmacology
`The Clinical Pharmacology review was conducted by David Lee, Ph.D., with secondary
`concurrence from Yun Xu, Ph.D. Their review included information submitted in the
`Complete Response application that consisted of the bioequivalence studies bridging the PR2
`Phase 3 clinical formulation and the TRF to-be-marketed tapentadol ER formulation. In order
`to provide adequate information to address the issues stated in the Complete Response with
`respect to clinical pharmacology, the Applicant needed to submit bioequivalence information
`for two doses, 50 and 250 mg strengths, comparing PR2 and TRF TBM formulations along
`with in vitro dissolution data in support of the biowaiver request for the intermediate strengths.
`The Applicant submitted bioequivalence information for all available strengths to address the
`concerns in the current complete response submission, negating the need for the biowaiver.
`
`BE studies were conducted comparing all strengths of the TRF formulation (50mg, 100mg,
`150mg, 200mg, and 250mg) with the PR2 formulation used in the Phase 3 studies. All
`strengths except the 50mg strength were demonstrated to be bioequivalent. You are referred to
`Dr. Lee’s review for details regarding the studies of the 100mg, 150mg, 200mg, and 250mg.
`
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`Reference ID: 2999214
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`The results of the study assessing the bioequivalence of the 50mg tablet are of interest because
`bioequivalence was not demonstrated, and this raises concern regarding the use of the 50mg
`tablet. As stated in Dr. Lee’s review:
`
`“Study HP5503/82 evaluated tapentadol 50 mg tablets. Sixty-four subjects (32 men and 32
`women) were enrolled for the study. The batch numbers for test (TRF 50-mg tablet) and
`reference (PR2 50-mg tablet) products were 9EG9279-X and PD3137, respectively. Subjects
`were excluded from bioequivalence analyses if they did not complete both treatments and
`vomited anytime during the treatments. The mean serum concentration-time profiles were
`somewhat dissimilar between two formulations.
`
`The mean serum concentration-time profiles for 50 mg tablets are shown in the table below:
`
`
`The tapentadol pharmacokinetic parameters and a summary of statistical results are
`presented below:
`
`Summary Statistics on the Pharmacokinetic Parameters of Tapentadol
`(Study HP5503/82: Pharmacokinetic Data Analysis Set)
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`Page 6 of 19
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`Reference ID: 2999214
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`Cross Discipline Team Leader Review
`NDA 200533 Nucynta ER
`August 1 l, 201 l
`
`Ellen Fields, M.D., M.P.H.
`
`The corresponding 90% CIfor AUC values were within the 80% to 125% range, but, not for
`the Cmax. Thus, the two formulations are not bioequivalent. However, 50 mg dose will be
`strictly used for a titration purpose. Therefore,
`the result is considered acceptable after
`discussion with the clinical team. "
`
`As stated in Dr. Lee’s review, the lack of bioequivalence between the two formulations based
`on the higher Cmax for the TRF formulation does not represent a safety concern because the
`Cmax is only approximately 30% higher, and because the 50mg is intended to be used only
`during titration.
`
`Dr. Lee also addressed the issue of the interchangeability of the 50mg tablets if they are
`administered as multiple units to achieve a particular dose instead of administering the higher
`dose unit. The following is taken from Dr. Lee’s review:
`
`The cross-study dose linearity assessment indicated that tapentadol 50 mg Cmax and AUCoo
`values are in line with higher doses and do not expect to provide greater exposure when a
`smaller-dose unit
`is administered as multiple units. The observed serum tapentadol
`concentrations following administration of a particular dose as combinations of 50-mg and
`I 00-mg TRF tablets, e.g., 200 mg: two 100 mg tablets or two 50 mg and one 100 mg tablets, in
`a Phase 3 study PAT-302 7/KF56 were within the 90 percent confidence interval established by
`the population pharmacokinetic model. However, the observed data do not provide a robust
`comparison, e.g., five units of 50 mg tablets compared to a single unit of 250 mg tablet, and
`can not be used as a strong supportive argument in the comparability discussion. In all, the
`results from the linearity assessment and the supportive information from the observed Phase
`3 trial indicate that patients would not be at riskfor over-exposure to tapentadol if multiple
`tablets are administered.
`
`Food Effect
`
`The determination regarding a food effect for tapentadol ER was made during the first cycle
`review, and the conclusion was that there is not a food effect for the to—be—marketed
`formulation based on a standard food effect study conducted in the United States. During her
`review of the complete response application, Dr. Alicja Lerner of the Controlled Substance
`Staff reviewed another food effect study conducted in Japan that was included in the complete
`response submission, and concluded that there is a food effect. Dr. Lee had the following
`comments in his clinical pharmacology review relative to the Japanese study:
`
`“..... a cursory review was conducted for Study HP5503/5I, a food ejflct study (with a
`‘standard Japanese meal - total calories are approximately 700 - 800 kcal; percentages of
`energy of contents of meal are: carbohydrate 50-70%, protein less than 20%, It id 20-30%
`
`
`TRF ER ormulation Ja anese healthy men (n=12 .
`
`
`This study was reviewed briefly since TRF ER formulation was utilized. The results indicated
`that the geometric means for Cmax and AUC of tapentadol under fed conditions were
`approximately 54 and 12% higher compared to under fasted conditions. The observed
`arithmetic mean Cmax and AUC values for fed and fasted conditions were 65.7 and 42.8
`ng/mL, and, 585 and 520 ng-h/mL, respectively. The provided information was considered not
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`to be critical for this application simply because this study utilized a ‘standard Japanese
`meal’, not an Agency’s recommended high-fat meal, and, the fact that the studied population
`does not represent the population majority in the US. Additionally, the high-fat food effect
`information was assessed in the original NDA submission, and, that study was considered as a
`pivotal food effect study; in that assessment, the AUC and Cmax increased by 6% and 17%,
`respectively, when TRF ER tablets were administered after a high-fat meal. The tmax was
`prolonged by about 1 hour with a median tmax of 6.00 hours (range: 2.98-12.0 hours) in the
`fed state and 5 hours (range: 2.00-12.0 hours) in the fasted state. In Phase 3 studies,
`tapentadol ER tablets were also administered without restriction to food. Therefore, we
`recommend that tapentadol ER tablets may be taken without restriction to food.”
`
`The Division’s conclusion regarding the food effect studies is that the results of the standard
`food effect study reviewed by the Clinical Pharmacology team provide adequate evidence of a
`lack of food effect for tapentadol ER, and that while the study conducted in Japan did show an
`effect of food, the interpretation of the study is limited due to the fact that the meal
`administered during the study was not the standard meal for US studies, and the study
`population did not represent the US population as a whole. The clinical studies demonstrated
`that taking tapentadol ER without regard to food did not result in safety concerns. The
`labeling for tapentadol ER will reflect that it may be taken without regard to food intake. See
`Section 5 of this review for additional discussion of this issue.
`
`Biopharmaceutics
`Since the Applicant conducted five BE studies linking all of the proposed strengths, the
`biowaiver request for the intermediate strengths was no longer required. The Applicant did
`submit dissolution specifications for all strengths of tapentadol ER tablets which were agreed
`upon with the biopharmaceutics team. The dissolution specifications were based on the mean
`dissolution profiles for data from registration stability batches, commercial site stability
`batches, and clinical (pivotal BE) batches, and were deemed acceptable from the
`biopharmaceutics perspective.
`
`According to the Clinical Pharmacology and Biopharmaceutics review teams, there are no
`issues that preclude approval for tapentadol ER tablets at this time.
`6. Clinical Microbiology
`Not applicable
`7. Clinical/Statistical- Efficacy
`No new efficacy trials were submitted with this Complete Response application. Details
`regarding efficacy findings for tapentadol ER are located in the clinical and statistical reviews
`of this NDA from the first cycle.
`8. Safety
`The original NDA submission included safety data on more than 4,000 subjects who received
`tapentadol ER in 38 clinical studies. In this submission the Sponsor included safety data
`collected since the cut-off date for the 4-month safety update in the original NDA submission,
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`October 1, 2009. This consisted of unblinded data on 1,700 study subjects from eight
`completed Phase 1 studies, and three completed Phase 2 and 3 studies. Additional data was
`submitted for 11 ongoing Phase 2 and 3 studies that included only numbers of deaths and
`serious adverse events. Phase 2 and 3 studies were conducted in patients with chronic pain due
`to osteoarthritis, chronic low back pain, cancer, postherpetic neuralgia, and diabetic peripheral
`neuropathy.
`
`The updated safety profile of tapentadol ER as reviewed by Dr. Kilgore is consistent with that
`noted during the first cycle review. There were no new or concerning safety signals detected
`during her review. The review of laboratory tests, ECG findings, and vital sign measurements
`did not indicate any potential clinically relevant safety concerns. There were no new deaths
`reported for the completed studies, and the SAEs reported in the update did not lead to concern
`regarding any new safety issues. The most frequently reported treatment emergent adverse
`events (TEAEs) in this update included gastrointestinal and nervous system disorders such as
`nausea, constipation, headache, and somnolence, which is consistent with the findings from
`the first cycle review.
`
`
`Special Safety Concerns
`During the post-action Type C meeting held between the Agency and Sponsor on November 9,
`2010, The Division identified concerns regarding the safety of tapentadol ER TRF (the to-be-
`marketed) tablet that should be addressed in the Complete Response submission, as follows:
`1. Because the 50mg TRF tablet did not meet bioequivalence criteria compared to the
`formulation used in the Phase 3 trials, the Applicant was asked to submit:
`a. Safety and pharmacokinetic information specifically for the 50mg TRF tablet.
`b. Supportive data for interchangeability of using different combinations of the
`50-mg TRF tablets to achieve a particular dose (e.g., a patient might use four
`50-mg TRF tablets during titration to reach an intended dose of 200 mg and
`then switch to the 200 mg TRF tablet).
`2. Because the to-be-marketed formulation of tapentadol ER contains polyethylene oxide,
`which for other drug products has been associated with causing tablets to become
`sticky or expand when moist making swallowing difficult and potentially resulting in a
`choking hazard, the Applicant was asked to evaluate whether this has been an issue and
`to demonstrate the safety of the product in this regard.
`
` am in agreement with Dr. Kilgore’s assessment that the Applicant’s responses regarding
`these issues are acceptable.
`
`Briefly, regarding the approvability of the 50mg TRF tablet, the Applicant provided the
`following rationale:
`o The 50mg TRF tablet is intended to be used only during initial dose titration, and the
`safety profile and pharmacokinetic data from the Phase 1 studies, and the Phase 3 DPN
`study that utilized this formulation support the use of the 50mg TRF tablet for dose
`titration
`o Serum tapentadol concentrations are dose-proportional, and the serum tapentadol
`plasma concentrations for the 50mg TRF tablets do not exceed the concentrations
`
` I
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`achieved with multiples of the 50mg tablets to achieve therapeutic doses of 100mg-
`250mg.
`o A cross-study comparison of the five Phase 1 BE studies showed the PK of tapentadol
`TRF are linear and systemic exposures are predictable for the dose range 50mg to
`250mg tested.
`o Use of the 50mg TRF tablet during titration in the open-label titration period of the
`DPN study produced a similar and comparable safety profile as the 50mg PR2 clinical
`formulation tablet used in other Phase 3 studies.
`
`
`The Applicant’s rationale regarding the interchangeability of a particular dose of tapentadol as
`multiple 50mg TRF tablets in place of a single dosage strength of a TRF tablet, in addition to
`the first bullet above, includes:
`o Serum tapentadol concentrations following administration of a particular tapentadol
`dose as combinations of 50mg and 100mg TRF tablets and as an equivalent single
`dosage strength PR2 tablet are similar.
`o The safety of taking multiple TRF tablets without any unexpected consequences is
`evidenced by the similar safety profiles for the 50mg PR2 tablet and the 50mg TRF
`tablet used in the open-label titration periods of DPN studies PAI-3015/KF36 and PAI-
`3027/KF56 respectively, and the data from an additional open-label safety study of the
`TRF formulation in patients with DPN support that the safety profile observed with
`tapentadol TRF is similar to that established with tapentadol PR2.
`
`
`Dr. Lee commented in his review on the Applicant’s rationale, as noted in Section 5 of this
`review, and is in general agreement that patients would not be at risk for overexposure to
`tapentadol if multiple 50mg tablets are administered.
`
`Regarding the safety of the TRF tablets in terms of choking and sticking, the Applicant has
`stated that there were no Product Quality Complaints submitted for the Phase 1 and Phase 3
`studies showing difficulty swallowing the TRF tablets, and there were no TEAEs that would
`suggest difficulty swallowing the tapentadol TRF tablets in the 845 subjects who took
`tapentadol TRF in the Phase 1 and Phase 3 studies. Dr. Kilgore also reviewed the adverse
`event data from studies utilizing the TRF formulation and did not detect any events likely
`associated with the tablets swelling or sticking in the throat or GI tract. This information
`appears adequate to address the choking/sticking issue from a premarketing perspective. The
`product label will include instructions to take one tablet at a time with adequate water to avoid
`choking or sticking, and the Applicant will be required to report to the Agency adverse events
`related to the stickiness of the tablets as 15-day expedited safety reports. If a safety signal
`appears in this regard during the postmarketing period, additional steps may be taken.
`
`Since the CR Action for this NDA, the required New Molecular Entity Post Marketing
`Evaluation (915 review) for Nucynta (NDA 22-304) was completed by OSE and DAAAP on
`November 22, 2010. As noted in this review, a Tracked Safety Application (TSI) was opened
`in May, 2010 to investigate events that may represent new safety signals for Nucynta as
`reported in Periodic Safety Reports to the Agency. These included events of hallucination,
`suicidal ideation, angioedema, and headache, and a higher than expected number of reports of
`seizure and serotonin syndrome (SS), that were included in the class labeling for tramadol and
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`Cross Discipline Tm Leader Review
`NDA 200533 Nucynta ER
`August 1 l, 201 l
`
`Ellen Fields, M.D., M.P.H.
`
`tapentadol products, but had not occurred during the clinical trials. Of note, it appears that the
`reports of serotonin syndrome included concomitant medications that would increase the SS
`risk. The following conclusions and recommendations were made:
`
`0 Hallucination and seizure are adequately described in revised Nucynta labeling of
`1 1/1/10.
`
`0 Reports of headache have likely been confounded by lmderlying medical conditions,
`and routing postrnarketing surveillance for these events should be continued.
`
`0 Serotonin syndrome, suicidal ideation, angioedema and palpitations should be added to
`the Nucynta label as postmarketing events.
`0 The Nucynta ER label will also reflect the above issues.
`
`3. Advisory Committee Meeting
`An Adviso Committee meetin was not convened for this a
`
`lication.
`
`
`
`4. Pediatrics
`
`The pediatric study requirements for drug products intended to treat chronic pain include
`studies in pediatric patients ages 7 to <17 years of age. Studies in patients under the age of 7
`years are not required, since the population of pediatric patients with chronic pain in this age
`group is too small to study. The types of studies required include those assessing eflicacy,
`safety, and pharmacokinetics. Although the Division’s current policy includes extrapolation of
`eflicacy from adults to pediatric patients two years and older for opioids, tapentadol is not a
`pure mu—opioid agonist, having the additional mechanism of action related to norepinephrine
`reuptake inhibition. For products such as this, that currently include tramadol and tapentadol,
`efficacy may not be extrapolated from findings in adults.
`
`The Sponsor submitted a pediatric plan that included a waiver request for pediatric patients
`under 7 years, and a deferral request for pharmacokinetic, eflicacy, and safety studies in
`patients ages 7-<l7 years, with the appropriate justifications. A timeline was submitted as
`shown below:
`
`0 Final protocol submission to Agency: May 28, 2014
`0 Study completion date:
`October 31, 2017
`0 Study report submission to Agency: March 26, 2018
`
`the
`is that
`The Sponsor’s rationale for the study start date (three years from now)
`determination of dosing in pediatric patients for tapentadol ER is dependent in part on the
`results of the PK studies of the IR formulation in pediatric patients.
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`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`The pediatric plan was presented to the Pediatric Research Committee (PeRC) on July 6, 2011,
`and was found acceptable by the Committee.
`5. Other Relevant Regulatory Issues
`DSI inspections
`A deficiency noted in the CR letter for this NDA was that the clinical investigator sites did not
`maintain independent source documentation of the data that were transmitted directly to
`eTrials via eDiaries, therefore verification of the source data at the CRO is required before the
`application may be approved.
`
`During the first review cycle, clinical inspections of four clinical sites and the Sponsor were
`conducted in response to a routine audit request. FDA inspection of one of the clinical sites
`(Dr. Alan Soo) documented instances where the clinical investigator failed to adequately
`document review of rescue medication use, as well as entry of pain scores in subjects’ diaries
`on the eDiary website. An inspection of the contract research organizations (CRO),
`
` was conducted in order to shed additional light on the reliability
`of specific data points for some subjects enrolled at this site.
`
`DSI filed a review addendum, dated July 14, 2011, in order to capture the assessment of the
`inspection of
`, which was pending at the time of the first cycle review
`(September 20, 2010) and to include the updated assessment of Dr. Soo’s inspection based on
`receipt and review of the EIR.
`
`
` was contracted to provide eDiaries and support services for the electronic
`diaries for the two Phase 3 clinical trials (Protocol KF5503/23 and Protocol KF5503/36).
`Although minor discrepancies in data were noted at one study site, these were not considered a
`regulatory violation on the part of the CRO. The conclusion of the DSI inspection of the CRO
`was that the studies appear to have been conducted adequately, and the data generated by this
`CRO appear acceptable in support of the application.
`
`Regarding Dr. Soo’s site, the July, 2011 DSI addendum stated that it is unlikely that the
`identified regulatory violations at this site would significantly impact overall data reliability.
`Also, there was no evidence of under-reporting of adverse events found during the inspection
`of this site, and the primary endpoint data from the site agreed with the data at
`
`. DSI deferred to the review Division to evaluate the impact, if any, of six subjects
`that were transitioned to the Maintenance Phase of the study, even though the subjects reported
`that they continued to take rescue medication within the last three days of the Titration Period,
`which was a protocol violation. In order to verify that this violation would not have an impact
`on the final efficacy determination, the Division requested that the statistical review team re-
`analyze the efficacy data excluding the six subjects who were subject of the protocol violation,
`and an additional analysis excluding the entire study site (32 subjects). In both cases, there
`were no changes in the overall treatment effect of tapentadol ER compared to placebo.
`
`DAAAP also requested that the Division of Bioequivalence and GLP Compliance, Office of
`Scientific Investigations (DBGC) inspect the clinical and analytical portions of study
`HP5503/84, the pivotal study to assess bioequivalence of tapentadol TRF 250mg in fasted
`
`Page 12 of 19
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`Reference ID: 2999214
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Cross Discipline Team Leader Review Ellen Fields, M.D., M.P.H.
`NDA 200533 Nucynta ER
`August 11, 2011
`healthy subjects. An audit of the clinical portion of the study was conducted at Celerion Inc.,
`Lincoln, NE, and an audit of the analytical portion of the study was conducted at
`
`. There were no significant findings at the clinical
`site; however a Form-483 was issued to the analytical site that included a number of concerns
`regarding the documentation and analyses of the samples.
` responded to all of the
`inspection concerns satisfactorily, and DBGC recommended that the analytical data be
`accepted for Agency review. Details regarding the inspection may be found in the DBGC
`review dated August 5, 2011.
`
`CSS consult:
`Dr. Alicja Lerner of the Controlled Substance Staff (CSS), with secondary concurrence from
`Michael Klein, Ph.D., filed two reviews for this NDA in order to address abuse-related safety
`issues, one during the first cycle dated September 9, 2010, and another during the current
`review cycle, dated July 12, 2011. The issues in the September, 2010 review were not
`addressed by the first cycle review team, and were deferred for internal discussion during the
`subsequent review cycle.
`
`The conclusions from Dr. Lerner’s first cycle review are summarized as follows:
`1. The