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

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Science
`Office of Biostatistics
`
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
`
`NDA/Serial Number:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`Review Priority:
`
`200-533
`
`NUCYNTA ER
`
`Management of moderate to severe chronic pain
`
`Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
`
`Letter date: Nov. 30, 2009
`PDUFA date: Oct. 1, 2010
`Standard
`
`
`
`
`
`II
`
`Biometrics Division:
`Statistical Reviewer:
`Yan Zhou, Ph.D.
`Concurring Reviewers: Dionne Price, Ph.D.
`Thomas Permutt, Ph.D.
`
`
`
`Division of Anesthesia and Analgesia Products
`
`Eric Brodsky, M.D.
`
`Dominic Chiapperino, Ph.D.
`
`
`
`
`Medical Division:
`Clinical Team:
`Project Manager:
`
`
`
`Keywords: NDA review, Clinical Studies, Missing data imputation
`
`
`
`
`
`

`

`
`
`Table of Contents
`STATISTICAL REVIEW AND EVALUATION .....................................................................................................1
`LIST OF TABLES.......................................................................................................................................................3
`LIST OF FIGURES.....................................................................................................................................................4
`1. EXECUTIVE SUMMARY .................................................................................................................................5
`1.1
`CONCLUSIONS AND RECOMMENDATIONS .......................................................................................................5
`1.2
`BRIEF OVERVIEW OF CLINICAL STUDIES........................................................................................................5
`1.3
`STATISTICAL ISSUES AND FINDINGS ...............................................................................................................6
`2.
`INTRODUCTION ...............................................................................................................................................8
`2.1
`OVERVIEW......................................................................................................................................................8
`2.2
`DATA SOURCES ..............................................................................................................................................9
`3. STATISTICAL EVALUATION ........................................................................................................................9
`3.1
`EVALUATION OF EFFICACY ............................................................................................................................9
`3.1.1
`Study PAI-3011/KF23............................................................................................................................9
`3.1.2
`Study PAI-3008/KF11..........................................................................................................................13
`3.1.3
`Study PAI-3015/KF36..........................................................................................................................15
`3.2
`EVALUATION OF SAFETY..............................................................................................................................19
`4.
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................................................19
`4.1
`GENDER, RACE AND AGE .............................................................................................................................19
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS ..................................................................................................20
`5. SUMMARY AND CONCLUSIONS ................................................................................................................22
`5.1
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE .......................................................................................22
`5.1.1 STATISTICAL ISSUES.................................................................................................................................22
`5.1.2
`COLLECTIVE EVIDENCE............................................................................................................................23
`5.2
`CONCLUSIONS AND RECOMMENDATIONS .....................................................................................................23
`APPENDICES............................................................................................................................................................30
`SUMMARY OF DEMOGRAPHICS AND BASELINE CHARACTERISTICS.................................................31
`SIGNATURE/DISTRIBUTION LIST.....................................................................................................................34
`
`
`
`
`
`2
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`

`

`
`LIST OF TABLES
`
`Table 1: Subjects’ Disposition of PAI-3011/KF23......................................................................................................10
`Table 2: Primary Efficacy Results (Study PAI 3011/KF23)........................................................................................12
`Table 3: Subjects’ Disposition of PAI-3008/KF11......................................................................................................14
`Table 4: Primary Efficacy Results (Study PAI 3008/KF11)........................................................................................14
`Table 5: Subjects’ Disposition of PAI-3015/KF36......................................................................................................16
`Table 6: Primary Efficacy Results (Study PAI 3015/KF36)........................................................................................17
`Table 7: Primary Efficacy Results by Subgroup (Study PAI-3011/KF23)..................................................................19
`Table 8: Primary Efficacy Results by Subgroup (Study PAI-3015/KF36)..................................................................20
`Table 9: Efficacy Results by Country (Study PAI-3011/KF23)..................................................................................21
`Table 10: Efficacy Results by prior opioid use and baseline pain intensity (Study PAI-3011/KF23).........................21
`Table 11: Efficacy Results by country, prior opioid use and baseline pain intensity (Study PAI-3015/KF36)...........22
`
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`3
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`

`

`
`LIST OF FIGURES
`
`Figure 1: Percent Improvement in Pain from Baseline at Week 12 of the Maintenance Period (Study PAI-
`3011/KF23)..................................................................................................................................................................12
`Figure 2: Percent Improvement in Pain from Baseline at Week 12 of the Maintenance Period (Study PAI-
`3008/KF11)..................................................................................................................................................................15
`Figure 3: Percent Improvement in Pain from Baseline at Week 12 of the Maintenance Period (Study PAI-
`3015/KF36) including 21 subjects who didn’t meet the randomization criterion........................................................18
`Figure 4: Percent Improvement in Pain from Baseline at Week 12 of the Maintenance Period (Study PAI-
`3015/KF36) excluding 21 subjects who didn’t meet the randomization criterion.......................................................18
`
`
`
`4
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`

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`
`1.
`
`
`EXECUTIVE SUMMARY
`
`1.1 Conclusions and Recommendations
`
`The applicant seeks approval to market NUCYNTA (tapentadol) extended-release (ER) tablets
`for the proposed 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 conducted four controlled clinical studies to assess the efficacy of NUCYNTA for
`the proposed indication. One study was conducted in subjects with chronic low back pain (LBP)
`while another study was conducted in subjects with diabetic peripheral neuropathy (DPN). Two
`studies included subjects with chronic pain due to osteoarthritis (OA) of the knee. In each study,
`the applicant evaluated the change in pain from baseline to the last week of the maintenance
`period. The applicant concluded that three studies demonstrated the superiority of NUCYNTA
`over placebo and that one OA study failed to demonstrate the efficacy of NUCYNTA. For the
`second OA study, my conclusions varied from those of the applicant. By using conservative
`missing data imputation methods, I found that the second OA study also failed to demonstrate
`the efficacy of NUCYNTA.
`
`
`Based on my review, I concluded that the LBP study and DPN study successfully demonstrated
`the superiority of NUCYNTA over placebo. Thus, there is sufficient evidence to support the
`efficacy of NUCYNTA for the treatment of moderate to severe chronic pain.
`
`1.2 Brief Overview of Clinical Studies
`
`
`Tapentadol, the active ingredient in NUCYNTA, is an analgesic being developed by the
`applicant in an extended-release tablet formulation. A tapentadol immediate-release (IR) tablet
`formulation has been approved in the United States for the relief of moderate to severe acute pain
`in patients 18 years of age or older. The development program for the extended-release
`formulation was discussed between the applicant and the agency at several meetings. Key
`discussions focused on the study designs, primary endpoint, and statistical strategies for handling
`missing data.
`
`The applicant conducted four Phase 2, four Phase 3 efficacy and safety studies, one long-term
`safety study and one study evaluating direct dose conversion between the tapentadol IR and ER
`formulations in adults suffering from three representative chronic pain conditions (chronic LBP,
`painful DPN and painful OA). The Phase 2 studies had different designs and were of shorter
`duration than the Phase 3 studies. The Phase 3 studies comprised the majority of subjects
`exposed and were the foundation for the overall efficacy of NUCYNTA.
`
`Studies PAI-3011/KF23, PAI-3008/KF11 and PAI-3009/KF12 were similar in design, doses,
`treatment titration, maintenance period duration, efficacy endpoint and planned analyses. The
`studies varied with respect to the enrollment countries and pain conditions. Study PAI-
`3011/KF23 was conducted in subjects with chronic LBP in North America and Australia. Study
`
`5
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`

`

`PAI-3008/KF11 was conducted in subjects with chronic painful OA in North America and
`Australia, while PAI-3009/KF12 was conducted in subjects with chronic painful OA in Europe.
`
`After a 2-week screening period, patients started a washout period by discontinuing all analgesic
`medication they had previously been taking. Eligible subjects who completed the washout
`period had their baseline pain intensities measured and then were randomized in a 1:1:1 ratio to
`one of three treatments: NUCYNTA, oxycodone controlled release (CR) or placebo. Following
`a 3-week flexible titration period to achieve an optimal therapeutic dose, subjects entered into a
`12-week maintenance period with controlled dose adjustment. The applicant’s primary efficacy
`endpoint was the change in average pain intensity from baseline to the last week of the
`maintenance period at Week 12. Daily pain intensity was measured on an 11-point numerical
`rating scale (NRS). The primary analysis was an analysis of covariance (ANCOVA) with
`baseline average pain intensity score as a covariate. The primary imputation method was last
`observation carried forward (LOCF).
`
`PAI-3015/KF36 was a randomized, multi-center, double-blind, placebo-controlled withdrawl
`design study in subjects with painful DPN. After washout and a pain evaluation period, subjects
`received open-label NUCYNTA titrated to an optimal dose over 3 weeks. Subjects who had at
`least 1-point improvement in pain intensity on the NRS at the end of the open-label titration
`period were then randomized to continue on their optimal dose or placebo. The applicant’s
`primary efficacy endpoint was the change from baseline at randomization in average pain
`intensity over the last week of the double-blind maintenance period at Week 12. Daily pain
`intensity was measured on an 11-point NRS. The primary analysis was an ANCOVA with
`baseline average pain intensity score at randomization as a covariate. The primary imputation
`method was LOCF.
`
`1.3 Statistical Issues and Findings
`
`In chronic pain studies, the LOCF method is not appropriate since patients who drop out for
`adverse events may have good pain scores carried forward even though they are not successfully
`treated. Although the Division stated concerns with the use of a LOCF imputation strategy
`during the development process, the applicant used LOCF as the primary method of handling
`missing data. They also conducted sensitivity analyses which included baseline observation
`carried forward (BOCF), worst observation carried forward (WOCF), placebo mean imputation
`(PMI), and modified BOCF.
`
`The BOCF and WOCF strategies have previously been used to address the Division’s concerns
`regarding missing data. However, the PMI and modified BOCF methods are more novel and
`require additional evaluation. In the PMI method, the mean outcome of completers in the placebo
`group was imputed for dropouts in both treatment groups. This methodology resulted in the
`estimated treatment effect being the product of the treatment effect among completers and the
`proportion of completers in the active arm. The mathematical formulation follows:
`
`
`• Let pa and pc be the proportions of completers in the active and placebo groups.
`• Let Ya and Yc be the mean outcomes for completers.
`
`
`
`6
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`

`

`• Then, the estimated treatment effect is the [paYa + (1 – pa)Yc] – [pcYc + (1 – pc)Yc],
`which is equal to [pa(Ya– Yc)].
`
`
`Since the estimated treatment effect is only influenced by the data from patients completing the
`study, the PMI method is similar to an analysis of completers. Analyzing completers is
`problematic since the outcome of patients completing the study may not represent the outcome of
`patients not completing the study. In the placebo group, patients completing the study are likely
`to be the less severely afflicted patients; while in the NUCYNTA group, patients completing the
`study are likely to be the more severely afflicted patients. As a result, the PMI method assigned
`good scores from the placebo completers to patients dropping out due to adverse events in the
`treatment group. Based on these reasons, I conclude that the PMI method is not appropriate.
`
`The applicant also proposed the modified BOCF imputation method as a sensitivity analysis.
`This method combined BOCF and LOCF based on the patient global impression of change
`(PGIC). If a subject rated their status as “much improved” or “very much improved” on the
`PGIC at their last post-baseline assessment, then LOCF was used, otherwise BOCF was applied
`to impute the missing pain intensity. This imputation method is not appropriate since it may
`assign treatment benefit to a patient that subsequently discontinued due to an adverse event.
`
`In the BOCF imputation method, baseline observations were carried forward to impute missing
`pain assessments after treatment discontinuation up to the end of the double-blind treatment
`period. In Study PAI-3015/KF36 which utilized a randomized withdrawl design, the applicant’s
`baseline was defined as the randomization baseline. However, imputing randomization baseline
`would assign efficacy benefit to study drug since subjects entering the randomization were those
`with at least 1-point improvement in pain intensity on the NRS at the end of the open-label
`titration period. In my analyses, I imputed the screening baseline.
`
`In Study PAI-3015/KF36, subjects with at least 1-point improvement in pain intensity on the
`NRS at the end of the open-label titration period were to be randomized. However, there were 21
`subjects who didn’t meet this criterion but were randomized. During the review, the agency
`requested the applicant clarify the discrepancies. The applicant responded that investigators were
`instructed to randomize only patients with a change in pain intensity of at least one, and this was
`detailed in the statistical analysis plan (SAP). Despite the investigator instructions, these
`directions were not followed. The applicant didn’t provide any further details regarding why
`investigators didn’t follow the directions. I conducted additional analyses excluding these 21
`subjects.
`
`After performing analyses that addressed the statistical concerns, I concluded that NUCYNTA
`reduced the pain intensity in patients with moderate to severe chronic pain when compared to
`placebo in the LBP and DPN populations.
`
`
`
`
`
`
`
`
`7
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`

`

`2.
`
`
`INTRODUCTION
`
`2.1 Overview
`
`
`NUCYNTA developed by Johnson & Johnson Inc. is an extended-release tablet formulation of
`Tapentadol proposed for the management of moderate to severe chronic pain in patients 18 years
`of age or older. The development program was discussed between the applicant and the division
`at several meetings.
`
`At the End-of-Phase 2 meeting on August 24, 2006 (IND 61,345), the agency agreed to the use
`of a controlled dose adjustment design but specified the need for a fixed-dose pivotal study with
`a 12-week maintenance phase. The agency also accepted a titration-to-optimal dose design with a
`statistical comparison of all subjects treated with the study drug as one active group against the
`placebo group. At the meeting, it was stated that LOCF was not considered appropriate as the
`primary method of handling missing data, BOCF was instead recommended as the primary
`imputation method. A continuous responder analysis treating all discontinuations as non-
`responders was also recommended. In addition, the agency recommended that the primary
`endpoint in the pivotal Phase 3 studies be defined as the change from baseline of the average
`daily pain intensity on an 11-point NRS over the last week of the maintenance period at Week
`12. The following is quoted from the meeting minutes.
`
`
`
`
`
`In the pre-NDA meeting on January 23, 2009, the agency requested submission of narratives and
`case report forms for tapentadol-treated subjects who discontinued treatment from the Phase 2 or
`Phase 3 clinical studies for reasons coded as “lost to follow-up”, “lack of efficacy”, “violation of
`inclusion/exclusion criteria”, “study medication non-compliant”, “subject choice (subject
`withdrew consent)” or “other”.
`
`The development program included a total of four Phase 2 and four Phase 3 efficacy studies from
`three chronic pain conditions (chronic LBP, painful DPN and painful OA). My review evaluates
`Phase 3 studies PAI-3011/KF23, PAI-3008/KF11 and PAI-3015/KF36. Study PAI-3009/KF12
`is not of focus in my review since the applicant concluded that the study failed on the primary
`efficacy analyses.
`
`
`
`
`
`8
`
`

`

`2.2 Data Sources
`
`
`All data was supplied by the applicant to the CDER electronic data room in SAS transport
`format. All necessary documentations, formats, and links were provided as well. The data and
`final study report for the electronic submission were archived under the network path location
`\\Cdsesub1\EVSPROD\NDA200533\0000\m5.
`
`
`3.
`
`
`STATISTICAL EVALUATION
`
`3.1 Evaluation of Efficacy
`
`3.1.1 Study PAI-3011/KF23
`
`Study Design and Endpoints
`
`PAI-3011/KF23 was a Phase 3, randomized, multi-center, double-blind, placebo- and active-
`controlled, parallel-group study conducted in North America and Australia. The primary
`objective was to evaluate the efficacy and safety of NUCYNTA in subjects with moderate to
`severe chronic LBP.
`
`After a 2-week screening period, patients started a washout period by discontinuing all analgesic
`medication they had previously been taking. Eligible subjects who completed the washout
`period had their baseline pain intensities measured and then were randomized in a 1:1:1 ratio to
`one of three treatments: NUCYNTA, oxycodone CR or placebo. Patients randomized to
`NUCYNTA initiated therapy with a dose of 50 mg b.i.d. for three days. Subsequent titration was
`allowed over a 3-week titration period to a dose of 100 mg to 250 mg b.i.d. to achieve an optimal
`therapeutic dose. A titration scheme and dosing regimen was used for the active-control and
`placebo perspectively. During the titration period, acetaminophen was allowed as a rescue
`medication, limited to a total of 1000 mg daily. Before entering into the maintenance period,
`subjects had to maintain a stable optimal dose for the last 3 days of the titration period. During
`the maintenance period, subjects were to continue their study drug intake for 12 weeks with
`controlled dose adjustment.
`
`Subjects were enrolled from 85 sites in the United States, 15 sites in Canada and 3 sites in
`Australia. Nine hundred and eighty-one subjects were randomized to three treatment groups.
`
`The primary efficacy endpoint was the change from baseline to the end of the maintenance
`period in the average overall pain. Pain was measured on an 11-point NRS scale (0 – 10) which
`assessed the patient’s overall pain during the past 12 hours. It was recorded twice daily
`(AM/PM) in the study diary. The baseline score was defined as the average of available pain
`intensity scores during the last 72 hours prior to randomization.
`
`
`
`
`
`
`9
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`

`

`Patient Disposition, Demographic and Baseline Characteristics
`
`The demographic and baseline characteristics are provided in the appendix. Most subjects were
`white (73%), and approximately 58% of all subjects were female. The mean age was 50 years.
`
`Table 1 shows the patient disposition by treatment group. The reasons for discontinuation are
`shown for the overall double-blind period as well as by phase. Many dropouts occurred in the
`titration period and the most common reasons for study discontinuation in the active-treatment
`groups were adverse events followed by subject choice, while the most common reason for study
`discontinuation in the placebo group was lack of efficacy.
`
`
`Table 1: Subjects’ Disposition of PAI-3011/KF23
`Placebo
`NUCYNTA
`(N=319)
`(N=318)
`n (%)
`n (%)
`161 (51)
`172 (54)
`
`Oxycodone CR
`(N=328)
`n (%)
`142 (43)
`
`
`
`Disposition Status/Discontinuation Reason
`Complete Double-Blind Treatment Period
`
`Discontinued During Double-blind
`Treatment Period
`Patient Choice
`Lost to Follow-up
`Adverse Event
`Lack of Efficacy
`Study Medication Non-compliant
`Other
`
`Discontinued During Titration Period
`Patient Choice
`Lost to Follow-up
`Adverse Event
`Lack of Efficacy
`Study Medication Non-compliant
`Other
`
`Discontinued During Maintenance Period
`Patient Choice
`Lost to Follow-up
`Adverse Event
`Lack of Efficacy
`Study Medication Non-compliant
`Other
`Source: Reviewer’s Analysis
`
`Statistical Methodologies
`
`For the primary efficacy variable, change from baseline to the last week of the maintenance
`period in the average pain intensity, the treatment groups were compared using an ANCOVA
`model with factors treatment, pooled center and baseline pain intensity as a covariate. The
`primary analysis population was the intention-to-treat (ITT) population which included all
`randomized subjects who took at least one dose of study drug following randomization.
`
`
`
`36 (11)
`6 ( 2)
`106 (32)
`9 ( 3)
`14 ( 4)
`15 ( 5)
`
`129 (39)
`19 ( 6)
`2 ( 1)
`87 (27)
`7 ( 2)
`9 ( 3)
`5 ( 2)
`
`57 (17)
`17 ( 5)
`4 ( 1)
`19 ( 6)
`2 ( 1)
`5 ( 2)
`10 ( 3)
`
`159 (50)
`
`30 (10)
`12 ( 4)
`15 ( 5)
`66 (21)
`20 ( 6)
`15 ( 5)
`
`108 (34)
`18 ( 6)
`8 ( 3)
`8 ( 3)
`51 (16)
`12 ( 4)
`11 ( 3)
`
`50 (16)
`12 ( 4)
`4 ( 1)
`7 ( 2)
`15 ( 5)
`8 ( 3)
`4 ( 1)
`
`146 (46)
`
`186 (57)
`
`32 (10)
`11 ( 4)
`53 (17)
`18 ( 6)
`21 ( 7)
`11 ( 4)
`
`83 (26)
`19 ( 6)
`4 ( 1)
`34 (11)
`13 ( 4)
`9 ( 3)
`4 ( 1)
`
`63 (20)
`13 ( 4)
`7 ( 2)
`19 ( 6)
`5 ( 2)
`12 ( 4)
`7 ( 2)
`
`10
`
`

`

`The applicant used LOCF as the primary method of handling missing data and their sensitivity
`analyses included BOCF, WOCF including baseline, modified BOCF and PMI. The LOCF
`method was not appropriate since patients who dropped out for adverse events may have good
`pain scores carried forward even though they were not successfully treated. The BOCF and
`WOCF strategies have previously been used to address the Division’s concerns regarding
`missing data. However, the PMI and modified BOCF methods are more novel and require
`additional evaluation. In the PMI method, the mean outcome of completers in the placebo group
`was imputed for dropouts in both treatment groups. This methodology resulted in the estimated
`treatment effect being the product of the treatment effect among completers and the proportion of
`completers in the active arm. The mathematical formulation follows:
`
`
`• Let pa and pc be the proportions of completers in the active and placebo groups.
`• Let Ya and Yc be the mean outcomes for completers.
`• Then, the estimated treatment effect is the [paYa + (1 – pa)Yc] – [pcYc + (1 – pc)Yc],
`which is equal to [pa(Ya– Yc)].
`
`
`Since the estimated treatment effect is only influenced by the data from patients completing the
`study, the PMI method is similar to an analysis of completers. Analyzing completers is
`problematic since the outcome of patients completing the study may not represent the outcome of
`patients not completing the study. In the placebo group, patients completing the study are likely
`to be the less severely afflicted patients; while in the NUCYNTA group, patients completing the
`study are likely to be the more severely afflicted patients. As a result, the PMI method assigned
`good scores from the placebo completers to patients dropping out due to adverse events in the
`treatment group. Based on these reasons, I concluded that the PMI method was not appropriate.
`The applicant also proposed the modified BOCF imputation method as a sensitivity analysis.
`This method combined BOCF and LOCF based on the patient global impression of change
`(PGIC). If a subject rated their status as “much improved” or “very much improved” on the
`PGIC at their last post-baseline assessment, then LOCF was used, otherwise BOCF was applied
`to impute the missing pain intensity. This imputation method is not appropriate since it may
`assign treatment benefit to a patient that subsequently discontinued due to an adverse event. I
`considered the PMI and modified BOCF strategies to be inappropriate, and consequently, I used
`the BOCF and WOCF including baseline strategies to impute missing values in the primary
`analyses.
`
`For the primary endpoint, the continuous responder curves were also generated by treatment
`groups. In this analysis, all non-completers are classified as non-responders, and the curves are
`cumulative, such that every patient who achieves a 50% reduction in pain from baseline is also
`included in every level of improvement below 50%.
`
`
`Results and Conclusions
`
`
`Table 2 shows the results of both applicant’s and my primary efficacy analyses. With the BOCF
`and WOCF imputation methods, my results indicate that NUCYNTA is statistically significantly
`different from and superior to placebo.
`
`
`
`11
`
`

`

`For the continuous responder analysis, my results confirmed the applicant results. As shown in
`Figure 1, the lines for the placebo and NUCYNTA show notable separation which indicates
`NUCYNTA is different from placebo.
`
`
`Endpoint
`
`Table 2: Primary Efficacy Results (Study PAI 3011/KF23)
`Imputation NUCYNTA
`Oxycodone CR
` (n=312)
` (n=323)
`
`
`
`
`
`Change in Average Pain from Baseline
`to Last Week of Maintenance
` Applicant’s results
`
`
`-2.9
`LOCF
` LS means
`<0.001
`
` p-value vs. placebo
`
`
`
` Reviewer’s results
`
`
`-1.8 (0.1)
`BOCF
` LS means (SE)
`0.002
`
` p-value vs. placebo
`
`
`
`-1.4 (0.2)
`WOCF
` LS means (SE)
`0.004
`
` p-value vs. placebo
` Source: Clinical Study Report Table 26 and Reviewer’s Analyses
`
`
`Figure 1: Percent Improvement in Pain from Baseline at Week 12 of the Maintenance Period (Study PAI-
`3011/KF23)
`
`Placebo
`(n=316)
`
`
`
`-2.1
`
`
`
`-1.3 (0.1)
`
`
`-0.8 (0.2)
`
`
`
`-2.9
`<0.001
`
`
`-1.5 (0.1)
`0.213
`
`-1.1 (0.2)
`0.149
`
`Continuous Responder Analysis
`Cumulative Distribution Function
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`100
`
`Percent Improvement in Pain rom Base ine at Week 12 of the Maintenance Period
`
`Treatment
`
`Placebo
`
`NUCYNTA ER
`
`Active Control CR
`
`
`
`12
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
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`0
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`3.1.2 Study PAI-3008/KF11
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`Study Design and Endpoints
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`PAI-3008/KF11 was a Phase 3, randomized, multi-center, double-blind, placebo- and active-
`controlled, parallel group study conducted in North America, Australia and New Zealand. The
`primary objective was to evaluate the efficacy and safety of NUCYNTA in subjects with
`moderate to severe chronic pain from OA of the knee. The study design and endpoint were the
`same as Study PAI-3011/KF23.
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`Subjects were enrolled from 87 sites in the United States, 15 sites in Canada, 4 sites in Australia
`and 6 sites in New Zealand. One thousand and thirty subjects were randomized to three treatment
`groups.
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`Patient Disposition, Demographic and Baseline Characteristics
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`The demographic and baseline characteristics are provided in the appendix. Most subjects were
`white (76%), and approximately 60% of all subjects were female. The mean age was 58 years.
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`Table 3 shows the patient disposition by treatment group. The reasons for discontinuation are
`shown for the overall double-blind period as well as by phase. As in Study PAI-3011/KF23,
`many drop-outs occurred in the titration period and the most common reasons for study
`discontinuation in the active-treatment groups were adverse events followed by subject choice.
`The most common reason for study discontinuation in the placebo group was lack of efficacy.
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`Results and Conclusions
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`The statistical methodology was the same as in Study PAI-3011/KF23. Table 4 shows the results
`of the applicant’s and my analysis. With the BOCF and WOCF imputation methods, none of the
`analyses provided sufficient evidence of a difference between NUCYNTA and placebo.
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` I
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` generated the continuous responder curves by treatment group, using the same approach as in
`Study PAI-3011/KF23. As shown in Figure 2, the lines for the placebo and NUCYNTA show
`little separation along the whole range of percent improvement from baseline. In addition,
`statistical tests of the curves did not yield significant results. This provides additional evidence
`that NUCYNTA is not different from placebo.
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`Table 3: Subjects’ Disposition of PAI-3008/KF11
`Placebo
`NUCYNTA
` (N=344)
`(N=337)
`n (%)
`n (%)
`207 (61)
`197 (57)
`
`Oxycodone CR
`(N=342)
`n (%)
`121 (35)
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`
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`Disposition Status/Discontinuation Reason
`Complete Double-Blind Treatment Period
`
`Discontinued During Double-blind
`Treatment Period
`Patient Choice
`Lost to Follow-up
`Adverse Event
`Death
`Lack of Efficacy
`Study Medication Non-compliant
`Other
`
`Discontinued During Titration Period
`Patient Choice
`Lost to Follow-up
`Adverse Event
`Lack of Efficacy
`Study Medication Non-compliant
`Other
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`Discontinued During Maintenance Period
`Patient Choice
`Lost to Follow-up
`Adverse Event
`Death
`Lack of Efficacy
`Study Medication Non-compliant
`Other
`Source: Reviewer’s Analysis
`
`
`
`130 (39)
`
`147 (43)
`
`28 ( 8)
`1 ( 0)
`22 ( 7)
`0 ( 0)
`56 (17)
`8 ( 2)
`15 ( 5)
`
`83 (25)
`17 ( 5)
`1 ( 0)
`13 ( 4)
`41 (12)
`4 ( 1)
`7 ( 2)
`
`47 (14)
`11 ( 3)
`0 ( 0)
`9 ( 3)
`0 ( 0)
`15 ( 5)
`4 ( 1)
`8 ( 2)
`
`38 (11)
`2 ( 1)
`66 (19)
`0( 0)
`22 ( 7)
`6 ( 2)
`13 ( 4)
`
`80 (23)
`17 ( 5)
`1 ( 0)
`37 (11)
`17 ( 5)
`1 ( 0)
`7 ( 2)
`
`67 (20)
`21 ( 6)
`1 ( 0)
`29 ( 8)
`0 ( 0)
`5 ( 2)
`5 ( 2)
`6 ( 2)
`
`221 (65)
`
`35 (10)
`0 ( 0)
`147 (43)
`1 ( 0)
`13 ( 4)
`12 ( 4)
`13 ( 4)
`
`169 (49)
`24 ( 7)
`0 ( 0)
`124 (36)
`8 ( 2)
`8 ( 2)
`5 ( 2)
`
`52 (15)
`11 ( 3)
`0 ( 0)
`23 ( 7)
`1 ( 0)
`5 ( 2)
`4 ( 1)
`8 ( 2)
`
`P