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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER:
`22511Orig1s000
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`STATISTICAL REVIEW(S)
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`

`

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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`
`S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N
`CLINICAL STUDIES
`
`NDA/Serial Number:
`Drug Name:
`Indication(s):
`
`Applicant:
`Date(s):
`
`22-511 / 00
`Vimovo® (naproxen/esomeprazole magnesium) Tablets
`Signs and symptoms of osteoarthritis, rheumatoid arthritis, and
`ankylosing spondylitis in patients at risk of developing NSAID
`associated gastric ulcers
`AstraZeneca
`Letter date: 6/30/09
`PDUFA date: 4/30/10
`Standard
`
`Biometrics Division:
`Division of Biometrics II
`Statistical Reviewer:
`Kate Meaker, M.S.
`Concurring Reviewers: Dionne Price, Ph.D.
`Statistical Reviewer for
`Freda Cooner, Ph.D. (DB3)
`DGP:
`Medical Division:
`
`Review Priority:
`
`
`
`Clinical Team:
`
`Division of Anesthesia and Analgesia Products (DAAP)
`Consult from Division of Gastroenterology Products (DGP)
`Medical Officer: Jin Chen, M.D. (DAAP)
`Medical Team Leader: Ellen Fields, M.D. (DAAP)
`Project Manager:
`Anne Simon (DGP)
`Keywords: Clinical studies; NDA review; Non-inferiority Comparisons
`
`

`

`
`
`1. EXECUTIVE SUMMARY OF STATISTICAL FINDINGS
`
`1.1 Conclusions and Recommendations
`
`1.2 Brief Overview of Clinical Studies
`
`1.3 Statistical Issues and Findings
`
`2. INTRODUCTION
`
`2.1 Overview
`
`2.2 Data Sources
`
`3. STATISTICAL EVALUATION
`
`3.1 Evaluation of Efficacy
`Study PN400-307 (conducted 4/08 to 12/08)
`Design
`Patient Disposition
`Baseline Demographics
`Efficacy Results
`Study PN400-309 (conducted 4/08 to 12/08)
`Design
`Patient Disposition
`Baseline Demographics
`Efficacy Results
`
`3.2 Evaluation of Safety
`
`4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`4.1 Gender, Race and Age
`
`4.2 Other Special/Subgroup Populations
`
`5. SUMMARY AND CONCLUSIONS
`
`5.1 Statistical Issues and Collective Evidence
`
`5.2 Label Issues
`
`5.3 Conclusions and Recommendations
`
`Signatures/Distribution List Page
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`2
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`

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`1. EXECUTIVE SUMMARY OF STATISTICAL FINDINGS
`
`1.1 Conclusions and Recommendations
`
`The applicant submitted results from four Phase 3 clinical studies intended to assess the efficacy
`of Vimovo (naproxen/esomeprazole magnesium) Tablets. The applicant is seeking an indication
`for treatment of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing
`spondylitis in patients at risk of developing NSAID-associated gastric ulcers.
`
`This review will only cover two of the clinical studies (307 and 309) which were conducted in
`patients with osteoarthritis (OA) of the knee and assessed the efficacy of VIMOVO for treatment
`of the signs and symptoms of OA. Both studies included three double-blind treatment arms:
`Vimovo 500 mg/20 mg twice daily, Celecoxib 200 mg once daily, and placebo.
`
`The applicant has requested the following language in the Clinical Studies section of the label
`(Section 14) which constitutes a comparative claim:
`
`
`
`
`
`
`
`
`
`
`
`
`
`The results of the two studies were conflicting,
`. In both studies, the results indicate that VIMOVO was not non-inferior to the
`celecoxib arm, but was statistically significantly superior to placebo. Based on the comparisons
`to placebo in the two studies, there is sufficient evidence to support the efficacy of VIMOVO for
`the indication of treatment of OA signs and symptoms.
`
`
`
`
`
`
`
`
`
`
`
`1.2 Brief Overview of Clinical Studies
`
`The naproxen component is currently approved for the treatment of signs and symptoms of
`osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Two of the clinical studies
`submitted assessed the efficacy of the combination product for this indication. Those studies
`(307 and 309) will be discussed in this review.
`
`The esomeprazole magnesium component is currently approved for treatment of
`gastroesophageal reflux disease and risk reduction of NSAID-associated gastric ulcer. Two
`clinical studies (301 and 302) assessed the efficacy of the combination product for the latter
`indication. Those studies will be reviewed by Dr. Freda Cooner (Division of Biometrics 3) for
`the Division of Gastroenterology Products (DGP).
`
`
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`The applicant conducted two prospectively planned, randomized, double-blind, active- and
`placebo-controlled clinical studies to assess the efficacy of Vimovo for the treatment of signs
`and symptoms of osteoarthritis (OA). Both studies (307 and 309) had the same design, treatment
`groups, patient population, efficacy endpoints, planned sample size, and planned analyses.
`
`Patients were adults, ages 50 and older, with a history of at least 6 months of osteoarthritis of the
`knee. They had to be on a stable dose of NSAIDs, COX-2 inhibitors, or other oral analgesic
`therapy for at least 6 weeks prior to screening. When the oral analgesic therapy was
`discontinued, patients who experienced an OA flare, defined as worsening of pain and patient
`global assessment, were eligible for randomization.
`
`The three double-blind treatment arms were VIMOVO 500 mg/20 mg twice daily (bid),
`celecoxib 200 mg once daily (qd), and placebo. In each study, eligible patients were randomized
`using a ratio of 2:2:1 to the three treatment groups.
`
`In both protocols, the applicant stated the primary objective was to demonstrate that VIMOVO
`was non-inferior to celecoxib 200 mg qd on three primary endpoints: WOMAC pain subscale,
`WOMAC function subscale, and Patient Global Assessment. All three endpoints are measured
`on 0-100 mm VAS scales. The applicant planned to show efficacy on all three endpoints and did
`not plan any statistical adjustment for multiplicity. These have historically been the three
`efficacy endpoints required by the Agency for the indication of the treatment of signs and
`symptoms of OA.
`
`Patients were treated for 12 weeks. The timepoint of interest was the change from baseline to
`Week 12 for the three efficacy measures. These studies did not assess the incidence of gastric
`ulcers.
`
`The planned primary analysis used an ANCOVA model with terms for treatment and baseline
`pain as the covariate. The applicant’s stated hypothesis was non-inferiority of the VIMOVO
`treatment group to the celecoxib treatment group on all three endpoints. Non-inferiority was
`assessed using 95% confidence intervals on the difference between the VIMOVO and celecoxib
`groups.
`
`The applicant stated in the protocols that a non-inferiority margin of 10mm on the 0-100 mm
`VAS scales would be used for the comparisons. This was not agreed to by the Agency prior to
`conducting the studies. Discussion with the Agency on June 10, 2008, described the factors of
`the analysis which would impact the NI conclusions, including the treatment effect sizes and
`consistency of treatment response.
`
`
`
`
`4
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`

`

`
`1.3 Statistical Issues and Findings
`
`The main issue is the applicant’s planned non-inferiority comparisons to celecoxib, with a non-
`inferiority margin of 10 mm on the three 0-100 mm VAS scales. The VAS scales used in studies
`307 and 309 were somewhat different questions, with different outcome scales, than were used
`to measure efficacy versus placebo in the original application for celecoxib (NDA 20-998;
`December 29, 1998). The clinical studies submitted to support efficacy of celecoxib used 11-
`point Likert scales, and the questions were worded differently. The information from the NDA
`review of celecoxib was not useful toward determining if the proposed 10 unit NI margin was
`reasonable. AstraZeneca, the applicant for this NDA, did not provide justification to support the
`10 unit NI margin.
`
`Since the two studies submitted for this application included both a celecoxib arm and a placebo
`arm, we evaluated the observed treatment effect sizes for celecoxib versus placebo in these
`studies as a potential source of information on what an appropriate NI margin would be. In
`Study 307, the celecoxib treatment effect sizes ranged from 6-7 mm versus placebo. In Study
`309, the celecoxib treatment group was not significantly different from placebo, with treatment
`effect sizes of 1-1.5 mm. These results indicated that the proposed
`10 mm NI margin was not reasonable.
`
`
`2. Introduction
`
`2.1 Overview
`
`VIMOVO consists of two active drug ingredients. Naproxen is a non-steroidal
`anti-inflammatory drug (NSAID) available in strengths of 250 mg, 375 mg, and 500 mg for oral
`administration. It is currently approved for treatment of signs and symptoms of osteoarthritis,
`rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, tendonitis, bursitis, and acute
`gout. It is used to reduce swelling and treat pain.
`
`Esomeprazole magnesium (Nexium) is a proton pump inhibitor (PPI) which reduces gastric acid
`secretion. It is available as an extended-release capsule in strengths of 20 mg or 40 mg for oral
`administration. The currently approved indications are: treatment of gastroesophageal reflux
`disease; risk reduction of NSAID-associated gastric ulcer; H. pylori eradication to reduce the
`risk of duodenal ulcer recurrence; and pathological hypersecretory conditions including
`Zollinger-Ellison Syndrome.
`
`The use of NSAIDs has a recognized risk of gastrointestinal adverse events. The naproxen label
`(and other NSAID labels) includes the following warning:
`
`
`NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
`ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at
`any time during use and without warning symptoms. Elderly patients are at greater risk for serious
`gastrointestinal events.
`
`
`
`5
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`

`

`
`Most osteoarthritis patients are in the higher risk age group, and also commonly require chronic
`therapy for their symptoms. For this reason, this patient population was selected by the
`applicant for the development of VIMOVO.
`
`
`This compound was developed by POZEN Inc. and AstraZeneca under IND 76,301. On
`June 10, 2008, the sponsor met with the Agency to discuss the Phase 3 clinical development
`plan. At that meeting the potential for a comparability claim was discussed, along with the
`factors which would be considered in establishing a non-inferiority margin. At the pre-NDA
`meeting (March 23, 2009) the sponsor stated they intended to use Last Observation Carried
`Forward (LOCF) imputation for the primary analysis. The Division of Anesthesia, Analgesia,
`and Rheumatology Products (DAARP) advised them that the results would be reviewed using a
`more conservative method of imputing data since most dropouts are nonrandom. Based on this
`discussion, the applicant included additional sensitivity analyses in the Integrated Summary of
`Efficacy (ISE) section of the application.
`
`
`2.2 Data Sources
`
`All data was supplied by the applicant to the CDER electronic data room (edr) in SAS transport
`format. All necessary documentation, 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\NDA022511\022511.ENX
`
`
`
`3. Statistical Evaluation
`
`3.1 Evaluation of Efficacy
`
`Study PN400-307 (conducted 4/08 to 12/08)
`
`Design and Statistical Methods
`
`Study 307 was a randomized, double-blind, parallel arm, multi-center study. The primary
`objective was to demonstrate that VIMOVO was non-inferior to celecoxib in the treatment of
`signs and symptoms of osteoarthritis. The applicant’s goal was to add comparability claims of
`VIMOVO to celecoxib in the Clinical Studies section of the label, not to demonstrate efficacy of
`VIMOVO for this indication. The study included three treatment arms: VIMOVO 500 mg bid,
`celecoxib 200 mg qd, and placebo. The applicant planned the study based on non-inferiority
`comparisons between the VIMOVO and celecoxib arms.
`
` Non-inferiority was assessed with three prespecified endpoints for signs and symptoms of
`osteoarthritis: the Western Ontario McMaster Universities (WOMAC) Osteoarthritis Index Pain
`Subscale, the WOMAC function subscale, and the Patient Global Assessment of OA (PGA)
`
`
`6
`
`

`

`visual analogue scale (VAS). Comparisons of the VIMOVO and celecoxib arms to the placebo
`arm for the endpoints were planned in the protocol as secondary objectives. Improvement on all
`three endpoints is required for the indication of treatment of signs and symptoms of OA.
`
`The WOMAC instrument consists of 24 items, each measured using a 100 mm VAS scale. The
`items assess pain, stiffness, and function. The WOMAC Pain subscale is the mean response to 5
`questions regarding how much pain a patient has during 5 common daily actions, where 0=no
`pain and 100=extreme pain. The WOMAC Function subscale is the mean response to 17 items
`regarding the degree of difficulty in doing daily physical activities such as moving around and
`looking after oneself, with 0=no difficulty and 100=extreme difficulty. On the WOMAC
`subscales, lower values indicate the desirable direction.
`
`The patient global assessment (PGA) is a single 0-100 mm VAS question: “Consider all the
`ways your arthritis affects you, how well are you doing?” with 0=very poor and 100=excellent.
`On this scale, higher values indicate the desirable outcome.
`
`Patients were age 50 and older, with at least a 6-month history of OA of the knee. They must
`have been on a stable dose of NSAIDs, COX-2 inhibitors, or other oral analgesic therapy for at
`least 6 weeks prior to screening, and expected to require continued treatment for at least 12
`weeks. After the initial screening visit to determine eligibility, patients discontinued their oral
`analgesic therapy during a 7-14 day washout period. Patients who experienced an OA flare,
`defined as worsening of pain on Question 1 of the WOMAC pain scale by at least 15 mm and
`worsening on a Patient Global Assessment of at least 1 level on a 1-5 Likert scale, during the
`washout period were eligible for randomization.
`
`Patients were randomized using a 2:2:1 ratio to the three treatment arms. A total of 619 patients
`were enrolled, with 248 randomized to receive VIMOVO, 247 randomized to receive celecoxib,
`and 124 randomized to receive placebo. An electronic diary was provided to subjects at the
`randomization visit to record the WOMAC pain subscale and other assessments daily during the
`treatment period. The items in the WOMAC function subscale and the PGA (VAS) question
`were not collected in the e-diary. Those were only recorded at the study visits: baseline
`(randomization), Week 1, Week 6, and Week 12 (or early discontinuation).
`
`In the protocol, the Intent-to-Treat (ITT) population was defined as all randomized subjects who
`received at least one dose of study drug and provided at least one post-baseline efficacy
`evaluation. This is not the preferred definition because subjects who received study drug but
`discontinued prior to collecting post-baseline efficacy data would be excluded from the analyses.
`This could result in an artificial inflation of the treatment effect. Instead for my analyses, I used
`the BOCF imputation for subjects who did not have on-treatment observations so that all
`randomized were included in the analysis.
`
`For each of the three efficacy endpoints, the applicant planned to test the null hypothesis that
`VIMOVO was inferior to celecoxib. The protocol planned to analyze the efficacy endpoints
`using an ANCOVA model with terms for treatment and baseline pain. The least square mean
`changes from baseline and 95% confidence intervals between VIMOVO and celecoxib would be
`
`7
`
`

`

`calculated. The applicant proposed a non-inferiority margin (delta) of 10 mm (out of 0-100 mm
`VAS scale) for each endpoint. Justification of the 10 point delta value was not discussed in the
`protocol.
`
`In the Statistical Analysis Plan (SAP) dated January 14, 2009, the applicant planned Last
`Observation Carried Forward (LOCF) imputation for missing data for the efficacy endpoints at
`Week 6 or Week 12. At the pre-NDA meeting on March 23, 2009, the sponsor was informed
`that the Agency preferred a more conservative imputation strategy. The applicant provided the
`results using the Baseline Observation Carried Forward (BOCF), hybrid LOCF/BOCF, and ITT
`without imputation (observed data only) in the Integrated Summary of Efficacy (ISE). The
`hybrid LOCF/BOCF strategy imputed the baseline value for all discontinuations due to adverse
`events or lack of efficacy and imputed the last observation prior to withdrawal for patients
`discontinuing due to all other reasons.
`
`The applicant specified in the protocol that no statistical adjustment for multiple comparisons
`was planned because the non-inferiority comparison had to be demonstrated for all three primary
`endpoints for the desired comparability claim. The applicant’s sample size calculations were:
`
`
`For the sample size and power calculations, under the null hypothesis it was assumed that
`Celebrex and PN 400 will have means of 35 and 25, respectively, for WOMAC Pain domain,
`and for the alternative hypothesis the assumptions were 35 and 33, respectively, with a
`common standard deviation of 25. With the above assumptions, this study requires 205
`subjects each in the celecoxib and PN 400 treatment arms. With an estimated 10% early
`discontinuation, this study will randomize approximately 228 subjects per active treatment arm
`and approximately 114 subjects to the placebo arm for a total of approximately 570 subjects,
`utilizing a 2:2:1 randomization ratio. The sample size is sufficient to reject, using 2.5% onesided
`test with 90% power, the null hypothesis that PN 400 is inferior to celecoxib, with noninferiority
`margins of 10 on 100-mm WOMAC Pain and WOMAC Function Domains and
`100-mm VAS PGA. Analysis of primary efficacy measures will be based on the intent-to-treat
`population.
`
`
`The applicant did not discuss the power for superiority comparisons of VIMOVO to placebo.
`Using these same values, if placebo has a mean of 25, and VIMOVO has a mean of 33 for
`WOMAC Pain domain, with a common standard deviation of 25, then the planned sample size of
`205 for VIMOVO and 103 for placebo would have power of 75% to detect a statistically
`significant difference. The applicant did not provide the values used for the sample size
`calculations for the other two endpoints, but stated that the planned sample size would be
`sufficient. This indicates the necessary sample sizes for the NI comparisons were no larger for
`those endpoints, so the power for the superiority comparison to placebo would have been at least
`75% for the other two endpoints under the same scenario.
`
`
`
`
`8
`
`

`

`Patient Disposition
`
`Patients were adult males and females with osteoarthritis. A total of 619 patients were
`randomized to the study, with 248 randomized to VIMOVO, 247 to celecoxib, and 124 to
`placebo. The dropout rate was consistent across all three groups (14-15%) with no notable
`differences between the treatment groups in terms of reasons for discontinuation. Table 1 shows
`the distribution of patient discontinuations by reason.
`
`Table 1: Patient Disposition (Study 307)
`
`
`
`Randomized
`Withdrew Prior to Treatment
`Treated
`Discontinued without efficacy data
`
`Vimovo
`500mg/20mg bid
`248
`1
`247
`1 (Moved)
`
`Celecoxib
`200mg qd
`247
`4
`243
`1 (Refused to
` do log pad)
`
`N=242
`
`34 (14%)
`
`16 (7%)
`3 (1%)
`9 (4%)
`2 (1%)
`4 (2%)
`
`Placebo
`
`124
`0
`124
`0
`
`
`N=124
`
`19 (15%)
`
`7 (6%)
`3 (2%)
`7 (6%)
`0 (0%)
`2 (2%)
`
`
`Intent-to-Treat
` (at least one post-baseline
` efficacy assessment reported)
`Discontinued from ITT Population
`
` Adverse event
` Lack of efficacy
` Withdrew Consent
` Lost to Follow-up
` Other
`
`Completed
`
`Sources: Clinical Study Report Table 4 and Table 14.1.1.
`
`
`N=246
`
`38 (15%)
`
`18 (7%)
`4 (2%)
`8 (3%)
`0 (0%)
`8 (3%)
`
`208 (85%)
`
`208 (86%)
`
`105 (85%)
`
`
`
`9
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`

`

`Baseline Demographics
`
`The three treatment groups were well balanced with respect to relevant demographic and
`baseline characteristics as shown in Table 2.
`
`Table 2: Patient Demographics for Intent-to-Treat (ITT) Population (Study 307)
`
`
`
`Vimovo
`500mg/20mg bid
`N=246
`
`62 (8)
`50, 84
`
`
`156 (63%)
`90 (37%)
`
`Celecoxib
`200mg qd
`N=242
`
`62 (8)
`49, 90
`
`
`164 (68%)
`78 (32%)
`
`Placebo
`
`N=124
`
`62 (8)
`50, 83
`
`
`83 (67%)
`41 (33%)
`
`Age (years)
` Mean (SD)
` Min, Max
`
`Age categories:
` <65 yrs
` ≥65 yrs
`
`Gender
` Female
` Male
`
`Race
` White
` Black
` Asian
` Other
`
`Ethnicity
` Hispanic or Latino
`
`Body Mass Index (BMI) kg/m2
` Mean (SD)
` Min, Max
`
`
`Sources: Clinical Study Report Table 6
`
`
`
`
`161 (65%)
`85 (35%)
`
`
`194 (79%)
`43 (17%)
`9 (4%)
`0
`
`
`12 (5%)
`
`
`33 (7)
`19, 57
`
`
`148 (61%)
`94 (39%)
`
`
`195 (81%)
`36 (15%)
`10 (4%)
`1 (<1%)
`
`
`10 (4%)
`
`
`33 (8)
`19, 62
`
`
`82 (66%)
`42 (34%)
`
`
`99 (80%)
`21 (17%)
`3 (2%)
`1 (1%)
`
`
`7 (6%)
`
`
`33 (7)
`19, 58
`
`
`
`10
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`

`

`Efficacy Results
`
`Although the applicant’s primary objective was to demonstrate the non-inferiority of VIMOVO
`to celecoxib for the purpose of a comparability claim, I initially evaluated the efficacy of the
`drug compared to placebo. Table 3 presents the results for the analyses of the three primary
`efficacy endpoints comparing Vimovo to placebo. I have included results from four different
`imputation approaches. The applicant only collected information on the osteoarthritis endpoints
`at Baseline, Week 6, and Week 12. Patients who discontinued prior to Week 6 had no on-
`treatment efficacy measurements to be carried forward. The applicant’s ITT-LOCF patient
`population, as defined in the protocol, did not include patients who did not have on-treatment
`measurements and was not the desired ITT population.
`
`The results are consistent across the three endpoints and the alternative imputation methods.
`These results support the efficacy of VIMOVO.
`
`
`
`
`11
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`

`

`
`
`
`Endpoint
`WOMAC
`Pain
`
`WOMAC
`Function
`
`
`
`
`
`
`
`Pt. Global
`Assessment
`
`
`
`Vimovo N=
`Placebo N=
`
`
`
`LS Mean: Vimovo
`LS Mean: Placebo
`Difference
`95% CI on Diff.
`p-value
`
`
`LS Mean: Vimovo
`LS Mean: Placebo
`Difference
`95% CI on Diff.
`p-value
`
`
`
`Vimovo N=
`Placebo N=
`
`
`LS Mean: Vimovo
`LS Mean: Placebo
`Difference
`95% CI on Diff.
`p-value
`
`187
`84
`
`
`-44.7
`-40.5
`-4.2
`(-10.2, 1.8)
`0.17
`
`
`-38.9
`-35.5
`-3.4
`(-9.4, 2.6)
`0.26
`
`
`192
`87
`
`23.3
`17.0
`6.4
`(-0.1, 12.9)
`0.055
`
`
`
`SAS datasets
`
`Applicant’s
`LOCF *
`
`226
`108
`
`
`
`
`-42.0
`-35.6
`-6.4
`(-12.0, -0.7)
`0.027
`
`
`-36.4
`-30.6
`-5.8
`(-11.3, -0.2)
`0.041
`
`
`242
`119
`
`21.2
`14.4
`6.8
`(1.1, 12.4)
`0.018
`
`Table 14.2.5.1
`
`Source:
`
`All comparisons from ANCOVA model with terms for treatment and baseline.
`* Applicant’s LOCF: If Week 12 missing, carry forward Week 6; If Week 6 also missing, drop from analysis.
`** BOCF: Any Week 12 missing data imputed from baseline (Change from baseline = zero)
`*** Hybrid LOCF/BOCF: If discontinued for Lack of Efficacy or Adverse events, then baseline carried forward;
`otherwise last observation (Week 6) carried forward.
`
`
`
`During the teleconference (June 10, 2008) to discuss Phase 3 clinical study issues, the applicant
`asked for advice on the proposed endpoints, non-inferiority margins, statistical testing approach,
`analysis population,
`
` The response from the Agency (including Dr. Permutt and Dr. Price) was:
`
`Table 3 - Efficacy Results: Vimovo Compared to Placebo (Study 307)
`
`
`
`
`
`Observed
`data
`
`BOCF **
`
`Hybrid ***
`LOCF/BOCF
`
`
`246
`124
`
`
`-37.7
`-30.4
`-7.3
`(-13.2, -1.4)
`0.015
`
`
`-33.0
`-25.9
`-7.1
`(-12.7, -1.5)
`0.013
`
`
`246
`124
`
`20.9
`12.8
`8.1
`(2.6, 13.7)
`0.004
`
`Table E2.29
`
`
`
`246
`124
`
`
`-34.6
`-26.3
`-8.3
`(-14.4, -2.2)
`0.008
`
`
`-30.3
`-22.7
`-7.6
`(-13.3, -1.8)
`0.010
`
`
`246
`124
`
`19.1
`10.5
`8.7
`(3.1, 14.2)
`0.002
`
`Table E2.28
`
`
`
` however we
`disagree with your proposed analyses of the two studies planned to assess the efficacy of PN 400 in
`
`
`
`12
`
`(b) (4)
`
`(b) (4)
`
`

`

`patients with OA of the knee using a placebo and an active comparator (celecoxib). The
`determination of “non-inferiority” will need to be performed in the context of the analyses of all study
`endpoints. Factors that will contribute to the determination will be the treatment effect sizes versus
`placebo for both active arms in the studies, the variability in the treatment response, and the degree to
`which the treatment effects from PN 400 and Celebrex are comparable.
`
`It is therefore not possible to establish an “acceptable” non-inferiority margin at this time. When the
`results of the study are analyzed, if there is any indication (i.e., any important endpoint) that PN 400 is
`inferior to Celebrex, there will not be a finding of non-inferiority.
`
`The analyses of endpoints in the proposed trials should be conducted on the intent-to-treat
`population and the per protocol population.
`
`The sponsor initially stated that the goal of the study was to establish efficacy in the osteoarthritis
`population. The Agency explained its understanding that the purpose of the study was to investigate
`the comparability of PN 400 to Celebrex and clarified that a placebo-controlled superiority trial would
`be required if the goal was to establish efficacy. To assess comparability, the Agency will evaluate the
`overall profile of PN 400 to Celebrex. The Agency further explained that the concerns regarding
`multiplicity which motivate the need for pre-specified endpoints and analyses in a trial designed to
`show efficacy do not apply in the same way to a study specifically designed to evaluate comparability.
`
`
`Based on the criteria outlined in that discussion, I considered both the comparison of VIMOVO
`to Celecoxib (see Table 4) and the treatment effect size for Celecoxib vs. placebo (see Table 5).
`
`
`
` Table 5 presents the comparisons of Celecoxib to placebo.
`
`
`Due to missing data in the applicant’s LOCF approach, and based on advice from the Agency to
`the applicant at the pre-NDA meeting, the BOCF and Hybrid LOCF/BOCF analyses will be the
`focus of my conclusions. In this study, the conclusions from either of those imputation
`approaches are consistent.
`
`In Table 4, for all three endpoints, the mean improvement for the VIMOVO group was
`numerically better than for Celecoxib, so there is no indication that VIMOVO is inferior to
`Celecoxib. For the confidence intervals shown in Table 4, the direction of interest to determine
`inferiority is underlined. All are in the range of 3-4 mm.
`
`In Table 5, the treatment effect sizes for celecoxib versus placebo are in the 6-7 mm range.
`Therefore, the appropriateness of the applicant’s proposed 10 mm difference is questionable
`since it is larger than the treatment effects observed in the studies.
`
`
`
`
`13
`
`(b) (4)
`
`

`

`Table 4 - Efficacy Results: Vimovo Compared to Celecoxib (Study 307)
`
`
`
`Observed
`data
`
`Applicant’s
`LOCF *
`
`BOCF **
`
`
`
`Hybrid ***
`LOCF/BOCF
`
`
`246
`242
`
`
`-37.7
`-37.0
`-0.6
`(-5.5, 4.2)
`
`
`-33.0
`-32.2
`-0.7
`(-5.4, 3.9)
`
`
`246
`242
`
`20.9
`19.8
`1.1
`(-3.4, 5.7)
`
` Applicant’s LOCF: If Week 12 missing, carry forward Week 6; If Week 6 also missing, drop from analysis.
`** BOCF: Any Week 12 missing data imputed to baseline (Change from baseline = zero)
`*** Hybrid LOCF/BOCF: If discontinued for Lack of Efficacy or Adverse events, then baseline carried forward;
`otherwise last observation (Week 6) carried forward.
`
`
`
`
`
`14
`
`
`
`Vimovo N=
`Celecoxib N=
`
`
`
`LS Mean: Vimovo
`LS Mean: celecox.
`Difference
`95% CI on Diff.
`
`
`LS Mean: Vimovo
`LS Mean: celecox.
`Difference
`95% CI on Diff.
`
`
`
`Vimovo N=
`Celecoxib N=
`
`
`LS Mean: Vimovo
`LS Mean: celecox.
`Difference
`95% CI on Diff.
`
`
`
`187
`179
`
`
`-44.7
`-43.2
`-1.5
`(-6.2, 3.3)
`
`
`-38.9
`-37.9
`-1.1
`(-5.8, 3.6)
`
`
`192
`180
`
`23.4
`23.2
`0.2
`(-5.1, 5.4)
`
`Table 14.2.3
`
`226
`221
`
`
`
`
`-42.0
`-41.8
`-0.2
`(-4.8, 4.3)
`
`
`-36.4
`-36.3
`-0.1
`(-4.6, 4.4)
`
`
`242
`230
`
`21.1
`21.6
`-0.5
`(-5.1, 4.1)
`
`Table 14.2.1
`
`
`
`246
`242
`
`
`-34.6
`-32.6
`-2.0
`(-7.0, 3.0)
`
`
`-30.3
`-28.7
`-1.7
`(-6.4, 3.1)
`
`
`246
`242
`
`19.1
`17.5
`1.6
`(-2.9, 6.1)
`
`Table E2.25
`
`Table E2.26
`
`
`
`
`Endpoint
`WOMAC
`Pain
`
`WOMAC
`Function
`
`
`
`
`
`
`
`Pt. Global
`Assessment
`
`Source:
`
` *
`
`

`

`Table 5 - Efficacy Results: Celecoxib Compared to Placebo (Study 307)
`
`
`
`Observed
`data
`
`Applicant’s
`LOCF *
`
`BOCF **
`
`
`
`Hybrid ***
`LOCF/BOCF
`
`
`242
`124
`
`
`-37.0
`-30.4
`-6.6
`(-12.5, -0.8)
`0.026
`
`
`-32.2
`-25.9
`-6.4
`(-12.0, -0.7)
`0.025
`
`
`242
`124
`
`19.8
`12.8
`7.0
`(1.5, 12.6)
`0.013
`
`Table E2.29
`
`Celecoxib N=
`Placebo N=
`
`179
`84
`
`
`
`
`
`LS Mean: celecox.
`LS Mean: Placebo
`Difference
`95% CI on Diff.
`p-value
`
`
`LS Mean: celecox.
`LS Mean: Placebo
`Difference
`95% CI on Diff.
`p-value
`
`
`
`Celecoxib N=
`Placebo N=
`
`
`LS Mean: celecox.
`LS Mean: Placebo
`Difference
`95% CI on Diff.
`p-value
`
`
`-43.2
`-40.5
`-2.7
`(-8.7, 3.2)
`0.36
`
`
`-37.9
`-35.5
`-2.3
`(-8.3, 3.6)
`0.45
`
`
`180
`87
`
`23.2
`17.0
`6.2
`(-0.1, 12.9)
`0.064
`
`
`
`SAS datasets
`
`221
`108
`
`
`
`
`-41.8
`-35.6
`-6.1
`(11.8, -0.5)
`0.032
`
`
`-36.3
`-30.6
`-5.7
`(-11.2, -0.1)
`0.045
`
`
`230
`119
`
`21.6
`14.4
`7.2
`(1.6, 12.9)
`0.013
`
`Table 14.2.5.1
`
`
`
`242
`124
`
`
`-32.6
`-26.3
`-6.3
`(-12.4, -0.2)
`0.043
`
`
`-28.7
`-22.7
`-5.9
`(-11.7, -0.2)
`0.044
`
`
`242
`124
`
`17.5
`10.5
`7.0
`(1.5, 12.6)
`0.013
`
`Table E2.28
`
`
`
`
`Endpoint
`WOMAC
`Pain
`
`WOMAC
`Function
`
`
`
`
`
`
`
`Pt. Global
`Assessment
`
`Source:
`
` *
`
` Applicant’s LOCF: If Week 12 missing, carry forward Week 6; If Week 6 also missing, drop from analysis.
`** BOCF: Any Week 12 missing data imputed to baseline (Change from baseline = zero)
`*** Hybrid LOCF/BOCF: If discontinued for Lack of Efficacy or Adverse events, then baseline carried forward;
`otherwise last observation (Week 6) carried forward.
`
`
`
`
`
`15
`
`

`

`Study PN400-309 (conducted 4/08 to 12/08)
`
`Design
`
`All aspects of the study design, patient population, and statistical analyses for Study 309 were
`identical to Study 307.
`
`
`Patient Disposition
`
`Patients were adults, ages 50 and over, with a history of OA of the knee. A total of 615 patients
`were randomized to the study, 244 to the Vimovo treatment group, 247 to the celecoxib
`treatment group, and 124 to the placebo group. Table 6 shows the distribution of patient
`discontinuations and reasons. The three groups were somewhat different in terms of their
`disposition. The celecoxib group had a higher rate of discontinuations (23%) than the Vimovo
`group (16%) or the placebo group (20%). The celecoxib group had a higher rate that
`discontinued due to an adverse event, while the placebo group had the higher rate who withdrew
`consent.
`
`Table 6: Patient Disposition (Study 309)
`
`
`
`Randomized
`Withdrew Prior to Treatment
`Treated
`Discontinued without efficacy data
`
`Vimovo
`500mg/20mg bid
`244
`1
`243
`2 (Family emerg.;
` Did not return)
`
`N=241
`
`Celecoxib
`200mg qd
`247
`2
`245
`1 (Refused to
` complete forms)
`
`N=244
`
`Placebo
`
`124
`2
`122
`0
`
`
`N=122
`
`24 (20%)
`
`5 (4%)
`2 (2%)
`14 (11%)
`1 (1%)
`2 (2%)
`
`
`Intent-to-Treat
` (at least one post-baseline
` efficacy assessment reported)
`Discontinued from ITT Population
`
` Adverse event
` Lack of efficacy
` Withdrew Consent
` Lost to Follow-up
` Other
`
`Completed
`
`Sources: Clinical Study Report Table 4 and Table 14.1.1.
`
`38 (16%)
`
`15 (6%)
`1 (<1%)
`15 (6%)
`3 (1%)
`4 (2%)
`
`56 (23%)
`
`22 (9%)
`0 (0%)
`23 (9%)
`3 (1%)
`8 (3%)
`
`208 (84%)
`
`188 (77%)
`
`98 (80%)
`
`
`
`16
`
`

`

`Baseline Demographics
`
`The three treatment groups were well balanced with respect to relevant demographic and
`baseline characteristics as shown in Table 7.
`
`Table 7: Patient Demographics for Intent-to-Treat (ITT) Population (Study 309)
`
`
`
`Vimovo
`500mg/20mg bid
`N=241
`
`62 (9)
`50, 88
`
`
`157 (65%)
`84 (35%)
`
`Celecoxib
`200mg qd
`N=244
`
`62 (8)
`50, 89
`
`
`160 (66%)
`84 (34%)
`
`Placebo
`
`N=122
`
`62 (9)
`50, 87
`
`
`84 (69%)
`38 (31%)
`
`Age (years)
` Mean (SD)
` Min, Max
`
`Age categories:
` <65 yrs
` ≥65 yrs
`
`Gender
` Female
`