CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204592Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`
`Joshua M. Lloyd, M.D.
`
`Cross—Discipline Team Leader Review
`
`
`Date
`September 30, 2013
`From
`Joshua M. Lloyd, MD.
`Clinical Team Leader, DAAAP
`
`Subject
`Cross—Discipline Team Leader Review
`NDA#
`204592
`
`A licant
`
`Iroko Pharmaceuticals
`
`A O .roval
`
`Date of Submission
`
`PDUFA Goal Date
`
`December 20, 2012
`
`October 20, 2013
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Zorvolex /
`Diclofenac
`
`Dosa_e forms / Stren_ h
`Pro a osed Indication s
`
`Oral Caisules/ 18 m and 35 mi
`For treatment of mild to moderate acute ain
`
`Recommended:
`
`1. Introduction
`
`for
`Iroko Pharmaceuticals (“Applicant”) submitted this New Drug Application (NDA)
`Zorvolex capsules, an immediate-release formulation of diclofenac, for the treatment of mild
`to moderate acute pain in adults. The Applicant conducted the clinical development program
`under IND 103,880 and proposes to market Zorvolex in two capsule strengths, 18 mg and 35
`mg, to be taken by mouth three times daily on an empty stomach. Diclofenac is a nonsteroidal
`anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic
`activities and is a potent inhibitor of both COX-1 and COX—2. Diclofenac is approved and
`marketed in the United States as various salt forms in oral (immediate-release and modified-
`release) and topical formulations for multiple painful conditions. The Applicant submitted this
`NDA under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act referencing the
`approved product Cataflam (diclofenac potassium; NDA 020142; Novartis Pharmaceuticals
`Corporation). Cataflam is approved for treatment of primary dysmenorrhea, relief of mild to
`moderate pain, and relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis;
`all in adults.
`
`The NDA submission consists of chemistry, manufacturing, and controls (CMC) information,
`nonclinical information, biopharmaceutics data, and clinical pharmacology and clinical data
`from two Phase 1 pharmacokinetic (PK) studies (DIC1-08-01 and DIC1-12-07), one Phase 2
`proof-of-concept study (DIC2-08-03), and one pivotal Phase 3 clinical trial (DIC3-08-04).
`The Phase 1 PK study DICl-12-07 and the pivotal Phase 3 clinical trial were conducted with
`the commercial, to-be-marketed formulation of Zorvolex, whereas the Phase 1 PK study
`DIC1-08-01 and the Phase 2 study were conducted using the proof-of-concept formulation.
`
`I have concluded that this
`This NDA submission was given a standard review designation.
`application should receive an Approval action and have discussed my reasons for this decision
`
`Page 1 of 27
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`Reference ID: 3381721
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`1
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`

`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`
`Joshua M. Lloyd, MD.
`
`in Section 13 below. This review will cover the safety and efficacy of Zorvolex for use in
`patients with mild to moderate acute pain, in addition to several issues that came up during the
`review cycle.
`
`2. Background
`
`The Applicant developed Zorvolex as a new formulation of diclofenac (in the acid form) with
`reduced particle size to, according to the Applicant, promote the dissolution and absorption of
`diclofenac. The Applicant fiirther purported that the improved dissolution properties of
`Zorvolex are associated with rapid absorption resulting in comparable pain relief to Cataflam
`tablets at an approximately 20% lower dose and that the lower dose may have the potential for
`an improved safety profile compared to Cataflam. However,
`it
`is uncertain how any
`potentially improved dissolution properties of a new formulation will substantially improve
`upon the absorption of diclofenac as Cataflam is completely absorbed (100%) following oral
`administration, with mean peak concentrations appearing within one hour.
`In addition, the
`Applicant did not provide any data comparing Zorvolex to Cataflam upon which to make any
`comparative safety or efficacy claims or to substantiate their rationale.
`
`During development,
`
`(mo,
`the Applicant designated their formulation as a
`(mo The Division informed the Applicant, during the
`End-of-Phase 2 meeting, that their formulation does not meet the Agency’s definigg’n of a
`The
`
`Applicant subsequently referred to their formulation as
`
`«no formulation.
`
`The Division held End-of-Phase 2 and Pre-NDA meetings with the Applicant during clinical
`development where agreement was reached on the overall design of the clinical development
`program. One positive adequate and well-controlled clinical efficacy trial in post—operative
`bunionectomy patients with acute pain was sufficient given that the Applicant was relying in
`part on previous findings of safety and efficacy for Cataflam for this 505(b)(2) application. A
`safety database of at least 350 patients is required. A discussion also took place regarding the
`labeling implications of a potential food effect on efficacy given the PK results. The Division
`advised that the Applicant conduct a food effect study on analgesic efficacy or include a food
`restriction in the clinical efficacy studies and the proposed labeling. Additionally, the Division
`issued a Special Protocol Assessment Agreement letter to the Applicant on January 29, 2010,
`for the pivotal clinical trial (Protocol DIC3-08-04) with agreement on the overall design,
`primary endpoint, and imputation methods and concurrence that the trial is acceptable to
`support an efficacy claim for the treatment of mild to moderate acute pain.
`
`3. CMC/Device
`
`The CMC review was conducted by Ying Wang, Ph.D., with secondary concurrence by Prasad
`Peri, Ph.D. There are no unresolved CMC issues. Dr. Wang noted in her review that “[t]his
`NDA is recommended for approval from a Chemistry, Manufacturing, and Controls (CMC)
`perspective” and that “24 months shelf life is proposed and granted when stored at 25°C
`
`Page 2 of 27
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`Reference ID: 3381721
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`2
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`

`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`
`Joshua M. Lloyd, M.D.
`
`(77°F) with excursions permitted to 15°C-30°C (59°F-86°F)” The following information
`summarizes the CMC review.
`
`(m4)
`Zorvolex capsules are provided in two strengths, 18 mg and 35 mg, which contain a
`(m4) white to off-white powder encapsulated in hard gelatin. The 18 mg capsules have a
`blue body imprinted with “IP—203” and a light green cap imprinted with “18 mg” in white ink.
`The 35 mg capsules have a blue body imprinted with “IP-20 ” and a green cap imprinted with
`“35 mg” in white ink. The commercial manufacturing process involves
`(m4)
`
`Dose strength is
`achieved by fill weight. The drug product is packaged in high density polyethylene (HDPE)
`bottles. The submitted drug product stability data include 12 months at long term storage
`conditions of 25°C/60%RH and 6 months at accelerated storage conditions of 40°C/75%RH
`for 3 batches of each strength. Dr. Wang notes that “[t]he stability data support the proposed
`24-month shelf life for the drug product when stored at the proposed 25°C (77°F), with
`excursions permitted between 15°C and 30°C (between 59°F and 86°F)” and that “[t]he drug
`product specifications as amended are adequate and meet ICH Q3B guideline.”
`
`M" powder. Dr. Wang notes
`The drug substance, diclofenac, is a white to off—white
`that “[s]pecificati0ns as amended are adequate and meet ICH Q3A guideline.”
`
`An overall “Acceptable” recommendation was issued by the Office of Compliance on June 13,
`2013.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The nonclinical pharmacology/toxicology review was conducted by Z. Alex Xu, Ph.D.,
`DABT, with secondary concurrence by Adam Wasserman, PhD. According to the nonclinical
`pharmacology/toxicology team, there are no issues that preclude approval for Zorvolex for the
`proposed indication, and the following information summarizes their review.
`
`There was limited nonclinical information submitted in support of Zorvolex as the Applicant is
`relying on findings of safety and efficacy for the reference drug. Zorvolex is a reformulation
`of diclofenac with reduced particle size, and Dr. Xu notes that “reduction of particle size does
`not appear to impose additional risk of toxicity since the particles will be dissolved in gastric
`fluid after administration.” The maximum recommended dose for Zorvolex is 35 mg taken
`three times daily for an acute pain indication. This dose is covered by the maximum dose for
`Cataflam (i.e., 50 mg three times daily) based on systemic exposure with a comparable
`treatment duration (i.e., acute pain), therefore, nonclinical toxicity studies are not required for
`the current application. The excipients in the drug product are not novel and are being used in
`amounts that do not exceed those in previously approved products.
`
`Three diclofenac-related impurities were identified in the drug substance and drug product
`(i.e., impurities A, B, and C), and all are below the qualification threshold levels as required in
`
`Page 3 of 27
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`Reference ID: 3381721
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`3
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`

`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`the ICH Q3A and Q3B guidelines. Therefore, additional nonclinical toxicity studies for
`impurity qualification are not required for this application. However, for impurities that are
`less than the qualification threshold but with a structural alert for genotoxicity, a
`computational genotoxicity assessment is required for qualification. Impurities B and C have
`structural alerts for genotoxicity. According to Dr. Xu’s review:
`
`
`The Applicant conducted a computational toxicity evaluation to assess the
`potential genotoxicity of impurity A, B, and C using the MC4PC system.
`MC4PC is a knowledge-based system using statistical correlation which is
`designed to evaluate/predict the associations between the structure of the
`chemicals and their potential activities in a specific biological assay such as
`Ames assay, in vitro chromosomal assay, and in vivo micronucleus assay, etc.
`MC4PC performs analysis using modules developed by the Informatics and
`Computational Safety Analysis Staff (ICSAS) group of the US FDA
`
` The results of the analysis predicted that all 3 impurities are
`negative in Ames assay, in vitro gene mutation assay, in vitro chromosomal
`assay, in vivo micronucleus assay, and in vivo gene mutation assay,
`suggesting these are non-genotoxic. Based on the current thinking of the
`Agency, only the Ames assay is considered for computational toxicology
`analysis because of the large variability and unreliability in the data of other
`assays. If the computational analysis for Ames assay is negative, there is no
`need to further investigate the genotoxicity potential of an impurity. Notably,
`the Applicant’s evaluation did not incorporate an evaluation in an expert rule-
`based QSAR model. Evaluation in models with both statistical correlation and
`expert rules are considered necessary by the Agency. Therefore, the structures
`of these compounds were sent to CDER computational toxicity group (CTG)
`for analysis of the association of the structures with the potential activity in
`Ames assay using MC4PC system and another knowledge-based system,
`Leadscope Model Appliers (LMA). Both MC4PC and LMA systems use
`statistical correlations to make predictions. In addition, a Derek analysis
`system which uses human expert rules for prediction was also used in the
`analysis conducted by CTG. The results of the analysis predicted that all 3
`known impurities of the Zorvolex are negative in Ames assay thus not
`considered to be mutagenic. Overall, the known impurities of Zorvolex were
`sufficiently qualified.
`
`
`Regarding labeling, Dr. Xu notes that:
`
`
`The current Cataflam label does not contain the Nonclinical toxicology
`section (13). In 2005, when revisions to all NSAID labeling was initiated, the
`Agency incorrectly informed sponsors to leave out the pregnancy or
`carcinogenicity data if toxic effects were not seen in their studies. In this
`submission, the Applicant cited Zipsor® (NDA 22-202, diclofenac potassium)
`for the Nonclinical toxicology section in the Zorvolex label. Of note, Zipsor
`was approved in 2009 as a 505 (b)(2) application which also referenced
`Cataflam. The language of Nonclinical Toxicology section in the original
`
`Page 4 of 27
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`Reference ID: 3381721
`
`4
`
`(b) (4)
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`(b) (4)
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`

`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`Cataflam label will be retrieved and compared with the proposed language of
`this section in Zorvolex label. Revision will be made if necessary.
`
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`Clinical Pharmacology
`The clinical pharmacology review was conducted by Suresh B Naraharisetti, Ph.D., with
`secondary concurrence by Yun Xu, Ph.D. According to the clinical pharmacology team, this
`NDA is acceptable provided that agreement can be reached between the Applicant and the
`Agency on the language in the package insert. The following information summarizes their
`review.
`
`Zorvolex capsules represent a reformulation of diclofenac (in the acid form) with reduced
`particle size. Zorvolex capsules are 20% lower in the molar diclofenac dose as compared to
`the reference drug, Cataflam tablets (diclofenac potassium salt). The two 20% lower Zorvolex
`doses are 18 mg and 35 mg and were compared to the 25 mg and 50 mg strengths of Cataflam,
`respectively. However, the 25 mg strength of Cataflam is discontinued, but not for reasons of
`safety or effectiveness. Please refer to the clinical pharmacology review for more details on
`how these dose comparisons were calculated.
`
`The Applicant submitted two clinical pharmacology studies in this application: DIC1-08-01
`and DIC1-12-07. DIC1-08-01 was conducted with the proof-of-concept formulation and was
`not reviewed by the clinical pharmacology team except to evaluate the food effect for
`Cataflam. DIC1-12-07; a relative bioavailability (BA), dose proportionality, and food effect
`study; was conducted with the commercial formulation, and according to Dr. Naraharisetti,
`fulfills the regulatory requirements to assess the clinical pharmacology information for this
`product.
`
`The BA of Zorvolex 35 mg capsules was compared to Cataflam 50 mg tablets, under fasting
`and fed conditions, in 35 healthy subjects:
`
`
`Under fasted conditions, the 20% lower dose of diclofenac in Zorvolex resulted in the
`following relative PK values compared to the reference drug, Cataflam:
`
` Cmax (peak concentration; geometric mean): 26% lower
` AUC0-t and AUC0-∞ (geometric mean): 23% lower
` Tmax (time to reach peak concentration): no difference (approximately 1 hour for
`both)
`
`
`
`
`
`
`
`
`
`
`Page 5 of 27
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`Reference ID: 3381721
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`

`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`Figure 1. Mean Diclofenac Plasma Concentration-Time Profiles After Administration of Zorvolex Capsules
`and Cataflam Tablets Under Fasting Conditions.
`
`Source: Figure 2.4.1a from Dr. Naraharisetti’s review
`
`
`
`
`Under fed conditions, the 20% lower dose of diclofenac in Zorvolex resulted in the
`following relative PK values compared to the reference drug, Cataflam:
`
` Cmax (peak concentration; geometric mean): 48% lower
` AUC0-t and AUC0-∞ (geometric mean): 26% and 23% lower, respectively
` Tmax (time to reach peak concentration): delayed by approximately 1 hour
`(Cataflam: 2.33 hours; Zorvolex: 3.32 hours)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Page 6 of 27
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`Reference ID: 3381721
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`

`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`Figure 2. Mean Diclofenac Plasma Concentration-Time Profiles After Administration of Zorvolex Capsules
`and Cataflam Tablets Under Fed Conditions.
`
`Source: Figure 2.4.1b from Dr. Naraharisetti’s review
`
`
`
`
`There was no difference in the elimination half-life between Zorvolex and Cataflam under
`fasted or fed conditions.
`
`
`Dr. Naraharisetti notes that:
`
`
`The smaller particle size of Zorvolex capsules, as claimed by the sponsor has
`provided no additional advantage in either rate (Cmax and Tmax) or the extent
`of absorption (AUC) compared to Cataflam when taken under fasted
`conditions. In contrast, when taken under fed conditions, Zorvolex capsules
`has delayed rate (decreased Cmax and delayed Tmax) of absorption compared
`to Cataflam.
`
`
` to describe the formulation do not
`As the particle size and use of the term
`appear relevant to the performance of the drug product compared to the reference drug
`Cataflam, these terms should not appear in labeling or promotional materials.
`
`The two strengths of Zorvolex (i.e., 18 mg and 35 mg) are compositionally proportional and
`result in dose proportional PK for Cmax and AUC under fasted conditions.
`
`The food effect was assessed for Zorvolex 35 mg capsules and Cataflam 50 mg tablets in 35
`healthy subjects:
`
`
`Page 7 of 27
`
`Reference ID: 3381721
`
`7
`
`(b) (4)
`
`

`

`
`
`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`The following relative PK parameters characterize Zorvolex in the fed state compared to
`Zorvolex in the fasted state:
`
` Cmax: 60% lower
` AUC0-t: 14% lower
` AUC0-∞: 11% lower
` Tmax: delayed by 2.32 hours (approximately 139 minutes; 1 hour fasted compared
`to 3.32 hours fed)
`
`
`Figure 3. Mean Diclofenac Plasma Concentration-Time Profiles After Administration of Zorvolex Capsules
`(35 Mg) Under Fasting and Fed Conditions.
`
`Source: Figure 2.4.2a from Dr. Naraharisetti’s review
`
`The following relative PK parameters characterize Cataflam in the fed state compared to
`Cataflam in the fasted state:
`
`
`
`
`
` Cmax: 43% and 28% lower in studies DIC1-08-01 and DIC1-12-07, respectively
` AUC: no change
`
`
`Dr. Naraharisetti notes that:
`
`
`The observed 60% lower Cmax for Zorvolex capsules in the food effect PK
`study is considered significant. Based on the single-oral-dose PK profile of
`Zorvolex capsules, the diclofenac is almost completely eliminated from the
`body by 8 hours (no accumulation). Since Zorvolex is administered TID
`(every 8 hr) and no accumulation from the previous dose, even after multiple
`dosing, every dose of Zorvolex capsules will have similar food effect as
`
`Page 8 of 27
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`Reference ID: 3381721
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`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`observed for a single dose. Hence, Zorvolex capsules are to be labeled as
`“Taking Zorvolex with food may cause a reduction in effectiveness compared
`to taking Zorvolex on an empty stomach.”
`
` I
`
` concur with Dr. Naraharisetti’s conclusion regarding the potential clinical significance of the
`food effect seen with Zorvolex and the recommended labeling changes to address this issue.
`
`Biopharmaceutics
`The biopharmaceutics review was conducted by Banu S. Zolnik, Ph.D., with secondary
`concurrence by Sandra Suarez-Sharp, Ph.D. The biopharmaceutics team was consulted to
`review the dissolution method and acceptance criterion. The dissolution method and
`dissolution acceptance criterion for diclofenac acid capsules, 18 mg and 35 mg, have been
`accepted by the ONDQA Biopharmaceutics team. This application is recommended for
`approval from their perspective.
`
`6. Clinical Microbiology
`N/A
`
`
`7. Clinical/Statistical- Efficacy
`
`
`The efficacy portion of this NDA review was conducted by Steven Galati, M.D., with
`secondary concurrence by me. The statistical review was conducted by Feng Li, Ph.D., with
`secondary concurrence by Janice Derr, Ph.D.
`
`The Applicant submitted the results of one pivotal Phase 3 clinical trial (DIC3-08-04) as
`evidence of efficacy for Zorvolex for the treatment of mild to moderate acute pain. They also
`submitted the results of one Phase 2, proof-of-concept study (DIC2-08-03) as supportive
`evidence. The Phase 2 study was conducted using the proof-of-concept formulation and not
`the commercial formulation.
`
`Dr. Galati conducted a full review of Study DIC3-08-04, as this is the pivotal trial intended to
`demonstrate efficacy for Zorvolex. I will review the salient study design features and the
`results below.
`
`Study DIC3-08-04
`
`Title: A Phase 3, Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Active- and
`Placebo-Controlled Study of Diclofenac
`formulation Capsules for the Treatment of Acute
`Postoperative Pain After Bunionectomy
`
`Primary Objective: To evaluate the analgesic efficacy of diclofenac capsules compared with
`placebo in subjects with acute postoperative pain after bunionectomy
`
`
`
`Page 9 of 27
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`Reference ID: 3381721
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`(b) (4)
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`

`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`Secondary Objectives:
` To evaluate the safety of diclofenac
` capsules compared with placebo in
`subjects with acute postoperative pain after bunionectomy
` To evaluate the time to onset of analgesia for diclofenac capsules compared with
`the standard formulation of celecoxib
`
`
`Design: Phase 3, randomized, double-blind, multiple-dose, parallel group, active- and placebo-
`controlled, multicenter clinical trial
`
`Duration: Study drug was administered for 48 hours after the first dose
`
`Population: Adult patients (≥ 18 and ≤ 65 years of age) with acute postoperative pain after
`bunionectomy who had a pain intensity rating of ≥40 mm on a 100-mm visual analog scale
`(VAS) within 9 hours of discontinuing regional anesthesia
`
`Treatment: Patients were randomized in a 1:1:1:1 fashion to the following treatment groups.
`Study drug (active or placebo) was administered four times daily to maintain the blind.
`
`
` Zorvolex 18 mg three times daily (TID)
` Zorvolex 35 mg TID
` Celecoxib 200 mg twice daily (BID)
` Placebo
`
`
`Rescue Medication: Hydrocodone/acetaminophen 10 mg/325 mg, one tablet every 4 to 6
`hours as needed for rescue; if patients were unable to tolerate hydrocodone/acetaminophen,
`oxycodone/acetaminophen 7.5 mg/325 mg, one tablet every 6 hours as needed could be used
`
`Food Restriction: The Applicant did not include a food restriction in the protocol, and food
`intake was not formally monitored. During the review cycle, the Applicant clarified that the
`majority of subjects received their initial dose of study medication on an empty stomach due to
`the nature of when the first dose was given (i.e., postsurgical, pre-breakfast) without pre-
`specified food restrictions for subsequent dosing.
`
`Primary Efficacy Variable: VAS summed pain intensity difference (calculated as time-
`weighted averages) over 0 to 48 hours (VAS SPID-48)
`
`Secondary Efficacy Variables (none identified as key secondary variables):
` VAS pain intensity difference (VAS PID) at each scheduled time point after Time 0
` VAS pain intensity score at each scheduled time point
` VAS SPID-4, VAS SPID-8, and VAS SPID-24
` Total Pain Relief over 0 to 4 hours (TOTPAR-4), TOTPAR-8, TOTPAR-24, and
`TOTPAR-48
` Time to onset of analgesia (measured as time to perceptible pain relief confirmed
`by meaningful pain relief [double stopwatch method])
` Pain relief score on a 5-point categorical scale at each scheduled time point after
`Time 0
`
`Page 10 of 27
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`Reference ID: 3381721
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`(b) (4)
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`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
` Peak pain relief
` Time to peak pain relief
` Time to first perceptible pain relief
` Time to meaningful pain relief
` Proportion of subjects using rescue medication
` Time to first use of rescue medication
` Total use of opioid rescue analgesia over 0 to 24 hours and over 0 to 48 hours
` Patient’s global evaluation of study drug
`
`
`Statistical Analysis Plan: Dr. Li notes in his review that:
`
`
`The primary efficacy variable was analyzed using an analysis of covariance
`(ANCOVA) model with baseline pain score as a covariate and treatment as a
`factor. The primary analysis population included all subjects who were
`randomized and received at least one dose of study medication. To control
`multiplicity, a sequential
`testing procedure was carried out for
`the
`comparisons of the two doses of diclofenac with placebo. Zorvolex 35 mg
`was compared to placebo first. Zorvolex 18 mg was compared to placebo
`only if Zorvolex 35 mg was significantly better than placebo. There were no
`comparisons between Zorvolex and celecoxib in the primary analysis.
`
`Missing pain assessments for subjects who discontinued early due to lack of
`efficacy or adverse events were imputed using a baseline observation carried
`forward approach (BOCF). Missing pain assessments due to other reasons
`were imputed using a last observation carried forward approach (LOCF). For
`subjects who took any dose of rescue medication, subsequent pain
`assessments after the first dose of rescue medication were disregarded and
`imputed using a BOCF approach. Intermittent missing pain assessments were
`imputed using linear interpolation.
`
`The applicant conducted a sensitivity analysis for the primary efficacy
`analysis by adding gender as a factor into the ANCOVA model. Sensitivity
`analyses for the methods to handling missing values were not conducted.
`
`Time to onset of analgesia was right censored at 8 hours for subjects who did
`not experience both perceptible pain relief and meaningful pain relief during
`the 48-hour interval or who required rescue medication prior to achieving
`perceptible or meaningful pain relief.
`
`
`Patient Disposition, Demographic and Baseline Characteristics:
`
`As noted in Dr. Li’s review:
`
`
`A total of 428 subjects were randomized. All randomized subjects received
`the study medications...Overall, a total of 421 (98%) subjects completed the
`study. No subjects in the Zorvolex 18 mg group discontinued the study early.
`
`Page 11 of 27
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`Reference ID: 3381721
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`

`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`Both the Zorvolex 35 mg and the celecoxib groups had one subject
`discontinued early due to investigator decision1 and subject request,
`respectively. Five subjects (5%) in the placebo group discontinued the study
`early, three of which due to lack of efficacy.
`
`The demographic and baseline characteristics were generally comparable
`across treatment groups. A summary of selected demographic and baseline
`characteristics is provided in [the] Table [below]. The summary for race was
`reproduced using the applicant’s dataset, which differed slightly from the
`clinical study report. The majority of the subjects were female and white.
`Overall, the mean age was about 40 years. Approximately 85% of the subjects
`were white.
`
`
`Table 1. Summary of Demographics and Baseline Characteristics
`
`
`
`Source: Table 2 from Dr. Li’s review; SD=standard deviation
`
`The distribution seen in the study population with respect to demographics and baseline
`characteristics (i.e., predominantly White or Caucasian women) is expected given the
`epidemiology of the underlying disease process (i.e., bunions).
`
`Baseline pain intensity was evenly balanced across treatment groups, as seen in the table
`below.
`
`
`1 Discontinued when the investigator learned that the subject did not meet inclusion/exclusion criteria for having a
`history of a gastric ulcer (i.e., protocol violation)
`
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`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`
`Joshua M. Lloyd. M.D.
`Table 2. Summary of Baseline Characteristics
`Diclofenac
`
`“)(Qt‘ormulation
`
`Celecoxib
`
`Capsule
`CaEule
`35 mg
`18 mg
`200 mg‘
`Placebo
`Total
`Variable
`n = 107
`n = 109
`n =106
`(n = 106
`N = 428
`
`Baseline pain intensity. mm
`n
`
`106
`
`428
`
`107
`
`109
`
`106
`
`Mean (81))
`Median
`
`Minimum. maximum
`Surgery duration. minutes
`n
`
`74.1 (16.1)
`75.0
`
`(72;)
`76.0
`
`74.2 (16.8)
`74.0
`
`(:23)
`77.0
`
`75.4 (16.3)
`76.0
`
`(44. 100)
`
`41. 100)
`
`(40. 100)
`
`(40. 100)
`
`(40. 100)
`
`107
`
`109
`
`106
`
`106
`
`428
`
`Mean (SD)
`Median
`
`28.2 (6.7)
`28.0
`
`28.9 (6.9)
`29.0
`
`29.7 (1 1.1)
`29.0
`
`29.9 (9.4)
`28.0
`
`29.2 (8.7)
`28.0
`
`(16. 48)
`Minimum. maximum
`Source ofdata: Section 14.1. Table 14.1.2
`Abbreviations: SD = standard deviation.
`"
`The initial dose of celecoxib was 400 mg: subsequent doses were 200 mu.
`Source: Table 9 from Dr. Galati’s review
`
`15. 52)
`
`(16.115)
`
`(16. 72)
`
`(15.115)
`
`Results:
`
`The results for the primary efficacy analysis are presented in the table below. The results were
`replicated by Dr. Li. Both Zorvolex 35 mg and 18 mg were superior to placebo on the primary
`efficacy endpoint.
`
`Table 3. Primary Efficacy Analysis
`
`
`Zorvolex
`
`Statistics
`35 mg TID
`18 mg TID
`Celecoxib BID
`Placebo
`n
`107
`109
`106
`106
`
`LS Mean (SE)
`95% Cl
`
`524 (86)
`(355. 693)
`
`393 (85)
`(225, 561)
`
`390 (86)
`(220. 560)
`
`77 (86)
`( -93. 247)
`
`313 (122)
`316 (121)
`447 (122)
`Difference in 1.8 mean(SF,)
`(72, 554)
`(77. 555)
`(207. 687)
`95% CI for diff. in LS mean
`
`_p-va1ue for treatment effect
`<0.001
`0.01
`0.01
`Source: Table 3 from Dr. Li’s review; SE=standard error; CI=confidence interval; LS=least square
`
`The high and differential frequencies in rescue medication use and the imputation method for
`subsequent pain scores have the potential to substantially influence the comparisons among
`treatments. As noted in Dr. Li’s review:
`
`The applicant replaced all the pain scores afier the first use of the rescue
`medication with the baseline observations. When the percentage of subjects
`who take rescue medications is high, the approach to handling the pain scores
`after rescue may substantially influence the comparisons among treatments. In
`the acute pain setting,
`it
`is often likely that subjects will
`take rescue
`medications. [The t]able [below] presents the percentage of subjects who took
`rescue medications for pain management during the study. For all treatment
`
`Page 13 of 27
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`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`groups, more than 80% of the subjects took rescue. Placebo group had the
`highest percentage of subjects who took rescue. The majority of the subjects
`took their first rescue within 8 hours after the first dose, that is, before the
`second dose of the study medication. [The f]igure [below] depicts the average
`pain intensity over time for each treatment group during the 48 hours after the
`first dose with pain scores after rescue imputed using a BOCF approach.
`Although the placebo group had the worst pain on average, there was not
`much pain reduction for all treatment groups. All the pain curves are rather
`flat after 10 hours. This is because the majority of the subjects took rescue
`during the first 8 hours and their pain scores after the first rescue were
`replaced by the corresponding baseline values.
`
`
`Table 4. Rescue Medication – Number (%) of Subjects
`
`Source: Table 4 from Dr. Li’s review
`
`Figure 4. Average Pain Over Time – BOCF After Rescue
`
`
`
`Source: Figure 1 from Dr. Li’s review
`
`Additionally, a higher percentage of patients in the placebo group used rescue medication at
`each frequency level (see figure below).
`
`
`
`
`Page 14 of 27
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`Reference ID: 3381721
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`Cross Discipline Team Leader Review
`NDA 204592 Zorvolex
`Joshua M. Lloyd, M.D.
`Figure 5. Percentage of Subjects with Different Frequency of Rescue Use
`
`Source: Figure 3 from Dr. Li’s review
`
`Dr. Li calculated the primary efficacy endpoint using the observed pain scores after rescue and
`conducted an analysis using the same approach as the one in the primary analysis, and those
`results are described below.
`
`
`
`
`[The f]igure [below] displays the average pain intensity over time for each
`treatment group without imputation for taking rescue, that is, the actual
`observed pain scores after rescue were used. The overall trend of actual pain
`reduction over time is apparent for each treatment group. Among the
`treatments, subjects in the placebo group experienced the least pain reduction.
`The separation of the pain curve of the placebo from the three active
`treatments occurred after approximately 3 hours after dosing. To compare the
`treatment effects under the influence of rescue medications in terms of the
`primary efficacy endpoint, I calculated the summed pain intensity difference
`over 48 hours using the observed pain scores after rescue and conducted an
`analysis using the same ANCOVA model as the one used in the primary
`analysis. The analysis results are presented in [the t]able [below]. The
`differences between the three active treatments and placebo were all
`statistically significant, which indicates that the active treatments in
`combination with the rescue medications produced superior analgesic effects
`to placebo in combination with the rescue medications.
`
`
`
`
`
`Page 15 of 27
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`Reference ID: 3381721
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`Cross Discipl