`RESEARCH
`
`
`APPLICATION NUMBER:
`
`022272Orig1s027
`
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`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 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/BLA #:
`Drug Name:
`Indication(s):
`
`Applicant:
`Date(s):
`Review Priority:
`
`NDA 022-272
`OxyContin (oxycodone hydrochloride) tablet
`Management of acute pain severe enough to require opioid
`treatment and for which alternative treatment options are
`inadequate
`Purdue Pharma L.P.
`Letter date: December 10, 2014, PDUFA date: June 8, 2015
`Priority
`
`Biometrics Division:
`Statistical Reviewer:
`Concurring Reviewers:
`
`II
`Feng Li, Ph.D.
`Freda Cooner, Ph.D.
`
`Medical Division:
`Clinical Team:
`Project Manager:
`
`Division of Anesthesia, Analgesia, and Addiction Products
`Javier Muniz, M.D.
`Diana Walker
`
`Keywords: NDA review, Pediatric Written Request (PWR), Clinical Studies
`
`Reference ID: 3749626
`
`
`
`Table of Contents
`
`LIST OF TABLES.......................................................................................................................................................3
`
`LIST OF FIGURES.....................................................................................................................................................4
`
`1. EXECUTIVE SUMMARY .................................................................................................................................5
`
`2.
`
`3.
`
`4.
`
`5.
`
`INTRODUCTION ...............................................................................................................................................6
`2.1
`OVERVIEW......................................................................................................................................................6
`2.2
`DATA SOURCES ..............................................................................................................................................7
`STATISTICAL EVALUATION ........................................................................................................................7
`3.1
`DATA AND ANALYSIS QUALITY .....................................................................................................................7
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................7
`3.2.1
`Study Design and Endpoints..................................................................................................................7
`3.2.2
`Statistical Methodologies.......................................................................................................................8
`3.2.3
`Patient Disposition, Demographic and Baseline Characteristics..........................................................8
`3.2.4
`Results and Conclusions ......................................................................................................................10
`3.3 EVALUATION OF SAFETY ....................................................................................................................................13
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................................................13
`GENDER, AGE AND RACE .............................................................................................................................13
`4.1
`OTHER SPECIAL/SUBGROUP POPULATIONS ..................................................................................................15
`4.2
`SUMMARY AND CONCLUSIONS ................................................................................................................15
`5.1
`STATISTICAL ISSUES.....................................................................................................................................15
`5.2
`COLLECTIVE EVIDENCE................................................................................................................................16
`5.3
`CONCLUSIONS AND RECOMMENDATIONS .....................................................................................................16
`5.4
`LABELING RECOMMENDATIONS ...................................................................................................................16
`APPENDIX.................................................................................................................................................................18
`
`Reference ID: 3749626
`
`2
`
`
`
`LIST OF TABLES
`
`Table 1: Subject Disposition..........................................................................................................................................9
`Table 2: Summary of Demographics and Baseline Characteristics ...............................................................................9
`Table 3: Summary of Efficacy Analysis Results .........................................................................................................11
`
`Reference ID: 3749626
`
`3
`
`
`
`LIST OF FIGURES
`
`Figure 1: Pain Assessments by Dose Interval..............................................................................................................12
`Figure 2: Total Supplemental Opioids by Dose Interval .............................................................................................12
`Figure 3: Pain Assessments by Age Group..................................................................................................................13
`Figure 4: Total Supplemental Opioids by Age Group .................................................................................................14
`Figure 5: Pain Assessments by Gender........................................................................................................................14
`Figure 6: Total Supplemental Opioids by Gender .......................................................................................................15
`
`Reference ID: 3749626
`
`4
`
`
`
`1.
`
`EXECUTIVE SUMMARY
`
`Purdue Pharma L.P. has submitted a supplemental NDA for OxyContin to apply for pediatric
`exclusivity and approval for updating the labeling to include the pediatric studies results in
`response to the Pediatric Written Request (PWR) #3, Amendment #2, issued on November 14,
`2011. OxyContin is an extended-release (ER) oral formulation of oxycodone hydrochloride
`(HCl) and currently indicated for the management of pain severe enough to require daily,
`around-the-clock, long-term opioid treatment and for which alternative treatment options are
`inadequate. The applicant submitted three studies to fulfill the requirement of the PWR. This
`review focuses on the efficacy study (Study 2) requested by the PWR. Based on my review, the
`efficacy study was not prospectively designed or powered to demonstrate superiority over
`placebo, and as such could not provide evidence for efficacy with appropriate statistical
`significance for the proposed pediatric indication.
`
`The submitted efficacy study (Study OXP3003) was a multicenter, double-blind, randomized,
`placebo-controlled, dose-ranging study designed to evaluate the pharmacokinetics, safety, and
`efficacy of Oxy Pediatric Liquid 1 mg/mL (oxycodone HCl oral solution) in patients aged 5 to 16
`years old. Patients were opioid-naïve at study entry or pre-operatively and had moderate to
`severe pain requiring opioid analgesics for at least 2 days. At randomization, a total of 68
`eligible patients were stratified into two groups (5 to < 12 years and 12 to ≤ 16 years) and
`randomly assigned in a 3:3:2 ratio to receive Oxy Pediatric Liquid 0.1 mg/kg, Oxy Pediatric
`Liquid 0.2 mg/kg, or placebo. Patients were administered Oxy Pediatric Liquid or placebo every
`6 hours for a total of 4 to 5 doses. All patients were permitted to receive patient controlled
`analgesia (PCA) or oral morphine sulfate as supplemental pain medication. Efficacy
`assessments included supplemental pain medication usage and pain intensity. The study was
`powered for pharmacokinetics evaluation and adverse events detection.
`
`Neither the protocol nor the Statistical Analysis Plan (SAP) clearly specified the primary or
`secondary efficacy endpoints for treatment comparisons. The study report presented analysis
`results for multiple variables evaluating pain scores and supplemental pain medication usage,
`respectively. A statistical test for dose response was performed on each of these efficacy
`variables using the Jonckheere-Terpstra approach. No adjustment for multiplicity was planned
`or performed. The full efficacy analysis population included the 65 patients who received at
`least one dose of study medication and had at least one subsequent efficacy evaluation. Efficacy
`outcomes were not collected for the discontinued patients after they stopped the randomized
`treatment pre-maturely. There was no imputation method proposed for missing efficacy
`assessments.
`
`Dose response was not established with statistical significance at a one-sided level of 0.025 or
`two-sided level of 0.05 for most of the efficacy variables. Nevertheless, it was observed that all
`of these efficacy variables were numerically in favor of oxycodone against placebo. Patients
`randomized to placebo reported slightly higher pain on average and used more supplemental pain
`medications during the study.
`
`5
`
`Reference ID: 3749626
`
`
`
`In summary, the efficacy study was not prospectively designed or powered to show superiority
`over placebo, and as such it could not provide evidence of efficacy with the usually required
`level of statistical significance.
`
`2.
`
`INTRODUCTION
`
`2.1 Overview
`
`OxyContin is an extended-release (ER) oral formulation of oxycodone hydrochloride (HCl) and
`currently indicated for the management of pain severe enough to require daily, around-the-clock,
`long-term opioid treatment and for which alternative treatment options are inadequate. Purdue is
`submitting this efficacy supplemental NDA in support of updating the OxyContin labeling to
`include the pediatric study results in accordance with the November 14, 2011 Written Request
`(WR) #3, Amendment #2.
`
`An initial PWR was issued in 1998. Thereafter, the division and the applicant have discussed
`revisions of the PWR on multiple occasions. The latest version was PWR #3, Amendment #2
`issued in November 2011 for both NDA 020553 and NDA 022272, which requested the
`following three studies:
`
`Study 1: Pharmacokinetic (PK) study of an age-appropriate formulation of oxycodone in opioid-naïve
`patients from birth up to less than four years of age.
`
`Study 2: Efficacy, safety, and PK study of an age-appropriate formulation of immediate release (IR)
`oxycodone in opioid-naïve patients from five years up to no more than 16 years of age.
`
`Study 3: Open-label safety and PK study of an oxycodone controlled-release tablet in opioid tolerant
`patients from six years to no more than 16 years of age with moderate to severe pain requiring around-the-
`clock opioid therapy for an extended period of time.
`
`The PWR specified that Study 2 should be active or placebo-controlled, double-blind, dose-
`ranging, in-patient, superiority study evaluating the pharmacokinetics (using a population
`pharmacokinetic approach) of oxycodone after single and repeated dosing (preferably at a steady
`state) of an age-appropriate population. This study should also include assessment of efficacy
`(i.e., pain intensity evaluations and rescue medication usage) and safety (i.e., adverse events).
`The study should enroll sufficient number of pediatric patients to demonstrate a clinically
`meaningful difference in pain intensity between active and comparator. The PWR further
`requested that confidence intervals and significance test for differences between treatment
`groups in pain scores and rescue medication use be computed, variability of patients within
`treatment groups be characterized.
`
`In the advice letter dated May 14, 2010, the division stated that completed Study OXP1005 and
`Study OXP3003 may be used as Studies 1 and 2, respectively. The applicant subsequently
`completed Study OTR3001 to fulfill Study 3 requirements. Both Study OXP1005 and Study
`
`6
`
`Reference ID: 3749626
`
`
`
`OTR3001 were open-label studies. Study OXP3003 was a randomized, double-blind, placebo-
`controlled dose-ranging study. This statistical review focuses on Study OXP3003.
`
`This review mainly evaluates whether the updated labeling was supported by the study data.
`
`2.2 Data Sources
`
`The efficacy data submitted for Study OXP3003 can be found at
`\\Cdsesub1\evsprod\NDA022272\0224\m5\datasets\oxp3003.
`
`3.
`
`STATISTICAL EVALUATION
`
`3.1 Data and Analysis Quality
`
`The applicant submitted study SDTM tabulation datasets and AdaM analysis datasets in CDISC
`format. The datasets and define files were of acceptable quality, and were sufficient for
`validating study results.
`
`3.2 Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`
`Study OXP3003 was a multicenter, double-blind, randomized, placebo-controlled, dose-ranging
`study designed to evaluate the pharmacokinetics, safety, and efficacy of Oxy Pediatric Liquid 1
`mg/mL (oxycodone HCl oral solution) in patients aged 5 to 16 years old. Patients were opioid-
`naïve at study entry or pre-operatively and had moderate to severe pain requiring opioid
`analgesics for at least 2 days. The primary objectives of this study stated in the protocol were to
`characterize in-patients the pharmacokinetics and safety of Oxy Pediatric Liquid 1 mg/mL. The
`secondary objective was to assess the efficacy of Oxy Pediatric Liquid 1 mg/mL compared with
`placebo. The study started enrollment in January 2003 and completed in April 2004.
`
`The protocol stated that sufficient number of patients would be enrolled to achieve 100 PK
`evaluable patients with approximately equal number of patients in the 5 to <12 year old age
`group and 12 to ≤16 year old age group. At randomization, eligible patients were stratified into
`the two age groups and randomly assigned in a 3:3:2 ratio to receive 0.1 mg/kg Oxy Pediatric
`Liquid, 0.2 mg/kg Oxy Pediatric Liquid, or placebo. Patients were administered Oxy Pediatric
`Liquid or placebo every 6 hours for a total of 4 to 5 doses. In the case of post-operative patients,
`study treatment could begin when the patients were ready to take oral medication. Dosing was
`based on the weight of the patients in this study. All patients were permitted to receive patient
`controlled analgesia (PCA) or oral morphine sulfate (if the intravenous route stopped
`functioning) as supplemental pain medication during the double-blind treatment.
`
`7
`
`Reference ID: 3749626
`
`
`
`Efficacy assessments included supplemental pain medication usage and pain intensity. Pain
`intensity (i.e., pain right now) was measured using the Faces Pain Scale-Revised (FPS-R) prior
`to and 1 hour after each dose, with additional recordings at 0.5, 1, 2, and 3 hours after the first
`dose. These pain intensities were recorded as scheduled pain assessments. Additionally,
`unscheduled pain intensity scores were recorded based an 11-point Numeric Rating Scale when
`nurse-administered PCA was given. All doses of PCA morphine and other supplemental pain
`medications were to be recorded in the case report form.
`
`According to the applicant, the study was powered for PK evaluation and adverse events
`detection instead of efficacy demonstration.
`
`3.2.2 Statistical Methodologies
`
`Neither the protocol nor the Statistical Analysis Plan (SAP) clearly specified the primary or
`secondary efficacy endpoints for treatment comparisons. The study report presented analysis
`results for multiple variables evaluating pain scores and supplemental pain medication usage,
`respectively. A statistical test for dose response was performed on each of these efficacy
`variables using the Jonckheere-Terpstra approach. No adjustment for multiplicity was planned
`or performed. The full efficacy analysis population included the 65 patients who received at
`least one dose of study medication and had at least one subsequent efficacy evaluation. Efficacy
`outcomes were not collected for the discontinued patients after they stopped the randomized
`treatment pre-maturely. There was no imputation method proposed for missing efficacy
`assessments.
`
`3.2.3 Patient Disposition, Demographic and Baseline Characteristics
`
`The protocol stated that sufficient number of patients would be enrolled to achieve 100 PK
`evaluable patients. However, according to the applicant, Study OXP3003 was terminated early
`due to reasons unrelated to safety and efficacy. A total of 68 patients were randomized. Three
`patients discontinued the study early prior to receiving the study treatments. The full analysis
`population included 65 patients, 19 receiving placebo, 24 receiving Oxy Pediatric Liquid 0.1
`mg/kg, and 22 receiving Oxy Pediatric Liquid 0.2 mg/kg (Table 1). Overall, approximately 17%
`of the patients discontinued the double-blind period early. The primary reason for
`discontinuation was subject’s choice. The discontinuation rate of the Oxy Pediatric Liquid 0.2
`mg/kg group was the lowest among the three treatment groups while the other two treatment
`groups had similar discontinuation rates. The dropout pattern was similar between the two age
`groups.
`
`The demographic and baseline characteristics were comparable across treatment groups (Table
`2). About 40% of the patients were less than 12 years old. The majority of the patients were
`female (63%). The median pre-dose pain score of the patients randomized to Oxy Pediatric
`Liquid 0.2 mg/kg was 2.5, notably lower than those of the other two groups. The median pre-
`
`8
`
`Reference ID: 3749626
`
`
`
`dose pain scores of the patients randomized to placebo and Oxy Pediatric Liquid 0.1 mg/kg were
`both 4.
`
`Table 1: Subject Disposition
`
`Age Group
`All patients
` Completed, n (%)
` Discontinued, n(%)
` Adverse event
` Subject’s choice
` Administrative
`Age group: 5 to <12 years
` Completed, n (%)
` Discontinued, n(%)
` Adverse event
` Subject’s choice
` Administrative
`Age group: 12 to ≤16 years
` Completed, n (%)
` Discontinued, n(%)
` Adverse event
` Subject’s choice
` Administrative
`Source: Clinical study report, Table 14.1.1
`
`Placebo
`N=19
`15 (79)
`4 (21)
`1 (5)
`3 (16)
`0
`N=7
`6 (86)
`1 (14)
`0
`1 (14)
`0
`N=12
`9 (75)
`3 (25)
`1 (8)
`2 (17)
`0
`
`0.1 mg/kg
`N=24
`18 (75)
`6 (25)
`1 (4)
`3 (13)
`2 (8)
`N=10
`7 (70)
`3 (30)
`1 (10)
`1 (10)
`1 (10)
`N=14
`11 (79)
`3 (21)
`0
`2 (14)
`1 (7)
`
`0.2 mg/kg
`N=22
`21 (95
`1(5)
`0
`1 (5)
`0
`N=9
`9 (100)
`0
`0
`0
`0
`N=13
`12 (92)
`1 (8)
`0
`1 (8)
`0
`
`Total
`N=65
`54 (83)
`11 (17)
`2 (3)
`7 (11)
`2 (3)
`N=26
`22 (85)
`4 (15)
`1 (4)
`2 (8)
`1 (4)
`N=39
`32 (82)
`7 (18)
`1 (3)
`5 (13)
`1 (3)
`
`Table 2: Summary of Demographics and Baseline Characteristics
`
`0.1 mg/kg
`(N=24)
`11 (3)
`
`10 (42)
`14 (58)
`
`9 (37)
`15 (63)
`
`16 (67)
`3 (12)
`1 (4)
`4 (17)
`
`43 (19)
`
`Mean age (SD)
`Age group, n (%)
` 5 to <12 years
` 12 to ≤16 years
`Gender, n (%)
` Male
` Female
`Race, n (%)
` White
` Black
` Asian
` Other
`Weight (kg)
` Mean (SD)
`Baseline pain intensity*
`3.3 (2.8)
`3.5 (2.6)
` Mean (SD)
`4
`4
` Median
`(0, 10)
`(0, 9)
` (Min, Max)
`Source: Clinical study report, Table 14.1.3; SD: standard deviation
`*: derived using the pre-dose FPS-R pain scores from the ADXP dataset.
`
`Placebo
`(N=19)
`12 (3)
`
`7 (37)
`12 (63)
`
`7 (37)
`12 (63)
`
`16 (84)
`1 (5)
`1 (5)
`1 (5)
`
`43 (14)
`
`Reference ID: 3749626
`
`0.2 mg/kg
`(N=22)
`11 (4)
`
`9 (41)
`13 (59)
`
`8 (36)
`14 (64)
`
`16 (73)
`1 (4)
`0
`5 (23)
`
`44 (23)
`
`2.8 (2.5)
`2.5
`(0, 8)
`
`Total
`(N=65)
`11 (3)
`
`26 (40)
`39 (60)
`
`24 (37)
`41 (63)
`
`48 (74)
`5 (8)
`2 (3)
`10 (15)
`
`44 (19)
`
`3.2 (2.6)
`3.5
`(0, 10)
`
`9
`
`
`
`3.2.4 Results and Conclusions
`
`The applicant provided a table of summary of efficacy results with p-values from the
`Jonckheere-Terpstra test for non-increasing dose response (Table 3). Confidence intervals for
`the treatment differences were not submitted. I was able to reproduce these results and noted that
`the p-values provided in the table are all one-sided.
`
`Denote T1, T2, and T3 as the median of an efficacy variable for placebo, Oxy Pediatric Liquid
`0.1 mg/kg, and Oxy Pediatric Liquid 0.2 mg/kg, respectively. The null hypothesis T1=T2=T3
`was tested against the alternative of non-increasing order, that is, T1≥T2≥T3, with at least one
`strict inequality. The applicant compared the left-tail p-value from the Jonckheere-Terpstra test
`to the significance level of 0.05 to determine if there was a statistically significant dose response
`for each efficacy variable and thus claimed that most of the efficacy variables demonstrated dose
`response with statistical significance. In particular, the applicant claimed that “During the 6 hour
`interval following first dose, pain scores were statistically significantly lower in the active
`treatment groups compared to the placebo group (p=.034)” in Section 14 of the labeling.
`
`To be comparable to a hypothesis testing based on a two-sided significance level of 0.05, which
`is the usual standard for efficacy comparisons, a statistical test based on a one-sided p-value
`should be compared to the threshold of 0.025. Thus, only the tests for dose responses in total
`PCA morphine usage excluding the first dosing interval and the maximum overall pain score
`reached nominal significance at the level of 0.025. However, since there was no multiplicity
`adjustment, the overall type-I error was not controlled and it is difficult to interpret these p-
`values. Nevertheless, all the analyses results were numerically in favor of oxycodone in
`comparison to placebo. Overall, placebo patients reported higher pain scores and used more
`supplemental pain medications than the two active treatment groups.
`
`Reference ID: 3749626
`
`10
`
`
`
`Table 3: Summary of Efficacy Analysis Results
`
` Source: Clinical Study Report, Table 11; SD: standard deviation
`
`The average pain score and total supplemental opioid usage are depicted by dose intervals for
`each treatment group in Figures 1 and 2, respectively. For all treatment groups, the average pain
`was not high at baseline and well-controlled during the study (Figure 1). Since all patients were
`on supplemental PCA throughout the study, it might cause difficulties to show analgesic dose
`response among treatments. Figure 1 shows that the separations among the pain curves for the
`treatments are small. In contrast, there is notable separation of the curve for the total
`supplemental opioid usage of the placebo patients from those of the oxycodone treated patients
`(Figure 2). Placebo-treated patients requested more supplemental opioids than oxycodone-
`treated patients throughout all dosing intervals. The two oxycodone-treated groups were similar
`in terms of pain scores and supplemental opioid usage. The total supplemental opioids usage
`included both PCA and non-PCA opioids usage. PCA morphine was the primary supplemental
`pain medication during the treatment period. Separate illustrations of PCA, non-PCA opioid and
`acetaminophen usages are further provided in the Appendix Figures 1, 2 and 3.
`
`The pain scores analyzed were the average of the scheduled pain assessments and those recorded
`before each PCA administration during the corresponding dose interval. Analyses utilizing only
`scheduled pain scores produced similar results. The mean scores of scheduled and unscheduled
`pain assessments are depicted for each treatment by dose intervals in the Appendix Figures 4 and
`5, respectively. Only several patients in each treatment group had unscheduled pain scores.
`
`11
`
`Reference ID: 3749626
`
`
`
`Figure 1: Pain Assessments by Dose Interval
`
`Figure 2: Total Supplemental Opioids by Dose Interval
`
`Reference ID: 3749626
`
`12
`
`
`
`3.3 Evaluation of Safety
`
`The evaluation of the safety data was conducted by the clinical reviewer, Dr. Javier Muniz.
`Please refer to Dr. Muniz’s review for detailed information regarding the adverse event profile.
`
`4.
`
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`The applicant presented subgroup summaries for Study OXP3003 in the Summary of Clinical
`Efficacy (Module 2.7.3) within this submission. I also conducted subgroup descriptive statistics
`and produced some plots (see below) for visual comparisons by dose intervals. Findings from
`the subgroup analyses were generally consistent with those observed in the overall population.
`
`4.1 Gender, Age and Race
`
`Subgroup analyses for race were not conducted since the majority of patients were White (74%).
`The average pain and average total supplemental opioids usage of each treatment group by dose
`intervals are depicted by age groups in Figures 3 and 4, respectively. It appears the differences
`between placebo- and active-treated groups are more apparent in the elder group, especially for
`the supplemental opioids usage. The subgroup plots by gender for pain scores and supplemental
`opioids usage are provided in Figures 5 and 6, respectively. The separation of the pain curves
`seems more evident for male patients, which may primarily due to the difference observed at
`baseline. The treatment effect on supplemental opioids usage in male was rather similar to that
`in female patients.
`
`Figure 3: Pain Assessments by Age Group
`
`Reference ID: 3749626
`
`13
`
`
`
`Figure 4: Total Supplemental Opioids by Age Group
`
`Figure 5: Pain Assessments by Gender
`
`Reference ID: 3749626
`
`14
`
`
`
`Figure 6: Total Supplemental Opioids by Gender
`
`4.2 Other Special/Subgroup Populations
`
`No other subgroup summaries were performed.
`
`5.
`
`SUMMARY AND CONCLUSIONS
`
`5.1 Statistical Issues
`
`Some statistical issues in the applicant’s efficacy analyses were identified.
`
`Firstly, neither the protocol nor the SAP clearly specified the primary or secondary efficacy
`endpoints and there was no multiplicity adjustment for the multiple tests conducted for multiple
`endpoints. Efficacy was evaluated by testing dose response for pain intensity and supplemental
`pain medication usage. Efficacy variables analyzed included, but not limited to, pain intensity
`and total amount of supplemental pain medications in the first dose interval, overall including the
`first dose interval, and overall excluding the first dose interval. In the absence of an appropriate
`multiplicity adjustment approach, the overall Type I error was not controlled and it is difficult to
`interpret the p-values. This may not be a concern when all the tests reached statistical
`significance favoring the active drug. However, most of the tests for the efficacy variables did
`not reach significance at the one-sided level of 0.025 or two-sided level of 0.05. The applicant
`incorrectly claimed that most of the tests reached significance by inappropriately comparing one-
`sided p-values to the usual threshold of 0.05, which is for two-sided tests.
`
`15
`
`Reference ID: 3749626
`
`
`
`Secondly, neither efficacy outcomes were collected nor imputation methods were implemented
`for the missing data from the patients who stopped the randomized treatment pre-maturely. The
`applicant’s efficacy analyses were based on available data only, which might be biased,
`especially for the total amount of supplemental pain medications usage. In the in-patient setting
`with 2-day treatment duration, it would have been sensible to continue to collect the efficacy
`outcomes off treatment from those discontinued patients.
`
`Lastly, the study was powered for PK and adverse events detection instead of efficacy
`evaluation, which might be the main reason why most of the efficacy variables did not reach
`statistical significance. Furthermore, the applicant applied the Jonckheere-Terpstra approach for
`testing a monotonic dose response among placebo, oxycodone 0.1 mg/kg, and oxycodone 0.2
`mg/kg. The Jonckheere-Terpstra approach is a valid test in this setting. However, the efficiency
`is not at its maximum when both active doses are superior to placebo but no difference between
`the two doses of oxycodone, which appeared to be the case observed in this study.
`
`5.2 Collective Evidence
`
`Dose response was not established with appropriate statistical significance for most of the
`efficacy variables assessing pain intensity or supplemental pain medication use. Nevertheless, it
`was observed that the results of the efficacy variables were all numerically in favor of
`oxycodone. Patients randomized to placebo reported slightly higher pain intensity on average
`and used more supplemental pain medications during the study. Overall, the observed data
`suggest that the two oxycodone doses may be efficacious for the desired indication in pediatric
`population. However, the study did not provide evidence of efficacy with the usually required
`level of statistical significance.
`
`5.3 Conclusions and Recommendations
`
`Study OXP3003 was the efficacy study conducted to fulfill the requirement of Study 2 specified
`in the PWR. However, the study was not powered for demonstrating efficacy. The efficacy
`results were only numerically in favor of oxycodone against placebo with respect to management
`of pain and reduction of usage of supplemental pain medication. Thus, the study did not meet
`the usual standard for providing substantial evidence of efficacy.
`
`5.4 Labeling Recommendations
`
`The applicant submitted the following wording to add to the clinical study section of the label for
`review:
`
`16
`
`Reference ID: 3749626
`
`
`
`Pediatric clinical studies
`
`
`
`I have the following recommendations to the applicant:
`
`lace
`Para ah42r
`
`”
`
`flanM: deletethe ‘—
`
`Para a h 4: Revised the last two sentences to be
`
`Reference ID: 3749626
`
`17
`
`
`
`Appendix
`
`Figure 1: PCA Morphine Usage by Dose Interval
`
`Figure 2: Total Non-PCA Morphine Usage by Dose Interval
`
`Reference ID: 3749626
`
`18
`
`
`
`Figure 3: Total Acetaminophen Usage by Dose Interval
`
`Figure 4: Scheduled Pain Assessments by Dose Interval
`
`Reference ID: 3749626
`
`19
`
`
`
`Figure 5: Unscheduled Pain Assessments by Dose Interval
`
`.-
`
`MU5L710)\lm{DOlll
`UnscheduledPainAsesments
`Mean
`
`—E— Placebo - e - 0.1 mgle "0 - - 0.2 mglkg
`
`PRE-DOSE1
`
`0 - <6 Hours
`
`6 - <12 Hours
`
`12 - <18 Hours
`
`18 - <24 Hours
`
`24 - 30 Hours
`
`0,2 mglkg
`Placebo
`
`N=7
`N=8
`N=7
`
`N=7
`N=B
`N=B
`
`N=4
`N=7
`N=7
`
`N=6
`N=6
`N=7
`
`N=1
`N=5
`N=7
`
`=1
`
`Dose lnlerval
`
`Reference ID: 3749626
`
`20
`
`
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`FENG LI
`05/07/2015
`
`FREDA COONER
`05/07/2015
`I concur
`
`Reference ID: 3749626
`
`
`
`STATISTICS FILING REVIEW
`
`
`
`NDA Number: 22272/027
`eCTD Sequence #: 0224
`Drug Name: OxyContin®
`(oxycodone hydrochloride)
`Tablets, extended-release
`
`Applicant: Purdue
`Pharma L.P.
`BLA Type: 505(A) NDA
`Pediatric Efficacy
`Supplement (Priority)
`
`Stamp Date: Dec 10, 2014
`
`Indication: Management of pain severe
`enough to require daily, around-the-clock,
`long-term opioid treatment and for which
`alternative treatment options are inadequate
`
`
`
`On initial overview of the Supplemental NDA application for RTF:
`
`
`Content Parameter for RTF
`
`1 Electronic Submission: Indexing and reference links within
`the electronic submission are sufficient to permit
`navigation through the submission, including access to
`reports, tables, data, etc.
`ISS, ISE, and complete study reports are available
`(including original protocols, subsequent amendments, etc.)
`Safety and efficacy were investigated for gender, racial,
`and geriatric subgroups investigated.
`
`2
`
`3
`
`4 Data sets in EDR are accessible and conform to applicable
`guidances (e.g., existence of define.pdf file for data sets).
`
`
`
`Yes No NA
`X
`
`
`
`X
`
`X
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`Comments
`
`
`
`
`
`Some subgroup
`analyses were not
`conducted; however,
`sufficient rationale
`was provided.
`
`
`Yes No
`
`NA Comment
`
`
`
`THE STATISTICAL SECTION OF THE APPLICATION IS FILEABLE
`
`Content Parameter (possible review concerns for 74-
`day letter)
`Designs utilized are appropriate for the indications requested. X
`Endpoints and methods of analysis are specified in the
`X
`protocols/statistical analysis plans.
`Interim analyses (if present) were pre-specified in the protocol
`and appropriate adjustments in significance level made.
`DSMB meeting minutes and data are available.
`Appropriate references for novel statistical methodology (if
`present) are included.
`Safety dat