CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`022272Orig1s027
`
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
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`

`

`Summary Review for Regulatory Action
`
`electronic stamp)
`Date
`haron Hertz, MD
`From
`
`Subject
`Division Director Summary Review
`NDA#ISu lement #
`22272/027
`
`Purdue Phanna
`A n nlicant Name
`
`Date of Submission
`December 10, 2014
`
`PDUFA Goal Date
`
`J1me 10, 2015
`
`OxyContin / Oxycodone hydrochloride extended-
`Proprietary Name /
`
`Established (USAN) Name
`release tablets
`Dosa_e Forms / Stren_th
`10, 15, 20, 30, 40, 60, 80 111'
`
`Proposed Indication(s)
`
`Action/Recommended Action:
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Medical Officer Review
`
`Statistical Review
`CMC Review/OBP Review
`
`Clinical Pharmacology Review
`
`OXYCONTIN is an opioid agonist indicated for pain
`severe enough to require daily, around-the-clock, long-
`term opioid treatment and for which alternative
`treatment options are inadequate in:
`
`0 Adults; and
`
`o Opioid-tolerant pediatric patients 11 years of age
`and older who are already receiving and tolerate a
`minimum daily opioid dose of at least 20 mg
`ox codone oral] or its e uivalent
`
`Javier Muniz, MD, John Feene , MD
`
`Feng Li, PhD, Freda Cooner, PhD
`Zedon Don PhD, Ramesh Ra - avachari, PhD
`
`Srikanth Nallani, PhD, Yun Xu, PhD
`Kevin Krudys, PhD
`Am Ta lor, MD, MHS, Linda Lewis, MD
`
`
`
`OSI
`
`John Lee, l\/ID, Janice Pohlman, MD, NIPH, Kassa
`
`CDTL Review
`
`OSE/DRISK
`
`Ayalew, MD, MPH
`John Feene , MD
`
`Danny S. Gonzalez, PhannD, MS, Joan Blair, RN,
`MPH, Kim Lehrfeld, PhannD, BCPS, Reema Mehta,
`PhannD, MPH
`
`Morgan Walker, Phann D, Barbara Fuller, RN, MSN,
`CWOCN, LaShawn Griffiths, MSHS-PH, BSN, RN,
`
`0ND=0fice ofNew Drugs
`DMIEPA=Division ofMedication Errors Prevention
`CD'IIFCross—Discipline Team Leader
`DCDP=Division of Consumer Drug Promotion
`DMPP=Division ofMedical Policy Program
`
`Koung Lee, RPh, MSHS, Samuel Skariah, Olga Salis
`—
`OSE= Ofice of Surveillance and Epidemiology
`OSI=0fice of Scientific Investigations
`0PDP=0flice ofPrescription Drug Promotion
`OWR ofMedical Policy Initiatives
`
`NDA 22272 Dep Dir Memo $027.doc
`
`Page 1 of 33
`
`Reference ID: 3805836
`
`

`

`Signatory Authority Review Template
`
`1. Introduction
`
`OxyContin is an extended-release formulation of oxycodone that was initially approved
`December 12, 1995, as 10 mg, 20 mg, and 40 mg tablets, under NDA 20553. An 80 mg tablet
`was approved January 6, 1997, followed by a 160 mg tablet on March 15, 2000, and 15 mg, 30
`mg and 60 mg tablets on September 18, 2006. The Applicant ceased distribution of the 160 mg
`tablet in April of 2001. The current formulation was approved in 2010 under NDA 22272 and
`represents a product intended to deter abuse through physicochemical properties that make the
`tablet difficult to prepare and abuse by the intranasal and intravenous routes of administration.
`
`The Applicant has submitted the current supplement in response to the FDA’s Written Request to
`conduct studies with oxycodone in pediatric patients. The Applicant requested pediatric
`exclusivity and to gain approval for new labeling for OxyContin that would include additional
`information from their pediatric studies.
`
`As described by Dr. Feeney and reproduced below, there is a public health need for medications
`to manage pain in pediatric patients.
`
`Like adults, pediatric patients are subject to the pain of both malignant and non-malignant
`conditions. Not infrequently, pediatric patients undergo complicated orthopedic procedures
`that can result in pain lasting weeks to months. In addition, there are a number of painful
`procedures involved in both the diagnosis and treatment of pediatric medical conditions.
`Over the last decade, pain in pediatric patients has received increasing attention with a
`focus on the development of proven analgesics.
`
`To encourage pediatric drug development, the Food and Drug Administration
`Modernization Act of 1997 was signed into law and established incentives for conducting
`pediatric studies for drugs for which exclusivity or patent protection exists. In 2002, the
`Best Pharmaceuticals for Children Act (BPCA) extended the provisions of FDAMA by
`continuing to offer an additional six months of patent exclusivity for drugs being tested for
`pediatric use. Later, in 2003, the Pediatric Research Equity Act (PREA) was passed and
`imposed certain requirements on the sponsors of new drug applications, i.e. a proposed
`timeline and plan for the submission of pediatric studies. The requirements of PREA are
`triggered by a new indication, a new dosage form, a new route of administration, a new
`dosing regimen, or a new active ingredient. Because the reformulated OxyContin was
`approved while the older formulation was still marketed (and is not considered a new
`dosage form), the requirements of PREA were not triggered by NDA 22272.
`
`NDA 22272 Dep Dir Memo S027.doc
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`Page 2 of 33
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`Reference ID: 3805836
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`

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`2. Background
`
`This supplemental application was submitted in response to a pediatric written request, initially
`issued to the Applicant in 1998 and subsequently amended a number of times. The details of the
`history of the written request are described in the reviews by Drs. Muniz and Feeney. At the time
`of the original written request, there were no extended-release opioid analgesics approved for use
`in the pediatric age range and information for the use of immediate-release oxycodone was
`available in literature, but not in product labeling. The extent of chronic pain in the pediatric age
`range was not entirely clear, although, at the time, there was less emphasis on the use of
`extended-release opioid analgesics for chronic pain rather than acute pain as evidenced by the
`studies initially conducted in support of the NDA for OxyContin.
`
`The final version of the written request called for the Applicant to conduct three studies:
`
`Study 1:
`
`Pharmacokinetic (PK) study of an age-appropriate formulation of oxycodone in
`opioid-naïve patients from birth up to < 4 years of age.
`
`Study 2: Efficacy, safety, and pharmacokinetic study of an age-appropriate formulation of
`immediate-release (IR) oxycodone in opioid-naïve patients from 5 years up to ≤ 16
`years of age.
`
`Study 3: Open-label, safety and pharmacokinetic study of an oxycodone extended-release tablet
`in opioid-tolerant patients from 6 years to ≤ 16 years of age.
`
`The Applicant used an immediate-release oral solution formulation for Studies 1 and 2. To
`address the requirements of the written request for Study 3, and in particular, whether it was
`possible to study the safety of an extended-release opioid in patients under the age of 17, the
`Applicant was asked to evaluate whether OxyContin was already being prescribed off-label for
`pediatric analgesia. The results of this evaluation indicated that the clinical settings for which
`OxyContin was prescribed for pediatric patients differed somewhat than in adults. Two of the
`most common reasons for chronic pain in adults, osteoarthritis and low back pain, are very
`infrequent in children. Rather, OxyContin was being used in pediatric patients treated for pain
`associated with cancer and pediatric patients undergoing extensive surgical procedures that
`resulted in the need for opioid analgesics to manage pain for two to four weeks. The protocol for
`Study 3 was then developed with the plan to enroll patients that were consistent with the existing
`use. The objective was to provide pharmacokinetic and safety data for prescribers who were
`treating these pediatric patients, rather than having them continue to rely on shared clinical
`experience alone.
`
`The written request would look somewhat different if it were to be issued today. Following a
`2009 scientific workshop, a publication described a number of issues associated with the use of
`analgesics for the treatment of pain in pediatric patients. Taking the information discussed and
`reference articles cited in this publication, it appears reasonable to extrapolate the efficacy of
`opioid analgesics known in adults to children as young as age 2.1 Efficacy studies would be
`
`1 Berde CB, Sethna, NF. Analgesics for the Treatment of Pain in Children. N Engl J Med 2002; 347(14): 1094-
`
`NDA 22272 Dep Dir Memo S027.doc
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`Page 3 of 33
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`Reference ID: 3805836
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`required for patients less than 2 years of age and studies to determine the pharmacokinetic profile
`and the safety of the opioid analgesic would be required for the entire pediatric age range.
`
`The following table from page 2 of Dr. Nallani’s review summarizes the study design of the eight
`studies submitted in support of this pediatric efficacy supplement. There were five multiple-dose
`(including studies OXP1005, OXP3003, and OTR3001) and one single-dose pediatric
`pharmacokinetic and safety studies, two single-dose bioavailability/ bioequivalence (BA/BE)
`studies in adults, and, a relative oral bioavailability study of the original formulation of
`OxyContin and immediate-release oxycodone tablets in pediatric patients (Study 0602) from
`1998. The following table from page 2 of Dr. Nallani’s review summarizes the study design of
`these studies.
`
`
`1103.
`
`NDA 22272 Dep Dir Memo S027.doc
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`Page 4 of 33
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`Reference ID: 3805836
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`

`

`Table: Studies Submitted to support pediatric population PK analysis.
`Treatment (Dose. Dosage Form.
`No. of Dosed Subjects.
`SM:
`Route)
`(warm
`(Cmm)
`Studx Objective“)
`Study Design
`[Product 11)].
`Age: mean (range)
`—— mm ——
`omozo
`'
`_
`on 10 15...:ng m.“ ,0
`mm
`-
`-
`'
`’
`[10mg cmomos]
`ma
`)
`'
`,
`[15 mg: cameos].
`13s y (916,-)
`[20 mg 03.200945]
`
`To evalmle safety. emery and
`OTRSOOI
`(MW) pliamucokineticsoIO'l'Rinopioid
`WRSMY 3
`tolampcdmmpmians
`
`To chm lliePKand safety of
`OXPIOOS
`luliinational mummy-nuns
`QWRSmdyl)
`followingldministnlionofm
`0mm hw'tlonde salmon
`
`.
`
`.
`
`'
`
`'
`
`'
`
`A
`
`'
`
`.
`,
`
`OTR 10. 15. 20. 30. «40
`tablets. po
`['1
`
`155 (6614899
`Pediaim'pauuns
`13.7 (6m 16y)
`
`Oxycodone HClonl scum;
`so (291mm
`o.os
`1:.01
`it and0.2
`’k. mm
`Ills 8
`“[180 8
`m8 3
`[14me4“)
`[0.05Mg1CB-2002-ll].
`'
`[0.] mg'kgCB-lOOZ-ll].
`[0,2 mgkgCB-ZOO’I-ll]
`65 (mum
`Oxyrodonel-ICIonl mm
`0.1-musket» mm
`Oral soliliom CB-2002-ll
`,
`l
`11437600163)
`l
`
`
`
`To emanate safetyof
`meeWP-m
`following administration ofIR
`by
`MW]
`.
`0.1 to 0.2 lug/kg q6li
`7 (SMJ'JF)
`Immediah Release 5 mg capsule. po
`To evaluate safety and
`Pediainc 1mm!
`[c1141. DH61]
`pliannacohnetlcs offlie won-d
`12,6y(7t016y)
`OCIOIIIgtablet. p0
`adultcommnnoaznfmm
`[DRoLEBJNl]
`mammkase (1100:)de
`qohmOqulliinpediauiepniems
`
`'
`
`'
`
`'
`
`.
`
`.
`
`'
`
`'
`
`'
`
`'
`
`.
`
`.
`
`-
`
`.
`
`0C 10 mg ubkt po
`[0C C25]
`Immediate Release 5 mg po
`[IR Oxycodone 962438]
`
`OTR 40 mgmblets. po [CB-200648]
`0C40mgtableis.po[W6tSGl]
`
`92 (61MBID
`Healihyadult subjects
`underfasungandundu'
`nallruoneblockade.
`31y (is—49y)
`
`omamomwsmdocsom
`Healthy m subjects
`“Mm- P0
`unis luluexone
`[OTR (UK) 30 m5— PNJML
`blockade.
`[0m(US)80mg: PN3374].
`My (1945»
`[0c so my mssso]
`F=hnalez Bandit-release: Mamie: 0C=uranal0xy€amn Tablets: 0mm OxyCulm Tabklswflhahxe-dflmunpmpemes:1!st
`WMMthlhwylZ m2WR=l1inanym_
`‘ MMmthmdyOWOOlufidlmmdm-IaJ-filp-fl FahohlflhphanthSRUIflWl.
`
`3. CMC/Device
`
`There were no changes to the currently marketed OxyContin tablets. As noted by Dr. Dong, the focus
`of the CMC review was whether the Applicant had made
`
`In response to information requests, three technical reports were submitted.
`
`From Dr. Doug’s review:
`
`A teleconference was held between FDA and Purdue Pharma L.P. on May 8, 2015. (1) When
`asked whether a
`”m
`
`NDA 22272 Dep Dir Memo $027.doc
`
`Page 5 of 33
`
`Reference ID: 3805836
`
`

`

`(b) (4)
`
`Based on the information provided by the applicant. it appears that Purdue Phanna
`
`(m4)
`
`I concur with the conclusions reached by the chemistry reviewer, that the Applicant made a
`mar There are no outstanding issues.
`
`4. Nonclinical Pharmacology/Toxicology
`
`No new nonclinical data were submitted in support of this application.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Dr. Nallani reviewed the pharmacokinetic data from all eight studies submitted in support of this
`supplemental application. The following section has been reproduced from Dr. Nallani’s review:
`
`Clinical pharmacology of OxyContin: Pharmacokinetic properties of oxycodone
`following single and multiple dose administration (10 — 80 mg) of OxyContin
`(reformulated product approved in 2010) have been fairly well investigated in adults.
`Dose proportionality has been established for OxyContin 10 mg — 80 mg tablet strengths
`for both peak plasma concentrations (Cmax) and extent of absorption (AUC). Given the
`short eliminationt1/2 of oxycodone (~5 hours), steady—state plasma concentrations of
`oxycodone are achieved within 24-36 hours of initiation of dosing with OxyContin.
`Oxycodone is extensively metabolized by multiple metabolic pathways to produce
`noroxycodone, oxymorphone and noroxymorphone, which are subsequently
`glucuronidated. Noroxycodone and noroxymorphone are the major circulating
`metabolites. CYP3A mediated N-demethylation to noroxycodone is the primary metabolic
`pathway of oxycodone with a lower contribution from CYP2D6 mediated O-
`demethylation to oxymorphone.
`
`Pediatric Studies with OxyContin and Immediate release Oxycodone formulations:
`
`NDA 22272 Dep Dir Memo $027.doc
`
`Page 6 of 33
`
`Reference ID: 3805836
`
`

`

`It is important to note most of the pediatric OxyContin studies (in the table above)
`conducted in support of this supplement recruited pediatric patients with moderate to
`severe pain who were already receiving oxycodone or other opiates for pain management
`and could be considered opioid tolerant. These patients were administered OxyContin
`only if they required at least 10 mg twice daily. Patients requiring less than 10 mg twice
`daily were not included in the study.
`
`Pharmacokinetics and safety of an age-appropriate oral formulation of immediate release
`oxycodone solution in opioid-naive hospitalized patients from birth up to < 4 years of age
`were evaluated in Study OXP1005 and PK of oxycodone in opioid-naive hospitalized
`pediatric patients 6 — 16 yrs. of age in Study OXP3003.
`(m4)
`, this review is
`focused on the use of OxyContin in pediatric patients and is not intended to provide
`dosing recommendations of this immediate release formulation in the pediatric
`population.
`
`Pediatric Bioavailability Study OC96—0602:
`
`In Study OC96-0602, pharmacokinetics of oxycodone following crossover administration
`of OxyContin (10 mg original formulation) was compared with IR oxycodone (5 mg
`tablet). Pediatric patients (N=l3) were previously receiving opiates other than oxycodone
`to qualify for this study. In this study, pediatric patients in the 6-12 yrs. age group
`receiving 10 mg OxyContin had a Cmax or peak plasma concentration of oxycodone ~22
`ng/mL; where as adults receiving the same dose would have a Cmax of ~ 11 ng/mL.
`OxyContin label indicates that a single 10 mg dose produces oxycodone AUC of about
`136 ng.hr/mL.
`
`Table: Summary of PK Parameters from Study 0C96-0602
`
`PK Metric
`AUC. (ng-h/mL)
`AUC- (ng~h/mL)
`0.... (ngImL)
`ta... 0!)
`t1)(elim) (h)
`MRT (h)
`
`Arithmetic Mean (SD)
`IR Oxycodono (5 mg) OxyContinO (10 mg)
`83.2 (43.0)
`201.0 (143.0)
`81.3 (39.1 )°
`174.6 (91 .1)‘
`20.2 (8.3)
`22.0 (13.0)
`2.1 (0.9)
`3.3 (1.7)
`2.6 (1 .0):
`5.2 (1 .8)c
`4.2 (1.2)
`8.7 (1.9)
`
`NDA 22272 Dep Dir Memo $027.doc
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`Page 7 of 33
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`Reference ID: 3805836
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`

`

`Figure: Box-Plot comparing Cmax (left figure) and AUC (right figure) of oxycodone in
`pediatric patients of 6 -12 yrs. age following administration of OxyContin 10 mg or IR
`oxycodone 5 mg (tablet) doses. Horizontal reference lines are label indicated mean Cmax
`(left figure) and mean AUC (right figure) of 10 mg OxyContin (bottom) and 20 mg
`OxyContin (top) in adults.
`
`The observed increase in exposure of oxycodone following OxyContin administration in
`the 6 -12 year age group is possibly due to decreased metabolic clearance in these patients
`with lower body weight.
`In another pediatric safety study (OTR3001) where OxyContin safety and PK was
`evaluated in 6 -16 year old patients, it was observed that for any given dose of OxyContin
`(10 – 30 mg) patients in 6 – 12 yr. age group had higher Cmax compared to 13 -16 yr. old
`patients (See appended results for OTR3001). The higher Cmax appeared to be a more
`consistent observation in pediatric patients < 60 kg bodyweight compared to >60 kg
`bodyweight (See figure below). Very limited number of subjects received doses ≥40 mg
`OxyContin; hence a comparison could not be made. These findings are consistent with the
`population pharmacokinetic analysis which demonstrated that body weight is an important
`covariate for the volume of distribution and clearance of oxycodone. A dose-proportional
`increase in Cmax and AUC was noted in pediatric patients in each age group or body
`weight group.
`It is important to note most of the pediatric studies conducted in support of this
`supplement (including study OTR3001) recruited pediatric patients who were already
`receiving oxycodone or other opiates for pain management and could be considered
`opioid tolerant. Hence, the observed difference in Cmax in pediatric patients with lower
`
`NDA 22272 Dep Dir Memo S027.doc
`
`Page 8 of 33
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`Reference ID: 3805836
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`

`

`age/bodyweight becomes clinically relevant when considering 10 mg OxyContin for
`opioid naive patients. In fact, pediatric patients in the age range of 6 — 12 yrs., especially
`those with lower body weight, might benefit from a 5 mg OxyContin formulation.
`
`mm
`
`It is noteworthy that pediatric patients 12 — 17 yrs old have similar
`exposure to oxycodone compared to adults receiving similar dose of OxyContin.
`
`Figure: Box-Plot comparing Cmax (first dose) of oxycodone in pediatric patients (Study
`OTR3001) of bodyweight <60 kg vs. >60 kg bodyweight following administration of
`different OxyContin doses. Horizontal reference lines are label indicated mean Cmax of
`10 mg OxyContin (bottom) and 20 mg OxyContin (top) in adults.
`70
`
`60
`
`30
`
`50 40
`
`
`
`
`
`IE]
`I—---—l
`
`Cmax 20 mg ORF in amlts
`
`I.-___J
`
`
`
`Cmax(ng.mL)
`
`
`
`10,
`10,
`15,
`15,
`20,
`20,
`30,
`30,
`40,
`40,
`60,
`<60 >60 <60 >60 <60 >60 <60 >60 <60 >60 <60
`
`Cmax 10 mg ORF in aOJlts
`
`k9
`n=25
`
`k9
`n=22
`
`kg
`n=8
`
`k9
`n=3
`
`kg
`n=13
`
`kg
`n=12
`
`kg
`n=7
`
`kg
`n=3
`
`kg
`n=1
`
`kg
`n=3
`
`kg
`n=1
`
`Note: Limited number of patients received doses 240 mg of OxyContin; hence a
`comparison could not be made.
`
`Data from several adult and pediatric studies (as indicated above) were combined in a
`population PK analysis to characterize the population pharmacokinetics of oxycodone in
`adult and pediatric subjects and to estimate the effects of individual-specific covariate
`factors. in particular, age and weight on the variability in pharmacokinetics. Full review of
`the population PK analysis is appended to this memo. The main conclusions of the
`analysis are discussed below. The final model identified weight as a predictor of
`variability in clearance (CL/F) and volume of distribution (V/F) and age as a predictor of
`variability in CL/F in patients less than one year of age. No other covariates investigated
`demonstrated any relationship in the graphical evaluation of unexplained variability in
`oxycodone PK.
`
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`Page 9 of 33
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`Reference ID: 3805836
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`

`

`Figure: A plot of oxycodone clearance against bodyweight of pediatric patients and
`healthy subjects (Based on final model).
`
`(L)
`VolumeofDistribution/F
`
`o
`
`25
`
`so
`
`75
`
`100
`
`125
`
`200
`
`100
`
`Clearance]F(L/hr)
`
`o
`
`25
`
`so
`
`75
`
`100
`
`125
`
`Weight (to)
`
`Weight (kg)
`
`The table below describes clearance and volume of distribution for oxycodone in different
`bodyweight groups.
`
`Table: Summary statistics of clearance and volume of distribution of oxycodone based on
`bodyweight groups from all studies.
`
`fl-Mflflfiflfi
`_lEl——MIEI
`mmmmmmm_
`manila!
`
`mmnmmmm
`
`These results provide further support that a 10 mg dose in lighter patients (i.e., less than
`10 years of age) would result in higher exposure than the same dose in the adult
`population. Therefore, pediatric patients would benefit from a 5 mg OxyContin
`formulation.
`
`We also note that the Sponsor’s phannacokinetic model has adequately characterized the
`pharmacokinetics of oxycodone throughout the entire pediatric population. Therefore, this
`model could potentially be used to derive pediatric dosing regimens of immediate release
`oxycodone formulation that would match the exposure in adults at dosing regimen of
`FDA-approved oxycodone products.
`
`I concur with the conclusions reached by the clinical pharmacology reviewer that the
`pharmacokinetic profile of OxyContin has been suffiicently characterized to support a pediatric
`indication and the dosing and administration information in the package insert. There are no
`outstanding clinical pharmacology issues that preclude approval.
`
`6. Clinical Microbiology
`N/A
`
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`

`

`7. Clinical/Statistical-Efficacy
`
`Based in large part on an understanding of neurodevelopment, the physiology of pain, and the
`pharmacology of opioid analgesics, as discussed by Berde et al.2, it is reasonable to extrapolate a
`finding of efficacy for oxycodone as an analgesic from adults to pediatric patients over the age of
`2 years. There is supportive evidence provided from Study OXP3003, although, as discussed by
`Dr. Li and presented below, this study was not adequately designed to provide a statistically
`rigorous assessment of efficacy.
`
`Study OXP3003 was a multicenter, double-blind, randomized, placebo-controlled, dose-ranging
`study with the primary objectives to the pharmacokinetics and safety of oxycodone hydrochloride
`oral solution, in opioid-naïve patients, 5 to 16 years of age with moderate to severe acute pain
`expected to last for at least 2 days. Efficacy was also evaluated in this study.
`
`Patients were stratified by age and randomized in a ratio of 3:3:2 to one of three treatment
`groups: oxycodone 0.1 mg/kg, oxycodone 0.2 mg/kg, or placebo, to be taken every six hours for
`18 to 24 hours. All patients were permitted intravenous patient (or nurse) controlled analgesia
`with morphine, or oral morphine as needed during the double blind treatment period.
`
`Figure 1. OXP3003 Study Schematic
`
`*EOS= End of Study
`(Source: OXP3003 Study Report, Figure 1, page 23)
`
`Details about the inclusion and exclusion criteria and safety monitoring can be found in Dr.
`Muniz’ review (starting on page 33). Patients were to be monitored with continuous pulse
`oximetry, and oxygen saturation levels and somnolence were to be assessed prior to each dose of
`study medication. Efficacy assessments included the amount of supplemental pain medication
`used expressed as IV morphine equivalents, and pain intensity.
`
`Although the study planned to enroll 100 patients, the study was terminated after 68 patients were
`enrolled. Subjects had pain as a result of a variety of clinical situations including major cardiac
`or orthopedic surgeries and pain following medical procedures. Overall, 83% of patients
`completed the study with the greatest number completing from the oxycodone 0.2 mg/kg
`
`2 Ibid.
`
`NDA 22272 Dep Dir Memo S027.doc
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`

`

`treatment group. Patient disposition is provided in the following table from Dr. Muniz’ review.
`(page 46).
`
`The extent of exposure was summarized by Dr. Muniz (page 47):
`
`The mean exposure to Oxy Pediatric Liquid was 18.6 hours overall. All patients in the
`safety population received at least 1 dose, while 91% of patients received at least 2
`doses, 89% received at least 3 doses, 86% received at least 4 doses, and 38%
`received 5 doses.
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`NDA 22272 Dep Dir Memo S027.doc
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`Page 12 of 33
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`Reference ID: 3805836
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`

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`According to the Applicant’s analyses, a finding of efficacy is supported by the results in the
`following table from Dr. Muniz review (page 48):
`
`During the initial six hours, all three groups used similar amounts of supplemental morphine, but
`subsequently, patients receiving the oral oxycodone required less supplemental morphine.
`Patients randomized to oral oxycodone had lower pain scores throughout the study.
`
`Dr. Li conducted an analysis of the protocol and results of Study OXP3003 and noted the
`following (pages 5 and 6):
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`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.
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`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
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`NDA 22272 Dep Dir Memo S027.doc
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`Page 13 of 33
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`Reference ID: 3805836
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`

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`against placebo. Patients randomized to placebo reported slightly higher pain on average
`and used more supplemental pain medications during the study.
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`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
`
`I concur with Drs. Muniz and Li that study OXP3003 provides support for a finding of efficacy
`for the analgesic effects of oxycodone, although not a statistically rigorous assessment. A finding
`of efficacy for OxyContin is primarily based on extrapolation from adults.
`8. Safety
`
`It is not acceptable to extrapolate safety from adults to pediatric patients. The safety database
`consists of data from Studies OXP1005, OXP3003, OTR3002, OC96-0602, OTR1020, and
`OTR3004. Study OXP3003 was described above. The remaining studies are described below.
`
`Study OXP1005 was an open-label pharmacokinetic and safety study of immediate-release
`oxycodone for acute pain for up to two days. Pediatric patients from birth to 4 years of age were
`enrolled and stratified into three age groups (birth to 30 days, 31 days to ≤ 6 months, and 7
`months to ≤ 4 years). Patients received oxycodone oral solution. The study plan was to start with
`a low dose, 0.05 mg/kg, followed by dose escalation to 0.1 mg/kg and then 0.2 mg/kg and based
`on an Investigator Steering Committee’s review of the patient safety data. Patients were also
`permitted supplemental oral morphine (0.1 to 0.3 mg/kg q2h) or nurse-controlled analgesia via
`PCA pumps with morphine sulfate 15 mcg/kg per dose with an 8-minute lockout for a maximum
`of six doses per hour on an as needed basis, based on an evaluation of pain intensity by the
`investigator or designated nurse. Details of the study design, conduct, and results can be found in
`Dr. Muniz’ review.
`
`Study OTR3001 was an open-label pharmacokinetic and safety study of OxyContin in pediatric
`patients from 6 to 16 years of age. This was the only study that provided safety information for
`the use of OxyContin in pediatric patients. One particular condition of enrollment was that
`patients must have been receiving at least 20 mg of oxycodone daily for at least the five
`consecutive days prior to dosing, and no more than 240 mg daily during the last 48 hours before
`the start of study drug dosing. This is because a 20 mg dose may have been too large for some
`smaller patients. By having patients initiate opioid treatment according to their healthcare
`provider’s standard approach using an immediate-release opioid prior to initiating treatment with
`OxyContin, patients could be titrated in increments smaller than 10 mg, the smallest strength of
`OxyContin. Patients were required to have an expected need for opioid treatment of pain of at
`least two weeks and up to four weeks. Patients could have been outpatients or inpatients at the
`time of enrollment and inpatients were to continue in the study upon hospital discharge. Under
`the supervision of the healthcare team, adjustment of the OxyContin dose up or down as needed
`for pain management or management of adverse events was permitted. Patients were to be dosed
`twice daily and asymmetric dosing was permitted. An extension study (OTR3002) permitted
`continued use of OxyContin and further follow up for patients requiring longer treatment of pain
`with an opioid analgesic.
`
`NDA 22272 Dep Dir Memo S027.doc
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`Page 14 of 33
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`Reference ID: 3805836
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`

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`A total of 155 patients were enrolled; 134 patients were enrolled at US sites. Nearly all patients
`were converted to OxyContin from an immediate-release formulation of oxycodone, morphine,
`hydromorphone, or hydrocodone. Most of the patients enrolled had undergone a major surgical
`or medical procedure or had cancer. Patients who had undergone surgery were not to be
`converted to OxyContin until at least five days following surgery.
`
`The following table from Dr. Muniz’ review (page 62) describes the study population:
`
`NDA 22272 Dep Dir Memo S027.doc
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`Page 15 of 33
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`Reference ID: 3805836
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`Although 40% of patients were to have been in the 6 up to 11 age group, only 15 patients less
`than 11 years of age were enrolled. The remaining 140 patients were 11 and older as
`demonstrated in the following figure from Dr. Muniz’ review (page 64).
`
`NDA 22272 Dep Dir Memo S027.doc
`
`Page 16 of 33
`
`Reference ID: 3805836
`
`

`

`Patient disposition is provided in the following table from Dr. Muniz’ review (page 70).
`
`NDA 22272 Dep Dir Memo S027.doc
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`Page 17 of 33
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`Reference ID: 3805836
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`

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`Approximately 80% of patients completed between two and four weeks, and 54 patients
`continued for four weeks or longer.
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`There was a wide range of doses across the study population as presented in the following table
`from Dr. Muniz’ review (page 71).
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`
`NDA 22272 Dep Dir Memo S027.doc
`
`Page 18 of 33
`
`Reference ID: 3805836
`
`

`

`While the mean oxycodone dose was 30 mg per day, the ranges show that some of the older
`patients required a much larger daily dose, as much as 160 mg per day.
`
`Pain scores were recorded, but as an open-label study without a comparator, the efficacy data
`cannot be used to support a finding of efficacy. The study was intended to provide safety data
`and pharmacokinetic data. Details of the study design, conduct, and results can be found in Dr.
`Muniz’ review.
`
`Twenty three patients continued to receive OxyContin in the extension study, OTR 3002. The
`range of daily doses was from 20 mg to 56 mg per day and 13 of the twenty three patients
`continued on OxyContin for at least 28 weeks.
`
`Study OC96-0602 was intended to be a study to evaluate the conversion of patients, ages 6 to 12
`years, from immed