CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022272Orig1s027
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`NDA 22272/Supplement 27 OxyContin
`
`Cross—Discipline Team Leader Review
`
`
`Date
`May 26, 2015
`From
`John Feene , MD
`m_ Cross-Disci line Team Leader Review
`NDA/BLA #
`22272/Supplement 27
`Sun vlement#
`
`Date of Submission
`
`December 10, 2014
`
`Purdue Phanna LP.
`
`June 8, 2015
`PDUFA Goal Date
`——
`Proprietary Name /
`OxyContin Tablets (oxycodone HCl extended-release
`Established
`S .
`tablets
`
`names
`
`Proposed Indication(s)
`
`Extended-Release Tablets
`Dosage forms / Strength
`
`10, 15, 20, 30, 40, 60, and 80 mg
`Management of pain severe enough to require daily,
`around-the-clock, long-term opioid treatment and for
`which alternative treatment options are inadequate;
`mo
`
`
`Recommended:
`
`A roval; oioid—tolerant oatients 11
`
`ears and older
`
`
`
`Material Reviewed
`
`Prim Medical Officer Review
`
`Statistical Review Efficac Stud
`
`Fen Li, PhD, Freda Cooner, PhD
`
`Yun Xu, PhD
`
`Ramesh Ra navachari, PhD
`
`“Wm 1mm“ “1” MPH
`
`Kassa A alew, MD, MPH
`
`1. Introduction
`
`OxyContin is an extended-release (ER) oral formulation of oxycodone. It is approved 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 has submitted the
`current supplement in response to the FDA’s Written Request (WR) for Purdue to conduct
`studies with oxycodone in pediatric patients. Purdue hopes to both obtain pediatric exclusivity
`and gain approval for new labeling for OxyContin that would include additional information
`for the treatment of pediatric patients.
`
`Oxycodone is an opioid-receptor agonist that is relatively selective for the mu-opioid receptor.
`In the United States, it is available as oral immediate—release (IR) and ER formulations. It is
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`Cross Discipline Team Leader Review
`NDA 22272/Supplement 27 OxyContin
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`available as both single—entity and combination products. Combination products typically
`contain non-narcotic pain medications such as acetaminophen. One combination product
`contains the opioid antagonist naloxone to deter abuse. Various generic oxycodone
`formulations have been approved. In addition to the solid oral dosage forms of oxycodone,
`oral liquid IR formulations are also available. Although parenteral formulations are in use in
`other countries, only oral formulations are approved in the United States.
`
`OxyContin was first approved in 1995 under NDA 20553 as the first formulation of
`oxycodone that allowed dosing every 12 hours instead of every 4 to 6 hours. Subsequently,
`reports of abuse, overdose, and death from OxyContin began to appear. The product was
`frequently abused after manipulations intended to defeat the ER properties, allowing the drug
`to be released more rapidly. Labeling for OxyContin was strengthened to add warnings about
`the drug’s potential for misuse and abuse and several government initiatives were undertaken
`in the hope of reducing harm from opioids.
`
`In 2010, a new formulation of OxyContin was approved under NDA 22272 that was designed
`to deter abuse. It was designed to be more difficult to crush, break, and dissolve. In 2013, the
`FDA determined that the reformulated product did in fact have properties that would be
`expected to make the product difficult to inject and to reduce abuse via snorting. The label
`was updated to reflect these findings. Of note, concurrent with the submission of this pediatric
`supplement,
`(m4)
`
`Also in 2010, public discussions began about initiating a class-wide Risk Evaluation and
`Mitigation Strategy alEMS) for all Extended-Release/Long Acting (ER/LA) opioids. The
`ER/LA REMS was implemented in 2012.
`
`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
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`NDA 22272/Supplement 27 OxyContin
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`marketed (and is not considered a new dosage form), the requirements of PREA were not
`triggered by NDA 22272.
`
`
`2. Background
`
`
`The approved label for OxyContin, in Section 8.4 Pediatric Use, states, “Safety and
`effectiveness of OxyContin in pediatric patients below the age of 18 years have not been
`established.” OxyContin is indicated in adults 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 labeled indication does not distinguish between the treatment of
`opioid-naïve adults and opioid-tolerant adults and dosing instructions are provided for both
`groups of patients.
`
`Pediatric pharmacokinetic (PK) and dosing information for IR oxycodone is available in the
`literature but has not been included in labeling for approved IR oxycodone products. The
`usual recommended starting dose for patients over six months of age is 0.1-0.2 mg/kg every 3-
`4 hours in patients < 50 kg and 5-10 mg every 3-4 hours for patients > 50 kg.1 Smaller per-
`kilogram starting doses are recommended for patients less than six months.
`
`BPCA allows the Agency to require studies of all relevant indications using all necessary
`dosage forms to meet the terms of a WR. Therefore, the WR for OxyContin outlined studies
`in acute pain as well as chronic pain. For the acute pain indication, an immediate release
`liquid formulation was ultimately used. The WR described three studies and the three studies
`submitted by the Sponsor to address those studies are listed below.
`
`
`Study 1: OXP1005
`
`Study 2: OXP3003
`
`Study 3: OTR3001
`
`Study OXP 1005 was an open-label (OL) PK and safety study of IR oxycodone for acute pain.
`Pediatric patients birth – 4 years were enrolled. It was a multinational study, with 9 clinical
`sites in Europe, Canada, and the US. A total of 60 patients were enrolled; 35 of them were
`enrolled at US sites. A single patient was enrolled in Canada. Study OXP 1005 was
`completed in 2004.
`
`Study OXP3003 was a placebo-controlled (PC) trial intended to collect PK, safety, and
`efficacy data for IR oxycodone for acute pain. By protocol, about 100 patients 5-16 years
`were to be enrolled, but the study was stopped early for administrative reasons in 2004.
`
`
`
`1 Berde CB, Sethna, NF. Analgesics for the Treatment of Pain in Children. N Engl J Med 2002; 347(14): 1094-
`1103.
`
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`Cross Discipline Team Leader Review
`NDA 22272/Supplement 27 OxyContin
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`Study OTR 3001 was an OL PK and safety study of OxyContin for chronic pain. Pediatric
`patients 6-16 years were enrolled. It was a multinational study, with 44 clinical sites in
`Europe, Middle East/Central Asia, Australia, Latin America, and the US. A total of 155
`patients were enrolled; 134 of them were enrolled at US sites. A single patient was enrolled in
`Latin America and two were enrolled in Australia.
`
`The first WR for OxyContin was issued in 1998. In it, the Sponsor was asked to perform two
`cross—over studies. A second WR was later issued and the three studies described in that WR
`
`were initiated in 2003. The first two were Studies OXP1005 and OXP3003 described above.
`
`The third study was OXP3004, an 0L safety study to evaluate the safety of the conversion
`from IR oxycodone to OxyContin in patients 6-16 years.
`
`However, in 2004, the Sponsor decided to stop the pediatric development program for
`OxyContin for administrative reasons. At that time, Study 1 had completed enrollment, n=60.
`Study 2 had enrolled 65 patients out of a planned 100. Study 3 had
`m“).
`
`In 2008, the Sponsor made a decision to re—start their pediatric development program and, after
`additional discussion with the agency, a new third WR was issued in 2010. The final version
`of that WR, WR #3, Amendment #2, issued in 2011 and represents the final WR upon which
`the current pediatric supplement is based. That WR was attached to NDA 22272.
`
`In WR #3, Amendment #2, Studies 1 and 2 remain essentially unchanged and it was
`understood that Study 1 completed in 2004 would be submitted with the hope of satisfying the
`WR. Likewise, Study 2 which was discontinued after 65 patients were enrolled would be
`submitted with the hope of satisfying the WR. Study 3, the only study of chronic pain and the
`only study to be conducted with OxyContin itself, took on a new design with the new WR.
`
`Study 3, Study OTR3001, was to be an OL safety and PK study of the new abuse-deterrent
`(AD) formulation of OxyContin in patients 6-16 years who were opioid tolerant as defined in
`the protocol and had pain severe enough to require daily, around-the-clock, long—term opioid
`treatment and for which alternative treatment options are inadequate. Study 3 was conducted
`between 2011 and 2014. The sponsor attempted to
`M“)
`
`. Those efforts were
`
`unsuccessful.
`
`In the current pediatric supplement, the Sponsor has submitted the three requested pediatric
`studies. Additionally, data has been submitted for four additional studies. Three of those
`studies were small or prematurely discontinued. The fourth is an 0L, continuation study,
`Study OTR3002, that enrolled patients who had completed four weeks of 0L treatment in
`Study 3 of the WR, Study OTR3001.
`
`Since the current version of the WR was issued, views about the need for pediatric studies
`have evolved. Based on what is known about the site of action of oxycodone and what is
`known about the developmental maturity of the mu-opioid receptor, efficacy now can be
`extrapolated from adults for most pediatric age groups. However, it is not as clear that
`efficacy can be extrapolated below the age of 2 years and for this reason, efficacy studies for
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`Cross Discipline Team Leader Review
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`patients birth - 2 years are required. This approach was discussed at a workshop sponsored by
`the FDA and summarized in the literature.2 Based on this new approach, for mu-opioid
`receptor agonists already studied in adults, sponsors are only required to study the safety and
`PK of that product in pediatric patients 2 years and older. Because enrollment in studies in
`patients less than 7 years with chronic pain is considered infeasible, studies in chronic pain
`below 7 years are not routinely required.
`
`For patients less than 2 years, there are a now a number of accepted pain models appropriate to
`this age group, recognizing that the traditional PC clinical trial may not be suitable for this
`patient population due to ethical concerns and difficulty assessing pain. Alternative study
`designs including add-on therapy and measurement of rescue use may be feasible.
`
`The studies outlined in WR #3, Amendment #2 differed from the current approach as follows:
`
`1) Study OXP3003 was to include efficacy assessments in patients 5 years and older with
`acute pain. An efficacy study in this age group would not be required under current standards.
`
`2) There was no study described in the WR to evaluate efficacy in patients with acute pain
`less than 2 years.
`
`3. CMC/Device
`
`The studies included in this supplement used three different formulations of oxycodone. The
`first was the Sponsor’s own proprietary oral solution. In the past, the Sponsor marketed an
`unapproved oral solution but the Sponsor does not currently market an oral solution
`(m4)
`The second
`
`formulation was the original formulation of OxyContin; this was used in the earlier studies that
`required an ER formulation. The re-formulated OxyContin was the third oxycodone
`formulation used.
`
`There were no CMC data submitted with the original submission of this sNDA. The CMC
`information in support of the IR oral solution was provided to IND 29,038 for those studies
`and cross-referenced in this sNDA.
`mu)
`
`There was one important CMC issue addressed during the review of this supplement however.
`The CMC Review of that issue was completed by Zedong Dong, PhD with concurrence from
`Ramesh Raghavachari, PhD. Dr. Dong’s review discusses whether the Sponsor has
`M“)
`
`2 Berde et al. Pediatric Analgesic Clinical Trial Designs, Measures. and Extrapolation: Report of an FDA
`Scientific Workshop. Pediatrics 2012; 129(2): 354-364.
`
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`Cross Discipline Team Leader Review
`NDA 22272/Supplement 27 OxyContin
`
`(m4) As discussed later in this review, Study 3 did not enroll the target population 6-12
`years and the distribution of ages for those enrolled in this cohort was skewed toward the older
`ages. Conceivably, the lack of a lower—dose-strength OxyContin tablet could have contributed
`to difficulty enrolling patients at the younger end of the 6—12 year age distribution. Also,
`OxyContin tablets are large tablets that can present a swallowing problem for younger children
`and a smaller tablet size could have facilitated enrollment.
`
`Dr. Dong describes a nlunber of interactions with the Sponsor during the review to assess the
`(m4). Finally, on May 8, 2015, a teleconference was held between the
`Sponsor and the agency to clarify remaining questions. Based on the available information,
`Dr. Dong concludes in his review, “Based on the information provided by the applicant, it
`appears that Purdue Phanna has made
`(m4)
`
`Previous attempts by the Sponsor to
`
`M“)
`
`4. Nonclinical Pharmacology/Toxicology
`
`No new Pharmacology/Toxicology data were presented in the supplement and no
`Pharmacology/Toxicology issues arose during the review.
`
`5. Clinical PharmacologyIBiopharmaceutics
`
`The Clinical Pharmacology Review was completed by Srikanth Nallani, PhD with concrurence
`from Kevin Krudys, PhD and Yun Xu, PhD. There are no outstanding clinical pharmacology
`issues and labeling recommendations have been made.
`
`As background to the new information presented in the supplement, Dr. Nallani summarized
`the clinical pharmacology of OxyContin as follows:
`
`“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 elimination t‘/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.
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`Cross Discipline Team Leader Review
`NDA 22272/Supplement 27 OxyContin
`
`CYP3A mediated N-demethylation to noroxycodone is the primary metabolic pathway of
`oxycodone with a lower contribution from CYP2D6 mediated O-demethylation to
`oxymorphone.”
`
`In support of the application, the Sponsor performed a population PK analysis of OxyContin
`and IR oxycodone. Dr. Nallani’s review describes the analysis that involved population PK
`modeling based on nonlinear mixed-effects modeling (NONMEM). From Dr. Nallani’s
`review:
`
`“This involved pooling of all available plasma oxycodone concentrations (intensive and
`sparse) from single- and multiple-dose PK studies. The pooled data represented oxycodone
`concentrations across a range of formulations [oral immediate release from liquid and tablet,
`extended release original OxyContin (OC) and reformulated OxyContin (OTR or ORF)] in
`pediatric patients and representative oral OxyContin data in adult subjects for the population
`pharmacokinetic (POPPK) dataset. A total of 5 Phase 1 and three Phase 3 clinical studies were
`included in the POPPK modeling of oxycodone in pediatric patients and adult subjects…The
`final oxycodone POP PK dataset consisted of 5567 oxycodone concentrations from 370
`subjects from 8 studies…There were 255 pediatric patients (< 18 years), with weights ranging
`from 2.4 to 112 kg.”
`
`PK data from all three studies described in the WR were among the data included in the
`analysis.
`
`The main conclusions of the analysis were as follows: “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.”
`
`From Study OTR3001, Dr. Nallani presents the data below.
`
`Figure: Observed Cmax with OxyContin Dosing (10-30 mg) in Patients 6-12 Years versus
`Patients 13-16 Years
`
`
`
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`Cross Discipline Team Leader Review
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`
`Consistent with the results of the Pop PK analysis, most of the differences between patients 6—
`12 years and 13-16 years can be explained by differences in weight. The results for patients
`13-16 years are similar to what is observed in adult patients. Therefore, the Dr. Nallani
`recommends the following statement for labeling: “In the pediatric age group of 11 years and
`older systemic exposure of oxycodone is expected to be similar to adults at any given dose of
`OxyContin.”
`
`Dr. Nallani also notes, “. . .the Sponsor’s pharmacokinetic model has adequately characterized
`the phannacokinetics 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.”
`mm)
`the Clinical Pharmacology review focused on the use of OxyContin in pediatric
`patients and did not develop dosing recommendations for the IR formulation in pediatric
`patients.
`
`Obviously, it would be
`the population PK analysis described here.
`
`(m5) based on
`(m5)
`
`Dr. Lee’s Clinical Inspection Summary identified an issue bearing on the integrity of the PK
`samples collected throughout Studies 1 and 2. Dr. Hammer at the Stanford site was an
`investigator in both Studies 1 and 2. The Form FDA 483 for his site noted that, “The
`temperature log for the freezer did not include temperature records for the first nine of the total
`15 months of PK blood sample storage.” Dr. Lee commented, “The inadequate freezer
`temperature log may indicate more than inadequate recordkeeping and may include inadequate
`PK blood sample handling and storage for much of the study period (nine of 15 months). A
`comparison of the PK data from this CI site with those from other CI sites may be helpful in
`evaluating the reliability of the PK data from this CI site.” The comments apply to Dr.
`Hammer’s involvement in both Studies 1 and 2. Twenty—six patients birth - 4 years were
`enrolled in Study 1 at his site, while an additional 26 patients 5-16 years were enrolled in
`Study 2 at his site.
`
`While it remains a possibility that this deficiency only represents a recordkeeping error, a
`failure to record the temperature at the stated times, Dr. Nallani has attempted to reconcile the
`finding in his Clinical Pharmacology review as follows:
`
`a) Document the long-term stability of the quality control (QC) solutions from the
`bioanalytical report;
`b) Document the stability of QC solutions over the fifteen fieeze/thaw cycles available
`from the bioavailability report;
`c) He compared PK data from Study OXP3003 to another study, OXP3001. Comparable
`clearance values are available from both studies for 5-16 year—old patients, suggesting
`that the data collected in OXP3003 were valid. By extrapolation, the comparability of
`the PK data across these two studies for patients in the 5-16 year age group would
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`Cross Discipline Team Leader Review
`NDA 22272/Supplement 27 OxyContin
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`suggest that the PK data collected in Study OXP1005 from younger patients were also
`valid.
`
`I agree that the comparable PK data across Studies OXP3003 and OXP3001 support the
`validity of the PK samples collected at the Stanford site for both Studies OXP3003 and
`OXP1005. I believe it is most likely that the lack of temperature data for the first nine months
`was a recordkeeping error. As such, the stability data provided by Dr. Nallani are reassuring
`for any short-term temperature variations that might have occurred. However, the stability of
`the analytes at ambient temperatures for long periods of time would be questionable. Further
`investigation and discussion with the Sponsor about this issue will be needed moving forward.
`For instance, if there were control samples stored concurrently with the patient samples in the
`Stanford refrigerator, the stability of those controls would provide additional evidence bearing
`on the validity of the patient samples. It is important to resolve this prior to any wide
`
`(m5)
`
`Dr. Nallani also addresses the Sponsor’s
`
`0!) (4)
`
`. This is also
`
`addressed by the CMC review. Consistent with the CMC review, Dr. Nallani agrees that(m4)
`
`6. Clinical Microbiology
`
`Not applicable.
`
`7. Clinical/Statistical- Efficacy
`
`The primary clinical review was performed by Javier Muniz, MD. The statistical review of the
`clinical efficacy study was performed by Feng Li, PhD with concurrence from his Team
`Leader, Freda Cooner, PhD.
`
`The Sponsor does not propose changing the Indication and Usage section of labeling. The
`indication would remain “. . .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 Sponsor proposes to include in the Pediatric Use section of labeling the
`following statement:
`
`(mm
`In Dosage and Administration, the Sponsor proposed the following
`m“)
`
`statement:
`
`As discussed earlier in this review, the current approach for mu-opioid receptor agonists is to
`allow extrapolation of efficacy in adults to pediatric patients 2 years and older if the PK
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`exposure is comparable between adult and pediatric patients. With this approach, the PK data
`provided in the supplement and discussed in Section 5 of this review allows for the
`extrapolation of efficacy of OxyContin to patients 6 years and older (6 years being the
`youngest age studied in Study OTR3001). Therefore, there is no need for adequate and well—
`controlled eflicacy data for OxyContin and none has been submitted.
`
`Using that same approach, the efficacy of an IR oral oxycodone product could be extrapolated
`to patients 2 years and older for the treatment of acute pain. In fact, consistent with the WR
`that was issued, the Sponsor submitted the results of a PC, parallel-group trial that investigated
`the efficacy of oxycodone 0.1 mg/kg and 0.2 mg/kg in the treatment of acute pain in patients 5
`years and older. As outlined below, this study, Study OXP3003, suffered from a number of
`methodological problems. Among them, the study was stopped early in 2004 when the
`Sponsor ceased their pediatric development program, no doubt leaving the study
`underpowered. As described in the reviews of Dr. Muniz and Dr. Li, the efficacy results from
`the study are not persuasive, but, importantly, the trends observed in the study do not
`contradict the efficacy that would be extrapolated based on adult efficacy and comparable PK
`exposure in pediatric patients. As described in Dr. Nallani’s review, dosing guidelines for an
`oxycodone IR oral solution can be developed with the information in this supplement.mmmm
`
`Current agency policy does not allow extrapolation of efficacy in adults to pediatric patients
`younger than 2 years. The agency now requires that efficacy trials be conducted in patients
`younger than 2 years and designs for those trials have been discussed.3 At the time of the WR,
`such an efficacy trial was not required for the acute pain indication.
`mama)
`
`Assessments of pain were collected throughout all three of the trials that were the subject of
`the WR. Other than Study OXP3003 for acute pain, no other studies were capable by design
`of assessing the efficacy for acute or chronic pain. Without control groups, the results of the
`pain assessments are difficult/impossible to interpret.
`
`Study OXP3003
`
`Study OXP3003 was a randomized, double-blind, PC, parallel-group study of the efficacy,
`safety, and pharmacokinetics (PK) of immediate-release (IR) oxycodone liquid for the
`treatment of acute moderate to severe pain. Pediatric patients 5-16 years were randomized to
`three groups: IR oxycodone oral solution 0.10 mg/kg, IR oxycodone oral solution 0.20 mg/kg,
`or placebo. It was a multinational study with 13 clinical sites in Europe, Canada, and the US.
`A total of 68 patients were randomized, sixty-one patients in the US, six in Europe, and one in
`
`3 Berde et al. Pediatric Analgesic Clinical Trial Designs. Measures. and Extrapolation: Report of an FDA
`Scientific Workshop. Pediatrics 2012: 129(2): 354-364.
`
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`Canada. A single site, Dr. Hammer’s site at Stanford, accounted for almost half of all patients;
`he enrolled 26 patients.
`
`The original protocol for the study was finalized by Purdue Pharma in 2002. There were
`several subsequent protocol amendments prior to study initiation that, among other things,
`clarified that patients must be opioid naïve at study entry or pre-operatively (for surgical
`patients) and that oxygen saturation would be monitored continuously for all patients when
`asleep and unattended. The study was conducted from January 2003 to April 2004, when it
`was terminated early for administrative reasons. The clinical study report was finalized and
`signed in 2011.
`
`Study OXP3003 provided PK and safety data for IR oxycodone in patients 5-16 years. It also
`provided supportive efficacy data for IR oxycodone for the treatment of acute pain.
`
`The WR asked that the study be powered to show a difference in pain scores between the
`randomized treatment groups. In fact, pediatric patients should not experience pain
`unnecessarily and a study designed to show such a difference could not be conducted ethically.
`The intent of the WR was for the differential use of rescue medication to serve as the outcome
`for the trial. Similar pain scores across treatment groups, but with the greater use of rescue
`medication by patients in the placebo group is in fact what was observed in the study.
`
`However, no primary outcome and no primary analysis plan were provided in the protocol and
`the primary objective of the protocol was stated to be characterization of the PK and safety of
`IR oxycodone. Therefore, both Dr. Muniz and Dr. Li have highlighted the fact that any
`efficacy analyses provided by the Sponsor are by nature post hoc and unadjusted for
`multiplicity. The protocol-stated sample size was about 100, but the study was stopped
`prematurely for administrative reasons in 2004 with a final n=65. If the study had been
`powered to show a difference in use of rescue medication, it would no doubt have been
`underpowered with this number of patients.
`
`Study Design
`
`All patients were to receive patient-controlled analgesia (PCA) or oral morphine sulfate as
`supplemental pain medication during the double-blind treatment period. After randomization,
`patients received study medication every 6 hours for 18 to 24 hours (4 to 5 doses).
`
`The study was stratified into two age groups (5 years to <12 years and 12 years to ≤16 years).
`Patients were randomized to receive treatment with 0.1 mg/kg IR oxycodone, 0.2 mg/kg IR
`oxycodone, or placebo and they were randomization on a 3:3:2 ratio.
`
`For efficacy, pain scores (pain right now) were obtained using the Faces Pain Scale – Revised
`(FPS-R) at the following timepoints: at baseline, 0.5, 1, 2, and 3 hours post-first-dose. For
`subsequent doses, pain scores were to be collected pre-dose and 1 hour post-dose. Pain scores
`were also to be obtained at the end of study. The FPS-R consists of 6 facial expressions. Each
`face is 25 x 35 millimeters with 13 millimeters between faces. Each patient was asked to point
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`NDA 22272/Supplement 27 OxyContin
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`to the face that reflected his or her pain. The end points are 0 = no pain and 10 = very much
`pain.
`
`All doses of PCA morphine were to be recorded by total amount of morphine (mg)
`administered per one-hour time periods, number of doses in one-hour time periods, and route
`of administration. All other supplemental pain medications were also to be recorded.
`
`For the PK evaluation, a maximum of eight blood samples (when feasible) were to be
`collected over the entire study period. Blood samples were to be tested for oxycodone,
`oxycodone metabolite, and morphine concentrations. Blood samples were to be obtained from
`an indwelling cannula or from a previously inserted central venous catheter or arterial catheter.
`Time windows for the samples were pre-designated in the protocol.
`
`Safety was to be assessed using adverse events, clinical laboratory tests, vital signs, physical
`examinations, oxygen saturation, and somnolence. Oxygen saturation and somnolence were to
`be obtained immediately prior to each dose and one hour after each dose and, again, at the end
`of the study. The University of Michigan Sedation Scale (a categorical scale 0=awake to
`4=unarousable to stimuli) was to be used to assess somnolence.
`
`Primary Outcome Measure
`
`There were two primary objectives stated in the protocol: to characterize the PK of oxycodone
`liquid in pediatric patients 5-16 years and to evaluate the safety.
`
`Secondary Outcome Measure
`
`The key secondary objective was to characterize the efficacy based on supplemental analgesic
`requirements and pain scores.
`
`Inclusion Criteria
`
`
` Male and female pediatric patients from 5 to ≤16 years of age
` Anticipated to have moderate to severe pain requiring conversion to treatment with an
`oral opioid analgesic for 2 or more days
` Must be inpatient at the time of enrollment
` Weight must be ≥15 kg at the time of study entry
` Patients of child-bearing potential must have a negative urine pregnancy test and must
`be using an acceptable form of birth control
` Sufficiently alert to communicate and perform study related procedures
` Written informed consent from parent or legal guardian and child assent if appropriate
` Postoperative surgical patients receiving intravenous PCA for pain control will be
`eligible for inclusion
`
`
`Exclusion Criteria
`
`
` American Society of Anesthesiologists Physical Status ≥4 (severe, life threatening
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`disease), except that patients with cancer who meet this criterion may be enrolled
` Unable to take clear liquids
` History of sleep apnea
` Cystic Fibrosis
` Malabsorption syndromes
` Sickle Cell Anemia
` Unable to take morphine
`