CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`22-272
`22-272
`
`APPLICA TION NUMBER:
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
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`
`
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`

`

` FDA CENTER FOR DRUG EVALUATION AND RESEARCH
` DIVISION OF ANALGESIA AND ANESTHESIA PRODUCTS
` 10903 NEW HAMPSHIRE AVENUE, BLDG 22, SILVER SPRING, MARYLAND 20993
`
`
`
`CDTL Review
`
`
`
`
`Review Date
`From
`Subject
`NDA #
`Applicant
`Date of Submission
`PDUFA Goal Date
`Proprietary Name/Established (USAN)
`names
`Dosage forms/Strength
`Proposed Indication
`
`April 5, 2010
`Ellen Fields, M.D., M.P.H.
`CDTL Review
`22-272
`Purdue Pharma
`February 5, 2010
`April 5, 2010
`Oxycontin/Controlled-Release Oxycodone
`
`Tablets 10, 15, 20, 30, 40, 60, and 80mg
`For the management of moderate to severe
`pain when a continuous, around-the-clock
`analgesic is needed for an extended period
`of time
`Approval
`
`Recommendation
`
`The focus of this review is the resubmission of NDA 22-272 submitted on February 5,
`2010, by Purdue Pharma in reply to the Complete Response (CR) letter issued by the
`Agency on December 30, 2009. The deficiency noted in the CR letter was that a Risk
`Evaluation and Mitigation Strategy (REMS) is necessary for the approval of Oxycontin,
`and although a REMS was submitted (on December 22, 2009), it was too late in the
`review cycle for adequate review, and another review cycle would be necessary. A brief
`summary of the regulatory history of the first two review cycles is below. For additional
`details the reader is referred to previously filed reviews.
`
`Regulatory Background
`NDA 22-272 for Purdue’s reformulated Oxycontin tablets was initially submitted for
`review on November 29, 2007. According to the Applicant, the reformulation was
`undertaken to create tablets with controlled-release features that would be less easily
`compromised by tampering than the original formulation, and thereby result in a
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`reduction in abuse. The proposed indication was the same as the marketed Oxycontin
`formulation.
`
`In accordance with section 505-1 of the FDCA, the Agency determined that a Risk
`Evaluation and Mitigation Strategy (REMS) is necessary for OxyContin to ensure that the
`benefits of the drug outweigh the risks of abuse, misuse, and overdose. As the Agency is
`currently in the process of formulating a class-wide opioid REMS for all long-acting
`opioids, an “interim REMS” will be required for these products individually until the
`class-wide REMS is implemented.
`
`The 2007 application included complete Chemistry, Manufacturing and Controls data,
`non-clinical studies,
`the results of a number of abuse-liability studies, and
`pharmacokinetic studies comparing
`the reformulated Oxycontin
`to
`the original
`formulation. This was the first submission to the Agency of an “abuse-resistant” opioid
`formulation, and was discussed at a joint public meeting of the Anesthesia and Life
`Support Drugs and the Drug Safety and Risk Management Advisory Committees on May
`5, 2008. The application received a Complete Response decision on October 3, 2008,
`primarily because of the poor quality of the studies submitted to support the Applicant’s
`proposed labeling claims regarding tamper resistance, the lack of an adequate REMS to
`assure that the benefits of the product outweigh its risks, and the Applicant’s plan to
`market the 60 mg and 80 mg higher-strength tablets in the original formulation at the
`same time and with the same name that they marketed the lower-strength tablets in the
`new formulation.
`
`The Applicant resubmitted NDA 22-272 in response to the October 3, 2008, CR letter on
`March 31, 2009. The submission included new detailed information on in vitro studies
`conducted to evaluate the tamper-resistant characteristics of the reformulated tablets,
`including the 60mg and 80mg strengths, with comparison to the tamper-resistant
`characteristics of the currently available Oxycontin.
`
` second joint Advisory Committee meeting was held to assess whether the studies
`performed by the Applicant were adequate to provide data on the abuse-deterrent
`characteristics of the reformulated Oxycontin product. The consensus of the committee
`was that the Applicant had provided adequate data. They also stated that the approval
`should be contingent upon a post-marketing requirement to perform an epidemiologic
`study to assess the impact of the reformulated Oxycontin on abuse and misuse in the
`community, as well as an adequate REMS. The PDUFA clock was extended from
`September 30, 2009, to December 30, 2009, because the Applicant submitted a REMS
`amendment on September 18, 2009, that represented a major amendment to the NDA.
`
`Upon completion of the REMS proposal review, the Agency determined that a
`Medication Guide and Communication Plan will not be adequate to ensure adequate
`training of healthcare providers to address the labeled risks of Oxycontin, and to prevent
`the occurrence of serious adverse events associated with those risks. Therefore the
`REMS requirements would be changed to include a Medication Guide, Element to
`Assure Safe Use, specifically, healthcare provider training under 505-1(f)(3)(A), and a
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`Timetable for Submission of Assessments, and issued a letter informing the Applicant of
`this change on December 11, 2009. The Applicant submitted their new REMS in
`response to this request on December 22, 2009, within a week of the action due date.
`With inadequate time for a thorough review of this new REMS, a CR action was taken,
`and review of the new REMS was planned to be to be conducted during our review of the
`Applicant’s response to our December 30, 2009, Complete Response letter.
`
`February 5, 2010 Resubmission
`This submission contained the following items in response to the December 30, 2009 CR
`letter:
`• Proposed REMS and REMS Supporting Document
`• Proposed labeling
`• Epidemiology Study Proposal
`• Safety Update
`•
`Inform Agency of
`
`
`
`
`)
`
`
`REMS Submission
`The requirements for the Oxycontin REMS as specified in the December 11, 2009, letter
`are as follows:
`
`Based on our current understanding of the risks of OxyContin (oxycodone
`hydrochloride), we have determined that the REMS must include a Medication
`Guide, elements to assure safe use, specifically training for healthcare providers
`as described under 505-1(f)(3)(A), and a timetable for the submission of
`assessments of the REMS.
`
`The Elements to Assure Safe Use must include, at a minimum, the following:
`
`
`1)
`
`A plan to ensure that OxyContin (oxycodone hydrochloride) will only be
`prescribed by healthcare providers who have particular training under 505-
`1(f)(3)(A) about the information described below. At a minimum the plan shall
`require that:
`(a) Healthcare providers are trained about:
`(i) Proper patient selection
`(ii) Appropriate product dosing and administration
`(iii) General opioid use including information about opioid
`abuse and how to identify patients who are at risk for
`addiction
`(iv) The risks of abuse, misuse, overdose, and addiction from
`exposure to opioids, including OxyContin (oxycodone
`hydrochloride)
`(v) The risks of OxyContin (oxycodone hydrochloride)
`including:
`1. The risk of overdose caused by exposure to an
`essentially immediate-release form of oxycodone
`
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`(b) (4)
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`to broken, chewed crushed or dissolved
`due
`OxyContin (oxycodone hydrochloride)
`2. The risk of addiction from exposure to OxyContin
`(oxycodone hydrochloride)
`3. The risk of overdose with use of 60 mg dosages and
`above in non-opioid-tolerant individuals
`(vi) Information to counsel patients on the need to store
`opioid analgesics safely out of reach of children and
`household acquaintances
`(vii)
`The importance of providing each patient a
`Medication Guide with each prescription and instructing
`the patient to read it.
`(b) Healthcare providers will be retrained periodically, at a specified
`interval.
`
`g.
`
`h.
`
`
`Information needed for assessment of the REMS may include but may not be
`limited to:
`
`a. An evaluation of patients’ understanding of the serious risks of OxyContin
`(oxycodone hydrochloride).
`b. A report on periodic assessments of the distribution and dispensing of the
`Medication Guide in accordance with 21 CFR 208.24.
`c. A report on failures to adhere to distribution and dispensing requirements, and
`corrective actions taken to address noncompliance.
`d. A report on the status of the training program for healthcare providers.
`e. An evaluation of healthcare providers’ awareness and understanding of the
`serious risks associated with OxyContin (oxycodone hydrochloride) (for
`example, through surveys of healthcare providers).
`f. Specification of measures that would be taken to increase awareness if surveys of
`healthcare providers indicate that healthcare provider awareness is not adequate.
`An analysis and summary of surveillance and monitoring activities for abuse,
`misuse and overdose, and any intervention taken resulting from signals of abuse,
`misuse and overdose.
`A claims study to evaluate OxyContin (oxycodone hydrochloride) utilization
`patterns
`including opioid-tolerant utilization patterns before and after
`implementation of the REMS.
`With respect to REMS goals, an assessment of the extent to which the
`elements to assure safe use are meeting the goals or whether the goals or such
`elements should be modified.
`
`Each assessment must assess the extent to which the elements to assure safe use
`of your REMS are meeting the goals of your REMS and whether the goals or
`elements should be modified.
`
`A Discipline Review Letter with REMS related comments based on review of the REMS
`submission of December 22, 2009, was sent to the Applicant on January 26, 2010.
`
`
`On February 5, 2010, the Applicant submitted a proposed REMS that included a
`Medication Guide, Elements to Assure Safe Use (ETASU), and a Timetable for
`Submission of Assessments. The ETASU is training for healthcare providers who
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`prescribe Oxycontin, and the training addresses items (i) through (vii) above. Prescribers
`are to be re-trained very two years, and the target audience of the ETASU is healthcare
`providers who are likely prescribers of Oxycontin and selected healthcare professional
`associations for distribution to their members. Included in the REMS is a Healthcare
`Provider Guide, “Prescribing Oxycontin Tablets CII: A Training Guide for Healthcare
`Providers.” The proposed Timetable for Submission of Assessments is six months and
`one year from the date that the REMS is approved, and annually thereafter.
`
`The REMS has been reviewed by the Office of Safety and Epidemiology, Division of
`Risk Management, and the Division, and a second set of comments was sent to the
`Applicant on March 17, 2010 in order to bring the contents of the REMS into compliance
`with the requirements conveyed to the Applicant. The Applicant responded to these
`comments acceptably on DATE, and a final REMS has been agreed upon that satisfies
`the Agency’s requirements.
`
`Labeling
`The name of the product will continue to be Oxycontin/oxycodone hydrochloride
`controlled-release tablets. Labeling changes to the current label are minimal, and include
`updates in the preclinical and clinical pharmacology sections.
`
`Additional information regarding potential drug-drug interactions that could affect
`patients taking OxyContin became available in the medical literature during this review
`cycle. The following language was added to the product label by the review team and its
`inclusion was agreed to by the Applicant:
`
`
`CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the
`metabolism of oxycodone and, therefore, may cause increased clearance of the drug which
`could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly,
`development of an abstinence syndrome in a patient who had developed physical
`dependence to oxycodone. A published study showed that the co-administration of rifampin,
`a drug metabolizing enzyme inducer, decreased oxycodone (oral) AUC and Cmax by 86%
`and 63%, respectively. If co-administration with OxyContin is necessary, caution is advised
`when initiating therapy with, currently taking, or discontinuing CYP3A4 inducers. Evaluate
`these patients at frequent intervals and consider dose adjustments until stable drug effects
`are achieved.
`
` A
`
` Medication Guide is included in the labeling and will be part of the REMS. There will
`be no information in the label regarding the physicochemical attributes of the formulation
`or claims regarding tamper- or abuse-resistance.
`
`Epidemiology Study Proposal
`The Applicant submitted a proposal for the conduct of seven postmarketing studies to
`fulfill the requirement stated in the December 30, 2009, CR letter. The proposal consisted
`of brief descriptions of the studies that are intended to address the outcomes requested in
`the CR letter, and a tentative timeline. Because of design and methodology challenges
`associated with the conduct of these types of studies, the Agency continues to be
`concerned that the proposed studies will not successfully capture the necessary
`information that will allow an assessment of the impact, if any, attributable to the change
`in the OxyContin formulation. It is likely that this issue will be brought to an Advisory
`
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`Committee in order to determine whether the Applicant’s proposal is adequate to assess
`whether the changes made to the OxyContin formulation that are the subject of this
`application and which are intended to provide deterrence of misuse and abuse actually
`result in a decrease in the risks of misuse and abuse, and their consequences, addiction,
`overdose and death.
`
`Safety Update
`The Applicant submitted a safety update containing data gathered after the March 31,
`2009, resubmission for NDA 022272. A total of 277 healthy subjects received doses
`ranging from 5 mg through 80 mg, in either the fed or fasted state, with or without
`naltrexone blockade. The adverse event profiles were similar for both the reformulated
`OxyContin and OxyContin treatments. The most common treatment-emergent adverse
`events reported were those known to be associated with opioids such as nausea,
`headache, dizziness, and vomiting. There were no unexpected safety findings. Results of
`laboratory tests, vital signs measurements, and SpO2 evaluations raised no safety
`concerns for any of the study treatments. Overall, the safety profiles of the reformulated
`OxyContin® as well as OxyContin® were as expected for oxycodone administered to
`fasted and fed, healthy, adult subjects with or without naltrexone HCl blockade.
`
`Recommendation for Regulatory Action
`Approval
`The Applicant has satisfactorily responded to the deficiencies communicated in the CR
`letter of December 30, 2009. As stated in my CDTL reviews from the first two cycles,
`the safety profile of the reformulated Oxycontin appears similar to that of the original
`formulation. The Applicant is planning to market all strengths as the reformulated
`Oxycontin, and will cease marketing of the original formulation.
`
`Recommendation for Postmarketing Risk Management Activities
`The Agency has made a determination that approval of extended-release opioids should
`not be delayed while the development of the class-wide REMS is in progress, as long as
`the safety profile of the drug is not worse than the currently marketed long-acting
`opioids. An interim REMS that meets the Agency’s requirements has been agreed upon,
`and will be implemented upon approval of this product. Oxycontin will become part of
`the class-wide opioid REMS when it is in place.
`
`Recommendation for other Postmarketing Study Requirements
`The Applicant is required to perform an epidemiologic study to address whether the
`changes made to the Oxycontin formulation result in a decrease in misuse and abuse, and
`their consequences: overdose, death, and addiction.
`
`Since this application does not trigger PREA, there are no pediatric postmarketing study
`requirements.
`
`Comments to Sponsor
`Because of design and methodology challenges associated with the conduct of these types
`of studies, the Agency continues to be concerned that the proposed studies will not
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`successfully capture the necessary information that will allow an assessment of the
`impact, if any, attributable to the change in the OxyContin formulation. Therefore we will
`continue discussion of your postmarketing study proposals and will plan to engage
`experts in the field for their advice on the design and methodology of the proposed
`studies.
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`Application
`Type/Number
`--------------------
`NDA-22272
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`PURDUE PHARMA
`INC
`
`------------------------------------------
`OXYCONTIN
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELLEN W FIELDS
`04/05/2010
`
`