CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
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`
`
`APPLICATION NUMBER:
`22-272
`22-272
`
`APPLICA TION NUMBER:
`
`SUMMARY REVIEW
`
`SUMMARY REVIEW
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`

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` FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF ANESTHESIA AND ANALGESIA PRODUCTS
`
`
`
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`Summary Review for Regulatory Action
`
`
`April 5, 2010
`Bob A. Rappaport, M.D.
`Director
`Division of Anesthesia and Analgesia Products
`Division Director Summary Review
`22-272
`Purdue Pharma, L.P.
`February 5, 2010 (Response to second CR letter)
`April 5, 2010
`OxyContin® Tablets
`Oxycodone hydrochloride controlled-release
`Extended-release tablets
`10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg
`For the management of moderate to severe pain when a
`continuous, around-the-clock opioid analgesic is
`needed for an extended period of time
`Approval
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`
`
`Date
`From
`
`Subject
`NDA #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`
`Proposed Indication
`
`Action:
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`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`Statistical Review
`
`Microbiology Review
`Clinical Pharmacology Review
`
`DDMAC
`
`DSI
`CDTL Review
`CSS
`
`OSE/DMEPA
`
`OSE/DPVII
`OSE/DRISK
`
`DEPI
`SEALD
`Maternal Health Team
`
`Jin Chen, M.D., Ph.D.
`(CMC only) Meiyu Shen, Ph.D.; Yi Tsong, Ph.D.; Stella
`Machado, Ph.D.
`Pharmacology Toxicology Review Elizabeth A. Bolan, Ph.D.; R. Daniel Mellon, Ph.D.
`CMC Review
`Craig M. Bertha, Ph.D.; Danae D. Christodoulou, Ph.D.; Ali
`Al-Hakim, Ph.D.; Prasad Peri, Ph.D.
`N/A
`Sayed Al Habet, R.Ph., Ph.D.; Sheetal Agarwal, Ph.D.; Suresh
`Doddapaneni, Ph.D.
`Michelle Safarik, PA-C; Mathilda Fienkeng, Pharm.D.; Twyla
`Thompson, Pharm.D.
`Jacqueline A. O’Shaughnessy, Ph.D.; C.T. Viswanathan, Ph.D.
`Ellen Fields, M.D.; Sharon Hertz, M.D.
`James Tolliver, Ph.D.; Silvia Calderon, Ph.D.; Michael Klein,
`Ph.D.
`Loretta Holmes, B.S.N., Pharm.D.; Linda Kim-Jung,
`Pharm.D.; Kristina Arnwine, Pharm.D.; Denise Toyer,
`Pharm.D.; Carol Holquist, R.Ph.
`Afrouz Nayernama, Pharm.D.
`Mary Dempsey; Jeane Perla, Ph.D.; Gita Toyserkani,
`Pharm.D.; Mary Willy, Ph.D.; Marcia Britt, Pharm.D.; Sharon
`Mills, B.S.N., R.N., C.C.R.P., Jodie Duckhorn, M.A.; Henry
`Francis, M.D.; Gerald Dal Pan, M.D.
`N/A
`Jeanne Delasko, RN, MS; Laurie Burke, R.Ph, M.P.H
`Richardae Araojo, Pharm.D.; Karen Feibus, M.D., Lisa
`Mathis, M.D.
`Suzanne Barone, Ph.D; Agnes Plante, B.S.N, R.N.
`Lisa Basham, M.S.; Parinda Jani
`
`OC/DRMS
`Administrative Reviews/Letters
`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEDP=Division of Medication Error Prevention
`DSI=Division of Scientific Investigations
`DRISK= Division of Risk Management
`DPVII=Division of Pharmacovigilance II
`CDTL=Cross-Discipline Team Leader
`DEPI= Division of Epidemiology
`CSS=Controlled Substance Staff
`SEALD=Study Endpoints and Labeling Development Team
`OC=Office of Compliance
`DRMS=Division of Risk Management and Surveillance
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`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
`
`2
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`1. Introduction
`
`
`On November 29, 2007, Purdue Pharma, L.P. submitted a new drug application for their
`reformulated OxyContin tablets. This reformulation was undertaken to create tablets with
`controlled-release features that would be less easily compromised by tampering. The sponsor
`submitted data from a number of studies to support the new formulation’s capacity to resist
`compromise of the controlled-release features. Based on our review of that application and the
`discussion of the application by a combined meeting of the Anesthetics and Life Support and
`the Drug Safety and Risk Management Advisory Committees on May 5, 2008, the sponsor
`received a Complete Response (CR) letter. A complete discussion of the deficiencies that
`were included in that CR letter may be found in my review of the original application which
`has been appended to this review. That review and my subsequent review dated December 30,
`2009, (also appended to this review) provide a complete summary of all of the details
`pertaining to the original application and the resubmission which is discussed in the following
`paragraphs.
`
`The response to the first CR letter, submitted by Purdue on March 30, 2009, provided adequate
`information to address all of the deficiencies with the exception of the requirement for a Risk
`Evaluation and Mitigation Strategy (REMS). On December 4, 2008, the Agency issued a
`letter to the sponsor informing them of our current efforts to develop an opioid REMS for the
`entire class of long-acting and extended-release opioid products and instructing them not to
`submit a REMS proposal until they received further guidance from the Agency. Therefore, a
`REMS proposal was not included in the sponsor’s response to the Agency’s October 3, 2008,
`CR letter. A REMS was submitted during the review cycle after additional advice was
`forwarded to the sponsor during the review cycle. However, the sponsor’s revised REMS was
`not received until too late in the review cycle for adequate review. A second CR letter was
`issued on December 30, 2009 which listed the following deficiencies:
`
`
`Because the REMS was submitted so late in the review cycle, FDA is deferring its review of the
`REMS to the next cycle.
`
`In addition, the following comments regarding the need for a post-marketing study were
`included in the letter:
`
`…FDA has determined that, if NDA 22272 is approved, you will be required pursuant to section
`505(o)(3) of the FDCA to conduct the following:
`
`
`An epidemiological study (or studies) to address whether the changes made to the
`OxyContin formulation that are the subject of this application result in a decrease in
`misuse and abuse, and their consequences: overdose, death and addiction.
`
`
`We acknowledge receipt of your proposals dated November 6 and December 16, 2009, containing
`your proposed brief outlines of possible postmarketing studies to fulfill this requirement. Because
`of design and feasibility challenges that we have noted in your proposal, we are concerned that the
`proposed studies will not successfully capture the necessary information that will allow us to
`assess the impact, if any, attributable to the change in the OxyContin formulation. Therefore,
`additional information concerning the methodology and feasibility of the proposed potential
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
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`3
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`studies, and possibly the addition of other studies, will be needed before agreement can be reached
`on the design of the postmarketing epidemiology study (or studies) that will assess the risks of
`reformulated OxyContin.
`
`
`
`It will be necessary for you to complete methodology and feasibility assessments for the proposed
`studies. In addition, you should consider other potential outcome models for use in studying the risks
`associated with OxyContin, including but not limited to: accidental overdose in patients, medication
`errors resulting in adverse events involving the actions of healthcare providers or caregivers,
`unintentional overdose and/or poisoning in children, accidental overdose in recreational abusers,
`accidental overdose in experienced abusers, and patterns of abuse.
`
`
`Our interactions with the sponsor regarding their resubmission and their proposed REMS are
`discussed in more detail below in Section 2.
`
`
`2. Background
`
`
`On June 17, 2009, during the second review cycle for this application, the Agency issued a
`REMS Notification Letter instructing the sponsor to submit a REMS proposal that included a
`Medication Guide, a Communication Plan, and a Timetable for Submission of Assessments.
`In response, the Sponsor submitted a REMS proposal on July 24, 2009. The REMS content
`was under negotiation and the sponsor submitted a REMS amendment to incorporate Agency
`changes on September 18, 2009. Due to the timing of this submission, the PDUFA review
`clock was extended by three months, providing for a new PDUFA date of December 30, 2009.
`Upon finalization of the review of the REMS proposal, the Agency determined that the REMS
`requirements would be changed to include a Medication Guide, an Element to Assure Safe
`Use, specifically, healthcare provider training under 505-1(f)(3)(A), and a Timetable for
`Submission of Assessments, and issued a letter informing the sponsor of the change on
`December 11, 2009. The sponsor 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 on December 30, 2009. The
`sponsor submitted their revised REMS on February 5, 2010, as a response to our second CR
`letter. The revised REMS has been thoroughly reviewed by the clinical review team and the
`DRISK review staff and has been found to be acceptable to serve as the interim REMS for this
`product until the class-wide opioid REMS has been finalized (see discussion of “interim” and
`“class-wide” opioid REMS in my appended review).
`
`3. CMC
`
`
`See my previous reviews for a summary of the CMC data. I concur with the CMC review
`team that no additional data is necessary for approval.
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`See my previous reviews for a summary of the pharmacology/toxicology data. I concur with
`the review team that no additional pharmacology or toxicology data is necessary for approval.
`
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
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`4
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`5. Clinical Pharmacology/Biopharmaceutics
`
`
`While there were no clinical pharmacology or biopharmaceutics deficiencies noted in the
`second CR letter, 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 sponsor:
`
`
`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.
`
` I
`
` concur with the clinical team that no additional clinical pharmacology data are necessary to
`support approval
`
`6. Clinical Microbiology
`
`
`No clinical microbiology data were necessary for this application.
`
`7. Clinical/Statistical-Efficacy
`
`
`No new efficacy data was required for or submitted with this response.
`
`8. Safety
`
`
`No new safety data was required for this response. However, the sponsor did submit a safety
`update which was reviewed by Dr. Fields. A total of 277 healthy subjects received doses of
`the new formulation ranging from 5 mg to 80 mg, some with and some without naltrexone
`blockade. The adverse event profile was similar to that seen with the original formulation with
`the most common adverse events being nausea, headache, dizziness and vomiting. There were
`no unexpected safety findings.
`
`9. Advisory Committee Meeting
`
`
`Discussion regarding the two advisory committee meetings held to discuss this application
`may be found in my earlier reviews for the CR actions.
`
`
`
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`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
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`5
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`10.
`
`Pediatrics
`
`
`Pediatric data was not submitted in this application and the application does not fall under the
`authority granted to FDA by PREA.
`
`11.
`Other Relevant Regulatory Issues
`
`
`Discussion regarding additional regulatory issues related to the abuse liability of OxyContin
`and this new formulation may found in my two earlier reviews for the CR actions.
`
`12.
`Labeling
`
`
`Final labeling, including the package insert, Medication Guide and package and container
`labels, has been agreed upon by both the review team and the sponsor.
`
`
`
`
`
`
`13.
`
`Decision/Action/Risk Benefit Assessment
`
`• Regulatory Action
`
`Approval
`
`• Risk Benefit Assessment
`
`
`As stated in my review of December 30, 2009:
`
`
`I concur with the review team and the advisory committee members that the
`sponsor has provided adequate data to demonstrate that their reformulated
`OxyContin product will potentially be more tamper-resistant based on changes
`to the controlled-release formulation, less likely to result in overdose when
`tampered with and ingested, and less likely to be insufflatable or
`syringeable/injectable. While this certainly does not solve the many problems
`associated with the misuse and abuse of OxyContin, it is an important
`incremental change. However, to fully support this approval, I again agree with
`the review team and the advisory committee members that the sponsor should be
`required to perform a post-marketing study to assess the impact of the new
`formulation in the community. This study should be undertaken as a Post-
`Marketing Requirement under the authorities granted the Agency in the Food
`and Drugs Administration Amendments Act.
`
`The sponsor has now provided an acceptable interim REMS and, therefore,
`there are no further impediments to approving this application. It is important
`to add, however, that all communications regarding this new formulation of
`OxyContin must include the following key points:
`
`
`(cid:131) The changes to the OxyContin formulation appear to provide
`some degree of increased resistance to manipulation of the
`controlled-release features making the new product less easy to
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
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`chew, crush or dissolve. These incremental improvements in the
`formulation will, hopefully, reduce the incidence of overdose
`due to abuse and misuse by ingestion or administration (e.g., via
`a nasogastric tube) of crushed or chewed OxyContin, which, due
`to the manipulation, would act as an immediate-release, high-
`dose oxycodone formulation. The formulation changes will also
`likely reduce overdose and abuse associated with insufflation or
`parenteral injection.
`
`(cid:131) Nevertheless, the product is not completely tamper-resistant and
`those intent on abusing this new formulation will likely find a
`means to do so.
`
`(cid:131)
`
` (cid:131)
`
`In addition, the product can still be misused or abused and result
`in overdose by simply administering or ingesting larger than
`recommended oral doses.
`
` The REMS approved for this product will, hopefully, mitigate to
`some degree the continued risks associated with OxyContin.
`
`(cid:131) While the improvements in tamper resistance produced by this
`new formulation will not provide a completely safe version of
`OxyContin, even incremental changes that increase the product’s
`resistance to tampering may reduce the misuse and abuse of
`OxyContin to some degree. The sponsor’s required post-
`marketing epidemiological study should help us determine
`whether this actually happens when the new formulation
`becomes the only one available on the market.
`
`
`
`
`
`
`
`• Required Postmarketing Studies
`
`
`With the February 5, 2010 resubmission, the sponsor submitted seven study
`proposals to address the requirement for a post-marketing epidemiological
`study to assess the impact of the new OxyContin formulation on abuse and
`misuse, but the review team felt that, even on face, these proposed studies
`would be unlikely to provide the necessary data for this assessment. We plan to
`have ongoing discussions with the sponsor regarding the design of this
`study(ies) and to have a public discussion of the final proposed study design at
`an advisory committee meeting. The following language has been included in
`the approval letter:
`
`
`We acknowledge receipt of your proposal, included in your February 5, 2010,
`resubmission to this application, that contains brief descriptions of possible
`postmarketing studies to fulfill this requirement. Because of design and
`methodology challenges, we continue to be concerned that the proposed studies
`will not successfully capture the necessary information that will allow us to
`assess the impact, if any, attributable to the change in the OxyContin
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
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`(Oxycodone Hydrochloride Controlled-Release) Tablets formulation.
`Therefore, we will continue discussion of your postmarketing study proposals at
`an advisory committee meeting in the fall of 2010 on the design and
`methodology of the proposed studies.
`
`For the study to be conducted first, you must submit the final protocol and the
`timetable for completion of the study by January 31, 2011. Likewise, for the
`study to be conducted last, you must submit the final protocol and timetable for
`completion of the study by March 1, 2011.
`
`• Required Postmarketing Risk Evaluation and Mitigation Strategy
`
` A
`
` final REMS, including a MedGuide, required prescriber educational
`materials and a timetable for submission of assessments was submitted during
`this cycle and has been reviewed by the clinical review team and the DRISK
`review team. The following comments on this plan have been reproduced from
`page 9 of Dr. Perla’s review:
`
`
`The REMS Supporting Document outlines the information that the Sponsor will
`use to assess the effectiveness of the REMS in meeting the goals. The Sponsor
`did not submit the patient and prescriber survey instruments or methodologies;
`however, this information does not need to be submitted for FDA review prior to
`approval of the REMS. The DR letter of March 18, 2010 indicated that the
`Sponsor must submit for review the detailed plans that will be used to evaluate
`patients’, prescribers’, and pharmacists’ understanding about the risks associated
`with and safe use of OxyContin® at least 90 days before the evaluation will be
`conducted. Please convey to the Sponsor that a pharmacist survey will not be
`necessary…
`
`Based on our current understanding of the risks of OxyContin®, DRISK believes
`that a REMS comprised of these components is appropriate until a class-wide
`opioid REMS is established.
`
`A summary of the prescriber education program, submitted as an Element to
`Assure Safe Use, has been reproduced from pages 5 through 7 of Dr. Perla’s
`review:
`
`3.2.3. Elements to Assure Safe Use
`1. Healthcare providers who prescribe OxyContin® will receive training.
`
`a. Purdue will ensure that training will be provided to healthcare providers
`who prescribe OxyContin®. To become trained, each prescriber will be
`provided with the OxyContin® Educational materials.
`
`The Training includes the following:
`
`i) Proper patient selection;
`
`ii) Appropriate OxyContin® dosing and administration;
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`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
`
`8
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`iii) General principles of safe opioid use, including information about
`opioid abuse and how to identify patients who are at risk for addiction;
`
`iv) Potential abuse, misuse, overdose and addiction from exposure to
`opioids, including OxyContin®;
`
`v)
`
` Risks of OxyContin®, including:
`
`1. The risk of overdose caused by exposure to an essentially
`immediate-release form of oxycodone by consuming broken,
`chewed, crushed or dissolved OxyContin® tablets;
`
`2. The risk of addiction from exposure to OxyContin®; and
`
`3. The risk of overdose in patients who have not developed tolerance
`to the sedating or respiratory-depressant effects of opioids from
`exposure to a single dose of OxyContin greater than 40 mg;
`
`vi) Information to counsel patients and caregivers on the need to store
`opioid analgesics safely out of reach of children and household
`acquaintances and the need to properly dispose of unused drugs when
`no longer needed by the patient; and
`
`vii) Importance of providing each patient a Medication Guide with each
`prescription and instructing the patient to read the Medication Guide.
`
`
`
`b. Purdue will ensure that at least 3 weeks prior to first availability of
`OxyContin® to healthcare professionals, a Dear Healthcare Professional
`letter will be mailed to prescribers most experienced in treating chronic pain
`with opioid agonists, including pain specialists, physiatrists, and primary
`care physicians. This letter is designed to convey and reinforce the risks of
`abuse, misuse, overdose and addiction of OxyContin® as well as the need to
`complete the OxyContin® REMS Educational Program. This letter will be
`available on the Purdue website (www.OxyContinrems.com) for 1 year
`from the date of mailing.
`
`c. The mailings will include the following OxyContin® REMS Educational
`Program materials:
`
`i) OxyContin® Medication Guide
`
`ii) Prescribing OxyContin® Tablets CII: A Guide for Healthcare Providers
`
`iii) OxyContin® Education Confirmation Form
`
`d. Additional printed educational material will be available through field-force
`distribution and by calling the toll-free number at Purdue (1-888-726-7535).
`
`
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
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`e. The educational material will also be available for download at
`www.OxyContinrems.com.
`
`f. Purdue will maintain a list of all prescribers who have completed the
`OxyContin® REMS Educational Program.
`
`Prescribers will be re-trained every two years or following substantial changes
`to the OxyContin® REMS. Substantial changes may include changes in the
`OxyContin® Full Prescribing Information, OxyContin® Medication Guide, or
`OxyContin® REMS that require substantial modification of the educational
`materials.
`
`The following materials are part of the REMS and are appended:
`o Dear Healthcare Professional Letter
`o Medication Guide
`o The Healthcare Provider Guide, “Prescribing OxyContin® Tablets CII:
`A Training Guide for Healthcare Providers”
`o OxyContin® Education Confirmation Form
`
`
`
`
`
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`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
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`FIRST AND SECOND REVIEWS RESULTING IN
`COMPLETE RESPONSE ACTIONS
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`April 5, 2010
`
`11
`
`2 Complete Response Summary Reviews (consisting of 26 pages) dated
`September 30, 2008 and December 30, 2009 from Bob Rappaport, M.D. has
`been removed immediately following this page and has been relocated to the
`Medical Review section of this NDA approval package.
`
`