CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`22-272
`22-272
`
`APPLICA TION NUMBER:
`
`MEDICAL REVIEW(S)
`MEDICAL REVIEWQSQ
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`Date
`From
`
` FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHESIA, ANALGESIA, AND RHEUMATOLOGY PRODUCTS
`
`
`
`
`
`Summary Review for Regulatory Action
`
`
`December 30, 2009
`Bob A. Rappaport, M.D.
`Director
`Division of Anesthesia, Analgesia and Rheumatology
`Products
`Division Director Summary Review
`22-272
`Purdue Pharma, L.P.
`March 31, 2009 (Response to CR letter)
`September 30, 2009; December 30, 2009 with clock
`extension
`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
`Complete Response
`
`Subject
`NDA #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`
`Proposed Indication
`
`Action:
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`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.
`N/A
`Sayed Al Habet, R.Ph., 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.; Kristina Arnwine,
`Pharm.D.; Denise Toyer, Pharm.D.; Carol Holquist, R.Ph.
`Afrouz Nayernama, Pharm.D.
`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 Dickhorn, M.A.; 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.
`Lisa Basham, M.S.; Parinda Jani
`
`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
`
`
`
`
`
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`2
`
`

`

`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. The most significant inadequacies in the
`application were the poor quality of the studies submitted to support the sponsor’s proposed
`labeling claims, the lack of an adequate REMS to assure that the benefits of the product
`outweigh its risks, and the sponsor’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 Agency clearly informed the sponsor at
`their pre-NDA meeting that this plan would be unacceptable due to the potential for a
`misconception among prescribers that the higher-strength tablets would also have abuse-
`deterrent features. This misconception could lead to significant safety problems. The
`Agency’s concern was strongly echoed by the Advisory Committee members. The October 3,
`2008, CR letter delineated the following deficiencies that would need to be addressed by the
`sponsor in their response:
`
`1. Provide a new product name for the reformulated strengths if you intend to continue to market the original
`formulation at any strength at the same time as you intend to market the reformulated tablets. It is not
`acceptable to have some reformulated strength tablets and the same original formulation strength tablets
`available on the market at the same time with the same product name.
`
`
`2. Provide studies of the new formulation that demonstrate the effects of physical and/or chemical manipulation
`and that incorporate the following:
`
`
`
`
`
`
`
`a. The testing must be conducted in a blinded manner, preferably by an independent third party.
`
`b. The methods used to assess the physical characteristics of the product must be reassessed. Consult
`individuals experienced in the intentional extraction of oxycodone from OxyContin for abuse to
`determine the methods for testing that will most likely replicate the methods encountered once the
`product is marketed. The resultant testing methods should then undergo a validation procedure to ensure
`they are conducted in a reproducible and meaningful manner.
`
`c. Consult experts on extraction techniques to fully assess your proposed extraction testing protocols and to
`evaluate the data upon completion.
`
`
`d. Provide data documenting the amount of oxycodone released if the reformulated tablet is chewed
`
`
`
`
`e. Conduct studies to determine the relative rate of release of the active pharmaceutical ingredient from all
` tablets to determine whether all dosage strengths retain the controlled-
`strengths of crushed
`release properties after crushing
` and that dose dumping does not occur.
`
`.
`
`
`
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`f. Provide data documenting how altering the grinding conditions,
`
` might affect the final particle size distribution of the
`tablets for all strengths and whether these efforts might render a product suitable for insufflation.
`
`3. As noted during Division of Scientific Investigations inspection of Study OTR1005, accuracy of Period 1
`oxycodone concentrations for subjects 5040-5042 in run 07307cga14a and subjects 5043, 5044, and 5046 in
`run 07307cgb14a cannot be assured. Therefore, before data from Study OTR1005 can be accepted, reanalyze
`and submit the data from study OTR1005 demonstrating bioequivalence after completely excluding data
`from subjects 5040, 5041, 5042, 5043, 5044, and 5045. Alternatively, reanalyze the plasma concentrations as
`identified and confirm the original values.
`
`
`4. For the reasons described below, you must submit a proposed Risk Evaluation and Mitigation Strategy
`(REMS).
`
`
`
`The response submitted by Purdue on March 30, 2009 included updated CMC data for the
`reformulated 60 mg and 80 mg tablets, a genetic toxicology study to support a proposed
`labeling change, pharmacokinetic studies of the 60 mg and 80 mg strengths, and updated data
`regarding the tamper-resistant features of reformulated Oxycontin. On December 4, 2008, the
`Agency issued a letter to the sponsor informing them of the current efforts to develop a class-
`wide REMS 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. This review will focus only on the
`sponsor’s response to the deficiencies outlined in the CR letter, and the need for a REMS and a
`post-marketing study to be defined as a Post-Marketing Requirement, as authorized under the
`Food and Drug Administration Amendments Act. All other details of the original application
`have been covered in my previous review which has been appended to this review.
`2. Background
`
`
`At the Agency’s request, the sponsor did not submit a proposed REMS with this resubmission.
`On June 17, 2009, 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, 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, we will need to take a
`CR action at this time and review the new REMS as a response to the CR letter during the next
`review cycle. For additional background information see Appendix.
`
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`4
`
`(b) (4)
`
`

`

`As the sponsor is now proposing to change all strengths of the OxyContin formulation at the
`same time, it is no longer necessary for the name to be changed.
`
`3. CMC
`
`
`Adequate data was submitted to support the quality, purity and stability of the reformulated 60
`and 80 mg strength tablets. I concur with the CMC review team that no additional data is
`necessary for approval.
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`Dr. Bolan reviewed the new in vitro chromosomal aberration assay in human peripheral blood
`lymphocytes conducted with oxycodone. The study showed that oxycodone did not produce
`clastogenicity. However, increased levels of polyploid cells were observed in cultures treated
`with oxycodone. The findings from this study will be described in the product label. I concur
`with the review team that no additional pharmacology or toxicology data is necessary for
`approval.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`The following has been reproduced from page 6 of Dr. Field’s review:
`
`
`The Applicant submitted three bioequivalence/dose-proportionality studies in the current
`application. Studies OTR1008 and OTR1009 demonstrated bioequivalence between a single
`80mg dose of the reformulated Oxycontin and an 80mg dose of the currently marketed
`formulation in fed and fasted subjects, respectively. Study OTR1012 demonstrated the dose
`proportionality of 40mg, 60mg, and 80mg reformulated Oxycontin. Dose proportionality of the
`lower strengths including 40mg had been demonstrated during the first review cycle.
`
`Per the Agency’s complete response letter dated October 3, 2008, the Applicant reanalyzed the
`data from the bioequivalence Study OTR1005 of the 40mg strength after excluding six subjects
`that were included in the statistical analysis in the original NDA. This action was necessary to
`ensure accuracy of the bioequivalence data based on the DSI inspection report. The exclusion of
`these subjects from the analysis did not change the original conclusions that the 40mg
`reformulated Oxycontin is bioequivalent to the 40mg marketed formulation.
`
`The Applicant also provided in vitro data that there was no effect of alcohol on the release rate of
`oxycodone from the 60mg and 80mg reformulated tablets. This plus the findings from the first
`cycle showing the same results for the 10mg through 40mg tablets confirms there is no evidence
`of dose dumping for this formulation at all proposed dosage strengths.
`
` 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.
`
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`5
`
`

`

`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 or submitted with this response. The only additional
`clinical experience was in the bioequivalence studies for which the subjects were naltrexone
`blocked and, thus, would not provide any meaningful safety experience to assess.
`
`9. Advisory Committee Meeting
`
` A
`
` joint meeting of the Anesthesia and Life Support and the Drug Safety and Risk Management
`Advisory Committees was held on September 19, 2009 to discuss the new data submitted to
`define the product’s tamper-deterrent features. The committee members voted 14 to 4 with 1
`abstention to approve the application. The consensus of the committee was that the
`reformulated product (all strengths) demonstrated an incremental increase in tamper-
`resistance, although it clearly maintained the previously acknowledged high risk for people
`who misused or abused the product by taking higher than safe doses of intact tablets. The
`advantages of the new formulation include:
`
`
`(cid:131) Perhaps most importantly, it cannot be crushed or chewed by standard mechanisms that
`may result in the ingestion of a lethal “immediate-release” dose by a casual or
`recreational abuser, or by a patient, e.g., when a nurse or caretaker attempts to crush
`and administer via a nasogastric tube.
`
`(cid:131)
`
`It cannot be altered to a consistency (i.e., powder) that can be insufflated or dissolved
`for injection using the standard household tools that the more hard-core abusers
`generally use.
`
`
`
`
`
`(cid:131) When dissolved in water it becomes a thick, gelatinous substance that cannot be
`syringed or injected with the usual needles and syringes used by hard-core abusers.
`
`
`The committee members acknowledged that the reformulated OxyContin tablets can be
`crushed and/or extracted by unusual means and, therefore, those intent on abusing the products
`by defeating the extended-release mechanism will still be able to do so. The committee
`members also acknowledged that that those abusing or misusing the product by ingesting more
`intact tablets or higher doses of intact tablets would not be provided with any protection from
`overdose with this reformulated product. Finally, the committee members were generally in
`consensus that a post-marketing epidemiology study to assess the impact of the reformulation
`on actual abuse in the community is essential to fully understand the value of the product and
`the level of risk management it will need, and that this study should be required as a post-
`marketing requirement for approval.
`
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`6
`
`

`

`Detailed in vitro testing to characterize the tamper-resistant properties of reformulated Oxycontin
`was conducted on all dosage strengths. The reformulated Oxycontin may provide enhanced
`protection over that provided by the currently marketed Oxycontin for the intended population
`against dose dumping when tablets are accidentally crushed or chewed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`The bulk of this submission consisted of the new studies performed to document the abuse-
`deterrent qualities of the new formulation. Dr. Tolliver of the Controlled Substances Staff
`provided a thorough review of those studies. The following is reproduced from page 7 of Dr.
`Fields’ review and summarizes Dr. Tolliver’s conclusions:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CSS determined that the Applicant’s testing of the physicochemical attributes of the Oxycontin
`reformulation was adequate. The tamper-resistant properties will have no effect on abuse by the
`oral route (the most common mode of abuse), however there may some limited, incremental effect
`on abuse and misuse by other means. While the reformulation is harder to crush or chew, possibly
`mitigating some accidental misuse, oxycodone HCl is still relatively easily extracted
`
`
`
`
`In general, the reformulated product should be viewed as an incremental improvement over the
`currently available Oxycontin
`
`
`During the Open Public Hearing portion of the September 24, 2009 Advisory Committee
`meeting one of the speakers made several statements about additional risks associated with
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`12.
`
`Labeling
`
`
`The sponsor’s proposed labeling has not been finalized on this review cycle.
`
`
`
`
`
`
`
`
`13.
`
`Decision/Action/Risk Benefit Assessment
`
`• Regulatory Action
`
`Complete Response
`
`• Risk Benefit Assessment
`
`
`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-
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`8
`
`(b) (4)
`
`

`

`Marketing Requirement under the authorities granted the Agency in the Food
`and Drugs Administration Amendments Act.
`
` Required Postmarketing Studies
`
`Based on the available scientific data and the strong recommendation of the
`advisory committee members, FDA has determined that the sponsor must
`conduct an epidemiological study to address whether the changes made to the
`OxyContin formulation that are the subject of this application and which are
`intended to provide misuse and abuse-deterrence actually result in a decrease in
`misuse and abuse, and their consequences, addiction, overdose and death, in the
`community. On December 16, 2009, the sponsor submitted a proposal for three
`studies to satisfy our request for this post-marketing requirement. The three
`studies proposed were:
`
`
` •
`
`
`
`No actual study design proposals were submitted and the brief descriptions of
`the studies were submitted within the last two weeks of the review cycle. On
`face, however, the proposed studies do not appear to be adequate to fully
`address the impact of the new formulation on misuse and abuse. We will
`continue to evaluate these proposed studies and, if necessary, require that the
`sponsor submit a new study design proposal with their response to the second
`CR letter so that they will, at the time of product approval, be able to provide a
`timetable according to which they will submit their final protocol, conduct their
`study and submit their final study report.
`
` Required Postmarketing Risk Evaluation and Mitigation Strategy
`
`As I stated in my review of the original submission, an adequate REMS will be
`necessary to assure that the benefits of this product outweigh its risks, which
`are substantial. Based on the Agency’s current efforts to develop a class REMS
`for long-acting or extended-release (such as this product) opioids and the fact
`that a number of these products are already approved and marketed with risk
`management programs of varying types, a decision was made to allow approval
`of new products that fall within this class with an interim REMS until the class
`REMS has been finalized. A letter was sent to the sponsor outlining this
`change in the requirements for their REMS on June 17, 2009. That letter stated
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`9
`
` •
`
`(b) (4)
`
`

`

`that they will be required to implement the class REMS when it is available.
`The letter noted that the interim REMS should consist of elements that are
`consistent with the currently existing risk management programs for the
`approved products that fall within this class, i.e., a MedGuide, a
`Communication Plan, and a Timetable for Submission of Assessments. The
`sponsor submitted their proposed REMS on July 24, 2009, based upon the
`requirements outlined in our letter, and submitted revisions based on Agency
`comments on September 18, 2009 and November 13, 2009. However, after
`further internal discussion and review of the proposed REMS, the Agency
`determined that the Medication Guide and Communication Plan will not be
`sufficient 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 interim REMS should not
`have a Communication Plan, but rather an Element to Assure Safe Use that
`would require prescriber education, in addition to the Medication Guide. The
`sponsor was sent a letter informing them of this change on December 11, 2009,
`and responded with their modified REMS on December 22, 2009. As this
`version of the REMS was submitted only one week before the action date for
`the application, there has not been adequate time for a thorough review.
`Therefore, we will not be able to approve this application at this time based on
`the absence of an agreed upon REMS.
`
`
`
`
`
`
`
`
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`10
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`APPENDIX
`
`NDA 22-272 OxyContin
`Division Director Summary Review for Regulatory Action
`December 30, 2009
`
`11
`
`Summary Review, dated 9/30/2008 is included in its entirety as an individual document
`within this review.
`
`

`

`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/
`----------------------------------------------------
`
`BOB A RAPPAPORT
`12/30/2009
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`December 30, 2009
`
`
`
`NDA 22-272 OxyContin
`Submitted March 31, 2009
`
`
`
`
`
`
`
`Sharon Hertz, M.D., Deputy Division Director
`
`Financial Disclosure
`
`Cross Discipline Team Leader Review
`
` FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF ANALGESIA, ANESTHESIA, AND RHEUMATOLOGY PRODUCTS
`HFD-170, Building 22, 10903 New Hampshire Ave. Silver Spring MD 20993
`Tel:(301)796-2280
`
`Memo to NDA
`
`
`
`DATE:
`
`
`TO:
`
`
`
`
`FROM:
`
`RE:
`
`
`Introduction and Background
`Purdue Pharma has submitted a Complete Response for their reformulated Oxycontin tablets.
`The original NDA was submitted on November 29, 2007, and Purdue was issued a Complete
`Response regulatory action on October 3, 2008.
`
`The reformulated Oxycontin is intended to reduce the abuse liability of the product by making
`the modified-release characteristics more robust. The changes to the formulation are purported
`to result in a tablet that is more difficult to crush or dissolve, and more resistant to the
`extraction of oxycodone by chemical means.
`
`The original NDA submitted in 2007 consisted of CMC data, non-clinical pharmacology
`studies, pharmacokinetic studies, and studies that assessed the attributes of the reformulation
`in terms of the effects of chemical and physical manipulation intended to defeat the modified-
`release characteristics of the product. During the development of the new formulation, the
`Applicant and the Division agreed that clinical efficacy and safety studies would not be
`required if the new formulation was bioequivalent with the original formulation. As the new
`formulation had been demonstrated to be bioequivalent to the original formulation, no clinical
`efficacy or safety studies were performed.
`
`The current Complete Response was submitted by Purdue on March 31, 2009 and included
`updated CMC data for the reformulated 60mg and 80mg tablets, genetic toxicology study to
`
`Page 1 of 2
`
`1
`
`

`

`Cross Discipline Team Leader Review
`
`support a proposed labeling change, pharmacokinetic studies of the 60mg and 80mg strengths,
`and updated data regarding abuse liability of reformulated Oxycontin.
`
` form 3454 was submitted on April 29, 2008 and documented that the applicant certified as
`to not having entered into any financial arrangement with the clinical investigators whereby
`the value of compensation to the investigator could be affected by the outcome of the study as
`defined in 21 CFR54.2(a), and that none of the listed clinical investigators disclosed any
`proprietary interest in the product or company. In addition, no listed investigator was the
`recipient of significant payments of other sorts ad defined in 21 CFR54.2(f). This
`documentation is adequate as it covers the necessary studies to support this application.
`
` A
`
`Page 2 of 2
`
`2
`
`

`

`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/
`----------------------------------------------------
`
`SHARON H HERTZ
`12/30/2009
`
`

`

` FDA CENTER FOR DRUG EVALUATION AND RESEARCH
` DIVISION OF ANALGESIA, ANESTHESIA, AND RHEUMATOLOGY PRODUCTS
` 10903 NEW HAMPSHIRE AVENUE, BLDG 22, SILVER SPRING, MARYLAND 20993
`
`
`
`
`
`DATE:
`
`NDA#:
`Date of
`Submission
`PDUFA date
`FROM:
`
`Addendum to CDTL Review
`
`December 30, 2009
`
`22-272 Oxycontin Complete Response
`March 31, 2009
`
`December 30, 2009
`Ellen Fields, M.D., M.P.H.
`Clinical Team Leader
`DAARP
`
`
`
`My CDTL memo for this application which was entered into DAARTS on September 30,
`2009, recommended a Complete Response regulatory action for this application based on
`the need for consensus between the Division and the Applicant regarding the
`postmarketing requirement for an epidemiologic study to assess the impact on abuse of
`the reformulated Oxycontin, and the lack of a final agreed-upon REMS. However, the
`decision was made by the Division on September 30, 2009 to extend the PDUFA clock
`since the submission of the final REMS would represent a major amendment to the NDA
`supplement.
`
`Postmarketing Requirements
`On December 16, 2009, the Applicant has submitted brief descriptions for three
`epidemiologic studies to assess the impact of the reformulation on the abuse of
`Oxycontin in the community. The proposed studies are as follows:
`
`
`
`
`1
`
`(b) (4)
`
`

`

`
`
`
`On face it appears that because of the design, methodological, and feasibility challenges
`noted in the proposal, there is concern that the proposed studies will not successfully
`capture the necessary safety information regarding the use of the reformulated
`OxyContin. Therefore, additional information concerning the methodology and feasibility
`of the proposed studies, as well as possible other studies, is needed before agreement can
`be reached on the design of the postmarketing epidemiology study (or studies) to address
`the safety profile of reformulated OxyContin. Agreement regarding the details of the
`conduct of the postmarketing epidemiologic studies is not required pre-approval,
`however at the time of approval, a timetable must be agreed upon for submission of the
`final protocols, the dates for starting and completing the studies, and the dates of
`submission to the Agency of the final study reports.
`
`REMS
`Although the Agency initially determined that an adequate REMS for this product (an
`interim or “place-holding” REMS until the class-wide opioid REMS is put in place)
`would consist of a Medication Guide and Communication plan, a decision was
`subsequently made that this plan will not be adequate to ensure training of healthcare
`professionals to address the labeled risks of abuse, misuse, overdose, and addiction, and
`to prevent the occurrence of serious adverse events associated with those risks. To that
`end, a letter was issued to the Applicant on December 11, 2009 stating that the Agency
`has determined that the REMS for OxyContin (oxycodone hydrochloride) should contain
`an element to assure safe use, specifically healthcare provider training under 505-
`1(f)(3)(A), to ensure that the benefits of OxyContin (oxycodone hydrochloride) outweigh
`the risks. The REMS must include a Medication Guide, elements to assure safe use,
`
`
`
`2
`
`(b) (4)
`
`

`

`specifically training of healthcare providers, and a timetable for the submission of
`assessments of the REMS.
`
`The Elements to Assure Safe Use must include, at a minimum, the following:
`
`
`
`
`
`
`
`
`
`
`3
`
`(b) (4)
`
`

`

`
`The Applicant submitted their proposed revised REMS on December 22, 2009. Because
`the REMS was submitted so late in the review cycle, the Agency is deferring its review
`of the REMS to the next cycle.
`
`Other Regulatory Issues
`The following is extracted directly from Dr. Rappaport’s Division Director Summary.
`
`
`During the open public hearing of the September 24, 2009 Advisory
`Committee meeting, an individual made several statements about risk
`
`
`
`4
`
`(b) (4)
`
`

`

`
`
`
`Recommendation for Regulatory Action
`Complete Response
`
`Please refer to my CDTL memo dated September 30, 2009 (attached) for details
`regarding the risk/benefit analysis.
`
`Deficiency
`1. FDA cannot approve this application until the content of the REMS is found to be
`acceptable.
`
`
`Information Needed to Address Deficiency
`1. The Division acknowledges the submission of the proposed REMS on December
`22, 2009 and because it was submitted so late in the review cycle, the review is
`being deferred to the next cycle.
`2.
`Postmarketing Requirements
`A postmarketing epidemiologic study(ies) is required to assess whether changes made to
`the Oxycontin formulation that are intended to provide misuse and abuse-deterrence
`actually result in a decrease in the risks of abuse and misuse, and their consequences
`including addiction, overdose, and death in the community.
`
`
`
`5
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`
`Cross Discipline Team Leader Review
`
`
`Date
`From
`Subject
`NDA/BLA #
`Supplement#
`Applicant
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) names
`Dosage forms / Strength
`Proposed Indication(s)
`
`September 29, 2009
`Ellen W. Fields, M.D., M.P