CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`22-272
`
`OTHER ACTION LETTER(s)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`COMPLETE RESPONSE
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`NDA 022272
`
`Purdue Pharma L.P.
`One Stamford Forum
`Stamford, CT 06901-3431
`
`Attention: Craig Landau, M.D.
`
`CMO & VP Clinical, Medical & Regulatory Affairs
`
`
`Dear Dr. Landau:
`
`Please refer to your new drug application (NDA) dated November 29, 2007, received November
`29, 2007, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`OxyContin (Oxycodone Hydrochloride Controlled-Release Tablets ) 10, 15, 20, 30, 40 mg.
`
`We acknowledge receipt of your amendments dated April 23, 2008, and March 30, May 18, June
`2, 10, and 16, July 13 and 24, August 7, and September 18, October 6 and 9, November 6, 17,
`19, and 23, and December 16 and 22, 2009.
`
`The March 30, 2009, amendment constituted a complete response to our October 3, 2008, action
`letter, and included the addition of the 60- and 80-mg dosage strengths. However, you
`subsequently amended the application several times, including most recently on December 22,
`2009, when you submitted a revised proposed Risk Evaluation and Mitigation Strategy (REMS).
`
`We have determined that we cannot approve this application in its present form. We have
`described below our reasons for this action and, where possible, our recommendations to address
`these issues.
`
`RISK EVALUATION AND MITIGATION STRATEGIES (REMS) REQUIREMENTS
`
`As described in our letter dated December 11, 2009, in accordance with section 505-1 of the
`Federal Food, Drug, and Cosmetic Act (FDCA), we have determined that a REMS is necessary
`for OxyContin to ensure that the benefits of the drug outweigh the risks of 1) use in non-opioid-
`tolerant individuals; 2) abuse; and 3) overdose, both accidental and intentional. We have
`determined that under section 505-1, the REMS for this product must include a Medication
`Guide and an element to assure safe use, specifically healthcare provider training under 505-
`1(f)(3)(A), and a timetable for submission of assessments. FDA cannot approve your application
`until we have found the content of your REMS acceptable.
`
`We acknowledge the submission of your proposed REMS on December 22, 2009. Because the
`REMS was submitted so late in the review cycle, FDA is deferring its review of the REMS to the
`next cycle.
`
`
`

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`NDA 022272
`Page 2
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`LABELING
`
`We reserve additional comments on the proposed labeling until the application is otherwise
`adequate. If you revise labeling, your response must include updated content of labeling
`[21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
`
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o) of the FDCA authorizes FDA to require holders of approved drug and biological
`product applications to conduct postmarketing studies and clinical trials for certain purposes, if
`FDA makes certain findings required by the statute (section 505(o)(3)(A)).
`
`The Anesthetic and Life Support Drugs Advisory Committee (ALSDAC) and Drug Safety and
`Risk Management Advisory Committee (DSaRM) Panel, at the joint meeting on September 24,
`2009, recommended that postmarketing studies be conducted 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 serious
`risks of misuse and abuse, and their consequences: addiction, overdose and death.
`
`
`FDA has determined that, if NDA 022272 is approved, you will be required to conduct
`postmarketing studies of OxyContin to assess the known serious risks of OxyContin, in
`particular, 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.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess the aforementioned risks
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these serious
`risks.
`
`Therefore, based on appropriate scientific data, 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:
`
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`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
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`

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`NDA 022272
`Page 3
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`OxyContin formulation. Therefore, additional information concerning the methodology and
`feasibility of the proposed potential 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.
`
`We will continue discussion of your postmarketing study proposals so that your complete
`response to this action letter contains adequately designed and acceptable studies.
`
`SAFETY UPDATE
`
`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
`clinical studies/trials of the drug under consideration regardless of indication, dosage form, or
`dose level.
`
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`1. Describe in detail any significant changes or findings in the safety profile.
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`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`
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`• Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as the original NDA submission.
`• Present tabulations of the new safety data combined with the original NDA data.
`•
`Include tables that compare frequencies of adverse events in the original NDA with
`the retabulated frequencies described in the bullet above.
`• For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
`
`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
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`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original NDA data.
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`

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`NDA 022272
`Page 4
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`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
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`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
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`
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`
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`8. Provide English translations of current approved foreign labeling not previously
`submitted.
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`OTHER
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`We acknowledge that in a telephone conversation on December 7, 2009, you stated that you are
`
` We request that you submit the results
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`of this study as soon as they become available.
`
`Within one year after the date of this letter, you are required to resubmit or take one of the other
`actions available under 21 CFR 314.110. If you do not take one of these actions, we will
`consider your lack of response a request to withdraw the application under 21 CFR 314.65. A
`resubmission must fully address all the deficiencies listed. A partial response to this letter will
`not be processed as a resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA’s Guidance for Industry -
`Formal Meetings Between the FDA and Sponsors or Applicants, May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
`
`If you have any questions, call Lisa Basham, Regulatory Project Manager, at (301) 796-1175.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Bob A. Rappaport, MD
`Director
`Division of Anesthesia, Analgesia and
` Rheumatology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`(b) (4)
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`

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`Application
`Type/Number
`--------------------
`NDA-22272
`
`Submission
`Type/Number
`--------------------
`ORIG-1
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`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
`
`

`

`
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
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`NDA 22-272
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`COMPLETE RESPONSE
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`
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`Purdue Pharma L.P.
`One Stamford Forum
`Stamford, CT 06901-3431
`
`Attention: Anthony C. Santopolo M.D.
`
`Vice President, Regulatory Affairs
`
`
`
`
`Dear Dr. Santopolo:
`
`Please refer to your new drug application (NDA) dated November 29, 2007, received November
`29, 2007, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for OxyContin (Oxycodone Hydrochloride Controlled-Release Tablets), 10, 15, 20, 30, and 40
`mg.
`
`We acknowledge receipt of your amendments dated November 30, December 19, 20, and 21,
`2007, and January 14, February 8, 12, 14 (2), and 15 (2), March 7, 10, 14, 18, 25 (2), and 27, April
`11 and 23, May 7, and August 20, and September 26, 2008.
`
`We also acknowledge receipt of your amendment dated April 23, 2008, which was not reviewed
`for this action. You may incorporate applicable sections of the amendment by specific reference
`as part of your response to the deficiencies cited in this letter.
`
`We have completed the review of your application, as amended, and have determined that we
`cannot approve this application in its present form. We have described below our reasons for this
`action and, where possible, our recommendations to address these issues.
`
`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.
`
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`2. Provide studies of the new formulation that demonstrate the effects of physical and/or
`chemical manipulation and that incorporate the following:
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`
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`

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`NDA 22-272
`Page 2
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`
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`a. The testing must be conducted in a blinded manner, preferably by an independent third
`party.
`
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`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.
`
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`d. Provide data documenting the amount of oxycodone released if the reformulated tablet is
`chewed
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`e. Conduct studies to determine the relative rate of release of the active pharmaceutical
`ingredient from all strengths of crushed
` tablets to determine whether all dosage
`strengths retain the controlled-release properties after crushing
` and that dose
`dumping does not occur.
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`f. Provide data documenting how altering the grinding conditions,
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`
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`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).
`
`5. We reserve comment on the proposed labeling until the application is otherwise adequate. If
`you revise labeling, your response must include updated content of labeling [21 CFR
`314.50(l)(1)(i)] in structured product labeling (SPL) format as described at
`http://www.fda.gov/oc/datacouncil/spl.html.
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22-272
`Page 3
`
`
`SAFETY UPDATE
`
`When you respond to the above deficiencies, include a safety update as described at 21 CFR
`314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical
`studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.
`
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`
`
`
`
`
`
`
`
`
`
`
`
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`
`
`• Present new safety data from the studies for the proposed indication using the same
`format as the original NDA submission.
`• Present tabulations of the new safety data combined with the original NDA data.
`•
`Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described in the bullet above.
`• For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
`
`3. Present a retabulation of the reasons for premature study discontinuation by incorporating
`the drop-outs from the newly completed studies. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical study or who did not complete a study because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original NDA data.
`
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`7. Provide a summary of worldwide experience on the safety of this drug. Include an updated
`estimate of use for drug marketed in other countries.
`
`8. Provide English translations of current approved foreign labeling not previously submitted.
`
`
`
`RISK EVALUATION AND MITIGATION STRATEGIES (REMS) REQUIREMENTS
`
`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007
`(FDAAA) amends the FDCA to authorize FDA to require the submission of a REMS if FDA
`determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the
`risks (section 505-1(a)). This provision took effect on March 25, 2008.
`
`

`

`NDA 22-272
`Page 4
`
`
`
`In accordance with section 505-1 of the FDCA, we have determined that a REMS is necessary for
`OxyContin (Oxycodone Hydrochloride Controlled-Release Tablets) to ensure that the benefits of
`the drug outweigh the risks of: 1) use in non-opioid-tolerant individuals; 2) abuse; and 3)
`overdose, both accidental and intentional. We have determined that under section 505-1, the
`REMS for this product must include a Medication Guide, elements to assure safe use, an
`implementation system, and must include a timetable for assessments. You must submit a
`proposed REMS and REMS Supporting Document prior to final approval of this new drug
`application. You have been directed to prepare a REMS for the previously approved formulation
`of OxyContin NDA 20-553. You should review the elements of that REMS in preparing this
`proposed REMS for NDA 22-272.
`
`Use the following designator to prominently label all submissions relating to this REMS:
`
`
`
`ADDITIONAL COMMENTS
`
`1. Serious consideration should be given to using a new trade name for the reformulated product,
`even if you do not intend to have the reformulated product available on the market at the same
`time as the current formulation. This would serve several purposes. First, it would give the
`context of a new product to support the new education program. Second, direct comparison as
`a “new and improved” OxyContin with the potential for a false sense of security would be
`avoided. Third, a novel name would permit national abuse monitoring and prescription
`databases to be able to track use and misuse of the new formulation immediately upon
`marketing and would avoid the situation of a transitional period with overlap of the two
`formulations during which time there could be no meaningful tracking of either product.
`
`NDA 22-272 PROPOSED REMS
`
`
`2. We strongly recommend that you submit all promotional material for review by the Agency
`prior to dissemination of the material. Submit all proposed materials in draft or mock-up form,
`not final print. Send one copy to this division and two copies of both the promotional
`materials and the package insert directly to:
`
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take one of the other
`actions available under 21 CFR 314.110. If you do not take one of these actions, we will consider
`your lack of response a request to withdraw the application under 21 CFR 314.65. A resubmission
`
`

`

`NDA 22-272
`Page 5
`
`
`must fully address all the deficiencies listed. A partial response to this letter will not be processed
`as a resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to discuss
`what steps you need to take before the application may be approved. If you wish to have such a
`meeting, submit your meeting request as described in the FDA Guidance for Industry Formal
`Meetings With Sponsors and Applicants for PDUFA Products, February, 2000
`(http://www.fda.gov/cder/guidance/2125fnl.htm).
`
`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
`
`If you have any questions, call Lisa Basham, Regulatory Project Manager, at (301) 796-1175.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Bob Rappaport, MD
`Director
`Division of Anesthesia, Analgesia and
` Rheumatology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Bob Rappaport
`10/3/2008 05:06:03 PM
`
`