CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`OTHER ACTION LETTER(S)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`NDA 201655
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`
`COMPLETE RESPONSE
`
`
`Endo Pharmaceuticals, Inc.
`100 Endo Boulevard
`Chadds Ford, PA 19317
`
`Attention: Robert A. Barto
`
`Vice President, Regulatory Affairs
`
`
`Dear Mr. Barto:
`
`Please refer to your New Drug Application (NDA) dated July 7, 2010, received July 7, 2010,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Oxymorphone
`Hydrochloride Extended-Release Tablets, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40
`mg.
`
`We acknowledge receipt of your amendments dated July 23, August 27 and 30, September 9, 14
`and 29, October 1, 6, 12, 13 and 27, November 4 and 12, and December 6, 17, 27, 28 and 29,
`2010, and January 3, 2011.
`
`We also acknowledge receipt of your amendment dated January 6, 2011, 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 our review of this application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this
`action below and, where possible, our recommendations to address these issues.
`
`
`CLINICAL
`
`An audit performed by the Agency of the bioequivalence study EN3288-103 identified
`deficiencies in the methods used at the analytical site. Because of these deficiencies, the
`bioequivalence study cannot be relied upon to establish bioequivalence of your proposed drug
`product to the reference product.
`
`This deficiency may be addressed by doing one of the following:
`
`
`1. Provided adequate samples are available, reanalyze blood samples collected in
`bioequivalence study EN3288-103 and submit data establishing the bioequivalence of
`
`
`Reference ID: 2888752
`
`

`

`NDA 201655
`Page 2
`
`
`
`Oxymorphone Hydrochloride Extended-Release 40 mg tablets with OPANA ER 40 mg
`tablets. Ensure that the inspectional findings identified in the Agency’s audit of study
`EN3288-103 are properly addressed in the reanalysis of blood samples.
`
`OR
`
`2. Conduct another pharmacokinetic study and establish the bioequivalence of
`Oxymorphone Hydrochloride Extended-Release 40 mg tablets with OPANA ER 40 mg
`tablets under fasting conditions using adequately validated analytical methodology.
`
`
`
`
`
`OR
`
`3. Conduct a clinical development program with clinical efficacy and safety studies to
`support your product.
`
`
`
`LABELING
`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/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
`
`
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`Section 505-1 of the FDCA authorizes 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)].
`
`We acknowledge receipt of your proposed REMS, included in your submission dated July 7,
`2010, and amended on December 17, 2010, which contains a Medication Guide, elements to
`assure safe use, an implementation system and a timetable for submission of assessments of the
`REMS. In accordance with section 505-1 of the FDCA, we agree that a REMS will be necessary
`for
` (oxymorphone hydrochloride extended-release), if it is approved, to ensure that the
`benefits of the drug outweigh the risks of abuse, misuse, overdose and addiction. The REMS,
`should it be approved, will create enforceable obligations. We will continue discussion of your
`proposed REMS after your complete response to this action letter has been submitted.
`
`As you know, we are considering what REMS elements should be implemented for a number of
`opioid products, including extended-release opioids to address the risks of: 1) use in non-opioid-
`tolerant individuals and 2) abuse, misuse, overdose, and addiction. As discussed, once that
`determination is made, we will notify you in writing and you will be required to submit a
`modified REMS incorporating those elements.
`
`
`
`
`Reference ID: 2888752
`
`(b) (4)
`
`

`

`NDA 201655
`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/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.
`
`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.
`
`
`Reference ID: 2888752
`
`

`

`NDA 201655
`Page 4
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the application. 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 E. Basham, Senior Regulatory Health Project Manager, at
`(301) 796-1175.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Bob A. Rappaport, M.D.
`Director
`Division of Anesthesia and Analgesia Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`Reference ID: 2888752
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`01/07/2011
`
`Reference ID: 2888752
`
`