CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`22-264
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`OTHER ACTION LETTER(s)
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`DEPARTMENT OF HEALTH & HUMAN
`SERVICES
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`Public Health Service
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`Food and Drug Administration
`Rockville, MD 20857
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`NDA 22-264
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`COMPLETE RESPONSE
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`Ortho-McNeil-Jansen Pharmaceuticals, Inc.
`Attention: Rodney Malchow
`Associate Director, Regulatory Affairs
`1125 Trenton-Harbourton Road
`P.O. Box 200
`Titusville, N.J. 80560
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`Dear Mr. Malchow:
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`Please refer to your new drug application (NDA) dated October 25, 2007, received
`October 26, 2007, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act for Invega Sustenna (paliperidone palmitate)
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`We acknowledge receipt of your submissions dated:
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`January 9, 2008
`December 12, 2007 December 21, 2007
`February 25, 2008
`February 27, 2008(2) May 2, 2008
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`May 21, 2008
`May 28, 2008
`May 29, 2008
`June 3, 2008
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`June 13, 2008
`June 26, 2008
`July 11, 2008
`July 15, 2008(2)
`August 20, 2008
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`We also acknowledge receipt of your amendment dated August 12, 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.
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`We have completed the review of your application, 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.
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`PRODUCT QUALITY
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`1. The Drug Master File
`to support the NDA.
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`February 21, 2008
`May 12, 2008
`June 2, 2008
`July 2, 2008
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` for
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` has been found to be inadequate
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 22-264
`Page 2
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`2. It is FDA policy that the strength of the drug substance has to be provided as part
`of the established name. The proposal to just remove the reference to strength
`(mg) from the product name is not sufficient. The historical evidence provided to
`justify your proposal is not sufficient because most products listed were approved
`quite awhile ago and do not reflect current practices. According to information
`you provided in the original NDA submission “paliperidone palmitate dissolves
`slowly after intramuscular injection before being hydrolyzed to paliperidone and
`absorbed into the systemic circulation”, which indicates that paliperidone
`palmitate is a prodrug and that the palmitate ester exerts a biopharmaceutic effect.
`3. Establish an acceptance criteria equal to or less than
` ppm for the two genotoxic
`impurities,
` and
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`4.
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`5. The syringe barrel should contain calibrated markings to indicate the appropriate
`volume of drug product in the syringe and allow for partial doses to be given from
`the syringe.
`6. A transparent label that allows for the viewing of the syringe calibration marks
`and drug product should be used for labeling of the syringes.
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`LABELING
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`Submit draft labeling that incorporates revisions in the attached labeling. In addition,
`submit 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.
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`When responding to this letter, submit labeling that includes all previous revisions, as
`reflected in the most recently approved package insert. To facilitate review of your
`submission, provide a highlighted or marked-up copy that shows all changes, as well
`as a clean Microsoft Word version. The marked-up copy should include annotations
`with the supplement number for previously-approved labeling changes.
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`Please submit draft carton and container labeling revised as follows:
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`Syringe Labeling
`1. The product strength should be relocated so that it no longer appears to be part
`of the proprietary name (e.g., TRADENAME 25 mg). Instead, the product
`strength should follow or be immediately adjacent to the established name.
`2. Express the strengths of the prefilled syringes in terms of milligrams per total
`volume (e.g., 25 mg/0.25 mL, 50 mg/0.5 mL, 75 mg/0.75 mL, and 100
`mg/mL) to decrease the potential for dose calculation errors. This information
`should be displayed on the syringe label and immediately following or
`adjacent to the established name.
`3. If space permits,
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`(b)
`(4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 22-264
`Page 3
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`4.
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`Carton Labeling
`1. Revise the fonts of the proprietary and established names so that the
`established name is at least one half the size of the proprietary name per 21
`CFR 201.10(g)(2).
`2. The product strength should be relocated so that it no longer appears to be part
`of the proprietary name (e.g., TRADENAME 25 mg). Instead, the product
`strength should follow or be immediately adjacent to the established name.
`3. Express the strengths of the prefilled syringes in terms of milligrams per total
`volume (e.g., 25 mg/0.25 mL, 50 mg/0.5 mL, 75 mg/0.75 mL, and 100
`mg/mL) to decrease the potential for dose calculation errors. This information
`should be prominently displayed on the principal display panel immediately
`following or adjacent to the established name so that it is not overlooked by
`the reader.
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`Dissolution Method and Specification
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`The following dissolution method and specification are acceptable for Invega Sustenna
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`(paliperidone palmitate)
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`Parameter
`Apparatus Type
`Media
`Volume
`Temperature
`Frequency
`Sampling Times
`Acceptance
`Criteria
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`Analysis
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`SAFETY UPDATE
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`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
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`Dissolution Method and Specification
`USP Type II (paddle)
`0.001 M HCL containing 0.489% Polysorbate 20 (Tween®20)
`900 ml
`25 ± 0.5 °C
`50 rpm
`8,20 and 45 minutes
`8 minutes
`20 minutes
`45 minutes
`HPLC UV detection
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` of Label Claim
` of Label Claim
` of Label Claim
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 22-264
`Page 4
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`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 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.
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`•
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`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.
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`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.
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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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`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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`8. Provide English translations of current approved foreign labeling not previously
`submitted.
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`PROPRIETARY NAME
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`The Division of Medication Error Prevention and Analysis (DMEPA) and the Division of
`Psychiatry Products do not object to the use of the proprietary name, Invega Sustenna, for
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`NDA 22-264
`Page 5
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`this product. However, if the product approval is delayed beyond 90 days of the review
`date, the proposed name must be resubmitted for evaluation.
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`OTHER
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`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.
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`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).
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`The drug product may not be legally marketed until you have been notified in writing that
`this application is approved.
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`If you have any questions, call Kimberly Updegraff, M.S., Regulatory Project Manager,
`at (301) 796-2201.
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`Sincerely,
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`{See appended electronic signature page}
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`Thomas Laughren, M.D.
`Director
`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`Enclosure
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`45 pp withheld immediately following this page as (b)(4) Draft Labeling
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`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
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` /s/
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`Thomas Laughren
`8/25/2008 01:37:30 PM
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