CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-264
`22-264
`
`
`APPLICA TION NUMBER:
`
`SUMMARY REVIEW
`
`SUMMARY REVIEW
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
` PUBLIC HEALTH SERVICE
`
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`July 31, 2009
`
`Thomas P. Laughren, M.D.
`Director, Division of Psychiatry Products
`HFD-130
`
`M E M O R A N D U M
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`
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`
`
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`
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`
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`
`
`DATE:
`
`FROM:
`
`
`
`
`
`SUBJECT: Recommendation for approval action for Invega Sustenna (paliperidone palmitate
`) for schizophrenia (both acute and maintenance efficacy)
`
`
`TO:
`
`
`
`File NDA 22-264
`[Note: This overview should be filed with the 2-3-09 response to the 8-25-08 CR
`letter.]
`
`BACKGROUND
`
`CHEMISTRY
`
`
`
`1.0
`
` is a depot formulation of paliperidone, an atypical
`Paliperidone palmitate
`antipsychotic (5HT2 and D2 receptor antagonist). Paliperidone is the major active metabolite of
`risperidone and has essentially the same pharmacological profile as risperidone which is
`approved for the treatment of schizophrenia and bipolar mania. Paliperidone is available in an
`extended release oral formulation for both the acute and maintenance treatment of schizophrenia.
`This NDA seeks a claim for this depot formulation for both the acute and maintenance treatment
`of schizophrenia, in a dose range of 25 to 150 mg eq intramuscular injections (either deltoid or
`gluteal) every month. As noted, a CR letter was issued for this NDA on 8-25-08. This letter
`identified a number of product quality issues and labeling issues, provided a proposed
`dissolution method and specifications, and requested a safety update. We met with the sponsor
`on 11-21-08 to discuss various issues pertinent to a resubmission of this application. These
`issues and their resolution will be summarized in the sections below. The application was
`resubmitted on 2-3-09.
`
`
`2.0
`
`Issues that needed resolution:
`
`
`Drug master file for the
`Issue: The DMF was noted to be inadequate in the CR letter.
`
`
`
`
`1
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Resolution: The sponsor has submitted information that has been determined to address
`the deficiencies.
`
`Expression of dose strengths of drug substance vs active portion of molecule in the package
`insert, syringe labeling, and carton labeling
`Issue: In their originally proposed package insert, syringe labeling, and carton labeling,
`the sponsor wanted to emphasize the active portion of the molecule (paliperidone mg
`equivalents), rather than actual drug substance strength (paliperidone palmitate). In the
`CR letter, we emphasized to the sponsor the problem this would pose for us in terms of
`FDA policy regarding what information is required in the established name. We
`discussed this issue at length at our 11-21-08 meeting with the sponsor, essentially
`indicating that it would be a review issue when they resubmitted the application. We
`have discussed this issue extensively within FDA subsequent to the resubmission of this
`application, and the FDA groups that would be most impacted by deviation from FDA
`policy on this matter (ONDQA, DMEPA, and OGD) argued strongly against permitting
`the sponsor to focus on paliperidone equivalents. The concerns are that this would be
`confusing, would be a potential source of medication errors, and would be very
`problematic at the point that a generic paliperidone depot formulation becomes available.
`Therefore, we have taken a position that the package insert, syringe labeling, and carton
`labeling should note only the drug substance strengths (i.e., 39, 78, 117, 156, and 234 mg
`of paliperidone palmitate), with no mention of the equivalents (i.e., 25, 50, 75, 100, and
`150 mg eq). We did subsequently agree to include mention of the equivalents in the
`Description section.
` We
`Resolution:
`have now provided advice in the Dosage and Administration section of labeling on
`switching from oral paliperidone to the depot (in the form of a conversion table).
`
`Desirability for transparent label and for calibrated markings and fill line on syringe
`barrel
`
`Issue: In the CR letter, we indicated that 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. The letter also noted that a transparent label
`that would allow for viewing of the syringe calibration marks and drug product should be
`used for labeling of the syringes
`
` In our 11-21-08 meeting, we agreed that
`calibrations would not be needed. We indicated that we still felt that a fill line was
`needed to allow determination by the user that the syringe had been filled properly, and a
`fill window.
`
`
`
`
`
`-We have had numerous subsequent internal discussions and interchanges regarding this
`issue. Some have continued to argue for the need for a fill line
`Resolution: The sponsor has agreed to make this change as a phase 4 commitment.
`
`
`
`
`2
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`

`

`” in drug product established name
`Use of “
`Issue: In the CR letter and attached labeling, we referred to this product as “Invega
`Sustenna
` In subsequent discussions with ONDQA, DMEPA,
`and other groups within FDA that have an interest in this question, the overwhelming
`consensus is that we cannot continue with the
` terminology. This
`is not official USP terminology and not recognized, and will cause multiple problems.
`ONDQA has recommended the following alternative terminology: “Invega Sustenna
`Extended Release Injectable Suspension.”
`Resolution: We have decided to adopt the alternative language recommended by
`ONDQA. The sponsor has reluctantly accepted this alternative language.
`
` and
`
`
`Establishing acceptable acceptance criteria for the two genotoxic impurities,
`
`Issue: In the CR letter, we asked the sponsor to establish acceptance criteria equal to or
`less than
` ppm for the two genotroxic inpurities,
`and
`
`Resolution: We now have agreement on a specification of
` ppm.
`
`
`
`Establishing a test and acceptance limit for
`Issue: In the CR letter, we asked the sponsor to include a test and acceptance limit for
` in the drug product specification.
`Resolution: We have now agreed with the sponsor that this test would not be needed.
`
`
`Other CMC syringe labeling and carton labeling issues
`Issues: In the CR letter we conveyed a number of comments on syringe and carton
`labeling.
`Resolution: Most of these issues have been resolved. We will include some final
`recommendations in approval letter, and also advise that they include mention of the
`frequency of dosing on the carton label to help clinicians distinguish this from other
`formulations,
`
`Dissolution method and specifications
`Issue: We still needed agreement on this issue.
`Resolution: We now have agreement on the dissolution method and specifications.
`
`PHARMACOLOGY
`
`
`
`3.0
`
`There are no pharmacology/toxicology issues at this point that would preclude an approval
`action for this NDA.
`
`
`
`4.0
`
`All biopharmaceutical issues have been resolved.
`
`
`
`BIOPHARMACEUTICS
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Efficacy Data
`
`CLINICAL DATA
`
`5.0
`
`5.1
`
`5.1.1 Overview of Studies Pertinent to Efficacy
`
`Original Application
`
`Short-Term Trials
`
`Our review of the original application focused on 3 short-term (9 to 13-week), double-blind,
`randomized, parallel group, placebo-controlled, fixed-dose trials in patients with acutely
`exacerbated schizophrenia and 1 maintenance study in schizophrenic patients stabilized on
`paliperidone depot. In all of these studies, the depot injections were administered in the gluteal
`muscle.
`
`Studies 3003 and 3004 were 13-week studies in which patients received 3 fixed doses of
`paliperidone depot or placebo (50, 100, and 150 for 3003; 25, 50, and 100 for 3004). Doses were
`given on days 1, 8, 36, and 64. The end-of-study visit was day 92. The primary endpoint in
`these studies was change from baseline to endpoint on the PANSS total score. No key secondary
`endpoints were clearly specified and no claims were sought by the sponsor based on secondary
`endpoints. There was a problem in treatment distribution in study 3003 such that only 30
`patients received the 150 mg eq dose. Thus, the data for this dose group are not meaningful.
`Study 201 was similar in design to studies 3003 and 3004 except that it was 9 weeks in duration
`and utilized only 2 fixed doses (50 and 100 mg eq). The 100 mg eq dose was statistically
`significantly superior to placebo each time it was tested (studies 3003, 3004, and 201). The 50
`mg eq dose was statistically significantly superior to placebo on 2 occasions it was tested
`(studies 3004 and 201), but not in study 3003. The 25 mg eq dose was statistically significantly
`superior to placebo on the one occasion it was tested (study 3004). There was a suggestion of
`numerical superiority of the 100 mg eq dose over the lower doses.
`
`
`
`
`Maintenance Study
`
`Study 3001 was a maintenance study involving a 33-week open label phase (9 weeks of
`transition and 24 weeks of stabilization) before randomization. During the double-blind
`randomized phase, patients who were stable responders were randomized to either paliperidone
`depot (monthly injections of 25, 50, or 100 mg eq) or placebo. The primary endpoint was time
`to recurrence. The protocol called for an interim analysis after 68 recurrence events had
`occurred. This analysis was done and was highly significant in favor of paliperidone depot
`(p<0.0001). Thus, the study was stopped (stopping threshold was p=0.0106).
`
`
`
`
`
`
`4
`
`(b) (4)
`
`

`

`Deltoid Injections
`
`Although the studies supporting the efficacy claim for paliperidone depot were conducted
`entirely with gluteal dosing, the sponsor proposed labeling that recommended deltoid dosing of
` mg eq on days 1 and 8, followed by either gluteal or deltoid dosing in a range of
`
`mg eq at monthly intervals. The rationale for such dosing upon initiation of treatment was a
`desire to achieve therapeutic plasma levels of drug more quickly. Since such dosing had not
`been studied in actual efficacy studies, the sponsor provided simulations to show that deltoid
`injections did provide higher concentrations earlier compared to gluteal injections, but that at
`steady state, the plasma concentrations by the deltoid and gluteal route were similar.
`Furthermore, head-to-head comparisons of deltoid and gluteal injections for safety in study 3005
`(at doses of 50, 75, and 100 mg eq) demonstrated comparable safety by these routes. Dr. Duan
`from OCP did not disagree with the sponsor’s simulations, however, he argued that the proposed
` eq starting dose produces plasma concentrations that are 24-34% higher than what is
`seen with a 6 mg eq dosing with paliperidone ER, the currently recommended starting dose.
`Thus, he recommended 75 mg eq deltoid dosing as an alternative.
`
`Original Draft Labeling
`
`The original draft labeling in our CR letter permitted claims for acute and maintenance treatment
`of schizophrenia, with a recommended initial dose of
` mg eq by the deltoid route on days
`1 and 8, followed by monthly dosing in a range of
` mg eq by either the deltoid or
`gluteal route.
`
`New Data in Resubmission
`
`The resubmission included data from one additional efficacy study, i.e., study 3007. This 13-
`week study was similar in design to the earlier short-term studies, i.e., it was a multicenter,
`randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study (25, 100, and 150
`mg eq) vs placebo. One important difference was the starting dose of 150 mg eq for all patients
`assigned to active drug. The rationale for this starting dose was essentially to provide a loading
`dose for new patients given the slow rise to an effective concentration for this formulation.
`Patients in the 3 active drug groups all received deltoid injections of 150 mg eq on day 1,
`followed by the randomized doses of 25, 100, or 150 mg eq on days 8, 36, and 64 (by the deltoid
`or gluteal route, at the investigator’s discretion). The primary analysis focused on change from
`baseline to endpoint in the PANSS total score. The sponsor did designate PSP as the key
`secondary endpoint in this trial. The study was positive for all 3 dose groups on the primary
`endpoint, and on the 2 highest doses on the PSP. The 150 mg eq dose group was numerically
`superior to the 100 mg eq group, however, a nominal p-value for this comparison was 0.59,
`raising a question about the relevance of this difference.
`
`
`
`
`
`
`
`
`
`
`5
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`

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`Pediatric Use
`
`The sponsor has requested a full pediatric waiver for schizophrenia, and we have accepted their
`arguments. Thus we have granted a full waiver.
`
`5.1.2 Conclusions Regarding Efficacy Data
`
`The sponsor has, in my view, provided sufficient evidence to support the claim of acute and
`maintenance efficacy of paliperidone depot in the treatment of schizophrenia. The sponsor has
`proposed a starting dose of 150 mg eq on day 1 and 100 mg eq on day 8, both by the deltoid
`route, followed by either deltoid or gluteal injections monthly of a 75 mg eq dose, with
`adjustments in a dose range of 25 to 150 mg eq, depending on individual patient tolerability and
`response. The rationale for the starting dose of 150 and 100 mg eq on days 1 and 8 respectively,
`by the deltoid route, is to quickly achieve plasma levels similar to those seen with 6 mg/day oral
`dosing with paliperidone ER. The clinical and OCP team has accepted the rationale for this
`dosing strategy, and I agree.
`
`5.2
`
`The safety data for this NDA considered in the original application were derived from a total of
`n=3012 subjects/patients exposed to paliperidone depot across 16 clinical trials comprising the
`paliperidone depot program. The patient breakdown included n=730 paliperidone depot-exposed
`subjects/patients in 10 phase 1 trials, and n=2282 paliperidone depot-exposed patients in 6 phase
`2-3 trials. The resubmission included additional data from study 3007 and study 3001 (the open
`label extension for study 3007). Data from an additional 488 paliperidone depot exposed
`patients were included in the resubmission. The safety of initial deltoid injections of 150 mg eq
`has been adequately established. The safety profile for the depot formulation of paliperidone
`was similar to that seen with the ER formulation, with the exception of injection site adverse
`events that are expected for a depot formulation. There were no unexpected findings and no new
`findings of concern. Thus, the safety findings of paliperidone depot can be adequately
`characterized in labeling.
`
`5.3
`
`We have made a number of modifications to the sponsor’s proposed labeling, and have now
`reached final agreement with the sponsor on labeling.
`
`
`6.0
`
`To my knowledge, paliperidone depot is still not approved anywhere at this time for the
`treatment of schizophrenia.
`
`
`
`
`
`FOREIGN REGULATORY ACTIONS
`
`6
`
`Safety Data
`
`Clinical Sections of Labeling
`
`

`

`7.0
`
`7.1
`
`As noted, we have now reached final agreement with the sponsor on labeling.
`
`7.2
`
`The AP letter includes the agreed upon final labeling and agreements on PREA requirements and
`one PMC for a reformulation including a fill line.
`
`
`8.0
`
` I
`
` has submitted sufficient data to support the conclusion that paliperidone depot
` believe that
`is effective and acceptably safe in the acute and maintenance efficacy treatment of
`schizophrenia, and we have reached final agreement with the sponsor on labeling. Thus, we will
`issue an approval letter with the agreed upon final label.
`
`
`
`cc:
`Orig NDA 22-264
`HFD-130
`HFD-130/TLaughren/MMathis/GZornberg/JZhang/KUpdegraff
`
`DOC: Paliperidone_Laughren_AP_Memo.doc
`
`
`
`
`
`
`7
`
`LABELING AND APPROVAL LETTER
`
`Labeling
`
`AP Letter
`
`CONCLUSIONS AND RECOMMENDATIONS
`
`(b) (4)
`
`

`

`Linked Applications Submission
`Type/Number
`--------------------
`--------------------
`NDA 22264
`ORIG 1
`
`Sponsor Name
`
`Drug Name / Subject
`
`------------------------------------------
`PALIPERIDONE PALMITATE 1
`MONTH INJECTION
`
`--------------------
`JOHNSON AND
`JOHNSON
`PHARMACEUTICA
`L RESEARCH AND
`DEVELOPMENT
`LLC
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`THOMAS P LAUGHREN
`07/31/2009
`
`