SOLUTION: NYU NDA Approval & Electronic Common Technical Document Submission Discussion

[ad_1]
CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209184Orig1s000 SUMMARY REVIEW Summary Review Summary Review Date From Subject NDA/BLA # Supplement# Applicant Date of Submission PDUFA Goal Date Proprietary Name / Established (USAN) names Dosage produces / Strength Proposed Indication(s) December 21, 2018 Gerald D. Podskalny DO, MPHS Summary Review NDA 209184 Recommended: Approval Acorda Therapeutics, Inc. 12/05/2017 (Resubmission succeeding Refuse to File) 01/05/2019 Extended Inbrija/Levodopa Inhaled Powder Inhaled Powder/42 mg capsules For the occasional tenor of OFF occurrences in unrepinings delay Parkinson’s sickness useed delay carbidopa/levodopa 1. Introduction and Background Inbrija (also named CVT-301 during outgrowth) is a new co-packaged garbage-device concert issue intended for the intermitted tenor of off occurrences in unrepinings delay Parkinson’s sickness (PD). The garbage factor of Inbrija is a new dosage produce (powder) for levodopa allowing spokenly-inhaled grant using a breath-actuated snuffr. The suitor submitted a 505(b)(2) NDA that references FDA’s judgment of clinical prophylactic, and nonclinical and clinical pharmacology notification for listed garbage Sinemet (carbidopa/ levodopa) 25/100 mg spoken tablets. Effectiveness and added prophylactic notification are supposing by clinical trials conducted by the suitor that are innate to the contact. The suitor originally submitted the NDA on June 27, 2017, but this was issued a refuse-tofile missive accordingly of CMC deficiencies. The suitor resubmitted the contact on January 5, 2017. 2. CMC/Device The Center for Devices and Radiological Health (CDRH) and the CDER Office of Product Quality (OPQ) completed a collaborative re-examination of the contact. The CDRH and OPQ re-examination team is bestowed in Table 1. Page 1 of 28 Reference ID: 4367981 1 Summary Review Table 1: CDRH and OPQ re-examination team Discipline Drug Substance Product and Labeling Process Facility Biopharmaceutics Regulatory Business Process Manager Application Technical Lead Laboratory (OTR) ORA Lead Environmental Lead Reviewer Device Biocompatibility Cleaning/Disinfection Primary Reviewer Secondary Reviewer Charles Jewell Ali al-Hakim Dan Berger Wendy Wilson-Lee Yaodong (Tony) Huang Nallaperumal Chidambaram Steve Hertz Akm Khairuzzaman Ruth Moore Ta-Chen Wu Dahlia Walters Martha Heimann N/A N/A N/A Brandon Blakely BiFeng Qian Christopher Dugard CDRH/ODE/DAGRID/RPDB CDRH/ODE/DAGRID/INCB CDRH/ODE/DAGRID/INCB The garbage pith (DS) make was referenced in a DMF for levodopa held by (b) (4) which was re-examinationed and build abundant to assistance the NDA. The DS has a USP disquisition, and the impurities picturesque in the disquisition were all bestow at levels that are at or under the USP limits. Three potential process impurities were abundantly administerled at levels under the menting initiation. The container, arrestation notification and post-laudation arrestation protocol and commitment were all acceptable. The garbage issue (DP) is a co-packaged garbage and project concert issue. The garbage factor is a capsule occupied delay levodopa scatter. The suitor singly plans to make a 42-mg capsule ability. The project is a proprietary metered-dose spoken snuffr. The DP contains two excipients, sodium chloride and dipalmitoylphosphatidylcholine (DPPC). A Missive of (b) (4) Authorization was supposing by the suitor to DMF for DPPC. DPPC is the important factor of civilized surfactant and it is a important element in a marketed issue, Surfaxin. The OPQ re-examinationer commented that the DPPC and sodium chloride are bestow in delicious (b) (4) levels and they The OPQ re-examinationer commented that arrestation proofing effects assistance a 24-month shelf-life for the capsules stored at capability sphere. The suitor’s commitment to fix the primeval 3 commercial concoctes on long-term arrestation as specific in the arrestation protocol, and a minimum of one concoct each year and ment the effects including any deviations is delicious. Page 2 of 28 Reference ID: 4367981 2 Summary Review The project is a metered dose snuffr that hands the scattered garbage issue. The medication dose is affordd by a capsule that is fixd in the collection of the snuffr. The mouthpiece is replaced on top of the collection containing the capsule (Figure 1). The mouthpiece is depressed which forces the capsule on to the tines at the top of the plunger which punctures the capsule. This releases the scattered garbage issue into the aerosol hall produceed by the space surrounding the staple train, collection and mouthpiece. The airflow caused by the unrepining inhaling through the mouthpiece hands the garbage. Patients are instructed to snuff through the mouthpiece of the project until they give-ear or feel a whirling probe. To hand the applauded dose of 84 mg of levodopa, the unrepining repeats the process, inhaling the variation of two 42 mg capsules. Figure 1. CVT-301 Inhaler Schematic Diagram (b) (4) CVT-301 Inhaler delay the Cap and Mouth-Piece Removed (b) (4) Page 3 of 28 Reference ID: 4367981 3 Summary Review CVT-301 Inhaler (b) (4) The manufacturing facilities interposed in the contact were applauded for laudation. The OPQ and CDRH re-examination team applaud laudation of the contact. 3. Nonclinical Pharmacology/Toxicology LuAnn McKinney, DVM, DACVP is the chief nonclinical re-examinationer for this contact. Dr. Lois Freed, PhD is the nonclinical overseer. Dr. Freed notes that the battery of nonclinical studies conducted by the surety is generally harmonious delay applaudations made by the Division during clinical outgrowth and delay relevant direction. The pre-eminent doses proofed in the toxicity studies do not afford a prophylactic margin compared to the apex applauded civilized dose (MRHD) of 420 mg/day, based on systemic levodopa exposure; notwithstanding, the systemic proceeds of levodopa are well-known in animals and civilizeds. The nonclinical grounds also afford a minimally delicious evaluation of local toxicity. Overall, the nonclinical grounds submitted are abundant to assistance laudation of the NDA. 4. Clinical Pharmacology Mariam Ahmed, PhD, is the chief Clinical Pharmacology re-examinationer for this contact. Drs. Kevin Krudys, PhD; Sreedharan Sabarinath, PhD are the Clinical Pharmacology overseers. The suitor conducted a bridging not-absolute bioavailability con-over (CVT-301-010) between CVT-301 and listed issue Sinemet 25/100 mg tablets. This was a single-dose, open-label, randomized, 3-period crossover con-over in 24 wholesome hardy and fehardy volunteers. Two doses of CVT-301 were proofed: 60 mg and 84 mg. Page 4 of 28 Reference ID: 4367981 4 Summary Review The judge for the bioavailability of levodopa succeeding government of CVT-301 84 mg, not-absolute to Sinemet 25/100 mg spoken tablets, is environing 70%. Tmax was environing 15 minutes earlier forthcoming government of CVT-301 84 mg, but Cmax and AUC 0-24 were really lower for CVT-301 84 mg compared delay spoken Sinemet (see Table 2). Table 2. Dose-Normalized AUC0-24h and Cmax for Levodopa forthcoming Spoken Doses of SINEMET® 25-100 and Inhaled Doses of 60 mg and 84 mg CVT-301- Unadjusted for Baseline PK Parameter (Unit) Treatment DN-Cmax (ng/mL/mg) DN-AUC0-24h (h•ng/mL/mg) Treatment vs. SINEMET® 25-100 mg Ratio (%)a 90% CI CVT-301 60 mg 53.9 47.1-61.8 CVT-301 84 mg 51.3 44.8-58.7 CVT-30160 mg 70.8 64.6-77.6 CVT-301 84 mg 69.1 63.1-75.7 The aspect of dose normalized AUC represents the bioavailability of CVT-301 60 mg and CVT-301 84 mg not-absolute to SINEMET® 25-100 mg. From the FDA Clinical Pharmacology Review The OCP re-examinationer commented that the con-over effects afford an abundant PK bridging to the listed garbage (LD). Studies in Subgroups Effects of Gender The re-examinationer noted a statistically symbolical (p • RI SUHGLFWHG DQG )(9)9& UDWLR ! LQ WKH 21 VWDWH Key Exclusion Criteria x Previous surgery for tenor of PD including intense brain stimulation x Continuous obstructive pulmonary sickness (COPD), asthma, or other continuous respiratory sickness delayin the conclusive 5 years x History of symptomatic orthostatic hypotension notwithstanding abundant tenor. Patients current con-over garbage kits and the IFU for use at home. Patients were instructed to grasp their plummet spoken PD medications as prescribed on their wonted schedule of government, which was not to be mitigated during the 12 weeks of con-over garbage tenor. Patients could use con-over garbage up to 5 spaces during the dawning day, as halt as likely to the space when they began to knowledge OFF symptoms, which could be motor or nonmotor. Primary endpoint The chief endsharp-end of the con-over was the modify from pre-dose in the Unified Parkinsons Disease Rating Lamina (UPDRS) sunder 3 (motor) mandible at 30 minutes post-dose, assessed in the clinic 12 weeks succeeding randomization. The UPDRS Sunder 3 sum mandible was conducive as the sum of the indivisible items of the UPDRS Sunder 3 individually at each space sharp-end. Patients came to the clinic succeeding preface their wonted dawning medications for PD. The arrived in the ON narrate. Patients were not undisputed to grasp added PD medications opportunity they waited in the clinic to adapt OFF. The UPDRS was assessed in the OFF narrate, followed by government of CVT-301. The UPDRS was assess at 10, 20, 30, and 60 minutes succeeding government of con-over medication. The unrepinings resumed preface their wonted PD medication succeeding the conclusive UPDRS was assessed at 60 minutes. Key Resultant Endpoints x Proportion of unrepinings achieving decomposition of an OFF to an ON narrate delayin 60 minutes succeeding con-over garbage is administered in the clinic and detaining the ON at 60 minutes succeeding con-over garbage government (per the examiner’s intellectual impost). x Change from pre-dose in UPDRS Sunder 3 motor mandible at 20 minutes forthcoming tenor of unrepinings experiencing an OFF occurrence in the clinic at Week 12. x PGI-C rating lamina measured predose at Week 12. Page 7 of 28 Reference ID: 4367981 7 Summary Review x Change from pre-dose in UPDRS Sunder 3 motor mandible at 10 minutes forthcoming tenor of unrepinings experiencing an OFF occurrence in the clinic at Week 12. x Change from baseline in unrepining-narrative sum daily OFF space, assessed by the unrepining and narrative in the PD Diary for 3 continuous days earlier to Week 12 Randomization was stratified by the Hoehn and Yahr (H&Y) lamina rating predicament (H&Y DV PHDVXUHG LQ WKH 21 VWDWH WR EDODQFH WKH VHYHULW RI 3DUNLQVRQ¶V GLVHDVH LQ each cluster and by screening spirometry effects measured by the solid expiratory book in 1 VHFRQG )(9 YHUVXV )(9• WR EDODQFH WKH SDWLHQW¶V LQKDOation space of the con-over garbage in each cluster. Figure 3. Unroving Sequence Hierarchical Testing Procedure Testing agoing delay the chief endsharp-end at the proud dose, forthcoming the direct illustrated in Figure 3. The proofing process ended if the p-compute associated delay an endsharp-end interposed in the hierarchy was 0.05 or prouder. The endsharp-end similitudes were hierarchically directed, so that the unroving sequential proofing system was applied to administer an overall likeness 1 fault. Study effects Three-hundred fifty-one (351) unrepinings were randomized in a 1:1:1 aspect to each of the three conflict of the con-over. Three-hundred-thirty-nine (339) unrepinings current at smallest one dose of CVT301. The scheme to use (ITT) and prophylactic population were selfsame, delay 339 sum subjects. The subjects enrolled in 65 sites in the United States (US) (52), Poland (8), Canada (4) and 1 site in Spain. Two-hundred-forty-eight subjects were from sites in the US. Page 8 of 28 Reference ID: 4367981 8 Summary Review The con-over population was closely one-quarter women and closely 95% pure, both usual demographic features in a PD con-over. Two-thirds of the population had a Hoehn and Yahr mandible at baseline of 2.5 or prouder (see Table 4). The division of unrepinings delay key demographic and sickness cruelty indicators were harmonious counter the tenor conflict. Table 4. Demographic and Baseline Characteristics of the Chief Segregation Set Characteristics Male Gender Female White Black Race Asian Other FEV1• H&Y Source: FDA statistical re-examination Age Placebo (n=112) 55 (49%) 57 (51%) 86 (77%) 26 (23%) 107 (95%) 0 (0%) 4 (4%) 1 (1%) 6 (5%) 106 (95%) 74 (66%) 38 (34%) CVT-301 60 mg (n=113) 54 (48%) 59 (52%) 80 (71%) 33 (29%) 107 (95%) 3 (3%) 0 (0%) 3 (2%) 6 (5%) 107 (95%) 74 (66%) 39 (34%) CVT-301 84 mg (n=114) 58 (51%) 56 (49%) 83 (73%) 31 (27%) 107(94%) 4 (4%) 2 (2%) 1 (1%) 7 (6%) 107 (94%) 72 (63%) 42 (37%) Total (n=339) 167 (49%) 172 (51%) 249 (74%) 90 (26%) 321 (95%) 7 (2%) 6 (2%) 5 (1%) 19 (6%) 320 (94%) 220 (65%) 119 (35%) Study effects are bestowed in Table 5. The statistical re-examinationer authorized the suitor’s effect for the chief endsharp-end using a adulterated example for continual measurements (MMRM). The CochranMantel-Haenszel (CMH) proof was used to stir the primeval key resultant endpoint. Table 5. Hierarchical Evaluation of the Chief and Key Resultant Effectiveness Endpoints at Tenor Visit 4 (Week 12) – CVT-301 84 mg and 60 mg versus Placebo (ITT Population) Endpoint Statistics Primary effectiveness endsharp-end for 84 mg The modify from pre-dose in the UPDRS sunder 3 motor mandible at 30 minutes post-dose at TV4 First key resultant effectiveness endsharp-end for 84 mg The adjustment of unrepinings who achieve decomposition of an OFF narrate to an ON narrate delayin 60 minutes succeeding con-over garbage government at the clinic at Page 9 of 28 Reference ID: 4367981 Placebo vs CVT301 84 mg Placebo vs CVT301 60 mg Least balance moderation destruction (moderation modify in CVT-301 84 mg – moderation modify in fixbo) 95% self-reliance Interval P-value -3.92 (-6.84, -1.00) 0.009 -3.07 (-5.99, -0.16) Common odds aspect (odds in CVT-301 84 mg / odds in placebo) 95% self-reliance Interval P-value 2.4 (1.35, 4.26) 0.003 2.25 (1.26, 4.02) 9 Summary Review TV4 and detain the ON narrate at 60 minutes post-dose Second key resultant effectiveness endsharp-end for 84 mg The modify from pre-dose in UPDRS sunder 3 motor mandible at 20 minutes post-dose at TV4 Patient Global Impression of Change (PGI-C) mandible at TV4. The adjustment of unrepinings who improved (a paltry improved, improved or ample improved) The modify from baseline to TV4 in unrepining-narrative sum daily OFF space as narrative in the Parkinson’s sickness diary for the 3 continuous days earlier to clinic visits The modify from baseline on the UPDRS sunder 3 motor mandible at 10 minutes post-dose at TV4 Least balance moderation destruction (moderation modify in CVT-301 84 mg – moderation modify in fixbo) 95% self-reliance Interval P-value Common odds aspect (odds in CVT-301 84 mg / odds in placebo) 95% self-reliance Interval Least balance moderation destruction (moderation modify in CVT-301 84 mg – moderation modify in fixbo) 95% self-reliance Interval Least balance moderation destruction (moderation modify in CVT-301 84 mg – moderation modify in fixbo) 95% self-reliance Interval Adapted from the FDA statistical re-examination. TV4 = Week 12. -2.55 (-5.22, 0.13) 0.062 (stop testing) -1.98 (-4.65, 0.70) 2.85 (1.56, 5.13) 1.94 (1.08, 3.46) 0.01 (-0.55, 0.56) -0.10 (-0.66, 0.46) -2.26 (-4.48, -0.04) -0.97 (-3.19, 1.24) The UPDRS sunder 3 is intended to assess the cruelty of the excellent motor judgments (e.g., tremor, rectilinearity, bradykinesia, postural fickleness) in unrepinings delay Parkinson’s sickness. It is insufficient, by itself, to settle the clinical moderationingfulness of the modify observed. The signicantly important adjustment of unrepinings on Inbrija, compared delay fixbo, who achieved decomposition of an OFF narrate to an ON narrate delayin 60 minutes succeeding con-over garbage government and maintained the ON narrate at 60 minutes post-dose, assistances the clinical moderationingfulness of the observed UPDRS Sunder 3 motor mandible modifys assessed in the chief endpoint. According to the suitor’s hierarchy, the segregation of effectiveness stopped succeeding the primeval key resultant endpoint, which had a p compute >0.05. However, the destruction between fixbo and CVT-301 84 mg on the modify from pre-dose in the UPDRS Sunder 3 motor mandible at 30 minutes post-dose at Week 12 was approximately statistically symbolical (p=0.062), and the similitude of the CVT-301 84 mg cluster and fixbo on the PGIC at Week 12 had a suppositious p-compute of Purchase counter-argument to see full attachment

[ad_2]
Source join