Describe the reasons for why e CTD software is needed to help in the submissions process, including details of HOW the software program (or programs) can help

In completing Writing Assignment students will have the opportunity to:

  • Demonstrate an understanding of the importance of choosing eCTD software to assist in eCTD submissions
  • Demonstrate an ability to interpret a publicly available information about different eCTD software solutions
  • Demonstrate an ability to apply information presented in RGA6207 regarding eCTD submissions and best practices to a real-world scenario

For this assignment, you are a Sr Manager of Regulatory Affairs at a small, emerging biotechnology company that has completed all aspects of development for a combination drug/device product called CVT-301.CVT-301 was developed for treatment of the symptoms of Parkinson’s Disease.It is now time for you to select an appropriate eCTD software tool (or tools) to best assist you in an eCTD-compliant submission of your company’s first NDA.

As the Sr Manager of Regulatory Affairs, it is your task to:

  • Describe the basics of NDA submission best practices
  • Describe the reasons for why eCTD software is needed to help in the submissions process, including details of HOW the software program (or programs) can help
  • List 3 to 5 eCTD software products on the market and briefly describe their capabilities (Is this software that helps with conversion of word documents to eCTD-compliant PDFs? Is this software that organizes the eCTD documents into their appropriate hierarchy/granularity?) A simple google search can help you to easily locate some different software products that are marketed to help regulatory professionals compile eCTD-compliant IND and NDA submissions.This Written Assignment should be comprised of 3-5 pages of content (including references).

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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 forms / 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 after Refuse to File) 01/05/2019 Extended Inbrija/Levodopa Inhaled Powder Inhaled Powder/42 mg capsules For the intermittent treatment of OFF episodes in patients with Parkinson’s disease treated with carbidopa/levodopa 1. Introduction and Background Inbrija (also called CVT-301 during development) is a new co-packaged drug-device combination product proposed for the intermitted treatment of off episodes in patients with Parkinson’s disease (PD). The drug component of Inbrija is a new dosage form (powder) for levodopa allowing orally-inhaled delivery using a breath-actuated inhaler. The applicant submitted a 505(b)(2) NDA that references FDA’s finding of clinical safety, and nonclinical and clinical pharmacology information for listed drug Sinemet (carbidopa/ levodopa) 25/100 mg oral tablets. Efficacy and additional safety information are provided by clinical trials conducted by the applicant that are essential to the application. The applicant originally submitted the NDA on June 27, 2017, but this was issued a refuse-tofile letter because of CMC deficiencies. The applicant resubmitted the application 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 review of the application. The CDRH and OPQ review team is presented in Table 1. Page 1 of 28 Reference ID: 4367981 1 Summary Review Table 1: CDRH and OPQ review 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 drug substance (DS) manufacture was referenced in a DMF for levodopa held by (b) (4) which was reviewed and found adequate to support the NDA. The DS has a USP monograph, and the impurities described in the monograph were all present at levels that are at or below the USP limits. Three potential process impurities were adequately controlled at levels below the reporting threshold. The container, stability information and post-approval stability protocol and commitment were all acceptable. The drug product (DP) is a co-packaged drug and device combination product. The drug component is a capsule filled with levodopa powder. The applicant only plans to manufacture a 42-mg capsule strength. The device is a proprietary metered-dose oral inhaler. The DP contains two excipients, sodium chloride and dipalmitoylphosphatidylcholine (DPPC). A Letter of (b) (4) Authorization was provided by the applicant to DMF for DPPC. DPPC is the major component of human surfactant and it is a major ingredient in a marketed product, Surfaxin. The OPQ reviewer commented that the DPPC and sodium chloride are present in acceptable (b) (4) levels and they The OPQ reviewer commented that stability testing results support a 24-month shelf-life for the capsules stored at room temperature. The applicant’s commitment to place the first 3 commercial batches on long-term stability as specified in the stability protocol, and a minimum of one batch each year and report the results including any deviations is acceptable. Page 2 of 28 Reference ID: 4367981 2 Summary Review The device is a metered dose inhaler that delivers the powdered drug product. The medication dose is supplied by a capsule that is placed in the body of the inhaler. The mouthpiece is replaced on top of the body 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 powdered drug product into the aerosol chamber formed by the space surrounding the staple guide, body and mouthpiece. The airflow caused by the patient inhaling through the mouthpiece delivers the drug. Patients are instructed to inhale through the mouthpiece of the device until they hear or feel a whirling sound. To deliver the recommended dose of 84 mg of levodopa, the patient repeats the procedure, inhaling the contents of two 42 mg capsules. Figure 1. CVT-301 Inhaler Schematic Diagram (b) (4) CVT-301 Inhaler with 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 included in the application were recommended for approval. The OPQ and CDRH review team recommend approval of the application. 3. Nonclinical Pharmacology/Toxicology LuAnn McKinney, DVM, DACVP is the primary nonclinical reviewer for this application. Dr. Lois Freed, PhD is the nonclinical supervisor. Dr. Freed notes that the battery of nonclinical studies conducted by the sponsor is generally consistent with recommendations made by the Division during clinical development and with relevant guidance. The highest doses tested in the toxicity studies do not provide a safety margin compared to the maximum recommended human dose (MRHD) of 420 mg/day, based on systemic levodopa exposure; however, the systemic effects of levodopa are well-known in animals and humans. The nonclinical data also provide a minimally acceptable evaluation of local toxicity. Overall, the nonclinical data submitted are adequate to support approval of the NDA. 4. Clinical Pharmacology Mariam Ahmed, PhD, is the primary Clinical Pharmacology reviewer for this application. Drs. Kevin Krudys, PhD; Sreedharan Sabarinath, PhD are the Clinical Pharmacology supervisors. The applicant conducted a bridging relative bioavailability study (CVT-301-010) between CVT-301 and listed product Sinemet 25/100 mg tablets. This was a single-dose, open-label, randomized, 3-period crossover study in 24 healthy male and female volunteers. Two doses of CVT-301 were tested: 60 mg and 84 mg. Page 4 of 28 Reference ID: 4367981 4 Summary Review The estimate for the bioavailability of levodopa after administration of CVT-301 84 mg, relative to Sinemet 25/100 mg oral tablets, is about 70%. Tmax was about 15 minutes earlier following administration of CVT-301 84 mg, but Cmax and AUC 0-24 were substantially lower for CVT-301 84 mg compared with oral Sinemet (see Table 2). Table 2. Dose-Normalized AUC0-24h and Cmax for Levodopa following Oral 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 ratio of dose normalized AUC represents the bioavailability of CVT-301 60 mg and CVT-301 84 mg relative to SINEMET® 25-100 mg. From the FDA Clinical Pharmacology Review The OCP reviewer commented that the study results provide an adequate PK bridging to the listed drug (LD). Studies in Subgroups Effects of Gender The reviewer noted a statistically significant (p<0.05) difference in LD’s exposure parameters between males and females. However, the difference was accounted for by the differences in body weight between the male and female patients. No dosing adjustment is necessary based on gender. Effects of Smoking The applicant conducted a study (CVT-301-007) to compare the safety and levodopa pharmacokinetics following a single-dose administration of CVT-301 in smoking and nonsmoking adults. The mean Cmax and AUC0-24h were slightly higher in smokers compared to non-smokers (Table 3). Table 3. Statistical analyses of the effects of smoking on the PK parameters of levodopa PK Parameter (Unit) Non-smokers Smokers Smokers vs. Non-smokers Ratio 90% CI CV% AUC0-24h (ng•hr/mL) 1368 (31) 1523 (25) 111.3 91.7, 135.2 45.2 AUC0-’ (ng·hr/mL) 1350 (30) 1497 (24) 110.9 91.0, 135.1 45.2 Cmax (ng/mL) 684 (31) 765 (25) 111.9 93.4, 134.1 41.9 Source: FDA Clinical Pharmacology Review Page 5 of 28 Reference ID: 4367981 5 Summary Review Study CVT-301-008 The applicant also conducted a study in patients with asthma. Study CVT-301-008 was a double-blind, randomized, placebo-controlled, 2-period, crossover study in 25 adults with asthma. Subjects took 3 doses of Inbrija or placebo, each separated by 4 hours on the first day of dosing, followed by a day of washout before a second day of receiving 3 doses. Overall, the PK of levodopa profile was similar between subjects in previous studies and asthmatic subjects in this study. Because of the risk of bronchospasm in patients with asthma, the applicant is proposing not to recommend Inbrija for use in these patients. Overall, the Office of Clinical Pharmacology recommends approval of the application. 5. Clinical/Statistical- Efficacy The primary statistical reviewer for this application was Dr. Sungwon Lee, PhD, with supervisory review provided by Drs. Kun Jin, PhD and James Hung, PhD. Dr. Susanne Goldstein was the clinical reviewer. Study CVT-301-004 is the pivotal study supporting efficacy in the application. Study CVT301-004 (referred to as Study 004) was a randomized, double-blind, placebo-controlled study that compared CVT-301 60 mg capsule dose (35 mg fine particle dose [FPD]) and 84 mg (50 mg FPD) to placebo, in parallel groups. The study included three periods: a 5-week screening period, a 12-week maintenance period, and a 1- or 2-week follow-up period. Patients completing the study were given the opportunity to enroll in an open-label extension study (CVT-301-400E) [see Figure 2]. Figure 2. Study CVT-301-400 Design Schematic The study inclusion and exclusion criteria appear reasonable and likely represent patients who will use this drug-device combination product. Page 6 of 28 Reference ID: 4367981 6 Summary Review Key Inclusion Criteria x Idiopathic PD (United Kingdom [UK] PD Society Brain Bank clinical criteria) x Male or female, age 30 to 85 years, inclusive x Stage 1 to 3 modified Hoehn & Yahr (H&Y) scale score of PD severity x A minimum of 2 hours of average daily OFF time per waking day (excluding early morning OFF time) on the PD Patient Diary x SFUHHQLQJ )(9 • RI SUHGLFWHG DQG )(9)9& UDWLR ! LQ WKH 21 VWDWH Key Exclusion Criteria x Previous surgery for treatment of PD including deep brain stimulation x Chronic obstructive pulmonary disease (COPD), asthma, or other chronic respiratory disease within the last 5 years x History of symptomatic orthostatic hypotension despite adequate treatment. Patients received study drug kits and the IFU for use at home. Patients were instructed to take their standard oral PD medications as prescribed on their usual schedule of administration, which was not to be modified during the 12 weeks of study drug treatment. Patients could use study drug up to 5 times during the waking day, as close as possible to the time when they began to experience OFF symptoms, which could be motor or nonmotor. Primary endpoint The primary endpoint of the study was the change from pre-dose in the Unified Parkinsons Disease Rating Scale (UPDRS) part 3 (motor) score at 30 minutes post-dose, assessed in the clinic 12 weeks after randomization. The UPDRS Part 3 total score was calculated as the sum of the individual items of the UPDRS Part 3 separately at each time point. Patients came to the clinic after taking their usual morning medications for PD. The arrived in the ON state. Patients were not allowed to take additional PD medications while they waited in the clinic to turn OFF. The UPDRS was assessed in the OFF state, followed by administration of CVT-301. The UPDRS was assess at 10, 20, 30, and 60 minutes after administration of study medication. The patients resumed taking their usual PD medication after the last UPDRS was assessed at 60 minutes. Key Secondary Endpoints x Proportion of patients achieving resolution of an OFF to an ON state within 60 minutes after study drug is administered in the clinic and maintaining the ON at 60 minutes after study drug administration (per the examiner’s subjective assessment). x Change from pre-dose in UPDRS Part 3 motor score at 20 minutes following treatment of patients experiencing an OFF episode in the clinic at Week 12. x PGI-C rating scale measured predose at Week 12. Page 7 of 28 Reference ID: 4367981 7 Summary Review x Change from pre-dose in UPDRS Part 3 motor score at 10 minutes following treatment of patients experiencing an OFF episode in the clinic at Week 12. x Change from baseline in patient-recorded total daily OFF time, assessed by the patient and recorded in the PD Diary for 3 consecutive days prior to Week 12 Randomization was stratified by the Hoehn and Yahr (H&Y) scale rating category (H&Y<2.5 YHUVXV + <• DV PHDVXUHG LQ WKH 21 VWDWH WR EDODQFH WKH VHYHULW\ RI 3DUNLQVRQ¶V GLVHDVH LQ each group and by screening spirometry results measured by the forced expiratory volume in 1 VHFRQG )(9 YHUVXV )(9• WR EDODQFH WKH SDWLHQW¶V LQKDOation capacity of the study drug in each group. Figure 3. Fixed Sequence Hierarchical Testing Procedure Testing started with the primary endpoint at the high dose, following the order illustrated in Figure 3. The testing procedure ended if the p-value associated with an endpoint included in the hierarchy was 0.05 or higher. The endpoint comparisons were hierarchically ordered, so that the fixed sequential testing method was applied to control an overall type 1 error. Study results Three-hundred fifty-one (351) patients were randomized in a 1:1:1 ratio to each of the three arms of the study. Three-hundred-thirty-nine (339) patients received at least one dose of CVT301. The intention to treat (ITT) and safety population were identical, with 339 total 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 study population was approximately one-quarter women and approximately 95% white, both typical demographic features in a PD study. Two-thirds of the population had a Hoehn and Yahr score at baseline of 2.5 or higher (see Table 4). The distribution of patients with key demographic and disease severity indicators were consistent across the treatment arms. Table 4. Demographic and Baseline Characteristics of the Primary Analysis Set Characteristics <65 • Male Gender Female White Black Race Asian Other FEV1<60% Spirometry )(9• H&Y<2.5 Disease severity + <• Source: FDA statistical review 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 results are presented in Table 5. The statistical reviewer verified the applicant’s result for the primary endpoint using a mixed model for repeated measurements (MMRM). The CochranMantel-Haenszel (CMH) test was used to analyze the first key secondary endpoint. Table 5. Hierarchical Evaluation of the Primary and Key Secondary Efficacy Endpoints at Treatment Visit 4 (Week 12) – CVT-301 84 mg and 60 mg versus Placebo (ITT Population) Endpoint Statistics Primary efficacy endpoint for 84 mg The change from pre-dose in the UPDRS part 3 motor score at 30 minutes post-dose at TV4 First key secondary efficacy endpoint for 84 mg The proportion of patients who achieve resolution of an OFF state to an ON state within 60 minutes after study drug administration at the clinic at Page 9 of 28 Reference ID: 4367981 Placebo vs CVT301 84 mg Placebo vs CVT301 60 mg Least square mean difference (mean change in CVT-301 84 mg – mean change in placebo) 95% confidence Interval P-value -3.92 (-6.84, -1.00) 0.009 -3.07 (-5.99, -0.16) Common odds ratio (odds in CVT-301 84 mg / odds in placebo) 95% confidence Interval P-value 2.4 (1.35, 4.26) 0.003 2.25 (1.26, 4.02) 9 Summary Review TV4 and maintain the ON state at 60 minutes post-dose Second key secondary efficacy endpoint for 84 mg The change from pre-dose in UPDRS part 3 motor score at 20 minutes post-dose at TV4 Patient Global Impression of Change (PGI-C) score at TV4. The proportion of patients who improved (a little improved, improved or much improved) The change from baseline to TV4 in patient-recorded total daily OFF time as recorded in the Parkinson’s disease diary for the 3 consecutive days prior to clinic visits The change from baseline on the UPDRS part 3 motor score at 10 minutes post-dose at TV4 Least square mean difference (mean change in CVT-301 84 mg – mean change in placebo) 95% confidence Interval P-value Common odds ratio (odds in CVT-301 84 mg / odds in placebo) 95% confidence Interval Least square mean difference (mean change in CVT-301 84 mg – mean change in placebo) 95% confidence Interval Least square mean difference (mean change in CVT-301 84 mg – mean change in placebo) 95% confidence Interval Adapted from the FDA statistical review. 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 part 3 is designed to assess the severity of the cardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability) in patients with Parkinson’s disease. It is insufficient, by itself, to establish the clinical meaningfulness of the change observed. The signicantly greater proportion of patients on Inbrija, compared with placebo, who achieved resolution of an OFF state to an ON state within 60 minutes after study drug administration and maintained the ON state at 60 minutes post-dose, supports the clinical meaningfulness of the observed UPDRS Part 3 motor score changes assessed in the primary endpoint. According to the applicant’s hierarchy, the analysis of efficacy stopped after the first key secondary endpoint, which had a p value >0.05. However, the difference between placebo and CVT-301 84 mg on the change from pre-dose in the UPDRS Part 3 motor score at 30 minutes post-dose at Week 12 was nearly statistically significant (p=0.062), and the comparison of the CVT-301 84 mg group and placebo on the PGIC at Week 12 had a nominal p-value of < 0.001. These results also support the clinical meaningfulness of the primary endpoint results. Results on most efficacy endpoints were numerically better for the 84-mg dose than for the 60mg dose of Inbrija. The statistical reviewer conducted sensitivity analyses of the primary endpoint to explore the effects on the primary endpoint of a site in Poland that had an unusually large effect on the primary outcome in favor of treatment with CVT-301. The results of the sensitivity analyses that used a monotone imputation method did not change the efficacy conclusion for the primary en …

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