1. Pre-IND meeting with FDA | Proposed clinical trial and overall NDA approach are discussed, with opportunity to ask questions about FDA’s opinion on any aspect of trial or NDA strategy. | Meeting request is lengthy formal document with background material sufficient to familiarize FDA with product and situation. The only topics discussed are those related to questions asked in package. |
2. Clinical trial planning | Protocols are written with aims designed to support proposed label indication. Statistics are critical. Reference standards must be clearly defined. Data collection must be designed to withstand FDA audit. | SAP is formal, signed, document and must be part of formal clinical trial. Analysis approach and statistical endpoints for proposed indication are committed a priori. |
3. Performance of clinical trial | Trial data are collected and formally documented. | Internal audits as trial progresses are important to ensure data are collected completely and correctly. |
4. Data lock and statistical analysis | All trial data are entered into FDA prescribed data format for statistical analysis. Database is locked. Statistical analysis is performed precisely according to SAP. | Before data lock, all trial data must be reviewed for accuracy and completeness. Statistical analysis is performed using SAS software versions prescribed by FDA. SAS code is submitted in application. |
5. Pre-NDA meeting with FDA | Preliminary safety and efficacy analysis results are shared with FDA. Questions to FDA about adequacy of data and questions on structure and content of NDA are discussed. | From output of this meeting, likelihood that data are sufficient to support indication should be clear. All major questions about format and content of application should have been answered. |
6. Writing of NDA document | NDA must be written and formatted into eCTD format, which consists of 5 modules. Module 5 is clinical trial study reports, clinical trial information, and tabulated data. Module 4 is nonclinical animal data. Module 3 is chemistry manufacturing and controls. Module 2 is introduction and summaries of modules 3–5. Module 1 is label and other institutional information. | eCTD submissions for NDAs have been required since 2017. Data within eCTD document have additional FDA-required formats, including clinical datasets, statistical code, and label formatting. These standards are changing. Implications for academic institutions submitting NDAs are unclear, but more expense will likely be required. |
7. Submission | Submission is via electronic eCTD submission. Electronic receipt will be issued when it passes FDA gateway. | |
8. Review and request for information | FDA has 2 mo to review application for completeness. FDA can refuse regulatory filing if critical information is missing or is of insufficient quality. If accepted, FDA has additional 6 mo for priority review or 10 mo for standard review. FDA will file additional requests for information during review. | Thirteen requests for information were received. The most serious addressed an algorithmic error in reference standard determination impacting classification of a handful of subjects. Delay in correcting and resubmitting tabulated data delayed Prescription Drug User Fee Act date by 3 mo. |