TABLE 1

Steps in NDA Process

Activity	Description	Comment
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.