ski, it’s a team of reviewers. Many of the “1.7 million pages” are supporting documents, such as the clinical case records, manufacturing development work, the statistical, and scientific analysis methods, etc., that the reviewers may want to examine to aid them in their assessments. You’re right though, much like lengthy court electronic documents, the relevant files are searchable. And no, regulators don’t “demand such a document.” They require companies that want to sell a product to the public to provide sufficient evidence to demonstrate that it’s safe and efficacious, the scientific methods used to prove that are adequate, and that it can be manufactured to meet high standards. It would be impossible to do that in 1000 pages.
Here’s the FDA’s review members and their responsibilities:
Review Team Responsibilities
The review teams analyze new drug applications (NDAs) and biologic licensing applications (BLAs). During drug development, the teams also review Investigational New Drug Applications (INDs). Each team member uses their expertise to answer these key questions:
* Is it reasonably safe to study an investigational drug in humans and will proposed studies provide data needed to show safety and efficacy? * Is the drug safe and effective in its proposed use and do the benefits of the drug outweigh the risks? * Is the proposed labeling appropriate and if not what should it contain? * Are the methods used in manufacturing the drug and the controls adequate?
I’ll highlight just their pre-submission activities. In light of recent delays, note the discussion/feedback provided to make the application acceptable (i.e. something may have been alerted):
CDER 21st Century Review Process Desk Reference Guide
Pre-submission Activities Ensure Readiness for Application through Pre-Submission Activities During this phase, applicants are strongly encouraged to request a meeting with the appropriate FDA review division prior to the submission of an NDA/BLA, particularly in the case of NMEs and BLAs covered under the PDUFA V “Program,” to discuss the planned content of their application. Meetings include the traditional pre-NDA/BLA meeting and other meetings such as the electronic pre-submission meeting, if necessary. Ideally, good FDA-industry IND interactions and use of pre-NDA/BLA meetings will help to ensure that all submitted applications are complete and fileable.
1.1 Pre-NDA/BLA Meeting (Pre-Submission Meeting)
Meeting Purpose: The purpose of a pre-NDA/BLA meeting is to discuss format and content of the anticipated application, including labeling and REMS (if applicable), presentation of data, dataset structure, acceptability of data for submission, as well as the projected submission date of the application. The meeting should be held sufficiently in advance of the planned submission of the application to allow for meaningful response to FDA feedback and should generally occur not less than two months prior to the planned submission. In cases where the FDA anticipates conducting an expedited review of the application and communicates this to the applicant, the pre-submission meeting may be held closer to the submission date.
Preparing for the Pre-Submission Meeting: In preparation for a pre-NDA/BLA meeting, the OND RPM evaluates the meeting request and meeting package, schedules the meeting with pertinent reviewers and provides them with the pre-meeting background package. The Office of Surveillance and Epidemiology (OSE) RPM is also given the meeting package and informs the OND RPM of the OSE reviewer assigned (as necessary) who should be invited to the meetings. The identified OSE staff members are invited to meetings if issues relating to a REMS, postmarketing safety study, or other safety concern(s) are identified. The information to be provided by the applicant for the meeting includes: * A timeline and list of prior FDA meetings and agreements, prior FDA advice, and any development changes. This would include meeting minutes and letters sent earlier, regulatory history, issues raised at the end-of-phase 2 meeting, etc. * A summary of technical information to be submitted in the NDA/BLA, including the results of the pivotal trials, if they are available, and the proposed dataset structure. * Highlights of any potential problems, including product quality issues, data integrity concerns, safety signals, etc. * Proposed draft labeling. * The proposed format for organizing the submission, including methods for presenting the data and a draft index if available. * A discussion of the need for a REMS or post-marketing study/trial for any safety issue(s) that has emerged during development or during foreign marketing. CDER 21st Century Review Process Desk Reference Guide Page 10
* Other information/issues that require discussion. * List of questions for FDA. ?Reviewers should review the meeting package and also be prepared to discuss internally the potential need for an Advisory Committee meeting, REMS, and PMRs. The reviewers draft responses to the pertinent questions submitted by the applicant. The project manager assembles reviewers’ comments and sends them to the applicant at least 48 hours prior to the meeting. ?Holding the Meeting: At the pre-NDA/BLA meeting, the FDA and the applicant will agree on the content of a complete application for the proposed indication(s), including preliminary discussions on the need for REMS or other risk management actions. Reviewers also describe how data should be presented in the NDA/BLA to facilitate its review. The agreement and discussions are summarized at the conclusion of the meeting and reflected in the FDA meeting minutes. ?For “Program” applications, during the pre-submission meeting the FDA and the applicant may reach agreement on submission of a?limited number of application components not later than 30 calendar days after the submission of the original application. These?components must be of a type that would not be expected to materially impact the ability of the review team to begin its review.?Examples of application components that may be appropriate for delayed submission include updated stability data (e.g., 15-month data?to update 12-month data submitted with the original submission) or the final audited report of a preclinical study (e.g., carcinogenicity) where the final draft report is submitted with the original application. Major components of the application (e.g., the complete study report of a Phase 3 clinical trial or the full study report of required long-term safety data) are to be submitted with the original application and are not subject to agreement for late submission. Any agreement that is reached on delayed submission of application components will be summarized at the conclusion of the meeting and reflected in the FDA meeting minutes. (See also: http://inside.fda.gov:9003/ProgramsInitiatives/Drugs/21stCenturyReview /ucm034190.htm) ?For applications where an expedited review is anticipated, FDA will communicate during the pre-submission meeting that the review team plans to conduct an expedited review and has targeted earlier timelines for certain review activities, including “Program” activities. These expedited timelines will be communicated during the course of the review provided no significant unexpected review issues arise and there are no unexpected changes to the workload priorities or staffing for the review team. FDA and the applicant may discuss at the meeting the applicant’s readiness to launch should an action occur early. ?FDA should request that the applicant submit information on all manufacturing facilities and/or preliminary data on pivotal clinical trials or bioequivalence study(ies) that would be useful in early determination of sites for inspection. ?Meeting discussions may include what data will be submitted to support sought-after labeling or how labeling annotations should be linked to the primary supporting information in the eCTD. Container and carton labels can also be addressed during pre-submission meetings. Review teams should direct applicants to the website for the new requirements for prescribing information. (See New Requirements for Prescribing Information) ?Applicants may request that an application be designated for fast-track review; applicants may also request to submit completed sections of the marketing application for review by FDA (rolling review). (See Fast Track, Accelerated Approval, and Priority Review). ?CDER 21st Century Review Process Desk Reference Guide Page 11
Pre-submission Activities
Minutes from the Pre-NDA/BLA meeting are prepared and archived by the RPM.
1.2 Electronic Pre-Submission Meeting If technical aspects of the submission have not been adequately addressed with the sponsor (e.g., at the pre-NDA/BLA meeting), an electronic pre- submission meeting may be held at the discretion of the review division 30-60 days prior to the submission of the application. The FDA may recommend this meeting for some applications. The focus of the NDA/BLA electronic pre-submission meeting is on navigation, formatting of electronic files, and layout of the application.
In preparation for an electronic submission meeting, the RPM evaluates the meeting request and works with the Division of Regulatory Review Support (email: esub@fda.hhs.gov) to load any provided (mock) data sets on the FDA computer system that support review of electronic applications. The review division prepares draft responses to any questions submitted by the applicant and sends them to the applicant prior to the meeting. Meeting minutes are prepared and archived by the RPM. . . .
