Product Application Review Process - Background
Each Center has systems in place to ensure consistency of product review across Divisions to the extent possible. These systems include the use of standard operating procedures and guidances that communicate policies and procedures governing product application review. Each Center has a comprehensive training program for new reviewers and makes additional training opportunities available for existing reviewers.
FDA encourages sponsors and applicants to attempt to resolve disagreements by starting with the review team within the division and then elevating the dispute, if necessary, to the Division Director. Sponsors may submit formal dispute resolution requests for any decision made at the Division Director level or above.
An Ombudsman is also available to mediate disputes sponsors may have with agency employees during the product application review process. Sponsors can contact the Ombudsman at any time for consultation and guidance on the dispute resolution procedure or for assistance in resolving a complaint or dispute.
Timeframes Governing Product Application Review
Performance goals associated with the complete review of animal drug product applications are set forth in the Animal Drug User Fee Act (ADUFA) and the Animal Generic Drug User Fee Act (AGDUFA).
The product application review process usually begins with a pre-submission conference between CVM employees and the potential applicant. During this conference, agreements regarding the product application or studies needed to support approval may be made.
Most sponsors participate in the Center’s phased review process. Phased review means that after the review of each technical section submission, the sponsor will receive a technical section complete letter or an incomplete letter. The incomplete letter describes the deficiencies the product review team noted in the application, and allows drug sponsors to address specific aspects of the application as the information becomes available. Once all of the technical sections are submitted and complete, the sponsor submits an administrative new animal drug application and the Center has 60 days to complete review.
When an application is submitted to FDA, a team is assigned to review that application. The Team Leader is the primary contact for any regulatory or science issues associated with the application. The contact information for that individual is provided to the sponsor. If that individual changes, the sponsor is notified.
Each new animal drug sponsor is assigned to a specific project manager. When the sponsor opens an application file and submits to the file certain information about a planned clinical study, the assigned project manager contacts the sponsor and provides his or her contact information. In addition, the project manager discusses the administrative process with the sponsor and explains the project manager role in those processes. If a project manager changes, the old and new project manager coordinate efforts to ensure that the sponsor is notified about the change. The assigned project manager is the primary contact for administrative issues.
After approval of an original new animal drug application or major supplemental application, the project manager contacts the sponsor and offers the sponsor an opportunity to attend a post-review meeting to discuss the review process.
Drugs for human use and biological products
FDA regulations provide that the FDA will make a determination about the approvability of a drug application within 180 days of receiving the application, unless the applicant and FDA have agreed otherwise or the sponsor has submitted a major amendment to the application. A detailed timeline for review of a new drug application or biologics license application is set forth in guidance to industry and review staff entitled, “Good Review Management Principles and Practices for PDUFA Products.” This guidance is available on the FDA Web site.
As set forth in this guidance, FDA sends the applicant an acknowledgement letter that notifies the applicant of the date of receipt of the application. This letter is sent within 14 days after the agency receives the application. Within 60 days of receipt of the application, the Center notifies the applicant of its decision regarding whether the application is sufficiently complete to permit a substantive review. At this time, the Center also notifies the Center whether the application will be classified priority (or expedited) review or standard review. By the 74th day following receipt of the application, the Center communicates to the applicant issues identified during the filing review. Information about planned review activities, including, for example, whether there will be an Advisory Committee meeting, the timing for discussion of risk evaluation and mitigation strategies (REMS) and other post-marketing safety commitments, is also communicated to the applicant by this date.
During the review, FDA may contact the applicant with questions about the application. An internal mid-cycle meeting is held to discuss the progress of the application review. A request may be sent to the applicant within 30 days of the mid-cycle meeting if additional information or analyses are needed.
Each application that is submitted is assigned a regulatory project manager (RPM). Contact information for the RPM is provided in the letter sent to the applicant acknowledging receipt of the application. If the RPM is changed during the course of the review, the applicant is notified by the new RPM. Contact information for the RPM is included with every communication to the applicant.
Performance goals associated with review of certain device submissions—premarket notification submissions (510(k)s), original premarket approval applications (PMAs) and premarket approval application supplements—are set forth in the Medical Device User Fee and Modernization Act, as amended by the Food and Drug Administration Amendments Act of 2007.
CDRH notifies the sponsor when a 510(k) or PMA has been received. Communication with the sponsor, application review, and coordination of any team review, if necessary, is handled by the primary reviewer. The reviewer notifies the sponsor that they are the reviewer for the application. If there is a change in reviewers in the midst of the review process, the new reviewer notifies the sponsor.
During the review, CDRH reviewers may contact the applicant with questions. For PMAs, a 100 day meeting or communication occurs with the sponsor about the status of the submission.
Electronic Product Application Regulatory Submissions
Some Centers accept certain formal regulatory submissions associated with the product approval process in electronic format. For example, CVM accepts Notices of Claimed Investigational Exemption for a New Animal Drug (NCIE) in electronic format. CDER accepts new drug applications (NDAs) and abbreviated new drug applications (ANDAs) in electronic format. CBER accepts biologics license applications (BLAs) in electronic format. CDRH encourages sponsors of premarket medical device submissions to include a copy of their submission in electronic form along with the required paper copies and accepts premarket notification applications (510(k)s) for in vitro diagnostic devices in electronic format.
FDA has published a draft guidance that sets forth general considerations for members of industry that elect to submit electronic submissions to the agency. This draft guidance applies to all of FDA’s centers.
In addition, some Centers have posted information regarding the Center’s preferences regarding the use of secure electronic mail for communications associated with product applications. CBER, CDER, and CDRH have posted a policy outlining expectations for the use of secure email.
Communicating with Sponsors During Product Review
FDA has established avenues through which sponsors of medical products can meet with agency personnel during and after the review process. All Centers have published guidelines for meeting with sponsors of medical products. These guidelines provide sponsors with an understanding of the process used to manage meeting requests and the information needed in preparation for the meeting, as well as set expectations regarding the conduct of the meeting.
CVM, CBER, CDER, and CDRH have targets related to holding meetings with industry set forth in the ADUFA, AGDUFA, Prescription Drug User Fee Act (PDUFA), and Medical Device User Fee and Modernization Act (MDUFMA), respectively.
CVM has posted its Program Policy and Procedures Manual, which includes a chapter on procedures for scheduling and meeting with outside parties, on the FDA Web site. CDRH has posted its guidelines for early collaboration meetings with sponsors considering submitting a PMA or with any person planning on investigating the safety or effectiveness of a Class III product or implant.
CBER and CDER have issued a guidance titled “Formal Meetings Between the FDA and Sponsors or Applicants” that describes procedures for requesting, preparing, scheduling, conducting and documenting formal meetings held between FDA employees and product sponsors or applicants. The guidance applies to applicants who have submitted an NDA or BLA to FDA for review. The CDER Office of Generic Drugs (OGD), in large part, also follows this guidance for meetings conducted with sponsors that submit an ANDA to FDA for review. However, the specific deadlines that have been negotiated as part of the PDUFA are not applicable to ANDAs, and thus, those provisions of the guidance are not followed by OGD.
As part of the Good Guidance Review Management Practices, CDER and CBER offer applicants submitting applications for new molecular entities and new biological products an opportunity to participate in a post-review teleconference or meeting. Such meetings are used to discuss the quality of the application and to evaluate the communication process during the drug development and marketing application review process. The purpose is to learn from successful aspects of the review process. FDA encourages these meetings in order to improve future application submissions and the quality of the review process.