FDA Guidance: Information Request and Discipline Review Letters Under the Prescription Drug User Fee Act
This guidance has been prepared by the Review Management Working Group comprising individuals in the Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER) at the Food and Drug Administration. Published in August, 1999, this guidance document represents the Agency's current thinking on information request and discipline review letters under the Prescription Drug User Fee Act. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
Introduction
Background
Explanation of Terms
Issuance and Use of Information Request and Discipline Review Letters
Introduction (Back to Top)
This guidance for industry explains how the Agency will issue and use information request (IR) letters and discipline review (DR) letters during the review of products in original human drug applications as defined in section 735(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 379g(1)) (PDUFA products). This guidance does not apply to supplemental applications, resubmissions, or to applications for non-PDUFA products.
In a November 1997 letter to Congress regarding the reauthorization of the Prescription Drug User Fee Act (PDUFA) as part of the Food and Drug Administration Modernization Act of 1997, the Secretary of Health and Human Services committed the Food and Drug Administration to certain user fee performance goals and additional procedures related to the review of PDUFA products. These include the goals of reviewing and acting on increasing%ages of applicants' original new drug applications (NDAs) or biologics license applications (BLAs), within 6 months for priority applications and within 10 months for standard applications for drugs and biologics. The term review and act on means the issuance of an action letter after the complete review of a filed application. In addition to the performance goals for application review, to help expedite the development of drugs and biologics, the Secretary specified that FDA intends to provide early Agency thoughts on possible deficiencies to applicants in a letter as each discipline finishes its initial review of its portion of the pending application (except when it results in the ability to issue an action letter).
Background (Back to Top)
Upon implementation of the Prescription Drug User Fee Act of 1992 (PDUFA 1), the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) undertook to review and act on complete NDAs and BLAs within agreed upon time frames. As part of this undertaking FDA instituted the use of two types of letters, action letters and IR letters. An action letter (not approvable, approvable or approval letter) was issued after a complete review of the application. If not an approval, the action letter contained a complete list of deficiencies in the application and completed the review cycle for the application. The next review cycle (resubmission) began when a complete response to all deficiencies listed in the letter was received by the Agency. CDER and CBER used IR letters to ask for information that would assist reviewers during the course of the review or to convey deficiencies identified in the application in advance of the issuance of an action letter. These IR letters did not stop the review clock, did not signal the completion of a review cycle, and were not used consistently across divisions or centers.
In discussions held to prepare for the reauthorization of PDUFA (PDUFA 2), industry proposed that applicants be notified of any deficiencies in an NDA or BLA as early as possible after a discipline review had been completed. It was agreed that deficiencies would be communicated in a specific type of letter. The company could then begin preparing a response to the deficiencies, thereby decreasing the response time to the Agency and potentially expediting availability of products to consumers. Although the enclosure to the PDUFA 2 goals letter signed by Secretary Shalala refers to these as IR letters, FDA finds that it will be less confusing if these letters are clearly identified as a unique type of letter, the discipline review (DR) letter. Consequently the Agency will continue to use an IR letter, if needed, to request information while a specific discipline review is in progress and institute the use of a DR letter to convey early thoughts on possible deficiencies in the discipline's section of the application when a discipline review is complete.
A discipline review refers to the review of sections of the NDA and BLA by staff with that expertise. These sections include, but are not limited to, the clinical section, the chemistry, manufacturing and controls section, the non-clinical pharmacology and toxicology section, and the human pharmacokinetics and bioavailability section. As part of their PDUFA 2 commitments at the conclusion of a discipline review, CBER and CDER will send a discipline review letter to the applicant identifying deficiencies in that particular discipline's portion of an application as described in this document, unless the discipline review completes the review of the application.
Explanation of Terms (Back to Top)
An action letter is a letter to an applicant that is issued after the complete review of a filed application. If the letter is not an approval letter, it will set forth in detail the specific deficiencies and, where appropriate, the actions necessary to place the application in condition for approval. An action letter may contain additional or fewer deficiencies than were provided in previously issued DR letters, depending on the final review of the application and supervisory evaluation by Division and/or Office Directors. The issuance of an action letter completes the review cycle for a pending application. It is the benchmark by which the Agency's performance against the PDUFA application review goals is measured.
A discipline review (DR) letter is a letter used to convey early thoughts on possible deficiencies found by a discipline review team for its portion of the pending application at the conclusion of the discipline review. DR letters are not considered to be action letters because they do not represent a complete review of the submission and, therefore, do not stop the user fee review clock. In addition, a DR letter does not necessarily reflect input from upper supervisory levels (i.e., Division or Office Directors). A single DR letter may contain comments from multiple discipline reviews if it is more efficient to do so. There is no obligation for FDA to review information submitted in response to a DR letter during the review cycle in which the DR letter was issued. FDA may review such information if it determines that such review would not adversely affect its ability to meet its PDUFA performance goal for that review cycle.
An information request (IR) letter is a letter sent to an applicant during an application review to request further information or clarification that is needed or would be helpful to allow completion of the discipline review. IR letters are not considered to be action letters because they do not represent a complete review of the submission and therefore do not stop the user fee review clock. As with DR letters, an IR letter does not necessarily reflect input from upper supervisory levels. However, IR letters are not like DR letters in that IR letters are issued while the discipline review continues. Information requested in IR letters should be information that would assist in the completion of the review and, as such, would usually be reviewed during the review cycle in which the IR letter was issued.
The user fee review clock measures the time elapsed during which an application is under review by CBER or CDER (i.e., a review cycle). The review clock starts at Agency receipt of an NDA or BLA that is subsequently filed, or a complete resubmission and stops when an action letter is issued to the applicant.
Issuance and Use of Information Request and Discipline Review Letters (Back to Top)
General
IR letters will be used by CBER and CDER to obtain clarifying information to assist in completing a review. Because the Agency issues IRs to obtain clarification, it is normally expected that the applicant will respond as quickly as possible. Such responses (if they are of a clarifying nature) are reviewed as part of the current review cycle of the application. However, if the response is of a significant nature, the response could constitute a major amendment. Review of a response may be deferred to the next review cycle, if the review team believes that the new information cannot be fully reviewed in the time remaining in the current review cycle or is ready to issue an action letter.
To help expedite the development of drug and biologic products, under PDUFA 2, CBER and CDER will generally convey early thoughts on possible deficiencies to applicants in the form of a DR letter as each discipline finishes its review of its section of the pending application, unless the discipline review completes the review of the application. A DR letter will be used to convey such thoughts on possible deficiencies found in a discipline review only if, in the Division's judgment, it is efficient to do so. The absence of a DR letter for a particular discipline should not be construed to mean that the action letter will not contain any deficiencies for that discipline. Comments in a DR letter will usually reflect the input of the review team but not that of the review division director or office director.
The DR letter will allow applicants to know as soon as possible the review team's early thoughts on possible deficiencies that have been identified within specific sections of the application. With this information they can begin to assemble the needed data to address these deficiencies. DR letters will only contain items that the review team believe require resolution prior to approval of the product. A DR letter intended to convey deficiencies found during a discipline review will be clearly distinguishable from IR letters which are requests for clarifications needed to proceed with the on-going review.
Applicants should be aware that because the DR letter will originate at the review team level, supervisors may add or delete items in the course of their evaluation resulting in more or fewer deficiencies in the subsequent action letter. In addition, as reviews from different disciplines are integrated, additional concerns might arise or previously stated concerns may be resolved. Therefore, applicants could spend time gathering information that in the end may not be necessary for responding to the action letter. This possibility was raised during PDUFA 2 discussions with industry representatives, and it was agreed during those discussions that the DR letter program should be evaluated to determine if it truly helps achieve the goal of reducing the time it takes to make products available to the consumer (i.e. if the benefit of early notification of possible deficiencies outweighs the possiblity of unnecessary extra work on the part of industry).
Applicant Response and Effect on the User Fee Clock
IR letters and DR letters will not affect the user fee review clock for a given review cycle. Responses to IR letters and DR letters will be reviewed during the current review cycle at the discretion of the review team. Normally, unless the amount and type of information is substantive or voluminous, the review of a clarifying IR letter response will occur during the current review cycle. A response to a DR letter conveying deficiencies identified in a discipline review may or may not be considered a major amendment which would extend the review time for the current review cycle. At the Division's discretion, it may review the response if the review can be completed in the current review cycle. The Agency is not obligated to review the response before the issuance of an action letter. If the Agency determines that it cannot review the newly submitted data before the user fee action due date, it may defer review of the response. If the review team is ready to issue an action letter, review of the response could also be deferred. When the review of a response has been deferred, it will be reviewed during the next review cycle for the application as part of the complete resubmission if the applicant references such response in the resubmission.
Deficiencies addressed in a response to an IR letter or a DR letter may appear in an action letter if the review of the response has been deferred or if concerns remain after review of the response. The action letter will include all deficiencies that must be answered in order to place the application in condition for approval.
If the applicant has already submitted what the applicant considers to constitute a complete response to all of the outstanding deficiencies, the applicant may simply refer to such responses in the complete resubmission that responds to the action letter; further reiteration of previously submitted information is not necessary. However, all such responses that are required to complete the resubmission should be clearly identified as such by the applicant in the resubmission.
Submit comments before December, 1999, to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. For questions on the content of the draft document, contact Murray Lumpkin (CDER), 301-594-5400 or Robert A. Yetter (CDER), 301-827-0373.