1. CBER Managed Review Process Sheryl A. Kochman Deputy Director, DBA, OBRR, CBER September 15, 2009

2. CBER 2 Outline Definitions Origin and Description of CBER’s Managed Review Process Milestones and Policy Steps and Timeline in Managed Review Process Review Completion

3. CBER 3 Definitions STN – Submission Tracking Number Milestone – Significant step in the review process with a specific goal date Filing Action – Determination if submission is complete Action Due Date – Date a final action should be reached Final Action – An action that stops the review clock – Complete response letter (CR) – Approval letter – Denial letter Action letter – A letter related to a submission that stops the review clock Resubmission – Applicant’s response to a CR letter BLS – Biologics License Supplement Review Cycle – The time from receipt of submission to a final action

4. CBER 4 Origin of CBER's Managed Review Process (MRP) A system that was put into place to meet the performance measures and backlog goals mandated in the Prescription Drug User Fee Act (PDUFA) of 1992 PDUFA enabled FDA to collect fees from regulated industry to provide additional review resources for review of drug submissions* so that the performance measures and goals could be met * While blood and blood components are defined as drugs, their review is not supported by drug user fees

5. CBER 5 Origin of CBER’s MRP (2) Described in detail in: “A Primer on CBER’s Regulatory Review Structure and Process,” Suzanne M. Sensabaugh*, in Drug Information Journal, Vol. 32, pp 1011-1030, 1998 * Ms. Sensabaugh worked in the Office of the Center Director of CBER at the time this was written and published

6. CBER 6 Description of CBER’s Managed Review Process Initially designed to manage the review of submissions for prescription drugs/biologics Later enhanced to include all regulatory submission types Modified as necessary to meet goals agreed to under MDUFMA* and PDUFA re-negotiations. The process establishes timeframes for specific review events so that managers can obtain current status of application review and to ensure that goals are met * Medical Device User Fee and Modernization Act – enabled FDA to collect fees from regulated industry to provide additional resources for review of medical device submissions so that the performance measures and goals could be met

7. CBER 7 Description of CBER’s MRP (2) The process incorporates: Milestones to ensure comprehensive and timely review Reviewer and supervisor accountability Timely final actions Quality Assurance

8. CBER 8 It is CBER policy that: All priority and standard license applications or supplements subject to PDUFA performance goals will be reviewed within established timeframes Non-PDUFA products will be reviewed under CBER’s Managed Review Process adhering to the performance goal timeframes as resources permit Blood and plasma submissions are voluntarily held to the review goals from PDUFA II even though reviews are not supported by user fees

9. CBER 9 General Review Process Use the first half of the review cycle to identify key hurdles to approval Use second half of review cycle to work interactively with the applicant to address and resolve perceived deficiencies – Interactive does not mean informal – All interactions must be documented Attempt to approve submission before or at review cycle endpoint Goal is a single cycle approval

10. CBER 10 General Review Process (2) In cases where single cycle approval is not achievable, CBER may issue a Complete Response (CR) letter – 21 CFR 601.3(a) All information submitted by the applicant has been reviewed but deficiencies remain at the end of the cycle CR letter: – Lists all remaining deficiencies – Recommends actions the applicant may take – Stops the review clock

11. CBER 11 General Review Process (3) When the applicant responds to the CR letter, the review clock is restarted and the second cycle begins – Review clock restarts only when the response(s) address all issues in the CR letter

12. CBER 12 21 CFR 601.3(c)(1) FDA may consider a biologics license applicant or supplement applicant's failure to either resubmit or withdraw the application or supplement within 1 year after issuance of a complete response letter to be a request by the applicant to withdraw the application or supplement – Unless the applicant has requested an extension of time in which to resubmit the application or supplement. FDA will grant any reasonable request for such an extension – FDA may consider an applicant's failure to resubmit the application or supplement within the extended time period or request an additional extension to be a request by the applicant to withdraw the application

13. CBER 13 21 CFR 601.3(c)(2) If FDA considers an applicant's failure to take action in accordance with paragraph (c)(1) of this section to be a request to withdraw the application, the agency will notify the applicant in writing The applicant will have 30 days from the date of the notification to explain why the application or supplement should not be withdrawn and to request an extension of time in which to resubmit the application or supplement – FDA will grant any reasonable request for an extension If the applicant does not respond to the notification within 30 days, the application or supplement will be deemed to be withdrawn

14. CBER 14 Specific Steps in the MRP Arrival in CBER’s Document Control Center (DCC) Logging into submission tracking database – Login number assigned – Receipt date noted – Barcode(s) applied – Minimal submission info recorded DCC sorts and delivers to product review office Product office staff logs receipt in submission tracking database Routes submission to designated reviewer/CSO Submission logged into regulatory database, STN assigned, and key submission info recorded

15. CBER 15 Specific Steps in the MRP (2) Review clock starts based on CBER receipt date Review schedule (target dates & milestones) generated by system Review for submission completeness, i.e., filing review and document findings If a supplement, review for correct reporting category under 21 CFR 601.12 and document findings STN assignment and filing letter created and issued Review submission and document findings Discuss deficiencies with applicant and request additional information

16. CBER 16 Specific Steps in the MRP (3) Log additional information as amendment Review amendment and document findings Discuss deficiencies with the applicant and request additional information Continue process until reviewer has all information necessary to complete submission Approval is not guaranteed

17. CBER 17 Approval For a BLA – the establishment(s) and the product meet the applicable requirements established in the CFR – 21 CFR 601.4(a) For a BLS – the applicant has shown the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product as they relate to safety or effectiveness of the product. – 21 CFR 601.12(a)(2)

18. CBER 18 Denial 21 CFR 601.4(b) If the Commissioner determines that the establishment or product does not meet the requirements established in this chapter, the biologics license application shall be denied The applicant shall be informed of the grounds for the decision The applicant shall be informed of the opportunity for a hearing on the matter pursuant to 21 CFR 12.21(b)

19. CBER 19 Specific Steps in the MRP (4) In cases where inspection is required, all inspection-related info is included in the file If a 483 was issued, the applicant should address the items on the 483 in writing to CBER Response to 483 is reviewed and documented Deficiencies discussed with applicant and additional response requested Repeat until all 483 issues have been resolved

20. CBER 20 Specific Steps in the MRP Review Completion Reviewer request compliance status check OCBQ performs check and send results to reviewer If compliance status not OK, CR letter issued listing all reasons submission cannot be approved yet If compliance status OK, reviewer assures all documentation, both FDA and applicant, is OK

21. CBER 21 Specific Steps in the MRP Review Completion (2) Generates approval letter Submission is QC’d Submission is routed for concurrence and sign off by supervisors and management Approval letter issued after sign off by approval authority