CBER Managed Review Process Sheryl A. Kochman Deputy Director,
DBA, OBRR, CBER September 15, 2009
Slide 2
CBER 2 Outline Definitions Origin and Description of CBERs
Managed Review Process Milestones and Policy Steps and Timeline in
Managed Review Process Review Completion
Slide 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 Applicants response to a
CR letter BLS Biologics License Supplement Review Cycle The time
from receipt of submission to a final action
Slide 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
Slide 5
CBER 5 Origin of CBERs MRP (2) Described in detail in: A Primer
on CBERs 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
Slide 6
CBER 6 Description of CBERs 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
Slide 7
CBER 7 Description of CBERs MRP (2) The process incorporates:
Milestones to ensure comprehensive and timely review Reviewer and
supervisor accountability Timely final actions Quality
Assurance
Slide 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 CBERs 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 14
CBER 14 Specific Steps in the MRP Arrival in CBERs 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
Slide 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
Slide 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
Slide 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)
Slide 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)
Slide 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
Slide 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
Slide 21
CBER 21 Specific Steps in the MRP Review Completion (2)
Generates approval letter Submission is QCd Submission is routed
for concurrence and sign off by supervisors and management Approval
letter issued after sign off by approval authority