[Congressional Record Volume 158, Number 165 (Thursday, December 20, 2012)]
[Senate]
[Pages S8277-S8295]
From the Congressional Record Online through the Government Publishing Office [www.gpo.gov]
LETTERS FROM THE SECRETARY OF HEALTH AND HUMAN SERVICES RE: MEDICAL
DEVICE USER FEE PROGRAM
=========================== NOTE ===========================
On page S8277, December 20, 2012, the Record reads: Mr.
HARKIN. Mr. President, I ask . . .
The online Record has been corrected to read: LETTERS FROM THE
SECRETARY OF HEALTH AND HUMAN SERVICES RE: MEDICAL DEVICE USER FEE
PROGRAM Mr. HARKIN. Mr. President, I ask . . .
========================= END NOTE =========================
Mr. HARKIN. Mr. President, I ask unanimous consent that, pursuant to
Public Law 112-144, the Food and Drug Administration Safety and
Innovation Act, the following letters from the Secretary of Health and
Human Services to the Chairman of the Committee on Health, Education,
Labor, and Pensions of the Senate and the Chairman of the Committee on
Energy and Commerce of the House of Representatives be printed into the
Record.
There being no objection, the material was ordered to be printed in
the Record, as follows:
MDUFA Performance Goals and Procedures
The performance goals and procedures agreed to by the
Center for Devices and Radiological Health (CDRH) and the
Center for Biologics Evaluation and Research (CBER) of the
United States Food and Drug Administration (``FDA'' or ``the
Agency'') for the medical device user fee program in the
Medical Device User Fee Amendments of 2012, are summarized
below.
FDA and the industry are committed to protecting and
promoting public health by providing timely access to safe
and effective medical devices. Nothing in this letter
precludes the Agency from protecting the public health by
exercising its authority to provide a reasonable assurance of
the safety and effectiveness of medical devices. Both FDA and
the industry are committed to the spirit and intent of the
goals described in this letter.
I. Process Improvements
A. Pre-Submissions
FDA will institute a structured process for managing Pre-
Submissions. Pre-Submissions subject to this process are
defined in Section VIII, Definitions and Explanations of
Terms. The Agency will continue to improve the Pre-Submission
process as resources permit, but not to the detriment of
meeting the quantitative review timelines and statutory
obligations. FDA will issue a draft guidance document and
final guidance document on Pre-Submissions.
Upon receipt of a Pre-Submission that requests feedback
through a meeting or teleconference, FDA intends to schedule
the meeting or teleconference to occur within a timely
manner. In the Pre-Submission, the applicant will provide at
least three suggested dates and times when the applicant is
available to meet.
It is FDA's intent that within 14 calendar days of receipt
of a request for a meeting or teleconference, FDA will
determine if the request meets the definition of a Pre-
Submission, and will inform the applicant if it does not meet
the definition. FDA will also determine if the request
necessitates more than one meeting or teleconference. A
determination that the request does not meet the definition
of a Pre-Submission will require the concurrence of the
branch chief and the reason for this determination will be
provided to the applicant. If the request meets the
definition of a Pre-Submission, FDA and the applicant will
set a mutually agreeable time and date for the meeting.
At least 3 business days prior to the meeting, FDA will
provide initial feedback to the applicant by email, which
will include: written responses to the applicant's questions;
FDA's suggestions for additional topics for the meeting or
teleconference, if applicable; or, a combination of both. If
all of the applicant's questions are addressed through
written responses, to the applicant's satisfaction, FDA and
the applicant can agree that a meeting or teleconference is
no longer necessary and the written responses provided by
email will be considered the final written feedback to the
Pre-Submission.
Meetings and teleconferences related to Pre-Submission will
generally be limited to 1 hour. A longer meeting or
teleconference time can be scheduled by mutual agreement by
the applicant and FDA.
Applicants will be responsible for developing draft minutes
for a Pre-Submission meeting or teleconference, and provide
the draft minutes via email to FDA within 15 calendar days of
the meeting. The minutes will summarize the meeting
discussions and include agreements and any action items. FDA
will provide any edits to the draft minutes to the applicant
via email within a timely manner. These minutes will become
final 15 calendar days after the applicant receives FDA's
edits, unless the applicant indicates that there is a
disagreement with how a significant issue or action item has
been documented. In this case, within a timely manner, the
applicant and FDA will conduct a teleconference to discuss
that issue with FDA. At the conclusion of that
teleconference, within a timely manner FDA will finalize the
minutes either to reflect the resolution of the issue or note
that this issue remains a point of disagreement.
FDA intends that feedback the Agency provides in a Pre-
Submission will not change, provided that the information
submitted in a future investigational device exemption (IDE)
or marketing application is consistent with that provided in
the Pre-Submission and that the data in the future submission
do not raise any important new issues materially affecting
safety or effectiveness. Modifications to FDA's feedback will
be limited to situations in which FDA concludes that the
feedback does not adequately address important new issues
materially relevant to a determination of safety or
effectiveness. Such a determination will be supported by the
appropriate management concurrence consistent with applicable
guidance and SOPs.
B. Submission Acceptance Criteria
To facilitate a more efficient and timely review process,
FDA will implement revised submission acceptance criteria.
The Agency will publish guidance outlining electronic copy of
submissions (e-Copy) and objective criteria for revised
``refuse to accept/refuse to file'' checklists. FDA will
publish draft and final guidance prior to implementation.
C. Interactive Review
The Agency will continue to incorporate an interactive
review process to provide for, and encourage, informal
communication between FDA and applicants to facilitate timely
completion of the review process based on accurate and
complete information. Interactive review entails
responsibilities for both FDA and applicants. As described in
the guidance document, Interactive Review for Medical Device
Submissions: 510(k)s, Original [Premarket Approvals] PMAs,
PMA Supplements, Original BLAs, and BLA Supplements, both FDA
and industry believe that an interactive review process for
these types of premarket medical device submissions should
help facilitate timely completion of the review based on
accurate and complete information. Interactive review is
intended to facilitate the efficient and timely review and
evaluation by FDA of premarket submissions. The interactive
review process contemplates increased informal interaction
between FDA and applicants, including the exchange of
scientific and regulatory information.
D. Guidance Document Development
FDA will apply user fee revenues to supplement the
improvement of the process of developing, reviewing,
tracking, issuing, and updating guidance documents. The
Agency will continue to develop guidance documents and
improve the Guidance Development process as resources permit,
but not to the detriment of meeting the quantitative review
timelines and statutory obligations.
FDA will update its website in a timely manner to reflect
the following:
1. The Agency's review of previously published device
guidance documents, including the deletion of guidance
documents that no longer represent the Agency's
interpretation of, or policy on, a regulatory issue, and
notation of guidance documents that are under review by the
Agency;
2. A list of prioritized device guidance documents (an ``A-
list'') that the Agency intends to publish within 12 months
of the date this list is published each fiscal year; and
3. A list of device guidance documents (a ``B-list'') that
the Agency intends to publish, as the Agency's guidance-
development resources permit each fiscal year.
The Agency will establish a process allowing stakeholders
an opportunity to:
1. Provide meaningful comments and/or propose draft
language for proposed guidance topics in the ``A'' and ``B''
lists.
[[Page S8278]]
2. Provide suggestions for new or different guidance
documents; and
3. Comment on the relative priority of topics for guidance.
E. Third Party Review
The Agency will continue to support the third party review
program and agrees to work with interested parties to
strengthen and improve the current program while also
establishing new procedures to improve transparency. The
Agency will continue to improve the third party review
program as resources permit, but not to the detriment of
meeting the quantitative review timelines and statutory
obligations.
F. Patient Safety and Risk Tolerance
FDA will fully implement final guidance on the factors to
consider when making benefit-risk determinations in medical
device premarket review. This guidance will focus on factors
to consider in the premarket review process, including
patient tolerance for risk, magnitude of the benefit, and the
availability of other treatments or diagnostic tests.
Over the period of MDUFA III, FDA will meet with patient
groups to better understand and characterize the patient
perspective on disease severity or unmet medical need.
In addition, FDA will increase its utilization of FDA's
Patient Representatives as Special Government Employee
consultants to CDRH to provide patients' views early in the
medical product development process and ensure those
perspectives are considered in regulatory discussions.
Applicable procedures governing conflicts of interest and
confidentiality of proprietary information will be utilized
for these consultations.
G. Low Risk Medical Device Exemptions
By the end of FY 2013, FDA will propose additional low risk
medical devices to exempt from premarket notification. Within
two years of such proposal, FDA intends to issue a final rule
exempting additional low risk medical devices from premarket
notification.
H. Emerging Diagnostics
FDA will work with industry to develop a transitional In
Vitro Diagnostics (IVD) approach for the regulation of
emerging diagnostics.
II. Review Performance Goals--Fiscal Years 2013 Through 2017 As Applied
to Receipt Cohorts
The overall objective of the review performance goals
stated herein is to assure more timely access to safe and
effective medical devices.
A. Original Premarket Approval (PMA), Panel-Track
Supplements, and Premarket Report Applications
The performance goals in this section apply to all Original
Premarket Approval, Panel-Track Supplements, and Premarket
Report Applications, including those that are accepted for
priority review (previously referred to as expedited).
FDA will communicate with the applicant regarding whether
the application has been accepted for filing review within 15
calendar days of receipt of the application. This
communication consists of a fax, email, or other written
communication that (a) identifies the reviewer assigned to
the submission, and (b) acknowledges acceptance/rejection of
the submission based upon the review of the submission
against objective acceptance criteria outlined in a published
guidance document.
If the application is not accepted for filing review, FDA
will notify the applicant of those items necessary for the
application to be considered accepted for filing review.
For those applications that are accepted for filing review,
FDA will communicate the filing status within 45 calendar
days of receipt of the application.
For those applications that are not filed, FDA will
communicate to the applicant the specific reasons for
rejection and the information necessary for filing.
If the application is filed, FDA will communicate with the
applicant through a Substantive Interaction within 90
calendar days of the filing date of the application for: 65%
of submissions received in FY 2013; 75% of submissions
received in FY 2014; 85% of submissions received in FY 2015;
and 95% of submissions received in FY 2016 through FY 2017.
When FDA issues a major deficiency letter, that letter will
be based upon a complete review of the application and will
include all deficiencies. Any subsequent deficiencies will be
limited to issues raised by the information provided by the
applicant in its response, unless FDA concludes that the
initial deficiencies identified do not adequately address
important new issues materially relevant to a determination
of safety or effectiveness. Such a determination will be
supported by the appropriate management concurrence
consistent with applicable guidance and SOPs. Issues related
to post-approval studies, if applicable, and revisions to
draft labeling will typically be addressed through
interactive review once major deficiencies have been
adequately addressed.
For submissions that do not require Advisory Committee
input, FDA will issue a MDUFA decision within 180 FDA Days
for: 70% of submissions received in FY 2013; 80% of
submissions received in FY 2014 and FY 2015; and 90% of
submissions received in FY 2016 and FY 2017.
For submissions that require Advisory Committee input, FDA
will issue a MDUFA decision within 320 FDA Days for: 50% of
submissions received in FY 2013; 70% of submissions received
in FY 2014; 80% of submissions received in FY 2015 and FY
2016; and 90% of submissions received in FY 2017.
If in any one fiscal year, the number of submissions that
require Advisory Committee input is less than 10, then it is
acceptable to combine such submissions with the submissions
for the following year(s) in order to form a cohort of 10 or
more submissions, upon which the combined years' submissions
will be subject to the performance goal for the fiscal year
in question. If the number of submissions that require
Advisory Committee input is less than 10 for FY 2017, it is
acceptable to combine such submissions with the submissions
in the prior year in order to form a cohort of 10 or more
submissions; in such cases, FDA will be held to the FY 2017
performance goal for the combined years' submissions.
To facilitate an efficient review prior to the Substantive
Interaction, and to incentivize submission of a complete
application, submission of an unsolicited major amendment
prior to the Substantive Interaction extends the FDA Day
review clock by the number of FDA Days that have elapsed.
Submission of an unsolicited major amendment after the
Substantive Interaction extends the FDA Day goal by the
number of FDA Days equal to 75% of the difference between the
filing date and the date of receipt of the amendment.
For all PMA submissions that do not reach a MDUFA decision
by 20 days after the applicable FDA Day goal, FDA will
provide written feedback to the applicant to be discussed in
a meeting or teleconference, including all outstanding issues
with the application preventing FDA from reaching a decision.
The information provided will reflect appropriate management
input and approval, and will include action items for FDA
and/or the applicant, as appropriate, with an estimated date
of completion for each party to complete their respective
tasks. Issues should be resolved through interactive review.
If all of the outstanding issues are adequately presented
through written correspondence, FDA and the applicant can
agree that a meeting or teleconference is not necessary.
In addition, information about submissions that miss the
FDA Day goal will be provided as part of FDA's Performance
Reports, as described in Section VI.
B. 180-Day PMA Supplements
FDA will communicate with the applicant through a
Substantive Interaction within 90 calendar days of receipt of
the submission for: 65% of submissions received in FY 2013;
75% of submissions received in FY 2014; 85% of submissions
received in FY 2015; and 95% of submissions received in FY
2016 through FY 2017.
FDA will issue a MDUFA decision within 180 FDA Days for:
85% of submissions received in FY 2013; 90% of submissions
received in FY 2014 and FY 2015; and 95% of submissions
received in FY 2016 through FY 2017.
C. Real-Time PMA Supplements
FDA will issue a MDUFA decision within 90 FDA Days for: 90%
of submissions received in FY 2013 and FY 2014; and 95% of
submissions received in FY 2015 through FY 2017.
D. 510(k) Submissions
FDA will communicate with the applicant regarding whether
the submission has been accepted for review within 15
calendar days of receipt of the submission. For those
submissions that are not accepted for review, FDA will notify
the applicant of those items necessary for the submission to
be considered accepted.
This communication includes a fax, email, or other written
communication that a) identifies the reviewer assigned to the
submission, and b) acknowledges acceptance/rejection of the
submission based upon the review of the submission against
objective acceptance criteria outlined in a published
guidance document. This communication represents a
preliminary review of the submission and is not indicative of
deficiencies that may be identified later in the review
cycle.
FDA will communicate with the applicant through a
Substantive Interaction within 60 calendar days of receipt of
the submission for: 65% of submissions received in FY 2013;
75% of submissions received in FY 2014; 85% of submissions
received in FY 2015; and 95% of submissions received in FY
2016 through FY 2017.
Deficiencies identified in a Substantive Interaction, such
as a telephone/email hold or Additional Information Letter,
will be based upon a complete review of the submission and
will include all deficiencies. Any subsequent deficiencies
will be limited to issues raised by the information provided
by the applicant in its response, unless FDA concludes that
the initial deficiencies identified do not adequately address
important new issues materially relevant to a determination
of substantial equivalence. Such a determination will be
supported by the appropriate management concurrence
consistent with applicable guidance and SOPs.
For submissions received in FY 2013, FDA will issue a MDUFA
decision for 91% of 510(k) submissions within 90 FDA Days.
For submissions received in FY 2014, FDA will issue a MDUFA
decision for 93% of 510(k) submissions within 90 FDA Days.
For submissions received in FY 2015 through FY 2017, FDA
will issue a MDUFA decision for 95% of 510(k) submissions
within 90 FDA Days.
For all 510(k) submissions that do not reach a MDUFA
decision within 100 FDA
[[Page S8279]]
Days, FDA will provide written feedback to the applicant to
be discussed in a meeting or teleconference, including all
outstanding issues with the application preventing FDA from
reaching a decision. The information provided will reflect
appropriate management input and approval, and will include
action items for FDA and/or the applicant, as appropriate,
with an estimated date of completion for each party to
complete their respective tasks. Issues should be resolved
through interactive review. If all of the outstanding issues
are adequately presented through written correspondence, FDA
and the applicant can agree that a meeting or teleconference
is not necessary.
In addition, information about submissions that miss the
FDA Day goal will be provided as part of FDA's Performance
Reports, as described in Section VI.
E. Clinical Laboratory Improvement Amendments (CLIA) Waiver
by Application
FDA will engage in a Substantive Interaction with the
applicant within 90 days for 95% of the applications.
During the pre-submission process, if the applicant informs
FDA that it plans to submit a dual submission (510(k) and
CLIA Waiver application), FDA will issue a decision for 90%
of such applications within 210 FDA days.
For ``CLIA Waiver by application'' submissions FDA will
issue a MDUFA decision for 95% of the applications that do
not require Advisory Committee input within 180 FDA days.
For ``CLIA Waiver by application'' submissions FDA will
issue a MDUFA decision for 95% of the applications that
require Advisory Committee input within 330 FDA days.
To provide greater transparency, FDA will issue guidance
regarding review and management expectations throughout the
entire submission process.
F. Original Biologics Licensing Applications (BLAs)
FDA will review and act on standard original BLA
submissions within 10 months of receipt for 90% of
submissions.
FDA will review and act on priority original BLA
submissions within 6 months of receipt for 90% of
submissions.
G. BLA Efficacy Supplements
FDA will review and act on standard BLA efficacy supplement
submissions within 10 months of receipt for 90% of
submissions.
FDA will review and act on priority BLA efficacy supplement
submissions within 6 months of receipt for 90% of
submissions.
H. Original BLA and BLA Efficacy Supplement Resubmissions
FDA will review and act on Class 1 original BLA and BLA
efficacy supplement resubmissions within 2 months of receipt
for 90% of submissions.
FDA will review and act on Class 2 original BLA and BLA
efficacy supplement resubmissions within 6 months of receipt
for 90% of submissions.
I. BLA Manufacturing Supplements Requiring Prior Approval
FDA will review and act on BLA manufacturing supplements
requiring prior approval within 4 months of receipt for 90%
of submissions.
III. Shared Outcome Goals
The program and initiatives outlined in this document are
predicated on significant interaction between the Agency and
applicants. FDA and representatives of the medical device
industry agree that the process improvements outlined in this
letter, when implemented by all parties as intended, should
reduce the average Total Time to Decision for PMA
applications and 510(k) submissions, provided that the total
funding of the device review program adheres to the
assumptions underlying this agreement. FDA and applicants
share the responsibility for achieving this objective of
reducing the average Total Time to Decision, while
maintaining standards for safety and effectiveness. Success
of this program will require the cooperation and dedicated
efforts of FDA and applicants to reduce their respective
portions of the total time to decision.
FDA will be reporting total time performance quarterly as
described in Section VI. FDA and industry will participate in
the independent assessment of progress toward this outcome,
as described in Section V above. As appropriate, key findings
and recommendations from this assessment will be implemented
by FDA.
A. PMA
Beginning in Fiscal Year 2013, FDA will report on an annual
basis the average Total Time to Decision as defined in
Section VIII.G for the three most recent closed receipt
cohorts. For submissions received beginning in Fiscal Year
2013, the average Total Time to Decision goal for FDA and
industry is 395 calendar days. For submissions received
beginning in Fiscal Year 2015, the average Total Time to
Decision goal for FDA and industry is 390 calendar days. For
submissions received beginning in Fiscal Year 2017, the
average Total Time to Decision goal for FDA and industry is
385 calendar days.
B. 510(k)
Beginning in Fiscal Year 2013, FDA will report on an annual
basis the average Total Time to Decision as defined in
Section VIII.G for the most recent closed receipt cohort. For
submissions received beginning in Fiscal Year 2013, the
average Total Time to Decision goal for FDA and industry is
135 calendar days. For submissions received beginning in FY
2015, the average Total Time to Decision goal for FDA and
industry is 130 calendar days. For submissions received
beginning in FY 2017, the average Total Time to Decision goal
for FDA and industry is 124 calendar days.
IV. Infrastructure
A. Scientific and Regulatory Review Capacity
The Agency will apply user fee revenues to reduce the ratio
of review staff to front line supervisors in the Pre-Market
review program and to enhance and supplement scientific
review capacity by hiring device application reviewers and
leveraging external experts needed to assist with the review
of device applications.
The Agency will seek to obtain streamlined hiring authority
for all MDUFA-related positions prior to and during the MDUFA
III period.
During MDUFA III, FDA will also work with industry to
benchmark best practices for retaining employees (both
financial and non-financial).
B. Training
Prior to the commencement of MDUFA III, CDRH will implement
its Reviewer Certification Program. FDA commits to holding a
minimum of two medical device Vendor Days each year.
CDRH will apply user fee revenues to supplement the
following training programs:
1) Management training for Branch Chiefs and Division
Directors.
2) MDUFA III Training Program for all staff.
3) Reviewer Certification Program for new CDRH reviewers.
FDA will publish the curriculum of this program and other
course offerings. FDA will consider comments from
stakeholders when making updates to courses and determining
course offerings.
4) Specialized training to provide continuous learning for
all staff.
C. Tracking System
FDA will continue efforts to improve its IT systems with a
future expectation of facilitating availability of real-time
status information for submissions.
V. Independent Assessment of Review Process Management
FDA and the device industry will participate in a
comprehensive assessment of the process for the review of
device applications. The assessment will include consultation
with both FDA and industry. The assessment shall be conducted
in two phases under contract to FDA by a private, independent
consulting firm capable of performing the technical analysis,
management assessment, and program evaluation tasks required
to address the assessment scope described below. For Phase 1,
FDA will award the contract no later than the end of the
second quarter of FY13. Findings on high-priority
recommendations (i.e., those likely to have a significant
impact on review times) will be published within six months
of award; final comprehensive findings and recommendations
will be published within 1 year of contract award. FDA will
publish an implementation plan within 6 months of receipt of
each set of recommendations. For Phase 2 of the independent
assessment, the contractor will evaluate the implementation
of recommendations and publish a written assessment no later
than February 1, 2016.
The assessment will address FDA's premarket review process
using an assessment framework that draws from appropriate
quality system standards, including, but not limited to,
management responsibility, document controls and records
management, and corrective and preventive action.
The scope of the assessment will include, but not be
limited to, the following areas:
1. Identification of process improvements and best
practices for conducting predictable, efficient, and
consistent premarket reviews that meet regulatory review
standards.
2. Analysis of elements of the review process (including
the Pre-Submission process, IDE, 510(k) and PMA reviews) that
consume or save time to facilitate a more efficient process.
This includes analysis of root causes for inefficiencies that
may affect review performance and total time to decision.
This will also include recommended actions to correct any
failures to meet MDUFA goals. Analysis of the review process
will include the impact of combination products, companion
diagnostics products, and laboratory developed tests on the
review process.
3. Assessment of FDA methods and controls for collecting
and reporting information on premarket review process
resource use and performance.
4. Assessment of effectiveness of FDA's Reviewer Training
Program implementation.
5. Recommendations for ongoing periodic assessments and any
additional, more detailed or focused assessments.
FDA will incorporate findings and recommendations, as
appropriate, into its management of the premarket review
program. FDA will analyze the recommendations for improvement
opportunities identified in the assessment, develop and
implement a corrective action plan, and assure its
effectiveness. FDA also will incorporate the results of the
assessment into a Good Review Management Practices (GRMP)
guidance document. FDA's implementation of the GRMP guidance
will include initial and ongoing training of FDA staff, and
periodic audits of compliance with the guidance.
VI. Performance Reports
The Agency will report its progress toward meeting the
goals described in this letter, as
[[Page S8280]]
follows. If, throughout the course of MDUFA III, the Agency
and Industry agree that a different format or different
metrics would be more useful, the reporting will be modified
accordingly as per the agreement of both FDA and Industry.
1. Quarterly reporting at the CDRH Division level/CBER
Center level (in recognition of the significantly smaller
number of submissions reviewed at CBER):
1.1. For 510(k) submissions, reporting will include:
i. Average and quintiles of the number of calendar days to
Substantive Interaction
ii. Average, and quintiles of the number of FDA Days,
Industry Days, and Total Days to a MDUFA decision
iii. Average number of review cycles.
iv. Rate of submissions not accepted for review
1.2. For PMA submissions, reporting will include:
i. Average and quintiles of the number of calendar days to
Substantive Interaction for Original PMA, Panel-Track PMA
Supplement, and Premarket Report Submissions
ii. Average and quintiles of the of FDA Days, Industry
Days, and Total Days to a MDUFA decision
iii. Rate of applications not accepted for filing review,
and rate of applications not filed
1.3. For Pre-Submissions, reporting will include:
i. Number of all qualified Pre-Submissions received
ii. Average and quintiles of the number of calendar days
from submission to meeting or teleconference (if necessary)
iii. Number of Pre-Submissions that require a meeting
1.4. For IDE applications, reporting will include:
i. Number of original IDEs received
ii. Average number of amendments prior to approval or
conditional approval of the IDE (this information will be
provided beginning no later than the quarter that starts 10/
1/2013)
2. CDRH will report quarterly, and CBER will report
annually, the following data at the Center level:
2.1. Rate of NSE decisions for 510(k) submissions
2.2. Rate of withdrawals for 510(k) and PMA submissions
2.3. Rate of Not Approvable decisions for PMA submissions
2.4. Key product areas or other issues that FDA identifies
as noteworthy because of a potential effect on performance,
including significant rates of Additional Information
requests
2.5. Specific topic or product area as it relates to
performance goals, agreed upon at the previous meeting
2.6. Number of submissions that missed the goals and the
total number of elapsed calendar days broken down into FDA
days and industry days
2.7. Newly released draft and final guidance documents, and
status of other priority guidance documents
2.8. Agency level summary of fee collections
2.9. Independent assessment implementation plan status
2.10. Results of independent assessment and subsequent
periodic audits and progress toward implementation of the
recommendations and any corrective action
2.11. Number of discretionary fee waivers or reductions
granted by type of submission
3. In addition, the Agency will provide the following
information on an annual basis:
3.1. Qualitative and quantitative update on how funding is
being used for the device review process, including the
percentage of review time devoted to direct review of
applications
3.2. How funding is being used to enhance scientific review
capacity
3.3. The number of Premarket Report Submissions received
3.4. Summary information on training courses available to
CDRH and CBER employees, including new reviewers, regarding
device review and the percentage of applicable staff that
have successfully completed each such course. CDRH will
provide information concerning any revisions to the new
reviewer training program curriculum.
3.5. Performance on the shared outcome goal for average
Total Time to decision
3.6. For 510(k) submissions, reporting will include:
i. Number of submissions reviewed by a Third Party
ii. Number of Special Submissions
iii. Number of Traditional Submissions
iv. Average and number of days to Accept/Refuse to Accept
v. Number of Abbreviated Submissions
3.7. For PMA submissions, reporting will include the number
of the following types of PMA submissions received:
i. Original PMAs
ii. Priority PMAs
iii. Premarket Reports
iv. Panel-Track PMA Supplement
v. PMA Modules
vi. 180-Day PMA Supplements
vii. Real-Time PMA Supplements
3.8. For De Novo Classification Petitions, reporting will
include:
i. Number of submissions received
ii. Average number of calendar days to a MDUFA decision
3.9. For CLIA waiver applications, reporting will include:
i. Number of CLIA waiver applications received
ii. Average and quintiles of the number of calendar days to
Substantive Interaction
iii. Average and quintiles of the number of FDA Days,
Industry Days, and Total Days to a MDUFA decision and a
discussion of any trends in the data
VII. Discretionary Waiver
The Agency will seek authority to grant discretionary fee
waivers or reductions in the interest of public health.
Notwithstanding any fee waivers or reductions granted by the
Agency under this discretionary authority, FDA remains
committed to meeting the goals described in this letter. Any
submission subject to a fee waiver or reduction under this
discretionary authority shall not be subject to the goals
specified in this letter and shall be reviewed by the Agency
as resources permit. This discretionary authority will expire
at the end of MDUFA III.
VIII. Definitions and Explanations of Terms
A. Applicant
Applicant means a person who makes any of the following
submissions to FDA: an application for premarket approval
under section 515; a premarket notification under section
510(k); an application for investigational device exemption
under section 520(g); a Pre-Submission; a CLIA waiver
application.
B. Electronic Copy (e-Copy)
An electronic copy is an exact duplicate of a paper
submission, created and submitted on a CD, DVD, or in another
electronic media format that FDA has agreed to accept,
accompanied by a copy of the signed cover letter and the
complete original paper submission. An electronic copy is not
considered to be an electronic submission.
C. FDA Days
FDA Days are those calendar days when a submission is
considered to be under review at the Agency for submissions
that have been accepted (510(k)) or filed (PMA). FDA Days
begin on the date of receipt of the submission or of the
amendment to the submission that enables the submission to be
accepted (510(k)) or filed (PMA).
D. MDUFA Decisions
Original PMAs: Decisions for Original PMAs are Approval,
Approvable, Approvable Pending GMP Inspection, Not
Approvable, Withdrawal, and Denial.
180-Day PMA Supplements: Decisions for 180-Day PMA
Supplements include Approval, Approvable, and Not Approvable.
Real-Time PMA Supplements: Decisions for Real-Time PMA
supplements include Approval, Approvable, and not Approvable.
510(k)s: Decisions for 510(k)s are substantially equivalent
(SE) or not substantially equivalent (NSE).
Submissions placed on Application Integrity Program Hold
will be removed from the MDUFA cohort.
E. Pre-Submission
A Pre-Submission includes a formal written request from an
applicant for feedback from FDA which is provided in the form
of a formal written response or, if the manufacturer chooses,
a meeting or teleconference in which the feedback is
documented in meeting minutes. A Pre-Submission meeting is a
meeting or teleconference in which FDA provides its
substantive feedback on the Pre-Submission.
A Pre-Submission provides the opportunity for an applicant
to obtain FDA feedback prior to intended submission of an
investigational device exemption or marketing application.
The request must include specific questions regarding review
issues relevant to a planned IDE or marketing application
(e.g., questions regarding pre-clinical and clinical testing
protocols or data requirements). A Pre-Submission is
appropriate when FDA's feedback on specific questions is
necessary to guide product development and/or application
preparation.
The following forms of FDA feedback to applicants are not
considered Pre-Submissions. However, if the requested
feedback meets the criteria for a Pre-Submission, outlined
above, FDA will contact the sponsor, and with the concurrence
of the sponsor, may convert the request to a Pre-Submission.
General information requests initiated through the Division
of Small Manufacturers, International and Consumer Assistance
(DSMICA)
General questions regarding FDA policy or procedures
Meetings or teleconferences that are intended to be
informational only, including, but not limited to, those
intended to educate the review team on new device(s) with
significant differences in technology from currently
available devices, or to update FDA about ongoing or future
product development, without a request for FDA feedback on
specific questions related to a planned submission
Requests for clarification on technical guidance documents,
especially where contact is recommended by FDA in the
guidance document. However, the following requests will
generally need to be submitted as a Pre-Submission in order
to ensure appropriate input from multiple reviewers and
management: recommendations for device types not specifically
addressed in the guidance document; recommendations for
nonclinical or clinical studies not addressed in the guidance
document; requests to use an alternative means to address
recommendations specified in a guidance document.
Phone calls or email messages to reviewers that can be
readily answered based on a reviewer's experience and
knowledge and do
[[Page S8281]]
not require the involvement of a broader number of FDA staff
beyond the routine involvement of the reviewer's supervisor
and more experienced mentors.
Interactions requested by either the applicant or FDA
during the review of a marketing application (i.e., following
submission of a marketing application, but prior to reaching
an FDA Decision).
F. Substantive Interaction
Substantive Interaction is an email, letter,
teleconference, video conference, fax, or other form of
communication such as a request for Additional Information or
Major Deficiency letters by FDA notifying the applicant of
substantive deficiencies identified in initial submission
review, or a communication stating that FDA has not
identified any deficiencies in the initial submission review
and any further minor deficiencies will be communicated
through interactive review. An approval or clearance letter
issued prior to the Substantive Interaction goal date will
qualify as a Substantive Interaction.
If substantive issues warranting issuance of an Additional
Information or Major Deficiency letter are not identified,
interactive review should be used to resolve any minor issues
and facilitate an FDA decision. In addition, interactive
review will be used, where, in FDA's estimation, it leads to
a more efficient review process during the initial review
cycle (i.e., prior to a Substantive Interaction) to resolve
minor issues such as revisions to administrative items (e.g.,
510(k) Summary/Statement, Indications for Use statement,
environmental impact assessment, financial disclosure
statements); a more detailed device description; omitted
engineering drawings; revisions to labeling; or clarification
regarding nonclinical or clinical study methods or data.
Minor issues may still be included in an Additional
Information or Major Deficiency letter where related to the
resolution of the substantive issues (e.g., modification of
the proposed Indications for Use may lead to revisions in
labeling and administrative items), or if they were still
unresolved following interactive review attempts. Both
interactive review and Substantive Interactions will occur on
the review clock except upon the issuance of an Additional
Information or Major Deficiency Letter which stops the review
clock.
G. Total Time to Decision
Total Time to Decision is the number of calendar days from
the date of receipt of an accepted or filed submission to a
MDUFA decision.
The average Total Time to Decision for 510(k) submissions
is calculated as the trimmed mean of Total Times to Decision
for 510(k) submissions within a closed cohort, excluding the
highest 2% and the lowest 2% of values. A cohort is closed
when 99% of the accepted submissions have reached a decision.
The average Total Time to Decision for PMA applications is
calculated as the three-year rolling average of the annual
Total Times to Decision for applications (for example, for
FY2015, the average Total Time to Decision for PMA
applications would be the average of FY2013 through FY2015)
within a closed cohort, excluding the highest 5% and the
lowest 5% of values. A cohort is closed when 95% of the
applications have reached a decision.
H. BLA-related Definitions
Review and act on--the issuance of a complete action letter
after the complete review of a filed complete application.
The action letter, if it is not an approval, will set forth
in detail the specific deficiencies and, where appropriate,
the actions necessary to place the application in condition
for approval.
Class 1 resubmitted applications--applications resubmitted
after a complete response letter that includes the following
items only (or combinations of these items):
(a) Final printed labeling
(b) Draft labeling
(c) Safety updates submitted in the same format, including
tabulations, as the original safety submission with new data
and changes highlighted (except when large amounts of new
information including important new adverse experiences not
previously reported with the product are presented in the
resubmission)
(d) Stability updates to support provisional or final
dating periods
(e) Commitments to perform Phase 4 studies, including
proposals for such studies
(f) Assay validation data
(g) Final release testing on the last 1-2 lots used to
support approval
(h) A minor reanalysis of data previously submitted to the
application (determined by the Agency as fitting the Class 1
category)
(i) Other minor clarifying information (determined by the
Agency as fitting the Class 1 category)
(j) Other specific items may be added later as the Agency
gains experience with the scheme and will be communicated via
guidance documents to industry
Class 2 resubmitted applications--resubmissions that
include any other items, including any item that would
require presentation to an advisory committee
PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES FOR FISCAL YEARS
2013 THROUGH 2017
The performance goals and procedures of the FDA Center for
Drug Evaluation and Research (CDER) and the Center for
Biologics Evaluation and Research (CBER), as agreed to under
the fifth authorization of the prescription drug user fee
program, are summarized below.
Unless otherwise stated, goals apply to cohorts of each
fiscal year (FY).
I. REVIEW PERFORMANCE GOALS
A. NDA/BLA Submissions and Resubmissions \1\
Note: \1\ Refer to Section II.A.4 for a description of the
review program for NME NDAs and original BLAs.
1. Review and act on 90 percent of standard NME NDA and
original BLA submissions within 10 months of the 60 day
filing date.
2. Review and act on 90 percent of priority NME NDA and
original BLA submissions within 6 months of the 60 day filing
date.
3. Review and act on 90 percent of standard non-NME
original NDA submissions within 10 months of receipt.
4. Review and act on 90 percent of priority non-NME
original NDA submissions within 6 months of receipt.
5. Review and act on 90 percent of Class 1 resubmitted
original applications within 2 months of receipt.
6. Review and act on 90 percent of Class 2 resubmitted
original applications within 6 months of receipt.
B. Original Efficacy Supplements
1. Review and act on 90 percent of standard efficacy
supplements within 10 months of receipt.
2. Review and act on 90 percent of priority efficacy
supplement within 6 months of receipt.
C. Resubmitted Efficacy Supplements
1. Review and act on 90 percent of Class 1 resubmitted
efficacy supplements within 2 months of receipt.
2. Review and act on 90 percent of Class 2 resubmitted
efficacy supplements within 6 months of receipt.
D. Original Manufacturing Supplements
1. Review and act on 90 percent of manufacturing
supplements requiring prior approval within 4 months of
receipt, and review and act on 90 percent of all other
manufacturing supplements within 6 months of receipt.
E. These review goals are summarized in the following tables:
ORIGINAL AND RESUBMITTED APPLICATIONS AND SUPPLEMENTS
------------------------------------------------------------------------
Submission cohort Standard Priority
------------------------------------------------------------------------
NME NDAs and original BLAs...... 90% in 10 months 90% in 6 months of
of the 60 day the 60 day filing
filing date. date
Non NME NDAs.................... 90% in 10 months 90% in 6 months of
of the receipt the receipt date
date.
Class 1 Resubmissions........... 90% in 2 months of 90% in 2 months of
the receipt date. the receipt date
Class 2 Resubmissions........... 90% in 6 months of 90% in 6 months of
the receipt date. the receipt date
Original Efficacy Supplements... 90% in 10 months 90% in 6 months of
of the receipt the receipt date
date.
Class 1 Resubmitted Efficacy 90% in 2 months of 90% in 2 months of
Supplements. the receipt date. the receipt date
Class 2 Resubmitted Efficacy 90% in 6 months of 90% in 6 months of
Supplements. the receipt date. the receipt date
------------------------------------------------------------------------
------------------------------------------------------------------------
Prior approval All other
------------------------------------------------------------------------
Manufacturing Supplements....... 90% in 4 months of 90% in 6 months of
the receipt date. the receipt date
------------------------------------------------------------------------
II. NEW MOLECULAR ENTITY NDA AND ORIGINAL BLA PERFORMANCE GOALS
A. Program for Enhanced Review Transparency and Communication
for NME NDAs and Original BLAs
To promote greater transparency and improve communication
between the FDA review team and the applicant, FDA will
establish a review model (hereafter referred to as ``the
Program'') that will apply to all New Molecular Entity New
Drug Applications (NME NDAs) and original Biologics License
Applications (BLAs), including applications that are
resubmitted following a Refuse-to-File action, received from
October 1, 2012, through September 30, 2017.\2\ The goal of
the Program is to improve the efficiency and effectiveness of
the first cycle review process and decrease the number of
review cycles necessary for approval, ensuring that patients
have timely access to safe, effective, and high quality new
drugs and biologics. The Program shall be evaluated by an
independent contractor with expertise in assessing the
quality and efficiency of biopharmaceutical development and
regulatory review programs. The parameters of the Program are
as follows:
Note: \2\ The decision as to whether the application is
included or excluded from the Program is distinct from FDA's
determination as to whether the drug product contains a ``new
chemical entity,'' as defined under 21 CFR 314.108(a).
Determinations regarding
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new chemical entity exclusivity are made at the time of
approval of an application.
1. Pre-submission meeting: The applicant is strongly
encouraged to discuss the planned content of the application
with the appropriate FDA review division at a pre-NDA/BLA
meeting
a) The pre-NDA/BLA 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 2 months prior to the planned submission
of the application.
b) 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 risk evaluation and mitigation strategies (REMS)
or other risk management actions. This meeting will be
attended by the FDA review team including appropriate senior
FDA staff. The agreement and discussions will be summarized
at the conclusion of the meeting and reflected in the FDA
meeting minutes.
c) At the meeting, the FDA and the applicant may also 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 submissions
must be of a type that would not be expected to materially
impact the ability of the review team to begin its review.
Any such 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.
(1) 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.
d) 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 expected to be
submitted with the original application and are not subject
to agreement for late submission.
2. Original application submission: Applications are
expected to be complete, as agreed between the FDA review
team and the applicant at the pre-NDA/BLA meeting, at the
time of original submission of the application. If the
applicant does not have a pre-NDA/BLA meeting with FDA, and
no agreement exists between FDA and the applicant on the
contents of a complete application or delayed submission of
certain components of the application, the applicant's
submission is expected to be complete at the time of original
submission.
a) All applications are expected to include a comprehensive
and readily located list of all clinical sites and
manufacturing facilities included or referenced in the
application.
b) Any components of the application that FDA agreed at the
pre-submission meeting could be submitted after the original
application are expected to be received not later than 30
calendar days after receipt of the original application.
c) Incomplete applications, including applications with
components that are not received within 30 calendar days
after receipt of the original submission, will be subject to
a Refuse-to-File decision.
(1) Applications that are subject to a Refuse-to-File
action, and are subsequently filed over protest, will not be
subject to the procedures of the Program, but will instead be
subject to the 6 and 10 month review performance goals for
priority and standard applications, respectively, as
described in Section I.
d) Since applications are expected to be complete at the
time of submission, unsolicited amendments are expected to be
rare and not to contain major new information or analyses.
(1) Review of unsolicited amendments, including those
submitted in response to an FDA communication of
deficiencies, will be handled in accordance with the guidance
``Good Review Management Principles and Practices (GRMPs) for
PDUFA Products.'' This guidance includes the underlying
principle that FDA will consider the most efficient path
toward completion of a comprehensive review that addresses
application deficiencies and leads toward a first cycle
approval when possible.
3. Day 74 Letter: FDA will follow existing procedures and
performance goals (see Section III) regarding identification
and communication of filing review issues in the ``Day 74
letter.'' For applications subject to the Program, the
timeline for this communication will be within 74 calendar
days from the date of FDA receipt of the original submission.
The planned review timeline included in the Day 74 letter for
applications in the Program will include the planned date for
the internal mid-cycle review meeting. The letter will also
include preliminary plans on whether to hold an Advisory
Committee (AC) meeting to discuss the application.
4. Review performance goals: For NME NDA and original BLA
submissions that are filed by FDA under the Program, the
PDUFA review clock will begin at the conclusion of the 60
calendar day filing review period that begins on the date of
FDA receipt of the original submission. The review
performance goals for these applications are as follows:
a) Review and act on 90 percent of standard NME NDA and
original BLA submissions within 10 months of the 60 day
filing date.
b) Review and act on 90 percent of priority NME NDA and
original BLA submissions within 6 months of the 60 day filing
date.
5. Mid-Cycle communication: The FDA Regulatory Project
Manager (RPM), and other appropriate members of the FDA
review team (e.g., Cross Discipline Team Leader (CDTL)), will
call the applicant, generally within 2 weeks following the
Agency's internal mid-cycle review meeting, to provide the
applicant with an update on the status of the review of their
application. Scheduling of the internal mid-cycle review
meeting will be handled in accordance with the GRMP guidance.
The RPM will coordinate the specific date and time of the
telephone call with the applicant
a) The update should include any significant issues
identified by the review team to date, any information
requests, information regarding major safety concerns and
preliminary review team thinking regarding risk management,
proposed date(s) for the late-cycle meeting, updates
regarding plans for the AC meeting (if an AC meeting is
anticipated), and other projected milestones dates for the
remainder of the review cycle.
6. Discipline Review (DR) Letters: The FDA review team will
follow existing guidance on issuance of DR Letters.
a) Since the application is expected to be complete at time
of submission, FDA intends to complete primary and secondary
discipline reviews of the application and issue DR letters in
advance of the planned late-cycle meeting. In cases where a
DR letter is not issued in advance of the planned late-cycle
meeting, substantive issues identified to date from that
discipline will be communicated in the brief memorandum
described in 7(b)(1).
7. Late-Cycle meeting: For all applications included in the
review Program, a meeting will be held between the FDA review
team and the applicant to discuss the status of the review of
the application late in the review cycle.
a) FDA representatives at the late-cycle meeting are
expected to include the signatory authority for the
application, review team members from appropriate
disciplines, and appropriate team leaders and/or supervisors
from disciplines for which substantive issues have been
identified in the review to date.
b) For applications that will be discussed at an Advisory
Committee (AC) meeting, the late-cycle meeting will occur not
less than 12 calendar days before the date of the AC meeting.
FDA intends to convene AC meetings no later than 3 months
(standard review) or no later than 2 months (priority review)
prior to the PDUFA goal date.
(1) The Agency briefing package for the late-cycle meeting
will consist of the Agency's background package for the AC
meeting, which will be sent to the applicant not less than 20
calendar days before the AC meeting, any discipline review
letters issued to date, current assessment of the need for
REMS or other risk management actions, and a brief memorandum
from the review team outlining substantive application issues
including potential questions and/or points for discussion
for the AC meeting. FDA intends to provide final questions
for the AC to the sponsor and the AC 2 calendar days in
advance of the AC meeting.
c) For applications that will not be discussed at an AC
meeting, the late-cycle meeting will generally occur not
later than 3 months (standard review) or two months (priority
review) prior to the PDUFA goal date.
(1) The Agency background package for the late-cycle
meeting, which will be sent to the applicant not less than 12
calendar days before the meeting, will consist of any
discipline review letters issued to date, current assessment
of the need for REMS or other risk management actions, and a
brief memorandum from the review team outlining substantive
application issues.
d) Potential topics for discussion at the late-cycle
meeting include major deficiencies identified to date; issues
to be discussed at the AC meeting (if planned); current
assessment of the need for REMS or other risk management
actions; information requests from the review team to the
applicant; and additional data or analyses the applicant may
wish to submit.
(1) With regard to submission of additional data or
analyses, the FDA review team and the applicant will discuss
whether such data will be reviewed by the Agency in the
current review cycle and, if so, whether the submission will
be considered a major amendment and trigger an extension of
the PDUFA goal date.
8. Inspections: FDA's goal is to complete all GCP, GLP, and
GMP inspections for applications in the Program within 6
months of the date of original receipt for priority
applications and within 10 months of the date of original
receipt for standard applications. This will allow 2 months
at the end of the review cycle to attempt to address any
deficiencies identified by the inspections.
9. Quality System: As part of a quality system approach to
managing review in the Program, FDA will implement a tracking
system that will document review team performance of the key
milestones for each of the applications reviewed under the
Program.
a) These milestones include: conduct of pre-NDA/BLA meeting
and agreement on content of complete application; submission
[[Page S8283]]
of any components of the application within 30 calendar days
of original application submission (as per pre-NDA/BLA
meeting agreement); issuance of the 74-day letter; completion
of mid-cycle communication with sponsor; completion of
primary and secondary reviews; DR letters issued; exchange of
late cycle meeting package; and conduct of late-cycle
meeting.
b) The process tracking information will support review
management, and inform the subsequent analysis to be
conducted by an independent third party (see below). The
performance information generated by the tracking system will
also be summarized and reported in the PDUFA annual
performance report.
B. Assessment of the Program
The Program described in Section IIA shall be evaluated by
an independent contractor with expertise in assessing the
quality and efficiency of biopharmaceutical development and
regulatory review programs. The statement of work for this
effort will be published for public comment prior to
beginning the assessment. The assessments will occur
continuously throughout the course of the Program. Metrics
for the assessments will include adherence by the applicant
and FDA to the current GRMP guidance, submission of a
complete application at the time of original submission,
number of unsolicited amendments submitted by the applicant,
timing and adequacy of Day 74 letters, mid-cycle
communications, provision of late-cycle meeting memorandum
outlining potential issues and questions for AC meeting
consideration and discipline review letters; specific
milestones of the Program as described in Section IIA; time
to approval; percentage of applications approved on the first
review cycle; and the percentage of application reviews
extended due to major amendments. Following issuance of an
FDA regulatory action at the completion of the first review
cycle, the independent contractor will assess the
completeness and thoroughness of the submitted application,
Day 74 letter, mid-cycle communication, discipline review
letters and late-cycle meeting. This assessment will include
interviews of the sponsor and members of the review team, as
appropriate.
1. Interim Assessment: An interim assessment of the Program
will be published by March 31, 2015, for public comment. By
June 30, 2015, FDA will hold a public meeting during which
public stakeholders may present their views on the success of
the Program to date including: improving the efficiency and
effectiveness of the first cycle review process; decreasing
the number of review cycles ultimately necessary for new
drugs and biologics that are approved; and helping to ensure
that patients have timely access to safe, effective, and high
quality new drugs and biologics. During the public meeting,
FDA will discuss the findings of the interim assessment,
including anonymized aggregated feedback from sponsors and
FDA review teams resulting from independent contractor
interviews. FDA will also address any issues identified to
date including actions proposed to improve likelihood of
success for the program.
2. Final Assessment: A final assessment of the Program will
be published by December 31, 2016, for public comment. FDA
will hold a public meeting by no later than March 30, 2017,
during which public stakeholders may present their views on
the success of the Program, including improving the
efficiency and effectiveness of the first cycle review
process and decreasing the number of review cycles ultimately
necessary for new drugs and biologics that are approved.
During the public meeting, FDA will discuss the findings of
the final assessment, including anonymized aggregated
feedback from sponsors and FDA review teams resulting from
independent contractor interviews and discuss any issues
identified and plans for addressing these issues.
III. FIRST CYCLE REVIEW PERFORMANCE
A. Notification of Issues Identified during the Filing Review
1. Performance Goal: For original NDA/BLA applications and
efficacy supplements, FDA will report substantive review
issues identified during the initial filing review to the
applicant by letter, teleconference, facsimile, secure e-
mail, or other expedient means.
2. The timeline for such communication will be within 74
calendar days from the date of FDA receipt of the original
submission.
3. If no substantive review issues were identified during
the filing review, FDA will so notify the applicant.
4. FDA's filing review represents a preliminary review of
the application and is not indicative of deficiencies that
may be identified later in the review cycle.
5. FDA will notify the applicant of substantive review
issues prior to the goal date for 90% of applications.
B. Notification of Planned Review Timelines
1. Performance Goal: For original NDA/BLA applications and
efficacy supplements, FDA will inform the applicant of the
planned timeline for review of the application. The
information conveyed will include a target date for
communication of feedback from the review division to the
applicant regarding proposed labeling, postmarketing
requirements, and postmarketing commitments the Agency will
be requesting.
2. The planned review timeline will be included with the
notification of issues identified during the filing review,
within 74 calendar days from the date of FDA receipt of the
original submission.
3. The planned review timelines will be consistent with the
Guidance for Review Staff and Industry: Good Review
Management Principles and Practices for PDUFA Products
(GRMPs), taking into consideration the specific circumstances
surrounding the individual application.
4. The planned review timeline will be based on the
application as submitted.
5. FDA will inform the applicant of the planned review
timeline for 90% of all applications and efficacy
supplements.
6. In the event FDA determines that significant
deficiencies in the application preclude discussion of
labeling, postmarketing requirements, or postmarketing
commitments by the target date identified in the planned
review timeline (e.g., failure to demonstrate efficacy,
significant safety concern(s), need for a new study(ies) or
extensive re-analyses of existing data before approval), FDA
will communicate this determination to the applicant in
accordance with GRMPs and no later than the target date. In
such cases the planned review timeline will be considered to
have been met. Communication of FDA's determination may occur
by letter, teleconference, facsimile, secure e-mail, or other
expedient means.
7. To help expedite the development of drug and biologic
products, communication of the deficiencies identified in the
application will generally occur through issuance of a DR
letter(s) in advance of the planned target date for
initiation of discussions regarding labeling, postmarketing
requirements, and postmarketing commitments the Agency may
request.
8. If the applicant submits a major amendment(s) (refer to
Section XVI.B for additional information on major amendments)
and the review division chooses to review such amendment(s)
during that review cycle, the planned review timeline
initially communicated will generally no longer be
applicable. Consistent with the underlying principles
articulated in the GRMP guidance, FDA's decision to extend
the review clock should, except in rare circumstances, be
limited to occasions where review of the new information
could address outstanding deficiencies in the application and
lead to approval in the current review cycle.
If the review division determines that the major amendment
will result in an extension of the PDUFA review clock, the
review division will communicate to the applicant at the time
of the clock extension a new planned review timeline,
including a new review timeline for communication of feedback
on proposed labeling, postmarketing requirements, and any
postmarketing commitments the Agency may request.
In the rare case where the review division determines that
the major amendment will not result in an extension of the
PDUFA review clock, the review division may choose to retain
the previously communicated planned review timeline or may
communicate a new planned review timeline to the applicant.
The division will notify the applicant promptly of its
decision regarding review of the major amendment(s) and
whether the planned review timeline is still applicable.
For original NME NDA and original BLA applications, the new
planned review timeline will include a new planned date for
the internal mid-cycle review meeting if appropriate
depending on when during the course of review the major
amendment(s) is accepted for review.
C. Report on Review Timeline Performance
1. FDA will report its performance in meeting the goals for
inclusion of a planned review timeline with the notification
of issues identified during the filing review in the annual
PDUFA performance report.
2. FDA will report its performance in meeting the planned
review timeline for communication of labeling comments,
postmarketing requirements, and postmarketing commitment
requests in the annual PDUFA performance report. The report
will include the percentage of applications for which the
planned target dates for communication of labeling comments,
postmarketing requirements, and postmarketing commitment
requests were met. The report will also note how often the
planned review timeline was met based on communication of
labeling comments, postmarketing requirements, and
postmarketing commitment requests by the target date, and how
often such communication did not occur due to FDA's
determination that significant deficiencies in the
application precluded communication of labeling comments,
postmarketing requirements, and postmarketing commitment
requests at the time initially projected. Communication of
labeling comments, postmarketing requirements, and
postmarketing commitment requests, or communication of FDA's
determination that significant deficiencies preclude
initiation of such discussions that occurs within 7 calendar
days of the target date stated in the planned review timeline
will be considered to have met the target date. FDA will also
report the number of times that the review timelines were
inapplicable due to the Agency's decision to review an
unsolicited major amendment or a solicited major amendment
that did not result in an extension of the review clock
(unless the review division chose to retain the previously
communicated planned review timeline).
IV. REVIEW OF PROPRIETARY NAMES TO REDUCE MEDICATION ERRORS
To enhance patient safety, FDA will utilize user fees to
implement various measures to
[[Page S8284]]
reduce medication errors related to look-alike and sound-
alike proprietary names and such factors as unclear label
abbreviations, acronyms, dose designations, and error prone
label and packaging design.
A. Review Performance Goals--Drug/Biological Product
Proprietary Names
1. Proprietary names submitted during IND phase (as early
as end-of-phase 2)
a) Review 90% of proprietary name submissions filed within
180 days of receipt. Notify sponsor of tentative acceptance
or non-acceptance.
b) If the proprietary name is found to be unacceptable, the
sponsor can request reconsideration by submitting a written
rebuttal with supporting data or request a meeting within 60
days to discuss the initial decision (meeting package
required).
c) If the proprietary name is found to be unacceptable, the
above review performance goals also would apply to the
written request for reconsideration with supporting data or
the submission of a new proprietary name.
d) A complete submission is required to begin the review
clock.
2. Proprietary names submitted with NDA/BLA
a) Review 90% of NDA/BLA proprietary name submissions filed
within 90 days of receipt. Notify sponsor of tentative
acceptance/non-acceptance.
b) A supplemental review will be done meeting the above
review performance goals if the proprietary name has been
submitted previously (IND phase after end-of-phase 2) and has
received tentative acceptance.
c) If the proprietary name is found to be unacceptable, the
sponsor can request reconsideration by submitting a written
rebuttal with supporting data or request a meeting within 60
days to discuss the initial decision (meeting package
required).
d) If the proprietary name is found to be unacceptable, the
above review performance goals apply to the written request
for reconsideration with supporting data or the submission of
a new proprietary name.
e) A complete submission is required to begin the review
clock.
V. MAJOR DISPUTE RESOLUTION
A. Procedure: For procedural or scientific matters
involving the review of human drug applications and
supplements (as defined in PDUFA) that cannot be resolved at
the signatory authority level (including a request for
reconsideration by the signatory authority after reviewing
any materials that are planned to be forwarded with an appeal
to the next level), the response to appeals of decisions will
occur within 30 calendar days of the Center's receipt of the
written appeal.
B. Performance goal: 90% of such answers are provided
within 30 calendar days of the Center's receipt of the
written appeal.
C. Conditions:
1. Sponsors should first try to resolve the procedural or
scientific issue at the signatory authority level. If it
cannot be resolved at that level, it should be appealed to
the next higher organizational level (with a copy to the
signatory authority) and then, if necessary, to the next
higher organizational level.
2. Responses should be either verbal (followed by a written
confirmation within 14 calendar days of the verbal
notification) or written and should ordinarily be to either
grant or deny the appeal.
3. If the decision is to deny the appeal, the response
should include reasons for the denial and any actions the
sponsor might take to persuade the Agency to reverse its
decision.
4. In some cases, further data or further input from others
might be needed to reach a decision on the appeal. In these
cases, the ``response'' should be the plan for obtaining that
information (e.g., requesting further information from the
sponsor, scheduling a meeting with the sponsor, scheduling
the issue for discussion at the next scheduled available
advisory committee).
5. In these cases, once the required information is
received by the Agency (including any advice from an advisory
committee), the person to whom the appeal was made, again has
30 calendar days from the receipt of the required information
in which to either deny or grant the appeal.
6. Again, if the decision is to deny the appeal, the
response should include the reasons for the denial and any
actions the sponsor might take to persuade the Agency to
reverse its decision.
7. N.B. If the Agency decides to present the issue to an
advisory committee and there are not 30 days before the next
scheduled advisory committee, the issue will be presented at
the following scheduled committee meeting to allow
conformance with advisory committee administrative
procedures.
VI. CLINICAL HOLDS
A. Procedure: The Center should respond to a sponsor's
complete response to a clinical hold within 30 days of the
Agency's receipt of the submission of such sponsor response.
B. Performance goal: 90% of such responses are provided
within 30 calendar days of the Agency's receipt of the
sponsor's response.
VII. SPECIAL PROTOCOL QUESTION ASSESSMENT AND AGREEMENT
A. Procedure: Upon specific request by a sponsor (including
specific questions that the sponsor desires to be answered),
the Agency will evaluate certain protocols and issues to
assess whether the design is adequate to meet scientific and
regulatory requirements identified by the sponsor.
1. The sponsor should submit a limited number of specific
questions about the protocol design and scientific and
regulatory requirements for which the sponsor seeks agreement
(e.g., is the dose range in the carcinogenicity study
adequate, considering the intended clinical dosage; are the
clinical endpoints adequate to support a specific efficacy
claim).
2. Within 45 days of Agency receipt of the protocol and
specific questions, the Agency will provide a written
response to the sponsor that includes a succinct assessment
of the protocol and answers to the questions posed by the
sponsor. If the Agency does not agree that the protocol
design, execution plans, and data analyses are adequate to
achieve the goals of the sponsor, the reasons for the
disagreement will be explained in the response.
3. Protocols that qualify for this program include:
carcinogenicity protocols, stability protocols, and Phase 3
protocols for clinical trials that will form the primary
basis of an efficacy claim. For such Phase 3 protocols to
qualify for this comprehensive protocol assessment, the
sponsor must have had an end of Phase 2/pre-Phase 3 meeting
with the review division so that the division is aware of the
developmental context in which the protocol is being reviewed
and the questions being answered.
4. N.B. For products that will be using Subpart E or
Subpart H development schemes, the Phase 3 protocols
mentioned in this paragraph should be construed to mean those
protocols for trials that will form the primary basis of an
efficacy claim no matter what phase of drug development in
which they happen to be conducted.
5. If a protocol is reviewed under the process outlined
above and agreement with the Agency is reached on design,
execution, and analyses and if the results of the trial
conducted under the protocol substantiate the hypothesis of
the protocol, the Agency agrees that the data from the
protocol can be used as part of the primary basis for
approval of the product. The fundamental agreement here is
that having agreed to the design, execution, and analyses
proposed in protocols reviewed under this process, the Agency
will not later alter its perspective on the issues of design,
execution, or analyses unless public health concerns
unrecognized at the time of protocol assessment under this
process are evident.
B. Performance goal: 90% of special protocols assessments
and agreement requests completed and returned to sponsor
within timeframes.
C. Reporting: The Agency will track and report the number
of original special protocol assessments and resubmissions
per original special protocol assessment.
VIII. MEETING MANAGEMENT GOALS
A. Responses to Meeting Requests
1. Procedure: Within 14 calendar days of the Agency's
receipt of a request from industry for a formal Type A
meeting, or within 21 calendar days of the Agency's receipt
of a request from industry for a formal Type B or Type C
meeting (i.e., a scheduled face-to-face, teleconference,
videoconference, or written response), CBER and CDER should
notify the requester in writing (letter or fax) of the date,
time, and place for the meeting, as well as expected Center
participants. In the case of pre-IND and Type C meeting
requests, the sponsor may request a written response to its
questions rather than a face-to-face meeting, videoconference
or teleconference. In some cases, while the sponsor may
request a face-to-face pre-IND or Type C meeting, the Agency
may determine that a written response to the sponsor's
questions would be the most appropriate means for responding
to the meeting request. When it is determined that the
meeting request can be appropriately addressed through a
written response to questions, FDA shall notify the requester
of the date it intends to send the response.
2. Performance Goal: FDA will provide this notification
within 14 days for 90% of Type A meeting requests and within
21 days for 90% of Type B and Type C meeting requests.
B. Scheduling Meetings
1. Procedure: The meeting date should reflect the next
available date on which all applicable Center personnel are
available to attend, consistent with the component's other
business; however, the meeting should be scheduled consistent
with the type of meeting requested. If the requested date for
any of these types of meetings is greater than 30, 60, or 75
calendar days (as appropriate) from the date the request is
received by the Agency, the meeting date should be within 14
calendar days of the requested date.
a) Type A Meetings should occur within 30 calendar days of
the Agency receipt of the meeting request.
b) Type B Meetings should occur within 60 calendar days of
the Agency receipt of the meeting request. In the case of a
written response for a pre-IND meeting, the response should
be transmitted by FDA within 60 calendar days of the Agency
receipt of the meeting request.
c) Type C Meetings should occur within 75 calendar days of
the Agency receipt of the meeting request. In the case of a
written response, the response should be transmitted by FDA
within 75 calendar days of the Agency receipt of the meeting
request.
2. Performance goal: 90% of meetings are held within the
timeframe, and 90% of written responses are sent within the
timeframe.
C. Meeting Minutes
1. Procedure: The Agency will prepare minutes which will be
available to the sponsor 30
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calendar days after the meeting. The minutes will clearly
outline the important agreements, disagreements, issues for
further discussion, and action items from the meeting in
bulleted form and need not be in great detail. Meeting
minutes are not required if the Agency transmits a written
response for pre-IND or Type C meetings.
2. Performance goal: 90% of minutes are issued within 30
calendar days of date of meeting.
D. Conditions
For a meeting to qualify for these performance goals:
1. A written request (letter or fax) should be submitted to
the review division; and
2. The letter should provide:
a) A brief statement of the purpose of the meeting, and in
the case of pre-IND and Type C meetings, the sponsor's
proposal for either a face-to-face meeting or a written
response from the Agency;
b) A listing of the specific objectives/outcomes the
requester expects from the meeting;
c) A proposed agenda, including estimated times needed for
each agenda item;
d) A listing of planned external attendees;
e) A listing of requested participants/disciplines
representative(s) from the Center; and
f) The approximate time that supporting documentation
(i.e., the ``backgrounder'') for the meeting will be sent to
the Center (i.e., ``x'' weeks prior to the meeting), but
should be received by the Center at the time of the meeting
request for Type A meetings and at least 1 month in advance
of the scheduled meeting for Type B and Type C meetings
(including those for which a written response will be
provided)
3. The Agency concurs that the meeting will serve a useful
purpose (i.e., it is not premature or clearly unnecessary).
However, requests for a ``Type B'' meeting will be honored
except in the most unusual circumstances.
4. In general, meetings regarding REMS or postmarketing
requirements that occur outside the context of the review of
a marketing application shall be classified as Type B
meetings.
5. In general, a post-action meeting requested by the
sponsor within three months after an FDA regulatory action
other than an approval (i.e., issuance of a complete response
letter) shall be classified as a Type A meeting.
6. FDA shall publish revised draft guidance on formal
meetings between FDA and sponsors no later than the end of FY
2013.
Sponsors are encouraged to consult available FDA guidance
to obtain further information on recommended meeting
procedures.
ix. enhancing regulatory science and expediting drug development
To enhance communications between FDA and sponsors during
drug development and to meet the challenges of emerging
science in the areas of clinical trial endpoint assessment
tools, biomarkers and pharmacogenomics, meta-analysis, and
development of drugs for rare diseases, FDA will conduct the
following activities:
A. Promoting Innovation Through Enhanced Communication
Between FDA and Sponsors During Drug Development
1. FDA's philosophy is that timely interactive
communication with sponsors during drug development is a core
Agency activity to help achieve the Agency's mission to
facilitate the conduct of efficient and effective drug
development programs, which can enhance public health by
making new safe and effective drugs available to the American
public in a timely manner.
2. By the end of FY 2013, FDA will develop a dedicated drug
development communication and training staff within the
Office of New Drugs in CDER and augment the manufacturers
assistance staff in CBER, focused on enhancing communication
between FDA and sponsors during drug development.
3. Within CDER, the drug development communication and
training staff will include (1) a dedicated liaison staff to
facilitate general and, in some cases, specific interactions
with sponsors and (2) a training staff for CDER staff
training and for communication of best practices to the
sponsor community.
4. The liaison staff will be composed of individuals who
are experienced and knowledgeable about the drug review
process (and in some cases may be on detail from the review
divisions), interact regularly with the staff in review
divisions, and are skilled in facilitating communications
between applicants and FDA staff.
5. The liaison staff will conduct a range of tasks
associated with enhancing communication between the review
team and sponsors including identification and dissemination
of best practices for enhanced communication, and development
of training programs for review staff. In addition, they will
work in collaboration with sponsor stakeholders to develop
training for sponsors and receive feedback on FDA's programs
regarding best practices for communication during drug
development (e.g., participation in workshops and other
meetings to communicate CDER's policy and practice to the
sponsor community and to receive feedback on recommended
improvements).
6. The liaison staff will serve as a point of contact for
sponsors who have general questions about drug development or
who need clarification on which review division to contact
with their questions. The staff will also serve as a
secondary point of communication within CDER for sponsors who
are encountering problems in communication with the review
team for their IND (e.g., in instances when they have not
received a response from the review team to a simple or
clarifying question or referral to the formal meeting process
within 30 days of the sponsor's initial request). In such
cases the liaison staff will assist in evaluating the issues
and working with the review team and the sponsor to
facilitate resolution of the problem.
7. By the end of FY 2014, the OND drug development and
communication staff will provide training to all CDER staff
involved in review of INDs. The training will include:
a) CDER's philosophy that timely interactive communication
with sponsors during drug development is a core activity to
help achieve our mission to facilitate the conduct of
efficient and effective drug development programs, which can
enhance public health by making new safe and effective drugs
available to the American public in a timely manner.
b) Best practices for triage of sponsor requests for advice
from the review team and timely communication of responses to
simple and clarifying questions or referral of more complex
questions to the formal meeting process.
c) Best practices for communication between the review team
and the sponsor including establishing clear expectations and
agreement on appropriate mechanisms (e.g., when
teleconferencing or secure email may be the most appropriate
means of communication) and frequency of such communications.
d) The role of the OND liaison staff in facilitating
overall enhanced drug development communication between CDER
and the drug development sponsor community and the staff's
role in facilitating resolution of individual communication
requests that have not been handled successfully in a timely
manner by the review team, which is the primary interface
with the sponsor regarding the drug under development.
8. By the end of the second quarter of FY 2015, FDA will
publish draft guidance for review staff and industry
describing best practices for communication between FDA and
IND sponsors during drug development. The guidance will
describe FDA's philosophy regarding timely interactive
communication with sponsors as a core activity, the scope of
appropriate interactions between the review team and the
sponsor, outline the types of advice that are appropriate for
sponsors to seek from FDA in pursuing their drug development
program, describe the general expectations for the timing of
FDA response to sponsor inquiries of simple and clarifying
questions or referral of more complex questions to the formal
meeting process, and describe best practices and
communication methods (including the value of person-to-
person scientific dialogue) to facilitate interactions
between the FDA review team and the sponsor during drug
development. FDA will publish final guidance within 18 months
of the close of the comment period for the draft guidance.
B. Advancing the Science of Meta-Analysis Methodologies
1. Develop a dedicated review team with appropriate
expertise to evaluate different scientific methods and to
explore the practical application of scientific approaches
and best practices, including methodological limitations, for
the conduct of meta-analyses in the context of FDA's
regulatory review process.
2. By the end of FY 2013, hold a public meeting engaging
stakeholders in discussing current and emerging scientific
approaches and methods for the conduct of meta-analyses, and
to facilitate stakeholder feedback and input regarding the
use of meta-analyses in the FDA's regulatory review process.
3. Considering feedback and input received through the
public meeting, publish a draft guidance document for comment
describing FDA's intended approach to the use of meta-
analyses in the FDA's regulatory review process by the end of
FY 2015. This guidance will promote a better understanding
and more consistency among Agency, industry, and other
stakeholders regarding meta-analyses and their role in
regulatory decisionmaking.
4. Complete the final guidance describing FDA's intended
approach to the use of meta-analyses in the FDA's regulatory
review process (or revised draft guidance, if appropriate)
within 1.5 years of the close of the public comment period.
C. Advancing the Use of Biomarkers and Pharmacogenomics
1. Develop staff capacity to review submissions that
contain complex issues involving pharmacogenomics and
biomarkers. This additional staff capacity will be integrated
into the clinical review divisions and the clinical
pharmacology and statistical review disciplines to ensure
greater understanding of biomarker use in application review
and efficient incorporation of qualified biomarkers in the
review process.
2. Provide training for FDA staff on approaches to
conducting a pharmacogenomics review of a new product
application. This training will focus on the following:
facilitation of a greater understanding of the challenges
that arise when using pharmacogenomic markers and other
biomarkers in a development program (including programs
involving companion diagnostics), development of approaches
to
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address these challenges, and promotion of consistency in
regulatory review through an understanding of best practices
in assessment of applications that use biomarkers in the drug
development program.
3. By the end of FY 2013, hold a public meeting to discuss
the current status of biomarkers and pharmacogenomics and
potential strategies to facilitate scientific exchanges in
regulatory and non-regulatory contexts.
D. Advancing Development of Patient-Reported Outcomes (PROs)
and Other Endpoint Assessment Tools
1. Develop clinical and statistical staff capacity to more
efficiently and effectively respond to submissions that
involve PROs and other outcomes assessment tools. These staff
will advance the development of these tools by providing IND
and qualification consultations and through promoting best
practices for review and qualification of outcomes assessment
tools. The additional capacity includes staff who will focus
on review and qualification of endpoint assessment tools,
including IND consultations with sponsors, as well as staff
who will be integrated into the review divisions to
facilitate evaluation of these tools and improve familiarity
and understanding of assessment tools among review staff.
These activities will allow for greater understanding of
challenges that arise during development of outcomes
assessment tools, potential strategies to overcome these
challenges, and greater consistency in FDA's approach to
review, qualification, and usage of these tools as part of
the drug development process.
2. By the end of FY 2014, hold a public meeting to discuss
FDA's qualification standards for drug development tools, new
measurement theory, and implications for multi-national
trials.
E. Advancing Development of Drugs for Rare Diseases
1. By the end of FY 2013, FDA will complete a staffing and
implementation plan for the CDER Rare Disease Program within
the Office of New Drugs and a CBER Rare Disease liaison
within the Office of Center Director.
2. FDA will increase by five the staff of the CDER Rare
Disease Program and establish and fill the CBER Rare Disease
liaison position.
3. On an ongoing basis, the staff in the Rare Disease
Programs of the two Centers will develop and disseminate
guidance and policy related to advancing and facilitating the
development of drugs and biologics for rare diseases,
including improving understanding among FDA reviewers of
approaches to studying such drugs; considering non-
traditional clinical development programs, study design,
endpoints, and statistical analysis; recognizing particular
challenges with post-market studies; and encouraging
flexibility and scientific judgment, as appropriate, on the
part of reviewers when evaluating investigational studies and
marketing applications for drugs for rare diseases. Rare
Disease Program staff will also engage in increased outreach
to industry regarding development of such drugs and to
patient representatives and organizations.
4. By mid-FY 2014, FDA, through the Rare Disease Program,
will conduct a public meeting to discuss complex issues in
clinical trials for studying drugs for rare diseases,
including such questions as endpoint selection, use of
surrogate endpoints/Accelerated Approval, and clinical
significance of primary endpoints; reasonable safety
exposures; assessment of dose selection; and development of
patient-reported outcome instruments. Participants in the
discussion will include FDA staff, academic and clinical
experts, and industry experts. A summary from the meeting
will be made available publicly through the FDA website.
5. By the end of FY 2015, FDA will develop and implement
staff training related to development, review, and approval
of drugs for rare diseases. The training will be provided to
all CDER and CBER review staff, and will be part of the
reviewer training core curriculum. Among the key purposes of
this training are to familiarize review staff with the
challenges associated with rare disease applications and
strategies to address these challenges; to promote best
practices for review and regulation of rare disease
applications; and to encourage flexibility and scientific
judgment among reviewers in the review and regulation of rare
disease applications. The training will also emphasize the
role of the Rare Disease Program staff as members of the
review team to help ensure consistency of scientific and
regulatory approaches across applications and review teams.
6. By the end of FY 2016, FDA, through the Rare Disease
Program, will develop an evaluation tool to evaluate the
success of the activities of the Rare Disease Program,
including the reviewer training. Among potential measures of
success are the development of a system to track rare disease
applications from IND submission through the post-marketing
period, increased number of reviewers receiving rare disease-
specific training, increased number of activities
contributing to regulatory and biomedical science for rare
disease drug development, and meeting of PDUFA goals for rare
disease applications.
X. ENHANCING BENEFIT-RISK ASSESSMENT IN REGULATORY DECISIONMAKING
A. FDA will develop a five-year plan to further develop and
implement a structured benefit/risk assessment in the new
drug approval process. FDA will publish its draft plan for
public comment by the end of the first quarter of FY 2013.
FDA will begin execution of the plan to implement the
benefit-risk framework across review divisions in the pre-and
post-market human drug review process by the end of the
fourth quarter of FY 2013, and the Agency will update the
plan as needed and post all updates on the FDA website.
The plan will include:
1. A description of FDA's intended approach to build on the
Agency's current efforts to integrate a structured benefit/
risk framework throughout the lifecycle of human drug
development.
2. A plan to conduct two public workshops on benefit-risk
considerations from the regulator's perspective that will
begin by the first quarter of FY 2014. The first workshop
will be primarily informational by focusing discussion on the
various frameworks and methods available and their
application to regulatory decision-making. The second
workshop will focus on the results and lessons learned in
implementing frameworks at regulatory agencies in the pre-
and post-market drug review process.
3. An evaluation plan to ascertain the impact of the
benefit-risk framework in the human drug review process. The
evaluation will consider the utility of the framework in
facilitating decision-making and review team discussions
across disciplines, risk management plan decision-making,
training of new review staff, and communicating regulatory
decisions. In particular, the evaluation will consider the
degree to which the framework supports or facilitates
balanced consideration of benefits and risks, a more
consistent and systematic approach to discussion and
decision-making, and communication of benefits and risks.
B. As appropriate, FDA will revise the CDER Clinical Review
Template, Office and Division Director Summary Memo
Templates, and corresponding Manuals of Policies and
Procedures (MaPP) [and equivalent documents in CBER] to
incorporate a structured benefit/risk assessment into the
human drug review process on a timeframe outlined in the
five-year plan described in (A).
C. Over the period of PDUFA V, FDA will initiate a public
process to nominate a set of disease areas that could benefit
from a more systematic and expansive approach to obtaining
the patient perspective on disease severity or unmet medical
need. FDA will convene 4 meetings per year (CDER will host 17
meetings and CBER will host 3 meetings throughout PDUFA V)
with each meeting focused on a different disease area. These
meetings will include participation of FDA review divisions,
the relevant patient advocacy community, and other interested
stakeholders. After each meeting, FDA will publish the
meeting proceedings and a summary analysis of the input
received by FDA that is relevant to FDA's consideration of
disease severity and unmet medical need. This knowledge will
be used to more fully develop an understanding of the disease
severity and an assessment of the current state of the
treatment armamentarium which are both critical components of
FDA's current benefit-risk framework in regulatory decision-
making and communication. After the first two meetings, FDA
will develop a proposal for how FDA will incorporate these
perspectives into the Agency's decision-making.
In addition, FDA will increase its utilization of FDA's
Patient Representatives as Special Government Employee
consultants to CDER and CBER to provide patients' views early
in the medical product development process and ensure those
perspectives are considered in regulatory discussions.
D. FDA will train review and management staff on the
revised templates and MaPPs described in (B) and fully
integrate structured benefit/risk assessment into the
regulatory review process by a date specified in the five-
year plan.
XI. ENHANCEMENT AND MODERNIZATION OF THE FDA DRUG SAFETY SYSTEM
FDA will continue to use user fees to enhance and modernize
the current U.S. drug safety system, including adoption of
new scientific approaches, improving the utility of existing
tools for the detection, evaluation, prevention, and
mitigation of adverse events, and enhancing communication and
coordination between post-market and pre-market review staff.
Enhancements to the drug safety system will improve public
health by increasing patient protection while continuing to
enable access to needed medical products. User fees will
provide support for 1) enhancing risk evaluation and
mitigation strategies (REMS) by measuring their effectiveness
and evaluating with stakeholder input appropriate ways to
better integrate them into the existing and evolving
healthcare system, and 2) continued development and
implementation of the Sentinel System.
A. Measure the Effectiveness of REMS and Standardize and
Better Integrate REMS into the Healthcare System
FDA will use user fee funds to continue to develop
techniques to standardize REMS and with stakeholder input
seek to integrate them into the existing and evolving (e.g.,
increasingly electronic) healthcare system.
1. By the end of FY 2013, FDA will develop and issue
guidance on how to apply the statutory criteria to determine
whether a REMS is necessary to ensure that the benefits of a
drug outweigh the risks.
2. By the end of FY 2013, FDA will hold one or more public
meetings to include the pharmaceutical industry, other
government
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healthcare providers, patient groups, and partners from other
sectors of the healthcare delivery system to explore
strategies to standardize REMS, where appropriate, with the
goal of reducing the burden of implementing REMS on
practitioners, patients, and others in various healthcare
settings. To move towards increased integration of REMS into
the healthcare delivery system, FDA will issue a report of
its findings by the first quarter of FY 2014 that will
identify at least one priority project in each of the
following areas including a workplan for project completion:
pharmacy systems, prescriber education, providing benefit/
risk information to patients, and practice settings.
3. By the end of FY 2013, FDA will initiate one or more
public workshops on methodologies for assessing whether REMS
are mitigating the risks they purport to mitigate and for
assessing the effectiveness and impact of REMS, including
methods for assessing the effect on patient access,
individual practitioners, and the overall burden on the
healthcare delivery system. FDA will issue guidance by the
end of FY 2014 on methodologies for assessing REMS. This
guidance should specifically address methodologies for
determining whether a specific REMS with elements to assure
safe use (ETASU) is: (i) commensurate with the specific
serious risk listed in the labeling of the drug and (ii)
considering the observed risk, not unduly burdensome on
patient access to the drug.
B. Sentinel as a Tool for Evaluating Drug Safety Issues That
May Require Regulatory Action
FDA will use user fee funds to conduct a series of
activities to determine the feasibility of using Sentinel to
evaluate drug safety issues that may require regulatory
action, e.g., labeling changes, PMRs, or PMCs. The activities
will be selected and designed to focus on issues that affect
classes of drugs or multiple products.
1. By the end of FY 2013, FDA will hold or support public
meetings engaging stakeholders to discuss current and
emerging Sentinel projects and facilitate stakeholder
feedback and input regarding Sentinel projects that would be
appropriate to meet the goals stated above.
2. Informed by the feedback and input received through the
public meeting, in FY 2013 through FY 2017, FDA will fund 4-6
activities, which will include multiple product or class-
specific studies or methodology development. These activities
will be specifically designed to further evaluate safety
signals that, in previous cases, have served as the basis for
regulatory action(s) or designed more broadly to help
determine the utility and validity of the Sentinel System to
evaluate other types of signals in population-based
databases. The following are examples of potential
activities:
a) Expanding the active surveillance mechanisms begun for
the H1N1 pandemic to substitute for the information gathered
in large ad hoc, manufacturer-conducted studies
b) Evaluating risk for class-wide adverse events (e.g.,
cardiovascular events, suicidality)
3. By the end of FY 2015, FDA will conduct (or fund by
contract) an interim assessment to evaluate the strengths,
limitations and the appropriate use of Sentinel for informing
regulatory actions (e.g., labeling changes, PMRs and PMCs) to
manage safety issues.
4. By the end of FY 2017, FDA will conduct (or fund by
contract) an assessment to evaluate the strengths,
limitations, and the appropriate use of Sentinel for
informing regulatory actions (e.g., labeling changes, PMRs
and PMCs) to manage safety issues.
C. Conduct and support activities designed to modernize the
process of pharmacovigilance
1. Continued use of expanded database resources: A critical
part of the transformation of the drug safety program is
maximizing the usefulness of tools used for adverse event
signal detection and risk assessment. Use of data other than
passive spontaneous reports, including population-based
epidemiological data and other types of observational data
resources will continue to enhance FDA's capability to
conduct targeted post-marketing surveillance, evaluate class
effects of drugs, and potentially conduct signal detection
using data resources other than reports from the Adverse
Event Reporting System (AERS). FDA will continue training and
development of existing staff on the use of these resources,
and develop the information technology infrastructure needed
to support access and analysis of data from these resources.
D. Information Systems and Infrastructure
FDA will continue the Agency's efforts on the following
standards-based information systems to support how FDA
obtains and analyzes post-market drug safety data and manages
emerging drug safety information:
1. Enhanced adverse event reporting system and surveillance
tools;
2. IT infrastructure to support access and analyses of
externally-linked databases; and
3. Workflow tracking system.
XII. IMPROVING THE EFFICIENCY OF HUMAN DRUG REVIEW THROUGH REQUIRED
ELECTRONIC SUBMISSIONS AND STANDARDIZATION OF ELECTRONIC DRUG
APPLICATION DATA
A. To enhance the quality and efficiency of FDA's review of
NDAs, BLAs, and INDs, FDA shall consult with stakeholders,
including pharmaceutical manufacturers and other research
sponsors, to issue draft guidance on the standards and format
of electronic submission of applications by December 31,
2012.
B. FDA will issue final guidance no later than 12 months
from the close of the public comment period on the draft
guidance. Such final guidance and any subsequent revisions to
the final guidance shall be binding on sponsors, applicants,
and manufacturers no earlier than twenty-four months after
issuance of the final guidance.
C. Requirements for electronic submission shall be phased
in according to the following schedule:
1. Twenty-four (24) months after publication of the final
guidance: All new original NDA and BLA submissions, all new
NDA and BLA efficacy supplements and amendments, all new NDA
and BLA labeling supplements and amendments, all new
manufacturing supplements and amendments, and all other new
NDA submissions.
2. Thirty-six (36) months after publication of the final
guidance: All original commercial INDs and amendments, except
for submissions described in section 561 of the Federal Food,
Drug, and Cosmetic Act.
D. Because of the significant investments required to
change regulatory submission and review software, initial FDA
guidance shall specify the format of electronic submission of
applications using eCTD version 3.2.2 unless, after notice
and an opportunity for stakeholder comment, FDA determines
that another version will provide for more efficient and
effective applicant submission or FDA review. In general,
when FDA revises final guidance requiring submission using a
new version of electronic standards or formats, FDA shall
also accept submissions using the previous version for no
less than twenty-four (24) months.
E. Clinical Terminology Standards: Using a public process
that allows for stakeholder input, FDA shall develop
standardized clinical data terminology through open standards
development organizations (i.e., the Clinical Data
Interchange Standards Consortium (CDISC)) with the goal of
completing clinical data terminology and detailed
implementation guides by FY 2017.
1. FDA shall develop a project plan for distinct
therapeutic indications, prioritizing clinical terminology
standards development within and across review divisions. FDA
shall publish a proposed project plan for stakeholder review
and comment by June 30, 2013. FDA shall update and publish
its project plan annually.
F. Development of terminology standards for data other than
clinical data: To address FDA-identified nonclinical data
standards needs, FDA will request public input on the use of
relevant already-existing data standards and the involvement
of existing standards development organizations to develop
new standards or refine existing standards. FDA will obtain
this input via publication of a Federal Register notice that
specifies a 60-day comment period.
G. FDA shall periodically publish final guidance specifying
the completed data standards, formats, and terminologies that
sponsors must use to submit data in applications. In the case
of standards for study data, new data standards and
terminology shall be applicable prospectively and only
required for studies that begin 12 months after issuance of
FDA's final guidance on the applicable data standards and
terminology.
XIII. PROGRESS REPORTING FOR PDUFA V AND CONTINUING PDUFA IV
INITIATIVES
On an annual basis, FDA will report on its website the
progress in each of the PDUFA V initiatives described in
Sections IX, X, XI, and XII. The annual reports will include:
(a) descriptions of the hiring and placement of new staff and
use of PDUFA resources to support the new initiatives in
Sections IX, X, XI.A, XI.B, and XII, and (b) progress reports
on achieving metrics described in each of the sections. Each
report will be posted on the FDA website no later than 120
days after the end of the fiscal year. The staff resources
will support the new initiatives described in Sections IX, X,
XIA, XIB and XII and the related work associated with these
initiatives to ensure their success.
XIV. INFORMATION TECHNOLOGY GOALS
A. Objective
FDA is committed to achieve the long-term goal of improving
the exchange, review, and management of human drug and
biologic applications throughout the product life cycle
through strategic investments in automated, standards-based
information technology (IT).
B. Communications and Technical Interactions
1. FDA will periodically update and publish to the FDA
website a five-year plan for business process improvement
enabled by IT investments.
a) The plan will frame the strategy for prioritizing IT-
enabled business process change, enumerate the business
process improvements expected from each IT investment, and
convey a consistent series of milestones for each initiative
to track pace and progress.
b) FDA will conduct an annual assessment of progress
against the plan and publish on the FDA website a summary of
the assessment within 3 months after the close of each fiscal
year.
c) FDA will publish updates to the plan as FDA deems
appropriate. FDA will publish on the FDA web site draft
revisions to the plan; solicit comments from the public on
those draft revisions; and consider the public comments
before completing and publishing updates to the plan.
2. The FDA and industry stakeholders will meet on a
quarterly basis to discuss prospective implementation of the
plan, progress toward the long term goal, potential impacts
that future activities may have on FDA or stakeholders, and
potential revisions to the plan.
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C. Metrics and Measures
On an annual basis, FDA will measure and report progress
toward achievement of the objectives defined in Section
XIV.A. Measures will include but are not limited to:
1. The number and percentage of IND, NDA, and BLA
submissions received in valid electronic format in compliance
with FDA standards, categorized by types of submissions.
Increasing the number and percentage of IND, NDA, and BLA
submissions received in valid electronic format is a goal
that is supported by the FDA and industry stakeholders.
Achievement of this goal requires the cooperation of
regulated industry. To support the assessment of this goal,
the following information will be tracked and reported:
a) Total number of submissions categorized by type of
submission
b) Total number of submissions in valid electronic format
in compliance with FDA standards
c) Total number of submissions received through the secure
electronic single point of entry versus other methods
d) Total number of submissions received substantially on
paper or non-standardized electronic format
e) Total number of standards-based electronic submissions
that fail to comply with FDA electronic submission standards,
along with a distribution of these submission failures across
categories of failure or problem type
2. Number and significance of IT technical specifications
or e-submission guidance implemented requiring industry to
change submission content that are not forecasted accurately
in the five year plan or those whose content has not been
available to industry at least twelve months prior to
required implementation.
3. Spending on Center IT systems and IT systems that are
common across the organizational divisions participating in
the process for the review of human drug applications. This
includes systems development versus maintenance spending;
infrastructure support; a report of total PDUFA fee-funded
spending versus appropriations-funded spending; FDA
enterprise versus PDUFA-program specific support.
XV. IMPROVING FDA PERFORMANCE MANAGEMENT
A. The studies conducted under this initiative are intended
to foster:
1. Development of programs to improve access to internal
and external expertise
2. Reviewer development programs, particularly as they
relate to drug review processes
3. Advancing science and use of information management
tools
4. Improving both inter- and intra-Center consistency,
efficiency, and effectiveness
5. Improved reporting of management objectives
6. Increased accountability for use of user fee revenues
7. Focused investments on improvements in the process of
drug review
8. Improved communication between the FDA and industry
B. Studies will include:
1. Assessment by an independent contractor of the Program
for NME NDAs and original BLAs as described in Section IIB.
2. Assessment of the impact of the benefit-risk framework
in the human drug review process as described in Section
X.A.3.
3. Development of a tool to evaluate the success of the
activities of the Rare Disease Program as described in
Section IX.D.6.
4. Assessment of the impact of electronic submissions and
data standards on the efficiency and other performance
attributes of the human drug review process beginning in FY
2015.
5. Assessments by an independent accounting firm of the
review activity adjustment methodology, as described in
section 736(c)(2), by the end of the second quarter of FY
2013 and by the end of the fourth quarter of FY 2015 with
recommendations for changes, if warranted.
XVI. DEFINITIONS AND EXPLANATION OF TERMS
A. The term ``review and act on'' means the issuance of a
complete action letter after the complete review of a filed
complete application. The action letter, if it is not an
approval, will set forth in detail the specific deficiencies
and, where appropriate, the actions necessary to place the
application in condition for approval.
B. Goal Date Extensions for Major Amendments
1. A major amendment to an original application, efficacy
supplement, or resubmission of any of these applications,
submitted at any time during the review cycle, may extend the
goal date by three months.
2. A major amendment may include, for example, a major new
clinical safety/efficacy study report; major re-analysis of
previously submitted study(ies); submission of a REMS with
ETASU not included in the original application; or
significant amendment to a previously submitted REMS with
ETASU. Generally, changes to REMS that do not include ETASU
and minor changes to REMS with ETASU will not be considered
major amendments.
3. A major amendment to a manufacturing supplement
submitted at any time during the review cycle may extend the
goal date by two months.
4. Only one extension can be given per review cycle.
5. Consistent with the underlying principles articulated in
the GRMP guidance, FDA's decision to extend the review clock
should, except in rare circumstances, be limited to occasions
where review of the new information could address outstanding
deficiencies in the application and lead to approval in the
current review cycle.
C. A resubmitted original application is a complete
response to an action letter addressing all identified
deficiencies.
D. Class 1 resubmitted applications are applications
resubmitted after a complete response letter (or a not
approvable or approvable letter) that include the following
items only (or combinations of these items):
1. Final printed labeling
2. Draft labeling
3. Safety updates submitted in the same format, including
tabulations, as the original safety submission with new data
and changes highlighted (except when large amounts of new
information including important new adverse experiences not
previously reported with the product are presented in the
resubmission)
4. Stability updates to support provisional or final dating
periods
5. Commitments to perform Phase 4 studies, including
proposals for such studies
6. Assay validation data
7. Final release testing on the last 1-2 lots used to
support approval
8. A minor reanalysis of data previously submitted to the
application
9. Other minor clarifying information (determined by the
Agency as fitting the Class 1 category)
10. Other specific items may be added later as the Agency
gains experience with the scheme and will be communicated via
guidance documents to industry
E. Class 2 resubmissions are resubmissions that include any
other items, including any items that would require
presentation to an advisory committee.
F. A Type A meeting is a meeting which is necessary for an
otherwise stalled drug development program to proceed (a
``critical path'' meeting) or to address an important safety
issue.
G. A Type B Meeting is a 1) pre-IND, 2) end of Phase 1 (for
Subpart E or Subpart H or similar products) or end of Phase
2/pre-Phase 3, or 3) a pre-NDA/BLA meeting. Each requestor
should usually only request 1 each of these Type B meetings
for each potential application (NDA/BLA) (or combination of
closely related products, i.e., same active ingredient but
different dosage forms being developed concurrently).
H. A Type C meeting is any other type of meeting.
I. The performance goals and procedures also apply to
original applications and supplements for human drugs
initially marketed on an over-the-counter (OTC) basis through
an NDA or switched from prescription to OTC status through an
NDA or supplement.
J. IT-specific definitions (refer also to Section XIV)
1. ``Program'' refers to the organizational resources,
procedures, and activities assigned to conduct ``the process
for the review of human drug applications,'' as defined in
the Prescription Drug User Fee Act.
2. ``Standards-based'' means compliant with published
specifications that address terminology or information
exchange between the FDA and regulated parties or external
stakeholders, as adopted by the FDA or other agencies of the
federal government, and often based on the publications of
national or international Standards Development
Organizations.
3. ``FDA Standards'' means technical specifications that
have been adopted and published by the FDA through the
appropriate governance process. FDA standards may apply to
terminology, information exchange, engineering or technology
specifications, or other technical matters related to
information systems. FDA standards often are based on the
publications of other federal agencies, or the publications
of national or international Standards Development
Organizations.
4. ``Product life cycle'' means the sequential stages of
human drug development, regulatory review and approval, post-
market surveillance and risk management, and where
applicable, withdrawal of an approved drug from the market.
In the context of the process for the review of human drug
applications, the product life cycle begins with the earliest
regulatory submissions in the Investigational New Drug (IND)
phase, continues through the New Drug Application (NDA) or
Biological Licensing Application (BLA) review phase, and
includes post-market surveillance and risk management
activities as covered under the process for the review of
human drug applications.
Generic Drug User Fee Act Program Performance Goals and Procedures
The performance efficiencies, metric goals and procedures
to which FDA will agree upon commencement of a generic drug
user fee act (GDUFA) program (``the program''), as jointly
proposed by FDA and industry, are summarized below.
Overall Purpose of the Generic Drug User Fee Program
To help FDA ensure that participants in the U.S. generic
drug system comply with U.S. quality standards, and to
increase the likelihood that American consumers get timely
access to low cost, high quality generic drugs, FDA and
industry have jointly agreed to a comprehensive user fee
program,
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to be supplemental to traditional appropriated funding, that
is focused on three key aims:
Safety--Ensure that industry participants, foreign or
domestic, who participate in the U.S. generic drug system are
held to consistent high quality standards and are inspected
biennially, using a risk-based approach, with foreign and
domestic parity.
Access--Expedite the availability of low cost, high quality
generic drugs by bringing greater predictability to the
review times for abbreviated new drug applications,
amendments and supplements, increasing predictability and
timeliness in the review process.
Transparency--Enhance FDA's ability to protect Americans in
the complex global supply environment by requiring the
identification of facilities involved in the manufacture of
generic drugs and associated active pharmaceutical
ingredients, and improving FDA's communications and feedback
with industry in order to expedite product access.
Recognizing the critical role generic drugs play in
providing more affordable, therapeutically equivalent
medicine, the Generic Drug User Fee program is designed to
keep individual fee amounts as low as possible to supplement
appropriated funding to ensure that consumers continue to
receive the significant benefits offered by generic drugs
which provided more than $824 billion in savings to the
nation's health care system in the last decade alone. The
additional resources called for under the agreement, an
inflation adjusted $299 million annually for each of the five
years of the program, will provide FDA with the ability to
perform critical program functions that could not otherwise
occur. This program is not expected to add significantly to
the cost of generic drugs: given that a reported 3.99 billion
retail prescriptions per year were dispensed in the United
States in 2010, and assuming that 78% of these prescriptions
were filled by generic drugs, it equates to less than a dime
per prescription for the average cost of a prescription
filled by a generic drug in the United States. Moreover, with
the adoption of user fees and the associated savings in
development time, the overall expense of bringing a product
to market may decline and result in reduced costs.
In addition to the public health benefits outlined above,
the program described in this letter is expected to provide
significant value to small companies and first time entrants
in the generic market who will benefit significantly from the
certainty associated with performance review metrics that
offer the potential to dramatically reduce the time needed to
commercialize a generic drug when compared to pre-GDUFA
review times.
In addition, the variety of funding sources for the program
will assure that participants in the generic drug industry,
whether finished dosage form (FDF) manufacturers or Active
Pharmaceutical Ingredient (API) manufacturers appropriately
share the financial expense and benefits of the program.
Given that the total amount of annual user fee funding is
expected to be derived from a broad funding source, including
an estimated 2000 FDF and API facilities supporting
Abbreviated New Drug Applications (ANDAs), as well as
approximately 750 ANDAs, 750 prior approval supplements
(PASs) and 350 Type II Active Pharmaceutical Drug Master
Files (DMFs) annually, user fees are expected to provide a
measurable return on investment related to predictability of
inspection, and review timelines. The program's goals of
ensuring FDA has necessary resources to conduct needed
inspections as part of the complete review framework and
achieve parity of Good Manufacturing Practice (GMP)
inspections for foreign and domestic facilities by the 5th
year of the user fee program will also provide significant
value to industry participants given that outstanding
inspections can result in delays of ANDA approvals.
Taken collectively, the user fee program and associated
performance metrics and fees are expected to provide
measurable public health benefits and are not expected to
competitively disadvantage any company or business sector
regardless of size or location.
END NOTES
1. Source: IMS Health Report--GPHA. Savings achieved through
the use of generic pharmaceuticals: 2000-2009, July 2010.
2. Source: ``The Use of Medicines in the United States:
Review of 2010'', Report by the IMS Institute for Healthcare
Informatics, slide 8, available at http://www.imshealth.com/
deployedfiles/imshealth/
Global/Content/IMS%20Institute/Static%20File/
IHII_UseOfMe_d_report.pdf.
3. Ibid., slide 22.
1. OVERVIEW
Overall Program Scope, Assumptions, and Aspirations
The goals to which FDA is committing for generic drugs are
premised on the following assumptions:
I. Funding for the program from user fees will be at
agreed-upon levels of approximately $299 million annually
adjusted for inflation and will supplement appropriated
funding from Congress as described further below.
II. It is estimated that FDA will receive the funding
through approximately 750 abbreviated new drug applications
(ANDAs) per year submitted electronically, approximately 750
prior approval supplements (PASs) approximately 350 newly
referenced drug master files (DMFs) per year and through
approximately 2000 facilities associated with ANDAs. While
the total revenue collected can be defined in advance and is
constant as the resourcing level must be constant, the
individual fee will be determined each year based on the
variability of the fee source.
III. Over the five year course of the program, there will
be no significant changes in the generic drug facility
inventory, either in terms of general number of facilities,
or the foreign and domestic facility split.
IV. FDA will have streamlined hiring authority for all
GDUFA-related positions prior to or concurrent with the
implementation date of the program.
V. FDA expects the program will be implemented starting on
the first day of Fiscal Year 2013, October 1, 2012 and
continue for five years, with the joint expectation that the
program will be continued at the end of five years under
terms to be negotiated before the end of FY 2017.
VI. Industry and FDA will populate and maintain databases
as necessary for facilities, fee assessments, efficiency and
other enhancements as described further below and as needed
to support the Generic Drug User Fee Act. Because certain
databases to implement this program will need to be built,
and existing systems need to be expanded or modified,
industry will submit necessary information in electronic
format to FDA using appropriate standards to be specified by
the agency or as specified in statute.
VII. FDA will aspire to the extent possible to maintain
levels of productivity at least similar to pre-GDUFA levels,
while hiring and training incremental staff necessary to
achieve the program performance goals, building necessary
systems and implementing outlined program changes in years 1
and 2 of the program (see goals for years 3-5 metrics).
VIII. FDA will utilize a complete review standard (as
defined below), will aspire to hold first cycle deficiency
teleconferences with industry to discuss complete response
questions at a level at least similar to pre-GDUFA levels in
years 1 and 2 of the program (see goals for years 3-5
metrics) and will utilize an approach similar to the NDA
review process whereby FDA uses telephone information
requests to address easily correctable deficiencies during
the review process before and after issuance of complete
response letters.
IX. FDA will aspire to complete reviews for applications
with only minor administrative amendments pending prior to
the expiration date of the controlling patent or applicable
exclusivity date regardless of the amendment(s) goal date.
X. FDA will work towards achieving performance goals to
reach parity of GMP inspections of foreign and domestic
establishments, will prioritize inspections using a risk-
based approach, and will prioritize inspections of
establishments associated with ANDAs that are otherwise
approvable or eligible for tentative approval except for an
outstanding inspection, as well as establishments associated
with ANDAs that have not been inspected previously. In
appropriate circumstances FDA can rely on a routine
surveillance inspection in lieu of an application-specific
inspection. Generally, among other considerations, FDA relies
on a previous inspection of a finished product site occurring
within 2 years of the current good manufacturing practice
(CGMP) evaluation for a pending application, 3 years for an
active pharmaceutical ingredient (API) site or a control
testing laboratory, and 4 years for a packaging-only site.
There are exceptions to this general practice, which are
usually related to the nature of the drug being processed or
the complexity of the associated processing operations. FDA
intends to continue the practice of using a risk-based
assessment in determining the length of time since the last
inspection, guided by a 2-year cycle for finished dosage
product sites and a 3-year cycle for API sites and
consideration of the type of finished product or API in the
application. Practically, this means that in making decisions
about pending applications for which FDA does not have
current inspection information within the time period
indicated, FDA may use previous FDA inspection information
and/or use inspection information from another regulatory
authority as appropriate.
XI. FDA will strive to review and act on all ANDAs that are
submitted on the first day that any valid Paragraph IV
application for the drug in question is submitted within 30
months of submission to avoid causing first applicants to
inadvertently forfeit 180-day exclusivity eligibility under
21 U.S.C. Sec. 355(j)(5)(D)(i)(IV).
XII. Because the agreed generic drug user fee program is
intended to be additive to budget appropriations, agreed upon
legislative language will require that annual program
appropriations from Congress must be equal to or exceed the
FDA appropriation for FY 2009.
XIII. In order to generate the agreed upon levels of user
fee funding to achieve the enclosed performance goals,
metrics and efficicienies, legislative language will require
that approximately 70% of GDUFA fees shall be derived from
facility fees (for facilities producing or pending review to
produce active pharmaceutical ingredients or finished dosage
forms for a generic drug application), approximately 30% of
GDUFA fees shall be derived from application fees (DMF Fees
and ANDA and PAS (Prior Approval Supplement) Fees). As
discussed and agreed by the various industry business
segments, overall fees will be divided 80 percent to 20
percent between the finished dosage form (FDF) and API and
manufacturers, respectively in industry. In the first year of
the
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program, $50 million of the total GDUFA user fee funding
shall be generated by a one time backlog fee for ANDAs
pending (except for ANDAs that are pending but have received
tentative approval) on October 1, 2012.
XIV. For appeals of decisions concerning procedural or
scientific matter involving review of pending ANDAs, ANDA
amendments and ANDA supplements FDA will aspire that the
response to appeals of decisions will occur within 30
calendar days of OGD receipt of the written appeal when
possible, though no reportable performance goals are
required.
Note: If these assumptions differ significantly from
actuality, FDA may not be able to achieve the goals and
efficiency enhancements outlined in this goals letter,
despite the supplemental funding provided by the program.
Summary of Major Program Goals including Five Year Goals
Major Program (including 5 year) goals can be summarized as
follows:
Note that FDA agrees to additional 5 year goals, as set
forth later in this goals letter, such as goals on
amendments, controlled correspondence, and prior approval
supplements, as well as goals for years prior to year 5 of
the program. The goals summarized in this section are a
subset of the complete year 5 goals, and are intended simply
to illustrate the scope of the program.
Application metrics--For Abbreviated New Drug Applications
(ANDAs) in the year 5 cohort, FDA will review and act on 90
percent of complete electronic ANDAs within 10 months after
the date of submission. Certain amended applications may have
differing metrics as discussed below.
Backlog metrics--FDA will review and act on 90 percent of
all ANDAs, ANDA amendments and ANDA prior approval
supplements regardless of current review status (whether
electronic, paper, or hybrid) pending on October 1, 2012 by
the end of FY 2017.
CGMP Inspection metrics--FDA will conduct risk-adjusted
biennial CGMP surveillance inspections of generic API and
generic finished dosage form (FDF) manufacturers, with the
goal of achieving parity of inspection frequency between
foreign and domestic firms in FY 2017.
Efficiency Enhancements--FDA will implement various
efficiency enhancements discussed below on October 1, 2012 or
upon enactment of the program, whichever is later.
Regulatory Science--FDA will continue, and for some topics
begin undertaking various regulatory science initiatives
discussed below on October 1, 2012 or upon enactment of the
program, whichever is later, focusing first on the
initiatives discussed below and with additional initiatives
to be identified with input from an industry working group.
Details follow.
2. EFFICIENCY ENHANCEMENTS TO BE UNDERTAKEN ON OCTOBER 1, 2012, OR UPON
ENACTMENT OF THE PROGRAM, WHICHEVER IS LATER
A. ANDA Review Efficiency Enhancements
Starting on October 1, 2012 or upon enactment of the
program, whichever is later, FDA will issue complete response
letters, rather than discipline specific letters, for all
ANDAs, including those pending on October 1, 2012.
Complete response letters will reflect full division-level
review of deficiencies from all relevant review disciplines,
including inspections, and address other matters relating to
the ANDA and associated DMFs as well as consults with other
agency components (these will be subsumed into the
application metrics).
FDA reviewers will make every reasonable effort to
communicate promptly to applicants easily correctable
deficiencies found in the ANDA and will utilize an approach
similar to the NDA review process whereby FDA uses telephone
information requests to address easily correctable
deficiencies during the review process before and after
issuance of complete response letters.
When requested by the ANDA sponsor within 10 business days
of FDA issuing a first cycle complete response letter, as
provided by the sponsor in a written request that outlines
specific written questions the applicant would like to
discuss (limited to the content of the letter), FDA will
schedule a 30 minute teleconference to clarify issues and
answer questions. Priority for such teleconferences will be
given to expedited and first major amendment applications.
Although FDA will begin to develop procedures and tracking
systems for such teleconferences coincident with the start of
the program, there will be no teleconference goals for the
first two years of the program although FDA will aspire to
conduct such teleconferences as requested when reportable
performance goals are not otherwise required. In the first
two years, FY 2013 and FY 2014, FDA would aspire to hold
teleconferences with industry to address complete response
questions at a level similar to pre-GDUFA levels.
Subsequently, the goals for number of reportable
teleconferences (although FDA may conduct more such
teleconferences) will be:
Closing out the teleconference request for 200 meetings in
FY 2015;
Closing out the teleconference request for 250 meetings in
FY 2016;
Closing out the teleconference request for 300 meetings in
FY 2017.
FDA will develop enhanced refusal to receive standards for
ANDAs and other related submissions by the end of year 1 of
the program and will publish such standards in advance of
implementation.
For ANDAs in the year 1 and 2 cohorts, FDA will expedite
review of Paragraph IV applications that are submitted on the
first day that any valid Paragraph IV application for the
drug in question is submitted. Expedited review will be
implemented consistent with existing procedure for expediting
applications as set forth in CDER's MAPP 5240.3, and will
also include those applications that become eligible for
approval during the review period as a result of no blocking
exclusivities, patent(s) and/or applicable stays based on
appropriate documentation submitted.
Review metric goals (described below) only apply to
submissions made electronically, following the eCTD format in
effect at the date of submission.
Backlog review metric goals (described below) apply to all
ANDA applications, amendments, and supplements regardless of
current review status in the queue as of October 1, 2012,
regardless of whether they were submitted in paper,
electronic, or hybrid format.
B. Drug Master File (DMF) Review Efficiency Enhancements
After the program's implementation date, upon payment of
the DMF fee by DMF holders anticipating reference by a
generic drug manufacturer, FDA will conduct a completeness
assessment of Type II API DMFs. Following a satisfactory
completeness assessment, FDA will deem the DMF available for
reference, placing the DMF number in a publicly available
list of Type II API DMFs available for reference.
Review metric goals (described below) will only apply to
Type II API DMFs submitted after the program's implementation
date, if they are submitted electronically. Electronic DMFs
will follow the eCTD format in effect at date of submission.
FDA will issue a letter detailing all identified
deficiencies, rather than discipline specific letters, for
all DMFs including those under review at the time of
enactment of the implementing legislation.
The DMF deficiency letters will reflect full division-level
deficiency review of deficiencies from all relevant review
disciplines, including inspections, and address other matters
relating to the DMF review such as consults with other agency
components (these will be subsumed into the DMF metrics).
FDA reviewers will make every reasonable effort to
communicate promptly to applicants easily correctable
deficiencies found in the DMF and will continue to utilize an
approach similar to the NDA review process whereby FDA uses
telephone information requests to address easily correctable
deficiencies during the review process before and after
issuance of complete response letters.
When requested by a DMF holder within 10 business days of
FDA issuing a first cycle DMF deficiency letter, as provided
by the DMF holder in a written request that outlines specific
written questions the DMF holder would like to discuss
(limited to the content of the letter), FDA will schedule a
30 minute teleconference with a limit of one teleconference
per DMF holder per month, with the total number of
teleconferences not to exceed the number of teleconferences
for ANDAs, a teleconference to clarify issues and answer
questions. Priority for such teleconferences will be given to
DMFs referenced in expedited and first major deficiency
applications. Although FDA will begin to develop procedures
and tracking systems for such teleconferences coincident with
the start of the program, there will be no teleconference
goals for the first two years of the program although FDA
will aspire to conduct such teleconferences as requested when
reportable performance goals are not otherwise required. In
the first two years, FY 2013 and FY 2014, FDA would aspire to
hold teleconferences with industry to address DMF deficiency
questions at a level similar to pre-GDUFA levels (although
FDA may conduct more such teleconferences).
Once a DMF has undergone a complete review and the ANDA
referencing same is either approved or tentatively approved--
at such time there being no further outstanding deficiencies
to the DMF--FDA will issue the DMF holder a letter to
indicate that the DMF does not have any further open matters
as part of the review associated with the referencing ANDA.
C. Inspection Efficiency Enhancements
To maximize the number of applications that can be reviewed
within the metric goals and to assist in securing the
pharmaceutical supply chain, FDA will employ a risk-adjusted
biennial CGMP surveillance inspection model for inspection of
generic API and FDF manufacturers, with the goal of achieving
parity of inspection frequency between foreign and domestic
establishments in FY 2017 and will prioritize inspections of
establishments associated with ANDAs that are otherwise
approvable or eligible for tentative approval except for an
outstanding inspection, as well as establishments that have
not been inspected previously.
FDA will make inspection classification results and date of
the last facility inspection available to the public and
industry on FDA's website on timely basis.
During the five years of the program, FDA will undertake a
study of foreign government regulator inspections (CGMP and
bioequivalence), report findings publicly, and develop a
program to utilize foreign inspection classifications when
and where appropriate.
[[Page S8291]]
D. Other Efficiency Enhancements
FDA will develop new and/or enhance existing facility
databases (API and FDF manufacturing and clinical/
bioequivalence site) to be populated by industry. These
databases will, at a minimum, contain information for
generics-related firms, including addresses and Data
Universal Numbering System (DUNS) numbers, and will link
facilities to DMFs and ANDAs and will contain other
information as necessary.
FDA will develop a current chemistry manufacturing and
controls (CMC) records database to aid in the efficiency of
review and inspection.
FDA will develop and issue electronic data submission
standards.
Because certain databases to implement this program will
need to be built, and existing systems need to be expanded or
modified, industry will submit necessary information in
electronic format to FDA using appropriate standards to be
specified by the agency or as specified in statute.
3. REGULATORY SCIENCE INITIATIVES
A. Working Group
FDA will convene a working group and consider suggestions
from industry and other stakeholders to develop an annual
list of regulatory science initiatives for review by CDER
Director.
B. FY 2013 Plan
The FY 2013 plan is appended.
4. METRIC GOALS/MEASUREMENTS
A. Human Resources Metrics
FDA will hire and train at least 25 percent of incremental
staff in FY 2013, 50 percent in FY 2014 and will strive to
complete GDUFA-funded human resources hiring goals in FY 2015
as necessary to achieve the program's performance metrics and
goals.
B. ANDA, ANDA Amendment, and ANDA Prior Approval Supplement Review
Metrics and DMF Reviews as Subsumed in Each
ANDAs will be categorized according to cohort year.
Once an ANDA is in a given year's cohort, dates of
submission of a subsequent amendment will not change the
cohort year. Regardless of the year in which an amendment is
submitted, any additional time periods to be added to the
base review period will be calculated using the time periods
corresponding to the original cohort year.
Original (complete) ANDA Review (Certain amended
applications may have differing metrics as discussed below.)
FDA will review and act on 60 percent of original ANDA
submissions within 15 months from the date of submission for
the year 3 cohort.
FDA will review and act on 75 percent of original ANDA
submissions within 15 months from the date of submission for
the year 4 cohort.
FDA will review and act on 90 percent of original ANDA
submissions within 10 months from the date of submission for
the year 5 cohort.
For ANDAs in the year 1 and 2 cohorts, FDA will expedite
review of Paragraph IV applications that are submitted on the
first day that any valid Paragraph IV application for the
drug in question is submitted.
Amendment Review
All amendment metric goals are incremental, and the time
periods specified are calculated from the date of submission.
They will be added to the original review goal, but in no
case shall they shorten the original goal date. (In other
words, an amendment with a 6 month metric which was submitted
4 months prior to original goal date would add 2 months to
the review clock).
An amendment pre Complete Response Letter adjusts the goal
date for the original application.
Subsequent amendments pre Complete Response Letter also
adjust the goal date for the application and are additive.
An amendment post Complete Response Letter sets a new goal
date for the application.
Subsequent amendments post Complete Response Letter also
adjust the goal date for the application and are additive.
Delaying amendments or amendments containing information
that FDA would otherwise ask for as a result of post ANDA
submission reference listed drug changes do not add to the
count of amendments.
If any amendment contains multiple elements, the longest
goal date shall apply.
Amendments shall be grouped as Tier 1, Tier 2 or Tier 3.
FDA agrees that unsolicited amendments that are submitted to
a pending ANDA that are neither Tier 1, Tier 2 or Tier 3
amendments, but rather are routine or administrative in
nature and do not require scientific review (e.g., requests
for final ANDA approval, patent amendments, general
correspondence, and USP monograph updates), will not lengthen
or impact the original review goal date.
Tier 1 amendments include:
All solicited first major and the first five minor
amendments
All unsolicited amendments indicated by sponsor and agreed
by FDA to be a result of either delaying actions as
determined by FDA's Office of Generic Drugs taking into
account the facts and information supplied by the ANDA
applicant or that otherwise would eventually be solicited.
Tier 2 amendments include:
All unsolicited amendments not arising from delaying
actions as determined by FDA's Office of Generic Drugs taking
into account the facts and information supplied by the ANDA
applicant excepting those amendments which only remove
information for review.
Tier 3 amendments include:
Any solicited major amendment subsequent to the first major
amendment
Any solicited minor amendment subsequent to the fifth minor
amendment
Tier 1 amendment goals:
First major amendment
FDA will review and act on 60 percent of first major
amendment submissions within 10 months from the date of
submission for the year 3 cohort.
FDA will review and act on 75 percent of first major
amendment submissions within 10 months from the date of
submission for the year 4 cohort.
FDA will review and act on 90 percent of first major
amendment submissions within 10 months from the date of
submission for the year 5 cohort.
Minor amendments (first--third)
FDA will review and act on 60 percent of first through
third minor amendment submissions within 3 months from the
date of submission for the year 3 cohort.
FDA will review and act on 75 percent of first through
third minor amendment submissions within 3 months from the
date of submission for year 4 cohort.
FDA will review and act on 90 percent of first through
third minor amendment submissions within 3 months from the
date of submission for the year 5 cohort.
Minor amendments (fourth--fifth)
FDA will review and act on 60 percent of fourth through
fifth minor amendment submissions within 6 months from the
date of submission for the year 3 cohort.
FDA will review and act on 75 percent of fourth through
fifth minor amendment submissions within 6 months from the
date of submission for year 4 cohort.
FDA will review and act on 90 percent of fourth through
fifth minor amendment submissions within 6 months from the
date of submission for the year 5 cohort.
Except that if any Tier 1 amendment requires an inspection,
the goal shall be 10 months.
Tier 2 amendment goals:
FDA will review and act on 60 percent of amendment
submissions within 12 months from the date of submission for
the year 3 cohort.
FDA will review and act on 75 percent of amendment
submissions within 12 months from the date of submission for
year 4 cohort.
FDA will review and act on 90 percent of amendment
submissions within 12 months from the date of submission for
the year 5 cohort.
Tier 3 amendment goals:
There will be no GDUFA metrics for tier 3 amendments.
Review of Complete Prior Approval Supplements (PASs)
(Certain amended PASs may have differing metrics as discussed
above in the Amendment Review section).
FDA will review and act on 60 percent of PASs not requiring
inspection within 6 months from the date of submission for
receipts in FY 2015; FDA will review and act on 60 percent of
PASs requiring inspection within 10 months from the date of
submission for receipts in FY 2015.
FDA will review and act on 75 percent of PASs not requiring
inspection within 6 months from the date of submission for
receipts in FY 2016; FDA will review and act on 75 percent of
PASs requiring inspection within 10 months from the date of
submission for receipts in FY 2016.
FDA will review and act on 90 percent of PASs not requiring
inspection within 6 months from the date of submission for
receipts in FY 2017; FDA will review and act on 90 percent of
PASs requiring inspection within 10 months from the date of
submission for receipts in FY 2017.
C. Controlled Correspondence Metrics
Controlled Correspondence
FDA will respond to 70 percent of controlled correspondence
in 4 months from date of submission in FY 2015.
FDA will respond to 70 percent of controlled correspondence
in 2 months from date of submission in FY 2016.
FDA will respond 90 percent of controlled correspondence in
2 months from date of submission in FY 2017.
If the controlled correspondence requires input from the
clinical division, one additional month will be added to the
goals outlined above.
In the case of controlled correspondence which raises an
issue or question that is the same as or related to the issue
or question that is the subject of one or more pending
citizen petitions, or petitions for stay or reconsideration,
the above goals will apply from the date FDA issues responses
to the pending petitions.
D. CGMP Inspection metrics
FDA will conduct risk-adjusted biennial CGMP surveillance
inspections of generic API and generic finished dosage form
(FDF) manufacturers, with the goal of achieving parity of
inspection frequency between foreign and domestic firms in FY
2017.
E. Backlog metrics
FDA will review and act on 90 percent of all ANDAs, ANDA
amendments, and ANDA prior approval supplements regardless of
current review status (whether electronic, paper, or hybrid)
pending on October 1, 2012 by the end of FY 2017.
Definitions
For the purposes of this goals letter:
Act on an application--means FDA will either issue a
complete response letter, an approval letter, a tentative
approval letter for an ANDA, or a refuse to receive action.
[[Page S8292]]
Active pharmaceutical ingredient--means (A) a substance, or
a mixture when the substance is unstable or cannot be
transported on its own, intended to be used as a component of
a drug and intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease, or to affect the
structure or any function of the human body; or (B) a
substance intended for final crystallization, purification,
or salt formation, or any combination of those activities, to
become the final active pharmaceutical ingredient as defined
in paragraph (A).
Backlog--refers to the queue of pending ANDAs, ANDA
amendments and ANDA supplements pending as of October 1,
2012.
Delaying amendments--refers to amendments to an ANDA from
the ANDA sponsor to address actions by a third party that
would cause delay or impede application review or approval
timing and that were not or may not have been initially
recognized by FDA as necessary when the application was first
submitted. FDA's Office of Generic Drugs shall have broad
discretion to determine what constitutes a delaying event
caused by actions generally outside of the applicants control
taking into account facts and information supplied by the
ANDA sponsor.
Closing out a request for a first cycle review
teleconference--means: 1) holding the teleconference; or 2)
responding to questions in the sponsor's teleconference
request in writing in lieu of holding the teleconference.
Cohort--The program is structured based on 5 cohorts of
submission dates (original ANDAs, PASs and DMFs),
corresponding to the five fiscal years to be covered by the
program. The year 1 cohort refers to the dates of submissions
made electronically in FY 2013 (October 1, 2012 to September
30, 2013). The year 2 cohort refers to the dates of
submissions made electronically in FY 2014 (October 1, 2013
to September 30, 2014). The year 3 cohort refers to the dates
of submissions made electronically in FY 2015 (October 1,
2014 to September 30, 2015). The year 4 cohort refers to
submissions made electronically in FY 2016 (October 1, 2015
to September 30, 2016). The year 5 cohort refers to
submissions made electronically in FY 2017 (October 1, 2016
to September 30, 2017).
Complete response letter--refers to a written communication
to an applicant or DMF holder from FDA usually describing all
of the deficiencies that the agency has identified in an
abbreviated application (including pending amendments) or a
DMF that must be satisfactorily addressed before the ANDA can
be approved. Complete response letters will reflect a
complete review and will require a complete response from
industry to restart the clock. Refer to 21 CFR 314.110 and
http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/LawsActsandRules/
ucm084138.htm for additional details. When a citizen petition
may impact the approvability of the ANDA, FDA will strive to
address, where possible, valid issues raised in a relevant
citizen petition in the complete response letter. If a
citizen petition raises an issue that would delay only part
of a complete response, a response that addresses all other
issues will be considered a complete response.
Complete review--refers to a full division-level review
from all relevant review disciplines, including inspections,
and includes other matters relating to the ANDA and
associated DMFs as well as consults with other agency
components.
Controlled correspondence--FDA'S Office of Generic Drugs
provides assistance to pharmaceutical firms and related
industry regarding a variety of questions posed as
``controlled documents.'' See http://www.fda.gov/AboutFDA/
CentersOffices/CDER/ucm 120610.htm. Controlled correspondence
does not include citizen petitions, petitions for
reconsideration or requests for stay.
DMF or Type II Active Pharmaceutical Ingredient Drug Master
File--means a submission of information to the Secretary by a
person that intends to authorize the Food and Drug
Administration to reference the information to support
approval of a generic drug submission without the submitter
having to disclose the information to the generic drug
submission applicant.
Electronic--refers to submissions in an all electronic eCTD
format in effect at the date of submission.
Expedited review of application--While generally, review of
original ANDAs, ANDA amendments and ANDA supplements are
reviewed in the order received, (first-in, first-reviewed),
certain applications may be identified at the date of
submission for expedited review, as described in CDER's MAPP
5240.3. (See http://www.fda.gov/downloads/AboutFDA/
CentersOffices/CDER/ManualofPoliciesProcedures/ucm079787.pdf)
which includes expedited review of the original submission
and amendment(s) associated with the expedited review
qualifying application. Products to respond to current and
anticipated public health emergencies, products under special
review programs, such as the President's Emergency Plan for
AIDS Relief (PEPFAR), products for which a nationwide
shortage has been identified, and first generic products for
which there are no blocking patents or exclusivities on the
reference listed drug currently may qualify for expedited
review. For ANDAs in the year 1 and 2 cohorts, FDA will
expedite review of Paragraph IV applications that are
submitted on the first day that any valid Paragraph IV
application for the drug in question is submitted.
Facility--means business or other entity under one
management either direct or indirect and at one geographic
location or address engaged in manufacturing or processing an
active pharmaceutical ingredient or a finished dosage form,
but does not include a business or other entity whose only
manufacturing or processing activities are one or more of the
following: repackaging, relabeling, or testing. For purposes
of this definition, separate buildings within close proximity
are considered to be at one geographic location or address if
the activities in them are closely related to the same
business enterprise, under the supervision of the same local
management, and are capable of being inspected by the Food
and Drug Administration during a single inspection.
Finished Dosage Form--means (A) a drug product in the form
in which it will be administered to a patient, such as a
tablet, capsule, solution, or topical application; (B) a drug
product in a form in which reconstitution is necessary prior
to administration to a patient, such as oral suspensions or
lyophilized powders; or (C) any combination of an active
pharmaceutical ingredient, as defined in paragraph (m)(2),
with another component of a drug product for purposes of
production of such a drug product.
First major deficiency application--means an ANDA which has
been issued its first complete response letter classified as
having major deficiency(ies).
Generic Drug Program--refers to all agency activities
related to the determination of approvability of an ANDA.
Major and minor amendments--All references to ``major'' and
``minor'' amendments in this goals letter are intended to
refer to the distinctions that FDA described in its Guidance
for Industry: Major, Minor, Telephone Amendments to
Abbreviated New Drug Applications. See http://www.fda.gov/
downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm072888.pdf
Parity--in reference to inspections, as between foreign and
domestic facilities, means inspection at an equal frequency
plus or minus 20 percent with comparable depth and rigor of
inspection.
Refuse to receive--means refusal to file an application.
See 21 CFR 314.101 and http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
UCM080561.pdf1993
Solicited amendment--an amendment submitted in response to
a Complete Response letter.
Submission date--is the date an ANDA, ANDA amendment, ANDA
supplement, or Type II active pharmaceutical drug master file
arrives in the appropriate electronic portal of the FDA.
Prior Approval Supplements--A prior approval supplement is
a submission to allow a company to make a change in a product
that already has an approved ANDA. CDER must approve all
important ANDA changes (in packaging or ingredients, for
instance) to ensure the conditions originally set for the
product are still met. (Source: http://www.fda.gov/Drugs/
InformationOnDrugs/ucm079436.htm#S)
Unsolicited amendment--an amendment with information not
requested by the FDA except for those unsolicited amendments
considered routine or administrative in nature and that do
not require scientific review (e.g., requests for final ANDA
approval, patent amendments, general correspondence, and USP
monograph updates).
FY 2013 Regulatory Science Plan
Topic 1: Bioequivalence of local acting orally inhaled drug
products
Impact: Continue to develop new and improved PD endpoints
and study designs or establishment of alternative approaches
to ensure equivalent local delivery of orally inhaled drug
product to the lung would lead to more efficient development
of generic products in a sector that lacks any generic
competition
Topic 2: Bioequivalence of local acting topical
dermatological drug products
Impact: Continue developing new bioequivalence methods in
order to reduce the need for relatively insensitive clinical
endpoint bioequivalence studies. Development of in vitro
release tests or other product characterization to ensure
consistent drug release or product performance
Topic 3: Bioequivalence of local acting gastro-intestinal
drug products
Impact: Developing new bioequivalence methods for direct
measurement of drug concentrations in the GI tract and
establishing better correlations between pharmacokinetic
measurements and GI concentration would allow more efficient
demonstration of bioequivalence than by clinical endpoint
studies.
Topic 4: Quality by design of generic drug products
Impact: Continue developing science-based recommendations
for product development, raw material, APIs and process
controls, and life-cycle management of complex dosage forms
(e.g. orally inhaled drug products and modified-release
dosage forms)
Topic 5: Modeling and simulation
Impact: Modeling and simulation (including in-vitro and in-
vivo correlations) is essential to efficient implementation
of quality by design and can help to identify and eliminate
unneeded in-vitro and/or in-vivo studies. Models (PK/PD,
exposure-response, clinical use simulation) support generic
drug evaluation policies especially for NTI drugs and complex
products.
[[Page S8293]]
Topic 6: Pharmacokinetic studies and evaluation of anti-
epileptic drugs
Impact: Improving public confidence in bioequivalent
generic epilepsy drugs.
Topic 7: Excipient effects on permeability and absorption
of BCS Class 3 Drugs
Impact: Extension of biowaivers to BCS Class 3 Drugs and
eliminating the need for unnecessary in vivo bioequivalence
studies
Topic 8: Product- and patient-related factors affecting
switchability of drug-device combination products (e.g.,
orally inhaled and nasal drug products and injection drug
products)
Impact: Establishing a systematic, science- and risk-based
approach to ensure device switchability, and improving the
patient's compliance and acceptability of generic devices
Topic 9: Postmarketing surveillance of generic drug usage
patterns and adverse events.
Impact: Improved data collection about usage patterns
(which strengths are used in which populations, extent of
switchability, back switches to RLD products, medication
errors) will be fed back into regulatory policy development
including those for excipients and impurities. Baseline data
collection on adverse event reports on switching to an
authorized generic would improve the ability to investigate
reports.
Topic 10: Evaluation of drug product physical attributes on
patient acceptability
Impact: Laboratory and human studies on physical attributes
such as tablet size, shape, coating, odor perception
(residual solvents), score configuration, taste masking or
color on the ability of patient to use (for example swallow)
or perceive quality (for example smell) will allow OGD to
provide better guidance to applicants on how these physical
attributes should be controlled and compared to the RLD.
Topic 11: Postmarking assessment of generic drugs and their
brand-name counterparts
Impact: Stronger public confidence in generic drugs because
of pro-active responses to product concerns. An integrated
response to product concerns involving laboratory
investigations and post-marketing data collection.
Topic 12: Physicochemical characterization of complex drug
substances
Impact: Developing analytical methods for demonstrating
pharmaceutical equivalence for complex drug substances (non-
small molecules) characterized by natural source origin,
polydisperse mixture, and/or supramolecular structure, and
therefore expanding the boundary of the generic drug program
for these complex drug products
Topic 13: Develop a risk-based understanding of potential
adverse impacts to drug product quality resulting from
changes in API manufacturing and controls.
Impact: The ability to predict the potential impacts of
manufacturing changes on product quality will allow
manufacturers to target assessments and controls on high-risk
areas for regulators to focus their reviews on these areas
too.
FY 2014 Regulatory Science Preliminary Topics for Consideration
In addition to those topics to be identified by the Working
Group described in section 3.A of this letter, topics will
include recommendations for draft guidances to clarify FDA
recommendations with regard to complex product development
and to help limit deficiencies in applications.
BIOSIMILAR BIOLOGICAL PRODUCT AUTHORIZATION PERFORMANCE GOALS AND
PROCEDURES FOR FISCAL YEARS 2013 THROUGH 2017
FDA proposes the following goals contingent on the
allocation of resources for each of the fiscal years 2013-
2017 of at least the inflation-adjusted value of $20 million
in non-user fee funds, plus collections of biosimilar user
fees, to support the process for the review of biosimilar
biological applications.
I. REVIEW PERFORMANCE GOALS
A. Biosimilar Biological Product Application Submissions and
Resubmissions
FY 2013
1. Review and act on 70 percent of original biosimilar
biological product application submissions within 10 months
of receipt.
2. Review and act on 70 percent of resubmitted original
biosimilar biological product applications within 6 months of
receipt.
FY 2014
1. Review and act on 70 percent of original biosimilar
biological product application submissions within 10 months
of receipt.
2. Review and act on 70 percent of resubmitted original
biosimilar biological product applications within 6 months of
receipt.
FY 2015
1. Review and act on 80 percent of original biosimilar
biological product application submissions within 10 months
of receipt.
2. Review and act on 80 percent of resubmitted original
biosimilar biological product applications within 6 months of
receipt.
FY 2016
1. Review and act on 85 percent of original biosimilar
biological product application submissions within 10 months
of receipt.
2. Review and act on 85 percent of resubmitted original
biosimilar biological product applications within 6 months of
receipt.
FY 2017
1. Review and act on 90 percent of original biosimilar
biological product application submissions within 10 months
of receipt.
2. Review and act on 90 percent of resubmitted original
biosimilar biological product applications within 6 months of
receipt.
B. Supplements with Clinical Data
1. Review and act on 90 percent of original supplements
with clinical data within 10 months of receipt.
2. Review and act on 90 percent of resubmitted supplements
with clinical data within 6 months of receipt.
C. Original Manufacturing Supplements
1. Review and act on 90 percent of manufacturing
supplements within 6 months of receipt.
D. Goals Summary Tables
ORIGINAL AND RESUBMITTED APPLICATIONS AND SUPPLEMENTS
--------------------------------------------------------------------------------------------------------------------------------------------------------
Performance goal
Submission cohort --------------------------------------------------------------------------------------------------------------------
2013 2014 2015 2016 2017
--------------------------------------------------------------------------------------------------------------------------------------------------------
Original Biosimilar Biological 70% in 10 months of 70% in 10 months of 80% in 10 months of 85% in 10 months of 90% in 10 months of
Product Application Submissions. the receipt date. the receipt date. the receipt date. the receipt date. the receipt date
Resubmitted Original Biosimilar 70% in 6 months of the 70% in 6 months of the 80% in 6 months of 85% in 6 months of 90% in 6 months of
Biological Product Applications. receipt date. receipt date. the receipt date. the receipt date. the receipt date
--------------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------
------------------------------------------------------------------------
Original Supplements with Clinical Data... 90% in 10 months of the
receipt date
Resubmitted Supplements with Clinical Data 90% in 6 months of the
receipt date
Manufacturing Supplements................. 90% in 6 months of the
receipt date
------------------------------------------------------------------------
II. FIRST CYCLE REVIEW PERFORMANCE
A. Notification of Issues Identified during the Filing Review
1. Performance Goal: For original biosimilar biological
product applications and supplements with clinical data, FDA
will report substantive review issues identified during the
initial filing review to the applicant by letter,
teleconference, facsimile, secure e-mail, or other expedient
means.
2. The timeline for such communication will be within 74
calendar days from the date of FDA receipt of the original
submission.
3. If no substantive review issues were identified during
the filing review, FDA will so notify the applicant.
4. FDA's filing review represents a preliminary review of
the application and is not indicative of deficiencies that
may be identified later in the review cycle.
5. FDA will notify the applicant of substantive review
issues prior to the goal date for 90% of applications.
B. Notification of Planned Review Timelines
1. Performance Goal: For original biosimilar biological
product applications and supplements with clinical data, FDA
will inform the applicant of the planned timeline for review
of the application. The information conveyed will include a
target date for communication of feedback from the review
division to the applicant regarding proposed labeling,
postmarketing requirements, and postmarketing commitments the
Agency will be requesting.
2. The planned review timeline will be included with the
notification of issues identified during the filing review,
within 74 calendar days from the date of FDA receipt of the
original submission.
3. The planned review timelines will be consistent with the
Guidance for Review Staff and Industry: Good Review
Management Principles and Practices for PDUFA Products
(GRMPs), taking into consideration the specific circumstances
surrounding the individual biosimilar biological product
application.
4. The planned review timeline will be based on the
application as submitted.
5. FDA will inform the applicant of the planned review
timeline for 90% of all applications and supplements with
clinical data.
6. In the event FDA determines that significant
deficiencies in the application preclude discussion of
labeling, postmarketing requirements, or postmarketing
commitments by the target date identified in the planned
review timeline (e.g., failure to demonstrate a biosimilar
biological product is highly similar to the reference
product, significant safety concern(s), need for a new
study(ies) or extensive re-analyses of existing data before
approval), FDA will communicate this determination to the
applicant in accordance with GRMPs and no later than the
target date. In such cases the planned review timeline will
be considered to have been met. Communication of FDA's
determination may occur by letter, teleconference, facsimile,
secure e-mail, or other expedient means.
7. To help expedite the development of biosimilar
biological products, communication
[[Page S8294]]
of the deficiencies identified in the application will
generally occur through issuance of a discipline review (DR)
letter(s) in advance of the planned target date for
initiation of discussions regarding labeling, postmarketing
requirements, and postmarketing commitments the Agency may
request.
8. If the applicant submits a major amendment(s) (refer to
Section VIII.B for additional information on major
amendments) and the review division chooses to review such
amendment(s) during that review cycle, the planned review
timeline initially communicated (under Section II.B.1 and 2)
will generally no longer be applicable. Consistent with the
underlying principles articulated in the GRMP guidance, FDA's
decision to extend the review clock should, except in rare
circumstances, be limited to occasions where review of the
new information could address outstanding deficiencies in the
application and lead to approval in the current review cycle.
If the review division determines that the major amendment
will result in an extension of the biosimilar biological
product review clock, the review division will communicate to
the applicant at the time of the clock extension a new
planned review timeline, including a new review timeline for
communication of feedback on proposed labeling, postmarketing
requirements, and any postmarketing commitments the Agency
may request.
In the rare case where the review division determines that
the major amendment will not result in an extension of the
biosimilar biological product review clock, the review
division may choose to retain the previously communicated
planned review timeline or may communicate a new planned
review timeline to the applicant.
The division will notify the applicant promptly of its
decision regarding review of the major amendment(s) and
whether the planned review timeline is still applicable.
III. REVIEW OF PROPRIETARY NAMES TO REDUCE MEDICATION ERRORS
To enhance patient safety, FDA will utilize user fees to
implement various measures to reduce medication errors
related to look-alike and sound-alike proprietary names and
such factors as unclear label abbreviations, acronyms, dose
designations, and error prone label and packaging design.
A. Review Performance Goals--Biosimilar Biological Product
Proprietary Names
1. Proprietary names submitted during the biosimilar
biological product development (BPD) phase
a) Review 90% of proprietary name submissions filed within
180 days of receipt. Notify sponsor of tentative acceptance
or non-acceptance.
b) If the proprietary name is found to be unacceptable, the
sponsor can request reconsideration by submitting a written
rebuttal with supporting data or request a meeting within 60
days to discuss the initial decision (meeting package
required).
c) If the proprietary name is found to be unacceptable, the
above review performance goals also would apply to the
written request for reconsideration with supporting data or
the submission of a new proprietary name.
d) A complete submission is required to begin the review
clock.
2. Proprietary names submitted with biosimilar biological
product application
a) Review 90% of biosimilar biological product application
proprietary name submissions filed within 90 days of receipt.
Notify sponsor of tentative acceptance/non-acceptance.
b) A supplemental review will be done meeting the above
review performance goals if the proprietary name has been
submitted previously (during the BPD phase) and has received
tentative acceptance.
c) If the proprietary name is found to be unacceptable, the
sponsor can request reconsideration by submitting a written
rebuttal with supporting data or request a meeting within 60
days to discuss the initial decision (meeting package
required).
d) If the proprietary name is found to be unacceptable, the
above review performance goals apply to the written request
for reconsideration with supporting data or the submission of
a new proprietary name.
e) A complete submission is required to begin the review
clock.
iv. major dispute resolution
A. Procedure: For procedural or scientific matters
involving the review of biosimilar biological product
applications and supplements (as defined in BsUFA) that
cannot be resolved at the signatory authority level
(including a request for reconsideration by the signatory
authority after reviewing any materials that are planned to
be forwarded with an appeal to the next level), the response
to appeals of decisions will occur within 30 calendar days of
the Center's receipt of the written appeal.
B. Performance goal: 90% of such answers are provided
within 30 calendar days of the Center's receipt of the
written appeal.
C. Conditions:
1. Sponsors should first try to resolve the procedural or
scientific issue at the signatory authority level. If it
cannot be resolved at that level, it should be appealed to
the next higher organizational level (with a copy to the
signatory authority) and then, if necessary, to the next
higher organizational level.
2. Responses should be either verbal (followed by a written
confirmation within 14 calendar days of the verbal
notification) or written and should ordinarily be to either
grant or deny the appeal.
3. If the decision is to deny the appeal, the response
should include reasons for the denial and any actions the
sponsor might take to persuade the Agency to reverse its
decision.
4. In some cases, further data or further input from others
might be needed to reach a decision on the appeal. In these
cases, the ``response'' should be the plan for obtaining that
information (e.g., requesting further information from the
sponsor, scheduling a meeting with the sponsor, scheduling
the issue for discussion at the next scheduled available
advisory committee).
5. In these cases, once the required information is
received by the Agency (including any advice from an advisory
committee), the person to whom the appeal was made, again has
30 calendar days from the receipt of the required information
in which to either deny or grant the appeal.
6. Again, if the decision is to deny the appeal, the
response should include the reasons for the denial and any
actions the sponsor might take to persuade the Agency to
reverse its decision.
7. Note: If the Agency decides to present the issue to an
advisory committee and there are not 30 days before the next
scheduled advisory committee, the issue will be presented at
the following scheduled committee meeting to allow
conformance with advisory committee administrative
procedures.
v. clinical holds
A. Procedure: The Center should respond to a sponsor's
complete response to a clinical hold within 30 days of the
Agency's receipt of the submission of such sponsor response.
B. Performance goal: 90% of such responses are provided
within 30 calendar days of the Agency's receipt of the
sponsor's response.
VI. SPECIAL PROTOCOL QUESTION ASSESSMENT AND AGREEMENT
A. Procedure: Upon specific request by a sponsor (including
specific questions that the sponsor desires to be answered),
the Agency will evaluate certain protocols and related issues
to assess whether the design is adequate to meet scientific
and regulatory requirements identified by the sponsor.
1. The sponsor should submit a limited number of specific
questions about the protocol design and scientific and
regulatory requirements for which the sponsor seeks agreement
(e.g., are the clinical endpoints adequate to assess whether
there are clinically meaningful differences between the
proposed biosimilar biological product and the reference
product).
2. Within 45 days of Agency receipt of the protocol and
specific questions, the Agency will provide a written
response to the sponsor that includes a succinct assessment
of the protocol and answers to the questions posed by the
sponsor. If the Agency does not agree that the protocol
design, execution plans, and data analyses are adequate to
achieve the goals of the sponsor, the reasons for the
disagreement will be explained in the response.
3. Protocols that qualify for this program include any
necessary clinical study or studies to prove biosimilarity
and/or interchangeability (e.g., protocols for comparative
clinical trials that will form the primary basis for
demonstrating that there are no clinically meaningful
differences between the proposed biosimilar biological
product and the reference product, and protocols for clinical
trials intended to support a demonstration of
interchangeability). For such protocols to qualify for this
comprehensive protocol assessment, the sponsor must have had
a BPD Type 2 or 3 Meeting, as defined in section VIII (F and
G), below, with the review division so that the division is
aware of the developmental context in which the protocol is
being reviewed and the questions being answered.
4. If a protocol is reviewed under the process outlined
above, and agreement with the Agency is reached on design,
execution, and analyses, and if the results of the trial
conducted under the protocol substantiate the hypothesis of
the protocol, the Agency agrees that the data from the
protocol can be used as part of the primary basis for
approval of the product. The fundamental agreement here is
that having agreed to the design, execution, and analyses
proposed in protocols reviewed under this process, the Agency
will not later alter its perspective on the issues of design,
execution, or analyses unless public health concerns
unrecognized at the time of protocol assessment under this
process are evident.
B. Performance goal:
For FY 2013, 70% of special protocols assessments and
agreement requests completed and returned to sponsor within
timeframes.
For FY 2014, 70% of special protocols assessments and
agreement requests completed and returned to sponsor within
timeframes.
For FY 2015, 80% of special protocols assessments and
agreement requests completed and returned to sponsor within
timeframes.
For FY 2016, 85% of special protocols assessments and
agreement requests completed and returned to sponsor within
timeframes.
For FY 2017, 90% of special protocols assessments and
agreement requests completed and returned to sponsor within
timeframes.
C. Reporting: The Agency will track and report the number
of original special protocol assessments and resubmissions
per original special protocol assessment.
[[Page S8295]]
VII. MEETING MANAGEMENT GOALS
A. Responses to Meeting Requests
1. Procedure: Within 14 calendar days of the Agency's
receipt of a request and meeting package from industry for a
BPD Type 1 Meeting, or within 21 calendar days of the
Agency's receipt of a request and meeting package from
industry for a Biosimilar Initial Advisory Meeting or a BPD
Type 2, 3, or 4 Meeting, as defined in section VIII(D-H),
below, CBER and CDER should notify the requester in writing
of the date, time, place, and format (i.e., a scheduled face-
to-face, teleconference, or videoconference) for the meeting,
as well as expected Center participants.
2. Performance Goal: FDA will provide this notification
within 14 days for 90 percent of BPD Type 1 Meeting requests
and within 21 days for 90 percent of Biosimilar Initial
Advisory Meeting and BPD Type 2, 3 and 4 Meeting requests.
B. Scheduling Meetings
1. Procedure: The meeting date should reflect the next
available date on which all applicable Center personnel are
available to attend, consistent with the component's other
business; however, the meeting should be scheduled consistent
with the type of meeting requested.
a) Biosimilar Initial Advisory Meeting should occur within
90 calendar days of the Agency receipt of the sponsor-
submitted meeting request and meeting package.
b) BPD Type 1 Meetings should occur within 30 calendar days
of the Agency receipt of the sponsor-submitted meeting
request and meeting package.
c) BPD Type 2 Meetings should occur within 75 calendar days
of the Agency receipt of the sponsor-submitted meeting
request and meeting package.
d) BPD Type 3 Meetings should occur within 120 calendar
days of the Agency receipt of the sponsor-submitted meeting
request and meeting package.
e) BPD Type 4 Meetings should occur within 60 calendar days
of the Agency receipt of the sponsor-submitted meeting
request and meeting package.
2. Performance goal:
For FY 2013, 70% of Biosimilar Initial Advisory Meetings
and BPD Type 1-4 Meetings are held within the timeframe.
For FY 2014, 70% of Biosimilar Initial Advisory Meetings
and BPD Type 1-4 Meetings are held within the timeframe.
For FY 2015, 80% of Biosimilar Initial Advisory Meetings
and BPD Type 1-4 Meetings are held within the timeframe.
For FY 2016, 85% of Biosimilar Initial Advisory Meetings
and BPD Type 1-4 Meetings are held within the timeframe.
For FY 2017, 90% of Biosimilar Initial Advisory Meetings
and BPD Type 1-4 Meetings are held within the timeframe.
C. Meeting Minutes
1. Procedure: The Agency will prepare minutes which will be
available to the sponsor 30 calendar days after the meeting.
The minutes will clearly outline the important agreements,
disagreements, issues for further discussion, and action
items from the meeting in bulleted form and need not be in
great detail.
2. Performance Goal: FDA will provide meeting minutes
within 30 days of the date of the meeting for 90 percent of
Biosimilar Initial Advisory Meetings and BPD Type 1-4
Meetings.
D. Conditions
For a meeting to qualify for these performance goals:
1. A written request (letter or fax) and supporting
documentation (i.e., the meeting package) should be submitted
to the appropriate review division or office. The request
should provide:
a) A brief statement of the purpose of the meeting, the
sponsor's proposal for the type of meeting, and the sponsor's
proposal for a face-to-face meeting or a teleconference;
b) A listing of the specific objectives/outcomes the
requester expects from the meeting;
c) A proposed agenda, including estimated times needed for
each agenda item;
d) A list of questions, grouped by discipline. For each
question there should be a brief explanation of the context
and purpose of the question.
e) A listing of planned external attendees; and
f) A listing of requested participants/disciplines
representative(s) from the Center.
g) Suggested dates and times (e.g., morning or afternoon)
for the meeting that are within or beyond the appropriate
time frame of the meeting type being requested.
2. The Agency concurs that the meeting will serve a useful
purpose (i.e., it is not premature or clearly unnecessary).
However, requests for BPD Type 2, 3 and 4 Meetings will be
honored except in the most unusual circumstances.
The Center may determine that a different type of meeting
is more appropriate and it may grant a meeting of a different
type than requested, which may require the payment of a
biosimilar biological product development fee as described in
section 744B of the Federal Food, Drug, and Cosmetic Act
before the meeting will be provided. If a biosimilar
biological product development fee is required under section
744B, and the sponsor does not pay the fee within the time
frame required under section 744B, the meeting will be
cancelled. If the sponsor pays the biosimilar biological
product development fee after the meeting has been cancelled
due to non-payment, the time frame described in section
VII.A.1 will be calculated from the date on which FDA
received the payment, not the date on which the sponsor
originally submitted the meeting request.
Sponsors are encouraged to consult FDA to obtain further
information on recommended meeting procedures.
3. FDA will develop and publish for comment draft guidance
on Biosimilar Initial Advisory Meetings and BPD Type 1-4
Meetings by end of second quarter of FY 2014.
VIII. DEFINITIONS AND EXPLANATION OF TERMS
A. The term ``review and act on'' means the issuance of a
complete action letter after the complete review of a filed
complete application. The action letter, if it is not an
approval, will set forth in detail the specific deficiencies
and, where appropriate, the actions necessary to place the
application in condition for approval.
B. Goal Date Extensions for Major Amendments
1. A major amendment to an original application, supplement
with clinical data, or resubmission of any of these
applications, submitted at any time during the review cycle,
may extend the goal date by three months.
2. A major amendment may include, for example, a major new
clinical safety/efficacy study report; major re-analysis of
previously submitted study(ies); submission of a risk
evaluation and mitigation strategy (REMS) with elements to
assure safe use (ETASU) not included in the original
application; or significant amendment to a previously
submitted REMS with ETASU. Generally, changes to REMS that do
not include ETASU and minor changes to REMS with ETASU will
not be considered major amendments.
3. A major amendment to a manufacturing supplement
submitted at any time during the review cycle may extend the
goal date by two months.
4. Only one extension can be given per review cycle.
5. Consistent with the underlying principles articulated in
the GRMP guidance, FDA's decision to extend the review clock
should, except in rare circumstances, be limited to occasions
where review of the new information could address outstanding
deficiencies in the application and lead to approval in the
current review cycle.
C. A resubmitted original application is a complete
response to an action letter addressing all identified
deficiencies.
D. A Biosimilar Initial Advisory Meeting is an initial
assessment limited to a general discussion regarding whether
licensure under section 351(k) of the Public Health Service
Act may be feasible for a particular product, and, if so,
general advice on the expected content of the development
program. Such term does not include any meeting that involves
substantive review of summary data or full study reports.
E. A BPD Type 1 Meeting is a meeting which is necessary for
an otherwise stalled drug development program to proceed
(e.g. meeting to discuss clinical holds, dispute resolution
meeting), a special protocol assessment meeting, or a meeting
to address an important safety issue.
F. A BPD Type 2 Meeting is a meeting to discuss a specific
issue (e.g., proposed study design or endpoints) or questions
where FDA will provide targeted advice regarding an ongoing
biosimilar biological product development program. Such term
includes substantive review of summary data, but does not
include review of full study reports.
G. A BPD Type 3 Meeting is an in depth data review and
advice meeting regarding an ongoing biosimilar biological
product development program. Such term includes substantive
review of full study reports, FDA advice regarding the
similarity between the proposed biosimilar biological product
and the reference product, and FDA advice regarding
additional studies, including design and analysis.
H. A BPD Type 4 Meeting is a meeting to discuss the format
and content of a biosimilar biological product application or
supplement submitted under 351(k) of the PHS Act.
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