[Congressional Record Volume 163, Number 131 (Wednesday, August 2, 2017)]
[Senate]
[Pages S4721-S4753]
From the Congressional Record Online through the Government Publishing Office [www.gpo.gov]
FOOD AND DRUG ADMINISTRATION USER FEE REAUTHORIZATION
Mr. ALEXANDER. Mr. President, I ask unanimous consent to have printed
in the Record a copy of the commitment 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
regarding reauthorization of the Biosimilar User Fee Act, Generic Drug
User Fee Act, Prescription Drug User Fee Act, and Medical Device User
Fee Amendments.
There being no objection, the material was ordered to be printed in
the Record, as follows:
Department of Health &
Human Services,
Washington, DC, January 4, 2017.
Hon. Lamar Alexander,
Chairman, Committee on Health, Education, Labor and Pensions,
U.S. Senate, Washington, DC.
Dear Mr. Chairman: The Generic Drug User Fee Amendments of
2012 (GDUFA) enacted as title III of the Food and Drug
Administration Safety and Innovation Act [Pub. L. 112-144],
expires at the end of Fiscal Year 2017. With this letter the
Administration is providing our recommendations for the
reauthorization of GDUFA for the Fiscal Years 2018-2022
(GDUFA II).
Under GDUFA, the revenues generated from fees paid by the
generic pharmaceutical industry have been used to expedite
the process for the review of generic drugs and to support
and augment regulatory science and drug development. The
expenditure of these funds is in accordance with the statute
and provides resources to meet the performance goals and
procedures that were developed by the Food and Drug
Administration [FDA] in consultation with representatives of
regulated industry. FDA estimates that the fees negotiated in
GDUFA II will average approximately $493.6 million per year,
adjusted annually for inflation.
Throughout this process, the FDA has solicited input and
worked with various stakeholders, including representatives
from consumer, patient, academic research, and health
provider groups, and negotiated with the regulated industry,
to develop reauthorization recommendations for GDUFA that
would build upon and enhance the success of the program. In
addition, we have complied with the statutory requirements to
solicit public comments on our recommendations, and the
summary of public comments is posted on the agency web site.
Our recommendations build upon the successes of existing
programs and performance goals with step-wise improvements
allowing FDA the resources to establish a generic drug review
program that can keep up with the ever-expanding generic drug
industry. The recommendations will bring all Abbreviated New
Drug Applications (ANDAs) under a common review goals scheme
which calls for faster review cycles of 10 months for
standard ANDAs and eight months for priority ANDAs. Priority
status will be reserved for drug shortages, first generics,
sole source generics and other public health priorities. The
negotiated recommendations provide that FDA will communicate
deficiencies to industry throughout rather than at the end of
a review cycle, increasing the chances for applicants to
remedy deficiencies and obtain approval in fewer cycles. This
will allow for improved predictability and transparency and
enable industry advanced business planning.
[[Page S4722]]
The agreement also establishes a robust Pre-ANDA program
for complex products. The program will include meetings with
applicants, guidance development and regulatory science
enhancements aimed at allowing applicants with complex
products to submit more complete applications and FDA to be
more prepared for such submissions.
FDA will also make improvements to the facility assessment
program in order to increase predictability, transparency and
safety. In addition, FDA has committed to accountability and
reporting enhancements. FDA will conduct activities to
evaluate the financial administration and resource
allocations of the GDUFA II program to help identify areas to
enhance operational and fiscal efficiency and transparency.
FDA will also expand GDUFA program performance reporting to
enable the regulated industry, patients and consumer groups,
and other stakeholders to better gauge the generic drug
program's performance.
Lastly, the agreement would revamp the user fee structure.
GDUFA II will be funded at a level commensurate with the
volume of ANDA submissions--the primary workload driver of
the program. This will allow FDA the resources necessary to
meet all of its commitments. In order to maintain a
predictable fee base and to more closely align fee
responsibility with program costs and fee-paying ability, FDA
and industry have agreed to shift the burden more toward
annual program fees. To address specific small business
concerns, FDA and industry have proposed three distinct small
business considerations. We anticipate that the proposed
GDUFA II will increase public access to affordable, generic
drug products.
The following five enclosures are provided for your
consideration: The proposed GDUFA II statutory language; a
redline of current law; the GDUFA Reauthorization Performance
Goals and Procedures--Fiscal Years 2018 through 2022; the
Background for the Proposed Changes for Reauthorization of
GDUFA in Fiscal Years 2018 through 2022; and the summary of
public comments.
Thank you for the opportunity to present our
recommendations to reauthorize this vital program. We would
be pleased to brief your staff on the details and want to
work closely with Congress in order to reauthorize the
program in a timely manner. The Office of Management and
Budget has advised that the bill and the enclosed performance
goals are in accord with the Administration's program.
Sincerely,
Sylvia Burwell,
Secretary.
____
Department of Health &
Human Services,
Washington, DC, January 4, 2017.
Hon. Patty Murray,
Ranking Member, Committee on Health, Education, Labor and
Pensions, U.S. Senate, Washington, DC.
Dear Senator Murray: The Generic Drug User Fee Amendments
of 2012 (GDUFA) enacted as title III of the Food and Drug
Administration Safety and Innovation Act [Pub. L. 112-144],
expires at the end of Fiscal Year 2017. With this letter the
Administration is providing our recommendations for the
reauthorization of GDUFA for the Fiscal Years 2018-2022
(GDUFA II).
Under GDUFA, the revenues generated from fees paid by the
generic pharmaceutical industry have been used to expedite
the process for the review of generic drugs and to support
and augment regulatory science and drug development. The
expenditure of these funds is in accordance with the statute
and provides resources to meet the performance goals and
procedures that were developed by the Food and Drug
Administration [FDA] in consultation with representatives of
regulated industry. FDA estimates that the fees negotiated in
GDUFA II will average approximately $493.6 million per year,
adjusted annually for inflation.
Throughout this process, the FDA has solicited input and
worked with various stakeholders, including representatives
from consumer, patient, academic research, and health
provider groups, and negotiated with the regulated industry,
to develop reauthorization recommendations for GDUFA that
would build upon and enhance the success of the program. In
addition, we have complied with the statutory requirements to
solicit public comments on our recommendations, and the
summary of public comments is posted on the agency web site.
Our recommendations build upon the successes of existing
programs and performance goals with step-wise improvements
allowing FDA the resources to establish a generic drug review
program that can keep up with the ever-expanding generic drug
industry. The recommendations will bring all Abbreviated New
Drug Applications (ANDAs) under a common review goals scheme
which calls for faster review cycles of 10 months for
standard ANDAs and eight months for priority ANDAs. Priority
status will be reserved for drug shortages, first generics,
sole source generics and other public health priorities. The
negotiated recommendations provide that FDA will communicate
deficiencies to industry throughout rather than at the end of
a review cycle, increasing the chances for applicants to
remedy deficiencies and obtain approval in fewer cycles. This
will allow for improved predictability and transparency and
enable industry advanced business planning.
The agreement also establishes a robust Pre-ANDA program
for complex products. The program will include meetings with
applicants, guidance development and regulatory science
enhancements aimed at allowing applicants with complex
products to submit more complete applications and FDA to be
more prepared for such submissions.
FDA will also make improvements to the facility assessment
program in order to increase predictability, transparency and
safety. In addition, FDA has committed to accountability and
reporting enhancements. FDA will conduct activities to
evaluate the financial administration and resource
allocations of the GDUFA II program to help identify areas to
enhance operational and fiscal efficiency and transparency.
FDA will also expand GDUFA program performance reporting to
enable the regulated industry, patients and consumer groups,
and other stakeholders to better gauge the generic drug
program's performance.
Lastly, the agreement would revamp the user fee structure.
GDUFA II will be funded at a level commensurate with the
volume of ANDA submissions--the primary workload driver of
the program. This will allow FDA the resources necessary to
meet all of its commitments. In order to maintain a
predictable fee base and to more closely align fee
responsibility with program costs and fee-paying ability, FDA
and industry have agreed to shift the burden more toward
annual program fees. To address specific small business
concerns, FDA and industry have proposed three distinct small
business considerations. We anticipate that the proposed
GDUFA II will increase public access to affordable, generic
drug products.
The following five enclosures are provided for your
consideration: The proposed GDUFA II statutory language; a
redline of current law; the GDUFA Reauthorization Performance
Goals and Procedures--Fiscal Years 2018 through 2022; the
Background for the Proposed Changes for Reauthorization of
GDUFA in Fiscal Years 2018 through 2022; and the summary of
public comments.
Thank you for the opportunity to present our
recommendations to reauthorize this vital program. We would
be pleased to brief your staff on the details and want to
work closely with Congress in order to reauthorize the
program in a timely manner. The Office of Management and
Budget has advised that the bill and the enclosed performance
goals are in accord with the Administration's program.
Sincerely,
Sylvia Burwell,
Secretary.
____
Department of Health &
Human Services,
Washington, DC, January 4, 2017.
Hon. Greg Walden,
Chairman, Committee on Energy and Commerce,
House of Representatives, Washington, DC.
Dear Mr. Chairman: The Generic Drug User Fee Amendments of
2012 (GDUFA) enacted as title III of the Food and Drug
Administration Safety and Innovation Act [Pub. L. 112-144],
expires at the end of Fiscal Year 2017. With this letter the
Administration is providing our recommendations for the
reauthorization of GDUFA for the Fiscal Years 2018-2022
(GDUFA II).
Under GDUFA, the revenues generated from fees paid by the
generic pharmaceutical industry have been used to expedite
the process for the review of generic drugs and to support
and augment regulatory science and drug development. The
expenditure of these funds is in accordance with the statute
and provides resources to meet the performance goals and
procedures that were developed by the Food and Drug
Administration [FDA] in consultation with representatives of
regulated industry. FDA estimates that the fees negotiated in
GDUFA II will average approximately $493.6 million per year,
adjusted annually for inflation.
Throughout this process, the FDA has solicited input and
worked with various stakeholders, including representatives
from consumer, patient, academic research, and health
provider groups, and negotiated with the regulated industry,
to develop reauthorization recommendations for GDUFA that
would build upon and enhance the success of the program. In
addition, we have complied with the statutory requirements to
solicit public comments on our recommendations, and the
summary of public comments is posted on the agency web site.
Our recommendations build upon the successes of existing
programs and performance goals with step-wise improvements
allowing FDA the resources to establish a generic drug review
program that can keep up with the ever-expanding generic drug
industry. The recommendations will bring all Abbreviated New
Drug Applications (ANDAs) under a common review goals scheme
which calls for faster review cycles of 10 months for
standard ANDAs and eight months for priority ANDAs. Priority
status will be reserved for drug shortages, first generics,
sole source generics and other public health priorities. The
negotiated recommendations provide that FDA will communicate
deficiencies to industry throughout rather than at the end of
a review cycle, increasing the chances for applicants to
remedy deficiencies and obtain approval in fewer cycles. This
will allow for improved predictability and transparency and
enable industry advanced business planning.
The agreement also establishes a robust Pre-ANDA program
for complex products.
[[Page S4723]]
The program will include meetings with applicants, guidance
development and regulatory science enhancements aimed at
allowing applicants with complex products to submit more
complete applications and FDA to be more prepared for such
submissions.
FDA will also make improvements to the facility assessment
program in order to increase predictability, transparency and
safety. In addition, FDA has committed to accountability and
reporting enhancements. FDA will conduct activities to
evaluate the financial administration and resource
allocations of the GDUFA II program to help identify areas to
enhance operational and fiscal efficiency and transparency.
FDA will also expand GDUFA program performance reporting to
enable the regulated industry, patients and consumer groups,
and other stakeholders to better gauge the generic drug
program's performance.
Lastly, the agreement would revamp the user fee structure.
GDUFA II will be funded at a level commensurate with the
volume of ANDA submissions--the primary workload driver of
the program. This will allow FDA the resources necessary to
meet all of its commitments. In order to maintain a
predictable fee base and to more closely align fee
responsibility with program costs and fee-paying ability, FDA
and industry have agreed to shift the burden more toward
annual program fees. To address specific small business
concerns, FDA and industry have proposed three distinct small
business considerations. We anticipate that the proposed
GDUFA II will increase public access to affordable, generic
drug products.
The following five enclosures are provided for your
consideration: The proposed GDUFA II statutory language; a
redline of current law; the GDUFA Reauthorization Performance
Goals and Procedures Fiscal Years 2018 through 2022; the
Background for the Proposed Changes for Reauthorization of
GDUFA in Fiscal Years 2018 through 2022; and the summary of
public comments.
Thank you for the opportunity to present our
recommendations to reauthorize this vital program. We would
be pleased to brief your staff on the details and want to
work closely with Congress in order to reauthorize the
program in a timely manner. The Office of Management and
Budget has advised that the bill and the enclosed performance
goals are in accord with the Administration's program.
Sincerely,
Sylvia Burwell,
Secretary.
____
Department of Health &
Human Services,
Washington, DC, January 4, 2017.
Hon. Frank Pallone,
Ranking Member, Committee on Energy and Commerce, House of
Representatives, Washington, DC.
Dear Representative Pallone: The Generic Drug User Fee
Amendments of 2012 (GDUFA) enacted as title III of the Food
and Drug Administration Safety and Innovation Act [Pub. L.
112-144], expires at the end of Fiscal Year 2017. With this
letter the Administration is providing our recommendations
for the reauthorization of GDUFA for the Fiscal Years 2018-
2022 (GDUFA II).
Under GDUFA, the revenues generated from fees paid by the
generic pharmaceutical industry have been used to expedite
the process for the review of generic drugs and to support
and augment regulatory science and drug development. The
expenditure of these funds is in accordance with the statute
and provides resources to meet the performance goals and
procedures that were developed by the Food and Drug
Administration [FDA] in consultation with representatives of
regulated industry. FDA estimates that the fees negotiated in
GDUFA II will average approximately $493.6 million per year,
adjusted annually for inflation.
Throughout this process, the FDA has solicited input and
worked with various stakeholders, including representatives
from consumer, patient, academic research, and health
provider groups, and negotiated with the regulated industry,
to develop reauthorization recommendations for GDUFA that
would build upon and enhance the success of the program. In
addition, we have complied with the statutory requirements to
solicit public comments on our recommendations, and the
summary of public comments is posted on the agency web site.
Our recommendations build upon the successes of existing
programs and performance goals with step-wise improvements
allowing FDA the resources to establish a generic drug review
program that can keep up with the ever-expanding generic drug
industry. The recommendations will bring all Abbreviated New
Drug Applications (ANDAs) under a common review goals scheme
which calls for faster review cycles of 10 months for
standard ANDAs and eight months for priority ANDAs. Priority
status will be reserved for drug shortages, first generics,
sole source generics and other public health priorities. The
negotiated recommendations provide that FDA will communicate
deficiencies to industry throughout rather than at the end of
a review cycle, increasing the chances for applicants to
remedy deficiencies and obtain approval in fewer cycles. This
will allow for improved predictability and transparency and
enable industry advanced business planning.
The agreement also establishes a robust Pre-ANDA program
for complex products. The program will include meetings with
applicants, guidance development and regulatory science
enhancements aimed at allowing applicants with complex
products to submit more complete applications and FDA to be
more prepared for such submissions.
FDA will also make improvements to the facility assessment
program in order to increase predictability, transparency and
safety. In addition, FDA has committed to accountability and
reporting enhancements. FDA will conduct activities to
evaluate the financial administration and resource
allocations of the GDUFA II program to help identify areas to
enhance operational and fiscal efficiency and transparency.
FDA will also expand GDUFA program performance reporting to
enable the regulated industry, patients and consumer groups,
and other stakeholders to better gauge the generic drug
program's performance.
Lastly, the agreement would revamp the user fee structure.
GDUFA II will be funded at a level commensurate with the
volume of ANDA submissions--the primary workload driver of
the program. This will allow FDA the resources necessary to
meet all of its commitments. In order to maintain a
predictable fee base and to more closely align fee
responsibility with program costs and fee-paying ability, FDA
and industry have agreed to shift the burden more toward
annual program fees. To address specific small business
concerns, FDA and industry have proposed three distinct small
business considerations. We anticipate that the proposed
GDUFA II will increase public access to affordable, generic
drug products.
The following five enclosures are provided for your
consideration: The proposed GDUFA II statutory language; a
redline of current law; the GDUFA Reauthorization Performance
Goals and Procedures--Fiscal Years 2018 through 2022; the
Background for the Proposed Changes for Reauthorization of
GDUFA in Fiscal Years 2018 through 2022; and the summary of
public comments.
Thank you for the opportunity to present our
recommendations to reauthorize this vital program. We would
be pleased to brief your staff on the details and want to
work closely with Congress in order to reauthorize the
program in a timely manner. The Office of Management and
Budget has advised that the bill and the enclosed performance
goals are in accord with the Administration's program.
Sincerely,
Sylvia Burwell,
Secretary.
Mr. ALEXANDER. Mr. President, I ask unanimous consent to have printed
in the Record a copy of the commitment letter for the Generic Drug User
Fee Act, GDUFA, reauthorization for fiscal years 2018 to 2022, known as
GDUFA II.
There being no objection, the material was ordered to be printed in
the Record, as follows:
GDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROGRAM ENHANCEMENTS FISCAL
YEARS 2018-2022
I. Submission Review Performance Goals
A. Original ANDAs and ANDA Amendments
B. PASs and PAS Amendments
C. Unsolicited ANDA and PAS Amendments
D. DMFs
E. Controlled Correspondence
F. GDUFA I Bridging
II. Original ANDA Review Program Enhancements
A. ANDA Receipt
B. ANDA Review Transparency and Communications Enhancements
C. Review Classification Changes During the Review Cycle
D. ANDA Approval and Tentative Approval
E. Dispute Resolution
F. Other ANDA Review Program Aspirations
III. Pre-ANDA Program and Subsequent Mid-Review-Cycle
Meetings for Complex Products
A. Rationale for Pre-ANDA Program, Guidance on Enhanced
Pathway for Complex Products
B. Controlled Correspondence
C. Product-Specific Guidance
D. Product Development Meetings
E. Pre-Submission Meetings
F. Inactive Ingredient Database Enhancements
G. Regulatory Science Enhancements
H. Safety Determination Letters
I. Other Pre-ANDA Program Aspirations
IV. DMF Review Program Enhancements
A. Communication of DMF Review Comments
B. Teleconferences to Clarify DMF First Cycle Review
Deficiencies
C. DMF First Adequate Letters
D. DMF No Further Comment Letters
E. Guidance on Post-Approval Changes to Type II API DMFs
V. Facilities
A. Guidance on Risk-Based Site Selection Model
B. Outreach to Foreign Regulators on Risk-Based Site
Selection Model
C. Export Support and Education of Other Health Authorities
D. Communications to Foreign Regulators
E. Communication Regarding Inspections
F. GDUFA II Facility Compliance Status Database
VI. Enhanced Accountability and Reporting
A. Resource Management Planning and Modernized Time
Reporting
B. Financial Transparency and Efficiency
[[Page S4724]]
C. Performance Reporting
VII. Definitions
GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal
Years 2018-2022
This document contains the performance goals and program
enhancements for the Generic Drug User Fee Act (GDUFA)
reauthorization for Fiscal Years (FYs) 2018-2022, known as
GDUFA II. It is commonly referred to as the ``goals letter''
or ``commitment letter''. The goals letter represents the
product of the Food and Drug Administration's (FDA's)
discussions with the regulated industry and public
stakeholders, as mandated by Congress. The performance goals
and program enhancements specified in this letter apply to
aspects of the generic drug review program that are important
for facilitating timely access to quality, affordable generic
medicines. FDA is committed to meeting the performance goals
specified in this letter and to continuous improvement of its
performance.
Unless otherwise stated, goals apply to cohorts of each
fiscal year (FY).
GDUFA Reauthorization Performance Goals And Procedures Fiscal Years
2018-2022
The performance goals and procedures of the FDA, as agreed
to under the first reauthorization of the generic drug user
fee program, are summarized below.
I. SUBMISSION REVIEW PERFORMANCE GOALS
A. Original ANDAs and ANDA Amendments
1. Review and act on 90 percent of standard original
Abbreviated New Drug Applications (ANDAs) within 10 months of
the date of ANDA submission.
2. Review and act on 90 percent of priority original ANDAs
within the applicable review goal.
a. Review and act on priority original ANDAs within 8
months of the date of ANDA submission, if the applicant
submits a Pre-Submission Facility Correspondence 2 months
prior to the date of ANDA submission and the Pre-Submission
Facility Correspondence is found to be complete and accurate
and remains unChanged.
b. Review and act on priority original ANDAs within 10
months of the date of ANDA submission if the applicant does
not submit a Pre-Submission Facility Correspondence 2 months
prior to the date of ANDA submission or facility information
changes or is found to be incomplete or inaccurate.
3. Review and act on 90 percent of standard major ANDA
amendments within the applicable review goal.
a. Review and act on standard major ANDA amendments within
8 months of the date of amendment submission if preapproval
inspection is not required.
b. Review and act on standard major ANDA amendments within
10 months of the date of amendment submission if preapproval
inspection is required.
4. Review and act on 90 percent of priority major ANDA
amendment submissions within the applicable review goal.
a. Review and act on priority major ANDA amendments within
6 months of the date of amendment submission if preapproval
inspection is not required.
b. Review and act on priority major ANDA amendments within
8 months of amendment submission if (i) preapproval
inspection is required and (ii) applicant submits a Pre-
Submission Facility Correspondence 2 months prior to the date
of amendment submission and the Pre-Submission Facility
Correspondence is found to be complete and accurate and
remains unchanged.
c. Review and act on priority major ANDA amendments within
10 months of amendment submission if (i) preapproval
inspection is required and (ii) the applicant does not submit
a Pre-Submission Facility Correspondence 2 months prior to
amendment submission, or facility information Changes or is
found to be incomplete or inaccurate.
5. Review and act on 90 percent of standard and priority
minor ANDA amendments within 3 months of the date of
amendment submission.
TABLE FOR SECTION I(A)(1) AND (2): ORIGINAL ANDAS
------------------------------------------------------------------------
Submission Type Goal
------------------------------------------------------------------------
Standard Original ANDAs................... 90% within 10 months of
submission date.
Priority Original ANDAs................... 90% within 8 months of
submission date if
applicant meets
requirements under
I(A)(2)(a).
90% within 10 months of
submission date if
applicant does not meet
requirements as described
under I(A)(2)(b).
------------------------------------------------------------------------
TABLE FOR SECTION I(A)(3)-(5): ANDA AMENDMENTS
------------------------------------------------------------------------
Submission Type Goal
------------------------------------------------------------------------
Standard Major ANDA Amendments............ 90% within 8 months of
submission date if
preapproval inspection not
required.
90% within 10 months of
submission date if
preapproval inspection
required.
Priority Major ANDA Amendments............ 90% within 6 months of
submission date if
preapproval inspection not
required.
90% within 8 months of
submission date if
preapproval inspection
required and applicant
meets requirements under
I(A)(4)(b).
90% within 10 months of
submission date if
preapproval inspection
required and applicant does
not meet requirements as
described under I(A)(4)(c).
Standard and Priority Minor ANDA 90% within 3 months of
Amendments. submission date.
------------------------------------------------------------------------
B. PASs and PAS Amendments
1. Review and act on 90 percent of standard Prior Approval
Supplements (PASs) within the applicable review goal.
a. Review and act on standard PASs within 6 months of the
date of PAS submission if preapproval inspection is not
required.
b. Review and act on standard PASs within 10 months of the
date of PAS submission if preapproval inspection is required.
2. Review and act on 90 percent of priority PASs within the
applicable review goal.
a. Review and act on priority PASs within 4 months of the
date of PAS submission if preapproval inspection is not
required.
b. Review and act on priority PASs within 8 months of the
date of PAS submission if (i) preapproval inspection is
required and (ii) the applicant submits a Pre-Submission
Facility Correspondence 2 months prior to the date of PAS
submission and the Pre-Submission Facility Correspondence is
found to be complete and accurate and remains unchanged.
c. Review and act on priority PASs within 10 months of PAS
submission if (i) preapproval inspection is required and (ii)
the applicant does not submit a Pre-Submission Facility
Correspondence 2 months prior to the date of PAS submission,
or facility information changes or is found to be incomplete
or inaccurate.
3. Review and act on 90 percent of major amendments to
standard PASs within the applicable review goal.
a. Review and act on major amendments to standard PASs
within 6 months of the date of amendment submission if
preapproval inspection is not required.
b. Review and act on major amendments to standard PASs
within 10 months of the date of amendment submission if
preapproval inspection is required.
4. Review and act on 90 percent of major amendments to
priority PASs within the applicable review goal.
a. Review and act on major amendments to priority PASs
within 4 months of the date of amendment submission if
preapproval inspection is not required.
b. Review and act on major amendments to priority PASs
within 8 months of the date of amendment submission if (i)
preapproval inspection is required and (ii) the applicant
submits a Pre-Submission Facility Correspondence 2 months
prior to the date of amendment submission and the Pre-
Submission Facility Correspondence is found to be complete
and accurate and remains unchanged.
c. Review and act on major amendments to priority PASs
within 10 months of amendment submission if (i) preapproval
inspection is required and (ii) the applicant does not submit
a Pre-Submission Facility Correspondence 2 months prior to
the date of amendment submission, or facility information
changes or is found to be incomplete or inaccurate.
5. Review and act on 90 percent of minor amendments to
standard and priority PASs within 3 months of the date of
amendment submission.
TABLE FOR SECTION I(B)(1) AND (2): PASs
------------------------------------------------------------------------
Submission Type Goal
------------------------------------------------------------------------
Standard PASs............................. 90% within 6 months of
submission date if
preapproval inspection not
required.
90% within 10 months of
submission date if
preapproval inspection
required.
Priority PASs............................. 90% within 4 months of
submission date if
preapproval inspection not
required.
90% within 8 months of
submission date if
preapproval inspection
required and applicant
meets requirements under
I(B)(2)(b).
90% within 10 months of
submission date if
preapproval inspection
required and applicant does
not meet requirements as
described under I(B)(2)(c).
------------------------------------------------------------------------
TABLE FOR SECTION I(B)(3)-(5): PAS AMENDMENTS
------------------------------------------------------------------------
Submission Type Goal
------------------------------------------------------------------------
Standard PAS Major Amendments............. 90% within 6 months of
submission date if
preapproval inspection not
required.
90% within 10 months of
submission date if
preapproval inspection
required.
Priority PAS Amendments................... 90% within 4 months of
submission date if
preapproval inspection not
required.
90% within 8 months of
submission date if
preapproval inspection
required and applicant
meets requirements under
I(B)(4)(b).
90% within 10 months of
submission date if
preapproval inspection
required and applicant does
not meet requirements as
described under I(B)(4)(c).
Standard and Priority Minor PAS Amendments 90% within 3 months of
submission date.
------------------------------------------------------------------------
C. Unsolicited ANDA Amendments and PAS Amendments
1. Review and act on unsolicited ANDA amendments and PAS
amendments submitted during the review cycle by the later of
the goal date for the original submission/solicited amendment
or the goal date assigned in accordance with Sections
(I)(A)(3), (4) and (5) and (I)(B)(3), (4) and (5),
respectively, for the unsolicited amendment.
2. Review and act on unsolicited ANDA amendments and PAS
amendments submitted between review cycles by the later of
the goal date for the subsequent solicited amendment or the
goal date assigned in accordance with Sections (I)(A)(3), (4)
and (5) and (I)(B)(3), (4) and (5), respectively, for the
unsolicited amendment.
D. DMFs
1. Complete the initial completeness assessment review for
90 percent of Type II Active Pharmaceutical Ingredient (API)
Drug Master Files (DMFs) within 60 days of the later of the
date of DMF submission or DMF fee payment.
TABLE FOR SECTION I(D): DMFs
------------------------------------------------------------------------
Submission Type Goal
------------------------------------------------------------------------
Type II API DMF........................... 90% of initial completeness
assessments within 60 days
of the later of the date of
DMF submission or DMF fee
payment.
------------------------------------------------------------------------
[[Page S4725]]
E. Controlled Correspondence
1. Review and respond to 90 percent of controlled
correspondences within the applicable review goal.
a. Review and respond to Standard controlled correspondence
within 60 days of the date of submission.
b. Review and respond to Complex controlled correspondence
within 120 days of the date of submission.
2. In the case of controlled correspondence that raises an
issue that relates to one or more pending citizen petitions,
the 60- or 120-day time period starts on the date FDA
responds to the petition (if there is only one petition) or
last pending petition.
3. FDA will review and respond to 90% of submitter requests
to clarify ambiguities in the controlled correspondence
response within 14 days of receipt of the request. The
response to the submitter's request will provide
clarification or advice concerning the ambiguity in the
controlled correspondence response.
TABLE FOR SECTION I(E): CONTROLLED CORRESPONDENCE
------------------------------------------------------------------------
Submission Type Goal
------------------------------------------------------------------------
Standard Controlled Correspondence........ 90% within 60 days of
submission date.
Complex Controlled Correspondence......... 90% within 120 days of
submission date.
------------------------------------------------------------------------
FDA will review and respond to 90% of submitter requests to clarify
ambiguities in the controlled correspondence request within 14 days of
request receipt.
------------------------------------------------------------------------
F. GDUFA I Bridging
1. Continue to review and act on ANDAs and ANDA amendments,
PASs and PAS amendments and controlled correspondence
submitted prior to October 1, 2017 that have been assigned
GDUFA I goal dates pursuant to the GDUFA I review metrics
applicable to those submissions.
2. Review and act on 90% of ANDAs and ANDA amendments with
Target Action Dates (TADs) by the goal date. The TAD for an
ANDA or ANDA amendment becomes its GDUFA II goal date.
(Attachment A shows how FDA, until September 30, 2017,
assigned TADs to ANDA amendments not subject to GDUFA I
review goals.)
3. Review and act on 90% of ANDAs and ANDA amendments
pending FDA as of October 1, 2017 that were not subject to
GDUFA I goal dates and either (a) were not previously
assigned TADs or (b) were previously assigned TADs that came
due prior to October 1, 2017 but remain pending in the same
review cycle as of October 1, 2017, by GDUFA II ANDA and ANDA
amendment goal dates that FDA will assign on October 1, 2017.
No such goal date shall be later than July 31, 2018.
4. Review and act on amendments received on or after
October 1, 2017, to any ANDAs submitted prior to October 1,
2017, pursuant to the amendment review goals set forth in
(A)(3)-(5) of this section.
II. ORIGINAL ANDA REVIEW PROGRAM ENHANCEMENTS
A. ANDA Receipt
1. FDA will strive to determine whether to receive ANDAs
within 60 days of the date of ANDA submission.
2. To enable FDA to rapidly determine whether to receive an
ANDA pursuant to 21 Code of Federal Regulations (CFR)
314.101, and with consideration of final agency guidances
that address ANDA receipt determinations, FDA will issue a
Manual of Policies and Procedures (MAPP) by October 1, 2017
setting forth procedures for filing reviewers on
communication of minor technical deficiencies (e.g., document
legibility); and on deficiencies potentially resolved with
information in the ANDA at original submission, in order to
provide applicants with an opportunity for resolution within
7 calendar days. If such a deficiency is resolved within 7
calendar days, that deficiency will not be a basis for a
refuse-to-receive decision.
3. At the time of receipt, FDA will notify the applicant in
the acceptance letter whether the ANDA or PAS is subject to
priority or standard review
B. ANDA Review Transparency and Communications Enhancements
To promote transparency and communication between FDA and
ANDA applicants, FDA will apply the review program
enhancements below to the review of all ANDAs. The goal of
these program enhancements is to improve predictability and
transparency, promote the efficiency and effectiveness of the
review process, minimize the number of review cycles
necessary for approval, increase the overall rate of
approval, and facilitate greater access to generic drug
products.
1. FDA will issue the appropriate Information Request(s)
(IR(s)) and/or Discipline Review Letter(s) (DRL(s)) from each
review discipline as soon as the discipline has completed its
review, with the first IR(s) and/or DRL(s) at about the mid-
point of the review.
2. Following the IR and/or DRL at about the mid-point of
the review, IRs and/or DRLs will, as appropriate, continue
from each review discipline on a rolling basis.
3. Neither IRs nor DRLs stop the review clock or add to a
GDUFA goal.
4. If an applicant is unable to completely respond within
the time frame requested by FDA, including any extensions
that may be granted by FDA, then FDA will generally issue a
Complete Response Letter (CRL).
5. FDA will continue to issue IRs and/or DRLs late in the
review cycle, until it is no longer feasible, within the
current review cycle, for applicant to develop and FDA to
review a complete response to the IR and/or DRL.
6. FDA should continue to work through the goal date if in
FDA's judgment continued work would likely result in an
imminent tentative approval that could prevent forfeiture of
180-day exclusivity or in an imminent approval.
7. FDA will strive to act prior to a goal date when the
review is done and there are no outstanding issues.
8. If in the ordinary course a Regulatory Project Manager
(RPM) learns that a major deficiency is likely forthcoming,
the RPM will notify the Authorized Representative that a
major deficiency is likely forthcoming. If the Authorized
Representative raises concerns or seeks additional
information regarding the forthcoming major deficiency, the
RPM will encourage the Authorized Representative to review
the forthcoming deficiency upon receiving it.
9. If in the ordinary course an RPM learns that FDA is
likely to miss the goal date for the submission, the RPM will
notify the Authorized Representative of the outstanding
discipline(s), the general nature of the delay (when
possible), and the estimated timeframe for receiving the
response.
10. The Authorized Representative may periodically request
a Review Status Update. In response to the Authorized
Representative's request, the RPM will timely provide a
Review Status Update.
11. FDA will include in the CRL its basis for classifying a
responding amendment Major.
12. Applicants may opt for a post-CRL teleconference to
seek clarification concerning deficiencies identified in a
CRL. FDA will grant appropriate requests for teleconferences
requested by applicants upon receiving first cycle major
complete response letters. FDA will also grant appropriate
requests for teleconferences requested by applicants upon
receiving subsequent major complete response letters or minor
complete response letters. FDA will provide a scheduled date
for 90 percent of post-CRL teleconferences within 10 days of
the request for a teleconference, and conduct 90 percent of
such post-CRL teleconferences held on the FDA-proposed date,
within 30 days of receipt of the written request.
C. Review Classification Changes During the Review Cycle
1. If during a review cycle of an ANDA or PAS, the review
classification of the ANDA or PAS changes from Standard to
Priority, FDA will notify the applicant within 14 days of the
date of the change.
2. If a previous ANDA or ANDA amendment was subject to
priority review, but a subsequent ANDA amendment is subject
to standard review, FDA will notify applicant within 14 days
of the date of receipt of the solicited amendment.
3. A request for a change may occur at any time during the
review.
4. Once an ANDA or PAS submission is classified as being
subject to priority review, the application will retain such
priority review classification status until FDA takes an
action on the submission.
5. FDA will include an explanation of the reasons for any
denial of a review status reclassification request.
6. If an applicant requests a teleconference as part of its
request to reclassify a major amendment or standard review
status, FDA will schedule and conduct the teleconference and
decide 90% of such reclassification requests within 30 days
of the date of FDA's receipt of the request for a
teleconference. This goal only applies when applicant accepts
the first scheduled teleconference date offered by FDA.
D. ANDA Approval and Tentative Approval
If applicants submit and maintain ANDAs consistent with the
statutory requirements for approval under 505(j); respond to
IRs and DRLs completely and within the time frames requested
by FDA and timely submit all required information under 21
CFR parts 314 and 210, including information concerning
notice (21 CFR 314.95), litigation status (21 CFR 314.107),
and commercial marketing (21 CFR 314.107); then FDA will
strive to approve approvable ANDAs in the first review cycle;
to approve potential first generics on the earliest lawful
ANDA approval date, if known to FDA; and to tentatively
approve first to file Paragraph IV ANDAs so as to avoid
forfeiture of 180-day exclusivity.
E. Dispute Resolution
1. An applicant may pursue a request for reconsideration
within the review discipline at the Division level or
original signatory authority, as needed.
2. The Office of Generic Drugs (OGD) Office of Regulatory
Operations Associate Director will track each request for
Division level reconsideration through resolution.
3. Following resolution of a request for reconsideration,
an applicant may pursue formal dispute resolution above the
Division level, pursuant to procedures set forth in the
September 2015 Guidance, Formal Dispute Resolution: Appeals
Above the Division Level.
4. FDA will respond to appeals above the Division level
within 30 calendar days of the Center for Drug Evaluation and
Research's (CDER's) receipt of the written appeal pursuant to
the applicable goal.
a. In FY 2018, the goal is 70 percent.
b. In FY 2019, the goal is 80 percent.
c. In FY 2020, 2021, and 2022 the goal is 90 percent.
[[Page S4726]]
5. CDER's Formal Dispute Resolution Project Manager (or
designee) will track each formal appeal above the Division
level through resolution
F. Other ANDA Review Program Aspirations
1. FDA aspires to continually improve the efficiency of the
ANDA review program.
2. The absence of a GDUFA II commitment for a specific
program function does not imply that the program function is
not important. For example, other program functions include
determinations whether listed drugs were voluntarily
withdrawn from sale for reasons of safety or effectiveness
and ANDA proprietary name reviews.
III. PRE-ANDA PROGRAM AND SUBSEQUENT MID-REVIEW-CYCLE MEETINGS FOR
COMPLEX PRODUCTS
A. Rationale for Pre-ANDA Program, Guidance on Enhanced
Pathway for Complex Products
The goal of the pre-ANDA program is to clarify regulatory
expectations for prospective applicants early in product
development, assist applicants to develop more complete
submissions, promote a more efficient and effective ANDA
review process, and reduce the number of review cycles
required to obtain ANDA approval, particularly for Complex
Products.
1. FDA will issue guidance describing an enhanced pathway
for Complex Products, including policies and procedures for
Product Development Meetings, pre-submission meetings, and
mid-review cycle meetings. An ANDA applicant who was granted
a Product Development Meeting has the option of a pre-
submission meeting with FDA and also the option of a mid-
review-cycle meeting with FDA, subject to policies and
procedures to be set forth in the guidance.
B. Controlled Correspondence
1. FDA will review and respond to standard controlled
correspondence and to complex controlled correspondence with
meaningful responses that can more consistently inform drug
development and/or regulatory decision making pursuant to the
applicable metric goals.
C. Product-Specific Guidance
1. FDA will issue product-specific guidance identifying the
methodology for developing drugs and generating evidence
needed to support ANDA approval, for 90 percent of new
chemical entity New Drug Applications that are approved on or
after October 1, 2017, at least 2 years prior to the earliest
lawful ANDA filing date.
2. This goal shall not apply to Complex Products. FDA will
strive to issue guidance for a Complex Product as soon as
scientific recommendations are available.
3. FDA will continue to develop and issue product-specific
guidance based on requests from industry and public health
priorities as set forth in the CDER Prioritization MAPP.
4. Industry may request that FDA develop product-specific
guidance via email to [email protected].
D. Product Development Meetings
1. FDA will grant a prospective applicant a Product
Development Meeting if, in FDA's judgment:
a. The requested Product Development Meeting concerns:
i. Development of a Complex Product for which FDA has not
issued product-specific guidance or
ii. An alternative equivalence evaluation (i.e., change in
study type, such as in vitro to clinical) for a Complex
Product for which FDA has issued product-specific guidance,
b. The prospective applicant submits a complete meeting
package, including a data package and specific proposals,
c. A controlled correspondence response would not
adequately address the prospective applicant's questions, and
d. A Product Development Meeting would significantly
improve ANDA review efficiency.
2. Dependent on available resources, FDA may grant a
prospective applicant a Product Development Meeting
concerning Complex Product development issues other than
those described in Section III(D)(1)(a) above if, in FDA's
judgment:
a. The prospective applicant submits a complete meeting
package, including a data package and specific proposals,
b. A controlled correspondence response would not
adequately address the prospective applicant's questions, and
c. A Product Development Meeting would significantly
improve ANDA review efficiency.
3. FDA will grant or deny 90% of Product Development
Meeting requests within the applicable goal.
a. In FYs 2018 and 2019, the goal is 30 days from receipt
of the request.
b. In FYs 2020, 2021 and 2022, the goal is 14 days from
receipt of the request.
4. FDA will conduct Product Development Meetings granted
pursuant to the applicable goal.
a. In FY 2018, FDA will conduct 60 percent of such meetings
within 120 days of granting them.
b. In FY2019, FDA will conduct 70 percent of such meetings
within 120 days of granting them.
c. In FY2020, FDA will conduct 80 percent of such meetings
within 120 days of granting them.
d. In FYs 2021 and 2022, FDA will conduct 90 percent of
such meetings within 120 days of granting them.
5. FDA can meet the Product Development Meeting Goal by
either conducting a meeting or providing a meaningful written
response that will inform drug development and/or regulatory
decision making to the prospective applicant, within the
applicable goal date.
6. Unless FDA is providing a written response to satisfy
the Product Development Meeting goal, FDA will provide
preliminary written comments before each Product Development
Meeting (and aspire to provide the written comments 5
calendar days before the meeting), and will provide meeting
minutes within 30 calendar days following the meeting.
E. Pre-Submission Meetings
1. Prospective applicants may request and FDA will conduct
pre-submission meetings, subject to Section III(A)(1). An
applicant's decision not to request a pre-submission meeting
will not prejudice the receipt or review of an ANDA.
2. FDA will grant or deny 90% of pre-submission meeting
requests within the applicable goal.
a. In FYs 2018 and 2019, the goal is 30 days.
b. In FYs 2020, 2021, and 2022, the goal is 14 days.
3. If an applicant did not have a Product Development
Meeting, FDA may grant a pre-submission meeting if in FDA's
judgment the pre-submission meeting would improve review
efficiency.
4. FDA will conduct pre-submission meetings granted
pursuant to the applicable goal.
a. In FY 2018, FDA will conduct 60 percent of such meetings
within 120 days of granting them.
b. In FY 2019, FDA will conduct 70 percent of such meetings
within 120 days of granting them.
c. In FY 2020, FDA will conduct 80 percent of such meetings
within 120 days of granting them.
d. In FYs 2021 and 2022, FDA will conduct 90 percent of
such meetings within 120 days of granting them.
5. If appropriate to the purpose of the meeting, FDA will
provide preliminary written comments 5 calendar days before
each meeting, and meeting minutes within 30 calendar days of
the meeting.
F. Mid-Review-Cycle Meetings for Complex Products
As set forth in guidance issued pursuant to Section
III(A)(1), the Project Manager and other appropriate members
of the FDA review team will call the applicant to provide the
applicant with an update on the status of the review of their
application. An agenda will be sent to the applicant prior to
the mid-review-cycle meeting. The Project Manager will
coordinate the specific date and time of the telephone call
with the applicant.
G. Inactive Ingredient Database Enhancements
1. By October 1, 2020, FDA will complete enhancements to
the Inactive Ingredient Database so users can perform
electronic queries to obtain accurate Maximum Daily Intake
and Maximum Daily Exposure information for each route of
administration for which data is available.
2. FDA will update the Inactive Ingredient Database on an
ongoing basis, and post quarterly notice of updates made.
Such notices will include each change made and, for each
change, the information replaced.
H. Regulatory Science Enhancements
FDA will conduct internal and external research to support
fulfilment of submission review and pre-ANDA commitments set
forth in Sections I and III, respectively.
1. Annually, FDA will conduct a public workshop to solicit
input from industry and stakeholders for inclusion in an
annual list of GDUFA II Regulatory Science initiatives.
Interested parties may propose regulatory science initiatives
via email to [email protected]. After considering
Industry and stakeholder input, FDA will post the list on
FDA's website.
2. If Industry forms a GDUFA II regulatory science working
group, then upon request of the working group to the Director
of the Office of Research and Standards in the Office of
Generic Drugs, FDA will meet with the working group twice
yearly to discuss current and emerging challenges and
concerns. FDA will post minutes of these meetings on its
website.
3. Annually, FDA will report on its website the extent to
which GDUFA regulatory science-funded projects support the
development of generic drug products, the generation of
evidence needed to support efficient review and timely
approval of ANDAs, and the evaluation of generic drug
equivalence.
I. Safety Determination Letters
1. FDA will issue 90% of safety determination letters
within 60 days of the date of submission of disclosure
authorization.
J. Other Pre-ANDA Program Aspirations
1. FDA aspires to continually improve the effectiveness of
its pre-ANDA activity.
2. The absence of a GDUFA II commitment for a specific
program function does not imply that the program function is
not important. For example, notwithstanding the absence of a
GDUFA II commitment, FDA aspires to respond to Suitability
Petitions in a more timely and predictable manner.
IV. DMF REVIEW PROGRAM ENHANCEMENTS
A. Communication of DMF Review Comments
1. FDA will ensure that DMF review comments submitted to
the DMF holder are issued at least in parallel with the
issuance of review comments relating to the DMF for
[[Page S4727]]
the ANDA. This commitment applies to comments to the
applicant issued in any ANDA CRL and comments issued in the
first IR letter by the drug product review discipline.
B. Teleconferences to Clarify DMF First Cycle Review
Deficiencies
1. FDA will grant and conduct teleconferences when
requested to clarify deficiencies in first cycle DMF
deficiency letters.
2. DMF holders must request such teleconferences in writing
within 20 business days of issuance of the first cycle DMF
deficiency letter, identifying specific issues to be
addressed. FDA may initially provide a written response to
the request for clarification, but if the DMF holder
indicates that a teleconference is still desired, FDA will
schedule the teleconference.
3. FDA will strive to grant such teleconferences within 30
days, giving priority to DMFs based on the priority of the
referencing ANDA.
4. In lieu of a teleconference, the DMF holder may submit a
request for an email exchange between FDA and the DMF holder.
The request must identify specific issues to be addressed.
After FDA responds to the request, the DMF holder may submit,
and FDA will respond to, one follow up email to obtain
additional clarification.
C. DMF First Adequate Letters
1. Once a DMF has undergone a full scientific review and
has no open issues related to the review of the referencing
ANDA, FDA will issue a First Adequate Letter.
D. DMF No Further Comment Letters
1. Once a DMF has undergone a complete review and the ANDA
referencing the DMF has been approved or tentatively
approved, FDA will issue a no further comment letter.
E. Guidance on Post-Approval Changes to Type II API DMFs.
1. By October 1, 2018, FDA will issue a guidance regarding
post-approval changes to a Type II API DMF and submission
mechanisms for ANDA applicants who reference the Type II API
DMF.
V. FACILITIES
A. Guidance on Risk-Based Site Selection Model--Issue a
guidance explaining the Agency's risk-based site surveillance
model for human pharmaceutical manufacturing establishments,
including a discussion of the risk factors incorporated in
the model and how the model is used to help determine which
establishments are scheduled to receive a surveillance
inspection each year.
B. Outreach to Foreign Regulators on Risk-Based Site
Selection Model--Undertake outreach activities to better
inform other pharmaceutical regulators of FDA's risk-based
surveillance model.
C. Export Support and Education of Other Health
Authorities--Support the export of safe and effective
pharmaceutical products by the U.S.-based pharmaceutical
industry, including but not limited to timely updates to
FDA's Facility Compliance Status Database as described below,
and educating other health authorities regarding FDA's
surveillance inspection program and the meaning of inspection
classifications.
D. Communications to Foreign Regulators--Upon receipt of a
written or email request by an establishment physically
located in the U.S. that has been included as part of a
marketing application submitted to a foreign regulator, issue
within 30 days of the date of receipt of the request a
written communication to that foreign regulator conveying the
current compliance status for the establishment.
E. Communication Regarding Inspections
1. By May 31, 2018, when FDA conducts an application-
related inspection of a facility or site named in the ANDA,
PAS, or associated Type II DMF and identifies outstanding
issues that could prevent approval of an ANDA or PAS, the
applicant will be notified that issues exist through an IR,
DRL or CRL pursuant to Section II(B)) above.
2. By October 1, 2018, FDA agrees to communicate to the
facility owner final inspection classifications that do not
negatively impact approvability of any pending application
within 90 days of the end of the inspection. FDA agrees to
ongoing periodic engagement with industry stakeholders to
provide updates on agency activities and seek stakeholder
feedback.
F. GDUFA II Facility Compliance Status Database--By January
1, 2019, FDA will update its existing, publicly available
database that describes the compliance status of GDUFA self-
ID facilities and sites. Compliance status is based on the
most recent inspection or related FDA action for facilities
involved in any manufacturing activities subject to Current
Good Manufacturing Practices (CGMP) inspection and for sites
involved in the conduct or analysis of bioanalytical or
clinical bioequivalence/bioavailability studies conducted to
support an ANDA. The database will be updated every 30 days
and will reflect FDA's final assessment of the facility or
site following an FDA inspection and review of the inspected
entity's timely response to any documented observations. The
public website containing the database will also include an
explanation of terms used to describe the compliance status
of facilities and sites.
VI. ENHANCED ACCOUNTABILITY AND REPORTING
FDA will build internal capacity to enable improved
productivity and performance through regular assessment of
progress towards GDUFA goals, consistent methodologies for
and timely reporting of GDUFA metrics, and transparent and
efficient administration; allocation and reporting of user
fee resources.
A. Resource Management Planning and Modernized Time Reporting
FDA is committed to enhancing management of the GDUFA
program in GDUFA II.
1. FDA will conduct activities to develop a resource
management planning function and modernized time reporting
approach in GDUFA II. FDA will staff a planning team
responsible for these activities and for publishing a GDUFA
program resource management planning and modernized time
reporting implementation plan no later than fourth quarter FY
2018.
2. FDA will obtain through a contract with an independent
third party an evaluation of options and recommendations for
a new methodology to accurately assess changes in the
resource needs of the human generic drug review program and
how to monitor and report on those needs moving forward. The
report will be published no later than the end of FY 2020 for
public comment. Upon review of the report and comments, FDA
will implement robust methodologies for assessing resource
needs of the program and tracking resource utilization across
the program elements.
B. Financial Transparency and Efficiency
FDA is committed to ensuring GDUFA user fee resources are
administered, allocated, and reported in an efficient and
transparent manner. FDA will conduct activities to evaluate
the financial administration of the GDUFA program to help
identify areas to enhance operational and fiscal efficiency.
FDA will also conduct activities to enhance transparency of
how GDUFA program resources are used.
1. FDA will contract with an independent third party to
evaluate and report on how the GDUFA program is resourced and
how those resources are utilized, and recommend improvements
to the process.
2. FDA will use the results of that evaluation to create an
ongoing financial reporting mechanism to enhance the
transparency of GDUFA program resource utilization.
3. FDA will publish a GDUFA 5-year financial plan no later
than the 2nd quarter of FY 2018. FDA will publish updates to
the 5-year plan no later than the 2nd quarter of each
subsequent fiscal year.
4. FDA will convene a public meeting no later than the
third quarter of each fiscal year starting in FY 2019 to
discuss the GDUFA 5-year financial plan, along with the
Agency's progress in implementing modernized time reporting
and resource management planning.
C. Performance Reporting
1. FDA will publish the following monthly metrics on its
website, using a consistent, publicly disclosed reporting
methodology:
a. Number of ANDAs and ANDA amendments, DMFs, Changes Being
Effected (CBEs) and PASs submitted in the reporting month
delineated by type of submission,
b. Number each of ANDAs and PASs FDA refused for receipt in
the reporting month,
c. Number of actions taken in the reporting month
delineated by the type of action.
For purposes of the metrics, actions shall include final
approvals, tentative approvals, complete response letters,
information requests, and discipline review letters (or other
such nomenclature as FDA determines to reflect the concepts
of an information request or complete response letter), and
d. Number of first cycle approvals and tentative approvals
in the reporting month.
2. FDA will publish the following quarterly metrics on its
website, using a consistent, publicly disclosed reporting
methodology:
a. Number of ANDAs and PASs withdrawn in each reporting
month,
b. Number of ANDAs awaiting applicant action, and
c. Number of ANDAs awaiting FDA action.
d. Mean and median approval and tentative approval times
for the quarterly action cohort.
3. FDA will publish the following metrics annually as part
of the GDUFA Performance Report:
a. Mean and median approval and tentative approval times by
FY receipt cohort,
b. Mean and median ANDA approval times, including separate
reporting of mean and median times for first cycle approvals,
c. Mean and median number of ANDA review cycles to approval
and tentative approval by FY receipt cohort,
d. Number of GDUFA related teleconferences requested,
granted, denied and conducted, broken down by type of
teleconference,
e. Number of applications received, refused to receive, and
average time to receipt decision,
f. Number of product development, pre-submission and mid-
review cycle meetings requested, granted, denied and
conducted, by face to face or in writing,
g. Number of inspections conducted by domestic or foreign
establishment location and inspection type (Pre-Approval
Inspection (PAI), Good Manufacturing Practices (GMP),
Bioequivalence (BE) clinical and BE analytical) and facility
type (Finished Dosage Form (FDF), API, etc.),
h. Median time from beginning of inspection to 483
issuance,
i. Median time from 483 issuance to Warning Letter, Import
Alert and Regulatory Meeting for inspections with final
classification of Official Action Indicated (OAI) (or
equivalent),
[[Page S4728]]
j. Median time from date of Warning Letter, Import Alert
and Regulatory Meeting to resolution of the OAI status (or
equivalent),
k. Number of ANDAs accepted for standard review and
priority review,
l. Number of suitability petitions pending a substantive
response for more than 270 days from the date of receipt,
m. Number of petitions to determine whether a listed drug
has been voluntarily withdrawn from sale for reasons of
safety or effectiveness pending a substantive response for
more than 270 days from the date of receipt,
n. Percentage of ANDA proprietary name requests reviewed
within 180 days of receipt,
o. Number of DMF First Adequate Letters issued, and
p. Number of email exchanges requested and conducted in
lieu of teleconferences to clarify deficiencies in first
cycle DMF deficiency letters.
VII. DEFINITIONS
A. Act on an application--means FDA will either issue a
complete response letter, an approval, a tentative approval,
or a refuse-to-receive action.
B. Ambiguity in the controlled correspondence response--
means the controlled correspondence response or a critical
portion of it, in FDA's judgment, merits further
clarification.
C. Appropriate, with respect to a request for a post-CRL
teleconference--means a complete and clear request for a
teleconference where the applicant's goal is to gain an
understanding of specific deficiencies and expectations for
resolution.
D. Authorized Representative--means the authorized point of
contact identified in applicant's letter of authorization or
Form 356h. An Authorized Representative may designate an
alternate to serve in the Authorized Representative's
absence.
E. Change, with respect to facility information--means a
change to information in the Pre-Submission Facilities
Correspondence that causes FDA to re-evaluate its facility
assessment (i.e., assess the impact of the change on its
previous recommendation), such as a change in facility (as
described by address, FDA Establishment Identification (FEI)
number, or Data Universal Numbering System (DUNS) number),
change in operation(s) performed by a facility, addition of a
new facility, withdrawal of a facility used to generate data
to meet application requirements or intended for commercial
production, or a change in inspection readiness (i.e., a
facility is no longer ready for inspection).
F. Complete response letter (CRL)--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 which includes an application-
related facilities assessment and will require a complete
response from industry to restart the clock. Refer to 21 CFR
314.110 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.
G. Complete review--refers to a full division-level review
from all relevant review disciplines, including inspections,
and includes other matters relating to the ANDAs and
associated DMFs as well as consults with other agency
components.
H. Complex controlled correspondence--means:
1. Controlled correspondence involving evaluation of
clinical content,
2. Bioequivalence protocols for Reference Listed Drugs with
Risk Evaluation and Mitigation Strategies (REMS) Elements To
Assure Safe Use (ETASU), or
3. Requested evaluations of alternative bioequivalence
approaches within the same study type (e.g., pharmacokinetic,
in vitro, clinical).
I. Complex Product--generally includes:
1. Products with complex active ingredients (e.g.,
peptides, polymeric compounds, complex mixtures of APIs,
naturally sourced ingredients); complex formulations (e.g.,
liposomes, colloids); complex routes of delivery (e.g.,
locally acting drugs such as dermatological products and
complex ophthalmological products and otic dosage forms that
are formulated as suspensions, emulsions or gels) or complex
dosage forms (e.g., transdermals, metered dose inhalers,
extended release injectables)
2. Complex drug-device combination products (e.g., auto
injectors, metered dose inhalers); and
3. Other products where complexity or uncertainty
concerning the approval pathway or possible alternative
approach would benefit from early scientific engagement.
J. Days--unless otherwise specified, means calendar days.
K. Discipline review letter (DRL)--means a letter used to
convey preliminary thoughts on possible deficiencies found by
a discipline reviewer and/or review team for its portion of
the pending application at the conclusion of the discipline
review.
L. Earliest lawful ANDA approval date--the first date on
which no patent or exclusivity prevents full approval of an
ANDA
M. First adequate letter--a communication from FDA to DMF
holder indicating that the DMF has no open issues related to
the review of the referencing ANDA. Issued only at the
conclusion of the first DMF review cycle that determines the
DMF does not have any open issues.
N. First generic--any received ANDA (1) that is a first-to-
file ANDA eligible for 180-day exclusivity or for which there
are no blocking patents or exclusivities and (2) for which
there is no previously approved ANDA for the drug product.
O. Information Request (IR)--means a letter that is sent to
an applicant during a review to request further information
or clarification that is needed or would be helpful to allow
completion of the discipline review.
P. Major amendment--means a major amendment as described in
CDER's December 2001 Guidance for Industry: Major, Minor and
Telephone Amendments to Abbreviated New Drug Applications.
Q. Mid-review-cycle meeting--after the last key discipline
has issued its IR and/or DRL, for ANDAs that were the subject
of prior Product Development Meetings or pre-submission
meetings, CDER will schedule a teleconference meeting with
the applicant to discuss current concerns with the
application and next steps.
R. Minor amendment--means a minor amendment as described in
CDER's December 2001 Guidance for Industry: Major, Minor and
Telephone Amendments to Abbreviated New Drug Applications.
S. Complete and accurate Pre-Submission Facility
Correspondence--lists all of the following:
1. All facilities involved in manufacturing processes and
testing for the ANDA and corresponding Type II API DMF as
required by 21 CFR 314.50(d)(1)(i) and (iii). For each
manufacturing or testing facility, the correspondence
includes facility name, operation(s) performed, facility
contact name, address, FEI number (if a required registrant
or one has been assigned), DUNS number, registration
information (for required registrants), a confirmation that
the facility is ready for inspection, a description of the
manufacturing process, and a certification by the applicant
that any Type II DMF has similarly complete and accurate
facility information as required by 21 CFR 314.50(d)(1)(i),
including complete facility information (i.e., facility name,
operation, facility contact name, address, FEI number and
DUNS number). Facility information that is included in a
corresponding Type II DMF is not required to be duplicated in
the Pre-Submission Facility Correspondence for the ANDA.
2. All sites or organizations involved in bioequivalence
and clinical studies used to support the ANDA submission as
described in 21 CFR 314.94(a)(7). This information is
provided using a standardized electronic format and includes
unique identifiers that are current and accurate, including
site or organization name, address and website; and study
information including a listing of study names, dates of
conduct and main investigators.
T. Pre-submission meeting--means a meeting in which an
applicant has an opportunity to discuss and explain the
format and content of an ANDA to be submitted. Although the
proposed content of the ANDA will be discussed, pre-
submission meetings will not include substantive review of
summary data or full study reports.
U. Priority--means submissions affirmatively identified as
eligible for expedited review pursuant to CDER's Manual of
Policy and Procedures (MAPP) 5240.3, Prioritization of the
Review of Original ANDAs, Amendments and Supplements, as
revised (the CDER Prioritization MAPP).
V. Product Development Meeting--means a meeting involving a
scientific exchange to discuss specific issues (e.g., a
proposed study design, alternative approach or additional
study expectations) or questions, in which FDA will provide
targeted advice regarding an ongoing ANDA development
program.
W. Review Status Update--means a response from the RPM to
the Authorized Representative to update the Authorized
Representative concerning, at a minimum, the categorical
status of relevant review disciplines with respect to the
submission at that time. The RPM will advise the Authorized
Representative that the update is preliminary only, based on
the RPM's interpretation of the submission, and subject to
change at any time.
X. Safety determination letter--a letter from FDA stating
that a bioequivalence study protocol contains safety
protections comparable to applicable REMS for the Reference
Listed Drug.
Y. Standard--means submissions not affirmatively identified
as eligible for expedited review pursuant to the CDER
Prioritization MAPP.
Z. Standard controlled correspondence--means controlled
correspondence
1. as described in CDER's September 2015 Guidance for
Industry, Controlled Correspondence Related to Generic Drug
Development, or
2. concerning post-approval submission requirements that
are not covered by CDER post-approval changes guidance and
are not specific to an ANDA.
AA. Target Action Date (TAD)--Under GDUFA I, FDA's
aspirational deadline for action on a pre-GDUFA I Year 3
original ANDA and/or a complete response amendment or
equivalent IR to an original ANDA.
[[Page S4729]]
GDUFA I TADs become GDUFA II goal dates on enactment of GDUFA
II.
BB. Teleconference--means a verbal communication by
telephone, and not a written response, unless otherwise
agreed to by the applicant.
CC. Unsolicited amendment--an amendment with information
not requested by FDA except for those unsolicited amendments
considered routine or administrative in nature that do not
require scientific review (e.g., requests for final ANDA
approval, patent amendments, and general correspondence).
GDUFA II COMMITMENT LETTER, ATTACHMENT A
------------------------------------------------------------------------
Pre-cohort Year 3
Category Pre-cohort Year 3 ANDAs (expedited
ANDAs status)
------------------------------------------------------------------------
Major Amendment (Complete 10 months......... 7 months
Response Letter).
Minor Amendment (Complete 5 months.......... 3 months
Response Letter).
Easily Correctable Deficiency... 3 months..........
Information Request............. 3 months..........
------------------------------------------------------------------------
Mr. ALEXANDER. Mr. President, I ask unanimous consent to have printed
in the Record a copy of the commitment letter for the Medical Device
User Fee Amendments of 2017.
There being no objection, the material was ordered to be printed in
the Record, as follows:
MDUFA Performance Goals and Procedures, Fiscal Years 2018 Through 2022
General
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 2017, 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. 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 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 below. As appropriate, key findings
and recommendations from this assessment will be implemented
by FDA.
A. PMA
FDA will report on an annual basis the average Total Time
to Decision as defined in Section VII.H for the three most
recent closed receipt cohorts.
For Original PMA and Panel Track Supplement submissions
received in Fiscal Years 2016 through 2018, the average Total
Time to Decision goal for FDA and industry is 320 calendar
days.
For Original PMA and Panel Track Supplement submissions
received in Fiscal Years 2017 through 2019, the average Total
Time to Decision goal for FDA and industry is 315 calendar
days.
For Original PMA and Panel Track Supplement submissions
received in Fiscal Years 2018 through 2020, the average Total
Time to Decision goal for FDA and industry is 310 calendar
days.
For Original PMA and Panel Track Supplement submissions
received in Fiscal Years 2019 through 2021, the average Total
Time to Decision goal for FDA and industry is 300 calendar
days.
For Original PMA and Panel Track Supplement submissions
received in Fiscal Years 2020 through 2022, the average Total
Time to Decision goal for FDA and industry is 290 calendar
days.
B. 510(k)
FDA will report on an annual basis the average Total Time
to Decision as defined in Section VII.H for the most recent
closed receipt cohort.
For 510(k) submissions received beginning in Fiscal Year
2018, the average Total Time to Decision goal for FDA and
industry is 124 calendar days.
For 510(k) submissions received beginning in Fiscal Year
2019, the average Total Time to Decision goal for FDA and
industry is 120 calendar days.
For 510(k) submissions received beginning in Fiscal Year
2020, the average Total Time to Decision goal for FDA and
industry is 116 calendar days.
For 510(k) submissions received beginning in Fiscal Year
2021, the average Total Time to Decision goal for FDA and
industry is 112 calendar days.-
For 510(k) submissions received beginning in Fiscal Year
2022, the average Total Time to Decision goal for FDA and
industry is 108 calendar days.
II. REVIEW PERFORMANCE GOALS--FISCAL YEARS 2018 THROUGH 2022 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. Pre-Submissions
FDA will continue the Pre-Submission program as described
in the Guidance on ``Requests for Feedback on Medical Device
Submissions: The Pre-Submission Program and Meetings with FDA
Staff'' with process improvements and performance goals as
noted in this section.
For all Pre-Submissions in which the applicant requests a
meeting or teleconference, the applicant will provide a
minimum of three proposed meeting dates in the initial
submission.
Within 15 calendar days of receipt of a Pre-Submission, FDA
will communicate with the applicant regarding whether the
application has been accepted and, if applicable, regarding
scheduling of the meeting or teleconference. Acceptance will
be determined based on the definition of pre-submission in
Section VII.F below and an acceptance checklist in published
guidance. This communication consists of a fax, email, or
other written communication that a) identifies the reviewer
assigned to the submission, b) acknowledges acceptance/
rejection of the submission, and c) if the submission
included a request for a meeting or teleconference and is
accepted, either confirms one of the applicant's requested
meeting dates or provides two alternative dates prior to day
75 from receipt of accepted submission. A determination that
the request does not qualify as a Pre-Submission will require
the concurrence of the branch chief and the reason for this
determination will be provided to the applicant in the above
written communication. FDA intends to reach agreement with
the applicant regarding a meeting date within 30 days from
receipt of accepted submission. For all requests for meetings
or teleconferences that do not have such a meeting or
teleconference scheduled by 30 days from receipt of an
accepted submission, an FDA manager will contact the
applicant to resolve scheduling issues by the 40th day.
FDA will provide written feedback that addresses the issues
raised in the pre-submission request within 70 calendar days
of receipt date or five calendar days prior to a scheduled
meeting, whichever comes sooner, for at least 1,530 Pre-
Submissions received in FY 2018, at least 1,645 Pre-
Submissions received in FY 2019, at least 1,765 Pre-
Submissions received in FY 2020, at least 1,880 Pre-
Submissions received in FY 2021, and at least 1,950 Pre-
Submissions received in FY 2022. FDA will provide such timely
written feedback for additional Pre-Submissions as resources
permit, but not to the detriment of meeting the quantitative
review timelines and statutory obligations. Written feedback
will be provided to the applicant by email or fax and 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 or fax will be considered the final written feedback to
the Pre-Submission.
Meetings and teleconferences related to Pre-Submission will
normally be limited to 1 hour unless the applicant justifies
in writing the need for additional time. FDA may extend the
time for such meetings and/or teleconferences.
Applicants will be responsible for developing draft minutes
for a Pre-Submission meeting or teleconference, and provide
the draft minutes to FDA within 15 calendar days of the
meeting. At the beginning and end of each meeting, the
applicant will affirmatively state that they will draft
minutes and provide them to FDA within 15 calendar days. 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
[[Page S4730]]
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 15 days 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 the information
submitted in a future IDE or marketing application is
consistent with that provided in the Pre-Submission and
documented in the Pre-Submission, and that the data and other
information in the future submission do not raise any
important new issues materially affecting safety or
effectiveness. The minutes described above will serve as the
record of the Agency's Pre-Submission feedback. 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 and/or effectiveness or substantial equivalence.
Such a determination will be supported by the appropriate
management concurrence consistent with applicable guidance
and SOPs.
By October 1, 2018, the Agency will update the Guidance on
``Requests for Feedback on Medical Device Submissions: The
Pre-Submission Program and Meetings with FDA Staff'' to
include: additional information to assist applicants in
determining the need for a Pre-Submission, an enhanced Pre-
Submission acceptance checklist, examples of frequently asked
Pre-Submission questions that lend themselves to productive
Pre-Submission interactions, and edits to reflect the revised
process outlined above. FDA will provide an opportunity for
the public to comment on the updated guidance. No later than
12 months after the close of the public comment period, the
Agency will issue a final guidance. FDA will implement this
guidance once final.
B. 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 and consistent with the statute and its
implementing regulations.
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 95%
of submissions.
When FDA issues a major deficiency letter, that letter will
be based upon a complete review of the application and will
include all deficiencies. All deficiency letters will include
a statement of the basis for the deficiencies (e.g., a
specific reference to applicable section of a rule, final
guidance, recognized standard unless the entire or most of
document is applicable). In the instance when the deficiency
cannot be traced in the manner above and relates to a
scientific or regulatory issue pertinent to the
determination, FDA will cite the specific scientific issue
and the information to support its position. All deficiency
letters will undergo supervisory review prior to issuance to
ensure the deficiencies cited are relevant to a determination
of safety and effectiveness. 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 90% of submissions.
For submissions that require Advisory Committee input, FDA
will issue a MDUFA decision within 320 FDA Days from receipt
of the accepted submission for 90% of submissions. FDA will
issue a MDUFA decision within 60 days of the Advisory
Committee recommendation, as resources permit, but not to the
detriment of meeting the quantitative review timelines and
statutory obligations. The Office Director shall review each
request for Advisory Committee input for appropriateness and
need for this input.
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. If the number of
submissions that require Advisory Committee input is less
than 10 for FY 2022, it is acceptable to combine such
submissions in the prior year to form a cohort of 10 or more
submissions: in such cases, FDA will be held to the FY2022
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.
Requests from FDA that a submission be made will not be
considered unsolicited.
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.
For PMA submissions that receive a MDUFA decision of
Approvable, FDA will issue a decision within 60 days of the
sponsor's response to the Approvable letter, as resources
permit, but not to the detriment of meeting the quantitative
review timelines and statutory obligations.
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.
C. 180-Day PMA Supplements
FDA will communicate with the applicant through a
Substantive Interaction within 90 calendar days of receipt of
95% of submissions.
FDA will issue a MDUFA decision within 180 FDA Days for 95%
of submissions.
D. Real-Time PMA Supplements
FDA will issue a MDUFA decision within 90 FDA Days for 95%
of submissions.
E. De Novo Submissions
FDA will issue draft and final guidance that includes a
submission checklist to facilitate a more efficient and
timely review process.
Deficiencies identified will be based upon a complete
review of the submission and will include all deficiencies.
All deficiency letters will include a statement of the basis
for the deficiencies (e.g., a specific reference to
applicable section of a rule, final guidance, recognized
standard unless the entire or most of document is
applicable). In the instance when the deficiency cannot be
traced in the manner above and relates to a scientific or
regulatory issue pertinent to the determination, FDA will
cite the specific scientific issue and the information to
support its position. All deficiency letters will undergo
supervisory review prior to issuance to ensure the
deficiencies cited are relevant to a classification
determination. 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 classification
determination. Such a determination will be supported by the
appropriate management concurrence consistent with applicable
guidance and SOPs. Issues related to revisions to draft
labeling will typically be addressed through interactive
review once major deficiencies have been adequately
addressed.
FDA will issue a MDUFA decision within 150 FDA days of
receipt of the submission for: 50% of de novo requests
received in FY 2018; 55% of de novo requests received in FY
2019; 60% of de novo requests received in FY 2020; 65% of de
novo requests received in FY 2021 and 70% of de novo requests
received in FY 2022. At Industry's request and as resources
permit, but not to the detriment of meeting the quantitative
review timelines, if a final decision has not been rendered
within 180 FDA days, FDA will discuss with the applicant all
outstanding issues with the submission preventing FDA from
reaching a decision. This discussion 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.
F. 510(k) Submissions
FDA will communicate with the applicant regarding whether
the submission has been
[[Page S4731]]
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 95% of submissions.
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. All deficiency letters will
include a statement of the basis for the deficiencies (e.g.,
a specific reference to applicable section of a rule, final
guidance, recognized standard unless the entire or most of
document is applicable). In the instance when the deficiency
cannot be traced in the manner above and relates to a
scientific or regulatory issue pertinent to the
determination, FDA will cite the specific scientific issue
and the information to support its position. All deficiency
letters will undergo supervisory review prior to issuance to
ensure the deficiencies cited are relevant to a determination
of substantial equivalence. 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.
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 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.
G. CLIA Waiver by Application
FDA will engage in a Substantive Interaction with the
applicant within 90 days for 90% of the applications.
Industry will inform FDA that it plans to submit a dual
submission (510(k) and CLIA Waiver application) during the
Pre-Submission process. FDA will issue a decision for 90% of
dual submission applications within 180 FDA days.
For ``CLIA Waiver by application'' submissions FDA will
issue a MDUFA decision for 90% of the applications that do
not require Advisory Committee input within 150 FDA days.
For ``CLIA Waiver by application'' submissions FDA will
issue a MDUFA decision for 90% of the applications that
require Advisory Committee input within 320 FDA days.
If in any one fiscal year, the number of submissions in any
CLIA Waiver by Application category 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 all CLIA waiver by application submissions and dual
submissions that do not reach a 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.
In addition, FDA will:
1. Hold CLIA Waiver Vendor Days, with the first to occur
before the end of FY2018.
2. Permit discussion of both 510(k) and CLIA waiver process
in Pre-Submissions.
3. Specifically permit discussion of appropriate reference/
comparator for both 510(k) and CLIA waiver submissions in
Pre-Submissions.
4. Provide a status report on completion and issuance of
revisions to Section V of the Guidance on ``Recommendations
for CLIA Waiver Applications'' to include appropriate use of
comparable performance between a waived user and moderately
complex laboratory user to demonstrate accuracy.
H. 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.
I. 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.
J. 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.
K. 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. Infrastructure
A. Quality Management
The Agency will establish a dedicated Quality Management
(QM) Unit that reports directly to the CDRH Director or
Deputy Director and establish a quality management framework
for the premarket submission process in CDRH. The Framework
will include infrastructure, senior management
responsibility, resource management, lifecycle management,
and quality management system evaluation.
At least once per year, the Agency will discuss with
industry the specific areas it intends to incorporate in its
ongoing audit plan. FDA will identify, with industry input,
areas to audit, which will include the effectiveness of
CDRH's Corrective and Preventive Action (CAPA) process. FDA
will expand the scope of its annual audits as it implements
and builds up its auditing capability. As part of these
ongoing audits, high-performing premarket review processes
utilized in one division will be identified and shared
accordingly with other divisions to improve efficiencies and
effectiveness. At a minimum, FDA audits in the following
areas will be completed by the end of FY 2020: Deficiency
Letters and Pre-Submissions. Additional audits in the
following areas will be completed by the end of FY 2022:
Submission Issue Meetings, Interactive Review, Withdrawals
and Special 510(k) conversions.
The effectiveness of the QM framework will be evaluated in
Phase 2 of the Independent Assessment (see Section V).
B. 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 premarket
review program to improve consistency. The Agency will also
apply user fee revenues to enhance and supplement scientific
review capacity by hiring device application reviewers as
well as leveraging external experts needed to assist with the
review of device applications.
To ensure such additional positions are filled by qualified
experts, the Agency will apply user fee revenues to
recruitment and hiring. The Agency will apply user fee
revenues to retain high-performing supervisors in the
premarket review program.
CDRH intends to enter into an Inter-Agency Agreement (IAA)
with the Office of Personnel Management (OPM) to provide
supplemental recruitment and staffing support throughout
MDUFA IV to augment existing FDA Human Resources services.
C. IT Infrastructure for Submission Management
FDA will enhance IT infrastructure that will allow FDA to
perform quality management audits and review consistency.
FDA will implement a new information management system that
provides an industry dashboard that displays near real-time
submission status.
FDA will develop electronic submission templates that will
serve as guided submission preparation tools for industry to
improve submission consistency and enhance efficiency in the
review process. By FY 2020, the Agency will issue a draft
guidance document on the use of the electronic submission
templates. FDA will provide an opportunity for public comment
on the guidance. No later than 12 months after the close of
the public comment period, the Agency will issue a final
guidance. FDA will implement the guidance once final. In
addition, the Agency will update the Guidance ``eCopy Program
for Medical Device Submissions'' to reflect the respective
changes to the technical standards and specifications.
FDA will link pre-submissions with subsequent premarket
submissions when identified by the applicant.
[[Page S4732]]
D. Training
FDA will continue to improve training for new and existing
reviewers under this agreement. FDA will achieve Kirkpatrick
Level 3 for curriculum-based premarket training through
assessment of work performance behavior change and evaluate
the effectiveness of the impact of curriculum-based premarket
training activities on relevant premarket program metrics and
goals (Kirkpatrick Level 4) by the end of FY 2020. FDA
training efforts will also be closely coordinated with the
Quality Management Unit described in item III.A above to
provide more targeted and personalized training to staff.
E. Time Reporting
FDA will implement complete time reporting by the end of
MDUFA IV such that data from time reporting can be used to
conduct workload analysis and capacity planning.
F. Fee Setting, Fee Collections, and Workload
FDA will seek authority to eliminate the fifth-year offset
provision and to maintain and use any and all fee
collections, including collections over the statutory total
revenue targets.
If the collections are in excess of the resources needed to
meet performance goals given the workload, or in excess of
inflation-adjusted statutory revenue targets, FDA and
industry will work together to assess how best to utilize
those resources to improve performance on submission types
with performance goals and/or quality management programs,
using, as input for the discussion: workload information,
performance objectives and ongoing reported performance.
IV. Process Improvements
A. 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 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 and is expected to support
reductions in total time to decision. The interactive review
process contemplates increased informal interaction between
FDA and applicants, including the exchange of scientific and
regulatory information.
B. Deficiency Letters
By October 1, 2017, the Agency will publish a level 2
update to the final guidance ``Suggested Format for
Developing and Responding to Deficiencies in Accordance with
the Least Burdensome Provisions of FDAMA; Final Guidance for
Industry and FDA Staff'' to reflect the following:
All deficiency letters will include a statement of the
basis for the deficiencies (e.g., a specific reference to
applicable section of a rule, final guidance, recognized
standard unless the entire or most of document is
applicable). In the instance when the deficiency cannot be
traced in the manner above and relates to a scientific or
regulatory issue pertinent to the determination, FDA will
cite the specific scientific issue and the information to
support its position. All deficiency letters will undergo
supervisory review prior to issuance to ensure the
deficiencies cited are relevant to a marketing authorization
decision (e.g., 510(k) clearance, PMA approval, and de novo
classification). Any additional best practices identified by
quality audits and/or the Independent Assessment will be
incorporated in updates to the guidance, as appropriate.
FDA will train staff and managers on this process
improvement and the updated guidance.
C. Device Accessories
FDA and Industry will explore additional mechanisms for a
streamlined, resource minimal pathway to reclassify
accessories previously classified as class III devices as a
part of a PMA review if they meet the requirements of a low
or moderate risk device.
D. Enhanced Use of Consensus Standards
FDA will establish an Accreditation Scheme for Conformity
Assessment (ASCA) Program using FDA-recognized consensus
standards. FDA will define the `scheme' and oversee the
Conformity Assessment (CA) model and ensure that there is
appropriate interaction with parties that serve as
Accrediting Bodies (ABs) to accredit test laboratories (TLs).
When a device type using the `scheme' is evaluated according
to a specific recognized standard by an accredited TL, FDA
intends to rely on the results from the accredited TL for the
purpose of premarket review (i.e., generally accept a
determination that a device conforms with the standard)
without the need to address further questions related to
standards conformance. Assuming that it meets established
criteria as outlined in the ASCA program, a device company's
internal TL will be eligible to participate in the ASCA
program. FDA will not review reports from accredited TLs
except as part of a periodic quality audit or if FDA becomes
aware of new information materially relevant to safety and/or
effectiveness.
Specific actions that FDA will undertake include the
following:
1. Conduct a Public Workshop by the end of FY 2018 to
discuss objectives for the establishment of ABs and TLs.
Discussion would include areas (specific FDA-recognized
consensus standards) where the ASCA Program can be piloted to
maximize initial impact of existing CA activities and
potential new areas.
2. Hold educational sessions with stakeholders by the end
of FY 2018 about the purpose of the ASCA Program
3. Develop and initiate the pilot of the ASCA program with
stakeholder input by the end of FY 2020.
a. FDA intends to pilot inclusion of recognized standards
of public health significance where specific pass/fail
criteria are part of the standard
4. Develop an internal IT system to track CA activities of
the ASCA Program
5. Establish a process for accreditation of ABs and TLs.
FDA will issue draft guidance by the end of FY 2019 and issue
final guidance within 12 months post initiation of the pilot.
a. In limited circumstances, the FDA may directly accredit
third-party TLs. For example, FDA could directly accredit
third party TLs, if FDA has not identified and recognized an
AB within 2 years after establishing the tenets of the ASCA
program.
6. Establish a process for reaccreditation and the
suspension or withdrawal of accreditation of poor performing
ABs and TLs. FDA will issue draft guidance by the end of FY
2019 and final guidance within 12 months post initiation of
the pilot.
7. Establish a publicly-accessible website listing TLs
accredited by ASCA and the FDA-recognized consensus
standard(s) for which they are accredited
8. FDA, in consultation with stakeholders, will identify
appropriate recognized consensus standards for consideration
as part of the pilot as the specific focus for ASCA.
a. By the end of FY 2022: FDA will have piloted, and
provided a report on the viability of, an ASCA program which
utilizes the schema identified in guidance to include
utilization of 5 appropriate cross-cutting/horizontal and/or
device-specific areas, at least one of which will be device-
specific.
b. Standards included as part of the ASCA Program will need
to have well established endpoints/acceptance criteria built
into the standard to allow effective tracking of TL
competence.
FDA will provide an annual report on the progress of the
ASCA program.
FDA will work with stakeholders for further input on
programmatic improvements and/or consideration for expansion.
E. Third Party Review
The Agency will take the following actions to improve the
Third Party Review program with a goal of eliminating routine
re-review by FDA of Third Party reviews:
1. Strengthen the process for accreditation of Third
Parties.
a. Provide training for Third Parties seeking accreditation
by FDA. This training shall include the opportunity for Third
Parties to have access to redacted review memos and other
information as appropriate.
b. When FDA's expectations for a particular device type
change, FDA will have in place a process to convey this
information to the Third Parties and to industry.
2. By the end of FY 2018, establish a plan for eliminating
routine re-review by FDA of Third Party reviews and implement
plan within 12 months.
3. Implement a program to audit reviews conducted by
accredited Third Parties.
a. Provide tailored re-training to accredited Third Parties
based on the results of audits.
4. By the end of FY 2018, issue draft guidance outlining
criteria for reaccreditation of 3rd Parties and the
suspension or withdrawal of accreditation of a Third Party.
FDA will issue final guidance within 12 months of the
conclusion of the public comment period.
5. Publish performance of individual accredited Third
Parties with at least five completed submissions on the web
(e.g., rate of NSE, average number of holds, average time to
SE).
6. Require the independent assessment of the Third Party
Review Program to evaluate efficiency including the
circumstances when FDA re-reviews were conducted; and to
suggest process improvements.
The Agency will seek greater authority to tailor the
program. Specifically, FDA intends to expand the scope of the
program to some product codes that require clinical data and
to remove product codes from eligibility when appropriate,
such as if/when safety signals arise.
As resources permit, FDA will identify pilot device areas
to be the specific focus of an effort where FDA would work
with willing industry partners to ensure that information
allowing for high quality Third Party reviews could be made
available to provide a proof of concept in certain device
areas and enable the development of a broader successful
program.
F. Patient Engagement & the Science of Patient Input
The Agency will take the following actions to advance
patient input and involvement in the regulatory process.
Where appropriate, the Agency will leverage public private
partnerships (PPPs) to advance these actions.
1. Develop clinical, statistical, and other scientific
expertise and staff capacity to respond to submissions
containing applicant-
[[Page S4733]]
proposed use of publicly available and validated, voluntary
patient preference information (PPI) or voluntary patient
reported outcomes (PROs). These staff will provide submission
review and early consultation/advice to industry during study
planning.
2. By the end of FY 2020, hold one or more public meetings
to discuss the topics below and publish the findings and next
steps.
a. Discuss approaches for incorporating PPI and PRO as
evidence in device submissions, as well as other ways of
advancing patient engagement;
b. Discuss ways to use patient input to inform clinical
study design and conduct, with a goal of reducing barriers to
patient participation and facilitating recruitment and
retention;
c. Public meetings should include specific examples and
case histories for PPIs and PROs to ensure clarity and
understanding by workshop attendees; and
d. Identify priority areas where decisions are preference-
sensitive and PPI data can inform regulatory decision-making,
in order to advance design and conduct of patient preference
studies in high impact areas. Publish the priority areas in
the Federal Register for public comment following the public
meeting.
3. FDA will undertake several activities to improve the
regulatory predictability and impact of PROs, including:
a. Clarify to device review divisions that use of PROs is
voluntary and may be one potential way of demonstrating
safety or effectiveness (or elements of either or both, such
as in a composite endpoint). Consistent with least burdensome
principles, applicants may use alternative approaches.
b. Modify the guidance to outline a flexible framework for
PRO validation evidentiary thresholds. These thresholds may
vary depending on the particular regulatory use of the PRO.
c. Work on developing a model for ``bridging studies'' to
make efficient use of existing validated PROs which may be
improved, or adapted to other subpopulations or other
regulatory uses in a more streamlined and expeditious manner
than creating novel PROs.
4. The existing dispute resolution process should be used
in the event of disagreement between the applicant and the
Agency on the need for PPI or PRO.
G. Emerging Diagnostics
FDA will work with industry to continue the pilot for
emerging diagnostics started under MDUFA III.
H. Real World Evidence (RWE)
1. The Agency will use user fee revenue to support the
National Evaluation System for health Technology (NEST) by
providing funding for the NEST Coordinating Center and hiring
FDA staff with expertise in the use of RWE. The NEST
governing board will include no fewer than 4 representatives
of the trade associations that participated in the MDUFA IV
negotiations (AdvaMed, MDMA, MITA, and ACLA), with each
association appointing an individual to serve. Industry
representation on the NEST governing board will make up at
least 25% of the governing board membership. The
representative from each trade association may be part of the
staff of the association or appointed from a member company.
If any of the trade associations elects not to participate on
the NEST governing board or for any additional seats
allocated to Industry, the participating trade associations
will determine how to fill any vacant Industry positions. The
governing board also will include, but not be limited to,
representation from patient organizations. By the end of
FY2019, NEST will implement pilots for at least two product
codes (and related product codes), one of which will cover
devices approved through the PMA process and the other of
which will cover devices cleared through the 510(k) process.
The NEST Coordinating Center will seek ways in which to make
NEST financially self-sustaining so as not to rely on MDUFA
user fees in the long term unless FDA and Industry determine
continued user fee support is warranted and provides a
sufficient return on investment.
2. FDA will contract with an organization to serve as the
NEST Coordinating Center to facilitate use of real world
evidence to support premarket activities. The contract will
specify actions the Coordinating Center will take to advance
the use of RWE, including:
a. Establish a framework to fund pilot projects to
determine the usability of RWE for:
i. Expanded indications for use
ii. New clearances/approvals
iii. Improved malfunction reporting
b. No later than October 1, 2020, the Coordinating Center
will hold a public meeting to review and evaluate the
progress and outcomes (as of the date of the public meeting)
of the pilots described in (H)(1) above.
c. The pilots will take place over a period of three years,
including data analysis and the Coordinating Center will
issue a publicly available report of the results.
d. The pilots will include devices not currently subject to
a registry.
e. At the conclusion of the pilots, an independent third-
party will conduct an assessment to evaluate the strengths,
limitations, and appropriate use of RWE for informing
premarket decision-making for multiple device types.
f. If warranted based on the results of the pilot(s)
described in (H)(1) above, FDA will revise its guidance on
the use of RWE to reflect what has been learned from the
pilots as to how RWE can be used to support:
i. Expanded indications for use; and
ii. New clearances/approvals.
If supported by the pilot(s) described in (H)(1) above, the
guidance will include discussion of how devices not currently
subject to a registry can benefit from RWE.
3. The Agency will establish criteria for streamlining MDR
requirements.
a. For most, if not all, device procodes, FDA will permit
manufacturers of such devices in those procodes to report
malfunctions on a quarterly basis and in a summary MDR
format. FDA will publish the list of eligible device procodes
within 12 months of receiving a proposed list from Industry.
The list will include, among other device procodes, Class II
implantable and Class III devices, as appropriate, and will
reflect FDA's consideration of Industry's proposed list.
b. FDA may determine that devices under a new procode in
existence for less than 2 years are not eligible for
reporting of malfunctions on a quarterly basis and in a
summary format.
c. If a new type of malfunction occurs that the
manufacturer has not previously reported to FDA, the
manufacturer must submit an individual report. The
manufacturer will notify FDA when the issue has been
resolved, using current requirements per 21 C.F.R. 803, 806.
d. FDA will maintain on its website the list of eligible
device procodes for which manufacturers are permitted to
report malfunctions on a quarterly basis and in a summary MDR
format.
e. FDA will establish a mechanism at the time it publishes
the list of eligible devices under 3(a) that permits
stakeholders to request device procodes be added to the list.
f. Nothing in this section precludes the Agency from
requiring individual malfunction reports from a specific
manufacturer and/or for a specific device if necessary to
protect public health. In these situations, FDA will notify
the manufacturer they are not eligible for quarterly summary
MDR reporting and provide an explanation for that decision
and the steps necessary to return to eligibility for
quarterly summary MDR reporting.
4. FDA will not require postmarket surveillance studies
(i.e., 522 Studies) for devices for which registries and/or
other real world data (RWD) sources exist if FDA has access
to the information/data in the RWD source and has determined
that the information/data in the RWD source is sufficient to
take the place of a postmarket surveillance study.
I. Digital Health
The Agency will build expertise and streamline and align
FDA review processes with software lifecycles for Software as
a Medical Device (SaMD) and software inside of medical
devices (SiMD). Specifically, the Agency will:
1. Establish a central digital health unit within CDRH's
Office of the Center Director to ensure proper coordination
and consistency across the Agency. The Agency will not
reorganize staff such that existing review staff would be
reassigned to the central digital health unit, while
retaining and not disrupting the existing digital health
talent within the reviewing divisions who have established,
long-term therapeutic and device expertise. The digital
health unit will perform, at a minimum, the following tasks:
a. Develop software and digital health technical expertise
(``Technical Experts'') to provide assistance for premarket
submissions that include SaMD, SiMD, interoperable devices,
or otherwise incorporate novel digital health technologies.
b. Utilize Technical Experts as appropriate or when
requested by the manufacturer for submissions that include
SaMD, SiMD, interoperable devices, or otherwise incorporate
novel digital health technologies; and
c. Incorporate appropriate metrics for digital health
improvements to monitor, track, analyze and report the
results of digital health premarket review timelines.
2. Publish final guidance addressing when to submit a
510(k) for a software modification to an existing device
within 18 months of the close of the comment period.
3. Explore opportunities to establish premarket approval/
clearance pathways tailored to SaMD, SiMD, and novel digital
health technologies that take into account real world
evidence while incorporating principles established through
international harmonization. To accomplish this task, the
Agency will:
a. Engage with stakeholders, including industry, through
roundtables, informal meetings, and teleconferences;
b. Hold a public workshop; and
c. Revise existing and/or publish new relevant guidance
documents, including publishing a draft revised version of
the ``Guidance for the Content of Premarket Submissions for
Software Contained in Medical Devices'' (issued in 2005) by
the end of FY2019, and within 12 months of the close of the
comment period, publish the final revised version. The Agency
will incorporate applicable concepts from its Guidance for
``Off-The-Shelf Software Used in Medical Devices.''
4. Participate in international harmonization efforts
related to digital health, including work on developing SaMD
and other digital health convergence efforts through the
International Medical Device Regulators Forum (IMDRF).
[[Page S4734]]
J. Guidance Document Development
FDA will apply user fee revenues to ensure timely
completion of Draft Guidance documents. The Agency will
strive to finalize, withdraw, reopen the comment period, or
issue a new draft guidance for 80% of draft guidance
documents within 3 years of the close of the comment periods
as resources permit. The Agency will strive to finalize,
withdraw, reopen the comment period, or issue a new draft
guidance for 100% of draft guidance documents within 5 years
of the close of the comment periods as resources permit. The
Agency will continue to develop guidance documents and
improve the development process as resources permit, but not
to the detriment of meeting quantitative review timelines and
statutory obligations.
K. Total Product Life Cycle (TPLC)
The establishment of CDRH's Office of In Vitro Diagnostic
Device Evaluation and Safety (now the Office of In Vitro
Diagnostics and Radiological Health (OIR)) has led to
improved consistency and predictability due to the enhanced
integration of premarket, postmarket, and compliance-related
activities and staff and improved information sharing among
staff. In addition, the successful development and evaluation
of medical devices depends on the integration of clinical
with scientific and engineering disciplines. CDRH will
explore transitioning to a similar TPLC model building in the
other device areas based on the lessons learned from its
experience with OIR and taking into account the Center's
mission, vision, strategic priorities, and development of a
patient-centric benefit-risk framework for regulatory and
non-regulatory decision making across the TPLC. Because an
essential element for the success of the Center's benefit-
risk decision making framework and approach to device
regulation (particularly emerging and innovative
technologies) is the incorporation of the clinical context
and the impact of a decision on patient health and quality of
life, CDRH will take steps to increase and enhance the
integration of its clinicians into its TPLC activities,
amongst themselves, and with the Center's scientists and
engineers. Building on the success of considering and
incorporating additional expertise and viewpoints into our
decision-making, such as through the use of the Network of
Experts and the leveraging of patient perspectives, CDRH will
also explore ways in which to better learn from and leverage
the expertise of clinicians in other parts of the agency and
outside of the agency to inform its decision making, enhance
consistency, and assure a more holistic clinical perspective.
Clinicians involved in device-related activities will have
appropriate training on and make recommendations consistent
with applicable device statutory provisions, regulations,
guidances, and this Commitment Letter. In addition, CDRH will
provide managerial oversight of clinician recommendations and
device submission decisions, except for those devices subject
to CBER oversight.
V. Independent Assessment of Review Process Management
FDA and the 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 within the
budget provided under this user fee agreement.
Phase 1
During the first phase, the contractor will complete an
evaluation of FDA's implementation of the corrective action
plan developed in response to recommendations from the MDUFA
III independent assessment.
For Phase 1, FDA will award the contract by the end of
CY2017. The contractor will evaluate the implementation of
MDUFA III recommendations and publish a written assessment
within 1 year of contract award.
Phase 2
During the second phase, the contractor will:
1. Evaluate FDA's premarket review program to identify
efficiencies that should be realized as a result of the
process improvements and investments under MDUFA III and IV;
2. Evaluate premarket review program infrastructure and
allocation of FTEs;
3. Assess the alignment of resource needs with the training
and expertise of hires;
4. Identify and share best practices across branches in ODE
and OIR;
5. Assess the effectiveness of programs targeted for
improvement under this agreement, including the:
a. Quality Management program,
b. Proportion of deficiencies in which FDA references the
basis for the deficiency determination,
c. Pre-Submission program (assess whether (a) CDRH is
providing guidance specific to the questions being asked; (b)
CDRH is using Pre-Submissions appropriately; and (c) CDRH and
Industry are adhering to the procedural aspects as set forth
in this agreement),
d. Third Party Review program (assess efficiency of program
and suggest process improvements),
e. Digital Health program,
f. Patient Engagement program, and
g. Real World Evidence program;
6. Analyze conversions of Special 510(k)s to Traditional
510(k)s; and
7. Assess other key areas identified by FDA and industry as
resources permit.
For Phase 2 of the independent assessment, FDA will award
the contract no later than 3/31/2020. However, the contractor
would not begin the audit of deficiency letters and Pre-
Submissions before 10/1/2020. The contractor will publish
comprehensive findings and recommendations within 1 year. For
all recommendations the contractor will provide an estimate
of additional resources needed or efficiencies gained, as
applicable.
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 and, as
appropriate, develop and implement a corrective action plan,
and assure its effectiveness.
VI. Performance Reports
The Agency will report its progress toward meeting the
goals described in this letter, as follows. If, throughout
the course of MDUFA IV, 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 that do not go through a 3rd
party, 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 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 de novo requests, reporting will include:
i. Average, and quintiles of the number of FDA Days,
Industry Days, and Total Days to a MDUFA decision
ii. Average number of review cycles.
iii. Rate of submissions not accepted for review, upon
final guidance
1.4. For Pre-Submissions, reporting will include:
i. Number of all qualified Pre-Submissions received
ii. Rate of submissions not accepted for review, upon final
guidance
iii. Average and quintiles of the number of calendar days
from submission to written feedback
iv. Number of Pre-Submissions that require a meeting
v. Percent of submissions with meetings for which industry
provided minutes within 15 days
1.5. 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
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), de novo, and PMA
submissions
2.3. Rate of Not Approvable decisions for PMA submissions
2.4. Rate of Denial decisions for de novo requests
2.5. 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
2.6. Specific topic or product area as it relates to
performance goals, agreed upon at the previous meeting
2.7. Number of submissions that missed the goals and the
total number of elapsed calendar days broken down into FDA
days and industry days
2.8. Newly released draft and final guidance documents, and
status of other priority guidance documents
2.9. Agency level summary of fee collections
2.10. Independent assessment implementation plan status
2.11. Results of independent assessment and subsequent
periodic audits and progress toward implementation of the
recommendations and any corrective action
2.12. 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
[[Page S4735]]
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 510(k) submissions that go through a 3rd party,
reporting will include:
i. Time from FDA receipt of third party report to FDA
decision at the 90% percentile
ii. Once 3rd party program enhancements have been
implemented, resources saved as a result of enhancements to
the 3rd party review program.
3.8. 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
viii. Number of submissions FDA classifies as unsolicited
major, solicited major, and minor amendments
3.9. For De Novo requests, reporting will include:
i. Number of submissions received
ii. Average and number of days to Accept/Refuse to Accept,
upon final guidance
3.10. 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
3.11. Report on the ASCA program
3.12. Data regarding the reduction in reviewer to manager
ratio.
3.13. Report on implementation of deficiency performance
improvements.
3.14. Report on quality management program
3.15. Summary of quality system audits
FDA will report annual and quarterly data on performance
within goals for 510(k), de novo, and PMA MDUFA decisions for
devices identified as LDTs by the submitter compared to all
non-LDT IVD devices. The following elements will be reported:
Number and percentage of LDT 510(k)s and non-LDT IVD
510(k)s completed within 90 FDA days
Number and percentage of LDT de novos and non-LDT IVD de
novos completed within 150 FDA days
Number and percentage of LDT PMAs and non-LDT IVD PMAs
completed within 180 FDA days
FDA commits to treat LDTs no less favorably than other
devices to which MDUFA performance goals apply.
On an annual basis, FDA and Industry will discuss the
return on investment, which may include process improvements,
improved performance, and other enhancements, under MDUFA IV.
VII. 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 of
the Federal Food, Drug, and Cosmetic Act (FDCA);
a premarket notification under section 510(k) of the FDCA;
an application for investigational device exemption under
section 520(g) of the FDCA;
a Pre-Submission;
a de novo request (evaluation of automatic class III
designation) under section 513(f)(2) of the FDCA;
a CLIA Waiver by application.
B. Electronic Copy (e-Copy)
An electronic copy is an exact duplicate of a 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. Electronic submission template
An electronic submission template, or eSubmission template,
is a guided submission preparation tool for industry. Similar
to an online form, the eSubmission template walks industry
through the relevant contents and components for the
respective premarket submission type and device in order to
facilitate submission preparation and enhance consistency,
quality, and efficiency in the premarket review process.
D. 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 de novo classification
request), filed (PMA) or submitted (CLIA Waiver by
application). 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).
E. 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).
De Novo Requests: Decisions for De Novo requests are grant,
withdrawal, and decline.
CLIA Waiver by Application Submissions: Decisions for CLIA
Waiver by Application Submissions are Approval, Withdrawal,
and Denial.
Submissions placed on Application Integrity Program Hold
will be removed from the MDUFA cohort.
F. 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 testing protocols or
data requirements; design and performance of clinical studies
and acceptance criteria). 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.
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).
General information requests initiated through the Division
of Industry and Consumer Education (DICE).
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 not require the involvement of a broader
number of FDA staff beyond the routine involvement of the
reviewer's supervisor and more experienced mentors.
G. 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
[[Page S4736]]
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.
H. 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 average 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
FY2018, the average Total Time to Decision for PMA
applications would be the average of FY2016 through FY2018)
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.
I. Accreditation Scheme for Conformity Assessment
Conformity Assessment is the demonstration that specified
requirements relating to a product, process, system, person
or body are fulfilled.
Accreditation is the formal recognition by an independent
body, generally known as an accreditation body, that an
organization is competent to carry out specific conformity
assessment activities. Accreditation is not obligatory but it
adds another level of confidence, as `accredited' means the
organization has been independently checked to make sure it
operates according to international standards.
A conformity assessment scheme is a system for assessing
the conformity of specified objects (e.g., medical devices or
management processes) to one or more consensus standards. The
system specifies the applicable standards as well as the
rules, procedures, and management requirements for carrying
out the conformity assessment to meet a regulatory need.
Informally, such a scheme may be referred to as an
accreditation scheme.
Testing laboratory is an organization that possesses the
necessary technical competence and capabilities to conduct
testing to making a determination that one or more
characteristics of an object are in conformance with a set of
predefined requirements.
J. 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.
Mr. ALEXANDER. Mr. President, I ask unanimous consent to have printed
in the Record a copy of the commitment letter for the Prescription Drug
User Fee Act, PDUFA, reauthorization for fiscal years 2018 to 2022,
known as PDUFA VI.
There being no objection, the material was ordered to be printed in
the Record, as follows:
PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES FISCAL YEARS
2018 THROUGH 2022
I. Ensuring the Effectiveness of the Human Drug Review
Program
A. Review Performance Goals
B. Program For Enhanced Review Transparency And
Communication For NME NDAs And Original BLAs
C. First Cycle Review Management
D. Review Of Proprietary Names To Reduce Medication Errors
E. Major Dispute Resolution
F. Clinical Holds
G. Special Protocol Question Assessment And Agreement
H. Meeting Management Goals
I. Enhancing Regulatory Science And Expediting Drug
Development
J. Enhancing Regulatory Decision Tools To Support Drug
Development And Review
K. Enhancement And Modernization Of The FDA Drug Safety
System
II. Enhancing Management of User Fee Resources
A. Resource Capacity Planning And Modernized Time Reporting
B. Financial Transparency And Efficiency
III. Improving FDA Hiring and Retention of Review Staff
A. Completion Of Modernization Of The Hiring System
Infrastructure And Augmentation Of System Capacity
B. Augmentation Of Hiring Staff Capacity And Capability
C. Complete Establishment Of A Dedicated Function To Ensure
Needed Scientific Staffing For Medical Product Review
D. Set Clear Goals For Drug Review Program Hiring
E. Comprehensive And Continuous Assessment Of Hiring And
Retention
IV. Information Technology Goals
A. Objective
B. Improve The Predictability And Consistency Of PDUFA
Electronic Submission Processes
C. Enhance Transparency And Accountability Of FDA
Electronic Submission And Data Standards Activities
V. Improving FDA Performance Management
VI. Progress Reporting for PDUFA VI and Continuing PDUFA V
Initiatives
VII. Definitions and Explanation of Terms
PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES FISCAL YEARS
2018 THROUGH 2022
This document contains the performance goals and procedures
for the Prescription Drug User Fee Act (PDUFA)
reauthorization for fiscal years (FYs) 2018-2022, known as
PDUFA VI. It is commonly referred to as the ``goals letter''
or ``commitment letter.'' The goals letter represents the
product of FDA's discussions with the regulated industry and
public stakeholders, as mandated by Congress. The performance
and procedural goals and other commitments specified in this
letter apply to aspects of the human drug review program that
are important for facilitating timely access to safe,
effective, and innovative new medicines for patients. While
much of FDA's work is associated with formal tracked
performance goals, the Agency and industry mutually agree
that it is appropriate to manage some areas of the human drug
review program with internally tracked timeframes. This
provides FDA the flexibility needed to respond to a highly
diverse workload, including unanticipated public health
needs. FDA is committed to meeting the performance goals
specified in this letter and to continuous improvement of its
performance regarding other important areas specified in
relevant published documents that relate to preapproval drug
development and post-approval activities for marketed
products. FDA and the regulated industry will periodically
and regularly assess the progress of the human drug review
program throughout PDUFA VI. This will allow FDA and the
regulated industry to identify emerging challenges and
develop strategies to address these challenges to ensure the
efficiency and effectiveness of the human drug review
program.
Unless otherwise stated, goals apply to cohorts of each
fiscal year (FY).
I. ENSURING THE EFFECTIVENESS OF THE HUMAN DRUG REVIEW PROGRAM
A. Review Performance Goals
1. NDA/BLA Submissions and Resubmissions
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.
c. Review and act on 90 percent of standard non-NME
original NDA submissions within 10 months of receipt.
d. Review and act on 90 percent of priority non-NME
original NDA submissions within 6 months of receipt.
e. Review and act on 90 percent of Class 1 resubmitted
original applications within 2 months of receipt.
f. Review and act on 90 percent of Class 2 resubmitted
original applications within 6 months of receipt.
2. Original Efficacy Supplements
a. Review and act on 90 percent of standard efficacy
supplements within 10 months of receipt.
b. Review and act on 90 percent of priority efficacy
supplement within 6 months of receipt.
3. Resubmitted Efficacy Supplements
a. Review and act on 90 percent of Class 1 resubmitted
efficacy supplements within 2 months of receipt.
b. Review and act on 90 percent of Class 2 resubmitted
efficacy supplements within 6 months of receipt.
4. Original Manufacturing Supplements
a. Review and act on 90 percent of manufacturing
supplements requiring prior approval within 4 months of
receipt
[[Page S4737]]
b. Review and act on 90 percent of all other manufacturing
supplements within 6 months of receipt.
5. Review Performance Goal Extensions
a. Major Amendments
i. 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.
ii. 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 Element 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.
iii. A major amendment to a manufacturing supplement
submitted at any time during the review cycle may extend the
goal date by two months.
iv. Only one extension can be given per review cycle.
v. 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.
b. Inspection of Facilities Not Adequately Identified in an
Original Application or Supplement
i. All original applications, including those in the
``Program,'' (see Section I.B.2) and supplements are expected
to include a comprehensive and readily located list of all
manufacturing facilities included or referenced in the
application or supplement. This list provides FDA with
information needed to schedule inspections of manufacturing
facilities that may be necessary before approval of the
original application or supplement.
ii. If, during FDA's review of an original application or
supplement, the Agency identifies a manufacturing facility
that was not included in the comprehensive and readily
located list, the goal date may be extended.
1) If FDA identifies the need to inspect a manufacturing
facility that is not included as part of the comprehensive
and readily located list in an original application or
efficacy supplement, the goal date may be extended by three
months.
2) If FDA identifies the need to inspect a manufacturing
facility that is not included as part of the comprehensive
and readily located list in a manufacturing supplement, the
goal date may be extended by two months.
6. These review goals are summarized in the following
tables:
TABLE 1.--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
------------------------------------------------------------------------
TABLE 2
------------------------------------------------------------------------
Prior Approval All Other
------------------------------------------------------------------------
Manufacturing Supplements....... 90% in 4 months of 90% in 6 months of
the receipt date. the receipt date
------------------------------------------------------------------------
B. Program for Enhanced Review Transparency and Communication
for NME NDAs and Original BLAs
To promote transparency and communication between the FDA
review team and the applicant, FDA will apply the following
model (``the Program'') to the review of 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 decision,
received from October 1, 2017, through September 30, 2022.
The goal of the Program is to promote the efficiency and
effectiveness of the first cycle review process and minimize
the number of review cycles necessary for approval, ensuring
that patients have timely access to safe, effective, and high
quality new drugs and biologics.
Approach to Application Review. The standard approach for
the review of NME NDAs and original BLAs is described in this
section. However, the FDA review team and the applicant may
discuss and reach mutual agreement on an alternative approach
to the timing and nature of interactions and information
exchange between the applicant and FDA, i.e., a Formal
Communication Plan for the review of the NME NDA or original
BLA. The Formal Communication Plan may include elements of
the standard approach (e.g., a mid-cycle communication or a
late-cycle meeting) as well as other interactions that
sometimes occur during the review process (e.g., a meeting
during the filing period to discuss the application, i.e., an
``application orientation meeting''). If appropriate, the
Formal Communication Plan should specify those elements of
the Program that FDA and the sponsor agree are unnecessary
for the application under review. If the review team and the
applicant anticipate developing a Formal Communication Plan,
the elements of the plan should be discussed and agreed to at
the pre-submission meeting (see Section I.B.1) and reflected
in the meeting minutes. The Formal Communication Plan may be
reviewed and amended at any time based on the progress of the
review and the mutual agreement of the review team and the
applicant. For example, the review team and the applicant may
mutually agree at any time to cancel future specified
interactions in the Program (e.g., the late-cycle meeting)
that become unnecessary (e.g. because previous communications
between the review team and the applicant are sufficient).
Any amendments made to the Formal Communication Plan should
be consistent with the goal of an efficient and timely first
cycle review process and not impede the review team's ability
to conduct its review.
Expedited Reviews. In certain cases, an application
reviewed in the Program will be for a product that the FDA
review team identifies as meeting an important public health
need. If the FDA review team determines that a first-cycle
approval is likely for such an application, the team intends
to make every effort to conduct an expedited review and act
early on the application. FDA conducts expedited reviews to
promote timely access to critically needed therapies for
patients without compromising FDA's high standards for
demonstrating the safety, efficacy, and quality of new
medicines. Expedited reviews are typically characterized by
frequent contact between the applicant and the FDA review
team throughout the review process. Any parameters of the
Program that are intended to facilitate expedited reviews are
noted throughout Section I.B.
If significant application deficiencies are identified by
the review team at any time during an expedited review, FDA
intends to revert, for the remainder of the review, to the
standard approach to the review of priority NME NDAs and
original BLAs (as described in this section), and will inform
the applicant accordingly.
The remainder of Section I.B describes the parameters that
will apply to FDA's review of applications in the Program.
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. This meeting will be attended by the FDA review
team, including appropriate senior FDA staff.
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. In addition to FDA's preliminary responses to the
applicant's questions, other potential discussion topics
include preliminary discussions on the need for REMS or other
risk management actions, and, where applicable, the
development of a Formal Communication Plan and a timeline for
review activities associated with a scheduling recommendation
under the Controlled Substances Act for drugs with abuse
potential. These discussions will be summarized at the
conclusion of the meeting and reflected in the FDA meeting
minutes.
c. The FDA and the applicant will agree on the content of a
complete application for the proposed indication(s) at the
pre-submission 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.
These agreements will be summarized at the conclusion of the
meeting and reflected in the FDA meeting minutes.
i. 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
[[Page S4738]]
(e.g., carcinogenicity) where the final draft report is
submitted with the original application.
ii. 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.
d. The following parameters will apply to applications that
are subject to a Refuse-to-File decision and are subsequently
filed over protest:
i. The original submission of the application will be
subject to the review performance goal as described in
Section I.B.4.
ii. The application will not be eligible for the other
parameters of the Program (e.g., mid-cycle communication,
late-cycle meeting).
iii. FDA generally will not review amendments to the
application during any review cycle. FDA also generally will
not issue information requests to the applicant during the
agency's review.
iv. The resubmission goals described in Section I.A.1.e and
I.A.1.f will not apply to any resubmission of the application
following an FDA complete response action. Any such
resubmission will be reviewed as available resources permit.
e. 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.
Review of unsolicited amendments, including those submitted
in response to an FDA communication of deficiencies, will be
handled in accordance with the GRMP guidance. 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
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. If applicable, the Day 74 letter will serve
as notification to the applicant that the review division
intends to conduct an expedited review.
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. An agenda will be sent to the applicant prior to
the mid-cycle communication. 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), an update regarding FDA's review activities
associated with a scheduling recommendation under the
Controlled Substances Act (if applicable), and other
projected milestone dates for the remainder of the review
cycle.
b. In the case of an expedited review, FDA will communicate
the timelines for the Late-Cycle Meeting and the Late-Cycle
Meeting background package (see Section I.B.6) which may
occur earlier with more condensed timeframes compared to a
review that is not expedited.
6. Late-Cycle and Advisory Committee Meetings: 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. Late-cycle meetings will generally be face-
to-face meetings; however, the meeting may be held by
teleconference if FDA and the applicant agree. Since the
application is expected to be complete at the time of
submission, FDA intends to complete primary and secondary
reviews of the application in advance of the planned late-
cycle meeting.
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 AC
meeting, the following parameters apply:
i. FDA intends to convene AC meetings no later than 2
months (standard review) or no later than 6 weeks (priority
review) prior to the PDUFA goal date. The late-cycle meeting
will occur not less than 12 calendar days before the date of
the AC meeting.
ii. FDA intends to provide final questions for the AC to
the sponsor and the AC not less than 2 calendar days before
the AC meeting.
iii. Following an AC Meeting, FDA and the applicant may
agree on the need to discuss feedback from the AC for the
purpose of facilitating the remainder of the review. Such a
meeting will generally be held by teleconference without a
commitment for formal meeting minutes issued by the agency.
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.
d. Late-Cycle Meeting Background Packages: The Agency
background package for the late-cycle meeting will be sent to
the applicant not less than 10 calendar days (or 2 calendar
days for an expedited review) before the late-cycle meeting.
The package will consist of a brief memorandum from the
review team outlining substantive application issues (e.g.,
deficiencies identified by primary and secondary reviews),
the Agency's background package for the AC meeting
(incorporated by reference if previously sent to the
applicant), potential questions and/or points for discussion
for the AC meeting (if planned) and the current assessment of
the need for REMS or other risk management actions. If the
application is subject to an expedited review, the background
package may be streamlined and brief using a bulleted list to
identify issues to be discussed.
e. Late-Cycle Meeting Discussion Topics: 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; status update of
FDA's review activities associated with a scheduling
recommendation under the Controlled Substances Act, if
applicable; information requests from the review team to the
applicant; and additional data or analyses the applicant may
wish to submit.
i. 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.
7. 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.
C. First Cycle Review Management
FDA and industry share a commitment to ensuring an
efficient and effective first cycle review process for all
applications subject to the PDUFA program. This commitment
was first articulated in the GRMP guidance finalized in 2005.
FDA will update this guidance in PDUFA VI to include review
activities (e.g., the NME Program, REMS) that have been added
to the human drug review program since the guidance was
finalized, principles regarding notification to applicants
regarding issues identified during FDA's initial review of
the application, principles regarding FDA's notification to
applicants regarding planned review timelines, and the
importance of internal review timelines that govern aspects
of the human drug review program that are not part of PDUFA
performance goals. FDA will publish a revised draft guidance
for public comment no later than the end of FY 2018.
[[Page S4739]]
D. Review of Proprietary Names to Reduce Medication Errors
To enhance patient safety, FDA is committed to 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. The following performance
goals apply to FDA's review of drug and biological product
proprietary names during development (as early as end-of-
phase 2) and during FDA's review of a marketing application:
1. Proprietary Name Review Performance Goals During Drug
Development
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 Name Review Performance Goals During
Application Review
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.
E. Major Dispute Resolution
1. 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.
2. Performance goal: 90% of such answers are provided
within 30 calendar days of the Center's receipt of the
written appeal.
3. Conditions:
a. 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.
b. 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.
c. 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.
d. 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 (AC).
e. In these cases, once the required information is
received by the Agency (including any advice from an AC), the
person to whom the appeal was made, again has 30 calendar
days from the receipt of the required information in which to
either grant or deny the appeal.
f. 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.
g. N.B. If the Agency decides to present the issue to an AC
and there are not 30 days before the next scheduled AC, the
issue will be presented at the following scheduled committee
meeting to allow conformance with AC administrative
procedures.
F. Clinical Holds
1. 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.
2. Performance goal:
90% of such responses are provided within 30 calendar days
of the Agency's receipt of the sponsor's response.
G. Special Protocol Question Assessment and Agreement
1. 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.
a. 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).
b. 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.
c. 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.
d. 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.
e. 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.
2. Performance goal:
90% of special protocol assessments and agreement requests
completed and returned to sponsor within the timeframe.
3. Reporting:
The Agency will track and report the number of original
special protocol assessments and resubmissions per original
special protocol assessment.
H. Meeting Management Goals
Formal PDUFA meetings between sponsors and FDA consist of
Type A, B, B(EOP), and C meetings. These meetings are further
described below.
Type A meetings are those meetings that are necessary for
an otherwise stalled drug development program to proceed
(i.e., a ``critical path'' meeting) or to address an
important safety issue. Post-action meetings requested within
three months after an FDA regulatory action other than
approval (i.e., issuance of a complete response letter) will
also generally be considered Type A meetings.
Type B meetings include pre-IND meetings and pre-NDA/BLA
meetings, while Type B (EOP) meetings are reserved for
certain End-of-Phase 1 meetings (i.e. for 21 CFR Part 312
Subpart E or 21 CFR Part 314 Subpart H or similar products)
and End-of-Phase 2/pre-Phase 3 meetings. Meetings regarding
REMS or postmarketing requirements that occur outside the
context of the review of a marketing application will also
generally be considered Type B meetings.
A Type C meeting is any other type of meeting.
1. Responses to Meeting Requests
a. Procedure: FDA will notify the requester in writing of
the date, time, and place for the meeting, as well as
expected Center participants following receipt of a formal
meeting request. Table 3 below indicates the timeframes for
FDA's response to a meeting request.
TABLE 3
------------------------------------------------------------------------
Response Time
Meeting Type (calendar days)
------------------------------------------------------------------------
A.................................................... 14
B.................................................... 21
B(EOP)............................................... 14
C.................................................... 21
------------------------------------------------------------------------
i. For any type of meeting, the sponsor may request a
written response to its questions rather than a face-to-face
meeting, videoconference or teleconference. FDA will review
the request and make a determination on whether a written
response is appropriate or whether a face-to-face meeting,
videoconference, or teleconference is necessary. If a written
response is deemed appropriate, FDA will notify the requester
of the date it intends to send the written response in the
[[Page S4740]]
Agency's response to the meeting request. This date will be
consistent with the timeframes specified in Table 4 below for
the specific meeting type.
ii. For pre-IND and Type C meetings, while the sponsor may
request a face-to-face meeting, the Agency may determine that
a written response to the sponsor's questions would be the
most appropriate means for providing feedback and advice to
the sponsor. When it is determined that the meeting request
can be appropriately addressed through a written response,
FDA will notify the requester of the date it intends to send
the written response in the Agency's response to the meeting
request. This date will be consistent with the timeframes
specified in Table 4 below for the specific meeting type.
b. Performance Goal: FDA will respond to meeting requests
and provide notification within the response times noted in
Table 3 for 90% of each meeting type.
2. Scheduling Meetings
a. Procedure: FDA will schedule the meeting on the next
available date at 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. Table 4 below indicates
the timeframes for the scheduled meeting date following
receipt of a formal meeting request, or in the case of a
written response, the timeframes for the Agency to send the
written response. If the requested date for any meeting type
is greater than the specified timeframe, the meeting date
should be within 14 calendar days of the requested date.
TABLE 4
------------------------------------------------------------------------
Meeting Scheduling or Written
Meeting Type Response Time
------------------------------------------------------------------------
A...................................... 30 calendar days from receipt
of meeting request
B...................................... 60 calendar days from receipt
of meeting request
B(EOP)................................. 70 calendar days from receipt
of meeting request
C...................................... 75 calendar days from receipt
of meeting request
------------------------------------------------------------------------
b. Performance goal: 90% of meetings are held within the
timeframe for each meeting type, and 90% of written responses
are sent within the timeframe for each meeting type.
3. Meeting Background Packages
The timing of the Agency's receipt of the sponsor
background package for each meeting type (including those
meetings for which a written response will be provided) is
specified in Table 5 below.
TABLE 5
------------------------------------------------------------------------
Meeting Type Receipt of Background Package
------------------------------------------------------------------------
A...................................... At the time of the meeting
request
B...................................... 30 calendar days before the
date of the meeting or
expected written response
B(EOP)................................. 50 calendar days before the
date of the meeting or
expected written response*
C6..................................... 47 calendar days before the
date of the meeting or
expected written response*
------------------------------------------------------------------------
* If the scheduled date of a Type B(EOP) or C meeting is earlier than
the timeframes specified in Table 4, the meeting background package
will be due no sooner than 6 calendar days and 7 calendar days
following the response time for Type B(EOP) and C meetings specified
in Table 3, respectively.
4. Preliminary Responses to Sponsor Questions
a. Procedure: The Agency will send preliminary responses to
the sponsor's questions contained in the background package
no later than five calendar days before the meeting date for
Type B(EOP) and C meetings.
b. Performance goal: 90% of preliminary responses to
questions for Type B(EOP) meetings are issued by FDA no later
than five calendar days before the meeting date.
5. Sponsor Notification to FDA
Not later than three calendar days following the sponsor's
receipt of FDA's preliminary responses for a Type B(EOP) or C
meeting, the sponsor will notify FDA of whether the meeting
is still needed, and if it is, the anticipated agenda of the
meeting given the sponsor's review of the preliminary
responses.
6. Meeting Minutes
a. Procedure: The Agency will prepare minutes that 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. Meeting minutes are not required if the Agency
transmits a written response for any meeting type.
b. Performance goal: 90% of minutes are issued within 30
calendar days of the date of the meeting.
7. Conditions
For a meeting to qualify for these performance goals:
a. A written request must be submitted to the review
division.
b. The written request must provide:
i. A brief statement of the purpose of the meeting and the
sponsor's proposal for either a face-to-face meeting or a
written response from the Agency;
ii. A listing of the specific objectives/outcomes the
requester expects from the meeting;
iii. A proposed agenda, including estimated times needed
for each agenda item;
iv. A listing of planned external attendees;
v. A listing of requested participants/disciplines
representative(s) from the Center with an explanation for the
request as appropriate; and
vi. The date that the meeting background package will be
sent to the Center. Refer to Table 5 for timeframes for the
Agency's receipt of background packages.
c. 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 or B(EOP) meeting will be
honored except in the most unusual circumstances.
8. Guidance
FDA will publish revised draft guidance on formal meetings
between FDA and sponsors no later than September 30, 2018.
I. Enhancing Regulatory Science and Expediting Drug
Development
To ensure that new and innovative products are developed
and available to patients in a timely manner, FDA will build
on the success of the FDA's regulatory science program that
included advancing the science of meta-analysis
methodologies, advancing the use of biomarkers and
pharmacogenomics, enhancing communications between FDA and
sponsors during drug development, and advancing the
development of drugs for rare diseases. The extension and
continuation of this work will encompass further evaluation
and enhancement of FDA-sponsor communications, ensuring the
sustained success of the breakthrough therapy program,
establishing early consultations between FDA and sponsors on
the use of new surrogate endpoints as the primary basis for
product approval, advancing rare disease drug development,
advancing the development of combination products, and
exploring the use of real world evidence for use in
regulatory decision-making.
1. Promoting Innovation Through Enhanced Communication
Between FDA and Sponsors During Drug Development
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. Accordingly, FDA will maintain dedicated drug
development communication and training staffs in CDER and
CBER, focused on enhancing communication between FDA and
sponsors during drug development.
One function of the staff is to serve as a liaison that
will facilitate general and, in some cases, specific
interactions between sponsors and each Center. The liaison
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 liaison will also serve as a secondary point
of contact in each Center for sponsors who are encountering
challenges 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 will work with the review team and the sponsor to
facilitate resolution of the issue.
The second function of the staff is to provide ongoing
training to the review organizations on best practices in
communication with sponsors. The content of training
includes, but is not limited to, FDA's philosophy regarding
timely interactive communication with sponsors during drug
development as a core Agency activity, best practices for
addressing sponsor requests for advice and timely
communication of responses through appropriate mechanisms
(e.g., teleconferences, secure email, or when questions are
best addressed through the formal meetings process), and the
role of the liaison staff in each Center in facilitating
communication between the review staff and sponsor community,
including the staff's role in facilitating resolution of
individual communication requests. The staff will also
collaborate with sponsor stakeholders (e.g., through
participation in workshops, webinars, and other meetings) to
communicate FDA's philosophy and best practices regarding
communication with sponsors during drug development.
To continue to enhance timely interactive communication
with sponsors during drug development in PDUFA VI, FDA will
do the following:
a. Independent Assessment. FDA will contract with an
independent third party to assess current practices of FDA
and sponsors in communicating during drug development. The
statement of work for this effort will be published for
public comment prior to beginning the assessment. The third
party will be expected to separately engage both FDA staff
and individual sponsors through contractor-led interviews as
part of the assessment. Due to the significant volume of FDA-
sponsor interactions in a given year, the assessment will be
based on a random subset of drug development programs
identified by IND number. The third party will identify best
practices and areas for improvement in communication by FDA
review staff and sponsors. FDA will publish the final report
of the assessment on FDA's website no later than the end of
FY 2020.
b. Public Workshop. FDA will convene a public workshop by
the end of March 2021 to discuss the findings of the
independent assessment, including anonymized, aggregated
feedback from sponsors and FDA review teams resulting from
the contractor interviews.
[[Page S4741]]
c. Guidance. FDA will consider the third party's
recommendations for best practices in communication and
update the current draft or final guidance on ``Best
Practices for Communication Between IND Sponsors and FDA
During Drug Development'' if appropriate. If FDA determines
that the guidance should be updated, based on the
recommendations of the third party and the feedback received
from the public workshop, FDA will update the guidance no
later than one year following the public workshop.
2. Ensuring Sustained Success of Breakthrough Therapy
Program
Breakthrough therapy designation is intended to expedite
the development and review of drug and biological products,
alone or in combination, for serious or life-threatening
diseases or conditions when preliminary clinical evidence
indicates that the drug may demonstrate substantial
improvement over existing therapies. A breakthrough therapy
designation includes the features of the fast track program,
intensive FDA guidance on an efficient drug development
program, and an organizational commitment by FDA involving
senior managers. Additional resources will enable the Agency
to continue to work closely with sponsors throughout the
breakthrough therapy designation, development, and review
processes. Both FDA and the regulated industry are committed
to ensuring the expedited development and review of
innovative therapies for serious or life-threatening diseases
or conditions by investing additional resources into the
breakthrough therapy program.
3. Early Consultation on the Use of New Surrogate Endpoints
FDA and industry believe that early consultation between
review teams and sponsors is important for development
programs where the sponsor intends to use a biomarker as a
new surrogate endpoint that has never been previously used as
the primary basis for product approval in the proposed
context of use. Early consultation in the drug development
program allows the review team to consult with FDA senior
management to evaluate the sponsor's proposal before
providing advice regarding the proposed biomarker as a new
surrogate endpoint to support accelerated or traditional
approval. Requests to engage with FDA on this topic will be
considered a Type C meeting request. The purpose of this
meeting is to discuss the feasibility of the surrogate as a
primary endpoint, and identify any gaps in knowledge and how
they might be addressed. The outcome of this meeting may
require further investigation by the sponsor and discussion
and agreement with the agency before the surrogate endpoint
could be used as the primary basis for product approval. To
qualify for this consultation, these Type C meeting requests
must be accompanied by the complete meeting background
package at the time the request is made that includes
preliminary human data indicating impact of the drug on the
biomarker at a dose that appears to be generally tolerable.
The remaining meeting procedures as described in Section I.H
of this document will apply.
4. Advancing Development of Drugs for Rare Diseases
FDA will build on the success of the Rare Disease Program
(RDP) in CDER and CBER by continuing to advance and
facilitate the development and timely approval of drugs and
biologics for rare diseases, including rare diseases in
children. The Rare Disease Program staff in CDER will be
integrated into review teams for rare disease development
programs and application review to provide their unique
expertise on flexible and feasible approaches to studying and
reviewing such drugs to include, for example, innovative use
of biomarkers, consideration of non-traditional clinical
development programs, use of adaptive study designs,
evaluation of novel endpoints, application of new approaches
to statistical analysis, and appropriate use of FDA's
expedited development and review programs (i.e., Fast Track,
Breakthrough, Priority Review, and Accelerated Approval).
CBER, through its Rare Disease Program Staff, will also
ensure that its review offices consider such flexible and
feasible approaches in review.
The RDP staff will also continue to provide training to all
CDER and CBER review staff related to development, review,
and approval of drugs for rare diseases as part of the
reviewer training core curriculum. The objective of
the training will be 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 drug development and application review. The training
will also emphasize the important role of the RDP staff as
members of the core review team to help ensure consistency of
scientific and regulatory approaches across applications and
review teams.
RDP staff will continue to engage in outreach to industry,
patient groups, and other stakeholders to provide training on
FDA's RDP. The staff will continue to foster collaborations
in the development of tools (e.g., patient reported outcome
measures) and data (e.g., natural history studies) to support
development of drugs for rare diseases. In addition, the
staff will also facilitate interactions between stakeholders
and FDA review divisions to increase awareness of FDA
regulatory programs and engagement of patients in FDA's
regulatory decision-making.
FDA will include updates on the activities and success of
the RDP in the PDUFA annual performance report to include,
for example, the number of training courses offered and staff
trained, the number of review programs where RDP staff
participated as core team members, and metrics related to
engagement with external stakeholders. FDA will also continue
to include information on rare disease approvals in its
annual reports on innovative drug approvals, including
utilization of expedited programs and regulatory flexibility
and appropriate comparative metrics to non-rare disease
innovative approvals.
5. Advancing Development of Drug-Device and Biologic-Device
Combination Products Regulated by CBER and CDER
a. FDA will develop staff capacity and capability across
the medical product centers and the Office of Combination
Products (OCP) to more efficiently, effectively, and
consistently review and respond to submissions that include
combination products. These staff will advance the
development of combination products by providing combination
product expertise as part of the core review team as
applicable, and through promoting best practices for review
of combination products. The additional capacity will include
staff who will focus on review of cGMP, engineering aspects,
human factors and bridging study protocols and study reports,
and labeling, to include instructions-for-use materials.
b. FDA will streamline the process for combination product
review and improve the Agency's ability to assess workload
and allocate resources to the review of combination products.
i. By no later than December 31, 2017, FDA will complete a
lean process mapping for combination product review in order
to inform changes to review work flow to improve the inter-
center consultation process.
ii. By no later than December 31, 2017, FDA will begin
tracking workload and timelines for cross-center
consultations to enable appropriate allocation of resources
and regularly assess the progress of combination product
review throughout PDUFA VI.
iii. By no later than September 30, 2018, for each
component within FDA that is consulted to participate in
review of combination products, FDA will outline in
appropriate internal documents the Agency's process for
resolving internally any scientific or regulatory issues that
arise, as well as a commitment for the medical product
centers and OCP to coordinate and complete reviews and
related activities when consulted in timelines set forth by
PDUFA and other published documents (e.g., the GRMP guidance
and GRMP MAPP).
c. FDA will establish Manuals of Policies and Procedures
(MAPPs) and Standard Operating Policy and Procedures (SOPPs)
to promote efficient, effective, and consistent combination
product development and review. The documents will describe
processes and procedures for conducting review of combination
products, including the expectations for consultation of
internal experts outside the reviewing Center. FDA will
describe the responsibilities of staff in each Center and
Office, expectations for core review team members and for
other consultant staff in activities and meetings related to
the combination product development program and application
review. FDA will define the key terms to be used by staff in
review of combination products to foster clear communication
within FDA and to regulated industry. The topic areas and
expected completion dates of these documents are specified
below:
i. Human Factors Assessments (March 31, 2019)
ii. Quality assessment of combination products, including
coordination of facility inspections (September 30, 2019)
iii. Patient-oriented labeling, including instructions-for-
use materials for those drug-device and biologic-device
combination products regulated by CBER and CDER (September
30, 2019)
d. By no later than December 31, 2018, FDA will make
available on FDA's website key points of contact in OCP and
the medical product centers for combination product review.
FDA agrees to maintain and update this information
periodically.
e. FDA will establish submission procedures for Human
Factors protocols no later than September 30, 2018. Beginning
in FY 2019, FDA will establish timelines to review and
provide comment on the protocols for Human Factors studies of
combination drug-device and biologic-device products within
60 days.
i. Procedure for review of human factors protocols for
combination products: Upon specific request by a sponsor
(including specific questions that the sponsor desires to be
answered) consistent with the steps below, the Agency will
evaluate human factors 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 human factors protocol design and
scientific and regulatory requirements for which the sponsor
seeks agreement (e.g., are the study participant groups
appropriate to represent intended users, is the study
endpoint adequate, are the critical tasks that should be
evaluated appropriately identified).
(2) Within 60 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
[[Page S4742]]
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) Performance goals for FDA will be phased in, starting
in FY 2019 as follows:
a. By FY 2019, review 50% of human factors protocol
submissions within 60 days and provide sponsor with written
comments.
b. By FY 2020, review 70% of human factors protocol
submissions within 60 days and provide sponsor with written
comments.
c. By FY 2021, review 90% of human factors protocol
submissions within 60 days and provide sponsor with written
comments.
f. By no later than December 31, 2018, FDA will begin staff
training related to development, review, and approval of
drug-device and biologic-device combination products reviewed
in CDER and CBER. The training will be provided to all CDER,
CBER, Center for Devices and Radiological Health (CDRH), and
Office of Combination Products (OCP) staff, and will be part
of the reviewer training core curriculum. The key purposes of
this training include familiarizing review staff with the
regulatory requirements and challenges associated with
combination product applications and strategies to address
these challenges; promoting best practices for review and
regulation of combination products regulated by CDER and
CBER, and helping ensure coordination and consistent
approaches within the Centers in the review and regulation of
combination product applications. The training will also
emphasize the role of various experts in the Centers as
members of the review team and OCP's roles and
responsibilities in order to help ensure consistency of
scientific and regulatory approaches across applications and
review teams.
g. FDA will contract with an independent third party to
assess current practices for combination drug product review.
This study will focus on areas where the needs for inter-
center coordination and consistent approaches are greatest,
including such areas as the Request-for-Designation, cGMPs/
facilities topics, human factors and bridging studies, and
labeling. The contractor will be expected to engage both FDA
staff and individual sponsors as part of the assessment. The
assessment will be based on a randomly selected subset of
combination products in various phases of development. The
assessment will identify best practices and areas for
improvement by FDA review staff and sponsors in the
submission and review of combination products for
consideration by both FDA and sponsors. FDA will publish the
final report of the assessment on FDA's website no later than
the end of FY 2020. FDA will consider the assessment findings
regarding best practices on the part of FDA review staff and
sponsors in any updates to relevant documents such as MAPPs,
SOPPs, and submission procedures for human factors protocols,
and in the review and submission of Combination Product
applications.
h. By the end of FY 2019, FDA will publish draft guidance
or update previously published guidance issued by the medical
product centers and OCP for review staff and industry
describing considerations related to drug-device and
biologic-device combination product on the topics noted
below. The draft guidance(s) will be finalized by the end of
FY 2022.
i. Bridging studies, including the bridging of data from
combination products that employ different device components
for the same drug or biologic and the same device component
across different drugs and biologics.
ii. Patient-oriented labeling (e.g., instructions-for-use).
6. Enhancing Use of Real World Evidence for Use in
Regulatory Decision-Making
As we participate in the current data revolution, it is
important that FDA consider the possibilities of using so-
called ``real world'' data as an important tool in evaluating
not only the safety of medications but also their
effectiveness. To accomplish this will require an
understanding of what questions to ask, including how such
data can be generated and used appropriately in product
evaluation, what the challenges are to appropriate generation
and use of these data, and how to address such challenges.
Towards this end, FDA will do the following:
a. By no later than the end of FY 2018, FDA will complete
one or more public workshop(s) with key stakeholders,
including patients, biopharmaceutical companies, and
academia, to gather input into issues related to Real World
Evidence (RWE) use in regulatory decision-making. The
workshop(s) should address, among other things, the following
topics:
Benefits to patients, regulators, and biopharmaceutical
companies of RWE in regulatory decision making;
RWE availability, quality, and access challenges, and
approaches to mitigate these;
Methodological approaches for the collection, analysis, and
communication of RWE; and
Appropriate contexts of use of RWE in regulatory decision-
making regarding effectiveness.
b. By no later than the end of FY 2019, FDA will initiate
(or fund by contract), appropriate activities (e.g., pilot
studies or methodology development projects) aimed at
addressing key outstanding concerns and considerations in the
use of RWE for regulatory decision making.
c. By no later than the end of FY 2021, considering
available input, such as from activities noted above, FDA
will publish draft guidance on how RWE can contribute to the
assessment of safety and effectiveness in regulatory
submissions, for example in the approval of new supplemental
indications and for the fulfillment of postmarketing
commitments and requirements. FDA will work toward the goal
of publishing a revised draft or final guidance within 18
months after the close of the public comment period.
J. Enhancing Regulatory Decision Tools to Support Drug
Development and Review
1. Enhancing the Incorporation of the Patient's Voice in
Drug Development and Decision-Making
To facilitate the advancement and use of systematic
approaches to collect and utilize robust and meaningful
patient and caregiver input that can more consistently inform
drug development and, as appropriate, regulatory decision
making, FDA will conduct the following activities during
PDUFA VI:
a. FDA will strengthen the staff capacity to facilitate
development and use of patient-focused methods to inform drug
development and regulatory decisions. This staff, composed
primarily of clinical, statistical, psychometric, and health
outcomes research expertise, will be integrated into review
teams as core members of the team during drug development and
application review where the sponsor intends to use patient
input or clinical outcome assessment (COAs) such as patient-
reported outcomes (PROs) as part of the development program.
A core responsibility of the staff will be to engage patient
stakeholders and provide timely development-phase
consultations to sponsors developing new tools to collect
patient and caregiver input. This additional capacity is
expected to advance the science of COA development and
analysis, and the staff will also support the public
qualification activities for COAs.
b. FDA will develop a series of guidance documents to focus
on approaches and methods to bridge from initial patient-
focused drug development meetings, like those piloted under
PDUFA V, to fit-for-purpose tools to collect meaningful
patient and caregiver input for ultimate use in regulatory
decision making. Prior to the issuance of each guidance, as
part of the development, FDA will conduct a public workshop
to gather input from the wider community of patients, patient
advocates, academic researchers, expert practitioners,
industry, and other stakeholders.
i. By the end of FY 2018, FDA will publish a draft guidance
describing approaches to collecting comprehensive and
representative patient and caregiver input on burden of
disease and current therapy. The guidance will address topics
including: standardized nomenclature and terminologies,
methods to collect meaningful patient input throughout the
drug development process, and methodological considerations
for data collection, reporting, management, and analysis.
ii. By the end of FY 2019, FDA will publish a draft
guidance describing processes and methodological approaches
to development of holistic sets of impacts that are most
important to patients. The guidance will address topics
including: methods for sponsors, patient organizations,
academic researchers, and expert practitioners to develop and
identify what are most important to patients in terms of
burden of disease, burden of treatment, and other critical
aspects. The guidance will address how patient input can
inform drug development and review processes, and, as
appropriate, regulatory decision making.
iii. By the end of FY 2020, FDA will publish a draft
guidance describing approaches to identifying and developing
measures for an identified set of impacts (e.g., burden of
disease and treatment), which may facilitate collection of
meaningful patient input in clinical trials. The guidance
will address methods to measure impacts in a meaningful way,
and identify an appropriate set of measure(s) that matter
most to patients.
iv. By the end of FY 2021, FDA will publish a draft
guidance on clinical outcome assessments, which, when final,
will, as appropriate, revise or supplement the 2009 Guidance
to Industry on Patient-Reported Outcome Measures. The draft
guidance will also address technologies that may be used for
the collection, capture, storage, and analysis of patient
perspective information. The guidance will also address
methods to better incorporate clinical outcome assessments
into endpoints that are considered significantly robust for
regulatory decision-making.
v. For each of the above, FDA will work toward the goal of
publishing a revised draft or final guidance within 18 months
after the close of the public comment period on the draft
guidance.
c. FDA will create and maintain a repository of publicly
available tools on FDA's website as a resource for
stakeholders. The repository will also include FDA's clinical
outcome assessment compendium, patient-focused drug
development meeting resources, and ongoing efforts on
patient-focused drug development.
d. As appropriate, FDA will revise existing MAPPs and SOPPs
to include suggested approaches for incorporating an
increased patient focus in other on-going or planned FDA
public meetings (e.g., FDA scientific workshops). In
addition, as appropriate, FDA will develop and implement
staff training related to processes, tools, and methodologies
described in this section.
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e. By the end of FY 2019, FDA will conduct a public
workshop, through a qualified third party, with the primary
purpose of gathering ideas and experiences of the patient and
caregiver community and their recommendations on approaches
and best practices that would enhance patient engagement in
clinical trials. The meeting may also gather input from
sponsors, academic researchers, and expert practitioners. The
meeting will result in a published report on proceedings and
recommendations from discussions at the meeting.
2. Enhancing Benefit-Risk Assessment in Regulatory
Decision-Making
FDA will further the agency's implementation of structured
benefit-risk assessment, including the incorporation of the
patient's voice in drug development and decision-making, in
the human drug review program through the following
commitments to be accomplished during PDUFA VI:
a. By March 31, 2018, FDA will publish an update to the
implementation plan titled ``Structured Approach to Benefit-
Risk Assessment in Drug Regulatory Decision-Making.'' The
update will include a report on the progress made during
PDUFA V and a plan for continued implementation during FYs
2018-2022.
b. By the end of FY 2019, FDA will convene and/or
participate in, at least one meeting, conducted through a
qualified third party, to gather industry, patient,
researcher, and other stakeholder input on key topics. This
would include applying the benefit-risk framework throughout
the human drug lifecycle, including best approaches to
communicating FDA's benefit-risk assessment.
c. By the end of FY 2020, FDA will publish a draft guidance
on benefit-risk assessments for new drugs and biologics. This
guidance will:
i. Articulate FDA's decision-making context and framework
for benefit-risk assessment, illustrating the application of
the benefit-risk framework throughout the human drug
lifecycle, using a case study approach, if appropriate.
ii. Discuss appropriate interactions between a sponsor and
FDA during drug development to understand the therapeutic
context (i.e., the severity of disease that represents the
targeted indication and the extent of unmet medical need in
the target population) regarding regulatory decisions for the
product at the various stages of drug development and
evaluation.
iii. Discuss appropriate approaches to communicate to the
public FDA's thinking on a product's benefit-risk assessment,
such as through product-specific discussions using the
benefit-risk framework at AC meetings.
d. Beginning in FY 2021, FDA will conduct an evaluation of
the implementation of the benefit-risk framework in the human
drug review program. This evaluation will assess how
reviewers across the organization apply the benefit-risk
framework and identify best practices in use of the benefit-
risk framework. The evaluation of the benefit-risk framework
implementation conducted in PDUFA V will serve as a baseline
for this PDUFA VI assessment.
e. As appropriate, FDA will revise relevant MAPPs and SOPPs
to include new approaches that incorporate FDA's benefit-risk
framework into the human drug review program.
3. Advancing Model-Informed Drug Development
To facilitate the development and application of exposure-
based, biological, and statistical models derived from
preclinical and clinical data sources, herein referred to as
``model-informed drug development'' (MIDD) approaches, FDA
will conduct the following activities during PDUFA VI:
a. FDA will develop its regulatory science and review
expertise and capacity in MIDD approaches. This staff will
support the highly-specialized evaluation of model-based
strategies and development efforts.
b. FDA will convene a series of workshops to identify best
practices for MIDD. Topics will include: (1) physiologically-
based pharmacokinetic modeling; (2) design analysis and
inferences from dose-exposure-response studies; (3) disease
progression model development, including natural history and
trial simulation; and (4) immunogenicity and correlates of
protection for evaluating biological products, including
vaccines and blood products. Each workshop will focus on
current and emerging scientific approaches, including
methodological limitations. FDA will produce a written
summary of the topics discussed in each workshop.
c. Starting in FY 2018, FDA will conduct a pilot program
for MIDD approaches. For sponsors participating in the pilot
program, FDA will grant a pair of meetings specifically
designed for this pilot program, consisting of an initial and
a follow-up meeting on the same drug development issues, to
occur within a span of approximately 120 days. These meetings
will be led by the clinical pharmacology or biostatistical
review components within CDER or CBER.
i. FDA will publish a Federal Register Notice announcing
the pilot program and outlining the eligibility criteria and
process for submitting to FDA requests to participate in the
pilot program.
ii. FDA will select 2-4 proposals (e.g., 1-2 per Center)
quarterly each year. FDA will convene an internal review
group to review proposals on a quarterly basis and provide
recommendations on prioritization and selection of proposals
and share knowledge and experience. Program selection will
take into account development programs where clinical data
are limited such that integration across non-traditional
sources may be needed, and for which MIDD can assess
uncertainties about issues such as dosing, duration, and
patient selection in a way that can inform regulatory
decision-making.
iii. Sponsors who do not participate in the pilot will have
an opportunity to interact with the Agency through
traditional channels.
d. By end of FY 2019, FDA will publish draft guidance, or
revise relevant existing guidance, on model-informed drug
development.
e. By end of FY 2021, FDA will develop or revise, as
appropriate, relevant MAPPs or SOPPs, and/or review templates
and training, to incorporate guidelines for the evaluation of
MIDD approaches.
4. Enhancing Capacity to Review Complex Innovative Designs
To facilitate the advancement and use of complex adaptive,
Bayesian, and other novel clinical trial designs, FDA will
conduct the following activities during PDUFA VI:
a. FDA will develop the staff capacity to enable processes
to facilitate appropriate use of these types of methods. This
staff will support the computationally intensive review work
necessary to evaluate complex adaptive, Bayesian, and other
novel clinical trial designs, with a particular focus on
clinical trial designs for which simulations are necessary to
evaluate the operating characteristics.
b. Starting in FY 2018, FDA will conduct a pilot program
for highly innovative trial designs for which analytically
derived properties (e.g., Type I error) may not be feasible,
and simulations are necessary to determine trial operating
characteristics. For INDs in the pilot program, FDA will
grant a pair of meetings specifically designed for this pilot
program, consisting of an initial and follow-up meeting on
the same design, to occur within a span of approximately 120
days. These meetings will be led by the biostatistical review
components within CDER or CBER. The opportunity for increased
interaction with the agency will provide better understanding
of the agency's requirements for trial simulations involved
in the use of the pilot study design and allow for iteration
of design modifications, if needed. In return, FDA's ability
to publicly discuss example designs will provide better
clarity on the acceptance of different types of trial designs
that should facilitate their use in future development
programs.
i. FDA will publish a Federal Register Notice announcing
the pilot program, clarifying pilot program eligibility, and
describing the proposal submission and selection process.
ii. FDA will select up to 2 proposals (e.g., 1 per Center)
quarterly each year. FDA will convene an internal review
group to review proposals on a quarterly basis and provide
recommendations on prioritization and selection of proposals
and share knowledge and experience. Program selection will be
prioritized based on trial design features and therapeutic
areas of high unmet need.
iii. To promote innovation in this area, trial designs
developed through the pilot program may be presented by FDA
(e.g., in a guidance or public workshop) as case studies,
including while the drug studied in the trial has not yet
been approved by FDA. Before FDA grants the initial meeting,
FDA and the sponsor will agree on the information that FDA
may share publicly in these case studies. Participation in
the pilot program, including such agreement on information
disclosure, will be voluntary and at the discretion of the
sponsor.
iv. FDA may periodically review the progress of the pilot
program and determine whether it is appropriate to adjust any
aspects of the program.
v. Sponsors who do not participate in the pilot will have
an opportunity to interact with the Agency through
traditional channels. The pilot program will not affect FDA's
existing procedures for providing advice on trial designs.
c. By end of 2nd Quarter FY 2018, FDA will convene a public
workshop to discuss various complex adaptive, Bayesian, and
other novel clinical trial designs, with a particular focus
on clinical trial designs for which simulations are necessary
to evaluate the operating characteristics, and the
acceptability of those designs in regulatory decision-making.
d. By end of FY 2018, FDA will publish draft guidance on
complex adaptive (including Bayesian adaptive) trial designs.
e. By end of FY 2020, FDA will develop or revise, as
appropriate, relevant MAPPs, SOPPs and/or review templates
and training to incorporate guidelines on evaluating complex
clinical trial designs that rely on computer simulations to
determine operating characteristics.
5. Enhancing Capacity to Support Analysis Data Standards
for Product Development and Review
To support the enhancement of analysis data standards for
product development and review in the human drug review
program, FDA will conduct the following activities during
PDUFA VI:
a. FDA will develop the staff capacity to efficiently
review and provide feedback to sponsors on the readiness of
submitted analysis data sets and programs for statistical
review. This staff will support pre- and post-submission
discussion of standardized datasets and programs, and
maintain the knowledge of and engage in collaborations about
standards models used in the design, analysis and review of
clinical and non-clinical studies. Examples of these
standards
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models could include the Standard for Exchange of Nonclinical
Data (SEND), Clinical Data Acquisition Standards
Harmonization (CDASH), Study Data Tabulation Model (SDTM),
and Analysis Data Model (ADaM).
b. In parallel, FDA will improve staff capacity to assist
with FDA development and updating of therapeutic area user
guides (TAUGs) to include the appropriate content for the
analysis data standards used in submission and review.
c. By end of FY 2019, FDA will convene a public workshop to
advance the development and application of analysis data
standards.
d. FDA will collaborate with external stakeholders and
participate in public workshops held by third parties such as
standards development organizations, on development of data
standards, processes, documentation and continuous
improvement of clinical trials and regulatory science.
e. By end of FY 2020, FDA will develop or revise, as
appropriate, relevant guidance, MAPPs, SOPPs and training
associated with submission and utilization of standardized
analysis datasets and programs used in review, and on the
processes, procedures, and responsibilities related to the
receipt, handling, and documentation of submitted analysis
data and programs.
6. Enhancing Drug Development Tools Qualification Pathway
for Biomarkers
To facilitate the enhancement of the drug development tools
qualification pathway for biomarkers, FDA will conduct the
following activities during PDUFA VI:
a. FDA will develop the staff capacity to enhance biomarker
qualification review by increasing base capacity. FDA will
also pilot processes to engage external experts to support
review of biomarker qualification submissions.
b. By the end of FY 2018, FDA will convene a public meeting
to discuss 1) taxonomy for biomarkers used in drug
development, and 2) a framework with appropriate standards
and scientific approaches to support biomarkers under the
taxonomy, including scientific criteria to determine
acceptance of a biomarker qualification submission and
essential elements of a formal biomarker qualification plan.
c. By the end of FY 2018, FDA will publish draft guidance
on proposed taxonomy of biomarker usage and related contexts
of use.
d. By the end of FY 2020, FDA will publish draft guidance
on general evidentiary standards for biomarker qualification
to be supplemented with focused guidance on specific
biomarker uses and contexts.
e. FDA will develop or revise, as appropriate and
necessary, relevant MAPPs and SOPPs on the biomarker
qualification process.
f. FDA will list biomarker qualification submissions that
are in the qualification process on a public website, to be
updated quarterly. Inclusion of a submission on this list
will be based on the consent of the submitter for FDA to
publish information about the submission, including stage and
current status of qualification and the proposed use of the
biomarker. Following qualification of a biomarker FDA will
post reviews and summary documents that outline the
qualification program and data supporting a qualification
decision.
g. Sponsors who do not use this qualification pathway will
have an opportunity to interact with the Agency through
traditional channels.
K. 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, standardization and integration
of REMS into the healthcare system, enhancing communication
and coordination between postmarketing and pre-market review
staff, and improving tracking, communication and oversight of
postmarketing safety issues. 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 A) advancing
postmarketing drug safety evaluation through expansion of the
Sentinel System and integration into FDA pharmacovigilance
activities, and B) timely and effective evaluation and
communication of postmarketing safety findings related to
human drugs.
1. Advancing Postmarketing Drug Safety Evaluation Through
Expansion of the Sentinel System and Integration into FDA
Pharmacovigilance Activities
FDA will use user fee funds to conduct a series of
activities to systematically implement and integrate Sentinel
in FDA pharmacovigilance practices. These activities will
involve augmenting the quality and quantity of data available
through the Sentinel System, improving methods for
determining when and how that data is utilized, and
comprehensive training of review staff on the use of
Sentinel.
a. FDA will work toward expanding the Sentinel System's
sources of data and enhancing the system's core capabilities.
b. FDA will enhance its communication with sponsors and the
public regarding general methodologies for Sentinel queries,
including what the Agency has learned regarding the most
appropriate ways to query and use Sentinel data. This can be
done through enhancement of existing mechanisms and/or
greater frequency of such mechanisms.
c. FDA will evaluate additional ways to facilitate public
and sponsor access to Sentinel's distributed data network to
conduct safety surveillance.
d. By the end of FY 2019, FDA will hold or support a public
meeting engaging stakeholders to discuss current and emerging
Sentinel projects and seek stakeholder feedback and input
regarding gaps in the current system to facilitate the
further development of Sentinel and its system of Active Risk
Identification and Analysis (ARIA).
e. By the end of FY 2020, FDA will establish policies and
procedures (MAPPs and SOPPs) to facilitate informing sponsors
about the planned use of Sentinel to evaluate a safety signal
involving their respective products. These MAPPs and SOPPs
will address what types of evaluations and what information
about the evaluations will be shared with sponsors, and the
timing of such communications.
f. By the end of FY 2020, FDA will facilitate integration
of Sentinel into the human drug review program in a
systematic, efficient, and consistent way through staff
development and by updating existing SOPPs and MAPPs, as
needed.
g. By the end of FY 2020, FDA will develop a comprehensive
training program for review staff (e.g., epidemiologists,
statisticians, medical officers, clinical analysts, project
managers, and other review team members) to ensure that staff
have a working knowledge of Sentinel, can identify when
Sentinel can inform important regulatory questions, and are
able to consistently participate in use of Sentinel to
evaluate safety issues.
h. By the end of FY 2022, FDA will analyze, and report on
the impact of the Sentinel expansion and integration on FDA's
use of Sentinel for regulatory purposes, e.g., in the
contexts of labeling changes, PMRs, or PMCs.
2. Timely and Effective Evaluation and Communication of
Postmarketing Safety Findings Related to Human Drugs
FDA will use user fee funds to continue to support the
review, oversight, tracking, and communication of
postmarketing drug safety issues.
a. FDA will make improvements to its current processes that
capture and track information, including enhancements to its
information technology systems, as needed, in order to
support the management and oversight of postmarketing drug
safety issues.
b. By the end of FY 2019, FDA will update existing policies
and procedures (MAPPs and SOPPs) concerning tracking
postmarketing safety signals to include consistent and timely
notification to a sponsor (1) when a serious safety signal
involving a product is identified and (2) to the extent
practicable, not less than 72 hours before public posting of
a safety notice under section 921 of the Food and Drug
Administration Amendments Act of 2007.
c. By the end of FY 2022, FDA will conduct, or fund by
contract, an assessment of how its data systems and
processes, as described in MAPPs and SOPPs, support review,
oversight, and communication of postmarketing drug safety
issues.
II. ENHANCING MANAGEMENT OF USER FEE RESOURCES
FDA will modernize the user fee structure to improve the
predictability of FDA funding and sponsor invoices, improve
efficiency by simplifying the administration of user fees,
and enhance flexibility of financial mechanisms to improve
management of PDUFA program funding. FDA is committed to
enhancing management of PDUFA resources and ensuring PDUFA
user fee resources are administered, allocated, and reported
in an efficient and transparent manner. FDA will conduct a
series of resource capacity planning and financial
transparency activities to enhance management of PDUFA
resources in PDUFA VI.
A. Resource Capacity Planning and Modernized Time Reporting
FDA is committed to enhancing management of PDUFA resources
in PDUFA VI. FDA will conduct activities to develop a
resource capacity planning function and modernized time
reporting approach in PDUFA VI.
1. FDA will publish a PDUFA program resource capacity
planning and modernized time reporting implementation plan no
later than the 2nd quarter of FY 2018. FDA will continue to
utilize information and recommendations from a third party
assessment of resource capacity planning, financial
analytics, and modernized time reporting for PDUFA as part of
the implementation plan.
2. FDA will staff a resource capacity planning team that
will implement and manage a capacity planning system across
the PDUFA program in PDUFA VI.
3. FDA will obtain through a contract with an independent
accounting or consulting firm an evaluation of options and
recommendations for a new methodology to accurately assess
changes in the resource and capacity needs of the human drug
review program. The report will be published no later than
end of FY 2020 for public comment. Upon review of the report
and comments, FDA will implement robust methodologies for
assessing resource needs of the program. This will include
the adoption of a new resource capacity adjustment
methodology, in place of the current PDUFA workload adjuster,
that accounts for sustained increases in PDUFA workload.
4. FDA recognizes that revenue generated by the workload
adjuster and the resource
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capacity adjustment will be allocated to and used by
organizational review components engaged in direct review
work to enhance resources and expand staff capacity and
capability. FDA will document in the annual financial report
how the workload adjuster and resource capacity adjustment
fee revenues are being utilized.
B. Financial Transparency and Efficiency
FDA is committed to ensuring PDUFA user fee resources are
administered, allocated, and reported in an efficient and
transparent manner. FDA will conduct activities to evaluate
the financial administration of the PDUFA program to help
identify areas to enhance efficiency. FDA will also conduct
activities to enhance transparency of PDUFA program
resources.
1. FDA will contract with an independent third party to
conduct an evaluation of PDUFA program resource management
during FY 2018 to ensure that PDUFA user fee resources are
administered, allocated, and reported in an efficient and
transparent manner in PDUFA VI. The study will include, but
is not limited, to the following areas:
a. Evaluate all components of the PDUFA program resource
planning, request, and allocation process from when FDA
receives the user fee funds through when funds are spent. The
contractor will recommend options to improve the process and
data needed to enhance resource management decisions.
b. Assess how FDA administers PDUFA user fees
organizationally, including, but not limited to, billing,
user fee collection, and execution. The contractor will
recommend options to enhance the efficiency of user fee
administration.
c. Evaluate FDA's existing PDUFA program financial and
administrative oversight and governance functions. Assess
alternative governance models including roles and
responsibilities, organizational location, and personnel
skill sets required. The contractor will recommend options on
the most effective governance model to support the human drug
review program.
d. Assess FDA's technical capabilities to conduct effective
financial management and planning in the context of generally
accepted government resource management and planning
practices. The contractor will recommend options for the
technical capabilities needed by financial personnel involved
in PDUFA resource management to enhance financial management
and planning.
e. Evaluate how FDA estimates fee paying units for annual
fee setting. The contractor will recommend options to enhance
the accuracy of FDA's PDUFA user fee estimation methods.
2. FDA will publish a PDUFA 5-year financial plan no later
than the 2nd quarter of FY 2018. FDA will publish updates to
the 5-year plan no later than the 2nd quarter of each
subsequent fiscal year.
3. FDA will convene a public meeting no later than the
third quarter of each fiscal year starting in FY 2019 to
discuss the PDUFA 5-year financial plan, along with the
Agency's progress in implementing modernized time reporting,
resource capacity planning, and the modernized user fee
structure.
III. IMPROVING FDA HIRING AND RETENTION OF REVIEW STAFF
To speed and improve development of safe and effective new
therapies for patients, enhancements to the human drug review
program require that FDA hire and retain sufficient numbers
and types of technical and scientific experts to efficiently
conduct reviews of human drug applications. In order to
strengthen this core function and increase the public health
impact of new therapies, the FDA will commit to do the
following:
A. Completion of Modernization of the Hiring System
Infrastructure and Augmentation of System Capacity:
1. Complete implementation of FTE-based position management
system capability.
a. FDA will complete development of Position Management
baseline accounting of all current positions and FTE counts
engaged in the human drug review program for each applicable
Center and Office including filled and vacant positions, a
governance structure for on-going position management that
will be accountable to FDA senior management, and Position
Management policy and guidance ratified by FDA senior
management, outlining processes for adding new positions,
deleting positions, and changing established positions.
b. FDA will complete implementation of the new Position-
Based Management System.
2. Complete implementation of an online position
classification system.
a. FDA will finalize the establishment of an online
Position Description (PD) library. The library will include
all current well-classified PDs and current standardized PDs.
Once operational, any new PDs classified using the on-line
classification tools, and any newly created standardized PDs,
will be stored and accessible within FDA's PD library and
available for FDA-wide use as appropriate.
3. Complete implementation of corporate recruiting.
a. For key scientific and technical disciplines commonly
needed across offices engaged in the human drug review
program, FDA will complete the transition from the use of
individual vacancy announcements for individual offices to
expanded use of a common vacancy announcement and certificate
of eligible job applicants that can be used by multiple
offices. As a part of this effort, FDA will complete the
transition from use of individual announcements that are
posted for a limited period to common vacancy announcements
with open continuous posting to maximize the opportunity for
qualified applicants to apply for these positions.
B. Augmentation of Hiring Staff Capacity and Capability
In recognition of the chronic and continuing difficulties
of recruiting and retaining sufficient numbers of qualified
Human Resources (HR) staff, FDA will engage a qualified
contractor to provide continuous support throughout PDUFA VI
to augment the existing FDA HR staff capacity and
capabilities. The utilization of a qualified contractor will
assist FDA in successfully accomplishing PDUFA goals for
recruitment and retention of human drug review program staff.
C. Complete Establishment of a Dedicated Function to Ensure
Needed Scientific Staffing for Human Drug Review Program
1. Rapid advances in the science and technology of human
drug development and manufacturing require FDA's human drug
review program staff to keep pace with science and learn
innovative methods and techniques for review of new
therapies. FDA will complete the establishment of a new
dedicated unit within the Office of Medical Products and
Tobacco charged with the continuous recruiting, staffing, and
retention of scientific, technical and professional staff for
the process for the review of human drug applications.
a. The unit will continuously develop and implement
scientific staff hiring strategies and plans, working closely
with the center review offices and the FDA HR office, to meet
discipline-specific hiring commitments and other targeted
staffing needs. It will function as a scientific-focused
recruiter conducting ongoing proactive outreach to source
qualified candidates, and conducting competitive recruiting
to fill vacancies that require top scientific, technical and
professional talent.
b. The unit will conduct analyses, no less than annually,
of compensation and other factors affecting retention of key
staff in targeted disciplines, providing leadership and
support for agency compensation oversight boards that
currently exist or may be established as needed to ensure
retention of key scientific, technical and professional
staff.
D. Set Clear Goals for Human Drug Review Program Hiring
1. FDA will establish priorities for management of the
metric goals for targeted hires within the human drug review
program staff for the years of PDUFA VI. These goals for
targeted hires are summarized in Table 6 below:
TABLE 6
----------------------------------------------------------------------------------------------------------------
FY 2018 FY 2019 FY 2020 FY 2021 FY 2022
----------------------------------------------------------------------------------------------------------------
CDER........................................... 43 57 45 17 9
CBER........................................... 16 8 7 1 0
Other FDA...................................... 12 9 6 0 0
----------------------------------------------------------------
Total FTE.................................. 71 74 58 18 9
----------------------------------------------------------------------------------------------------------------
2. FDA will confirm progress in the hiring of PDUFA V FTEs.
FDA will report on progress against the hiring goals for FY
2018-2022 on a quarterly basis posting updates to the FDA
website PDUFA Performance webpage.
E. Comprehensive and Continuous Assessment of Hiring and
Retention
FDA hiring and retention of staff for the human drug review
program will be evaluated by a qualified, independent
contractor with expertise in assessing HR operations and
transformation. This will include continuous assessments
throughout the course of implementation of the performance
initiatives identified in sections III.A-D, and metrics
including, but not limited to, those related to recruiting
and retention in the human drug review program including, but
not limited to, specifically targeted scientific disciplines
and levels of experience. The contractor will conduct a
comprehensive review of current hiring processes and hiring
staff capacity and capabilities that contribute to
achievement of successes, potential problems, or delays in
human drug review program staff hiring. This includes the
entire hiring function and related capabilities. FDA and
regulated industry leadership will periodically and regularly
assess the progress of hiring and retention throughout PDUFA
VI.
[[Page S4746]]
1. Initial Assessment: The assessment will include an
initial baseline assessment to be conducted and completed no
later than December 31, 2017. The initial baseline study will
include an evaluation of the current state and provide
recommended options to address any identified gaps or areas
identified as priorities for improvement, and a study report
to be published no later than December 31, 2017. FDA will
hold a public meeting no later than December 31, 2017, to
present and discuss report findings, and present its specific
plans, including agency senior management oversight, and
timeline for implementing recommended enhancements to be
fully operational by no later than December 31, 2018.
2. Interim Assessment: An interim assessment will be
published by March 31, 2020, for public comment. By June 30,
2020, FDA will hold a public meeting during which the public
may present their views. FDA will discuss the findings of the
interim assessment, including progress relative to program
milestones and metrics, and other aggregated feedback from
internal customers and participants in HR services that may
be included in the continuous assessment. FDA will also
address any issues identified to date including actions
proposed to improve the likelihood of success of the program.
3. Final Assessment: A final assessment will be published
by December 31, 2021, for public comment. FDA will hold a
public meeting by no later than March 30, 2022, during which
the public may present their views. FDA will discuss the
findings of the final assessment, including progress relative
to program milestones and metrics, and other aggregated
feedback from internal customers and participants in HR
services that may be included in the continuous assessment.
FDA will also address any issues identified and plans for
addressing these issues.
IV. INFORMATION TECHNOLOGY GOALS
A. Objective
FDA is committed to achieve the long-term goal of improving
the predictability and consistency of the electronic
submission process (Section IV.B), and enhancing transparency
and accountability of FDA information technology related
activities (Section IV.C). FDA is pursuing these objectives
through IT investments that support the PDUFA program.
B. Improve the Predictability and Consistency of PDUFA
Electronic Submission Processes
1. Electronic Submission Documentation:
By December 31, 2017, FDA will publish and maintain up-to-
date documentation for the following:
a. The electronic submission process, including key
electronic submission milestones and associated sponsor
notifications. The description should cover the complete
process undergone by a submission from the completion of its
upload to the Electronic System Gateway (ESG) through the
time the submission is made available to the review team.
b. The rejection process for electronic submissions.
c. The electronic submission validation criteria.
d. Software names and versions for Electronic Common
Technical Document (eCTD) validation and data validation
tools.
2. Electronic Submission and System Status:
By September 30, 2018, FDA will:
a. Publish targets for and measure ESG availability overall
(including scheduled downtime) and during business hours (8am
to 8pm Eastern Time). ESG availability is defined for the
purposes of this commitment letter as the ability for an
external user to complete a submission from each entry point
to its delivery to the appropriate FDA Center.
b. Post current ESG operational status on its public
website.
c. Publish submission instructions to use in the event of
an ESG service disruption.
3. By December 31, 2017, FDA will publish target time
frames for the 1) expected submission upload duration(s) and
2) timeframe between key milestones and notifications as
defined in 1(a).
4. By September 30, 2018, FDA will implement the ability to
communicate electronic submission milestone notifications,
including final submission upload status (e.g., successfully
processed or rejected), to sender/designated contact.
5. FDA will provide expert technical support for electronic
submissions to FDA review staff for submission navigation and
troubleshooting.
6. For those systems that sponsors interact with directly,
FDA will invite industry to provide feedback and/or
participate in user acceptance testing in advance of
implementing significant changes that impact industry's
interaction with the system.
7. By December 31, 2017, FDA will document and implement a
process to provide ample advance notification of systems and
process changes commensurate with the complexity of the
change and the impact to sponsors for ESG scheduled
unavailability and user interface changes.
C. Enhance Transparency and Accountability of FDA Electronic
Submission and Data Standards Activities
1. FDA staff and industry will jointly plan and hold
quarterly meetings and will share performance updates prior
to each meeting. The meeting will address current challenges
and emerging needs.
2. Beginning no later than September 30, 2018, FDA will
hold annual public meetings to seek stakeholder input related
to electronic submission system past performance, future
targets, emerging industry needs and technology initiatives
to inform the FDA IT Strategic Plan and published targets.
3. By December 31, 2017, FDA will post, at least annually,
historic and current metrics on ESG performance in relation
to published targets, characterizations and volume of
submissions, and standards adoption and conformance.
4. By December 31, 2017, FDA will incorporate strategic
initiatives in support of PDUFA goals into the FDA IT
Strategic Plan. Milestones and metrics for PDUFA initiatives
will be included in the plan. The plan will be updated and
discussed annually during a meeting described in Section
IV.C.1.
5. FDA will:
a. Collaborate with Standards Development Organizations and
stakeholders to ensure long-term sustainability of supported
data standards.
b. Publish a data standards action plan updated at least
quarterly.
c. Publish and maintain a current FDA Data Standards
Catalog.
V. 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 the human drug review program
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 for
the review of human drug applications
8. Improved communication between the FDA and industry
B. Studies Will Include
1. Assessment of current practices of FDA and sponsors in
communicating during drug development as described in Section
I.I.1.
2. Assessment of the current practices for combination drug
product review as described in Section I.I.5.
3. Evaluation of how reviewers across the organization
apply the benefit-risk framework and identify best practices
in use of the benefit-risk framework as described in Section
I.J.2.
4. Analysis of the impact of the Sentinel expansion and use
for regulatory purposes as described in Section I.K.1.
5. Assessment of how FDA data systems and processes, as
described in MAPPs and SOPPs, support review, oversight, and
communication of postmarketing drug safety issues, as
described in Section I.K.2.
6. Evaluation of options and recommendations for a new
methodology to accurately assess changes in the resource and
capacity needs of the human drug review program as described
in Section II.A.3.
7. Evaluation of PDUFA program resource management to
ensure that PDUFA user fee resources are administered,
allocated, and reported in an efficient and transparent
manner in PDUFA VI as described in Section II.B.1.
8. Comprehensive and continuous assessment of hiring and
retention as described in Section III.E.
VI. PROGRESS REPORTING FOR PDUFA VI AND CONTINUING PDUFA V INITIATIVES
A. FDA will include in the annual PDUFA Performance Report
information on the Agency's progress in meeting the specific
commitments identified in Sections I.I-K of this document.
B. FDA will include in the annual PDUFA Financial Report
information on the Agency's progress in the hiring of new
staff used to support the new initiatives as identified in
Section III.
VII. DEFINITIONS AND EXPLANATION OF TERMS
1. ``Human drug applications'' refers to new drug
applications submitted under section 505(b) of the Federal
Food, Drug, and Cosmetic Act and biologics license
applications submitted under section 351(a) of the Public
Health Service Act, as defined in the Prescription Drug User
Fee Act.
2. ``Human drug review program'' refers to the activities
to conduct ``the process for the review of human drug
applications,'' as defined in the Prescription Drug User Fee
Act.
3. 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.
4. A resubmitted original application is a complete
response to an action letter addressing all identified
deficiencies.
5. 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):
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
[[Page S4747]]
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
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
6. Class 2 resubmissions are resubmissions that include any
other items, including any items that would require
presentation to an advisory committee.
7. 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.
8. As used in this commitment letter, ``regulatory decision
making'' may include, for example, FDA's process for making a
regulatory decision regarding a drug or biological product
throughout the product lifecycle, such as during drug
development, following FDA's review of a marketing
application, including review of proposed labeling for the
product, or in the post-approval period (e.g., FDA's decision
regarding a supplement to an approved application).
Mr. ALEXANDER. Mr. President, I ask unanimous consent to have printed
in the Record a copy of the commitment letter for the Biosimilar User
Fee Act, BsUFA, reauthorization for fiscal years 2018 to 2022, known as
BsUFA II.
There being no objection, the material was ordered to be printed in
the Record, as follows:
Biosimilar Biological Product Reauthorization Performance Goals and
Procedures Fiscal Years 2018 Through 2022
I. Ensuring the Effectiveness of the Biosimilar Biological
Product Review Program
A. Review Performance Goals
B. Program for Enhanced Review Transparency and
Communication for Original 351(k) BLAs
C. First Cycle Review Management for Supplements with
Clinical Data
D. Guidance
E. Review of Proprietary Names to Reduce Medication Errors
F. Major Dispute Resolution
G. Clinical Holds
H. Special Protocol Question Assessment and Agreement
I. Meeting Management Goals
II. Advancing Development of Biosimilar Biological Products
Through Further Clarification of the 351(k) Regulatory
Pathway
III. Enhancing Capacity for Biosimilar Regulations and
Guidance Development, Reviewer Training, and Timely
Communication
IV. Enhancing Management of User Fee Resources
A. Resource Capacity Planning and Modernized Time Reporting
B. Financial Transparency and Efficiency
C. Management of Carryover Balance
V. Improving FDA Hiring and Retention of Review Staff
A. Completion of Modernization of the Hiring System
Infrastructure and Augmentation of System Capacity
B. Augmentation of Hiring Staff Capacity and Capability
C. Complete Establishment of a Dedicated Function to Ensure
Needed Scientific Staffing for Human Drug Review Including
for Review of Biosimilar Biological Products
D. Set Clear Goals for Biosimilar Biological Product Review
Program Hiring
E. Comprehensive and Continuous Assessment of Hiring and
Retention
VI. Definitions and Explanation of Terms
Biosimilar Biological Product Authorization Performance Goals and
Procedures for Fiscal Years 2018 Through 2022
This document contains the performance goals and procedures
for the Biosimilar User Fee Act (BsUFA) reauthorization for
fiscal years (FYs) 2018-2022, known as BsUFA II. It is
commonly referred to as the ``goals letter'' or ``commitment
letter.'' The goals letter represents the product of FDA's
discussions with the regulated industry and public
stakeholders, as mandated by Congress. The performance and
procedural goals and other commitments specified in this
letter apply to aspects of the biosimilar biological product
review program that are important for facilitating timely
access to safe and effective biosimilar medicines for
patients. FDA is committed to meeting the performance goals
specified in this letter, enhancing management of BsUFA
resources, and ensuring BsUFA user fee resources are
administered, allocated, and reported in an efficient and
transparent manner.
Under BsUFA II, FDA is committed to ensuring effective
scientific coordination and review consistency, as well as
efficient governance and operations across the biosimilar
biological product review program. In addition, FDA is
committed to the principles articulated in the Good Review
Management Principles and Practices (GRMP) guidance,\1\ which
FDA intends to update and apply to the review of biosimilar
and interchangeable products.
FDA and the regulated industry will periodically and
regularly assess the progress of the biosimilar biological
product review program throughout BsUFA II. This will allow
FDA and the regulated industry to identify emerging
challenges and develop strategies to address these challenges
to ensure the efficiency and effectiveness of the biosimilar
biological product review program.
I. ENSURING THE EFFECTIVENESS OF THE BIOSIMILAR BIOLOGICAL PRODUCT
REVIEW PROGRAM
A. Review Performance Goals
1. Biosimilar Biological Product Application Submissions
and Resubmissions
a. Review and act on 90 percent of original biosimilar
biological product application submissions within 10 months
of the 60 day filing date.
b. Review and act on 90 percent of resubmitted original
biosimilar biological product applications within 6 months of
receipt.
2. Supplements with Clinical Data
a. Review and act on 90 percent of original supplements
with clinical data within 10 months of receipt.
b. Review and act on 90 percent of resubmitted supplements
with clinical data within 6 months of receipt.
3. Original Manufacturing Supplements
a. In FY 2018, review and act on 70 percent of
manufacturing supplements requiring prior approval within 4
months of receipt.
b. In FY 2019, review and act on 75 percent of
manufacturing supplements requiring prior approval within 4
months of receipt.
c. In FY 2020, review and act on 80 percent of
manufacturing supplements requiring prior approval within 4
months of receipt.
d. In FY 2021, review and act on 85 percent of
manufacturing supplements requiring prior approval within 4
months of receipt.
e. In FY 2022, review and act on 90 percent of
manufacturing supplements requiring prior approval within 4
months of receipt.
f. Review and act on 90 percent of all other manufacturing
supplements within 6 months of receipt.
4. Goals Summary Tables
TABLE 1.--ORIGINAL AND RESUBMITTED APPLICATIONS AND SUPPLEMENTS
------------------------------------------------------------------------
------------------------------------------------------------------------
Original Biosimilar Biological Product 90% in 10 months of the 60
Application Submissions. day filing date.
Resubmitted Original Biosimilar Biological 90% in 6 months of the
Product Applications. 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.
------------------------------------------------------------------------
TABLE 2.--MANUFACTURING SUPPLEMENTS
------------------------------------------------------------------------
Prior approval All other
------------------------------------------------------------------------
Manufacturing Supplements....... FY 2018: 90% in 6 months of
70% in 4 months the receipt date.
of the receipt
date.
FY 2019:
75% in 4 months
of the receipt
date
FY 2020:
80% in 4 months
of the receipt
date
FY 2021:
85% in 4 months
of the receipt
date
FY 2022:
90% in 4 months
of the receipt
date
------------------------------------------------------------------------
5. Review Performance Goal Extensions
a. Major Amendments
i. 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.
ii. A major amendment may include, for example, a major new
clinical 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.
iii. A major amendment to a manufacturing supplement
submitted at any time during the review cycle may extend the
goal date by two months.
iv. Only one extension can be given per review cycle.
v. 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.
[[Page S4748]]
b. Inspection of Facilities Not Adequately Identified in an
Original Application or Supplement
i. All original applications and supplements are expected
to include a comprehensive and readily located list of all
manufacturing facilities included or referenced in the
application or supplement. This list provides FDA with
information needed to schedule inspections of manufacturing
facilities that may be necessary before approval of the
original application or supplement.
ii. If, during FDA's review of an original application or
supplement, the Agency identifies a manufacturing facility
that was not included in the comprehensive and readily
located list, the goal date may be extended.
1. If FDA identifies the need to inspect a manufacturing
facility that is not included as part of the comprehensive
and readily located list in an original application or
supplement with clinical data, the goal date may be extended
by three months.
2. If FDA identifies the need to inspect a manufacturing
facility that is not included as part of the comprehensive
and readily located list in a manufacturing supplement, the
goal date may be extended by two months.
B. Program for Enhanced Review Transparency and Communication
for Original 351(k) BLAs
To promote transparency and communication between the FDA
review team and the applicant, FDA will apply the following
model (``the Program'') to the review of all original
Biologics License Applications (BLAs) submitted under section
351(k) of the Public Health Service Act (``351(k) BLAs''),
including applications that are resubmitted following a
Refuse-to-File decision, received from October 1, 2017,
through September 30, 2022. The goal of the Program is to
promote the efficiency and effectiveness of the first cycle
review process and minimize the number of review cycles
necessary for approval, ensuring that patients have timely
access to safe, effective, and high quality biosimilar and
interchangeable biological products.
The standard approach for the review of original 351(k)
BLAs is described in this section. However, the FDA review
team and the applicant may discuss and reach mutual agreement
on an alternative approach to the timing and nature of
interactions and information exchange between the applicant
and FDA, i.e., a Formal Communication Plan for the review of
the original 351(k) BLA. The Formal Communication Plan may
include elements of the standard approach (e.g., a mid-cycle
communication or a late-cycle meeting) as well as other
interactions that sometimes occur during the review process
(e.g., a meeting during the filing period to discuss the
application, i.e., an ``application orientation meeting'').
If appropriate, the Formal Communication Plan should specify
those elements of the Program that FDA and the sponsor agree
are unnecessary for the application under review. If the
review team and the applicant anticipate developing a Formal
Communication Plan, the elements of the plan should be
discussed and agreed to at the pre-submission meeting (see
Section I.B.1) and reflected in the meeting minutes. The
Formal Communication Plan may be reviewed and amended at any
time based on the progress of the review and the mutual
agreement of the review team and the applicant. For example,
the review team and the applicant may mutually agree at any
time to cancel future specified interactions in the Program
(e.g., the late-cycle meeting) that become unnecessary (e.g.
because previous communications between the review team and
the applicant are sufficient). Any amendments made to the
Formal Communication Plan should be consistent with the goal
of an efficient and timely first cycle review process and not
impede the review team's ability to conduct its review.
The remainder of this Section I.B. describes the parameters
that will apply to FDA's review of applications in the
Program.
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 BPD Type 4
(pre-351(k) BLA) meeting. This meeting will be attended by
the FDA review team, including appropriate senior FDA staff.
a. The BPD Type 4 (pre-351(k) 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. In addition to FDA's preliminary responses to the
applicant's questions, other potential discussion topics
include preliminary discussions regarding the approach to
developing the content for REMS, where applicable, patient
labeling (e.g., Medication Guide and Instructions For Use)
and, where applicable, the development of a Formal
Communication Plan. These discussions will be summarized at
the conclusion of the meeting and reflected in the FDA
meeting minutes.
The FDA and the applicant will agree on the content of a
complete application for the proposed indication(s) at the
pre-submission 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.
These agreements will be summarized at the conclusion of the
meeting and reflected in the FDA meeting minutes.
i. Examples of application components that may be
appropriate for delayed submission include; stability
updates, the final audited report of a preclinical study
(e.g., toxicology) where the final draft report is submitted
with the original application, or a limited amount of the
data from an assessment of a single transition from the
reference product to the proposed biosimilar biological
product, where applicable.
ii. Major components of the application (e.g., the complete
analytical similarity assessment, the complete study report
of a comparative clinical study or the full study report of
necessary immunogenicity 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 BPD Type 4 (pre-351(k) BLA)
meeting, at the time of original submission of the
application. If the applicant does not have a BPD Type 4
(pre-351(k) 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.
d. The following parameters will apply to applications that
are subject to a Refuse-to-File decision and are subsequently
filed over protest:
i. The original submission of the application will be
subject to the review performance goal as described in
Section I.A.1.a.
ii. The application will not be eligible for the other
parameters of the Program (e.g., mid-cycle communication,
late-cycle meeting).
iii. FDA generally will not review amendments to the
application during any review cycle. FDA also generally will
not issue information requests to the applicant during the
agency's review.
iv. The resubmission goal described in Section I.A.1.b will
not apply to any resubmission of the application following an
FDA complete response action. Any such resubmission will be
reviewed as available resources permit.
e. 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.
Review of unsolicited amendments, including those submitted
in response to an FDA communication of deficiencies, will be
handled in accordance with the GRMP guidance. 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
regarding identification and communication of substantive
review issues identified during the initial filing review to
the applicant in the ``Day 74 letter.'' If no substantive
review issues were identified during the filing review, FDA
will so notify the applicant. 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.
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
timeline for review of the application included in the Day 74
letter for applications in the Program will include:
a. the planned date for the internal mid-cycle review
meeting,
b. preliminary plans on whether to hold an Advisory
Committee (AC) meeting to discuss the application,
c. a target date for communication of feedback from the
review division to the applicant regarding proposed labeling
and any postmarket requirements or postmarket commitments the
Agency will be requesting.
4. Review performance goals: For original 351(k) BLA
submissions that are filed by FDA under the Program, the
BsUFA 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 original 351(k) BLA
submissions within 10 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
[[Page S4749]]
applicant with an update on the status of the review of their
application. An agenda will be sent to the applicant prior to
the mid-cycle communication. 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.
The update should include any significant issues identified
by the review team to date, any information requests, and
information regarding major concerns with the following:
a. The analytical similarity data, including the potential
relevance of any issues (e.g. data analysis issues or
potential clinical impact of observed analytical
differences), intended to support a demonstration that the
proposed biosimilar biological product is highly similar to
the reference product.
b. The data intended to support a demonstration of no
clinically meaningful differences, including discussion of
any immunogenicity issues.
c. The data intended to support a demonstration of
interchangeability.
d. CMC issues.
In addition, the update should include preliminary review
team thinking regarding the content of the proposed REMS,
where applicable, proposed date(s) for the late-cycle
meeting, updates regarding plans for the AC meeting (if an AC
meeting is anticipated), and other projected milestone dates
for the remainder of the review cycle.
6. Late-Cycle and Advisory Committee Meetings: 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. Late-cycle meetings will generally be face-
to-face meetings; however, the meeting may be held by
teleconference if FDA and the applicant agree. Since the
application is expected to be complete at the time of
submission, FDA intends to complete primary and secondary
reviews of the application in advance of the planned late-
cycle meeting.
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 following parameters apply:
i. FDA intends to convene AC meetings no later than 2
months prior to the BsUFA goal date. The late-cycle meeting
will occur not less than 12 calendar days before the date of
the AC meeting.
ii. FDA intends to provide final questions for the AC to
the sponsor and the AC not less than 2 calendar days before
the AC meeting.
iii. Following an AC meeting, FDA and the applicant may
agree on the need to discuss feedback from the committee for
the purpose of facilitating the remainder of the review. Such
a meeting will generally be held by teleconference without a
commitment for formal meeting minutes issued by the agency.
c. For applications that will not be discussed at an AC
meeting, the late-cycle meeting will generally occur not
later than 3 months prior to the BsUFA goal date.
d. Late-Cycle Meeting Background Packages: The Agency
background package for the late-cycle meeting will be sent to
the applicant not less than 10 calendar days before the late-
cycle meeting. The package will consist of any discipline
review (DR) letters issues to date, a brief memorandum from
the review team outlining substantive application issues
(e.g., deficiencies identified by primary and secondary
reviews), the Agency's background package for the AC meeting
(incorporated by reference if previously sent to the
applicant), potential questions and/or points for discussion
for the AC meeting (if planned) and the current assessment of
the content of proposed REMS or other risk management
actions, where applicable.
e. Late-Cycle Meeting Discussion Topics: Potential topics
for discussion at the late-cycle meeting include:
i. major deficiencies identified to date;
ii. analytical similarity data, including the potential
relevance of any issues (e.g. data analysis issues or
potential clinical impact of observed analytical
differences), intended to support a demonstration that the
proposed biosimilar biological product is highly similar to
the reference product;
iii. data intended to support a demonstration of no
clinically meaningful differences, including discussion of
any immunogenicity issues;
iv. data intended to support a demonstration of
interchangeability;
v. CMC issues;
vi. inspectional findings identified to date;
vii. issues to be discussed at the AC meeting (if planned);
viii. current assessment of the content of proposed REMS or
other risk management actions, where applicable;
ix. information requests from the review team to the
applicant; and additional data or analyses the applicant may
wish to submit.
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
BsUFA goal date.
7. Inspections: FDA's goal is to complete all GCP, GLP, and
GMP inspections for applications in the Program within 10
months of the date of original receipt of the application.
This will allow 2 months at the end of the review cycle to
attempt to address any deficiencies identified by the
inspections.
8. Assessment of the Program: The Program described in this
Section I.B shall be evaluated to determine its impact on the
efficiency and effectiveness of the first review cycle for
biosimilar biological products. The assessment shall be
conducted 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.
Aspects and other measures of the Program that will be
assessed by the independent contractor include, but are not
limited to the following:
adherence by the applicant and FDA to the current GRMP
guidance or the GRMP guidance as updated in accordance with
Section I.D, as applicable
completeness and quality of the submitted application
number of unsolicited amendments submitted by the
applicant
timing and adequacy of Day 74 letters
conduct of the mid-cycle communication
any DR letters issued
late-cycle meeting background package
conduct of the late-cycle meeting
time to approval
percentage of applications that are approved during the
first review cycle
percentage of application reviews that are extended due to
a major amendment
number of review cycles for applications that are
ultimately approved
time to resubmission for applications that receive a
complete response in the first review cycle
This assessment will also include a de-identified analysis
of the issues typically discussed during the mid-cycle
communication and the late-cycle meeting and the ability of
the additional FDA-applicant communications to (a) achieve
resolution of these issues during the remainder of the review
clock, or (b) allow the applicant to better prepare for a
resubmission of the application. Following an FDA regulatory
action, the independent contractor will conduct separate
interviews of the applicant and the FDA review team to
understand each party's perspectives on the review of the
application, including whether issues were or should have
been identified at the BPD meetings to facilitate application
review.
An interim and final assessment of the Program will be
published for public comment, with each report followed by a
public meeting during which public stakeholders may present
their views on the success of the Program to date, including
the ability of the Program to help ensure that patients have
timely access to safe, effective, and high quality biosimilar
biological products. During each public meeting, FDA and the
independent contractor 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 discuss any issues identified
to date including any proposed plans to improve the
likelihood of the Program's success.
a. Interim Assessment: An interim assessment of the Program
will be published by December 31, 2020, and FDA will hold a
public meeting by March 31, 2021.
b. Final Assessment: A final assessment of the Program will
be published by June 30, 2022, and FDA will hold a public
meeting by September 30, 2022.
C. First Cycle Review Management for Supplements with
Clinical Data
1. Notification of Issues Identified during the Filing
Review
a. Performance Goal: For supplements with clinical data,
FDA will report substantive review issues identified during
the initial filing review to the applicant by letter.
b. The timeline for such communication will be within 74
calendar days from the date of FDA receipt of the supplement.
c. If no substantive review issues were identified during
the filing review, FDA will so notify the applicant.
d. 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.
e. FDA will notify the applicant of substantive review
issues prior to or on the goal date for 90% of applications.
2. Notification of Planned Review Timelines
a. Performance Goal: For 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.
b. 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 supplement.
c. The planned review timelines will be consistent with the
GRMP guidance.
d. The planned review timeline will be based on the
supplement as submitted.
[[Page S4750]]
e. FDA will inform the applicant of the planned review
timeline for 90% of all supplements with clinical data.
f. In the event FDA determines that significant
deficiencies in the supplement preclude discussion of
labeling, postmarketing requirements, or postmarketing
commitments by the target date identified in the planned
review timeline (e.g., 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.
g. To help expedite the development of biosimilar
biological products, communication of the deficiencies
identified in the supplement may 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.
f. If the applicant submits a major amendment(s) (refer to
Section I.A.5.a 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 I.C.2.a and b)
will generally no longer be applicable. Review of unsolicited
amendments, including those submitted in response to an FDA
communication of deficiencies, will be handled in accordance
with the GRMP guidance. This guidance includes the underlying
principle that FDA will consider the most efficient path
toward completion of a comprehensive review that addresses
supplement deficiencies and leads toward a first cycle
approval when possible.
D. Guidance
FDA and industry share a commitment to ensuring an
efficient and effective first cycle review process for all
applications subject to the BsUFA program. This commitment is
consistent with the principles articulated in the GRMP
guidance, which FDA applies to the review of biosimilar and
interchangeable products. FDA will update the GRMP guidance
during BsUFA II to ensure that it encompasses all review
activities for biosimilar and interchangeable products,
including principles regarding notification to applicants
regarding issues identified during FDA's initial review of
the application, principles regarding FDA's notification to
applicants regarding planned review timelines, and the
importance of internal review timelines that govern aspects
of biosimilar and interchangeable product review that are not
part of BsUFA performance goals. FDA will publish a revised
draft guidance for public comment no later than the end of FY
2018. FDA will work toward the goal of publishing a revised
draft or final guidance within 18 months after the close of
the public comment period.
E. Review of Proprietary Names to Reduce Medication Errors
To enhance patient safety, FDA is committed to 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. The following performance
goals apply to FDA's review of biosimilar biological product
proprietary names during the biosimilar biological product
development (BPD) phase and during FDA's review of a
marketing application:
1. Proprietary Name Review Performance Goals During The 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 Name Review Performance Goals During
Application Review
a. Review 90% of biosimilar biological product 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.
F. Major Dispute Resolution
1. 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.
2. Performance goal: 90% of such responses are provided
within 30 calendar days of the Center's receipt of the
written appeal.
3. Conditions:
a. 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.
b. 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.
c. 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.
d. 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).
e. 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.
f. 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.
g. 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.
G. Clinical Holds
1. 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.
2. Performance goal: 90% of such responses are provided
within 30 calendar days of the Agency's receipt of the
sponsor's response.
H. Special Protocol Question Assessment and Agreement
1. 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.
a. 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).
b. 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.
c. Protocols that qualify for this program include any
necessary clinical study or studies to prove biosimilarity
and/or interchangeability (e.g., protocols for
pharmacokinetics and pharmacodynamics studies, protocols for
comparative clinical studies 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
studies 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 I.I, 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.
d. 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
[[Page S4751]]
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.
2. Performance goal: 90% of special protocols assessments
and agreement requests completed and returned to sponsor
within 45 days.
3. Reporting: The Agency will track and report the number
of original special protocol assessments and resubmissions
per original special protocol assessment.
I. Meeting Management Goals
Formal BsUFA meetings between sponsors and FDA consist of
Biosimilar Initial Advisory and BPD Type 1-4 meetings. These
meetings are further described below.
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.
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.
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
may include substantive review of summary data, but does not
include review of full study reports.
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.
A BPD Type 4 Meeting is a pre-submission meeting to
discuss the format and content of a complete application for
an original biosimilar biological product application under
the Program or supplement submitted under 351(k) of the PHS
Act. The purpose of this meeting is to discuss the format and
content of the planned submission and other items, including
identification of those studies that the sponsor is relying
on to support a demonstration of biosimilarity or
interchangeability, discussion of any potential review issues
identified based on the information provided, identification
of the status of ongoing or needed studies to adequately to
address the Pediatric Research Equity Act (PREA), acquainting
FDA reviewers with the general information to be submitted in
the marketing application (including technical information),
and discussion of the best approach to the presentation and
formatting of data in the marketing application.
1. Response to Meeting Requests
a. Procedure: FDA will notify the requester in writing of
the date, time, and place for the meeting, as well as
expected Center participants following receipt of a formal
meeting request and background package. Table 1 below
indicates the timeframes for FDA's response to a meeting
request.
TABLE 1
------------------------------------------------------------------------
Response time
Meeting type (calendar
days)
------------------------------------------------------------------------
Biosimilar Initial Advisory............................. 21
BPD Type 1.............................................. 14
BPD Type 2-4............................................ 21
------------------------------------------------------------------------
For Biosimilar Initial Advisory and BPD Type 2 meetings,
the sponsor may request a written response to its questions,
rather than a face-to-face meeting, videoconference or
teleconference. If a written response is deemed appropriate,
FDA will notify the requester of the date it intends to send
the written response. This date will be consistent with the
timeframes specified in Table 2 below for the specific
meeting type.
b. Performance Goal: FDA will respond to meeting requests
and provide notification within the response times noted in
Table 1 for 90 percent of each meeting type.
2. Scheduling Meetings
a. Procedure: FDA will schedule the meeting on the next
available date at 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. Table 2 below indicates
the timeframes for FDA to schedule the meeting following
receipt of a formal meeting request and background package,
or in the case of a written response for Biosimilar Initial
Advisory and BPD Type 2 meetings, the timeframes for the
Agency to send the written response. If the requested date
for any meeting type is greater than the specified timeframe,
the meeting date should be within 14 calendar days of the
requested date.
TABLE 2
------------------------------------------------------------------------
Meeting scheduling or written
Meeting type response time
------------------------------------------------------------------------
Biosimilar Initial Advisory............ 75 calendar days from receipt
of meeting request and
background package.
BPD 2.................................. 90 calendar days from receipt
of meeting request and
background package.
Meeting Scheduling Time ...............................
BPD 1.................................. 30 calendar days from receipt
of meeting request and
background package.
BPD 3.................................. 120 calendar days from receipt
of meeting request and
background package.
BPD 4.................................. 60 calendar days from receipt
of meeting request and
background package.
------------------------------------------------------------------------
b. Performance goal:
TABLE 3
------------------------------------------------------------------------
Meeting type Goal
------------------------------------------------------------------------
BPD Type 2............................. FY 2018-2019: 80% of meetings
are held or written responses
are sent within the timeframe.
FY 2020-2022: 90% of meetings
are held or written responses
are sent within the timeframe.
Biosimilar Initial Advisory............ 90% of meetings are held or
written responses are sent
within the timeframe.
BPD Type 1, 3, and 4................... 90% of meetings are held within
the timeframe for each meeting
type.
------------------------------------------------------------------------
3. Preliminary Responses
a. Procedure: The Agency will send preliminary responses to
the sponsor's questions contained in the background package
no later than five calendar days before the face-to-face,
videoconference or teleconference meeting date for BPD Type 2
and Type 3 meetings.
b. Performance goal:
TABLE 4
------------------------------------------------------------------------
Meeting type
------------------------------------------------------------------------
BPD Type 2............................. FY 2018: 70% of
preliminary responses to
questions are issued by FDA no
later than five calendar days
before the meeting date.
FY 2019, 75% of
preliminary responses to
questions are issued by FDA no
later than five calendar days
before the meeting date.
FY 2020, 80% of
preliminary responses to
questions are issued by FDA no
later than five calendar days
before the meeting date.
FY 2021, 85% of
preliminary responses to
questions are issued by FDA no
later than five calendar days
before the meeting date.
FY 2022, 90% of
preliminary responses to
questions are issued by FDA no
later than five calendar days
before the meeting date.
BPD Type 3............................. 90% of preliminary responses to
questions are issued by FDA no
later than five calendar days
before the meeting date.
------------------------------------------------------------------------
4. Meeting Minutes
a. 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. Meeting minutes are not necessary if the Agency
transmits a written response for Biosimilar Initial Advisory
and BPD Type 2 meetings.
b. Performance Goal: 90% of minutes are issued within 30
calendar days of the date of the meeting.
5. Conditions: For a meeting to qualify for these
performance goals:
a. A written request and supporting documentation (i.e.,
the background package) must be submitted to the appropriate
review division or office.
b. The request must provide:
i. 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, teleconference, or for a
written response (Biosimilar Initial Advisory and BPD Type 2
meetings only);
ii. A listing of the specific objectives/outcomes the
requester expects from the meeting;
iii. A proposed agenda, including estimated times needed
for each agenda item;
iv. A list of questions, grouped by discipline. For each
question there should be a brief explanation of the context
and purpose of the question.
v. A listing of planned external attendees; and
vi. A listing of requested participants/disciplines
representative(s) from the Center with an explanation for the
request as appropriate.
vii. 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.
c. 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
(i.e., Biosimilar Initial Advisory, or BPD Type 1-4) 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
744H 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 744H, and the
sponsor does not pay the fee within the time frame required
under section 744H, 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
[[Page S4752]]
section I.I.1.a 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 available FDA guidance
to obtain further information on recommended meeting
procedures.
6. Guidance
a. FDA will publish revised draft guidance on Formal
Meetings Between the FDA and Biosimilar Biological Product
Sponsors or Applicants no later than September 30, 2018.
b. FDA will update the current draft or final guidance on
Best Practices for Communication Between IND Sponsors and FDA
During Drug Development, as appropriate, to apply to
communications between IND sponsors and FDA during biosimilar
biological product development. FDA will publish a revised
draft or final guidance by December 31, 2018.
II. advancing development of biosimilar biological products through
further clarification of the 351(k) regulatory pathway
A. On or before December 31, 2017, FDA will publish draft
guidance describing considerations in demonstrating
interchangeability with a reference product. FDA will work
toward the goal of publishing a revised draft or final
guidance within 24 months after the close of the public
comment period.
B. On or before December 31, 2017, FDA will publish draft
guidance describing statistical considerations for the
analysis of analytic similarity data intended to support a
demonstration of ``highly similar'' for biosimilar biological
products. FDA will work toward the goal of publishing a
revised draft or final guidance within 18 months after the
close of the public comment period.
C. On or before March 31, 2019, FDA will publish draft
guidance describing processes and further considerations
related to post-approval manufacturing changes for biosimilar
biological products. FDA will work toward the goal of
publishing a revised draft or final guidance within 18 months
after the close of the public comment period.
D. FDA will work towards the goal of publishing revised
draft guidance or final guidance documents on or before May
31, 2019 for draft guidances published between January 1,
2014 and September 30, 2017, other than those described in
(II.A-C). These draft guidances will include:
1. Clinical Pharmacology Data to Support a Demonstration of
Biosimilarity to a Reference Product (draft guidance
published in May 2014)
2. Nonproprietary Naming of Biological Products (draft
guidance published in August 2015)
3. Labeling for Biosimilar Biological Products (draft
guidance published in March 2016)
III. enhancing capacity for biosimilar regulations and guidance
development, reviewer training, and timely communication
A. FDA will strengthen the staff capacity to develop new
regulations and guidance to clarify scientific criteria for
biosimilar development and approval to provide certainty to
industry and other stakeholders related to key regulatory
issues including the scope of eligible biosimilar biological
products.
B. FDA will strengthen staff capacity to develop or revise
MaPPs, SOPPs, and review templates to facilitate rapid update
and application of new policies and guidance by review staff,
and to develop and deliver timely comprehensive training to
all CDER and CBER review staff and special government
employees involved in the review of 351(k) BLAs.
C. FDA will strengthen staff capacity to deliver timely
information to the public to improve public understanding of
biosimilarity and interchangeability.
D. FDA will strengthen staff capacity to deliver
information concerning the date of first licensure and the
reference product exclusivity expiry date, to be included in
the Purple Book.
FDA will update the Purple Book to include the following
information: the BLA number, product name, proprietary name,
date of licensure, interchangeable or biosimilar
determination, and whether the BLA has been withdrawn. FDA
will update this information in the Purple Book within 30
days after approval or withdrawal. In addition, within 30
days after FDA determines the date of first licensure, the
date of first licensure and the reference product exclusivity
expiry date will be included in the Purple Book.
IV. enhancing management of user fee resources
FDA will establish an independent user fee structure and
fee amounts to ensure stable and predictable user fee
funding, improve the predictability of FDA funding and
sponsor invoices, improve efficiency by simplifying the
administration of user fees, and enhance flexibility of
financial mechanisms to improve management of BsUFA program
funding. FDA is committed to enhancing management of BsUFA
resources and ensuring BsUFA user fee resources are
administered, allocated, and reported in an efficient and
transparent manner. FDA will conduct a series of resource
capacity planning and financial transparency activities to
enhance management of BsUFA resources in BsUFA II.
A. Resource Capacity Planning and Modernized Time Reporting
FDA is committed to enhancing management of BsUFA resources
in BsUFA II. FDA will conduct activities to develop a
resource capacity planning function and modernized time
reporting approach in BsUFA II.
1. FDA will publish a resource capacity planning and
modernized time reporting implementation plan that includes
BsUFA no later than the 2nd quarter of FY 2018. FDA will
continue to utilize information and recommendations from a
third party assessment of resource capacity planning,
financial analytics, and modernized time reporting for BsUFA
as part of the implementation plan.
2. FDA will staff a resource capacity planning team that
will implement and manage a capacity planning system across
the BsUFA program in BsUFA II.
3. FDA will obtain through a contract with an independent
accounting or consulting firm an evaluation of options and
recommendations for a new methodology to accurately assess
changes in the resource and capacity needs of the biosimilar
biological product review program. The BsUFA evaluation will
be conducted under the same contract and by the same
independent accounting or consulting firm that will evaluate
options and recommendations for a new methodology to
accurately assess changes in the resource and capacity needs
of the human drug review program in PDUFA VI. The report will
be published no later than end of FY 2020 for public comment.
Upon review of the report and comments, FDA will implement
robust methodologies for assessing resource needs of the
program. This will include the adoption of a new resource
capacity adjustment methodology that accounts for sustained
increases in BsUFA workload.
4. FDA recognizes that revenue generated by the capacity
adjustment will be allocated to and used by organizational
review components engaged in direct review work to enhance
resources and expand staff capacity and capability. FDA will
document in the annual financial report how the capacity
adjustment fee revenues are being utilized.
B. Financial Transparency and Efficiency
FDA is committed to ensuring BsUFA user fee resources are
administered, allocated, and reported in an efficient and
transparent manner. FDA will conduct activities to evaluate
the financial administration of the BsUFA program to help
identify areas to enhance efficiency. FDA will also conduct
activities to enhance transparency of BsUFA program
resources.
1. FDA will contract with an independent third party to
conduct an evaluation of BsUFA program resource management
during FY 2018 to ensure that BsUFA user fee resources are
administered, allocated, and reported in an efficient and
transparent manner in BsUFA II. The BsUFA evaluation will be
conducted under the same contract and by the same independent
third party that will conduct an evaluation of the PDUFA
program resource management. The study will include, but is
not limited to, the following areas:
a. Evaluate all components of the BsUFA program resource
planning, request, and allocation process from when FDA
receives the user fee funds through when funds are spent. The
contractor will recommend options to improve the process and
data needed to enhance resource management decisions.
b. Assess how FDA administers BsUFA user fees
organizationally, including, but not limited to, billing,
user fee collection, and execution. The contractor will
recommend options to enhance the efficiency of user fee
administration.
c. Evaluate FDA's existing BsUFA program financial and
administrative oversight and governance functions. Assess
alternative governance models including roles and
responsibilities, organizational location, and personnel
skill sets required. The contractor will recommend options on
the most effective governance model to support the biosimilar
biological product review program.
d. Assess FDA's technical capabilities to conduct effective
financial management and planning in the context of generally
accepted government resource management and planning
practices. The contractor will recommend options for the
technical capabilities needed by financial personnel involved
in BsUFA resource management to enhance financial management
and planning.
2. FDA will publish a BsUFA five-year financial plan no
later than the 2nd quarter of FY 2018. FDA will publish
updates to the five-year plan no later than the 2nd quarter
of each subsequent fiscal year.
3. FDA will convene a public meeting no later than the
third quarter of each fiscal year starting in FY 2019 to
discuss the BsUFA five-year financial plan, report on the
contribution of the BsUFA spending trigger to the BsUFA
program, along with the Agency's progress in implementing
modernized time reporting, resource capacity planning, and
the modernized user fee structure.
C. Management of Carryover Balance
FDA is committed to reducing the carryover balance to no
greater than 21 weeks of the FY 2022 target revenue by the
end of FY 2022. However, if FDA is unable to reduce the
carryover balance to no greater than 21 weeks during the
final year (e.g., over collections in FY 2022 that increase
the carryover balance beyond 21 weeks), FDA will (1) outline
its plan to reduce the carryover balance to no greater than
21 weeks in the FY 2022 BsUFA financial report and (2) update
the BsUFA five-year financial plan.
V. improving fda hiring and retention of review staff
To speed and improve development of safe and effective
biosimilar biological products
[[Page S4753]]
for patients, enhancements to the biosimilar biological
review program require that FDA hire and retain sufficient
numbers and types of technical and scientific experts to
efficiently conduct reviews of 351(k) applications. In order
to strengthen this core function and increase public access
to biosimilar biological products, the FDA will commit to do
the following:
A. Completion of Modernization of the Hiring System
Infrastructure and Augmentation of System Capacity
1. Complete implementation of FTE-based position management
system capability.
a. FDA will complete development of position management
baseline accounting of all current positions and FTE counts
engaged in the biosimilar biological product review program
for each applicable Center and Office including filled and
vacant positions, a governance structure for on-going
position management that will be accountable to FDA senior
management, and position management policy and guidelines
ratified by FDA senior management, outlining processes for
adding new positions, deleting positions, and changing
established positions.
b. FDA will complete implementation of the new position-
based management system.
2. Complete implementation of an online position
classification system
a. FDA will finalize the establishment of an online
Position Description (PD) library. The library will include
all current well-classified PDs and current standardized PDs.
Once operational, any new PDs classified using the on-line
classification tools, and any newly created standardized PDs,
will be stored and accessible within FDA's PD library and
available for FDA-wide use as appropriate.
3. Complete implementation of corporate recruiting
a. For key scientific and technical disciplines commonly
needed across offices engaged in the biosimilar biological
product review program, FDA will complete the transition from
the use of individual vacancy announcements for individual
offices to expanded use of a common vacancy announcement and
certificate of eligible job applicants that can be used by
multiple offices. As a part of this effort, FDA will complete
the transition from use of individual announcements that are
posted for a limited period to common vacancy announcements
with open continuous posting to maximize the opportunity for
qualified applicants to apply for these positions.
B. Augmentation of Hiring Staff Capacity and Capability
In recognition of the chronic and continuing difficulties
of recruiting and retaining sufficient numbers of qualified
Human Resources (HR) staff, FDA will engage a qualified
contractor to provide continuous support throughout BsUFA II
to augment the existing FDA HR staff capacity and
capabilities. The utilization of a qualified contractor will
assist FDA in successfully accomplishing BsUFA II goals for
recruitment and retention of biosimilar biological product
review program staff.
C. Complete Establishment of a Dedicated Function to Ensure
Needed Scientific Staffing for Human Drug Review
Including for Review of Biosimilar Biological Products
1. Rapid advances in the science and technology of
biosimilar biological product development and manufacturing
require FDA's biosimilar biological product review program
staff to keep pace with science and learn innovative methods
and techniques for review of new therapies. FDA will complete
the establishment of a new dedicated unit within the Office
of Medical Products and Tobacco charged with the continuous
recruiting, staffing, and retention of scientific, technical,
and professional staff for the PDUFA and BsUFA review
programs.
a. The unit will continuously develop and implement
scientific staff hiring strategies and plans, working closely
with the center review offices and the FDA HR office, to meet
discipline-specific hiring commitments and other targeted
staffing needs. It will function as a scientific-focused
recruiter conducting ongoing proactive outreach to source
qualified candidates, and conducting competitive recruiting
to fill vacancies that require top scientific, technical, and
professional talent.
b. The unit will conduct analyses, no less than annually,
of compensation and other factors affecting retention of key
staff in targeted disciplines and provide leadership and
support for agency compensation oversight boards that
currently exist or may be established as needed to ensure
retention of key scientific, technical, and professional
staff.
D. Set Clear Goals for Biosimilar Biological Product Review
Program Hiring
1. FDA will establish priorities for management of the
metric goals for targeted hires within the biosimilar
biological product review program staff for BsUFA II. In
particular, FDA will target hiring 15 FTE in FY 2018, to
enhance capacity for biosimilar guidance development,
reviewer training, and timely communication.
2. FDA will confirm progress in the hiring of BsUFA I FTEs.
FDA will report on progress against the hiring goal for BsUFA
II on a quarterly basis posting updates to the FDA website
BsUFA Performance webpage.
E. Comprehensive and Continuous Assessment of Hiring and
Retention
FDA hiring and retention of staff for the biosimilar
biological product review program will be evaluated by a
qualified, independent contractor with expertise in assessing
HR operations and transformation. The BsUFA II assessment
will be conducted under the same contract and by the same
independent contractor that will conduct the assessment
related to hiring and retention of staff for the human drug
review program in PDUFA VI. It will include continuous
assessments throughout the course of implementation of the
performance initiatives identified in Sections V.A-D, and
metrics including, but not limited to, those related to
recruiting and retention in the PDUFA and BsUFA review
programs including, but not limited to, specifically targeted
scientific disciplines and levels of experience. The
contractor will conduct a comprehensive review of current
hiring processes and hiring staff capacity and capabilities
that contribute to achievement of successes, potential
problems, or delays in PDUFA or BsUFA review program staff
hiring. This includes the entire hiring function and related
capabilities. FDA and regulated industry leadership will
periodically and regularly assess the progress of hiring and
retention throughout BsUFA II.
1. Initial Assessment: The assessment will include an
initial baseline assessment to be conducted and completed no
later than December 31, 2017. The initial baseline study will
include an evaluation of the current state and provide
recommended options to address any identified gaps or areas
identified as priorities for improvement, and a study report
to be published no later than December 31, 2017. FDA will
hold a public meeting no later than December 31, 2017, to
present and discuss report findings, and present its specific
plans, including agency senior management oversight, and
timeline for implementing recommended enhancements to be
fully operational by no later than December 31, 2018.
2. Interim Assessment: An interim assessment will be
published by March 31, 2020, for public comment. By June 30,
2020, FDA will hold a public meeting during which the public
may present their views. FDA will discuss the findings of the
interim assessment, including progress relative to program
milestones and metrics, and other aggregated feedback from
internal customers and participants in HR services that may
be included in the continuous assessment. FDA will also
address any issues identified to date including actions
proposed to improve the likelihood of success of the program.
3. Final Assessment: A final assessment will be published
by December 31, 2021, for public comment. FDA will hold a
public meeting by no later than March 30, 2022, during which
the public may present their views. FDA will discuss the
findings of the final assessment, including progress relative
to program milestones and metrics, and other aggregated
feedback from internal customers and participants in HR
services that may be included in the continuous assessment.
FDA will also address any issues identified and plans for
addressing these issues.
V. 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. A resubmitted original application is a complete
response to an action letter addressing all identified
deficiencies.
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