|
Timeline |
Reference[7] |
Responsibility |
||
Begin at time of assignment |
|
Review Team Consultants Signatory Authority, as needed |
||
|
Interaction of primary and secondary reviewers |
|
||
|
Interdisciplinary interaction |
|
||
|
Team meetings |
|
||
|
Issue IR Letter or other requests for information, as needed |
|
||
By End of Month 5 (3)
|
Mid-Cycle Meeting |
|
||
|
Update on progress and findings of all reviews, consults, and inspections |
|
||
|
Define need for additional interaction with applicant related to labeling, risk management, postmarketing commitments |
|
||
|
Revise review plan, if needed |
|
||
|
Brief signatory authority |
|
||
By End of Month 8 (5) |
Complete Primary Review
|
|
Review Team |
Review Phase |
|||
Timeline |
Activity |
Reference |
Responsibility |
Variable |
Secondary Sign-Off |
CBER SOPP 8006, Resolution of Differences in Scientific Judgment in the Review Process CDER MAPP 4151.1, Resolution of Disputes: Roles of Reviewers, Supervisors, and Management — Documenting Views and Findings and Resolving Differences CDER MAPP 6020.8, Action Packages for NDAs and Efficacy Supplements |
|
Variable |
Issue DR Letters, as appropriate |
FDA guidance, Information Request and Discipline Review Letters Under the Prescription Drug User Fee Act |
The review division, in consultation with the office director, may decide to convene an advisory committee (AC) meeting. A review division may seek AC input, for example, when: (1) the application is for a new molecular entity (NME), especially if it is the first member of a new class of drug; (2) the clinical study design used novel clinical or surrogate endpoints; (3) the application raises significant issues on the safety and/or effectiveness of the drug or biologic; or (4) the application raises significant public health questions on the role of the drug or biologic in the diagnosis, cure, mitigation, treatment, or prevention of a disease. The decision to hold an AC meeting should be made and communicated to the applicant early in the first cycle review process.
The FDA and the applicant should work together during AC meeting planning to share issues and avoid redundant presentations. Applicants are strongly discouraged from submitting amendments that contain significant new data after the review division has sent the FDA background package to the AC members and the applicant, because this does not allow the review division sufficient opportunity to review and consider the new data before the meeting. There are also strict timelines for clearance of background packages for public dissemination before the meeting, so the FDA is not able to accommodate applicant requests for changes in FDA background materials, other than to correct factual errors (e.g., issuance of an errata sheet).
Based on the discussions at the AC meeting and committee recommendations, the FDA may ask an applicant to submit additional data or analyses for review. We encourage applicants to provide these amendments in a timely manner.
Timeline |
Reference[8] |
Responsibility |
||
Begin when need for AC meeting is identified |
|
Review Team Consultants, as needed FDA Advisors and Consultants Staff |
||
Variable |
|
Formulation of questions for AC |
|
|
By 2 weeks before AC meeting |
|
Disseminate and disclose applicant and FDA background materials[9] |
|
|
By End of Month 8 (5)
|
Conduct AC Meeting |
FDA guidance, Implementation of Section 120 of the Food and Drug Administration Modernization Act of 1997 — Advisory Committees |
|
|
Variable |
Follow-Up to AC |
|
|
|
Within 2 weeks after AC meeting |
|
Internal meeting to integrate AC input into review outcomes and request or conduct additional analyses |
|
Review Team |
With Action |
|
Confidential memo to AC to announce action and interpretation of AC input |
|
Review Division Director |
The outcomes of all review activity are integrated during wrap-up, the first part of the action phase. An internal meeting facilitates the development of a comprehensive understanding of the safety, efficacy, and quality of the proposed product and a preliminary decision on the regulatory action. Consideration should be given to critical elements such as risk management, major labeling issues, and postmarketing commitments.
Review wrap-up determinations help form the basis for labeling discussions with the applicant to complete the labeling for products whose approval can be anticipated (i.e., approval and most approvable actions). Since essential labeling discussions by necessity occur toward the end of the review cycle when available time is limited, it is important that communication between the FDA and applicants be clear and efficient. Adherence to the review timeline, including completion of primary and secondary reviews well in advance of the PDUFA goal date, allows time to resolve labeling content issues and avoids crisis management of these issues near the PDUFA goal date.
Applicants can support labeling discussions by not submitting large amounts of new data in support of proposed labeling text, and by clearly explaining their basis for changes from the review division’s recommended labeling language. Applicants are discouraged from printing labels for commercial distribution before receipt of an approval letter, because the label can change until it is approved. Labels printed in advance of the actual receipt of an approval letter are done so at the applicant’s risk.
When the review division director in CDER has signature authority for an application, the team leader from each review discipline should write a summary of the basis for the recommended action from that discipline. In CBER, the review discipline branch chief will write a summary of the basis for the recommended action from that discipline only if he or she disagrees with the findings or conclusions of the primary reviewer (see Section IV.B., Review Phase). The division director of the responsible office should also write a summary to document the basis for the regulatory action, taking into account the input from the entire review team. The division director summary should describe the resolution of difficulties or disagreements and clarify any issues that need attention during the postapproval period. In some instances, particularly when there has been little disagreement during the review process, the medical team leader in CDER, or the review team leader in CBER, may write the summary of the basis of the recommended action from the multidisciplinary perspective. The division director should document concurrence with the team leader’s statement as part of the signatory process, or document in writing the basis for nonconcurrence, if necessary.
When the office director has signature authority, the previously described documentation is warranted as well as an additional written summary review by the office director.
The goals of the regulatory action and FDA policy on communicating regulatory actions are described in Section III.B., Operational Principles. The FDA processes and reviews marketing applications with the goal of completing the review and issuing an official written regulatory action by the PDUFA goal date. It is important that any communication with the applicant before the official regulatory action makes it clear that a decision has not yet been made, and there should be no speculation on the nature of the final action.
Action Phase |
|||||
Timeline |
Reference[10] |
Responsibility |
|||
By End of Month 8 (5)
|
|
Review Team Consultants Signatory Authority |
|||
|
Integrate outcomes of reviews, consults, inspection reports, and AC input |
|
|||
|
Consider need for center level input (e.g., Regulatory Briefing) |
|
|||
Internal Briefings for Signatory Authority, as needed |
|
||||
4 Weeks Before Approval Action |
Preapproval Safety Conference (for NMEs in CDER) |
CDER MAPP 6010.1, NDAs: Preapproval Safety Conferences |
Review Team ODS |
||
Initiate Compliance Check Request (BLAs) |
|
RPM |
|||
Begin 3 Weeks Before Division Sign-Off |
Labeling Discussions (for Approval and Approvable Actions) |
|
Review Team Consultants, in CDER: ODS DDMAC Study and Endpoints Labeling Team Consultants, in CBER: OBE APLB OCBQ |
||
|
Apply labeling review checklist |
CBER SOPP 8412, Review of Product Labeling |
|||
|
Meeting/teleconference with applicant and/or secure e-mail exchange of proposed labeling |
|
|
||
|
Finalize labeling based on data |
FD&C Act, section 502 21 CFR Part 201 |
Review Team Signatory Authority |
||
|
Finalize dependent materials (PPI, MedGuide) |
|
Review Team Consultants |
||
Negotiation of Postmarketing Commitments, if needed |
|
|
|||
Negotiation of Risk Management Program, if needed |
|
|
|||
Action Phase |
|||||
Timeline |
Activity |
Reference |
Responsibility |
||
By 6 (4-6) Weeks Before Action
|
CBER SOPP 8401, Administrative Processing of Biologics License Application (BLA); SOPP 8405, Complete Review and Issuance of Action Letters CDER MAPP 6020.8, Action Packages for NDAs and Efficacy Supplements |
RPM |
|||
Draft Action Letter with Conditions of Approval (for Approval Actions) |
Approval: 21 CFR 314.105 21 CFR 601.4(a) |
||||
Draft Action Letter with Comprehensive List of Deficiencies (for Actions Other than Approval) |
NDA Approvable: 21 CFR 314.110 NDA Not Approvable: 21 CFR 314.120 BLA Denial of License: 21 CFR 601.4(b) |
RPM |
|||
Circulate and Review Action Package and Letter |
|
Review Team Signatory Authority |
|||
|
To primary reviewers (and consultants, as needed) |
|
|||
|
To secondary reviewers (when signatory authority is the Division Director) OR To Division Director (when signatory authority is the Office Director) |
|
|||
By 3 (2-3)Weeks Before Action |
|
To signatory authority, with revision as needed |
|
||
By PDUFA Goal Date |
Action |
|
Signatory Authority |
||
|
Archive signed letter |
|
RPM |
||
|
Send official copy to applicant (by facsimile, secure e-mail, or postal service) |
|
|||
|
Verify and document applicant receipt |
|
|||
|
Distribute approval information (for approval action) |
CBER SOPP 8106, Submission of Product Approval Information for Dissemination to the Public CDER MAPP 4520.1, Communicating Drug Approval Information CDER MAPP 4520.2, Providing General Consumer Information on NMEs on CDER’s Web Site |
|||
During the post-action phase, the Agency and applicants should focus on learning from the successful aspects of the review process and identifying other aspects of the review process that could benefit from future improvement.
For actions
other than approvals, it is optimal to direct activities toward
improving outcomes for subsequent review cycles by creating a
clear understanding on the part of both the FDA and the applicant
of deficiencies and the expected responses. This can be
accomplished by scheduling a post-action teleconference or meeting
to discuss the deficiencies. A presubmission meeting between the
review division and the applicant can also be scheduled to discuss
the applicant’s planned response to the action letter and help
avoid incomplete responses. Applicants can help optimize the
outcome of subsequent review cycles by responding clearly and
completely to issues identified in the action letter.
Timeline |
Reference[11] |
Responsibility |
||
After PDUFA Goal Date |
|
Review Team Signatory Authority Consultants |
||
|
Lessons learned |
|
||
|
Clarify deficiencies and expected responses (actions other than approvals) |
21 CFR 314.102(d) CBER SOPP 8405.1, Procedures for the Classification of Resubmissions of an Application for a Product Covered by PDUFA CDER MAPP 6020.4, Classifying Resubmissions of Original NDAs in Response to Action Letters FDA guidance, Formal Dispute Resolution: Appeals Above the Division Level |
||
|
Dispute Resolution (when necessary, can occur throughout review process) |
21 CFR 314.103 FDA guidance, Formal Dispute Resolution: Appeals Above the Division Level |
The GRMPs are based in part on the Agency’s current best practices. Implementation activity, including reviewer training and performance evaluation, began in October 2003 and will continue with additional training on this guidance.
In accordance with commitments under the reauthorization of PDUFA, an independent expert consultant under contract with the FDA will carry out the performance evaluation. The consultant, with input from the FDA and the public, will be responsible for developing an evaluation study design that identifies key questions, data requirements, data collection plans, and planned analyses in accordance with the PDUFA goals.
AC Advisory Committee
APLB Advertising and Promotional Labeling Branch (CBER)
BiMo Bioresearch Monitoring Branch (CBER)
BLA Biologics License Application
BLS Biologics License Supplement
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
CFR Code of Federal Regulations
CMA Continuous Marketing Application
CMC Chemistry, Manufacturing, and Controls
CPMS Chief, Project Management Staff
DDMAC Division of Drug Marketing, Advertising, and Communications (CDER)
DE Division of Epidemiology (CBER)
DMPQ Division of Manufacturing and Product Quality
DR Discipline Review
DSI Division of Scientific Investigations (CDER)
EA Environmental Assessment
EER Establishment Evaluation Request
EOP2 End-of-Phase 2
FDA U.S. Food and Drug Administration
FD&C Act Federal Food, Drug, and Cosmetic Act
GRMP Good Review Management Principles and Practices
HRQL Health-Related Quality of Life
IND Investigational New Drug Application
IR Information Request
MAPP Manual of Policies and Procedures (CDER)
NDA New Drug Application
NME New Molecular Entity
OBE Office of Biostatistics and Epidemiology (CBER)
OBP Office of Biotechnology Products (CDER)
OCBQ Office of Compliance and Biologics Quality (CBER)
OCPB Office of Clinical Pharmacology and Biopharmaceutics (CDER)
ODS Office of Drug Safety (CDER)
ONDC Office of New Drug Chemistry (CDER)
PDUFA Prescription Drug User Fee Act
PI Package Insert
PPI Patient Package Insert
PREA Pediatric Research Equity Act
PRO Patient-Reported Outcome
P/T Pharmacology/Toxicology
RMP Risk Management Plan
RPM Regulatory Project Manager
RTF Refusal to File
SOPP Standard Operating Policies and Procedures (CBER)
SPA Special Protocol Assessment
U.S.C. U.S. Code
The guidances for industry, MAPPs, and SOPPs for FDA staff referenced in this document are listed below. This is not a comprehensive list of available information from CDER and CBER. Consult the following CDER and CBER Web pages for additional information:
http://www.fda.gov/cder/guidance/index.htm
http://www.fda.gov/cber/guidelines.htm
Presubmission
FDA Guidances
· Formal Meetings with Sponsors and Applicants for PDUFA Products
· Special Protocol Assessment
· Continuous Marketing Application: Pilot 1
· Continuous Marketing Application: Pilot 2
Filing Determination and Review Planning Phase
FDA Guidance
· Refusal to File
CBER SOPPs
· 8401 Administrative Processing of Biologics Licensing Application
(BLA)
· 8401.1 Issuance and Review of Responses to Information Requests and
Discipline Review Letters to Pending Applications
· 8401.2 Administrative Processing of Biologics License Application
Supplement (BLSs) [Except Blood, Blood Components, and Source
Plasma]
· 8401.3 Filing Action: Communication Options
· 8110 Submission of Regulatory Documents to CBER
· 8406 Verification of User Fee Data Sheet and Payment
· 8405 Complete Review and Issuance of Action Letters
· 8404 Refusal to File Procedures for Biologic Licensing Applications
· 8404.1 Procedures for Filing an Application When the Applicant Protests
a Refusal to File Action (File Over Protest)
CDER MAPPs
· 7600.7 Processing an Electronic New Drug Application
· 6050.1 Refusal to Accept Application for Filing from Applicants in
Arrears
· 6020.3 Priority Review Policy
· 6010.5 NDAs: Filing Review Issues
· 4200.3 Consulting the Controlled Substance Staff on Abuse Liability,
Drug Dependence, Risk Management, and Drug Scheduling
Review Phase
FDA Guidance
· Information Request and Discipline Review Letters Under the Prescription Drug User Fee Act
CBER SOPPs
· 8006 Resolution of Differences in Scientific Judgment in the Review
Process
· 8401.1 Issuance and Review of Responses to Information Requests and
Discipline Review Letters to Pending Applications
CDER MAPP
· 4151.1 Resolution of Disputes: Roles of Reviewers, Supervisors, and
Management — Documenting Views and Findings and Resolving
Differences
Advisory Committee Meeting Phase
FDA Guidance
· Implementation of Section 120 of the Food and Drug Administration Modernization Act of 1997 — Advisory Committees
CBER Draft Guidance
· Disclosing Information Provided to Advisory Committees in Connection with Open Advisory Committee Meetings Related to the Testing or Approval of Biologic Products and Convened by the Center for Biologics Evaluation and Research Beginning on June 1, 2001
CDER Draft Guidance
· Disclosing Information Provided to Advisory Committees in Connection with Open Advisory Committee Meetings Related to the Testing or Approval of New Drugs and Convened by the Center for Drug Evaluation and Research Beginning on January 1, 2000
Action Phase
CBER SOPPs
· 8405 Complete Review and Issuance of Action Letters
· 8106 Submission of Product Approval Information for Dissemination to
the Public
· 8412 Review of Product Labeling
CDER MAPPs
· 6010.1 NDAs: Preapproval Safety Conferences
· 6020.8 Action Packages for NDAs and Efficacy Supplements
· 4520.1 Communicating Drug Approval Information
· 4520.2 Providing General Consumer Information on NMEs on CDER’s
Web Site
Post-Action Phase
FDA Guidance
· Formal Dispute Resolution: Appeals Above the Division Level
CBER SOPP
· 8405.1 Procedures for the Classification of Resubmissions of an
Application for a Product Covered by the Prescription Drug User
Fee Act (PDUFA III)
CDER MAPP
· 6020.4 Classifying Resubmissions of Original NDAs in Response to
Action
[1]
This guidance has been prepared by the Center for Drug
Evaluation and Research (CDER) and the Center for Biologics
Evaluation and Research (CBER) at the Food and Drug
Administration.
[2]
The letter was sent to Congress
with identical copies addressed to the Chairman and Ranking
Minority Members of the Committee on Health, Education, Labor,
and Pensions, United States Senate; and the Committee on Energy
and Commerce, House of Representatives. The PDUFA goals can be
found at
http://www.fda.gov/oc/pdufa/PDUFAIIIGoals.html
[3] The FDA mission statement can be
found at
http://www.fda.gov/opacom/morechoices/mission.html
[4] All guidances referenced in this
guidance are available on the Internet at
http://www.fda.gov/cder/guidance/index.htm
[5] The references listed in this
table are considered important to this topic, but are not all
inclusive.
[6] The number in parentheses
indicates modification of timeline for priority status reviews.
[7] The references listed in this
table are considered important to this topic, but are not all
inclusive.
[8] The references listed in this
table are considered important to this topic, but are not all
inclusive.
[9]
The
following draft guidances are references for this activity:
CDER draft guidance Disclosing Information Provided to
Advisory Committees in Connection with Open Advisory Committee
Meetings Related to the Testing or Approval of New Drugs and
Convened by the Center for Drug Evaluation and Research
Beginning on January 1, 2000; and CBER draft guidance
Disclosing Information Provided to Advisory Committees in
Connection with Open Advisory Committee Meetings Related to the
Testing or Approval of Biologic Products and Convened by the
Center for Biologics Evaluation and Research Beginning on June
1, 2001. Once finalized, these draft guidances will
represent the FDA’s current thinking regarding these topics.
[10] The references listed in this
table are considered important to this topic, but are not all
inclusive.
[11] The references listed in this
table are considered important to this topic, but are not all
inclusive.
Back to Top Back to Guidance Page
Date created: March 31, 2005