Manual of Standard Operating Procedures and Policies
Regulatory - License and Drug Applications |
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Postmarketing Commitment Related Submissions - Administrative Handling, Review, and CBER Reporting |
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SOPP 8413 |
Version #4 |
January 28, 2008 |
- Purpose
- Definitions
- Required PMC - A study or studies required by FDA as a condition of marketing approval. Two examples are:
- accelerated approval clinical benefit studies, where the applicant is required to verify clinical benefit after approval (21 CFR 314.510 and 601.41); and
- deferred pediatric studies, where the applicant must assess the safety and efficacy of the product in all relevant pediatric subpopulations. >
- Agreed Upon PMC - A study or studies that the FDA and applicant have agreed are necessary, generally to address a specific aspect of the safety or efficacy of the product. The agreement may be reached before or after approval of the application or supplement.
- PMC study protocols,
- status updates,
- application supplements,
- annual reports, and
- final study reports.
- Background
- Policy
- Responsibilities
- Receive all PMCRSs;
- Log all PMCRSs into the appropriate tracking system (DATS);
- Send copies of the PMCRSs to the appropriate application divisions;
- Route copies to assigned reviewers upon receipt of routing instructions;
- Maintain files for PMCRSs by STN, NDA number or IND number, as appropriate.
- Identify a product or clinical reviewer for each PMC;
- Participate in discussions and decisions pertaining to PMC fulfillment issues;
- Ensure that review goals for PMC submissions are met.
- Monitor due dates for each PMC;
- Conduct an administrative review of each PMCRS;
- Ensure that Annual Reports/PMCs do not contain any other type of notification or submission;
- Ensure that Annual Reports/PMCs are accompanied by Form FDA 2252;
- Ensure that a PMC Annual Report Review Form (see Appendix A) is generated for each such submission.
- Ensure that all necessary information regarding the PMCRS is accurately and promptly entered into the regulatory database, e.g., enter as a second or third level STN in RMS-BLA as appropriate;
- Ensure that a reviewer is named for each PMC after consultation with appropriate division director or branch chief;
- Ensure that the PMCRS is routed to all appropriate reviewers and coordinate the review;
- Ensure that applicant-reported statuses are verified by the reviewer (on the PMC Annual Report Review Form for such submissions), and the verification is entered in the appropriate database;
- Ensure that the review(s) of the PMCRS is performed within established timeframes (if any) and documented;
- Serve as the primary point of contact for all communications with the applicant related to the PMC;
- Ensure that a letter issues to the applicant on a final study report for 506B PMCs;
- Ensure that the CBER's decision on final study reports for non-506B PMCs is communicated to the applicant (in writing if necessary, e.g., written confirmation requested by applicant);
- Ensure that the data in the regulatory databases are quality checked before the periodic reports are run on PMCs.
- Determine that the PMC study status and status explanation submitted by the applicant are appropriate and consistent with the original agreed upon timeframes, and contact the applicant to resolve any discrepancies;
- Complete the PMC Annual Report Review Form for such submissions.
- Perform a complete technical, scientific, or clinical review of the PMCRS within the designated time frame;
- Determine whether a PMC has been fulfilled;
- Document the PMCRS review in memorandum format (or using the PMC Annual Report Review Form for 601.70 submissions), including determinations and recommendations for any necessary actions (e.g., letter to applicant).
- Ensure that all necessary tracking elements for the PMC are available in the regulatory databases;
- Periodically quality check the data in the regulatory databases related to the PMC and resolve any problems with the appropriate RPM or office information specialist;
- Ensure that necessary PMC data are verified by the offices and provided in a timely manner to the Agency coordinator for the Federal Register and to the CBER Web master for the Web site reports;
- Consult with the Center Freedom of Information Officer on PMC information releasability issues.
- Post a monthly report on all 506B PMCs on the CBER website
- Procedures
- Conducts an initial administrative review as appropriate for the type of submission.
- Checks that the submission has been properly classified in the appropriate regulatory database.
- Assures through all steps of the process that the regulatory database is updated, whether the submission is made to a BLA, NDA, or IND.
- Contacts the applicant to amend the submission if it is a 601.70 Annual Report/PMC Annual Report and:
- not all of the outstanding 506B PMCs have been addressed,
- non-506B or other notifications have been included with the 601.70 report (they must be submitted separately)
- the Form FDA-2252 has not been submitted,
- the applicant has failed to provide a current schedule with projected completion date.
- Generates a PMC Annual Report Review Form for 601.70 submissions and attaches it to the submission for the reviewer to complete.
- Determines who should review the submission and requests routing from DCC. If the submission pertains to an epidemiologic study (observational study, registry, or survey), two copies should be routed to OBE; one copy to the appropriate Division of Epidemiology Branch Chief (TBSB or VSB) and one copy to the Division of Biostatistics.
- Conducts a technical, scientific, or clinical review of the submission.
- Checks that all outstanding 506B PMCs are addressed if the submission is an Annual Report/PMC Annual Report;
- Checks that information on the study status and the status summary provided by the applicant are appropriate to the extent that can be determined by the submission, including whether the study is proceeding in accordance with the original schedule; resolves any discrepancies or questions by contacting the applicant; provides the RPM as soon as possible with any resulting data corrections or changes for the regulatory database(s).
- If the PMCRS is an Annual Report/ PMC or a PMC Submission/Final Study Report, and the applicant does not amend the submission in the agreed upon time, the submission should be reclassified as a PMC Submission/Correspondence and the review clock stopped.
- If the final report is being reviewed, determines whether the applicant has fulfilled the commitment and contacts the RPM to initiate final action on the commitment, e.g., , written notification to the applicant. Discusses issues with the branch chief, division director, applicant and/or other reviewers as appropriate.
- Completes the PMC Annual Report Review Form for such submissions and returns it to the RPM to update RMS-BLA.
- Documents the review in writing, with any comments, questions or requests for additional information for the applicant.
- Following specific office procedures, obtains necessary clearances, assures that the RPM receives the review, and returns the submission and review to DCC either directly or through the division coordinator or RPM.
- References
- Appendix
- Effective Date
- History
The purpose of this document is to describe the procedures for administrative handling and regulatory review of postmarketing commitment (PMC) Annual Reports, Final Study Reports, and other PMC submissions to CBER for Biological License Applications (BLAs) and New Drug Applications (NDAs). This document also describes the process for reporting on the compliance of applicants with regard to PMC submissions as required by the Federal Food, Drug, and Cosmetic Act (the Act).
Postmarketing Commitment - Any written commitment made by an applicant before or after FDA has granted approval to market a product or approval of a supplement to conduct a post approval investigation. The commitment may be to conduct a study or studies, or to otherwise gather additional information about product safety, efficacy, or use; or to further evaluate chemistry or manufacturing issues. There are generally two types of Postmarketing Commitments:
506B Reportable Studies - Postmarketing studies for which applicants must submit annual reports under 506B of the Act and 21 CFR 601.70 (314.81(b)(2) for NDAs). All Required studies, and Agreed Upon clinical safety, clinical efficacy, clinical pharmacology, and non-clinical toxicology studies are 506B reportable. All other postmarketing commitments are "non-506B."
Postmarketing Commitment Related Submission (PMCRS) - A submission related to a PMC generated by approval of an application or supplement, or (rarely) in response to another type of submission (e.g., an annual report or product correspondence). Such submissions include:
The submission may be made to an IND or BLA/NDA, depending on the type of PMC submission.
Voluntary (Applicant Initiated) Postmarketing Study - A study initiated by an applicant without a request by FDA. Voluntary studies are not required or agreed upon postmarketing commitments
In the FDA Modernization Act of 1997 (FDAMA), Congress attempted to address concerns by FDA and patient/consumer groups about the timely completion of agreed upon PMC studies by drug and biologic manufacturers. FDAMA section 130 added section 506B to the Food, Drug and Cosmetic Act. Section 506B, Reports of Postmarketing Studies, requires applicants that have agreed to conduct a postmarketing study to submit annual reports to the Agency on the study's status until completed or terminated. Further, Section 506B requires FDA to publish annually in the Federal Register information on the compliance of the applicants with this reporting requirement.
In implementing Section 506B, CBER and CDER developed revisions to 21 CFR 314.81(b)(2)(vii) (NDA annual reporting requirements) and 21 CFR 601.37 (annual reports of postmarketing pediatric studies for biologics); and a new regulation (21 CFR 601.70) for annual progress reports of postmarketing studies for biologics.
Section 506B does not apply to animal drugs or biologics meeting the definition of a device under the Act. Further, the requirements for reporting under 21 CFR 601.70 are limited to postmarketing commitments that concern a biologic's clinical safety, clinical efficacy, clinical pharmacology, and non-clinical toxicology .
CBER requests postmarketing investigations when additional information is necessary to clarify, verify, or otherwise substantiate the identity, purity, potency, safety or efficacy of the product.
Applicant and CBER reporting requirements are detailed in FDA guidance for industry (see Section 8. References).
The procedures detailed in this document apply to all PMCs for licensed biologics (including licensed devices) and drugs regulated by CBER, whether or not they fall under Section 506B. They do not apply to PMCs for Premarket Device Applications (PMAs). Although all non-voluntary PMCs are tracked in CBER's databases, only the 506B (601.70 reportable) PMCs are required to be reported in the Federal Register and on the Web site.
Voluntary postmarketing studies, i.e. those that are not required or agreed upon, are not commitments and are not covered by this SOPP; such studies are generally not tracked in the regulatory databases or reported on.
| Postmarketing Study Type | Covered under this SOPP? | Tracked in RMS-BLA or BLT? | Annual Report required under 601.70 or 314.81? | Reportable by FDA under 506B? |
|---|---|---|---|---|
| Required (Accelerated approval and Deferred Pediatric) | Yes | Yes | Yes | Yes |
| Agreed Upon (clinical safety, clinical efficacy, clinical pharmacology, and non-clinical pharmacology ) | Yes | Yes | Yes | Yes |
| All other Agreed Upon studies (e.g., stability) | Yes | Yes | No* | No |
| Voluntary | No | No | No* | No |
* NDA regulations require that all PMCs be reported on in the 314.81 annual report, including non-506B PMCs and voluntary studies. 601.70 does not require reporting of these types of studies for biologics. Although voluntary NDA postmarketing studies are reported on, they are not tracked in CBER's databases.
| Person or Area | Responsibilities |
|---|---|
| Document Control Center (DCC) | |
| Division Director and/or Branch Chief | |
| Regulatory Project Manager (RPM) (or Office designated PMC Coordinator) | |
| Reviewer | |
| Regulatory Information Management Staff (RIMS) |
Initial Data Entry of PMC
When a BLA/NDA application or supplement is approved, any PMC described in the approval letter (or other communications referred to in the approval letter), must be entered into RMS-BLA. All data fields must be completed to allow accurate tracking and reporting. NDA PMCs are entered into BLT; however, since the system does not yet have specific fields for capturing PMCs, the comments fields should be used.
Ideally, there should only be one study per PMC, and the letter to the applicant describing the required or agreed upon PMCs should so list them, and they should be entered into RMS-BLA as individual PMCs.
See RMS-BLA Data Entry for Postmarketing Commitments and Related for detailed instructions on entering PMC information and updates in the licensing system.
Postmarketing Commitment Related Submissions
A PMCRS may be made to an IND, BLA or NDA as follows:
| PMCRS Type | IND (BIMS/BIRAMS) |
BLA (RMS-BLA) |
NDA (BLT)* |
|---|---|---|---|
| PMC Protocol | Amendment | PMC Submission/Correspondence | Correspondence (PMC Protocol) |
| PMC Annual Report (506B only) | Annual Report** | Annual Report/PMC | Correspondence (PMC Annual Report) |
| Status Update (non-506B) | Amendment | PMC Submission/Status Update | Correspondence (Status Update) |
| Final Study Report | Amendment** | Supplement or PMC Submission/Final Study Report | Supplement or Correspondence (Final Study Report) |
| All Other PMC Submissions | Amendment | PMC Submission/Correspondence | Correspondence (PMC Submission/Correspondence) |
* BLT does not yet have specific submission types for PMCRS. The submissions should be entered as Correspondence, and the type (e.g., PMC Protocol) should be entered in the comments field.
** PMC annual reports and final study reports must be submitted to the BLA or NDA. They may be submitted to the IND, but if they are, a submission must also be sent to the BLA or NDA referencing the IND submission.
Administrative Handling and Review of PMCRSs
The timeframes for reviewing PMCRSs, including administrative handling by the entire process team, are as follows:
Annual Report/PMC Annual Report: 3 months;
Final Study Report - PMC Submission/Final Study Report: 12 months;
Final Study Report - BLA/NDA Supplement:
- Standard Efficacy: 10 months
- Priority Efficacy: 6 months
- Prior Approval: 4 months (user fee products); 6 months (non-user fee)
- Changes Being Effected (CBE) or 30-Day CBE: 6 months.
Other types of PMC Submissions, such as those to INDs, status updates, correspondence, do not have review timeframes.
| Procedures for Processing PMCRSs |
a. Upon receipt of a PMCRS, DCC logs it into the appropriate regulatory database and processes it according to usual procedures for the type of submission: BLA PMC submission or Annual Report/PMC, NDA correspondence or annual report, BLA/NDA supplement, or amendment to an IND. DCC routes the submission to the Applications Division with product responsibility. |
b. Upon receipt of the PMCRS in the Applications Division, the RPM (or office designee): If the submission has not been adequately amended within a specified time period, the submission type is changed to PMC Submission/Correspondence in the regulatory database and the review clock stops. |
c. DCC routes the copies to the designated reviewer(s). |
The reviewer: |
d. The RPM initiates necessary action, including written communication to the applicant concerning FDA's evaluation of the final study report for 506B PMCs and an appropriate communication for non-506B PMCs (a letter must be sent if the applicant requests it), and ensures that the regulatory database is appropriately updated with regard to the PMC status. |
e. The RPM forwards the completed final action file, including the applicant's submissions and all CBER reviews, forms, and correspondence to DCC following the appropriate DCC Procedures Guides. |
Postmarketing Commitment Reports
Web Site Report
At the end of each quarter, the review offices assure that all information on PMCs is updated in the regulatory databases. This process is completed by a date announced by RIMS each quarter.
RIMS checks the system data and reconciles any discrepancies with the review offices.
RIMS drafts the Web site PMC Status Report update, which includes any manual entries necessary for NDAs, and at least two weeks before the web report is due, sends it to the application review offices for a final check. The offices are asked to respond within 10 working days.
Once all data corrections have been made, RIMS sends the required data for the Web site report electronically for posting on the CBER Web site. This is done by the last day of the first month of the quarter.
Federal Register Report
Annually, RIMS generates a summary PMC report for the Federal Register. The information for this report is derived from the quarterly Web site report data. The reports are based on the same procedures for checking and clearance, and have the same timeframes. The finalized report is sent to the designated Agency unit for drafting the Federal Register notice. RIMS assures the accuracy of the draft Federal Register notice with regard to CBER data.
Federal Food, Drug, and Cosmetic Act, Section 506B
21 CFR 314.81(b)(2), Other Postmarketing Reports (for NDAs
21 CFR 601.70, Annual Progress Reports of Postmarketing Studies
RMS-BLA Data Dictionary for End Users (available in the Resources Web Page under the Help menu in RMS-BLA.)
RMS-BLA Data Entry for Postmarketing Commitments and Related Submissions
Instructions for Completing the PMC Annual Report Review Form (PARRF) (PDF, 71 KB)
January 28, 2008
| Written/Revised | Approved | Approval Date | Version Number | Comment |
|---|---|---|---|---|
| O'Leary/RIMS | Robert A. Yetter, PhD | January 28, 2008 | 4 | Reference and form were updated to reflect database changes |
| Eastep/RIMS | Robert A. Yetter, PhD | April 13, 2007 | 3 | Updated procedures and clarifications of previous version |
| Eastep/RIMS | Robert A. Yetter, PhD | August 21, 2006 | 2 | Revisions to reflect changes in reporting procedures |
| Eastep/RMCC | Robert A. Yetter, PhD | January 16, 2001 | 1 | Original version |