Manual of Standard Operating Procedures and Policies

Regulatory - License and Drug Applications
Procedures for Developing Postmarketing Requirements and Commitments
SOPP 8415	Version #1	Date: September 15, 2008

Purpose

This SOPP defines postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for drugs and biologics and describes the policies and procedures to be used by the Center for Biologics Evaluation and Research (CBER) staff to develop them. This SOPP provides documentation of the PMR/PMC processes, roles, and responsibilities. It spans the timeframe from reviewer identification of an issue in a product application that could potentially lead to a PMR/PMC to the time the PMR/PMC is documented in the signed product approval letter or another letter to the applicant subsequent to approval.

This SOPP (and the corresponding Center for Drugs Evaluation and Research Manual of Policies and Procedures (MaPP)) is intended to improve consistency, when appropriate, in PMRs/PMCs that are required or agreed upon across divisions/offices and across centers. It is also intended to improve clarity and transparency by documenting the rationale for the PMR/PMC, ensuring that the PMR/PMC is clearly written, and following Good Review Management Principles and Practices (GRMPs) recommendations for discussion of PMR/PMCs with the applicant prior to the action goal date.

This SOPP applies to the development of all:

PMRs
Agreed-upon 506B PMCs
Agreed-upon non-506B commitments (i.e., CMC and stability).

This SOPP does not:

Address a product-specific determination regarding whether a study or clinical trial should be conducted pre-approval or if it can be conducted as a PMR/PMC;
Address the type of study/clinical trial or level of evidence needed to fulfill a PMR/PMC;
Describe the criteria for determining whether a postmarketing study or clinical trial should be a PMR or a PMC.
Include procedures and responsibilities for PMR/PMC tracking and review (i.e., after a PMR/PMC is issued). Those topics are addressed in SOPP 8413: Postmarketing Commitment Related Submissions – Administrative Handling, Review, and CBER Reporting
Describe the criteria for determining non-compliance with the conduc t of PMRs or the required reporting for PMRs/PMCs.
Apply to biological products that meet the definition of device under Section 506B of the Federal Food, Drug, and Cosmetic Act (“the Act”), i.e., devices under PMAs, 510k’s, or BLAs.

Background

In the past, FDA has used the term “postmarketing study commitments (PMCs)” to refer to studies or clinical trials conducted by the applicant after FDA has approved a product for marketing/licensing that are intended to further refine the safety, efficacy or optimal use of a product, or to ensure consistency and reliability of product quality. These commitments were either agreed-upon by the FDA and the applicant, or required by FDA in the following situations:

Accelerated approval confirmatory studies (21 CFR 314.510/Subpart H and 601.41/Subpart E), where subsequent studies are required to describe and verify clinical benefit
Deferred pediatric studies (21 CFR 314.55(b) and 601.27(b)), where studies are required under the Pediatric Research Equity Act (PREA)
Animal Efficacy Rule Clinical Efficacy and Safety Studies (21 CFR 314.610(b)(1)/Subpart I and 601.91(b)(1)/Subpart H), where studies to demonstrate safety and efficacy in humans are required at the time of use

Section 130(a) of Title I of the Food and Drug Administration Modernization Act of 1997 (FDAMA) added a new provision (section 506B) to “the Act” which mandated applicants to report annually on the status of required and agreed-upon PMCs [see Definitions] and obligated FDA to make certain information about PMCs publicly available.

In 2007, Section 901 of the Food and Drug Administration Amendments Act (FDAAA) created section 505(o) of the Act which authorized FDA to require postmarketing studies or clinical trials at the time of approval, or after approval if FDA becomes aware of new safety information. FDAAA states that studies and clinical trials may be required for one of three purposes:

To assess a known serious risk related to the use of the drug
To assess signals of serious risk related to the use of the drug
To identify an unexpected serious risk when available data indicates the potential for a serious risk

In 2006, FDA commissioned a study of PMC-related processes by Booz Allen Hamilton (BAH), as part of its continuous improvement effort for the drug and biologic review process. The study reviewed the PMC development process in order to identify ways to improve the decision-making process. The final study report identified two main areas for improvement in the PMC development process: communication of the review issues and proposed PMCs to the applicant earlier in the review process, and increased consistency and transparency of the decision-making process through better documentation.

Under PDUFA IV, FDA was obligated to draft harmonized standard operating procedures, to be finalized by the end of FY 08, that articulate the Agency's policy and procedures (e.g., timing, content, rationale and vetting process) for requesting postmarketing study commitments. When developing the procedures described in this SOPP, CBER took into consideration the findings of the BAH study of current Agency procedures as required under PDUFA IV, and the MaPP being developed by Center for Drug Evaluation and Research.

A recommendation in the BAH Quality System Framework document based on the study findings was to create a “PMR/PMC Development Coordinator” role as an important part of the process to help assure that PMRs/PMCs that were agreed upon with or required of the applicant were appropriate and consistent across offices. Because of its organizational structure and review processes, CBER determined that the responsibilities of the Development Coordinator role could best be carried out by supervisors within the existing review activities without adding another individual to the process.

The scope of this SOPP was extended to include new FDAAA-related procedures. The following table summarizes the scope of this SOPP.

PMR/PMC Categories	Types	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 Studies/Clinical Trials	Accelerated Approval (21 CFR 314.510 Subpart H and 601.41 Subpart E)	Yes	Yes	Yes	Yes
	Deferred Pediatric (21 CFR 314.55(b) and 601.27(b))	Yes	Yes	Yes	Yes
	Animal Efficacy ( 21 CFR 314.610(b)(1) and 601.91(b)(1))	Yes	Yes	Yes	Yes
	FDAAA Safety (Section 901)	Yes	Yes	Yes	Yes
Agreed Upon Studies/Clinical Trials	Clinical Safety, Clinical Efficacy, Clinical Pharmacology, and Non-Clinical Pharmacology (Section 130 FDAMA, 506B of FD&C Act)	Yes	Yes	Yes	Yes
All other Agreed Upon Studies	CMC, Stability, etc.	Yes	Yes	No*	No
Elective Studies**	N/A	No	No	No*	No

* NDA regulations require that all PMCs be reported on in the 314.81 annual report, including non-506B PMCs and elective studies. 601.70 does not require reporting of these types of studies for biologics. Although elective NDA postmarketing studies are reported on, they are not tracked in CBER's databases.

** Non-requested, non-required studies that the applicant has or plans to initiate on its own with generally no expectation that the results will be submitted to FDA.

Definitions

Postmarketing Commitment (PMC) – Any commitment to obtain additional information to further the knowledge of the effective use of a product that an applicant has agreed, in writing, post-approval of a marketing/licensing application or supplement. These are not PMRs. The commitment may be to conduct a study(s) or clinical trial(s), or to otherwise gather additional information about product safety, efficacy, or use; or to further evaluate chemistry or manufacturing issues. The agreement may be reached before or after approval of the application or supplement.
Postmarketing Requirement (PMR) – Any study or clinical trial that an applicant is required to conduct post-approval of a marketing/licensing application or a supplement. Studies or clinical trials may be required under PREA (21 CFR 14.55(b) and 601.27(b)), Animal Rule ( 21 CFR 314.610(b)(1) and 601.91(b)(1)), Accelerated Approval (21 CFR 314.510 and 601.41), or FDAAA (Title IX, Section 901) (section 505(o)(3)(A) of “the Act.
Clinical Trial/Study – For the purposes of implementing Section 901 of FDAAA, clinical trials and studies are defined as follows:

Clinical trial: any prospective investigation in which the applicant or investigator determines the method of assigning treatment or other interventions to one or more human subjects.
Study : any other investigation, such as an investigation in humans that is not a clinical trial as defined above (e.g., an observational epidemiologic study), an animal study, or a laboratory experiment.

506B-Reportable Postmarketing Commitments – Postmarketing studies or trials for which annual status reports must be submitted by the applicant. These studies or trials concern clinical safety, clinical efficacy, clinical pharmacology, or nonclinical toxicology that applicants have agreed to or are required to conduct as described in FDAMA section 130:

Clinical Safety – Human studies intended to gather additional information on the safety of a product, e.g. at different dosage levels. These include immunogenicity studies intended to further define an immune response elicited by the introduction of an antigen (e.g., protein).
Clinical Efficacy – Human studies intended to further characterize the effectiveness or optimal use of a product.
Clinical Pharmacology – Human studies to further determine the effects of the product on the body including pharmacokinetics (what happens to the product while in the body), pharmacodynamics (the effects of the product, as pertaining to a subject’s biochemistry and physiology), toxicity, and drug interaction.
Non-Clinical Toxicology – Non-human studies (e.g., animal studies, in vivo animal models) to further characterize carcinogenicity, teratogenicity, reproductively toxicology, biopharmaceutic and pharmacokinetic properties of a product.

FDA is required to make certain information about these PMCs publicly available.

PMR/PMC-Related Submissions – A formal applicant submission sent to address an established PMR/PMC Such submissions may include:

PMR/PMC Protocols
PMR/PMC Correspondence/Status Updates
Annual Status Reports
Final Reports
Application supplements submitted to address a PMR/PMC

PMR/PMC Schedule Milestones – The specific study schedule dates for completing activities related to conducting a PMR/PMC. Note that these milestones were originally established for 506B PMCs under FDAMA. Although FDAAA has a reporting timetable for PMRs, these PMC milestones will likely also be applicable to PMRs.

The applicant must report a PMR’s/PMC’s status in each annual status report according to the original study schedule that was established for the PMR/PMC. These dates should be captured and updated as necessary in the PMR/PMC section of CBER’s regulatory database, and may include:

Final protocol submission date
Study/clinical trial initiation date or time frame with reference to the final protocol submission date (e.g., X months after final protocol submission)
Completion of patient or subject accrual date or a date in relation to another milestone listed above (e.g., X months after final protocol submission or Y months after study/trial initiation)
Study/trial completion date or a date in relation to another milestone listed above (e.g., X months after final protocol submission or Y months after study/trial initiation)
Projected final report due date or a date in relation to the actual completion date (e.g., within X months from completion)

Timetable for Completion of PMR Safety Studies – FDAAA Required Studies (505(o))

For each study:

A report of the status of the study, including whether any difficulties in completing the study have been encountered

For each clinical trial

A report of the status of the trial, including whether enrollment has begun and whether any difficulties in completing the trial have been encountered
The number of participants enrolled
The expected completion date
Registration information with respect to the requirements under section 402(j)

Policy

CBER will:

Develop and communicate all PMRs/PMCs using a standardized process;
Meet the recommended PMR/PMC communication goals of the GRMPs by notifying the applicant of the planned communication timeline for PMR/PMC discussions (e.g., three weeks before Office/Division sign-off) in the filing letter, if possible;
Communicate issues that may lead to PMRs/PMCs to the applicant as early as possible in the review process, to facilitate discussion of these issues prior to the action goal date;
Document all discussions and agreements with the applicant relating to PMRs/PMCs as per the appropriate CBER SOPPs;
Review the rationale for a PMR/PMC. A PMC that must be agreed-upon between FDA and the applicant will be requested only if the objectives are important to further the knowledge of the effective use of a product. Those studies not required or requested by the FDA but that the sponsor has chosen to do will not be included in the approval letter nor tracked in the PMR/PMC database;
Review each PMR/PMC within the Office/Division to ensure it is consistent with the PMR/PMC decision process applied for all PMRs/PMCs within the Office/Division and across the Center;
Review each PMR/PMC within the Office/Division to ensure that it is clearly written, will have a stated end date, and will result in timely submission of the appropriate data to address the issue that prompted the PMR/PMC;
Not request a PMR/PMC for a study/clinical trial that is covered by other regulations (e.g., safety data updates or adverse event reporting). However, there may be specific circumstances where an exception needs to be made. In those situations, the rationale for the PMR/PMC will be documented and archived electronically;
Collaborate with the applicant on the proposed schedule for each PMR/PMC until there is agreement. For FDAAA PMRs, agreement with the applicant does not have to be reached; CBER may unilaterally determine the schedule;
Include a clear and concise justification for the determination as to whether a postmarketing commitment or requirement is needed, as well as whether the study/trial will be 506B reportable or not. Use of the Development Template in Appendix B is encouraged to ensure consistency in review, presentation and ultimately documentation.

Responsibilities and Procedures

The following sections outline the responsibilities regarding the development and decision-making process for a PMR/PMC. A high-level graphic summary of the process is provided in Appendix A.

PMR/PMC Overall Responsibilities

Center Director, Associate Director for Review Management

Ensure that the PMR/PMC development process steps, as defined in this SOPP, are implemented consistently across the Center
Provide an opportunity for Office Directors/Division Directors to share updates on any PMR/PMC development process issues or changes on a periodic basis

Associate Director for Review Management

Support continuous process improvement by coordinating the development of appropriate guidance as well as updates to applicable SOPPs
Provide process support and training to the review Offices, Divisions, and Branches

Office Directors, Division Directors (depends on who has application or supplement approval authority)

Ensure that staff are aware of and adhere to established policies regarding PMR/PMC development
Ensure that adequate resources can be committed to future tracking and review of each PMR/PMC established
Receive periodic updates on PMR/PMC status within the Office
Provide concurrence on all PMRs/PMCs prior to issuing the Action Letter

Branch/Lab Chief

Ensure that a clear and concise rationale for requiring or recommending a PMR/PMC is clearly described in review documentation
Ensure that the PMR/PMC description clearly communicates the objectives of the PMR/PMC in order to be adequately addressed by the applicant
Ensure that the review staff resolve differences with the applicant, if any, between the objectives, study/clinical trial design and study/clinical trial schedule milestones of the draft and final PMRs/PMCs
Ensure that all PMRs/PMCs are applied consistently across the Review Office/Division and meet the general policy guidelines in this SOPP
Ensure that the PMR/PMC development and communication procedures are followed by the review team (e.g., timely notification of PMR/PMC review timelines)
Review and reach agreement on the PMR/PMC rationale (documented by the Reviewer) and study schedule milestones as part of the review sign-off. Ensure that the final study schedule is both feasible and reasonable
Provide concurrence of the list of PMRs/PMCs before they are sent to the applicant via the Regulatory Project Manager (RPM)
Support and/or participate in a forum (e.g., quarterly meetings) where PMRs/PMCs are reviewed for lessons learned and consistency across the organization

Reviewers

Fully describe in the review a clear and concise rationale for each PMR/PMC to provide historical background for future reviewers of PMR/PMC-related submissions for the product
Draft the list of PMRs/PMCs and circulate to the Branch/Lab Chief(s) for review/concurrence prior to communication to the applicant by the RPM. Ensure that the PMR/PMC description clearly communicates the objectives of the PMR/PMC for the applicant to address
Review and resolve differences, if any, between the objectives and study schedule milestones after the draft list of PMRs/PMCs have been circulated

Regulatory Project Managers (RPMs)

In the filing letter, provide the applicant with the timeframe for when PMR/PMC discussions are tentatively planned to begin
Send the draft PMRs/PMCs to the applicant as specified in GRMPs
Ensure that each PMR/PMC is drafted and numbered sequentially in the approval or PMR/PMC letter in accordance with the appropriate letter template
Check to ensure that the PMR/PMC tracking system is populated post-approval with the required and/or agreed-upon PMRs/PMCs, including the study schedule milestones
Coordinate review-specific communications (e.g., protocol review comments from the review team) with the applicant for PMR/PMC content-related issues pre– and post-approval

PMR/PMC Tracking Coordinators (RPM or other designated persons)

Once a PMR/PMC is entered into the PMR/PMC tracking system by the Regulatory Information Management Staff, assumes tracking responsibilities for the PMR/PMC until it is released or fulfilled according to SOPP 8413 - Postmarketing Commitment Related Submissions – Administrative Handling, Review, and CBER Reporting

Regulatory Information Management Staff (RIMS)

Provide the status of the process implementation to Center Director, Associate Director for Review Management and Office Directors/Division Directors on a periodic basis
Conduct periodic process audits to determine compliance with the defined policies and procedures

PMR/PMC Development Procedures

Identify potential PMR/PMC review issue(s) for internal discussion and inform applicant of issue

The following outlines the initial steps after a review issue has been identified, but a decision about whether a PMR or PMC is needed has not been made. A reviewer from any discipline may identify a potential PMR/PMC review issue and should discuss the issue with his/her Branch/Lab Chief in addition to the rest of the review team. The review team may first request clarification or additional information from the applicant before a final decision on PMR/PMCs is made.

Reviewers

Identify potential PMR/PMC review issue(s) and discuss with the review team, Branch/Lab Chief(s) and Office Directors/Division Directors; determine how the issue(s) should be communicated to the applicant (i.e., as a potential PMR/PMC or a request for more information)

Branch/Lab Chief

Participate in discussions and provide input on potential PMR/PMC review issue(s) being discussed by the review team
Ensure that all potential review issue(s) are discussed internally prior to the date specified in the filing letter

Office/Division Director

Ensure that all potential PMR/PMC review issue(s) are discussed internally prior to the date specified in the filing letter
Participate in the discussions of the review issue(s) and how they should be communicated as appropriate

RPMs

Communicate potential PMR/PMC review issue(s) with the applicant as soon as possible in the review cycle

Discuss Review Issue with Review Team and Draft PMR/PMC

This process describes identifying review issue(s) and clearly documenting rationale for PMR/PMC and the vetting process prior to communicating these issues to the applicant.

Reviewers

Discuss review issue(s) with review team and Office/Division Director; decide if the issue(s) will result in a PMR or PMC
Document technical rationale for each PMR/PMC in the review. It is recommended that the PMR/PMC Development Guide be used to help determine whether the proposed postmarketing study/clinical trial would be appropriate, and whether it should be a PMR or PMC (see Appendix B)
Draft the PMR/PMC, ensuring that the description clearly communicates the objective and necessary study design details for applicant review and agreement, provide the draft to Branch/Lab Chief(s) for concurrence. See PMR/PMC Schedule Milestones under 2. Definitions for the milestones that should be established when proposing or requesting schedule milestones dates from the applicant
Revise draft PMR/PMC as needed based on feedback from Branch/Lab Chief

Branch/Lab Chief

Review the stated objectives and schedule milestones for clarity and appropriateness for each PMR/PMC
Review the draft PMRs/PMCs for clarity, consistency, feasibility (e.g., study schedule, if proposed by reviewer), importance of objectives to the knowledge of the safe and/or effective use of the product, applicability of FDAAA or other regulations, and level of effort (i.e., value to FDA to commit resources to track and review PMR/PMC)
Document the PMR/PMC deficiencies/concerns, if any, and communicate them to the reviewer
Provide concurrence for the draft list of PMRs/PMCs before they are sent to the applicant via the RPM
Route the PMRs/PMCs to the Office/Division Director for concurrence

Office/Division Director

Review the draft list of PMRs/PMCs and provide comment/concurrence

RPMs

Once the draft list of PMRs/PMCs has been vetted through the Branch/Lab Chief(s) and Office Directors/Division Directors, compile the draft list of PMRs/PMCs from all disciplines for conveyance to the applicant

Provide draft PMRs/PMCs to Applicant and discuss as needed

During this part of PMR/PMC development, the goals and objectives of the studies or clinical trials may be discussed and refined. Schedule milestones are generally proposed by the applicant and should be reviewed and evaluated by the review team.

Branch/Lab Chief

Participate in discussions when PMRs/PMCs content and schedule milestones are being negotiated by the review team and applicant

Reviewers

Work with the RPM, discipline review offices, and applicant to discuss PMR/PMC content
If schedule milestones were not previously suggested to the applicant, review the applicant’s proposed milestones to determine if they are feasible and reasonable (e.g., final protocol submission date, study initiation date, completion of patient accrual date, projected completion date, final study report submission date, or other dates as necessary).

RPMs

Provide draft PMRs/PMCs to applicant at time specified in GRMPs
Request written agreement from applicant to conduct study(ies)

Office/Division Director

Participate in discussions when PMR/PMC content and schedule milestones are discussed by the review team and applicant as needed

Finalize List of PMRs/PMCs and Schedule Milestones

This process is to resolve outstanding issues concerning the study schedule and to gain final concurrence for inclusion into the approval letter.

RPMs

Collate final list of PMRs/PMCs
If differences are identified, resolve differences with the respective discipline reviewer for resolution

Reviewers

Address/resolve differences, if any, between the draft and final lists of PMRs/PMCs
If study schedule milestones were not previously proposed to the applicant, review the applicant’s study schedule milestones to determine if they are both feasible and reasonable
Provide final list of PMRs/PMCs and study schedule milestones to the Branch/Lab Chief(s) for final concurrence

Branch/Lab Chief

Ensure that differences, if any, between the objectives and study schedule milestones of the draft and final lists of PMRs/PMCs, are addressed and resolved by the review team
Review final PMR/PMC description and schedule milestones for clarity, feasibility, and consistency with other similar PMRs/PMCs
Provide concurrence for the final list of PMRs/PMCs, including schedule milestones, and route to the Division Directors

Office/Division Director

Provide concurrence for the final list of PMRs/PMCs, including schedule milestones, for inclusion in the approval letter by the RPM.

Include PMRs/PMCs in Approval or PMR/PMC Letter

Document finalize list of PMRs/PMCs in the approval or PMR/PMC letter by uniquely identifying each PMR/PMC according to the template letters located on CBER’s Letter Template web page.

RPMs

Ensure that each PMR/PMC is numbered sequentially in the Approval or PMR/PMC Letter by following the template letters
Consult with the RIMS as needed to review PMR/PMC description for appropriate wording/details
Finalize approval letter using the content/format specified in the standardized letter templates
Ensure that the PMR/PMC Tracking Coordinator and RIMS is provided a copy of the final FDA approval or PMR/PMC letter

Enter PMRs/PMCs into PMR/PMC Tracking System

This process describes entering the PMRs/PMCs into the PMR/PMC tracking system. RIMS must receive all letters that contain newly established PMRs/PMCs

RPMs

Ensure approval/ PMR/PMC letter is processed in the appropriate regulatory database

RIMS

Enter all newly established PMRs/PMCs into the PMR/PMC tracking system according to established procedures and ensure all relevant fields for tracking purposes are populated (e.g., PMR/PMC description, study schedule milestones, and other PMR/PMC properties)

PMR/PMC Tracking Coordinator

Perform a quality check to ensure that the PMR/PMC tracking system has been populated with all the required and/or agreed-upon PMRs/PMCs documented in the approval/ PMR/PMC letter, including the study schedule milestones
For PMRs/PMCs with dates that refer to other study schedule milestone dates (e.g., study initiation must occur within X months of final protocol submission), ensures that once the first referenced date has occurred (e.g., final protocol submission), all subsequent dates are calculated and captured in the PMR/PMC tracking system as actual dates and provided as a reminder to the applicant in a letter

Appendices

Appendix A – PMR/PMC Development Process (PDF, 28 KB)

Appendix B – PMR/PMC Development Guide (PDF, 33 KB)

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References

References that may be useful for the process in developing PMR/PMCs:

Effective Date

September 15, 2008

History

Comment / Revision	Approved By	Approval Date	Version Number	Comment
Eastep/RIMS	Robert A.Yetter, PhD	9/12/2008	1	Original

Manual of Standard Operating Procedures and Policies

Regulatory - License and Drug Applications

Procedures for Developing Postmarketing Requirements and Commitments

SOPP 8415

Version #1

Date: September 15, 2008