In July 2023, the FDA released draft guidance describing the factors that FDA considers, as well as actions the FDA may take, when applicants are noncompliant with certain post-marketing requirements (PMRs) for prescription drugs.1
Under section 505(o)(3) of the FD&C Act, the FDA may require a Post Marketing Requirement (PMR) at the time of approval or if there is new safety information. The applicant is then responsible for providing a timetable for study completion and milestones, which generally includes the date that the applicant will submit the final protocol and the date that the last subject enrolled in the study completes the last observation or evaluation. Interim milestones may also be included. When a milestone is missed, the FDA considers the applicant to be noncompliant, unless the applicant can adequately demonstrate good cause to the satisfaction of the FDA.
Noncompliance is subject to enforcement action by the FDA, which may involve:
- Issuance of a warning letter (which is posted on the FDA’s website) or an untitled letter (which does not quite meet the regulatory significance of a warning letter);
- Misbranding charges;
- Civil monetary penalties not more than $250,000 per violation, and not exceeding $1,000,000 for all violations in a single proceeding. If the violation continues, amounts can double every 30 days.
Manufacturers often struggle to comply with PMRs for a variety of reasons: Submission of proposed protocols that the FDA considers unsatisfactory to address the PMR, applicant resource constraints (e.g., labor, resource allocation, time), inadequate patient recruitment, failure to complete data analyses relevant to inform study completion, and submission of data that the FDA finds inadequate to address the original intent of the PMR.
However, sponsors can implement successful post marketing compliance strategies by leveraging an experienced partner to implement a proactive plan to navigate the post marketing study landscape resulting in compliance with FDA guidance:
- Submitting a well-organized and complete protocol in advance of the final protocol submission milestone.
- Meeting the trial completion milestone by ensuring adequate subject recruitment and completion of prespecified and feasible interim data analyses.
- Meeting the final report submission deadline.
In addition to adequate pre-planning, and careful ongoing monitoring, proactively engaging the FDA is a good rule of thumb, particularly when it looks like a milestone may be missed. This will help smooth follow-on discussions around extensions or support rationale for why a study cannot be completed.
Sponsors can rely on UBC with expertise and experience in planning and managing PMRs. Specifically, UBC can support PMR study design and execution through:
- Protocol development and drafting of subsequent amendments as needed.
- Study design, incorporating forward thinking decentralized study designs involving modern technology to optimize data acquisition and reduce patient and Health Care Provider burden.
- Study start-up planning, including a site enrollment plan, a data management plan, and a risk management plan that includes mitigation.
- Patient engagement, ensuring that there is adequate site support and patient support consistent with study needs, including recruitment, engagement, and retention tactics. Also, data collection should be kept to a minimum to keep the burden low.
- Data analysis and report development
- Project management, including careful ongoing monitoring. Partners can develop dashboards to track progress and identify risk areas for follow-up.
- Agency engagement, supporting a sponsor’s proactive engagement with the FDA when a milestone is going to be missed.
UBC has more than 30 years of experience in operationalizing real-world, late phase studies, including studies to meet PMRs. The UBC team includes operational experts, dedicated project managers, data scientists, epidemiologists, technologists, site managers, clinical nurses, and patient and physician service providers, bringing full end-to-end support to meet all PMR study needs.
About the Authors
Judith Lytle, PhD, MBEE, PMP, is the Executive Director of Real-World Evidence Study Solutions at UBC. She utilizes her extensive expertise to help biopharma develop evidence generation strategies, powered by rigorous science, that are designed to demonstrate value.
Bruce Smith, PharmD, is the Executive Director or Clinical Research at UBC. He has a unique understanding of the real-world landscapes in rare diseases, implementation of expanded access programs and clinical studies, and application of real-world evidence to meeting post-marketing requirements.
- S. FDA. Postmarketing Studies and Clinical Trials: Determining Good Cause for Noncompliance with Section 505(o)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act Draft Guidance for Industry. Accessed 08/04/2023. https://www.fda.gov/media/170187/download