Historically, postmarket surveillance (PMS) has not been an area of focus for many medical device manufacturers. However, recent FDA PMS guidance (2016) has established stringent PMS requirements that have changed that thinking. The FDA is imposing specific requirements for PMS methodology instead of reliance on quality metrics on patient use such as complaints, MDRs etc.
The goal of the new PMS requirements is to identify product safety issues as early as possible, therefore lessening the impact on patient and user safety. Manufacturers face some major compliance challenges due to the introduction of these new PMS requirements. It is critical to understand and integrate the PMS programs into current systems and procedures to maintain compliance with current PMS regulations and guidance.
FDCA Grants the FDA Greater Authority
The Federal Food, Drug, and Cosmetic Act (FDCA) provides the FDA with the authority to require manufacturers to conduct PMS of certain class II or class III devices. However, the FDA has consistently noted that PMS is not a substitute for obtaining the necessary premarket information to support 510(k) clearances, PMA, HDE, or PDP approval, or grant of de novo order.
The Food and Drug Administration Safety and Innovation Act (FDASIA) specified that the agency may issue a PMS order at the time of device approval or any time thereafter. Under what’s known as a “522 order,” the FDA can call on companies to conduct such PMS studies. (Please note that these PMS studies are separate from the FDA’s requirement that manufacturers conduct post approval studies and data on PMA devices as a condition of approval.)
Section 522 of the FDCA provides the FDA with a broader authority to require PMS for class II and class III devices, and requires these studies once products are on the market. Additionally, the FDA can request PMS data on pediatric devices according to the Amendments to Section 522 of the FDCA. This amendment is also applicable to devices that are not just labeled for use in the pediatric population, but is expected to be used in the pediatric population whether or not it is labeled as such.
Exploring ‘Section 522’
Section 522 of the Act, 21 U.S.C. § 3601, authorizes the FDA to require PMS for a class II or class III device at the time of approval of a device or at any time thereafter, in the following instances:
- Failure of the device would be reasonably likely to have a serious adverse health consequence
- The device is expected to have significant use in pediatric populations
- The device is intended to be implanted in the body for more than one year
- The device is intended to be a life-sustaining or life-supporting device used outside of a user facility
Manufacturers are required to submit a PMS plan to the FDA within 30 days of receipt of a 522 order. What’s more, surveillance must be initiated no later than 15 months after the day the order is issued. The 2016 guidance document describes the content of the plan as very similar to a vigorous clinical investigational plan. The PMS plan must meet the requirements of 21 CFR § 822.9 and § 822.10 and include the timing of the study, as well as the study completion dates.
There are numerous types of PMS designs that may be used including randomized clinical trials, prospective and retrospective cohort studies, cross-sectional studies, enhanced and active surveillance, meta-analyses, and bench and animal studies. In addition, prospective and retrospective real-world data (RWD) can be utilized as part of the surveillance data.
Considerations for use of Real World Data
The FDA issued the Real World guidancein August 2017 to clarify how the FDA evaluates RWD to determine whether it is sufficient for generating the types of real-world evidence (RWE). The guidance describes the conditions for which RWD may be used to support FDA decisions. This guidance can and should be used when drafting PMS programs since the FDA highlights that as a potential use of RWD. It also describes factors the FDA considers when evaluating whether specific RWD is of sufficient quality to inform or support a regulatory decision.
The guidance describes examples of RWD, such as data derived from electronic health records (EHRs), claims and billing data, data from product and disease registries, patient-generated data (including in home-use settings), and data gathered from other sources that can inform on health status, such as mobile devices.
This information is desirable for inclusion in the PMS plans in that the usage, and potential benefits or risks, of a medical device are critical to any comprehensive PMS surveillance program. Manufacturers can benefit from RWD as it may fulfill specific FDA PMS criteria, which subsequently can reduce the regulatory hurdles when designing prospective PMS clinical studies.
Once submitted, the FDA has 60 calendar days to determine if a PMS plan is administratively complete, and determine if the proposal provides evidence to address the surveillance criteria. FDA may issue one of the following decision letters for the proposed surveillance plan:
- Not Acceptable Letter, which is when a submission is found to be administratively incomplete (CDRH offers a checklist for determining whether a submission is administratively complete in the guidance)
- Approval Letter
- Minor Deficiency Letter, which cites specific minor deficiencies that must be addressed in order for a plan to be approved
- Major Deficiency Letter, which would include serious deficiencies that must be addressed
- Disapproval Letter, which means the FDA has determined it is not likely the surveillance plan will result in the collection of useful data to address the postmarket questions. This letter also directs the manufacturer to provide an entirely new submission to address the post-market questions
The guidance states that during the review period, the FDA is willing to interactively discuss surveillance plans. Therefore, it is recommended that manufacturers work interactively with FDA to finalize the PMS plan to ensure data collection can be initiated within 15 months from the date the 522 order was issued.
Manufacturers have an option to meet with the Office Director of FDA’s Office of Surveillance and Biometrics if they disagree with FDA about the content of the plan or if the plan is disapproved. In addition, under 21 CFR 10.75 the manufacturer can request an informal hearing or a review by the Medical Devices Dispute Resolution Panel of the Medical Devices Advisory Committee.
Enforcement action may be taken if a manufacturer fails to meet the requirements for obtaining PMS plan approval and commence PMS within 15 months after a 522 order is issued. Utilizing the interactive review time to design and negotiate the PMS plan should ensure that it will meet the objectives of both the manufacturer and the FDA and evade any enforcement actions.
It is recommended that manufacturers utilize the 2016 PMS Guidance as well as the 2017 Real World Guidance to obtain critical information on designing and maintaining PMS programs. Information available on completed post-approval studies and 522 studies on the FDA’s website is limited, but can be referenced during this process. The PMS and RWE guidance documents provide sound guidance and a solid strategy for the design of PMS programs using well-crafted clinical investigational plans in parallel with real world evidence.
- Postmarket Surveillance Under Section 522 of the Federal Food, Drug, and Cosmetic Act Page 1 of 22 Guidance for Industry and Food and Drug Administration Staff GUIDANCE Issued on May 16, 2016. The draft of this document was issued on August 16, 2011. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm268141.pdf
- Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices 1 Guidance for Industry and Food and Drug Administration Staff Document issued on August 31, 2017 –https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf