Post-Market Clinical Follow-up: Best Practices for PMCF

How to meet PMCF regulatory requirements as quickly as possible

Post-market clinical follow-up is increasingly being criticized by the notified bodies. And this is after the manufacturers have successfully mastered the hurdle before: the initial clinical evaluation.

This article provides manufacturers of medical devices with

• a quick overview of the regulatory requirements for PMCF,
• a description of the key methods used in post-market clinical follow-up, and
• tips to avoid the most common non-conformities and, therefore, unnecessary delays and costs.

1. PMCF: The basics

a) Objective and definition

The MDR requires manufacturers to demonstrate the safety, performance, and benefits of their medical devices throughout the product lifecycle as part of the clinical evaluation. This evidence also requires clinical data. Consequently, manufacturers must collect and evaluate this clinical data throughout the complete product life cycle.

This continuous process of updating the clinical evaluation (and thus updating the clinical data) is called post-market clinical follow-up. This is also how it is defined in Part B of Annex XVI of the MDR:

An assessment of whether the identified risks are still acceptable or whether new risks have been identified is part of the PMCF.

b) Distinction

The PMCF is a subset of post-market surveillance (PMS). PMS involves collecting all types of information from the field, such as service reports, hotline calls, customer complaints, etc. The objectives of PMS are broader than the objectives of PMCF.

2. Regulatory requirements

a) General requirements

Many jurisdictions require the continuous collection and evaluation of clinical data. However, the concept of post-market clinical follow-up comes from the MDR. This EU regulation requires in Article 10, paragraph 3, that clinical evaluation include post-market clinical follow-up of medical devices.

In Annex II, paragraph 6.1 (d) of the MDR, both the plan and the report of the post-market clinical follow-up (PMCF) are counted as clinical data. The documents are, therefore, part of the technical documentation of a medical device under the requirements of the MDR.

b) Requirements for the process

PMCF is conducted according to a methodology outlined in a post-market clinical follow-up plan. The MDR requires in Annex XIV, Part B, 6.1:

The notified body must verify that the PMCF plan and its implementation are adequate.

This review of the clinical evaluation by the notified body also includes the manufacturer's procedures and documentation of PMCF measures, as well as justification for noncompliance with the PMCF, if applicable.

c) Requirements for the documentation

Documents overview

Notified bodies review in their clinical evaluation assessment report (CEAR) whether a PMCF plan is listed and PMCF activities are documented in a PMCF evaluation report:

To meet these objectives, the Medical Device Coordination Group (MDCG) provides medical device manufacturers with important guidance on PMCF documentation.

PMCF plan according to MDCG 2020-7

The template for a post-market clinical follow-up (PMCF) plan - a guide for manufacturers and notified bodies (MDCG 2020-07) comprises 12 pages that can be filled out by the manufacturer in a product-specific manner. The information is always requested in table format.

Section C lists the PMCF activities planned for the medical device. In doing so, manufacturers should first identify the objective of each PMCF activity and then provide a rationale for its appropriateness. It is also necessary to indicate deadlines within which the activities are to be performed. These deadlines should be quarterly or at least annually.

The template gives examples of PMCF activities that include the following:

• medical device registry – search
• PMCF study
• real-world evidence ("real-world evidence").
• surveys

For each activity, add,

• from which document the claim of the planned PMCF activity comes,
• a description of the planned activity (general method and implementation),
• the objective of the PMCF activity,
• methodology that will be used as part of the activity,
• description of the rationale for the appropriateness of the chosen methodology, and
• deadline and timeline.

PMCF assessment report according to MDCG 2020-8

The PMCF assessment report, according to MDCG 2020-8, lists the outputs of the planned PMCF activities in accordance with the requirements of the MDR. It is a document of the technical documentation of your medical device.

The conclusions of the PMCF assessment report will be considered when updating:

• clinical evaluation
• risk management file
• PMCF Plan
• summary safety and clinical performance report (SSCP).

Specifically, for class III devices and implantable devices, the PMCF assessment report will be updated at least annually based on this data. The PMCF assessment report is part of the clinical evaluation report and technical documentation.

d) Exceptions

Not all cases require post-market clinical follow-up activities. The MDR writes in this regard:

A major problem is that there is no guidance on which product groups or classifications this can be applied to, nor examples of wording that can be used to provide justification.

Notified bodies review in their clinical evaluation assessment report (CEAR) whether a rationale is stated and adequate:

There are medical devices that do not have an intended medical purpose or for which the collection of clinical data is not useful. Examples include accessories and some medical devices, such as bedpan flushers for cleaning bedpans or turbines for dental drills.

In these cases, where clinical data are inappropriate to demonstrate conformity with the essential safety and performance requirements, a clinical evaluation is performed based on Article 61 (10). Then, the manufacturer may rely on other evidence, such as non-clinical test methods, including performance evaluation and technical inspection ("bench testing"). Since there are no clinically relevant endpoints, there is no need to collect PMCF data.

This is also confirmed by MDR:

To justify why PMCF activities are not necessary, use the formulations or considerations

• from MDCG 2020-6 to describe well-established technology,
• based on risk management and considering the specific characteristics of the interaction between the device and the human body, the intended clinical performance, and the device's claims.

3. Types of PMCF activities

a) Overview and minimum requirement

The MDR distinguishes PMCF activities as general PMCF methods and procedures and specific PMCF methods and procedures:

As a minimum, product-specific literature searches must be conducted to obtain so-called pivotal data from reports published in peer-reviewed scientific literature.

For implantable devices and class III devices for which clinical inspections have not been carried out in accordance with Article 61(4), the PMCF plan shall include post-market studies to confirm the safety and performance of a device.

b) Additional PMCF activities

Overview

Furthermore, the following activities are part of the post-market clinical follow-up:

Tab. 1: Details of PMCF activities

Clinical investigations

Clinical investigations are mostly confirmatory in nature and require elaborate study planning and a clear description of the study conditions. Each confounding factor can lead to an increased dispersion and thus have a considerable influence on the statistically necessary number of cases.

It is, therefore, not surprising that the study population should be kept as homogeneous as possible by means of suitable inclusion and exclusion criteria. This saves time and costs but also leads to ideal conditions under which the desired clinical endpoints of a medical device are reviewed. The extent to which the clinical data generated in this way still represents routine use may well be questioned in the case of one or the other study.

In contrast to clinical investigations, the use of medical devices can also be tested in everyday care. The study conditions and especially the selection of participants are not controlled by inclusion and exclusion criteria. The output of such pragmatic clinical investigations (PCT, pragmatic clinical trials) is real world data (RWD), which can be used to close the gaps between the experimental and the routine use of a medical device.

4. Common mistakes

a) Lack of product-specific clinical data

Equivalence consideration no longer possible under MDR

The previous strategy of clinical evaluations under the MDD largely involved evidence via clinical data on equivalence products. The requirements for demonstrating equivalence have increased under the MDR.

However, in the post-approval process, the collection of further clinical data on the actual device was neglected. This leads to the fact that

• long-term effects of devices were not collected and evaluated,
• not considered risks remained undiscovered, as well as
• extensions of the clinical indications were not taken into account.

Requirement of PMCF studies for MDR certification

The explicit requirement for proactive collection of clinical data in the PMCF process is intended to address these issues. They are used to improve the safety of medical devices and to continuously review their predicted performance.

In general, there must be sufficient clinical evidence to confirm the safety, performance, and acceptability of the benefit-risk determination in relation to the state of the art for legacy devices prior to CE marking under the MDR. PMCF studies may even need to be conducted to address the defect in clinical data.

MDCG 2020-6 provides for PMCF studies in the absence of equivalence and for product-specific risks:

Conclusion: such evidence should not rely on new PMCF studies initiated under MDR to fill gaps (e.g., indications not supported by clinical evidence).

b) No consideration of off-label data

Off-label use for indication expansion

Manufacturers often question whether off-label data can be used to expand the intended purpose or indications. How to handle these data is described in the Team-NB position paper.

 “Off-label use” of a medical device is generally understood to occur when a device is used outside of its approved use, i.e., not as described in the instructions for use:

• outside of specific patient populations, e.g., in pediatrics
• for a different stage or severity of the disease
• for a similar (not identical) clinical condition
• introduction into the body via other routes

The term “off-label use” is mentioned in the MDR in Annex XIV, Part B in the context that the manufacturer's PMCF plan must identify systematic misuse or off-label use of the device to review whether the intended purpose of the device is correct. However, “off-label use” or “misuse” are not defined in the MDR.

Off-label data may be quantitatively sufficient, especially when systematic off-label use has been identified, but they often lack sufficient quality in terms of meaningful conclusions. Off-label data are typically collected outside of formal protocols, and the lack of protocols ultimately results in insufficient quality and an inability to draw evidence-based conclusions.

“Foreseeable misuse”, “unsystematic misuse” and “systematic misuse”

Manufacturers must identify foreseeable misuse through usability studies, or clinical investigation reports prior to placing on the market. However, it is often difficult to predict areas of future misuse, and without the manufacturer's direct oversight of each device's use, it is inevitable that misuse will occur. When misuse is identified, the manufacturer must eliminate or control the risks in accordance with risk control measures.

Further information

Please also note the article on risk management.

The manufacturer should differentiate between systematic misuse and unsystematic misuse in documented off-label use:

Tab. 2: Unsystematic and systematic off-label use

When manufacturers identify systematic off-label use, they should take appropriate action not only to curb misuse but also to determine whether there is a genuine need in the medical community for the newly identified use in relation to the specific medical purpose/indication.

c) Periods of documentation and implementation of the measures are not appropriate

The MDR specifies timeframes for the preparation of the PSUR, which must include the key outputs of the PMCF process. However, this does not mean that the performance and evaluation of PMCF activities are linked to it.

There are activities that should be conducted more frequently, such as a literature review. Furthermore, interim analyses of PMCF studies or user surveys provide information to derive appropriate measures or to make adjustments to the study protocol or design, e.g., in case of changes in the number of patients or study centers. 

The MDR differentiates in the documentation of PMCF activities with regard to the classification of devices:

In each case, a summary of the main outputs of the PMCF assessment report is required in the PSUR. This means that the PMCF assessment report contains a detailed analysis and evaluation of the PMCF data (MDCG document 2020-8), and "only" the main points are included in the PSUR (MDCG document 2022-21).

Now, during a two-year period for PSUR preparation, multiple PMCF assessment reports may be prepared because the interval for doing so is shorter or there are multiple activities with different intervals. It is recommended that a brief summary of each PMCF assessment report be included in the PSUR.

In any case, before each PSUR is prepared, it is appropriate to go through all the PMCF analyses and assessment reports that have been incurred during the period being assessed and see if everything has been completed. If PMCF activities have not yet been completed, the PSUR must explain why there may have been a deviation from the plan or why sufficient PMCF outputs are not yet available.

5. Conclusion and support

Medical devices should be safe, efficient, and effective throughout their life cycle. PMCF activities are a measure required by the MDR and the essential method to demonstrate this. However, this does not mean that PMCF processes or PMCF studies are always mandatory.

The scope should be appropriate to the nature, classification, intended purpose, and risks of the device in question.

As part of the clinical evaluation, gaps in clinical data are identified, and initial proactive PMCF activities are defined. 

Get the appropriate support in the preparation of your entire clinical evaluation file as well as in the design, implementation, and evaluation of your PMCF activities. The Johner Institute offers:

• outsourcing your clinical evaluation and planning your clinical data collection
• clinical evaluation seminars to acquire the necessary competencies

Contact us right away with a proposed appointment for a free, non-binding meeting.