Importance and Design of PMCF Studies for Medical Devices in Europe: framework and principles

Medical Device Regulation (MDR) 2017/745, which has been enforced since May 26, 2021, has significantly reinforced the regulatory requirements for the medical device (MD) industry within the European Union. To maintain the CE marking of their devices, manufacturers must now – more than ever – engage in continuous post-market assessment of their devices, including the generation and proactive collection of clinical data and evidence. Post-market clinical follow-up (PMCF) is part of the overall post-market surveillance (PMS) process, and adopts an approach based on the device life cycle. 

Although regulatory texts and supporting guides were released years ago, many manufacturers continue to have questions about the stakes of PMCF. This article, the first in a series dedicated to the topic of PMCF, provides a synthesis on the nature of PMCF with a particular focus on the role of a PMCF study in the generation of clinical data that meets regulatory requirements.

What is PMCF?

According to the Medical Device Coordination Group (MDCG) 2020-7 guidelines, PMCF is a continuous process that updates the clinical evaluation and must be integrated into the manufacturer’s PMS plan. The objective of PMCF, as defined in Annex XIV, Part B, Section 6.1 of the MDR, is to: 

• confirm the safety and performance, including the clinical benefit if applicable, of the device throughout its expected lifetime;
• identify previously unknown side-effects and monitor the identified side-effects and contraindications;
• identify and analyze emergent risks on the basis of factual evidence;
• ensure the continued acceptability of the benefit-risk ratio, referred to in Section 1 and 9 of Annex I in the MDR;
• identify possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct.

PMCF must be implemented according to a predetermined plan and schedule that meets clear objectives, in accordance with the clinical evaluation report and the risk management documents. The plan specifies the methods that will be used and justifies their choice and appropriateness. Various texts and guidelines discuss general or specific methods that can be employed, without necessarily fully characterizing them. Specific approaches are based on retrospective studies, registries, and prospective clinical investigations under Article 74 or 82 of the MDR. For general approaches, one can distinguish between the collection of complaints and vigilance data, literature review, general user feedback, field surveys, and even user questionnaires (surgeons, patients). Regarding surveys, the distinction between a general approach and a specific approach can be elusive depending on the type and granularity of the implemented questionnaire.

Finally, PMCF may rely on clinical data from equivalent or similar devices, or refer, where appropriate, to relevant common specifications or harmonized standards. Today, PMCF activities are central to the generation of additional clinical evidence for maintaining a medical device on the market, and within this context, PMCF studies play an increasingly important role.

1. PMCF Studies and Regulatory Framework

PMCF studies are amongst the “specific” strategies for conducting PMCF activities. The different types of PMCF studies and their implementation are based on the risk associated with the device, its invasiveness, and the PMCF issues to be addressed. 

Since May 26, 2021, French law has fully integrated MDR 2017/745 for the conduct of clinical investigations (CI) on medical devices within its territory.

Classification of clinical investigations (CI) (adapted from ANSM classification^[1])

Before their implementation, these CIs must be reviewed by various parties. On the one hand, the ANSM (National Agency for the Safety of Medicines and Health Products), defined as the French competent authority for vigilance, validates the submission files and in some cases, provides the authorization to conduct the CI. The Committee for the Protection of Persons (CPP) is an ethics committee that provides a favorable opinion on all CIs.

In the context of a PMCF study conducted to establish the conformity of the MD, the MDR provides a framework only in cases where the CE-marked MD is used according to its intended purpose and involves additional invasive or burdensome procedures (category 3 of CIs according to the ANSM classification). When a CI does not involve such additional procedures, it falls into category 4. For example, when access to the patient is necessary for prospective data collection via questionnaires (e.g., quality of life questionnaires), it will be classified as a CI, but with non-burdensome and non-invasive additional procedures (i.e.  category 4.1 according to the ANSM for a CE-marked MD of any class used according to its intended purpose and promoted by the manufacturer).

These studies must also comply with the General Data Protection Regulation (GDPR) and the French Data Protection Act (Loi Informatique et Libertés, I&L) for the processing of personal health data. The application of the CNIL’s reference methodology MR-001 ensures compliance and provides exemptions regarding the need to request authorization for data processing from the CNIL.

When the need for clinical data can rely solely on the collection of individual existing data (e.g., from the medical record), the study does not fall within the scope of the MDR and will be considered as research not involving the human person under French law and is therefore subject only to the GDPR and I&L. Data processing must either comply with a reference methodology or obtain the favorable opinion of CESREES (the ethical and scientific committee for research, studies and evaluations in health) combined with an authorization from the CNIL.

Finally, for PMCF CIs with one or more additional invasive or burdensome procedures (case 3), the Sponsor must be adequately insured. This is not necessary for PMCF CIs with non-burdensome and non-invasive additional procedures (case 4.1).

2. Designing a PMCF Study: the Principles

To design a PMCF study, it is crucial to define the objectives, methodology, study population, the methods for data collection and the methods for data analysis.

• Objectives and endpoints: The primary objective should be articulated as clearly as possible. It will directly influence the size of the study population and should reflect the issues identified in the PMCF plan. This primary objective is then translated into a primary endpoint, that is, the measurable expression of the primary objective (e.g., measurement of a clinical benefit through the change from baseline in a score on a validated scale, or the occurrence rate of an adverse event related to the device under investigation). The endpoint must be reliable, sensitive, specific, repeatable, and reproducible. These properties determine the choice of its measurement method. Secondary objectives and endpoints are also determined based on similar principles, except that they do not condition the calculation of the study’s sample size. The objectives and endpoints should support the performance, safety and clinical benefits claims of the manufacturers for their products.

• Methodology: Defining the study methodology will involve determining whether it is a retrospective or prospective study, single-group or multi-group (e.g., one group exposed to the MD and another group without the MD, with or without an alternative treatment), comparative or non-comparative, etc. The duration of the study will depend on what needs to be evaluated and should be adapted to the lifespan of the device. The study population will be established based on inclusion and exclusion criteria that allow for the selection of patients that are representative of the device’s intended use as described in its instructions for use.

• Population: Data collection methods will be chosen to capture and evaluate the endpoints, the study population, exposure data to the MD under study, and safety and performance data.

• Data Collection Methods: Data collection methods will be chosen to capture and evaluate the endpoint, the study population, the exposure data to the medical device under study, as well as safety and performance data. It is essential to use methods that are consistent with the literature data (use of scientifically validated scales/questionnaires, follow-up of medically relevant clinical event, measure of a biological parameter with a validated method…). This ensures good comparability and relevance of the data with respect to the state of the art.

• Data analysis methods: Statistical considerations and data analysis methods will be established to meet the study objectives: descriptive approach, comparative (superiority, equivalence, non-inferiority), confounding variables (elements that may affect the results), definition of analysis populations, handling of missing data, formal calculation of sample size. For the latter, assumptions will have to be formulated, either based on prior clinical experience or on data from the literature. Typically, it will be up to the statistician and clinical experts to determine, based on the nature of the chosen primary endpoint, its expected variability in the presence and/or absence of exposure to the MD under investigation, the difference that one wishes to demonstrate, the significance level (type I error or alpha risk), and the power (depending on the type II error or beta risk) in the case of formal statistical tests. The method of calculating the sample size will reflect the analysis method of the study’s primary endpoint.

And so? 

PMCF studies are an essential element supporting the compliance of MDs with MDR (EU) 2017/745 requirements. They not only confirm the safety and performance of devices throughout their lifecycle but also enable the identification and management of emerging risks, thus ensuring a favorable benefit-risk balance. The rigorous implementation of a PMCF study, with a well-defined methodology tailored to the specifics of the device, is essential to meet regulatory and ethical requirements. Moreover, these studies contribute to the continuous improvement of MDs, optimizing their clinical use, and help to consolidate trust among users and health authorities. Therefore, PMCF studies are not just a regulatory obligation but a strategic tool for manufacturers who wish to maintain and enhance the presence of their products on the European market while ensuring patient safety and device performance. 

In a forthcoming article, a brief application of the design of a PMCF study will be proposed.

Do you need to design, set up and conduct a PMCF study? The various experts within our clinical CRO, Soladis Clinical Studies by Efor, can help you with:

• Literature review 
• Definition of the objectives, design and complete methodology of the PMCF clinical investigation
• Drafting or review of study documents
• Overall support with the implementation and conduct of a PMCF clinical investigation
• Expertise via our hotline for specific questions requiring a rapid response

Contact us at the following address: onedt@efor-group.com

^[1]  https://ansm.sante.fr/uploads/2022/02/10/20220210-classification-et-process-devaluation-des-investigations-cliniques-dm-selon-le-reglement-2017-745-et-adaptations-nationales.pdf (in French)