Are there different PMCF studies? Is it enough if I comply with the regulations?

Different PMCF Studies in Europe: Types and Classifications – Not Solely Based on Regulatory Framework!

Confusing, but indeed: The Medical Device Regulation (MDR), the Medizinprodukterecht-Durchführungsgesetz (MPDG), the Digitale-Gesundheitsanwendungen-Verordnung (DiGAV) and general principles of clinical research broadly define a multitude of types of clinical investigations following the placing on the market of a medical device (Post-Market Clinical Follow-up, PMCF) studies.

It is repeatedly stated that clinical investigations outside the intended purpose are the most resource-intensive clinical investigations (formally: clinical investigations). This article aims to dispel this misconception.

Beyond the regulatory perspective, the resource intensity of clinical investigations must also be differentiated according to, for example:

• required level of evidence
• requirements from competent authorities or health insurance funds
• scientific significance
• number and type of required patients
• specific characteristics of a particular indication
• achievement of market segments – both according to indication and whether specific target groups are to be convinced (e.g. critical scientists or physicians) or the competitive situation
• existing evidence base
• overall risk of the investigation

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This leads in part to considerably higher requirements for the design, preparation, conduct and evaluation of these post-market clinical follow-up (PMCF) investigations of medical devices. This is often overlooked in this context, and in addition to the expertise of legal experts and regulatory affairs professionals, the scientific and clinical perspective and in-depth knowledge and experience of the specific field are required to assess such a project from the outset in terms of required time, budget, quality and risk management.

It is therefore entirely insufficient to focus solely on regulatory aspects prior to commencing such a project. In our experience, this frequently leads to a series of incorrect decisions. And indeed, it is important to inform the highest decision-making level and investors about these aspects from the outset. Thereafter, such a clinical investigation belongs in the experienced and competent hands of specialists.

Regulatory Framework

According to Annex XIV, Part B of the MDR with scope of application for the European area, PMCF is a continuous process planned and implemented by a manufacturer in which clinical data from the use of a device that has been placed on the market are collected and evaluated in order to update the clinical evaluation and to confirm that the benefit-risk profile of the device remains acceptable. These PMCF are intended to update the clinical evaluation (Article 61 and Annex XIV Part A) for a medical device placed on the market.

When a manufacturer of a medical device requires clinical data for various reasons, they initiate the conduct of a PMCF. A few fundamental points must now be observed, which can be answered with the following questions.

1. Does the CE-marked medical device have the appropriate intended purpose for what I wish to investigate in the investigation?
If yes, question 2 may be examined. If no, Articles 62 to 81 of the MDR apply.

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2. Do I intend to subject the patients to anything burdensome for them?
If no, question 3 may be examined. If yes, Articles 62 to 81 of the MDR apply.

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3. Must anything invasive, for example a blood sample, be performed for the purpose of my clinical investigation?
If yes, Articles 62 to 81 of the MDR apply.

ONLY if all 3 questions can be answered with NO may the PMCF be conducted pursuant to Article 74(1) first sentence MDR. Laws implementing Union law provisions concerning medical devices then apply, in Germany the Medizinprodukterecht-Durchführungsgesetz (MPDG).

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Further details and to determine which regulatory framework applies in which scenario, see also below:

PMCF plan

‍ Clinical investigations of medical devices with CE marks

Non-interventional clinical investigations

PMCF as part of clinical evaluations

Reporting and approval requirements and vigilance for PMCF studies

The need for clinical investigations (Art. 62 of MDR)

General requirements for clinical investigations for conformity assessment

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Irrespective of how a PMCF investigation is assessed, further aspects, such as dimensions, must be considered which determine whether a clinical investigation with medical devices is reasonable, appropriate or expedient.

The individual dimensions are briefly listed here.

Levels of Evidence

Clinical evidence is hierarchically classified into levels of evidence, which are central for authorisation, reimbursement and guideline recommendations for innovative medical devices – including DiGA and IVD.

Levels of evidence are defined differently by different institutions; for example, Grade Ia (highest evidence quality with broad data basis) and Grade IV or Grade V have the lowest evidence quality.

For developing companies, it may be expedient to align with the different stakeholder groups (e.g. competent authorities, health insurance funds, GKV-Spitzenverband) at an early stage. Regulation (EU) 2017/745 (MDR) does not use the term "evidence" as such in the original text; instead, formulations such as "clinical data", "clinical evidence", "demonstration", "substantiation" or "scientifically valid" are found. For topics relating to evidence, the MPDG systematically uses different terminology, e.g. "clinical investigation", "performance study", "documentation", "demonstration", "evaluation" and references to the MDR/IVDR (e.g. Article 62 MDR, Article 58 IVDR). The term "evidence" is also not found in ISO 14155 on clinical investigation of medical devices.

Further details on levels of evidence and why they are important for what:

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Levels of evidence

EMA guideline for quantitative evidence synthesis

Evidence generation with DTC-MED^(R)

Basics of clinical studies

AI and evidence generation

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Investigation Design

The investigation design describes the systematic, pre-planned structure and methodology of the investigation (e.g. prospective/retrospective, randomised, controlled, single or multicentre, digital elements), on the basis of which it is examined whether safety, performance and clinical benefit of the device are demonstrable. It determines, inter alia, objectives, inclusion and exclusion criteria, comparator groups, endpoints, statistical evaluation and procedure.

Further details can be found here:

Development of a clinical investigation plan

Types of clinical investigations

Basics of clinical studies

Study designs in clinical and other clinical investigations of medical devices

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Scientific Validity, Requirements from e.g. Competent Authorities or Health Insurance Funds

The different competent authorities and institutions require for post-market investigations of medical devices primarily high levels of evidence (Ia/Ib) with randomised, controlled investigation designs (GKV-Spitzenverband, G-BA, BfArM), whereby for novel devices prospective, comparative investigations with control groups are preferred, whilst BfArM primarily monitors scientific validity and compliance with MDR requirements. Health insurance funds, however, focus on different aspects than scientific evidence with emphasis on the – for them important economic – comparison with existing comparator therapy derived from the clinical context. To be considered here is the selection of a design appropriate to the research question.

Further details see also:

The need for clinical investigations for CE-certified medical devices

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There are therefore not only 3 different forms of clinical investigations for medical devices following placing on the market, as the classification according to regulatory framework would suggest. Rather, these 3 – merely regulatory-classified – types of PMCF are to be further subdivided, depending on the purpose according to required level of evidence, existing literature also outside medical device literature, elements of investigation design, indications, general market conditions or specific requirements of the respective stakeholder groups. Early consideration of these dimensions leads to appropriate quality, early realistic time and budget estimation, permits the necessary quality management and thus ultimately long-term success!

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Would you like early advice on this based on many years of experience and expertise? Feel free to arrange a non-binding consultation with us!