On May 5, 2017, the Active Implantable Medical Devices Directive (90/385/EEC — AIMD) and the Medical Devices Directive (93/42/EEC — MDD) were replaced by the Medical Device Regulations (MDR) 2017/745, and the In-Vitro Diagnostic Medical Devices Directive (89/79/EC — IVDD) was replaced by the In-Vitro Diagnostic Regulations (IVDR) 2017/746. Both of these new regulations put a heavy emphasis on post-market surveillance activities for a product. Post-market clinical follow-up studies, or performance studies as called in the IVDR, are an integral part of the post-market surveillance requirements of the newly released regulations. PMCF studies must be initiated by the manufacturer...

2. Post-Market Clinical Follow up Studies Under EU MDR and IVDR
Introduction
On May 5, 2017, the Active Implantable Medical Devices Directive (90/385/EEC -- AIMD) and
the Medical Devices Directive (93/42/EEC -- MDD) were replaced by the Medical Device
Regulations (MDR) 2017/745, and the In-Vitro Diagnostic Medical Devices Directive (89/79/EC
-- IVDD) was replaced by the In-Vitro Diagnostic Regulations (IVDR) 2017/746.
Both of these new regulations put a heavy emphasis on post-market surveillance activities for a
product. Post-market clinical follow-up studies, or performance studies as called in the IVDR,
are an integral part of the post-market surveillance requirements of the newly released
regulations. PMCF studies must be initiated by the manufacturer.
In the EU MDR, PMCF is defined as the process where a manufacturer “shall proactively collect
and evaluate clinical data from the use in or on humans of a device which bears the CE marking
and is placed on the market or put into service within its intended purpose as referred to in the
relevant conformity assessment procedure, with the aim of confirming the safety and
performance throughout the expected lifetime of the device, of ensuring the continued
acceptability of identified risks and of detecting emerging risks on the basis of factual
evidence”1
, and in the EU IVDR, it is defined as the process where a manufacturer “shall
proactively collect and evaluate performance and relevant scientific data from the use of a device
which bears the CE marking and is placed on the market or put into service within its intended
purpose as referred to in the relevant conformity assessment procedure, with the aim of
confirming the safety, performance and scientific validity throughout the expected lifetime of the
device, of ensuring the continued acceptability of the benefit-risk ratio and of detecting emerging
risks on the basis of factual evidence.”2
In the EU MDD, PMCF is defined as “clinical data based on the use of a CE-marked device
corresponding to a particular design dossier or on the use of a group of medical devices
belonging to the same subcategory or generic device group as defined in Directive 93/42/EEC.
The objective is to confirm clinical performance and safety throughout the expected lifetime of
the medical device, the acceptability of identified risks, and to detect emerging risks on the basis
of factual evidence.”3
1
EU Commission (April 2017) REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and
Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC retrieved on
07/10/2020 from https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745
2
EU Commission (April 2017) REGULATION (EU) 2017/746 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision
2010/227/EU retrieved on 07/10/2020 from https://eur-lex.europa.eu/legal-
content/EN/TXT/PDF/?uri=CELEX:32017R0746&rid=6
3
EU Commission (June 1993) COUNCIL DIRECTIVE 93/42/EEC
of 14 June 1993 concerning medical devices retrieved on 07/10/2020 from https://eur-lex.europa.eu/legal-
content/EN/TXT/PDF/?uri=CELEX:31993L0042&from=DE

3. PMCF under the MDR and IVDR
Since grandfathering of devices under the EU MDR and IVDR is not allowed, all devices which
are placed on the market for years still have to prove their clinical safety in their technical file.
This means that the manufacturer must provide this clinical information either by conducting
clinical trials, strong literature reviews, or proving substantial equivalence under a contractual
arrangement between the manufacturers to share the clinical data. This would mean that majority
of the devices will require clinical studies in order to prove their safety and effectiveness.
For in-vitro diagnostic devices, post-market clinical follow-up studies are referred to as post-
market performance follow up studies simply because of the nature of diagnostic devices is to
provide quantitative data to assess for post-market performance. However, the requirements
under both the EU MDR and IVDR for a post-market study remains the same, but their study
designs may differ.
The results or the conclusions drawn from the post-market follow up clinical studies are then
used to update the pre-market data submitted in the clinical evaluation report of the device.
Image source:
Post-Market Clinical/Performance Plan
Before conducting a PMCF study, a PMPF plan must be submitted and approved by the notified
body which describes how the process and the correct level of documentation practices are
followed throughout the process. It specifies the methods and procedures for proactively
collecting and evaluating such data, the quality assurance activities required, and a rationale on
how the manufacturer concluded why the particular methods and procedures were used. The plan
https://www.johner-institute.com/articles/regulatory-affairs/and-more/post-market-
surveillance/

4. also contains the specific objectives to be addressed, any harmonized standards utilized, and a
justified timeline for the activities.4
During the transition from the EU MDD or IVDD to the MDR or IVDR, conducting a thorough
gap analysis of the available clinical data against the MDR requirements and discussing the
PMCF plan with the notified body is key.
PMCF Investigation
The EU MDR defines the PMCF investigation as a “clinical investigation conducted to further
assess, within the scope of its intended purpose, a device which already bears the CE marking.”1
This definition also implies that the requirements that apply to a clinical investigation such as
protection of human subjects and research ethics also apply to post-market clinical studies.
In the case where the clinical study will submit subjects to additional procedures that are
invasive or burdensome for the participants of the study, the sponsor of the study is obligated to
inform the concerned member state.
Some of the parameters that a PMCF study must evaluate include:2
• Confirming the safety and performance of the device throughout its expected lifetime,
• Identifying previously unknown side-effects and monitoring the identified side-effects
and contraindications,
• Identifying and analyzing emergent risks based on factual evidence,
• Ensuring the continued acceptability of the benefit-risk ratio from the risk file of the
device, and
• Identifying possible systematic misuse or off-label use of the device, to verify that the
intended purpose is correct.
In the case of IVDs, some additional factors must also be considered during data evaluation
such as:2
• Analytical Sensitivity
• Analytical Specificity
• Trueness
• Precision (Repeatability and Reproducibility)
• Accuracy
• Limits of Detection and Quantitation
• Measuring Range
• Linearity
• Cut off
• Determination of appropriate criteria for specimen collection and handling
• Control of known relevant endogenous and exogenous interference
• Cross Reactions
• Diagnostic Sensitivity
4
Emergo (Sept 2017) Post-Market Clinical Follow up Studies retrieved on 07/11/2020 from
https://www.emergobyul.com/resources/white-paper-how-conduct-medical-device-pmcf-studies

5. • Diagnostic Specificity
• Positive Predictive Value
• Negative Predictive Value
• Likelihood Ratio
• Limits of Detection and Quantitation
• Expected values in normal and affected populations
Role of Member States
If you plan on conducting the study in one of the European member states, an application needs
to be submitted to the member state. If the performance study is to be conducted in more than
one member state, then a single application may be submitted which is transferred to all member
states via an electronic system.2
If sponsors intend to introduce modifications to a performance study that is likely to have a
substantial impact on the safety, health, or rights of the subjects or the robustness or reliability of
the data generated by the study, the sponsor must inform the member state within a week’s time,
the reason and description of such change. The sponsor may implement the modifications 38
days after the notification unless it gets rejected by the member state.2
Role of the Manufacturer
The manufacturer prepares the PMCF plan and submits it to the notified body for approval. The
manufacturer then prepares the study protocol using a sound clinical study design pre-approved
as part of the PMCF plan. During the execution of the study, the sponsor must fully record all of
the following:2
• Any adverse event type identified in the study plan as being critical to the
evaluation of the results of that study;
• Any serious adverse event;
• Any device deficiency that might have led to a serious adverse event if
appropriate action had not been taken, the intervention had not occurred;
• Any new findings concerning any event referred to in the points above.
The manufacturer must also report these findings to the member state in which the study is being
conducted. Reporting requirements must take into account the severity of the event.
When the study ends, the manufacturer is responsible for notifying the member state within 15
days and submit the results of the study within one-year post-completion. Where, for scientific
reasons, it is not possible to submit the performance study report within one year of the end of
the study, it must be submitted as soon as it is available.2
If a sponsor chooses to temporarily halt or terminate a study, the Member States must be notified
within 15 days through the electronic system. In the event that the sponsor has temporarily halted
or terminated the study on safety grounds, it is required to inform all Member States within 24
hours. The sponsor must submit a study report to the member states irrespective of the outcome
within three months of the temporary halt or early termination.2

6. Role of the Notified Body
The role of a Notified Body in a PMCF study is to review the appropriateness of the
manufacturer’s general post-market surveillance procedures and plans, including plans for the
PMCF. When working with Notified Bodies to review a PMCF plan, the process is most
efficient and beneficial to manufacturers when it is initiated during the early stages of
development. At this time, manufacturers can present and revise ideas for the PMCF, and
Notified Bodies can challenge any elements that will not stand up to scrutiny.5
PMCF Study Designs
PMCF study designs depend on the subject device and the parameters to be tested. It is essential
to test the long-term outcome of the device along with the residual risks outlined in the risk
management file of the device post-market and update the file accordingly. Some common study
designs include:
- Post-market performance study using a previously certified controlled intervention device
whose performance parameters can be compared to the subject device.
- Retrospective medical record reviews of patients who have been treated or diagnosed
using the subject device.
- Focus groups and surveys to test the performance outcome of the device post-market
from the patients.
As per MEDDEV 2.12-2, REV.2, a PMCF study protocol must contain the following
elements:5
• Patient population
• Inclusion/exclusion criteria
• Controls
• Selection of sites and investigators
• Endpoints and statistical considerations
• Number of subjects
• Duration of study
• Data to be collected
• Study endpoints
• Analysis plan, including interim reporting
• Procedures/criteria for early study termination.
PMCF studies may include extended follow up of patients involved in pre-market studies, new
clinical investigations, or a review of relevant retrospective data from patients previously
exposed to the device.
MEDDEV 2.12-2, REV. 2 references ISO 14155:2011 as the basis for clinical studies.
5
BSI- THE POST-MARKET PRIORITY Understanding and Meeting Demand for Effective Post-Market Clinical Follow-
Up retrieved on 07/15/2020 from https://www.bsigroup.com/globalassets/meddev/localfiles/de-
de/whitepapers/bsi-md-the-post-market-priority-whitepaper-de-de.pdf

7. The standard defines good clinical practice for the design, conduct, recording, and reporting of
clinical investigations carried out in human subjects to assess the safety or performance of
medical devices for regulatory purposes.
PMCF Exemptions
PMPF studies are usually only needed in the case of novel products because for most other
devices, clinical performance can be established through analytical testing and literature reviews.
A justification needs to be provided and documented in the performance evaluation report if a
PMPF/PMCF is not appropriate for a specific device.2
Conclusion
A well-designed PMCF study will help the manufacturer to not just comply with the
requirements, but extends the benefits to economic advantage for the manufacturer as it helps in
obtaining real-world evidence for the medical device, thus driving innovation and sales.5

8. Bibliography
1. EU Commission (April 2017) REGULATION (EU) 2017/745 OF THE EUROPEAN
PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices,
amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No
1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC retrieved on
07/10/2020 from https://eur-lex.europa.eu/legal-
content/EN/TXT/PDF/?uri=CELEX:32017R0745
2. EU Commission (April 2017) REGULATION (EU) 2017/746 OF THE EUROPEAN
PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on in vitro diagnostic medical
devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU
retrieved on 07/10/2020 from https://eur-lex.europa.eu/legal-
content/EN/TXT/PDF/?uri=CELEX:32017R0746&rid=6
3. EU Commission (June 1993) COUNCIL DIRECTIVE 93/42/EEC of 14 June 1993
concerning medical devices retrieved on 07/10/2020 from https://eur-lex.europa.eu/legal-
content/EN/TXT/PDF/?uri=CELEX:31993L0042&from=DE
4. Emergo (Sept 2017) Post-Market Clinical Follow up Studies retrieved on 07/11/2020
from https://www.emergobyul.com/resources/white-paper-how-conduct-medical-device-
pmcf-studies
5. BSI- THE POST-MARKET PRIORITY Understanding and Meeting Demand for
Effective Post-Market Clinical Follow-Up retrieved on 07/15/2020 from
https://www.bsigroup.com/globalassets/meddev/localfiles/de-de/whitepapers/bsi-md-the-
post-market-priority-whitepaper-de-de.pdf