The European Union’s Medical Device Regulation (MDR 2017/745[i]) has fundamentally redefined the requirements for bringing and keeping medical devices to the market.

A central pillar of this regulation is the increased demand for robust clinical evidence to substantiate a device’s safety and performance claims. For all professionals involved in clinical research—from sponsors and CROs to investigators and regulatory affairs specialists—a clear understanding of the different clinical investigation pathways is no longer optional; it is essential for regulatory success.

This blog post provides an overview of the different types of clinical investigations as defined by the MDR, providing a comprehensive overview of each category. We will explore the nuances of pre-market investigations for CE marking, post-market clinical follow-up, and other types of clinical research, all based on the framework detailed by the EU MDR.

In all cases, if the sponsor is not established in the EU, they must appoint a legal representative within the Union to act on their behalf.

The CE Mark: Your Passport to the EU Market

The CE mark is the mandatory conformity marking for products sold within the European Economic Area. For medical devices, it declares that the product meets the General Safety and Performance Requirements (GSPRs) outlined in the MDR. Obtaining and maintaining this mark is based on a comprehensive technical documentation file, of which the Clinical Evaluation Report (CER) – supported by solid clinical data – is a fundamental element. Clinical investigations are the primary means of generating this essential data.

1.   Pre-Market Investigations for Conformity Purposes (Articles 62[ii] & 74.2[iii])

When a manufacturer wants to introduce a new medical device to the EU market, or expand the use of an existing device, they must provide strong clinical evidence of its safety and performance. This is where pre-market clinical investigations for conformity purposes come in.

This pathway is designed to gather the definitive clinical data required to apply for a CE mark. These are typically the most rigorous and data-intensive studies, as their results form the basis of the initial conformity assessment.

This category is further divided based on the device’s status:

1. Article 62

This article applies to investigations of non-CE-marked devices. It is the standard pathway for new technologies and devices seeking their first entry into the EU market.

Primary objectives:

• • To verify that the device is designed, manufactured, and packaged to be suitable for its intended purpose under normal use conditions.
  • To establish and verify that the device achieves the performance intended by its manufacturer under normal condition of use.
  • To establish and verify the clinical benefits of the device.
  • To establish the clinical safety of the device.

2. Article 74.2

This article corresponds to devices that already have a CE mark but are being investigated for a new or expanded intended purpose. Even though the device has a CE mark, using it outside its original intended purpose requires a new conformity assessment.

Article 74.2 refers to Article 62, the same objectives apply.

Key Requirements for Pre-Market Investigations: 

• Authorization: The sponsor must obtain authorization from the competent authority of each Member State where the investigation will be conducted.
• Ethical Review: A positive opinion from an ethics committee is mandatory to ensure that patient perspectives are considered.
• Submit the required documentation, as outlined in Annex XV of the MDR[iv].
• Informed Consent: Subjects must be fully informed about the investigation and provide their voluntary, informed consent to participate.
• Robust Data: The data generated must be scientifically valid, reliable, and robust.

2.   Post-Market Clinical Follow-up (PMCF) Investigations (Article 74.1ⁱⁱ)

Obtaining a CE mark is not the end of a manufacturer’s obligations; it is the beginning of a continuous process of monitoring and confirming the device’s performance in real-world use. This is the role of Post-Market Clinical Follow-up (PMCF).

Objective: To proactively collect clinical data on a CE-marked device used within its intended purpose to confirm its long-term safety and clinical performance and to identify any emerging risks.

While PMCF includes various activities (e.g., literature reviews, analysis of registries, Real World Data,…), a formal PMCF investigation becomes necessary when the data collection involves submitting subjects to procedures that are additional to those performed under normal conditions of use and are invasive or burdensome.

Key Requirements: Compared to pre-market investigations, the requirements for PMCF investigations are less stringent, but still significant. The sponsor must:

• Notify the competent authorities of the relevant Member States at least 30 days before the start of the investigation.
• Ethical Review: A positive opinion from an ethics committee is mandatory to ensure that patient perspectives are considered.
• Submit the required documentation, including ICF, as outlined in Annex XV of the MDRⁱⁱⁱ.
• Comply with provisions related to modifications, adverse event reporting, and other aspects as specified in the regulation.

PMCF investigations are a critical tool for identifying rare or long-term risks that may not have been apparent in the pre-market phase, ensuring that devices remain safe and effective for patients over the long term.

3.    Other Clinical Investigations (Article 82[v])

This category serves as a framework for clinical investigations that are not conducted for the purpose of a conformity assessment. These studies are crucial for scientific advancement and innovation within the medical field.

Objective: To facilitate clinical research for scientific purposes that do not fall under the pre-market or PMCF framework.

This category is broad and can include:

• Investigator-initiated studies: A clinician or academic researcher initiates a study to explore:
  • a new scientific hypothesis using a device,
  • or a new clinical application for a CE-marked device that is not part of the manufacturer’s intended purpose.
• Studies on custom-made devices: These are devices made for a specific patient, and while they are not subject to the same conformity assessment procedures, clinical data may still be needed to ensure their safety and performance.
• Pilot or feasibility studies: Early-stage research to gather initial data on a novel concept.
• Research on in-house devices: Hospitals or other health institutions may develop and use their own devices, and clinical investigations may be conducted to evaluate them.

Key Requirements:  Article 82 ensures that patient safety and ethical principles remain predominant by requiring compliance with key provisions of Article 62, investigations shall comply to the following:

• Protection of subjects’ rights, safety, and well-being (Article 62.²ⁱⁱ),
• Ethics Committee review (Article 62.3ⁱⁱ),
• Specific information to be in the application (Article 62.4 (points: b, c, d, f, h and l) ⁱⁱ),
• Sponsor responsibilities (Article 62.6ⁱⁱ),
• Additional requirements: these investigations are subject to the national laws of the Member State in which they are conducted, which may impose additional requirements.

Conclusion:

Understanding the distinction between these three clinical investigation pathways is a strategic imperative. For sponsors and the CROs that support them, selecting the correct pathway is fundamental to designing a compliant, efficient, and successful clinical development plan. For all clinical research professionals, this knowledge is crucial for ensuring that studies are conducted ethically, efficiently, and in full alignment with the complex demands of the EU MDR.

Ultimately, a thorough understanding of these regulatory frameworks enables the entire research community to not only meet compliance obligations but also to contribute effectively to the shared goal of advancing medical technology and ensuring patient safety across Europe.

What is the primary goal of your clinical research?

Goal 1: To Obtain or Modify a CE Mark	Goal 2: To Confirm Safety of a CE-Marked Device	Goal 3: For Scientific Research (Non-Conformity)
Pre-market investigation	Post-Market Clinical Follow-Up (PMCF)	“Other” clinical investigation
MDR Articles: • Art. 62 (for non-CE-marked devices) • Art. 74.2 (for CE-marked devices, new purpose)	MDR Article: • Art. 74.1	MDR Article: • Art. 82
Purpose: To generate pivotal data to prove the device is safe and performs as intended, allowing it to be sold in the EU.	Purpose: To proactively collect real-world data to confirm long-term safety and performance. Required if the study involves extra invasive or burdensome procedures.	Purpose: To advance science and medical knowledge.
Key Regulatory Step: AUTHORIZATION You must get formal permission from the Competent Authority and a positive Ethics Committee opinion before starting.	Key Regulatory Step: NOTIFICATION You must inform the Competent Authority at least 30 days before starting. An Ethics Committee opinion is also needed.	Key Regulatory Step: ETHICAL & NATIONAL OVERSIGHT Must comply with national laws and core ethical principles (e.g., Ethics Committee approval), but not for conformity purposes.

 

Abbreviations:

CER: Clinical Evaluation Report  

CRO: Clinical Research Organization

EU MDR: European Union’s Medical Device Regulation

GSPRs: General Safety and Performance Requirements

ICF: Inform Consent Form

MDR: Medical Device Regulation

PMCF: Post-Market Clinical Follow-up

Sources 

english.ccmo.nl

Guidance – MDCG endorsed documents and other guidance – European Commission

Regulation – 2017/745 – EN – Medical Device Regulation – EUR-Lex

References

[i] Regulation – 2017/745 – EN – Medical Device Regulation – EUR-Lex

[ii] MDR – Article 62 – General requirements regarding clinical investigations conducted to demonstrate conformity of devices – Medical Device Regulation

[iii] MDR – Article 74 – Clinical investigations regarding devices bearing the CE marking – Medical Device Regulation

[iv] ANNEX XV – Medical Device Regulation

[v] MDR – Article 82 – Requirements regarding other clinical investigations – Medical Device Regulation

At XPER, we specialize in guiding medical device manufacturers through the full process of designing and executing clinical studies in Europe. Our team combines deep knowledge of MDR requirements with operational excellence to help you:

• Identify optimal countries and sites
• Navigate ethics and regulatory submissions efficiently
• Design studies that meet both EU and FDA evidence expectations
• Accelerate patient recruitment and data collection
• Compile and present study results in an MDR-compliant Clinical Investigation Report (CIR)

If you’re designing your next study, and you are unsure about the interpretation of the MDR guidelines, don’t hesitate to contact us to adequately inform you on the applicable requirements.

Contact us for more information