Understanding and mastering the differences between clinical evaluation and clinical investigation of medical devices

In the field of medical devices (MDs), the distinction between clinical investigations and clinical evaluations is crucial, yet the two terms are still too often confused by many stakeholders.

Although both activities aim to provide evidence of performance and safety, they differ significantly in terms of methodology, objectives, and regulatory requirements. This article explores these differences in order to clarify their respective roles and implications for medical device manufacturers.

1. Understanding the issues and differences: definitions and objectives

1.1 Focus on clinical investigations

Clinical investigations are studies conducted on human subjects to assess the safety and performance of a device. The European Regulation (EU) 2017/745 on medical devices defines them as ‘any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device.‘ The term “Clinical Investigation” remains specific to devices; in other contexts (pharma, biotech, epidemiology…), terms such as “clinical trial”, “clinical study”, or “clinical research” are used.

The main objective is to collect robust clinical data demonstrating that the product is safe and effective for its intended use. In the case of MDs with no clinical performance— meaning their performance can be demonstrated without clinical data acquired from humans—a clinical investigation is not required. This is the case, for example, for a surgical mask or a syringe, the non-clinical performance of which is demonstrated through compliance with reference standards.

Before obtaining CE marking— a mandatory certification indicating that a medical device meets safety requirements and is necessary for commercialization in the European Union—such studies are referred to as pre-market studies. During any first use in humans, these are called “first-in-human” (also “feasibility” or “proof of concept”) studies, intended to collect initial clinical data on device use. These are generally pilot studies. They can be distinguished from pivotal investigations, conducted at more advanced stages of development, which formally demonstrate the safety and performance of the device in the target population in line with its intended use.

Once CE marking is obtained, post-market clinical follow-up (PMCF) studies are conducted. These serve to confirm device safety and performance, including clinical benefit, in a broader population and/or over a longer period of time. It is also possible to collect data on new populations in order to expand the device’s indications. PMCF is a mandatory activity required by European medical device regulations to ensure ongoing monitoring of the product’s safety and performance throughout its lifetime and commercialization.

1.2 Focus on clinical evaluation

Clinical evaluation, on the other hand, is a continuous process involving the collection, analysis, and assessment of clinical and non-clinical data related to a device. It forms part of the technical documentation and is mandatory for all types of devices, regardless of risk class or novelty (see our dedicated article). Thus, the surgical masks mentioned earlier, although exempt from clinical investigation, must have their own clinical evaluation.

It must be considered from the earliest stages of device design and carried out before CE marking. Once the product is on the market, it is updated according to the frequency defined in the manufacturer’s procedures—and at least annually for high-risk devices (e.g., implantable MDs or Class III devices). Clinical evaluation ensures that performance, safety, and a positive benefit-risk profile are maintained throughout the device’s lifecycle, in line with its intended use. Combined with the Post-Market Surveillance (PMS) processes—which includes PMCF—clinical evaluation supports proactive risk management by enabling manufacturers to identify emerging risks and implement corrective measures. Newly identified risks feed into the risk analysis and may require modifications to the instructions for use.

2. Understanding the regulatory requirements for medical devices

2.1 Regulatory framework for clinical investigations

Clinical investigations are highly regulated. In Europe, they must comply with Regulation (EU) 2017/745 on medical devices. In the United States, they are regulated by the Food and Drug Administration (FDA) under the Investigational Device Exemptions (IDE) framework. These regulations require detailed protocols, informed consent, safety reporting, and compliance with a quality management system. They are conducted with the validation or authorization from Competent Authorities (in France, the Agence Nationale de Sécurité du Médicament et des produits de santé, or ANSM) and a favorable opinion from an independent Ethics Committee (in France, the Comité de Protection des Personnes, or CPP).

They must also comply with Good Clinical Practices (GCP), notably ISO 14155 (Clinical investigation of medical devices for human subjects — Good clinical practice).

2.2 Regulatory framework for clinical evaluations

Clinical evaluation is also subject to strict regulatory requirements. Regulation (EU) 2017/745, together with MEDDEV 2.7/1 Rev.4, defines the methodology and requirements for drafting the Clinical Evaluation Plan (CEP) and Clinical Evaluation Report (CER). Various Medical Device Coordination Group (MDCG) guidelines are regularly published to clarify certain aspects, including clinical evaluation of software (MDCG 2020-1), orphan devices (MDCG 2024-10), equivalence (MDCGs 2020-5 and 2023-7), clinical evidence expected for legacy devices (MDCG 2020-6), or clinical evaluation of Annex XVI products (MDCGs 2023-5 and 2023-6). Deliverables from clinical evaluation, such as PMCF plans and reports or the Summary of Safety and Clinical Performance (SSCP), also have their own MDCG guidance (MDCGs 2020-7, 2020-8, 2019-9).

An ISO standard dedicated to clinical evaluation is under development, and certain Notified Bodies have published their own guidance documents to support manufacturers in conducting and writing clinical evaluations.

3. Methodological roadmap: structuring clinical investigations and clinical evaluations

3.1 Focus on clinical investigations

Clinical investigations follow strict protocols and are usually conducted under controlled conditions. They may be comparative, i.e., controlled (e.g., device under evaluation versus control device or placebo). They may involve random allocation of treatments (randomized studies), longitudinal follow-up (cohort studies), and other methodological considerations (blinding, patient questionnaires, specific medical examinations) adapted to the objectives of the investigation.

Conducting a clinical investigation is generally a lengthy process. Several years may pass between recruitment of participants and completion of patient follow-up to ensure long-term device safety. They require the involvement of various specialists for drafting scientific and medical documents (synopsis, clinical investigation plan, clinical report, etc.), clinical operations (regulatory submissions, coordination, monitoring), data management (collection and data quality), and statistics (sample size calculation, analyses). They necessarily involve healthcare professionals— whether affiliated with hospitals, clinics, or private practice— who play a key role in implementing the clinical investigation plan, recruiting participants, and ensuring follow-up.

When a clinical investigation is required, Regulation (EU) 2017/745 does not specify the number or scope of investigations. At a minimum, it requires at least one pivotal investigation generating pivotal data (MDCG 2023-7).

3.2 Focus on clinical evaluation

Clinical evaluation is based on the analysis of various types of data, whether favorable or unfavorable, including state-of-the-art data (e.g., scientific literature), preclinical tests, clinical studies, user surveys, risk analysis results, PMS data, and vigilance data for the device under evaluation or on similar devices.

To determine which types of data or evidence are required to demonstrate device safety, performance, and benefit-risk, a state-of-the-art review early on can be useful. A comprehensive review of the scientific literature allows manufacturers to: 

• Define the indications, intended purpose, and claims of the device under evaluation, from which the clinical evaluation strategy and types of supporting data will be derived.
• Identify existing technologies and their performance, determine evaluation criteria, and set benchmarks for performance and safety (laying the groundwork for a pre-market clinical study) (see our dedicated article).
• Identify risks applicable to the device that will feed into the risk analysis.

There are several strategies for conducting a clinical evaluation. For devices that do not have clinical performance or direct clinical benefit (e.g., surgical masks), Article 61(10) of Regulation (EU) 2017/745 allows demonstration of safety and performance based on non-clinical data. For devices with clinical performance or direct clinical benefit, clinical evaluation may rely on literature, own clinical data, equivalence, or “well-established technology (WET)” approaches.

4. Links between clinical evaluation and clinical investigation

In addition to confirming that performance, safety, and a positive benefit-risk balance are achieved in line with the device’s intended use, clinical evaluation also helps identify gaps between available data and expected data, particularly clinical data. When a lack of clinical data is identified (e.g., uncovered target population or indication), a PMCF study may be required to generate the missing data. This study is described in the PMCF plan, and once results are available, they are included in the PMCF report. This report enriches the clinical evaluation by providing the necessary data to fill the initially identified gap, thereby demonstrating device performance and safety across all intended uses.

5. When generating clinical data is not mandatory for high-risk devices

Clinical investigations are required for implantable devices and Class III devices (Regulation (EU) 2017/745, Article 61(4-6), MDCG 2023-7). However, they may be waived if the device under evaluation is a modification of a product already marketed by the same manufacturer, provided that equivalence between the two is demonstrated and validated by the Notified Body, and the clinical evaluation of the original device is sufficient to demonstrate conformity of the modified device. In this case, the Notified Body must verify that the PMCF plan is appropriate.

A manufacturer may also be exempted from generating its own clinical data if its clinical evaluation is based on an equivalent device marketed by another manufacturer, provided that there is a contract ensuring full access to the technical documentation, and that the equivalent device’s clinical evaluation complies with Regulation (EU) 2017/745. The equivalent device’s clinical data must be sufficient to demonstrate safety and performance of the device under evaluation for its intended conditions of use. The PMCF plan must include PMCF studies to confirm the performance and safety of the evaluated device.

Finally, clinical investigations are not required for certain implantable or Class III devices already compliant with the previous Directives (90/385/EEC or 93/42/EEC), or for specific devices considered WET (e.g., sutures, staples, screws), as long as their clinical evaluation relies on sufficient data and complies with applicable common specifications.

6. Conclusion

In summary, while clinical investigations and clinical evaluations of MDs share common objectives of ensuring safety and performance, they differ considerably in methodology, regulatory requirements, and implications for manufacturers. Understanding these differences is essential to navigating the complex regulatory landscape and ensuring that products brought to market comply with general safety and performance requirements.

Need help?

Our experts in clinical evaluation and investigation can advise and support you in:

• Choosing the best clinical strategy for your device,
• Defining your indications, intended purpose, and clinical/non-clinical claims,
• Conducting part or all of your clinical investigations through our scientific and medical, clinical operations, data management, and biostatistics teams,
• Drafting your state-of-the-art reviews, clinical evaluation documents, and PMCF documentation,
• Training your teams through our in-house training center,
• Quickly answering your questions through our hotline.

Contact us at: technicaldivision@efor-group.com