A clinical investigation under MDR is a systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a medical device. It is defined in MDR Article 2(45), governed by MDR Article 62 and the framework of Articles 63 to 82 and Annex XV of Regulation (EU) 2017/745, and executed under the Good Clinical Practice standard EN ISO 14155:2020+A11:2024. A clinical investigation is mandatory for most implantable and Class III devices under MDR Article 61(4), with specific exemptions defined in Article 61(5) and (6) and clarified by MDCG 2023-7. For many other devices, a clinical investigation is one possible source of clinical evidence — not an automatic requirement — and a disciplined startup can often avoid one by building the clinical evaluation from literature, equivalence, and recognised standards instead.

By Tibor Zechmeister and Felix Lenhard. Last updated 10 April 2026.

TL;DR

  • A clinical investigation is a formal study on human subjects, defined in MDR Article 2(45) and governed by MDR Article 62, Articles 63 to 82, and Annex XV.
  • Clinical investigation is not the same as clinical evaluation. Clinical evaluation is the overall process of generating clinical evidence. Clinical investigation is one specific source of that evidence.
  • For implantable devices and Class III devices, clinical investigations are required as a general rule under MDR Article 61(4), with narrow exemptions in Article 61(5) and (6).
  • MDCG 2023-7 (December 2023) is the authoritative guidance on when an exemption under Article 61(4) to (6) actually applies.
  • For devices that are neither implantable nor Class III, a new clinical investigation is often avoidable when literature, equivalence, and harmonised standards cover the clinical claims.
  • A Graz-based company we worked with saved EUR 400,000 to 500,000 and 1 to 1.5 years by recognising that its established measurement methods were already covered by recognised standards, removing the need for pre-market clinical investigations on those aspects.
  • Every clinical investigation runs under EN ISO 14155:2020+A11:2024, requires ethics committee approval, and triggers sponsor obligations that do not scale down for small companies.

A Graz story: the clinical investigation that never had to run

A company in Graz came to us with a device built around two measurement methods. The methods were not new. They were established in the scientific literature, codified in recognised standards, and used in industry for years. What was new was the combination and the clinical use case.

Their first plan was the plan most founders reach for the moment they read the words "clinical evidence" in the MDR. Run clinical investigations. Two or three of them. Recruit patients, set up sites, fund a statistician, write protocols under EN ISO 14155:2020+A11:2024, submit to ethics committees, wait. The number on the budget line was the kind that turns a startup runway into a single row in a spreadsheet. One and a half years. Four to five hundred thousand euros. Possibly more.

The question we asked before agreeing to the plan was simple. Do the measurement methods have existing scientific validation in the literature? Yes. Are they covered by recognised standards that already address the specific performance characteristics in question? Yes. Is there a defensible argument that the clinical performance of these established methods does not need to be re-demonstrated from scratch, as long as the genuinely novel aspects of the intended purpose are addressed by other means?

The argument held. The Notified Body accepted it. The company saved EUR 400,000 to 500,000 and 1 to 1.5 years — not by avoiding the Regulation, but by reading it carefully. Their clinical evaluation under MDR Article 61 and Annex XIV Part A was built from literature and standards-based evidence. No new pre-market clinical investigation was required for those aspects. The investigation they never had to run is the cleanest illustration of the rule every founder should internalise before they commit to a study: the clinical investigation is not the default. It is one option among several, and the choice is governed by what the Regulation actually requires for your specific device.

This post is the companion to that lesson. It explains what a clinical investigation actually is under MDR, when you have to run one, when you can avoid one, and what the framework looks like once the decision is made.

What a clinical investigation actually is under MDR

MDR Article 2(45) defines a clinical investigation as "any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device." Four elements of that definition do most of the work.

First — systematic. An informal "let me try the device on a colleague and see what happens" is not a clinical investigation. It is unauthorised clinical use. A clinical investigation has a written plan, pre-specified endpoints, a defined statistical analysis, and a controlled execution.

Second — human subjects. Bench testing, simulated-use testing, animal studies, and usability evaluation on non-patient volunteers outside a clinical context are not clinical investigations under MDR Article 2(45). The moment a human subject is enrolled for the purpose of generating safety or performance data on the device, Article 62 and the rest of the Chapter VI framework apply.

Third — safety or performance of a device. The purpose of the study is to generate regulatory-grade evidence about the device itself, not about a disease, a procedure, or a comparator therapy unrelated to the device.

Fourth — the device is the subject of the study. The investigation is centred on the device's own performance or safety profile. This distinguishes clinical investigations from general clinical research that happens to involve a device peripherally.

A clinical investigation under MDR sits inside a broader legal framework. MDR Article 62 lays out the general requirements. Articles 63 to 82 cover informed consent (Article 63), the application and notification procedures (Article 70 and around it), sponsor obligations (Article 72), adverse event recording and reporting (Article 80), reporting at the end or after termination (Article 77), and the various procedural and oversight requirements that surround the study. Annex XV specifies, in detail, the content of the clinical investigation plan, the investigator's brochure, the documentation of the device under investigation, and the reporting obligations. And EN ISO 14155:2020+A11:2024 — Clinical investigation of medical devices for human subjects — Good clinical practice — is the harmonised standard that provides the operational rulebook for compliance.

A startup does not get to scale any of this down because it is small. A two-person company running a 20-subject investigation has the same sponsor obligations under Article 72 as a multinational running a 2,000-subject multi-centre Class III trial. What changes is the scope of the study, not the discipline required to run it.

Clinical evaluation vs clinical investigation — the distinction that trips up most founders

This distinction is the one founders miss most often, and it matters enormously for cost and timeline. We walk through it in depth in our pillar post What Is Clinical Evaluation Under MDR?, but here is the short version.

Clinical evaluation is the overall, ongoing, lifecycle process of generating, collecting, analysing, and assessing the clinical data pertaining to a device, in order to verify its safety, performance, and clinical benefits. It is defined in MDR Article 2(44), governed by Article 61, and structured by Annex XIV Part A. It applies to every medical device on the EU market without exception.

Clinical investigation is one specific source of clinical data that may feed into a clinical evaluation. It is a formal study on human subjects, defined in Article 2(45) and governed by Article 62 and Annex XV. It does not apply to every device. Many devices complete their clinical evaluation without ever running a new clinical investigation.

The shorthand that keeps founders out of trouble: every device needs clinical evaluation. Not every device needs a clinical investigation. Conflating the two is where startups commit to million-euro study budgets that the Regulation never required in the first place.

When a clinical investigation is mandatory — MDR Article 61(4)

MDR Article 61(4) establishes the general rule for implantable devices and Class III devices. For these devices, clinical investigations shall be performed, except where the device has been modified from a predecessor by the same manufacturer, or where reliance on existing clinical data meets specific conditions set out in Article 61(5) and (6).

The default, in other words, is that implantable devices and Class III devices need clinical investigations. This is the legal starting point. The exemptions are the exception. A founder of a novel Class III or implantable device should assume from day one that a pre-market clinical investigation is part of the project, and plan the runway accordingly. Discovering at month 18 that an investigation is required and was never planned is one of the most expensive regulatory mistakes in MedTech.

The general rule applies to the device itself. If a Class III or implantable device is genuinely novel — no predecessor, no equivalent device the manufacturer has access to, no common specification that would remove the requirement — then the clinical investigation is not optional. Under Article 62, Annex XV, and EN ISO 14155:2020+A11:2024, it must be designed, authorised, and executed before the device can be CE-marked.

When exemptions apply — MDCG 2023-7 and Article 61(5) and (6)

Article 61(5) and (6) define the narrow circumstances in which the general rule of Article 61(4) does not require a new pre-market clinical investigation. MDCG 2023-7 (Guidance on exemptions from the requirement to perform clinical investigations pursuant to Article 61(4) to (6) MDR and on 'sufficient levels of access' to data needed to justify claims of equivalence, December 2023) is the authoritative guidance on how these paragraphs are applied in practice.

MDCG 2023-7 clarifies four cases in which implantable and Class III devices may be exempted from the general requirement to run pre-market clinical investigations.

Case 1 — Modifications of a device already marketed by the same manufacturer. A new version is modified from a predecessor that the same manufacturer has already placed on the market, equivalence has been demonstrated, and the existing clinical evaluation is sufficient to cover the modified version.

Case 2 — Equivalence to a device marketed by another manufacturer. Strict conditions apply, including "sufficient levels of access" to the technical documentation of the equivalent device on an ongoing contractual basis. This is the case MDCG 2023-7 clarifies in the most practical detail, because the "sufficient levels of access" requirement is the part Notified Bodies scrutinise most carefully.

Case 3 — Devices previously placed on the market under the former Directives. Specific conditions on clinical data sufficiency and, where applicable, compliance with product-specific common specifications apply.

Case 4 — Certain well-established devices. A narrowly defined set of devices — sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips, and connectors — where the conditions of Article 61(6)(b) are met, clinical evidence is sufficient, and product-specific common specifications (if any) are complied with.

For most startups building genuinely novel implantable or Class III devices, none of the four cases apply. The exemptions exist for specific product histories and equivalence relationships, not for founders who would prefer to skip the study. Any founder who reads MDCG 2023-7 carefully and believes their situation fits one of the cases should verify that belief with an expert before committing to the exemption route — the cost of being wrong is measured in months of delay and a full investigation started far too late.

For a deeper treatment of these exemptions, see our dedicated post MDR Article 61(4) to (6) Exemptions from Clinical Investigation and MDCG 2023-7 Clinical Investigation Exemptions Explained.

When you choose to run a clinical investigation even if you are not required to

There are situations where a clinical investigation is not legally mandatory but is the right call anyway. Three come up most often.

The scientific question cannot be answered another way. Literature is thin. No equivalent device is accessible. The clinical claim is specific to the device and the intended purpose in a way that no existing data addresses. A targeted investigation is the only honest path to the evidence the clinical evaluation needs.

The Notified Body will not accept the alternatives. Even when an exemption or a literature-only route is technically defensible, some Notified Bodies — based on their experience with the product category — will push back on it and require a study. A smart sponsor has this conversation with the Notified Body early, not after the CER is written.

The commercial strategy depends on comparative evidence. The Regulation may not require a head-to-head comparison, but payers, clinicians, or key opinion leaders do. A well-designed investigation can serve both the regulatory file and the market entry story, as long as the regulatory side drives the primary endpoint and the commercial side rides along on secondary ones.

None of these is a reason to skip the Subtract to Ship discipline. Every investigation, whether mandatory or chosen, should still be scoped down to the minimum viable study that answers the specific question it exists to answer. See our companion post How to Run a Lean Clinical Investigation as a Startup with Limited Budget for the operational procedure.

The framework at a glance — Articles 62 to 82 and Annex XV

Once the decision is made to run a clinical investigation, the MDR framework is not optional or negotiable. Here is the skeleton.

Article 62 — General requirements. Investigations must be designed, authorised, conducted, recorded, and reported in accordance with Articles 62 to 80, acts adopted under Article 81, and Annex XV. The investigation must be scientifically sound. The rights, safety, dignity, and well-being of subjects must be protected. The risks must be justified by the expected benefits. The data must be reliable and robust.

Article 63 — Informed consent. Subjects must give freely given, informed, written consent before participation. The information provided must be comprehensible, complete, and honest about the risks and benefits.

Article 70 and surrounding articles — Application and notification. The sponsor submits an application to the competent authority of the member state or states where the investigation will run. Which authorities must be notified and which must authorise depends on the device class and the purpose of the investigation.

Article 72 — Sponsor obligations for conducting the investigation. The sponsor is responsible for the integrity of the investigation and for compliance with the Regulation. Sponsor obligations do not scale down for small companies.

Article 77 — Reporting at the end, temporary halt, or early termination. The sponsor submits a clinical investigation report within defined timeframes after the end of the investigation or after a halt or termination.

Article 80 — Recording and reporting of serious adverse events and certain device deficiencies that occur during the investigation, within defined short timelines, to the competent authority and to the ethics committee as required by national procedure.

Articles 63 to 82 as a whole — Cover informed consent of incapacitated subjects, minors, pregnant and breastfeeding women, emergency situations, damages compensation, communication between member states, withdrawal and rejection of applications, corrective measures, and related procedural provisions.

Annex XV — Specifies, in detail, the content of the clinical investigation plan, the investigator's brochure, the documentation of the device under investigation, and the reporting requirements.

EN ISO 14155:2020+A11:2024 — The harmonised Good Clinical Practice standard. It is the operational floor for compliance with Articles 62 to 82 and Annex XV. It covers sponsor, investigator, and ethics committee responsibilities, the content of the investigation plan, informed consent procedures, data management, monitoring, adverse event handling, reporting, and archiving.

None of this is abstract. Every single one of these articles and annex provisions applies to your investigation if you run one, and the Notified Body and the competent authority will expect to see traceable compliance with each of them.

Ethics and sponsor obligations

Two parts of the framework deserve a closer look because they are the two places founders most often underestimate the workload.

Ethics committee approval. No clinical investigation under MDR may start without approval from the ethics committee of the member state or states where the study runs. The submission is built from the clinical investigation plan required by Annex XV, the investigator's brochure, the informed consent documents required by Article 63, insurance documentation, principal investigator CVs, and whatever national-specific forms the committee requires. The ethics committee process is governed partly by national law, which is why the specifics differ between member states. What does not differ is the absolute nature of the approval requirement. No approval, no investigation. No exceptions. No "informal pilot" that the competent authority will later accept as legitimate evidence.

Sponsor obligations. Under Article 72 and EN ISO 14155:2020+A11:2024, the sponsor — the legal entity that takes responsibility for the investigation — is accountable for the integrity of the study, the quality of the data, the safety of subjects, the qualification of investigators, the maintenance of the investigational device, the monitoring of the sites, the reporting of adverse events, the archiving of records, and the final report. For a startup, the sponsor is typically the company itself. Taking on sponsor obligations requires genuine competence in clinical operations, monitoring, data management, and regulatory reporting. Small sponsors can meet these obligations — often with support from advisors or contract research organisations for specific functions — but they cannot ignore them or outsource them invisibly.

Our dedicated post Sponsor Obligations Under MDR Articles 62 and 72 walks through the sponsor role in detail.

Common founder misunderstandings

A short list of the mistakes we see most often when founders first encounter this topic.

"We need a clinical trial" as shorthand for "we need clinical evidence." Clinical evidence is the broad requirement. Clinical investigation is one way to produce it. Conflating the two leads directly to over-scoped study budgets.

"We can test the device informally before the real study starts." No, you cannot. Any systematic use of the device on human subjects for the purpose of generating safety or performance data is a clinical investigation under Article 2(45) and requires full ethics committee approval and the applicable authority notifications. There is no informal pre-investigation exemption.

"Our Class III device is basically like the one X makes, so we can claim equivalence." Maybe. Equivalence under MDR and MDCG 2020-5 is strict. For implantable and Class III devices, MDCG 2023-7 clarifies that "sufficient levels of access" to the equivalent device's data typically requires an ongoing contract between the manufacturers. A one-off data purchase or a public comparison is not enough.

"We will start the investigation after we finish the technical file." Wrong direction. The clinical evaluation (which includes the results of any clinical investigation) is part of the technical documentation submitted for conformity assessment. For devices that require a new investigation, the investigation must be completed and the results integrated into the CER before the technical file is ready for Notified Body review.

"A smaller study means weaker evidence." A well-designed small study answers its scientific question better than an over-enrolled large study that was designed by committee. The Notified Body is not impressed by sample size for its own sake. They are impressed by studies that map cleanly onto the clinical claims in the intended purpose.

The Subtract to Ship angle

Clinical investigation is the highest-stakes application of the Subtract to Ship Evidence Pass. The pass runs in a specific order and the order matters.

First, define the intended purpose tightly and honestly, in the form that will appear on the label, the IFU, and the clinical evaluation itself. Second, identify the specific GSPRs that actually require clinical evidence — not all of them do. Third, for each piece of clinical evidence needed, evaluate the three data sources in order of cost: literature, equivalence (under MDCG 2020-5 and for implantable/Class III devices under MDCG 2023-7), and clinical investigation. Fourth, assemble the clinical evaluation plan around the cheapest combination of sources that genuinely answers the questions the GSPRs pose. Fifth, only then — and only for the gaps the first three sources cannot close — design the clinical investigation.

The Graz story at the start of this post is a textbook Evidence Pass. The company started with "we need to run clinical investigations." The pass reversed the order. Literature first. Standards second. Equivalence where applicable. Clinical investigation only for the genuinely novel aspects — and in that specific case, no investigation was needed at all. The result was a clinical evaluation that satisfied MDR Article 61 and Annex XIV Part A, withstood Notified Body scrutiny, and cost a fraction of the original plan.

This is not a permission slip to avoid required work. When MDR Article 61(4) applies, when the four exemptions of MDCG 2023-7 do not fit, when literature and equivalence cannot answer the scientific question, the clinical investigation is the right answer and it must be done properly. The Evidence Pass is the discipline of not defaulting to the most expensive pathway before the cheaper ones have been honestly evaluated. Our methodology pillar The Subtract to Ship Framework for MDR Compliance covers the pass in full.

Reality Check — Where do you stand?

  1. Can you tell the difference, in one sentence each, between a clinical evaluation and a clinical investigation, without conflating the two?
  2. Is your device implantable or Class III? If yes, have you read MDR Article 61(4) and MDCG 2023-7 and checked whether any of the four exemption cases apply to your specific situation?
  3. If your device is not implantable and not Class III, have you honestly evaluated literature and equivalence routes before defaulting to a clinical investigation?
  4. Do you know which specific claims in your intended purpose require clinical evidence, and which can be supported by other means?
  5. If you are planning an investigation, can you write the single scientific question it is designed to answer on one line, without hedging?
  6. Have you budgeted for the full sponsor obligations under MDR Article 72 and EN ISO 14155:2020+A11:2024, or only for the "visible" parts of the study (sites, patients, monitoring)?
  7. Is the ethics committee pathway in your planned member state or states clear, and do you know the national procedure for application and approval?
  8. Have you mapped the reporting obligations of MDR Article 80 (adverse events) and Article 77 (end-of-investigation reporting) and assigned them to specific people in your team?
  9. Does your pre-clinical test programme (bench, simulated use, biocompatibility, electrical safety, software verification) genuinely support the safety argument the competent authority will expect to see before they authorise the investigation?
  10. If an investigation is mandatory under Article 61(4) and none of the MDCG 2023-7 exemptions fit, is the investigation on your project timeline early enough that it will not become the critical path that blocks CE marking?

Frequently Asked Questions

What is the legal definition of a clinical investigation under MDR? MDR Article 2(45) defines a clinical investigation as "any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device." The definition is broad enough to cover any structured study on humans whose purpose is to generate safety or performance data on a medical device. The framework around it — Articles 62 to 82 and Annex XV of Regulation (EU) 2017/745 — is the binding legal basis, and EN ISO 14155:2020+A11:2024 is the harmonised Good Clinical Practice standard that operationalises compliance.

When is a clinical investigation mandatory under MDR? As a general rule, clinical investigations are mandatory for implantable devices and for Class III devices under MDR Article 61(4). The exemptions are defined in Article 61(5) and (6) and clarified by MDCG 2023-7 (December 2023). For devices that are neither implantable nor Class III, a new clinical investigation is not automatically required; the clinical evaluation under Article 61 can often be built from literature, equivalence, and recognised standards, provided the evidence is sufficient for the claims in the intended purpose.

Can a startup avoid a clinical investigation under MDR? Sometimes, yes, but only through legitimate pathways defined by the Regulation. For non-implantable, non-Class III devices, a clinical evaluation built from literature, equivalence (under MDCG 2020-5), and harmonised standards can often satisfy MDR Article 61 without a new investigation. For implantable and Class III devices, the four exemption cases in Article 61(5) and (6) as clarified by MDCG 2023-7 are narrow and must be demonstrated rigorously. "Avoiding" an investigation by running one informally without ethics approval is illegal and career-ending — it is not an option and should not be considered one.

What is the difference between MDR Article 61 and MDR Article 62? Article 61 governs clinical evaluation — the overall process of generating and assessing clinical evidence for a device — and it is the article that establishes when clinical investigations are required (paragraphs 4 to 6) and when exemptions apply. Article 62 governs clinical investigations specifically — the general requirements for how an investigation must be designed, authorised, conducted, recorded, and reported when one is undertaken. Article 61 decides whether you need an investigation. Article 62 governs how you run one once you do.

Do I need ethics committee approval for every clinical investigation? Yes. Every clinical investigation on human subjects under MDR requires ethics committee approval in each member state where the investigation runs. This is not a formality and cannot be skipped, deferred, or worked around. National procedures for which committee reviews and how the submission is structured differ between member states, but the absolute requirement for approval before the first subject is enrolled does not.

What standard governs Good Clinical Practice for MDR investigations? EN ISO 14155:2020+A11:2024 — Clinical investigation of medical devices for human subjects — Good clinical practice. It is the harmonised standard that provides the operational framework for compliance with MDR Articles 62 to 82 and Annex XV, covering sponsor, investigator, and ethics committee responsibilities, the content of the clinical investigation plan, informed consent, data management, monitoring, adverse event handling, reporting, and archiving.

How long does it take to set up a clinical investigation under MDR? For a disciplined single-site or two-site startup investigation, the time from first protocol draft to first subject enrolled is typically measured in many months — driven by the clinical investigation plan drafting, the ethics committee submission and review, the competent authority application under Article 70 and the surrounding provisions, the site contracts and training, and the insurance and logistics setup. A realistic plan includes meaningful contingency for review cycles. Starting the process late is the single most common reason investigations become the critical path that blocks CE marking.

Sources

  1. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, Article 2(45) (definition of clinical investigation), Article 61 (clinical evaluation), Article 61(4)-(6) (clinical investigations for implantable and Class III devices and exemptions), Article 62 (general requirements regarding clinical investigations conducted to demonstrate conformity of devices), Articles 63 to 82 (clinical investigations framework), Annex XV (clinical investigations). Official Journal L 117, 5.5.2017.
  2. MDCG 2023-7 — Guidance on exemptions from the requirement to perform clinical investigations pursuant to Article 61(4)-(6) MDR and on 'sufficient levels of access' to data needed to justify claims of equivalence, December 2023.
  3. EN ISO 14155:2020+A11:2024 — Clinical investigation of medical devices for human subjects — Good clinical practice.

This post sits in the Clinical Evaluation & Clinical Investigations cluster of the Subtract to Ship: MDR blog. Authored by Felix Lenhard and Tibor Zechmeister. If you are trying to decide whether your device actually requires a clinical investigation — and whether MDCG 2023-7 offers a legitimate path around one — Zechmeister Strategic Solutions works with founders on exactly that decision, where the Regulation, the device, and the runway have to agree on the same answer.