---
title: First-in-Human Studies Under MDR: Extra Requirements and Precautions
description: A first-in-human study under MDR demands extra pre-clinical evidence, sponsor rigour, and ethics oversight. Here is what Article 62 actually requires.
authors: Tibor Zechmeister, Felix Lenhard
category: Clinical Evaluation & Investigations
primary_keyword: MDR first-in-human study requirements
canonical_url: https://zechmeister-solutions.com/en/blog/first-in-human-studies-mdr
source: zechmeister-solutions.com
license: All rights reserved. Content may be cited with attribution and a link to the canonical URL.
---

# First-in-Human Studies Under MDR: Extra Requirements and Precautions

*By Tibor Zechmeister (EU MDR Expert, Notified Body Lead Auditor) and Felix Lenhard.*

> **A first-in-human study under MDR is the first time a device is used on a human subject for investigational purposes. It triggers every clinical investigation obligation in Articles 62 to 82 and Annex XV of Regulation (EU) 2017/745, plus an elevated pre-clinical evidence burden because there is no prior human data to rely on. The sponsor must demonstrate that bench testing, animal data where appropriate, risk management per EN ISO 14971:2019+A11:2021, and biocompatibility under EN ISO 10993-1:2025 together justify exposing the first human being to the device. The investigation must run under full ethics committee approval, full competent authority authorisation per Article 70 where required, and full Good Clinical Practice compliance under EN ISO 14155:2020+A11:2024. There is no lighter-touch version of a first-in-human investigation. If anything, the scrutiny is higher, not lower, because the first subject carries risk no earlier subject has absorbed.**

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

---

## TL;DR

- A first-in-human study is the first investigational use of a medical device on a human subject. Under MDR it is a full clinical investigation under Articles 62 to 82 and Annex XV — not a pilot, not a feasibility check, not an informal trial.
- The pre-clinical evidence burden is higher than for any later study because there is no prior human data. Bench testing, risk management per EN ISO 14971:2019+A11:2021, biocompatibility, and where appropriate animal data must carry the full safety argument.
- Competent authority authorisation under MDR Article 70 is almost always required for a first-in-human investigation, and the review is substantive.
- The sponsor must apply extra risk mitigation: conservative inclusion criteria, aggressive stopping rules, intensive monitoring, and a serious adverse event reporting process that works from day one under MDR Article 80.
- EN ISO 14155:2020+A11:2024 applies in full. There is no lean version of Good Clinical Practice for first-in-human studies. The standard is the floor.
- Testing on employees, founders, friends, or friendly clinicians outside an approved investigation is not a first-in-human study. It is an unlawful clinical use of a device and it ends companies.

---

## Why first-in-human matters differently

Felix has sat across the table from founders who thought the first-in-human study was a milestone to rush toward. It is not. It is the moment the risk profile of the entire project changes in a single afternoon. Every decision made in the two years before that afternoon is now being validated, or invalidated, on a human being who has trusted the sponsor to have done the work.

The expensive version of this story goes like this. A startup compresses the pre-clinical programme under investor pressure for "first clinical data." The risk file is thin in places nobody wants to talk about. The ethics committee receives an answer that is technically accurate but incomplete. The investigation is authorised. Then a device deficiency nobody had planned for shows up in the first five patients, the competent authority pauses the study, and six months of runway evaporate while the sponsor rebuilds an argument that should have been airtight on day one.

The disciplined version does not look heroic. The pre-clinical programme ran long. The risk analysis was painful because it was honest. The first subject was enrolled only when the sponsor, the principal investigator, and the ethics committee were each independently convinced the safety argument held. First-in-human is the step where shortcuts compound. Everything in this post is about making sure none of them are taken.

## What the MDR actually requires for a first-in-human investigation

A first-in-human investigation is not a distinct legal category in MDR. It is a clinical investigation in the sense of Article 62, and every obligation in Articles 62 to 82 and Annex XV applies without modification. What changes is how those obligations bind in practice when there is no prior human experience to lean on.

> *"Clinical investigations shall be designed, authorised, conducted, recorded and reported in accordance with the provisions of this Article and Articles 63 to 80, acts adopted pursuant to Article 81, and Annex XV."* — Regulation (EU) 2017/745, Article 62, paragraph 1.

Article 62(4) sets out the general conditions under which a clinical investigation may be conducted, including scientific and ethical review, authorisation by the member state concerned, a favourable ethics committee opinion, conduct by a suitably qualified investigator at a suitable site, and protection of the rights, safety, dignity and well-being of subjects. None of these preconditions is relaxed for a first-in-human study. All of them bind harder.

Article 63 governs informed consent. For a first-in-human study, the consent conversation must explicitly address the absence of prior human experience with the device. Article 64 sets out the additional protections for incapacitated subjects, and Articles 64 to 66 address further specific subject populations — first-in-human investigations in any of these populations face even higher scrutiny than first-in-human in healthy adult volunteers.

Article 70 governs the application procedure. For a first-in-human investigation of a device not yet CE marked, the sponsor submits an application to the competent authority of the member state in which the investigation will run, and the competent authority reviews the safety rationale, the pre-clinical data, the risk management file, the investigator's brochure, and the clinical investigation plan. The substantive depth of the review is higher for a first-in-human study because the authority is deciding whether to allow a device to be used on a human for the first time.

Article 72 sets out the sponsor's obligations for conducting the investigation. Article 80 requires the sponsor to record and report serious adverse events and device deficiencies within defined timeframes — a reporting process that has to be operational from the day the first subject is screened, not set up after enrolment begins. Annex XV specifies the content of the clinical investigation plan, the investigator's brochure, the device description, and the reporting requirements. EN ISO 14155:2020+A11:2024 is the harmonised standard operating across all of this, and applies in full to first-in-human investigations.

## The extra weight a first-in-human study carries

Three things are genuinely different for first-in-human, and the sponsor has to treat them as non-negotiable.

**The pre-clinical evidence burden is higher.** In a later study, prior human data absorbs part of the safety argument. In a first-in-human study, there is none. The full argument has to come from bench testing, simulated-use testing, biocompatibility under EN ISO 10993-1:2025 where material contact is in scope, electrical safety under EN 60601-1 where relevant, software verification and validation under EN 62304:2006+A1:2015 where software is part of the device, and — where the device and indication warrant it — animal data. The risk management file under EN ISO 14971:2019+A11:2021 must be current, complete, and traceable from hazard to control to residual risk acceptability. This is where the 600 to 3,000 pre-clinical tests a disciplined startup runs stop looking like over-engineering and start looking like the minimum viable safety argument.

**The risk mitigation inside the protocol has to be more conservative.** Inclusion criteria are tighter than they will be in any later study. Stopping rules are more aggressive. Monitoring intensity is higher. Follow-up is more frequent. The dose, duration, or usage window is stepped up cautiously, starting at the most conservative end of the planned range. The ethics committee and the competent authority expect these precautions, and a protocol that does not include them will be sent back.

**The sponsor capability to run the investigation must be real from day one.** Serious adverse event reporting under MDR Article 80 cannot be a process that "will be finalised before first enrolment." It has to be rehearsed. The monitoring plan has to name real monitors with real training. The data management system has to be live. The medical monitor has to be contactable. The principal investigator has to have run investigations before, or be paired with someone who has. First-in-human is not the study on which a sponsor learns to be a sponsor.

## A worked scenario: a Class IIb active device entering first-in-human

Consider a Class IIb active device developed by a small EU team. The device has completed bench testing, simulated-use testing on a validated physical model, a full risk analysis under EN ISO 14971:2019+A11:2021, biocompatibility evaluation of every patient-contacting material under EN ISO 10993-1:2025, electrical safety and EMC testing under the applicable parts of the EN 60601 series, and software verification and validation under EN 62304:2006+A1:2015. The sponsor has recruited one principal investigator who has run medical device investigations before.

The first-in-human investigation is designed to enrol 10 subjects under tight inclusion criteria, with staged enrolment — the first three subjects complete a defined observation window before the next three are enrolled. Stopping rules are written for defined safety signals. The investigator's brochure consolidates the pre-clinical evidence into a safety argument that addresses every foreseeable hazard in the risk file.

The sponsor submits the ethics committee application and the MDR Article 70 competent authority application in parallel where the national procedure permits. Both reviews generate questions. The sponsor answers them from the pre-clinical evidence base — not from "we will address this during the study." Approval arrives. The staged design catches a usability observation in subject two that leads to a protocol amendment and an IFU revision before subject four. The investigation completes, the report is written under Annex XV and EN ISO 14155:2020+A11:2024, and the data feeds into the clinical evaluation under MDR Article 61.

That is what a first-in-human investigation looks like when the sponsor has absorbed the extra weight in the right places.

## The first-in-human readiness playbook

Before the first subject is screened, the sponsor should be able to answer yes to all of the following.

1. The risk management file under EN ISO 14971:2019+A11:2021 is current, complete, and signed off.
2. The pre-clinical evidence base — bench, simulated-use, biocompatibility, electrical safety, software, animal data where appropriate — supports every claim in the investigator's brochure.
3. The investigator's brochure has been reviewed by the principal investigator and reflects what the device actually does today, not what the device was six months ago.
4. The clinical investigation plan complies with Annex XV in structure and content, and every endpoint traces to a GSPR claim in the clinical evaluation.
5. The ethics committee application is complete. Informal engagement with the committee has happened before formal submission.
6. The MDR Article 70 application to the competent authority is complete where required, and the sponsor can defend the pre-clinical safety argument in a review meeting.
7. The serious adverse event reporting process under MDR Article 80 is written down, rehearsed, and operational. The medical monitor is contactable.
8. The monitoring plan names a qualified monitor and a monitoring frequency appropriate for a first-in-human study.
9. Inclusion criteria, stopping rules, and staged enrolment design are conservative enough to protect subjects against the risks that cannot yet be quantified from human data.
10. Informed consent documents address the first-in-human nature of the investigation in plain language the subject can understand, per MDR Article 63.

If any of these is incomplete, the first subject is not ready to be screened. That is the whole playbook.

## Reality Check — Where do you stand?

1. Is your pre-clinical evidence base strong enough to carry the full safety argument without leaning on prior human experience that does not exist?
2. Have you built staged enrolment, conservative inclusion criteria, and explicit stopping rules into the protocol, or is the design modelled on a later-stage study?
3. Has your principal investigator run a first-in-human investigation before, or are they learning alongside you?
4. Is your MDR Article 80 adverse event reporting process rehearsed with a named medical monitor, or is it still a document to be finalised?
5. Can the investigator's brochure survive a substantive question from a competent authority reviewer about a specific hazard in the risk file?
6. Has any human exposure to the device already happened outside the boundaries of an ethics-approved investigation? If yes, stop and call a regulatory lawyer before anything else.

## Frequently Asked Questions

**Is a first-in-human study a separate regulatory category under MDR?**
No. MDR does not create a distinct legal category for first-in-human investigations. A first-in-human study is a clinical investigation under Article 62 and is bound by every obligation in Articles 62 to 82 and Annex XV. What makes it different is the weight of the pre-clinical evidence that has to carry the safety argument, not the statute.

**Do I always need competent authority authorisation under MDR Article 70 for a first-in-human investigation?**
In practice, for a first-in-human investigation of a device that is not yet CE marked, yes — Article 70 applies and the competent authority review is substantive. The exact procedure and scope of what must be authorised depends on the device class and the nature of the investigation. A sponsor planning a first-in-human study should assume the full Article 70 route applies and plan the submission accordingly.

**Can a first-in-human study be small to save money?**
Yes, small first-in-human investigations are common and appropriate. A staged 10-subject design can be the right answer where the scientific question allows it. Small is not the same as lightweight — the full Good Clinical Practice framework under EN ISO 14155:2020+A11:2024 still applies, and the sponsor obligations do not scale down with subject count.

**Do we need animal data before first-in-human?**
Sometimes. Whether animal data is required depends on the device type, the indication, the risk profile, and what bench and simulated-use testing can substitute for. For implantables and devices with novel material-tissue interactions, animal data is effectively non-negotiable. For others, comprehensive bench and simulated-use testing can carry the argument. The decision is made during risk management planning and defended in the investigator's brochure.

**What happens if a serious adverse event occurs in the first subject?**
The sponsor must report the event to the competent authority and the ethics committee under MDR Article 80 within the defined timeframes, and the protocol stopping rules determine whether enrolment pauses while the event is investigated. The staged enrolment design exists precisely so that a serious event in the first subject does not expose subjects two through ten before the sponsor understands what happened.

## Related reading

- [How to Run a Lean Clinical Investigation as a Startup with Limited Budget](/blog/lean-clinical-investigation-startup) — the operational playbook inside which first-in-human sits as the hardest case.
- [What Is a Clinical Investigation Under MDR?](/blog/what-is-clinical-investigation-mdr) — the definitional groundwork for everything in this post.
- [Pre-Clinical Testing and Documentation Under MDR](/blog/pre-clinical-testing-documentation) — the evidence base that carries the first-in-human safety argument.
- [The Clinical Investigation Plan Under MDR Article 62](/blog/clinical-investigation-plan-mdr-article-62) — the document that anchors the investigation.
- [Informed Consent Under MDR Article 63](/blog/informed-consent-mdr-article-63) — the specific requirements for subject consent, which bind harder in first-in-human studies.

## Sources

1. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, Article 62 (general requirements regarding clinical investigations conducted to demonstrate conformity of devices), Article 63 (informed consent), Article 64 (clinical investigations on incapacitated subjects), Article 70 (application for clinical investigations), Article 72 (conduct of a clinical investigation), Article 80 (recording and reporting of adverse events that occur during clinical investigations), Annex XV (clinical investigations). Official Journal L 117, 5.5.2017.
2. EN ISO 14155:2020+A11:2024 — Clinical investigation of medical devices for human subjects — Good clinical practice.
3. EN ISO 14971:2019+A11:2021 — Medical devices — Application of risk management to medical devices.
4. EN ISO 10993-1:2025 — Biological evaluation of medical devices — Part 1: Requirements and general principles for the evaluation of biological safety within a risk management process.

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*This post is part of the Clinical Evaluation & Clinical Investigations series in the Subtract to Ship: MDR blog. Authored by Felix Lenhard and Tibor Zechmeister. If you are preparing a first-in-human investigation and the pre-clinical evidence base, the investigator's brochure, and the competent authority submission all have to land at the same time, Zechmeister Strategic Solutions works with founders on exactly this readiness question.*

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*This post is part of the [Clinical Evaluation & Investigations](https://zechmeister-solutions.com/en/blog/category/clinical-evaluation) cluster in the [Subtract to Ship: MDR Blog](https://zechmeister-solutions.com/en/blog). For EU MDR certification consulting, see [zechmeister-solutions.com](https://zechmeister-solutions.com).*