MDCG 2024-5 Investigator’s Brochure: MDR Content Checklist

Preparing an Investigator’s Brochure (IB) for an EU medical device clinical investigation is not simply a matter of completing a regulatory template. The document needs to give investigators, site teams, ethics committees and competent authorities a coherent picture of the device, the evidence already available, the remaining uncertainties and the measures that will protect subjects during the investigation.

MDCG 2024-5 provides detailed guidance on how sponsors should prepare the Investigator’s Brochure required under the EU Medical Devices Regulation (MDR).

The objective is not to reproduce the full technical documentation or create the longest possible document. The IB should present the information that is relevant to the investigation in a concise, objective, balanced and non-promotional form that investigators can actually use.

For sponsors preparing an application or reviewing an existing IB, the most important question is therefore not only whether every required section exists, but whether the document explains what is known about the device, what remains uncertain and how those uncertainties are being managed in the clinical investigation.

The main regulatory and standards references are:

Reference	Role in the Investigator’s Brochure
Regulation (EU) 2017/745, Annex XV Chapter II	Establishes the documentation required for applicable clinical investigation submissions, including the Investigator’s Brochure.
MDR Article 71(4)	Allows a Member State to refuse an investigation when the submitted documents, particularly the Clinical Investigation Plan (CIP) and IB, do not correspond to the state of scientific knowledge.
MDCG 2024-5	Provides detailed guidance and a cross-reference checklist for compiling and reviewing the IB.
ISO 14155:2026	The current international edition of the Good Clinical Practice standard for clinical investigations of medical devices.
EN ISO 14155:2020 with A11:2024	The edition currently cited as a harmonised standard under the MDR.

When is an Investigator’s Brochure required under the EU MDR?

One of the first questions sponsors should resolve is which regulatory pathway applies to the planned investigation.

This is particularly important for CE-marked devices. A CE mark does not automatically mean that an Investigator’s Brochure is irrelevant.

The device’s regulatory status, the purpose of the investigation and whether the device is being studied within or outside its intended purpose all affect the applicable MDR pathway.

Clinical investigation scenario	MDR pathway	Investigator’s Brochure
Investigation conducted for one of the purposes in MDR Article 62(1), with an application under Article 70	Articles 62 and 70	The application includes the Annex XV Chapter II documentation, including the IB.
CE-marked device studied within its intended purpose as a PMCF investigation, where subjects undergo additional invasive or burdensome procedures	Article 74(1)	The notification includes the Annex XV Chapter II documentation, including the IB.
CE-marked device investigated outside the scope of its intended purpose	Article 74(2)	Articles 62 to 81 apply, bringing the relevant clinical investigation documentation requirements into scope.
Other clinical investigations not performed for an Article 62(1) purpose	Article 82	Member States may define additional national requirements, so the requirements must be assessed country by country.

This distinction is one that David Tome, President and former Head of Clinical Operations at MDx CRO, sees sponsors misunderstand in practice:

“The mistake I see most often is with CE-marked devices. Some sponsors think that once the device has a CE mark, the IB is no longer relevant. I would not look at it that way. I would first ask, what regulatory pathway are you using, and are you studying the device within or outside its intended purpose?”

David Tome | President at MDx CRO

Where the correct pathway is uncertain, sponsors should resolve that question before finalising the submission package. Our guide to MDCG 2021-6 Rev. 1 and EU MDR clinical investigation pathways examines Articles 62, 74 and 82 in greater detail.

What an MDR Investigator’s Brochure must enable

The Investigator’s Brochure has several audiences, but its primary practical purpose is to give investigators and site teams enough relevant information to understand the device and conduct the investigation safely.

A useful IB should allow them to:

• understand the investigational device, its intended purpose and its stage of development;
• identify exactly which model, configuration, accessories and software version are being investigated;
• assess the relevant clinical and non-clinical evidence;
• understand known and foreseeable risks, contraindications, warnings and residual uncertainties;
• understand how the device should be used safely and correctly;
• evaluate the available evidence supporting exposure of participants to the investigational device; and
• identify the information and training required before using the device.

The IB should also be consistent with the Clinical Investigation Plan, risk-management documentation, instructions for use, investigation-specific training and the actual device configuration supplied to sites.

That consistency is critical. A technically complete IB can still generate questions if the device, risks or procedures described in it do not match the rest of the clinical investigation dossier.

MDCG 2024-5 Investigator’s Brochure content checklist

MDCG 2024-5 provides sponsors with a structured approach for compiling and reviewing the content of the Investigator’s Brochure.

The following checklist translates those requirements into the main areas that should be addressed during preparation and pre-submission review.

1. Document identification and control

Clearly identify the Investigator’s Brochure and the version being used.

Include:

• document title;
• document number;
• version;
• release date;
• sponsor;
• manufacturer;
• investigational device; and
• revision history.

The revision history should identify what changed, why the document was revised and which previous version it replaces.

Document control should make it possible to confirm that investigators, sites and reviewers are using the correct current version.

2. Device identification and intended purpose

Describe the investigational device clearly enough that an investigator or reviewer can distinguish it from other models, configurations or generations.

Include, where applicable:

• device name, model and relevant identifiers;
• manufacturer;
• device classification and regulatory status;
• intended purpose;
• indications;
• contraindications;
• intended users;
• target patient population;
• operating principle or mechanism of action;
• accessories and components;
• software;
• configurations or variants included in the investigation;
• previous or alternative versions of the device; and
• CE-marking status.

If the device is already CE marked, state whether it is being investigated within or outside its intended purpose.

Where the investigation involves a use outside the existing intended purpose, clearly explain how the investigational use differs and whether this creates additional or different risks.

The description needs to be sufficiently practical for the investigator to understand which exact device is being studied and how it is expected to be used.

This is an area where apparently small omissions can become significant.

David explains:

“Sometimes you read the IB and you still do not have a clear picture of exactly what device is being investigated or how the investigator is supposed to use it. That becomes a real issue when you have different configurations, accessories, software versions, or a procedure that depends a lot on user technique. The investigator should be able to understand what the device is, how it works, how to use it, and what the main limitations are.”

David Tome | President at MDx CRO

3. Design, development and manufacture

Summarise the design and development information that is relevant to the clinical investigation and to the safe use of the device.

The IB should not reproduce the complete technical documentation. Instead, select the information that helps investigators and reviewers understand the device being investigated.

Depending on the device, this may include:

• relevant materials;
• patient-contacting components;
• energy sources;
• software functions;
• sterility;
• packaging;
• storage conditions;
• expected service life;
• manufacturing considerations relevant to safety or performance; and
• design changes affecting the investigational configuration.

Where the device has evolved during development, clearly identify which version is used in the investigation.

The IB, CIP, device labelling, training materials and physical or software configuration supplied to sites should all refer to the same investigational device.

4. Non-clinical evidence

Summarise and evaluate the non-clinical evidence relevant to the device and its proposed clinical use.

Depending on the technology, this may include:

• bench and performance testing;
• verification and validation;
• design calculations;
• mechanical testing;
• electrical safety;
• reliability and durability testing;
• software verification and validation;
• biocompatibility and biological safety;
• sterilisation validation;
• animal studies;
• in vitro or ex vivo testing; and
• usability or human factors evidence.

A common weakness is reducing this evidence to a statement that the device “passed testing”.

The investigator and reviewer need more than the conclusion.

The IB should explain:

1. what was evaluated;
2. what the results demonstrated;
3. what relevant limitations or uncertainties remain; and
4. why the totality of the available evidence supports proceeding to the proposed clinical investigation.

David sees this frequently during review:

“Very often, the manufacturer actually has the information, but the IB does not tell the story properly. You may have bench testing, verification and validation, biocompatibility, animal data, usability data, or information from previous device versions, but only a small part of that appears in the IB. The sponsor says, ‘the device passed all testing,’ but that is not enough. I want to understand what was tested, what the results showed, what is still uncertain, and why the available evidence supports moving into the clinical investigation.”

David Tome | President at MDx CRO

The goal is not to overwhelm investigators with raw reports. It is to translate the relevant evidence into a clear explanation of the device’s state of development and remaining clinical questions.

5. Existing clinical evidence

Present the available clinical information relevant to the safety, performance and expected clinical benefit of the investigational device.

This may include evidence from:

• previous clinical investigations;
• ongoing investigations;
• published scientific literature;
• post-market experience, where applicable;
• earlier generations of the device;
• comparable devices;
• complaints;
• adverse events;
• device deficiencies;
• corrective actions; and
• experience with the device in other markets.

Be clear about the origin of the evidence.

Evidence generated with the actual investigational device should not be presented as equivalent to evidence generated with a previous generation or a different device without explaining the relationship.

Where evidence gaps remain, identify them directly and explain how the proposed investigation is intended to address them.

This makes the rationale for the investigation easier to understand and reduces the risk that the IB appears to present existing evidence more strongly than it supports.

6. Benefit-risk analysis and risk management

Summarise the benefit-risk analysis and risk-management information relevant to the investigational device and the clinical investigation.

Include, as appropriate:

• known and foreseeable device-related risks;
• risks associated with investigation-specific clinical procedures;
• undesirable side effects;
• contraindications;
• warnings;
• precautions;
• residual risks following risk controls;
• relevant risk acceptability considerations;
• measures used to prevent, identify or mitigate harm;
• risks associated with investigational use outside an existing intended purpose; and
• how relevant safety information will be monitored during the investigation.

The IB should not operate as an isolated summary of the risk-management file.

For every clinically important risk, the sponsor should consider what that risk means for the actual conduct of the study.

For example, it may affect:

• eligibility or exclusion criteria;
• additional subject monitoring;
• follow-up;
• investigator training;
• stopping criteria;
• emergency procedures; or
• device-use instructions.

David considers this alignment one of the most important aspects of IB review:

“I often see an IB where the risks are described, but the connection with the actual study is weak. If a risk is important enough to appear in the IB, I would expect to see how it is managed in the CIP. For me, the IB, the risk management file and the CIP need to be aligned. If they are telling three slightly different stories, that normally creates questions.”

David Tome | President at MDx CRO

A good review therefore does not ask only whether a risk appears in the IB. It asks whether the same risk is consistently recognised and managed across the entire investigation package.

7. Devices incorporating medicinal substances or tissues

Where relevant, provide the information required for devices incorporating:

• a medicinal substance;
• human blood or plasma derivatives; or
• non-viable tissues or cells of human or animal origin, or their derivatives.

Describe the relevant constituent, its source and function, associated risks and risk-control measures, and the rationale for its incorporation into the device.

Where the requirement is not applicable to the investigational device, state that explicitly rather than leaving the section unanswered.

8. General Safety and Performance Requirements

Explain how the applicable General Safety and Performance Requirements in MDR Annex I have been addressed at the stage of development reached by the investigational device.

Identify, as relevant:

• harmonised standards applied;
• other standards or specifications applied;
• standards applied only in part;
• alternative solutions used to address requirements;
• requirements that are not applicable, with justification; and
• aspects of conformity that remain subject to clinical investigation.

Use clear references to the supporting evidence.

Avoid duplicating a complete technical-documentation GSPR checklist inside the IB when a controlled reference provides a clearer and more maintainable way for reviewers to locate the relevant information.

9. Safe and correct use during the investigation

The IB should give investigators and site personnel the information required to use the device correctly and respond appropriately to foreseeable problems.

Depending on the device, address:

• preparation;
• installation;
• configuration;
• setup;
• operating instructions;
• investigator or site training;
• storage;
• handling;
• transport;
• cleaning;
• disinfection;
• sterilisation;
• calibration;
• maintenance;
• emergency procedures;
• device accountability;
• device return;
• device deficiencies; and
• safety-event reporting.

Instructions should be consistent with the labelling, investigation-specific instructions and training materials provided to sites.

For devices where performance depends strongly on technique or user interaction, this section deserves particular attention.

How should the IB be adapted for software and complex devices?

A generic Investigator’s Brochure template should not determine the content of the document.

The IB needs to reflect the technology actually being investigated.

Software is a common example of where traditional templates can create problems. A document originally designed around a physical device may contain several pages on materials, sterilisation and packaging while providing very little explanation of how the software works or how its output should be interpreted.

For medical device software, relevant information may include:

• the software version used in the investigation;
• key system components;
• relevant interfaces and dependencies;
• the principal data inputs;
• outputs generated by the software;
• how those outputs are intended to be used;
• known failure modes;
• limitations;
• behaviour when data are incomplete or incorrect;
• required hardware or operating environment;
• relevant user interaction;
• update or configuration controls; and
• cybersecurity considerations where they could affect safety or performance.

The appropriate level of detail depends on the device and the investigation.

The objective is to provide the investigator with enough information to understand how the system behaves, how its output should be used and where its limitations could affect clinical use.

As David puts it:

“For software, I want the investigator to understand what goes into the system, what comes out, how the output is used, and where the limitations are. The main point is that you should adapt the IB to the actual device. Do not force a complex software device into a generic template and assume that is enough.”

David Tome | President at MDx CRO

For further guidance on software under the MDR, see our Software, Digital Health & AI regulatory services.

10. References, annexes and traceability

MDCG 2024-5 encourages sponsors to make the information needed by the investigator available within the IB.

Detailed supporting evidence can still be maintained in annexes or other controlled documents, but references need to be precise.

Where information is located elsewhere, identify:

• document title;
• document number;
• version;
• section; and
• page, where appropriate.

Avoid vague references such as “see technical documentation”.

The investigator or reviewer should be able to locate the evidence without reconstructing the entire technical file.

MDCG 2024-5 Appendix A is particularly useful for mapping individual MDR requirements to their location in the IB or wider application dossier.

Three gaps that commonly create questions during IB review

An Investigator’s Brochure can contain all of the expected headings and still be difficult to review.

In David’s experience, three recurring weaknesses are particularly important.

The evidence exists, but the IB does not explain what it means

The manufacturer may have substantial bench, verification, validation, biological safety, usability or previous-generation evidence.

The problem is sometimes not a lack of evidence but a lack of synthesis.

An effective IB explains what the relevant evidence demonstrates and where uncertainties remain. It gives the reader enough context to understand why the investigation is an appropriate next step.

Risk management is disconnected from study conduct

Risks should not appear in one document while the measures used to control them appear disconnected in another.

The relationship between the IB, risk-management documentation and CIP should be visible.

If an important risk requires additional monitoring, investigator training, an exclusion criterion or a stopping rule, the clinical investigation documentation should reflect that consistently.

The exact investigational device is not clear

This is particularly problematic for:

• devices with multiple configurations;
• systems with accessories;
• devices that have changed between development stages;
• software with multiple versions;
• combination systems; and
• procedures where performance depends on user technique.

A reviewer should not need to compare several documents simply to determine which configuration is actually being investigated.

Four steps for reviewing an Investigator’s Brochure before submission

A final review should go beyond proofreading the IB itself.

Step 1: Map every applicable requirement

Use MDCG 2024-5 Appendix A to map each relevant Annex XV requirement to the document, section and page where it is addressed.

If an item is not applicable, document the rationale.

If evidence is missing, distinguish a genuine evidence gap from information that exists elsewhere but has not yet been incorporated or referenced correctly.

Step 2: Review the IB, CIP and risk-management documentation together

David’s preferred final check is simple:

“I would put the IB, the CIP and the risk management documentation next to each other and compare them. That is probably the most useful final check you can do.”

David Tome | President at MDx CRO

Compare at least:

• device description;
• investigational configuration;
• intended purpose;
• study population;
• key risks;
• warnings;
• contraindications;
• instructions for use; and
• relevant risk-control measures.

For each important risk, ask:

1. Is it adequately explained in the IB?
2. Is it supported and controlled in the risk-management documentation?
3. Does the CIP show how it will be managed during the investigation?

Small inconsistencies between documents can be easy to miss when each document is reviewed independently.

Step 3: Record gaps and applicability decisions

Document:

• missing evidence;
• incomplete analyses;
• unresolved inconsistencies; and
• requirements considered not applicable.

Provide a justification for applicability decisions and assign responsibility for each unresolved item before submission.

Not every gap necessarily prevents the investigation from proceeding, but unexplained gaps make it difficult for a reviewer to understand what is known and what remains uncertain.

Step 4: Release and distribute a controlled version

Complete the required scientific, regulatory, clinical and quality reviews.

Then:

• approve the controlled version;
• archive the superseded version;
• maintain the revision history; and
• document distribution to investigators and relevant sites.

The version referenced in the submission package should correspond to the version being used operationally.

When should the Investigator’s Brochure be updated during an active investigation?

The Investigator’s Brochure is not a document that should be finalised at submission and then ignored for the remainder of the investigation.

Under MDR Annex XV, relevant newly available information and updates to the IB should be brought to investigators’ attention in a timely manner.

Potential triggers for review include:

• new safety information;
• new adverse-event information;
• relevant new clinical evidence;
• relevant new non-clinical evidence;
• newly identified risks;
• changes to existing risk estimates;
• device changes;
• software changes;
• new warnings or contraindications;
• new limitations; and
• changes that affect how the device should be used or subjects monitored.

David uses a practical test:

“Does this information change how the investigator should use the device, monitor the subject, or assess risk? If the answer is yes, you should assess whether the IB needs to be updated.”

David Tome | President at MDx CRO

Where an update is needed, document control should remain clear:

1. issue a new version and date;
2. record what has changed;
3. maintain the revision history;
4. approve the new controlled version; and
5. document communication and distribution to investigators and sites.

The sponsor should then assess the regulatory impact of the underlying change separately.

An IB update does not automatically mean that the investigation has undergone a substantial modification.

Under MDR Article 75, a modification is considered substantial when it is likely to have a substantial impact on the safety, health or rights of subjects, or on the robustness or reliability of the clinical data generated by the investigation.

Where that threshold is met, the sponsor must follow the applicable substantial-modification procedure and submit the updated relevant documentation.

This distinction is important: document control answers what information investigators need now, while the regulatory assessment determines whether the change also requires formal notification or authorisation before implementation.

National processes should also be checked for every Member State involved in the investigation.

MDCG 2024-5 and ISO 14155:2026

MDCG 2024-5 was published in April 2024, when ISO 14155:2020 was the current edition of the international Good Clinical Practice standard for medical device clinical investigations.

ISO published the fourth edition, ISO 14155:2026, in March 2026.

Sponsors should distinguish between two related but different concepts:

• ISO 14155:2026 is the current international ISO edition.
• EN ISO 14155:2020, together with A11:2024, remains the version currently cited as a harmonised standard under the MDR.

Harmonised standards are voluntary. When their references are published in the Official Journal of the European Union, their use can provide a presumption of conformity with the MDR requirements covered by the standard.

Sponsors should therefore not treat publication of a new ISO edition and EU harmonisation as the same event.

For an EU clinical investigation being planned today, MDCG 2024-5 remains the MDR-specific reference for structuring and cross-referencing the Investigator’s Brochure. The implications of the newer ISO edition should be assessed as part of the investigation’s Good Clinical Practice and state-of-the-art framework while taking account of the harmonisation status applicable under the MDR.

For a detailed discussion of the new edition, see ISO 14155:2026: What Changed and What It Means for Your Clinical Investigation.

Frequently asked questions

Preparing an IB that works as part of the complete submission

The strongest Investigator’s Brochures do more than satisfy a content checklist.

They allow an investigator or reviewer to follow a clear chain:

1. this is the device being investigated
2. this is what we already know about it
3. these are the remaining risks and uncertainties
4. this is how those risks are controlled in the study
5. this is the information investigators need to use the device and protect participants

Before submission, one of the most useful checks is therefore to review the Investigator’s Brochure, Clinical Investigation Plan and risk-management documentation together.

If the device description, intended purpose, key risks, warnings, contraindications or risk controls differ between those documents, resolve the inconsistency before submission rather than expecting the reviewer to interpret it.

MDx CRO supports medical device sponsors with clinical investigation strategy, Investigator’s Brochure and Clinical Investigation Plan development and review, risk and evidence alignment, EU submissions, study management and clinical investigation reporting.

Explore our MedTech Clinical Solutions or contact MDx CRO to discuss your planned clinical investigation.