MDCG 2024-3: What the Latest Guidance on Clinical Investigation Plans (CIP) Tells Us

A clinical investigation plan (CIP) is the document in which the investigation’s sponsor will lay out the rationale, objectives, design, conduct, record-keeping and analysis methods for the clinical study they want to carry out. It’s meant to be a comprehensive and detailed manual for the investigators, ethics committee, and competent authorities who will review the proposed study before it can begin.

Given how much information needs to be included in the CIP—and how much rides on its approval—it’s essential that sponsors are able to include all necessary elements. To that end, the Medical Device Coordination Group (MDCG) has put out a new guidance document, MDCG 2024-3 - Guidance on content of the Clinical Investigation Plan for clinical investigations of medical devices. 

The guidance includes 19 sections that must be included within the CIP. In this article, I’ll provide some context for the guidance, as well as recap each section of the CIP to help you understand how it all fits together.

BONUS RESOURCE: Click here to download a free template that will help you know what to include in your Clinical Investigation Plan (CIP).

Why has MDCG 2024-3 been released?

In the European Union, the sponsor of a clinical investigation must submit an application to the Member State(s) in which they want to carry out their study. This application must be accompanied by specific documentation that is laid out in Chapter II, Annex XV of the European Union Medical Device Regulation (EU MDR). The clinical investigation plan is a major component  of this documentation, and the content of the CIP is described in Section 3 of Chapter II, Annex XV. 

However, we need to keep in mind that the international standard for clinical investigations of medical devices—ISO 14155:2020—also describes what should be included in a CIP in Annex A of the standard. 

MDCG 2024-3 uses the requirements from Annex A of ISO 14155:2020 as well as the requirements from Annex XV of EU MDR to create a guide to the information in a CIP that is considered best practice in the EU. It’s also worth noting that if there are any discrepancies between EU MDR and ISO 14155:2020, the regulation takes precedence over the standard. MDCG 2024-3 is not legally binding, but it is an excellent guide to putting together a CIP for a clinical investigation in the EU. 

So let’s take a look at what’s in it.

Device description and benefit-risk analysis

Sections 3.1 through 3.3 of MDCG 2024-3 cover information related to the device and the benefits and risks of undertaking the investigation.

• Section 3.1 includes general information such as the name of the sponsor, principal and coordinating investigators, study sites, and the manufacturer of the device. Here, you’ll also need to lay out the different roles, responsibilities and qualifications of all the investigators involved in your study.
• Section 3.2 covers the investigational device itself, and you’ll need to provide a thorough description of the device, including its intended purpose in the study and its intended patient populations and indications for use.
• Section 3.3 includes the information you’ll need to submit regarding the benefits and risks of the device, clinical procedures, and the clinical investigation as a whole. You will need to include all benefits and risks, as well as a benefit-risk ratio and your rationale for that ratio

Description of the clinical investigation and patient population

Sections 3.4 through 3.6 of the guidance document cover the information you’ll need to include regarding your justification for this investigation, the objectives and hypotheses you’ve chosen, and the design of the study. 

• Section 3.4 is about the relevance of the clinical investigation, specifically in the context of the state of the art in clinical practice. In other words, here you’ll justify your clinical investigation based on your clinical evaluation and describe how this study fits into the clinical development of the device. Is it a pilot study? Pivotal? A post-market clinical investigation?
• Section 3.5 covers the objectives of your clinical investigation, as well as the hypotheses you are attempting to prove. Your objectives should be categorized as primary, secondary, or exploratory endpoints, as necessary. All endpoints must be determined and assessed using scientifically valid methodologies.
• Section 3.6 is quite lengthy, as it includes the design of your clinical investigation. This will include:
  
  • The type of investigation along with a rationale for choosing it and its endpoints and variables.
  • Information on the device and any comparators that will be used in the study.
  • Information on subjects, selection criteria, size of investigation population, representativeness of investigation population in relation to target population and, if applicable, information on vulnerable subjects involved.
  • What steps you’ll be taking to minimize bias, such as randomization.
  • A description of the clinical procedures and diagnostic methods relating to the clinical investigation, highlighting any deviation from normal clinical practice.
  • Your monitoring plan for the study
    
    

Data management and statistical analysis

Sections 3.7 through 3.8 of MDCG 2024-3 provide context for the information you’ll include regarding the way you manage clinical data and the methods you’re planning on using to analyze that data.

• Section 3.7 covers the description and justification of your statistical design and analysis of the clinical investigation, which includes, but is not limited to, information like:
  • Descriptive statistics of baseline data, treatments, safety data and where applicable, primary and secondary endpoints
  • Sample size calculation and justification
  • Measures of precision such as confidence intervals
  • Pass/fail criteria to be applied to the results of the clinical investigation
  • Procedures for reporting any deviations(s) from the original statistical plan
• Section 3.8 includes a description of the procedures you’re implementing to guarantee the data that your study generates is reliable and robust. In other words, what will you do to ensure that the data is recorded, processed, handled, and stored in such a way that it can be accurately reported, interpreted, and verified? This also includes the steps you’re taking to ensure the confidentiality of personal data of the study subjects, including steps to mitigate any adverse effects of a data breach.

BONUS RESOURCE: Click here to download a free template that will help you know what to include in your Clinical Investigation Plan (CIP).

Modifications, deviations, and consent

Sections 3.9 through 3.13 of MDCG 2024-3 cover a number of different items within the CIP related to compliance, consent, and accountability.

• Section 3.9 provides information on what to include regarding modifications to your CIP. This section states the importance of making it clear that you will notify the competent authority of any proposed changes to your CIP that are likely to have an effect on the safety, health, or rights of subjects, or the quality of the data generated by the study.
• Section 3.10 covers deviations from the CIP. In other words, you’ll need a statement specifying that your investigators are not allowed to deviate from the CIP unless it’s to protect participants under emergency circumstances. You’ll also need to document the procedures for recording, reporting, and analyzing the deviation. 
• Section 3.11 describes the information you’ll need to include for device accountability. This includes adequate procedures for the accountability and traceability of the device. You must be able to describe in detail how use of the investigational device is restricted so that it may only be used according to the CIP, as well as the record that will be kept to document that use.
• Section 3.12 covers the statements of compliance your CIP requires. These are:
  
  • Statement specifying that the clinical investigation shall be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
  • Statement specifying compliance with any relevant international standards and/or consensus guidance, such as the latest version of the international standard ISO 14155.
  • Statement specifying compliance with the national legislation and MDR.
  • Statement specifying that the clinical investigation shall not begin until the required regulatory and ethical assessments have been completed with non-negative outcomes, in accordance with MDR and national legislation.
  • Statement specifying that any additional requirements imposed by the Ethics Committee or regulatory authority shall be followed, if appropriate.
  • Statement specifying the type of insurance that shall be provided for subjects, if appropriate.
• Section 3.13 requires the inclusion of your process for obtaining informed consent, including the process for providing subjects with new information and the process for compensation. If your clinical investigation includes minors, you must provide a summary of how you meet the requirements of EU MDR Article 65, including informed consent of the minor’s legally designated representative.

Adverse events and premature termination

Sections 3.14 through 3.16 cover adverse events, early termination or suspension of the study, and arrangements for subjects following participation.

• Section 3.14 directs sponsors to list definitions for adverse events, adverse device effects, device deficiencies, serious adverse events, and serious adverse device effects, including a list of foreseeable adverse events and adverse device effects. You’ll also need a process for recording and reporting adverse events and device deficiencies.
• Section 3.15 covers what you’ll need to include to define the end of the clinical investigation. This includes appropriate stopping criteria and requires justification for any temporary halt or early termination of the study. Sponsors must also submit a clinical investigation report to the competent authority within one year of the end of the clinical investigation.
• Section 3.16 directs sponsors to describe the arrangements for taking care of patients after their participation in the study if additional care is required because of their participation.

Publication, technical documentation, and bibliography

Sections 3.17 through 3.19 cover documentation requirements related to publication, your technical documentation, and references.

• Section 3.17 directs sponsors to include the following statements:
  • Statement that the clinical investigation will be registered in a publicly available database.
  • Statement indicating that the results of the clinical investigation will be made publicly available.
  • Statement indicating the conditions and timeframes under which the results of the clinical investigation will be offered for publication including the role of the sponsor and criteria for authorship.
• Section 3.18 covers the technical and functional features of the device that the sponsor must list, including a tabular presentation of the relevant product characteristics and a statement of the expected clinical performance outcomes.
• Section 3.19, the final element of the CIP, is your bibliography. List all references related to the clinical investigation here. 

Greenlight Guru Clinical helps keep your clinical investigations compliant from the very start

With so many standards, regulations, and guidance documents out there, it can be difficult to know how to keep your clinical investigation and data collection compliant. That’s why at Greenlight Guru, we built compliance into our electronic data capture (EDC) solution for MedTech companies. 

Greenlight Guru Clinical comes pre-validated for the clinical requirements of EU MDR, FDA, and ISO 14155:2020, so you can ensure compliance from the start. With more than a dozen ready-to-use and customizable compliance document templates and world-class customer service on hand, you’ll have everything you need to collect and manage reliable, high-quality clinical data from your studies.

If you’re ready to see how a MedTech-specific EDC solution can streamline your next clinical investigation, then get your free demo of Greenlight Guru Clinical→.