MDCG 2024-10: Clinical Evaluation Guide for Orphan Medical Devices

The MDCG 2024-10 “Clinical evaluation of orphan medical devices” guideline of June 2024 provides comprehensive information on the clinical evaluation of orphan medical devices (medical devices for rare diseases) in accordance with the EU Medical Devices Regulation (MDR). The focus is on the requirements in MDR Chapter VI and Annex XIV, excluding custom-made products, self-manufactured products without a medical purpose in accordance with Annex XVI and in vitro diagnostics.

A medical device is considered an orphan device (OD) if it is intended for the treatment, diagnosis or prevention of a disease or condition affecting a maximum of 12,000 people in the EU each year. In addition, there must either be inadequate alternatives or the product must provide expected clinical benefits compared to available alternatives.

Clinical data for orphan medical devices

The challenges of generating clinical data for orphan products allow market approval under certain conditions, with acceptable restrictions on preclinical data. However, sufficient clinical evidence should be available for the expected clinical benefit and intended performance with acceptable safety.

The requirements for clinical evaluation of orphan medical devices apply in accordance with Article 61 and Annex XIV of the MDR. Non-clinical data such as laboratory tests, animal studies and computer simulations can then be used to support the clinical evaluation of orphan products. The clinical evaluation plan must take disease-specific and product-specific factors into account. For older orphan products, clinical data from previous use or from unapproved (off-label) uses may be taken into account under certain circumstances.

Clinical investigations of orphan medical devices

Conducting clinical investigations for orphan products can be challenging due to the limited number of patients, which is why specific strategies for recruitment and study design are recommended. Particularly in this context, it appears useful to involve clinical experts and patient representatives in study planning, recruitment strategies and cooperation with several centers in order to achieve sufficient numbers of participants.

Clinical testing of orphan medical devices before entering the market

Annex A.2 of the MDCG 2024-10 document provides recommendations for clinical investigations of orphan medical devices before they enter the market. This includes:

1. Careful definition of the study population, which is often small and vulnerable
2. Setting goals that focus on short to medium term clinical benefits, patient safety, and the benefit-risk balance.
3. Selection of appropriate endpoints, including patient-reported results
4. Adapting the study design to the challenges of orphan products, e.g. through cross-over, adaptive or sequential designs.
5. Consideration of alternative statistical approaches such as Bayesian methods due to limited patient numbers.
6. Careful selection of comparison groups, where active comparisons are preferred but historical controls or open studies may also be acceptable.
7. Appropriate quality assurance to ensure patient safety.

For orphan indications, extrapolation of clinical data from non-orphan populations may be appropriate, with Annex A.3 providing guidance on the correct data transfer.

Clinical investigations of orphan devices after market entry

Post-market clinical follow-up (PMCF) as part of purpose or post-market surveillance (PMS) is of particular importance for orphan devices. Due to limited pre-market clinical data, a structured PMCF plan is essential to ensure the safety and performance of these products over their entire life cycle.

It is recommended that the PMCF plan includes detailed information on identified data gaps, how to fix them, type of data to be generated, and time frames. Continuous assessment of the benefit-risk profile is of crucial importance. PMCF tests should include long-term follow-up and include as many patients as possible, ideally over 90% of patients treated with the product.

Registries are also recommended as a tool for generating knowledge. Where possible, manufacturers should use existing registers of national institutions or medical associations. In addition to PMCF tests and registries, other clinical data from routine use (real world data) can also be used for evaluation. These are particularly relevant for older orphan products and help identify rare complications and understand influencing factors such as ethnicity, gender, physiology, etc. A detailed risk management plan is recommended to monitor, assess and mitigate risks during PMCF. Manufacturers should be able to take appropriate action if the data collected raises new concerns about the safety or performance of the products.

Roles and duties of notified bodies in the context of orphan medical devices

A key aspect is the early review of orphan device status by a notified body, followed by a thorough evaluation of technical documentation and clinical evaluation. Particular attention should be paid to the special features of orphan devices, in particular to potentially limited preclinical data and planned PMCF activities.

To ensure flexibility, notified bodies can issue certificates with specific conditions, such as the implementation of specific PMS or PMCF activities or requirements to adequately inform users. Continuous monitoring is intended to ensure the safety and effectiveness of the product. In addition, compliance with certification conditions should be strictly controlled, and failure to comply should result in suspension or withdrawal of the certificate in extreme cases. These measures aim to ensure the safety and effectiveness of orphan medical devices despite potential restrictions on preclinical data.

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The MDCG 2024-10 Guideline provides comprehensive information on the clinical evaluation of orphan medical devices in accordance with the EU Medical Devices Regulation (MDR) and highlights the importance of clinical evidence for expected benefits and performance with acceptable safety, highlighting specific strategies for clinical investigations, post-marketing clinical follow-up and the role of notified bodies in evaluating and certifying orphan medical devices.

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Source and detailed information: https://health.ec. europa.eu/document/download/daa1fc59-9d2c-4e82-878e- d6fdf12ecd1a_en?filename=mdcg_2024 -10_en.pdf (delete spaces for link)

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