Understanding the MDCG 2024-10 Guidance: Will it really help patients that need orphan medical devices?

By Bianca Lutters, Head of Clinical Operations

This week, the Medical Device Coordination Group (MDCG) published a new guidance document: MDCG 2024-10. The MDCG 2024-10 guidance document provides input on what is considered sufficient clinical data for orphan medical devices under the European Medical Device Regulation (EU MDR).  

The guidance document provides the criteria that a medical device should meet to be regarded as an orphan medical device: 

“The device is specifically intended to benefit patients in the treatment, diagnosis, or prevention of a disease or condition that presents in not more than 12,000 individuals in the European Union per year; and at least one of the following criteria are met:  

  • there is insufficiency of available alternative options for the treatment, diagnosis, or prevention of this disease/condition, or  
  • the device will offer an option that will provide an expected clinical benefit compared to available alternatives or state of the art for the treatment, diagnosis, or prevention of this disease/condition, taking into account both device and patient population-specific factors.” 

A manufacturer that claims the device is an orphan device should provide a justification for the orphan device’s status in the clinical evaluation report. This justification should cover the requirements as covered in the criteria for an orphan device.  

Assessment and Certification of Orphan Medical Devices under EU MDR 

A Notified Body should check the justification for orphan device status as early as possible, for example as part of the structured dialogue. Once orphan device status is established, theNotified Body should take this guidance into account for the assessment of the clinical evaluation. If deemed necessary, the Notified Body can voluntarily involve the expert panel in this assessment. During the transition period for the EU MDR (until 31 December 2027 or 31 December 2028 depending on the classification of the device), the manufacturer can also involve the expert panel provided that this request does not interfere with the assessment by the Notified Body.  

The Notified Body is allowed to issue certificates with special conditions, such as the requirement to conduct Post Market Clinical Follow-up (PMCF) activities within a specified timeframe for orphan devices for which the clinical evidence is sufficient but needs to be completed or confirmed through PMCF.  

Clinical evaluation 

In section 5 on Acceptability of limitations in pre-market clinical data of this guidance, it is noted that in general a limited level of pre-market clinical data is acceptable. However, this must be justified. In the clinical evaluation report, available clinical and non-clinical data need to be summarized. Furthermore, compliance with the relevant General Safety and Performance Requirements (GSPR) needs to be demonstrated based on an acceptable benefit-risk ratio. Difficulties with generating further clinical data within an acceptable time frame need to be explained and a PMCF plan that covers the remaining limitations in clinical data needs to be available. Lastly, these limitations in clinical data for the orphan device need to be disclosed to the user.  

The guidance provides detailed instructions on how to approach the writing of the clinical evaluation in section 7 and annex A1. This is not different from the writing of a clinical evaluation for any other device with two exceptions: 

  • MDCG 2024-10 specifically mentions that any available off-label use data may be a valuable source of clinical data for legacy devices.  
  • Annex A3 provides guidance on how to extrapolate clinical data from non-orphan indications to orphan indications.  

This may help in reducing the burden for gathering pre-market clinical data on an orphan device. 

Clinical investigation 

Clinical investigations for orphan devices are covered in section 8 and annex A2. It is acknowledged that clinical investigations for orphan devices may be challenging. The strategy for the clinical investigation should cover potential challenges, including recruitment, and related sample size implications. Annex A2 specifically covers the design of clinical investigations for orphan devices. This follows the general design considerations for clinical investigations with the exception that surrogate endpoints can be used instead of clinical endpoints if properly justified. Use of surrogate endpoints will most likely result in a lower sample size for the clinical investigation. This may also help to reduce the burden for gathering pre-market clinical data on orphan devices.  

Post-Market Surveillance (PMS) and PMCF 

MDCG 2024-10 puts a lot of focus on completing or confirming available clinical data with PMCF. Section 9 describes how a manufacturer of an orphan device can approach PMCF. This section and annex A2 of this guidance, provides the following information on what is required for PMCF: 

  • Post-market clinical investigations and/or registries are most likely required to further support the safety and performance of the orphan device and should cover the limitations in clinical data for the orphan device.  
  • It is indicated that if a PMCF study is performed, the manufacturer should aim to enroll a representative majority (greater than 90% where feasible) of the patients exposed to the device at each site.  
  • Long-term follow-up of patients is specifically mentioned and must be considered if relevant for the device.  
  • Although surrogate endpoints may be acceptable for pre-market clinical investigations, clinical endpoints should be investigated, where possible, in PMCF studies.  

This means in practice that a (relatively) large PMCF study is expected. Knowing that the enrollment rate will be low in such a study, the costs will be high as the timeline of a clinical investigation is one of the major drivers for the costs.  

Implications for patients 

Although this guidance may limit the pre-market burden for clinical data on orphan medical devices, the total burden will not change. Although the costs for clinical data collection will be spread over a longer period, this guidance does not help with the costs for obtaining and maintaining certification. With these costs remaining at the same level and a low sales volume for those devices, no manufacturer that has decided to discontinue devices that qualify as orphan medical devices will be encouraged to reconsider their decision to discontinue sales. This leads to the unfortunate conclusion that this guidance itself will not help patients that need those orphan devices. However, knowing that more guidance is expected on orphan devices, this is a step in the right direction!  

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