MDCG 2024-10, published in June 2024, addresses the difficulties in generating clinical data for devices specifically intended for use in rare diseases/conditions or specific indications for rare cohorts of patients with non-rare diseases/conditions.
The MDCG introduces the phrase orphan devices to identify those devices that have precise indications used in a small patient population where gathering sufficient pre-market clinical data can be challenging, particularly given the increased requirements of the Medical Device Regulation (MDR).
Similarly, the guidance applies to devices that may have multiple indications, some of which are mainstream (non-orphan indications) and more accessible to collect clinical data for, and others where they may only be used in a limited and unique patient population (orphan indications).
The increased cost of bringing a medical device to market under the MDR, particularly for orphan indications where the sales volumes will be low, may be prohibitive to manufacturers and prevent them from placing the device on the market. This can leave a minority of patients without the care they need. MDCG 2024-10 provides a framework and guidance to address this inequality.
The following provides an overview of the MDCG. As always, there are some nuances with the guidance that may not be covered below, so be sure to read it in full yourself.
What constitutes an orphan device?
For a device to be defined as an orphan device, it must meet the following criteria:
- The device must be specifically intended for the treatment, diagnosis, or prevention of a disease or condition that presents in ≤12,000 individuals in the European Union per year.
- There is insufficient available 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.
The status as an orphaned device does not give it exclusive market access, and multiple orphan devices may be available for the same niche indication. These other devices must be considered similar or alternate devices within the context of the clinical evaluation.
How does a manufacturer justify orphan device status?
The manufacturer must provide a scientific rationale that, at the minimum, addresses epidemiological and device-related factors.
The manufacturer’s epidemiological justification must:
- Describe the specific disease/condition that it is aiming to treat
- Identify the size and characteristics of the patient population they intend to treat, taking into consideration that it must not represent >12,000 individuals in the EU per year
When identifying the size and characteristics of the population, the guidance allows for orphan subpopulations to be identified, i.e., the overall treatment population might be >12,000. However, the subpopulation, such as pediatrics or patients with a diversity of anatomy within the overall population, will be ≤12,000.
The manufacturer must describe the device and its intended purpose, as well as provide a scientific rationale why its use is considered necessary in the orphan population or subpopulation. As with all clinical evaluations, the manufacturer must position its device within the state-of-the-art, considering similar devices and alternate therapies and comparing the expected performance, safety, and clinical benefits.
What if my device has a widely accepted indication(s) and an orphan indication?
Some devices may be used in a large population for a particular indication but are also appropriate for use in a subpopulation for a different indication. The principles outlined in the guidance can be applied to support the regulatory compliance of the subpopulation. However, the expectations for presenting clinical data for the main population, per the MDR, remain unchanged.
What concession does the guidance bestow for orphan devices?
Orphan devices may be granted market access with acceptable limitations in the amount and quality of pre-market clinical data. However, it remains the responsibility of the manufacturer to evaluate the available data, identify the gaps or limitations, and provide a justification as to why it is not feasible or proportionate to generate further clinical data.
In all other regards, the device must meet the applicable requirements of the MDR.
Do I need to carry out Post-Market Clinical Follow-up (PMCF)?
Yes, PMCF is critical in following up and addressing any gaps in the clinical data over the long term. When cases are few and far between, the method of collecting data needs to be considered. It will be essential to have good relationships and clear lines of communication with the users to ensure all data-collecting opportunities are realized. PMCF is critical in supporting the determination of ongoing risk/benefit.
Do I need to communicate the limitations of orphan devices to the user?
Yes, as per MDR GSPR 23.4(s), the user must be informed of any warnings, precautions, contraindications, or limitations of the device, including its orphan status. Furthermore, for implantable and Class III devices, the Summary of Safety and Clinical Performance (SSCP) must provide the relevant information for the user and patient to make an informed choice.
What role does non-clinical data play?
Non-clinical data becomes more relevant for orphan devices because it will be used to support the case for having less pre-market clinical data and help justify CE marking with limitations of clinical data that can be met through PMCF.
Is the clinical evaluation process different for orphan devices?
No. Fundamentally, the clinical evaluation process is the same as for any other device. The clinical evaluation must consider the disease-specific factors, including the epidemiology, the patient population affected by the disease, the severity of the disease condition, and factors of the disease or condition that contribute to the challenges and difficulties of generating pre-market clinical data in this population. These factors may be legal or ethical.
Can clinical data from off-label use be used in the clinical evaluation?
If the clinical community has been using the device off-label for several years there may be a substantial body of real-world data. In that case, this can be leveraged in the clinical evaluation. However, the data must be evaluated for quality and sufficiency. This scenario only applies to legacy devices.
Can I discuss the status of the orphan device with the Notified Body before I submit my CE application?
Yes. In theory, the guidance indicates that the orphan device status of the device should be checked by the Notified Body as early as possible, for example, as part of structured dialogue before or during initial conformity assessment activities. However, only time will tell if the Notified Bodies are amenable to open dialogue. As to the quality of that dialogue, the limitation on Notified Bodies being seen as providing consultancy remains a challenge, which continues to frustrate manufacturers that want an even playing field.
Can I consult the expert panels?
Yes. For devices that fall into the scope of Article 61(2), manufacturers are able to consult the expert panels for feedback on their orphan device justification and clinical strategy. However, the scope and availability of the panels remain an issue.
How will the Notified Body assess orphan devices?
Once orphan device status has been established, the technical documentation will be assessed in the same manner as for non-orphan medical devices. The Notified Body can apply some discretion when reviewing the clinical evaluation, taking into account the orphan device status, the robustness of the preclinical and pre-market clinical data, and the robustness of the PMCF plan to address any gaps. Unfortunately, not all Notified Bodies are equal, so inevitably, there will be inconsistencies in the decision-making process.
Will my CE certification have conditions?
Because of the perceived increased risk of certifying an orphan device, the Notified Body may issue a CE certificate with certain limitations, for example, to conduct PMCF activities within a specified time frame.
Conclusion
MDCG 2024-10 allows the manufacturer of devices used in the treatment of rare diseases/conditions or in small niche populations to claim orphan device status and reduce the burden of collecting pre-market clinical data. However, the onus remains on the manufacturer to demonstrate that they meet the requirements of the MDR and that they have sufficient data to support the safety, performance, and clinical benefit claims of their device.
The guidance permits Notified Bodies to apply a healthy dose of pragmatism when CE marking devices used to treat rare diseases/conditions in small populations, ensuring specialist devices are available to those who need them. It will take time for Notified Bodies to align and become consistent in their assessment of orphan devices. Still, it is good to see that the Commission recognizes that the MDR is not one size fits all, and some concessions are necessary to ensure patients get the devices and treatment they need.
If you would like NAMSA support to establish the orphan status of your device and to develop a clinical strategy, including a clinical evaluation report, please get in touch with us. We have a team of regulatory and clinical experts ready to help.
Paul Risborough
Paul Risborough holds the position of Principal Regulatory Consultant at NAMSA. Until recently, Paul worked as the Global Head of Active Implantable Medical Devices at BSI, Notified Body, overseeing the Medical Device compliance of Active Implantable Medical Devices. Before becoming a Manager at BSI, Paul was an Active Implantable Device Technical Specialist, Scheme Manager and ISO 13485 Auditor. Previously, Paul worked as an electronics design engineer, project leader, and engineering manager involved in designing and manufacturing syringe pumps, large volume pumps; RF, ultrasonic, and gas plasma surgical tools; needle-free injectors, and SpO2 meters. Paul has an education in Systems Engineering, BEng (Hons).