Orphan medical devices: balancing the needs for clinical evidence 

Rare diseases in the EU 

In the European Union (EU), 27 to 36 million people live with one of the estimated 6,000 to 8,000 rare diseases, which can affect anywhere from a few patients to as many as 245,000.¹ Approximately 80% of these diseases are genetic, with 70% beginning in childhood.¹ For many years surgeons have used off-label or self-assembled medical devices for the prevention, diagnosis or treatment of rare disorders², because the rarity of these conditions often means that there is limited financial incentive for companies to develop and market treatments or devices, as the potential market is small, and the development costs can be high. In many cases, orphan devices are intended for use solely or predominantly in minors and paediatric populations, and/or in emergency situations.³  

Generating clinical data quickly in small patient groups is especially difficult, as it involves ethical and regulatory requirements to protect these vulnerable populations. This is even more challenging for specific groups like infants and children due to practical difficulties in conducting clinical studies.  Given their unique challenges, and in the absence of specific provisions in the Medical Device Regulation (MDR), the application of MDR requirements to orphan devices needs to be balanced and proportionate so that the pre-market clinical evidence requirements are sufficiently met without unduly hindering or delaying patient access to these.² 

Orphan medical devices: criteria 

Orphan medical devices, intended for such small number of patients with rare diseases, address unmet medical needs but lack specific guidance, leading to differing views among manufacturers, notified bodies, and regulators on the clinical evidence requirements needed for market certification. With this in mind, the Medical Device Coordination Group (MDCG) has recently released a guidance with the criteria and specific considerations that need to be fulfilled for market authorization in the EU of orphan medical devices.³  

As such, according to the guidelines, an orphan device is a medical device or accessory intended to treat, diagnose, or prevent a condition affecting no more than 12,000 individuals annually in the EU; and it must either address a lack of available alternatives or provide a clinical benefit over existing options, considering both device and patient population-specific factors.³  

Orphan medical devices: pre-clinical, non-clinical and real-world data 

As with all devices, orphan devices must meet the general Safety and Performance Requirements (GSPRs) that apply to it. For relevant GSPRs, there must be sufficient clinical evidence to demonstrate conformity. The manufacturer must specify and justify the level of clinical evidence necessary for demonstrating conformity with those relevant GSPRs, taking into consideration the characteristics of the device and its intended purpose. In an effort to balance the needs for evidence and market availability, the guidance states that limited pre-market clinical data is acceptable if: all available non-clinical and clinical data has been reviewed, limitations identified, existing data meets MDR requirements with an acceptable benefit-risk ratio; further data is infeasible to gather pre-market; there is an adequate post-marketing clinical follow-up (PMCF) plan to address data limitations; and users are informed of the device’s orphan status, data limitations, and reporting instructions. Furthermore, useful sources of non-clinical data are acceptable to support market authorization, and can include results from laboratory and animal tests, computer modelling and simulated use testing, ex vivo and cadaveric studies, data from similar non-equivalent devices, information on the state of the art technology, previously collected patient health datasets for device testing, and other relevant human data that doesn’t qualify as MDR clinical data. 

For certain legacy devices, there may be circumstances where the device has been systematically used off-label for an orphan indication by the clinical community across the EU/world for many years, to the extent that it is now considered by clinical experts as part of best clinical practice for the management of that disease or condition. As such, there may be an existing substantial body of clinical data, e.g. real-world data (RWD), supporting this indication that can be used as part of the clinical evaluation. 

When clinical investigations are needed 

For implantable and/or class III orphan devices, MDR Article 61(4) mandates the need for clinical investigations unless specific exemptions apply. As stated above, conducting these investigations is challenging. As such, proper study design should involve clinical experts, patient engagement, and considerations of patient recruitment and retention strategies by collaborating with multiple centres across the EU to enhance participation and generalizability of results.

Conclusions

There is an increased recognition that a compromise is needed between the highest level of evidence and the lack of evidence for orphan medical devices, particularly paediatric devices that have specific considerations and unique barriers for their development. Considering the device’s nature, existing knowledge from adult use, extrapolated paediatric data, and the condition being treated, in some cases, bench and animal testing may suffice, while in others, clinical data from proper investigations will be requested.

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