In a recent document for manufacturers and notified bodies the medical device consortium group (MDCG) issued guidance on the clinical evaluation of orphan devices (MDCG 2024-10). In August, the EMA opened a pilot program to enable both manufacturers and notified bodies to seek advice from an cross-discipline expert panel on the criteria for an orphan device and subsequent clinical evaluation. In this blog the first EU definition of an orphan device and the key aspects for clinical evaluation of orphan devices are discussed. The expert panel advice pilot scheme is also described.

 

Devices in Rare Disease or Limited Use Settings (Orphan Device)

Orphan devices are used in a diverse range of diseases and with widely different purposes. Similarly to rare disease drug development, it is often clinicians or academia that are the source of innovation and who develop devices in response to the clinical need. Many orphan devices are used in the paediatric setting and in emergency use situations, as well as routine clinical settings.

 

Some examples of orphan devices are;

• Coronary Stent Graft, such as in the treatment of free perforations.
• Corneal implants, such as prescription-specific implants in the treatment of keratoconus.
• Wound dressings, such as a dressing matrix impregnated with a patient’s own epithelial cells for burns treatment.
• Prosthetics, such as patient-specific talus ankle spacers for avascular necrosis of the ankle joint.

 

The US FDA and Japan’s PMDA have a regulatory framework for devices used in small populations. The FDA Humanitarian Device Exemption (HDE) Program is intended for devices benefitting patients with a disease or condition affecting not more than 8,000 individuals in the United States annually. Japan’s PMDA recognises an orphan device if it is intended for use in less than 50,000 patients in Japan and for which there is a high medical need. There are challenges in generating evidence for safe use in the intended population in a timely manner when few patients are available and the unmet need is high. These frameworks recognise this challenge and provide additional options to device manufacturers working in the orphan space.

In the EU there is no similar framework for market authorisation of orphan devices and the EU medical devices regulation (MDR) does not define orphan devices or specifically recognise the additional challenge of generating pre-market clinical evidence for rare diseases. To address this gap the Medical Device Coordination Group (MDCG) issued a position paper in August 2022 and at the same time established a task force (comprised of notified bodies, industry, academic societies, and healthcare professionals). In June 2024 the Medical Device Coordination Group (MDCG) published the final guidance ‘MDCG 2024-10, Clinical evaluation of orphan medical devices’. In August 2024 the European Medicines Agency (EMA) opened a pilot aimed at both manufacturers and notified bodies to seek expert panel feedback on orphan status, and, orphan status plus clinical evaluation, this pilot closes in Oct 2024. Further information on the pilot and the request for applicants was shared in an European Medicines Agency (EMA)-led information session in September 2024.

 

 

 

New Guidance and Advice Scheme

The June 2024 Guidance (MDCG 2024-10) is for use by both notified bodies and device manufacturers, nonetheless, there is currently no activity to incorporate the definition of an orphan device into the medical devices regulation (MDR). The orphan device expert panel advice made available through the pilot scheme is not legally binding, however, manufacturers and notified bodies are expected to view advice letters with great authority and not optional to follow. The purpose of the European Medicines Agency (EMA) pilot scheme is to improve access to multi-discipline experts to support the development of innovative devices in the rare disease space.

 

The guidance outlines 2 main areas;

1. a definition of an orphan device and
2. considerations for the clinical evaluation of orphan devices.

Both of which are detailed further in sections below.

 

The scope of the guidance is;

• relevant to the clinical evaluation of medical devices and accessories that qualify as orphan devices and medical devices and accessories that have an orphan indication, within the meaning of this guidance.
• relevant to devices that require clinical data to demonstrate conformity with GSPRs. Guidance is not provided in this document for those specific circumstances where MDR Article 61(10) applies to an orphan device.
• applicable across all risk classes of devices.
• relevant to custom-made devices, in-house devices, and products without an intended medical purpose listed in MDR Annex XVI. In vitro diagnostic medical devices are outside the scope of the guidance.

 

 

Orphan device expert panel advice overview

Advice is anticipated in either at;

• Early stage i.e. during the design of clinical evaluation, requested by manufacturers

or

• Later stage i.e. when clinical evaluation is advanced or completed, requested by either the manufacturer or notified body.

 

The pilot scheme’s scope includes Class III and Class IIb active medical devices destined to administer and/or remove a medicinal substance (ARMP) devices.

The scheme offers 2 options with different timelines;

1. Advice on the orphan device status (outcome letter within 60 days from procedure start)
2. Advice on orphan device status AND clinical evaluation (advice meeting with applicant followed by outcome letter within 90 days from procedure start. An optional pre-submission meeting is also possible).

 

 

Definition of an Orphan Device

This first EU-wide definition of an orphan device shows when there is a genuine challenge to gathering data, it is not just based on small numbers but also includes the expectation the device will have significant benefit to patients. There is both a quantitative element and a qualitative part. This emulates the orphan medicines definition which is based on the prevalence of a condition and the extent to which the medicine can fulfil an unmet need (Article 3, REGULATION (EC) No 141/2000).

 

Quantitative Definition

The orphan criteria are met if;

‘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;

Setting the threshold at 12,000 for the EU population is derived from the existing FDA threshold for a Humanitarian Device Exemption (HDE) of no more than 8,000 individuals US. Furthermore, this threshold for the EU is intended not to undermine the criteria for Orphan Medicine status i.e. a condition with a prevalence less than 5 in 10,000 in the EU.

 

There is flexibility on how the evidence regarding the number of individuals targeted by the device is calculated and both device-specific and patient-specific factors can be included;

• Orphan population – If there is epidemiological evidence that the disease/condition in which the device will be used does not occur in more than 12,000 individuals in the EU then that can be sufficient.
• Orphan sub-population – If the device will be used in a sub-set of a broader disease/condition then evidence to identify the clinically valid patient population for which the device is intended and rationale for the sub-set used can be presented can be sufficient.

The guidance recommends the use of peer-reviewed literature and EU databases but acknowledges that in some cases there may be limited data available. Extrapolation to the EU from registries or country-specific sources may be acceptable.

 

Qualitative Definition

The orphan criteria are met if the threshold criteria is met 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’

The guidance outlines the need to describe the intended use or intended indication and the current existing state of the art. In addition, there is the need to describe alternative therapies if any, or the lack of these, and the expected clinical benefit over alternatives. For the latter, medical literature or consensus statements from clinical experts, societies of patient representative groups that detail the gaps in clinical management could be used. Non-clinical and/or clinical data on the device may also be used.

 

 

Considerations for the Clinical Evaluation

The new guidance provides advice to manufacturers and notified bodies on 5 key areas.

 

1.  Acceptability of limitations for pre-market clinical data

The guidance provides specific justifications that would support limited pre-market clinical data, and highlights the importance of the use of an adequate post post-market clinical follow-up (PMCF, detailed in Annex XIV Part B of the MDR) to resolve limitations in pre-market data. Justifications can be based on complete evaluation of the existing non-clinical and clinical data and an understanding of the risks along with clarity of the insufficiency of the available options for patients and the lack of feasibility of generating further clinical data in acceptable time. This is on the basis that the relevant General Safety and Performance Requirements (GSPRs) in Annex I of the MDR are met.

 

2. The role of non-clinical data

The guidance highlights the elevation in importance that non-clinical data can have when limited clinical data is anticipated and also highlights potential sources of non-clinical supporting data.

 

3. Clinical evaluation overview

MDR Article 61 and Annex XIV apply for the clinical evaluation of orphan devices, the new guidance identifies specific considerations for orphan evaluation and provides some expectations on what should be addressed. The clinical evaluation report (CER) will need to include orphan device-specific information including (but not limited to) how the device meets orphan criteria, a summary of the data evaluations, a discussion of limitations and residual risks, and a detailed post-market clinical follow-up (PMCF) plan.  Annex A1 of the guidance provides orphan device-specific information to be included in the Clinical Evaluation Report (CER).

 

4. Generating pre-market clinical data for orphan devices

The highest validity approach of randomised clinical trials (RCTs) is the ideal, however, the challenge to generating these data in the orphan setting is recognised and alternative designs and approaches are discussed in the guidance. Expert Panel Advice in early phase before clinical investigation is complete can be supportive. There is recognition that device clinical data is different from that of medicine clinical data and the use of observational data is more usual. Annex A2 of the new guidance outlines considerations for the clinical investigation of orphan devices.

 

5. Post-market surveillance and Post-market Clinical Follow-up (PMCF) for orphan devices

Post-market surveillance and clinical follow-up processes are more important for the life-cycle evaluation of orphan devices than standard devices. The guidance has direction on post-market clinical follow-up (PMCF) plans and advises on the information that should be included, such as identifying the limitations of the pre-market data and gaps to be addressed post-market along with justification for how the proposed post-market clinical follow-up (PMCF) will meet this gap. The manufacturer should be aware that long-term clinical investigations may be necessary and all possible sources of data collection in the real-world should be evaluated. Post-market data collection should ideally focus on high-validity registries as most important tool to generate clinical evidence where possible.

 

 

Pilot Expert Panel Advice Process

Early Advice – the current medical device regulation (MDR) includes an article setting out the option for manufacturers to seek expert panel advice (Article 61(2)) regarding the clinical development plan. This prospective advice can be particularly useful for orphan medicines and is based on the questions and supporting positions provided by the applicant in a briefing book. The pilot aims to simplify the access to experts by manufacturers where the manufacturers can seek advice on the orphan status alone (60-day procedure) or the orphan status and clinical development strategy (90-day procedure with advice meeting).

Early advice can be sought on;

• Orphan device status
• Data sets required for clinical evaluation
• Justification of the limited clinical data
• Acceptability of clinical uncertainty and limitations of data
• Acceptability of proposed post-market clinical follow-up activities

Practically, advice scheme requests are submitted via an online portal and an EMA account registration will be needed first. For further advice on clinical evaluation, an optional pre-submission meeting is also available.

 

Late-stage advice
The process is the same for advice sought once clinical data has been compiled or during conformity assessment, however this is under medical device regulation (MDR) article 106(11). Both manufacturers and Notified bodies can seek late-stage advice but this must be done in communication with the other party and the aim is not to interfere with the conformity assessment. This can be useful for example if the notified body is not in agreement about the orphan device status claim.

 

 

Summary

The definition of an orphan device as well as the supporting guidance for clinical evaluation is a welcome impetus for both manufacturers and notified bodies that will provide an aligned expectation on the approach for generating pre and post market data for orphan devices.  The EMA pilot advice scheme will build knowledge on how to implement the guidance within MDR and support the delivery of safe and effective devices to patients with rare diseases. Some questions remain, such as how the outcome of pilot advice will be shared and if future advice will remain free to manufacturers, but with this step forward the outlook for patients is improving in the EU.