The European Union has for the first time introduced measures to facilitate the development of medical devices for rare conditions, and has recently published the Medical Devices Coordination Guidance on the clinical evaluation of orphan devices (the MDCG Guidance). Key aspects of the document include defining “orphan devices” and guidance on their clinical evaluation, including when it may be justified to certify a product with limitations in the pre-market clinical data.

The MDCG Guidance also envisages further assistance to manufacturers of orphan devices and their Notified Bodies through the provision of scientific advice by expert panels. To help implement the new guidance, the European Medicines Agency (EMA) is operating a pilot programme to provide scientific advice for manufacturers of orphan devices. The pilot programme is intended to operate until the end of this year, with the intention that scientific advice from expert panels will subsequently be rolled out on a wider basis.

What are the challenges in bringing orphan medical devices to the market?

It is often challenging to bring medical products for rare diseases to the market, principally because:

  • it is difficult to obtain the required clinical data to demonstrate the performance (or efficacy) and safety of the product, as by definition there is a small patient population in which to conduct clinical studies; and
  • it is often not economically attractive to invest in the development of products given the small market.

The EU medicines regulatory regime has long contained a specific framework for orphan medicinal products. That seeks to address the above challenges primarily by providing a period of market exclusivity to orphan medicinal products, though also provides other incentives such as access to scientific advice during the development of the medicine.

Until now, the EU medical device regulatory framework has not contained any specific acknowledgement of orphan devices. With all devices (including legacy devices) required to undergo a new conformity assessment under the new medical devices Regulations (the MDR and IVDR), along with the increased clinical evidence requirements under those Regulations, the challenges above have only become more acute. This has led to concerns that even devices that were previously available for use for rare conditions are being withdrawn from the market as manufacturers decide it is unviable to put them through a new conformity assessment.

What is an “orphan device” under the MDCG Guidance?

To fall within the definition of an “orphan device” under the MDCG Guidance, a device must meet the following criteria:

  • 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.

The manufacturer must justify that a device satisfies these criteria during the conformity assessment process.

What does the guidance say on the clinical evidence requirements for orphan devices?

The MDR and IVDR significantly increased the requirements for both pre-market and post-market clinical evidence to demonstrate compliance of a device with the applicable General Safety and Performance Requirements (GSPRs) under those Regulations. Recognising the challenges manufacturers of orphan devices will have in meeting the pre-market clinical evidence requirements, the MDCG Guidance provides that the pre-market conformity assessment of an orphan device may be completed with “acceptable limitations” in the amount of clinical evidence. Where there are limitations in the data, an even greater focus will be placed on post-market data, and the manufacturer’s Post-Market Clinical Follow-Up (PMCF) plan must address the limitations in the pre-market data.  

The MDCG Guidance permits this flexibility in the level of clinical evidence required in the pre-market stage where certain conditions are met. These include:

  • all available non-clinical and clinical data relevant to the device has been evaluated;
  • that data is sufficient to demonstrate the relevant GSPRs are met, the benefit-risk ratio is acceptable and the device is expected to provide a clinical benefit taking into account the current clinical context of the condition; and
  • it is not feasible or proportional to generate further clinical data within an acceptable time frame in the pre-market setting.

The MDCG Guidance also indicates where it may be appropriate to rely on alternative sources of data rather than clinical investigation data, such as data from off-label use of an existing non-orphan product and non-clinical data.

The MDCG Guidance also provides detailed advice on the design of clinical investigations for orphan devices.

What procedural measures apply to the assessment of orphan devices?

There are certain procedural measures that can be used to facilitate the development of medical devices contained in the Regulations, and the MDCG Guidance endorses their use in the context of orphan devices:

  • Conditional Notified Body Certificates: The MDR already envisages the possibility of Notified Bodies granting certificates with specific conditions attached or imposing milestones for further review. The MDCG Guidance encourages the use of such certificates in the context of orphan devices to account for any limitations in pre-market data. The MDCG Guidance suggests that the conditions could be specific requirements to conduct certain Post-Market Surveillance or PMCF activities to assess the conformity of the device, or could be risk management measures such as warnings to users. Notified Bodies must assess compliance with any conditions through their surveillance activities.
  • Advice of Expert Panels: Advice from expert panels can be on the qualification of a device as an orphan device and/or the clinical evidence required to demonstrate its conformity. Manufacturers at an early stage of clinical development can choose to obtain early scientific advice on their clinical evidence development strategy. This scientific advice is however only available to class III devices and class IIb devices intended to administer and/or remove a medical device. Consultation of an expert panel is voluntary and it remains the responsibility of the manufacturer to justify orphan status of a device and the level of clinical evidence supporting conformity. This is not intended to override the assessment by the Notified Body. However, expert panel advice endorsement of a manufacturer’s proposed amount of clinical evidence will likely give a Notified Body comfort that the level of clinical evidence is sufficient.

For devices that are in a more advanced stage of the clinical evaluation or where it has been completed, the Notified Body may request advice from an expert panel, though it is recommend they should consult the manufacturer before submitting such a request. The Notified Body may, amongst other things, ask for the panel’s opinion on any justifications for limitations in the clinical data.

For a limited time during the MDR transitional period, the MDCG Guidance also provides that this option of later stage scientific advice can be utilised by manufacturers, though only where the manufacturer will be able to update the clinical evaluation report taking into account the advice prior to the review by the Notified Body.

Could there be further incentives for orphan devices in the future?

Encouraging the development of orphan and paediatric devices is a focus area as the EU considers revisions to the medical devices Regulations. The recent European Parliament resolution on the urgent need to revise the MDR called for adapted rules for orphan and paediatric devices, including more efficient conformity assessment procedures for medical devices serving small markets. Industry is hopeful that, in time, specific measures for orphan devices will be introduced into the legislation, rather than these only being contained in non-binding guidance. It seems likely that such reforms will take the form of formalising and extending the scope of some of the arrangements envisaged by the MDCG Guidance, such as scientific advice. However, it will be difficult for incentives similar to the market exclusivity seen in the medicines regulatory framework to be introduced in the devices context, given the differences in the pre-market assessment procedures.