Regulatory flexibility under the MDR for orphan devices

Why a ‘one size fits all’ approach fails when it comes to rare diseases.

Rare diseases are anything but rare when considered collectively. However, individual indications affect only a very small number of people. In the European Union, a disease is considered rare if no more than 5 in 10,000 people (i.e. approximately 1 in 2,000) are affected.

With such small patient groups, the question inevitably arises: who actually develops medical devices or medicines for these people, and how can these products be approved through the regulatory process when traditional large-scale studies are hardly feasible?

Orphan devices: sensible, but high-risk for manufacturers

On paper, the development of orphan devices sounds like a clear win-win situation: urgently needed solutions for patients with significant medical needs. In practice, however, this field is extremely challenging for many manufacturers, both economically and operationally.

Typical hurdles:

• Limited market: Due to the small number of patients per indication, the revenue potential is severely limited – even at higher price points.
• High development costs: Clinical development, manufacturing, quality management, regulatory approval and related costs can easily run into the high tens to hundreds of millions – regardless of whether the patient group is large or small.
• Difficult clinical trials: Patients are rare, geographically scattered and often multimorbid. Traditional randomised, large-scale trials are often simply not realistic.
• Uncertainty following approval: Even once the product is approved, it often remains unclear how high the actual revenues will be – for instance, due to difficult price negotiations or restricted access.

Manufacturers who nevertheless focus on orphan devices therefore require a strong financial foundation, in-depth medical and regulatory expertise, access to patient networks and registries, and a highly robust yet flexible QMS and data ecosystem.

Orphan devices in the context of the MDR – more than just a niche

The EU has been supporting orphan medicines for years with clear criteria and incentives such as up to 10 years of market exclusivity. At the same time, the requirement remains unchanged:

Orphan products must also be effective and safe, and this must be substantiated by robust evidence.

For medical devices, this means that the requirements for clinical evidence, post-market surveillance (PMS), registries and long-term data are often particularly high, precisely because the data available on diseases and therapies is limited.

Regulatory flexibility: What does the MDR actually allow?

In certain cases, the MDR allows for more flexible approaches to clinical evidence, particularly for very small patient groups. Specific guidance is provided by Guideline MDCG 2024-10, which deals with orphan devices.

For a notified body to accept a more flexible approach, several conditions must be met. Firstly, a plausible orphan status is required: the product addresses a rare disease affecting a small patient group for which traditional large-scale studies are not realistically feasible, and there is a clear medical need, ideally with few or no alternative treatments. Furthermore, even with limited pre-market data, a positive benefit-risk ratio must be demonstrated, i.e. comprehensible clinical plausibility, consistent technical and clinical data, and appropriate risk management.

It remains the case that all General Safety and Performance Requirements (GSPR) set out in Annex I of the MDR must be fully met – including biological safety, technical safety and performance, clinical performance, and risk-benefit analysis. The MDR therefore does not lower safety requirements for orphan devices, but merely allows for more flexible strategies for generating clinical evidence. Another key component is a robust PMCF (Post-Market Clinical Follow-up) plan: manufacturers must clearly demonstrate how additional data will be collected via PMCF studies and registries following market launch, which clinical questions will be addressed, and how the risk-benefit ratio will be continuously monitored and adjusted where necessary.

What does regulatory flexibility look like in practice?

Less extensive pre-market clinical data possible

For standard high-risk products, large, randomised, controlled trials are often expected. For orphan devices, the Notified Body may, under certain conditions, accept:

• smaller sample sizes,
• non-randomised studies,
• single-arm studies without a traditional control group,
• pragmatic study designs that take real-world feasibility into account.

The key factor is that the overall body of evidence – pre-market and post-market – is consistent and sufficient.

Use of alternative data sources

Alternative sources of evidence can be drawn upon more extensively for clinical evaluation, for example:

• real-world data from healthcare settings,
• registry data,
• historical controls,
• literature on the condition and comparable products,
• data from similar indications or product variants.

However, these sources must be evaluated using sound methodology and incorporated into a coherent clinical argument.

Greater shift towards the post-market phase

A key aspect of flexibility is: more data after market launch rather than exclusively before.

Typical tools:

• PMCF studies specifically for rare diseases,
• indication-specific patient registries,
• structured long-term data collection,
• defined milestones for reassessing the risk-benefit ratio.

The principle of proportionality in the MDR

The MDR requires ‘proportionate clinical evidence’. This means that the scope and depth of the clinical evidence must be proportionate to:

• the rarity of the condition,
• the severity of the condition and the medical need,
• the availability or unavailability of alternatives,
• realistic possibilities for studies.

The MDR is demanding, but not blind to the realities of rare diseases.

Conclusion: Flexibility yes – responsibility too

Orphan devices operate in a tension between high medical need, limited data and high regulatory standards.

The MDR – supported by guidelines such as MDCG 2024-10 – deliberately creates scope here so as not to hinder manufacturers with unrealistic study designs. At the same time, the standards for safety and clinical performance remain as high as ever.

Regulatory flexibility is not a ‘compromise’ on safety, but an invitation to work together to find feasible ways of still providing patients with rare diseases with safe and effective medical devices.