Orphan to BtX: What’s Changing in EU Medical Device Regulation?

If you're developing a device for a rare disease or a small patient population, you already know the hard part often isn't the science, it's the evidence. Under MDR and IVDR, generating enough clinical data where there simply aren't many patients can slow a device down or stop it from reaching the market at all. 

Why are things changing for orphan devices?

Well, because the current system (MDR/IVDR) is… tough, and it is especially challenging for: devices targeting rare diseases (small patient populations = limited clinical data), and devices using novel technologies (innovation uncertainty and lack of established evaluation methods). The EU is now addressing that challenge. Two new guidance documents are driving the shift by introducing more flexibility within the existing regulatory framework while maintaining high safety standards.

The big idea? Moving away from an “up-front evidence generation” mindset toward a “lifecycle-based evidence” approach without compromising patient safety. For orphan device manufacturers in particular, this is both an opportunity and a shift in regulatory thinking that intends to provide a faster route for innovative devices to reach the patients who need them.

Is your device an orphan or breakthrough device?

Both guidances share a fundamental rule: regulatory requirements are not lowered by applied proportionately. There is no exemption from FSPRs (Annex I), nor clinical evaluation (Annex XIV). Instead, there is greater flexibility in how evidence is generated and assessed. 

Clinical evidence: a ‘friendlier’ development model for small populations

Traditionally under MDR and IVDR, most of the clinical evidence is required before CE marking. With the new guidance, both orphan and breakthrough devices can benefit from a new lifecycle model where clinical evidence is gradually built up during pre-market (demonstration of initial safety and performance), post-market (generation of confirmatory evidence), and continuous (ongoing benefit to risk monitoring). This means there is strong reliance on real-world evidence, PMCF/PMPF, and post-market surveillance.

For orphan devices, manufacturers may expand the use of non-clinical evidence, use smaller clinical datasets, and rely on case series, registries and literature. However, all limitations must be justified, transparent, and documented in the Clinical Evaluation Report (CER).

For breakthrough devices, manufacturers may develop lifecycle evidence strategies, demonstrate initial benefit–risk, and plan post-market confirmation of performance.

Both guidances significantly elevate the importance of post-market activities, as they require robust PMS systems, structured PMCF/PMPF plans and continuous benefit–risk evaluation. This means post-market data is no longer supportive; it is a core element of compliance.

Can it be both an orphan and BtX device?

So maybe now you might be wondering: what about a device that targets a rare disease, is highly innovative, and has positive clinical impact? Can it be both an orphan and BtX device? Absolutely. The two designations are not mutually exclusive, and in fact many cutting-edge devices will fall into this category. If your device qualifies for both, you’re essentially operating under a combined framework, and you should take advantage of both perspectives:

• From orphan guidance → justify limited data (small populations, alternative data sources)
• From breakthrough guidance → build a structured lifecycle evidence strategy
  
  

How about notified bodies and expert panels? Are they changing too?

Yes, and in a good way. The new MDCG guidances suggest a shift from reactive assessments to proactive collaboration and early engagement with notified bodies and expert panels. (Image: Author Silvia Anghel).

So instead of “submit and wait,” it is more like “talk early, align early.” But not everything will be a smooth ride. With more flexibility comes more variability. It remains to be seen in practice how notified bodies and expert panels will deal with resource constraints, consistency across notified bodies, and managing expectations (without becoming “consultants”).

What should manufacturers do differently to turn MDCG 2024-10 into an advantage?

• Assess positioning early: determine if your device is orphan, breakthrough or both.

• Adopt a lifecycle evidence mindset: plan evidence from development to post-market, moving from “complete evidence pre-market” to “phased evidence generation.”

• Engage regulators proactively: early interaction is critical.

• Prepare technical documentation: it must demonstrate a clear rationale for orphan or breakthrough status and show strong linkage between risk management, clinical evidence, and PMS strategy.

• Invest in post-market capabilities: PMS, PMCF, and real-world evidence are now strategic assets.

• Align global strategy: combine EU frameworks with the FDA Breakthrough Device Program or other international pathways.
  
  

A fundamental shift in philosophy: MDCG 2024-10 offers a clearer path to patient access for orphan devices in the EU

MDCG 2024-10 and MDCG 2025-9 collectively represent a fundamental shift in EU regulatory philosophy: from rigid, pre-market evidence expectations to adaptive, lifecycle-based regulatory approaches. They address two distinct but complementary challenges: rare diseases (data scarcity) and innovation (uncertainty and novelty).

The common message is clear: the future of EU medical device regulation is not about reducing evidence; it is about generating the right evidence at the right time across the product’s lifecycle. For orphan device developers, that shift can be the difference between a device that stalls for lack of data and one that reaches the patients who have no alternative.

For a deeper dive on the breakthrough side, read our companion post on BtX in Europe.

If your device may qualify as an orphan device, evaluate early and plan strategically.

Orphan status can open real advantages, but only if the evaluation and evidence strategy are built well from the start. That means confirming fit early, justifying where clinical data will necessarily be limited, and shaping a lifecycle evidence plan your notified body will accept. If you think your device targets a rare disease or small population, get in touch with our EU regulatory team to pressure-test the opportunity and map the right path forward. Veranex builds its EU MDR and IVDR support around strategic, practical implementation and documentation planning, exactly the kind of early assessment orphan devices require.

Contact us for orphan device and BtX evaluation and regulatory strategy support. We can tell you where you stand, justify your evidence approach, and execute the technical documentation, clinical evaluation, and post-market planning needed to make the most of the opportunity.

About Regulatory Affairs at Veranex — Full lifecycle strategy that shapes upstream decisions and streamlines downstream review

Regulatory strategy developed in isolation from design, clinical, and commercial realities leads to misaligned submissions, avoidable questions, and costly delays. Regulatory Affairs provides strategic consulting and submission support across FDA (510(k), De Novo, PMA), EU MDR/IVDR, and international pathways integrated with Engineering & Development, Preclinical Services, Clinical Research, and Quality Consulting from the earliest stages of development. Upstream, our regulatory experts inform design inputs and align evidence generation with submission requirements before studies launch. Downstream, regulatory strategy shapes Medical Writing deliverables and post-market surveillance planning. Because our experts have shaped the evidence rather than inherited the documentation, they anticipate reviewer questions instead of reacting to them.

About the authors:

Silvia Anghel, PhD, has a unique combination of scientific research expertise and industry experience in the field of in vitro diagnostics (IVD). Her background includes research conducted in prestigious laboratories across Canada and Switzerland, focusing on oncology, metabolism-related disorders, including cardiovascular diseases, and gastroenterology. She has more than 15 years of industry experience, managing projects related to the development, manufacturing, regulatory compliance and quality management of IVD devices. At Veranex, Silvia guides manufacturers through regulatory pathways and performance evaluation strategies, leveraging her comprehensive understanding of product lifecycles from development through commercialization. She provides strategic guidance in quality management system implementation, technical documentation development, and critical negotiations with Competent Authorities and Notified Bodies.

Francisca Lameiras, PhD, has over eight years of experience from working with Quality Assurance and Regulatory Affairs within MedTech in Sweden.​ She is an experienced project manager, highly proficient in developing and implementing quality management systems aligned with ISO standards and has a strong track record in ensuring compliance and operational excellence. ​Her experience includes quality system implementation, accreditation processes and lifecycle compliance aligned with global frameworks such as EU MDR and EU IVDR requirements. She supports customers through key processes, including technical documentation preparation, regulatory registrations, and post-market obligations.​ Prior to Veranex, she has held Head of QA/RA, Head of Laboratory and Laboratory Engineer roles in a Cancer Diagnostics company.​