The Process: How to Apply for Orphan Device Status

A Step-by-Step Guide to Eligibility, Data Preparation, and Regulatory Engagement for Approval

Successfully navigating the orphan device approval pathway in the European Union requires a clear understanding of the process, eligibility criteria, and regulatory expectations.

[Download the EU Orphan Device Clinical and Regulatory Playbook]

The Medical Device Coordination Group (MDCG) guidance outlines a structured approach to help manufacturers determine whether their device qualifies and how to prepare a compelling application.

Step 1: Determining Eligibility

Before applying for orphan device status, manufacturers must first confirm that their device meets the three core criteria outlined in the MDCG guidance:

• Prevalence Threshold – The device must address a condition affecting fewer than 12,000 patients per year in the EU. This number is based on epidemiological data, not projected sales.
• Limited Treatment Options – The device must serve an unmet medical need where existing treatment options are inadequate.
• Demonstrated Clinical Benefit – If alternatives exist, the orphan device must offer a clear advantage in terms of safety, effectiveness, or patient outcomes.

Step 2: Gathering Supporting Data

Manufacturers must justify their orphan device status with robust scientific and clinical evidence. Since traditional clinical data may not always be available for rare diseases, alternative sources can be used, including:

• Epidemiological studies and disease registries – Data from national and international databases, including WHO reports and EU healthcare records.
• Scientific literature and meta-analyses – Published research on incidence rates and treatment gaps.
• Professional societies and expert recommendations – Data from specialized medical organizations, such as cardiology or neurosurgery associations.
• Real-world evidence and post-market data – Information from past use of similar devices, including off-label applications in legacy products.
• In silico modeling and preclinical studies – Computational simulations that predict device performance in rare patient populations.

Step 3: Engaging with Notified Bodies and Expert Panels

Manufacturers should seek early regulatory engagement to avoid delays and ensure their approach aligns with expectations. This involves:

• Consulting with a notified body – Orphan devices still require full MDR compliance, and manufacturers must work with a notified body to determine clinical and technical requirements.
• Applying for expert panel review – The European Commission is offering free advisory services through 2025 for manufacturers seeking orphan device designation. These panels provide guidance on eligibility, clinical expectations, and alternative data acceptance.

Step 4: Preparing the Clinical Evaluation and Justification Report

The clinical evaluation process for orphan devices differs from standard MDR approvals. Given the rarity of the conditions involved, regulators allow more flexibility in the type and quality of evidence submitted. Key components of the application include:

• Justification for orphan device designation – Clear documentation explaining how the device meets the eligibility criteria.
• Clinical evidence and risk-benefit analysis – A structured presentation of available data, highlighting why standard clinical trials may not be feasible.
• Post-market clinical follow-up (PMCF) plan – A commitment to collect additional real-world data after approval to compensate for limited pre-market evidence.

Step 5: Submitting the Application and Engaging in Structured Dialogue

Once the documentation is prepared, the formal submission process begins. Structured dialogue with regulators and notified bodies is essential to:

• Clarify any regulatory uncertainties.
• Discuss the acceptability of alternative clinical data.
• Define post-market commitments for long-term data collection.

The orphan device pathway is still evolving, and early adopters will help shape future interpretations of the regulations. Engaging proactively with regulators increases the likelihood of a successful approval and ensures manufacturers are aligned with emerging best practices.

Why Early Engagement Matters

Manufacturers who act now can take advantage of expert panel reviews at no cost, making this an opportune time to pursue orphan device status. By following a structured approach—from determining eligibility to engaging with regulatory bodies—companies can streamline their approval process and bring life-saving technologies to market faster.