The Medical Device Coordination Group (MDCG) has published MDCG 2026-6, introducing dedicated guidance on the clinical evidence requirements for orphan in vitro diagnostic medical devices (IVDs) under Regulation (EU) 2017/746.
Published in November 2026, the guidance addresses the particular challenges associated with generating sufficient clinical evidence for IVDs intended for rare diseases, rare conditions or uncommon clinical circumstances.
Why Orphan IVDs Need a Specific Approach
The IVDR requires manufacturers to demonstrate sufficient clinical evidence before placing an IVD on the market.
For orphan IVDs, however, this can be particularly challenging because:
patient populations are very small;
clinical specimens may be difficult to obtain;
prospective studies may be impractical;
commercial volumes may be low;
many orphan diagnostics are developed or used in specialised healthcare settings.
MDCG therefore states that IVDR requirements should be applied in a balanced and proportionate manner, without unnecessarily delaying access to clinically important diagnostics.
Scope of MDCG 2026-6
The guidance is intended for:
manufacturers;
notified bodies;
expert panels;
health institutions;
regulators.
It applies to orphan IVDs across all risk classes and focuses particularly on clinical performance as part of the broader IVDR performance evaluation and clinical evidence framework.
The guidance is also relevant to in-house IVDs manufactured and used within EU health institutions, particularly when demonstrating compliance with the applicable General Safety and Performance Requirements.
What Is an Orphan IVD?
Under MDCG 2026-6, an IVD may be considered an orphan IVD when it is specifically intended to test persons for a disease, condition or circumstance that presents in no more than 12,000 individuals in the European Union per year.
In addition, at least one of the following must apply:
there are insufficient available alternatives; or
the IVD is expected to provide a clinical benefit compared with available alternatives or the state of the art.
The epidemiological threshold relates to the number of affected individuals rather than the total number of tests performed.
Orphan Status Does Not Provide Market Exclusivity
MDCG makes clear that orphan status does not provide market exclusivity.
More than one CE-marked orphan IVD may be available for the same disease, condition or circumstance.
This distinguishes the concept from certain orphan medicinal product frameworks.
Manufacturers Must Justify Orphan Status
Manufacturers claiming orphan IVD status must provide a scientific justification.
This should include:
epidemiological evidence;
description of the disease or clinical circumstance;
definition of the intended target population;
available alternatives;
expected clinical benefit.
Authoritative epidemiological sources such as peer-reviewed literature, public health statistics, European Reference Network registries, EMA records or Orphanet data may be used where available.
Orphan Subpopulations Are Also Possible
An IVD may qualify for an orphan indication even when the broader disease or condition affects more than 12,000 individuals per year.
In such cases, the manufacturer may justify use in a clinically valid orphan subpopulation of no more than 12,000 individuals annually.
However, arbitrary restriction of the intended use merely to meet the incidence threshold is not acceptable.
The manufacturer must provide a scientific rationale showing why the IVD is specifically appropriate for that subpopulation.
Specific Orphan Indications
MDCG also recognises that an IVD may have both:
non-orphan indications;
orphan indications.
Where clinical evidence is difficult to generate only for the orphan indication, the principles in MDCG 2026-6 may be applied specifically to that indication.
This creates an important pathway for manufacturers with broader diagnostic platforms that also support rare-disease applications.
Limited Pre-Market Clinical Performance Data May Be Acceptable
One of the most important elements of MDCG 2026-6 is the recognition that orphan IVDs may reach the market with justified limitations in pre-market clinical performance data.
MDCG states that the level of clinical evidence required for an orphan IVD does not necessarily need to be identical to that expected for a non-orphan IVD.
However, there must still be sufficient evidence to demonstrate:
expected clinical benefit;
acceptable benefit-risk profile;
intended performance;
compliance with applicable GSPR.
Conditions for Accepting Limited Evidence
A limited amount of pre-market clinical performance data may be acceptable when the manufacturer can justify that:
all available data have been evaluated;
the limitations are clearly identified;
existing evidence supports conformity with the relevant GSPR;
benefit-risk remains acceptable;
further pre-market data generation is not feasible or proportionate;
appropriate PMPF and PMS plans are in place.
Users must also be informed of the orphan status and relevant evidence limitations through the IFU, labeling, SSP or other accompanying documentation where appropriate.
Non-Clinical Data Can Play a Greater Role
MDCG highlights the importance of non-clinical evidence for orphan IVDs.
Relevant sources may include:
scientific literature;
analytical performance data;
registries;
in silico modelling;
simulations;
tissue models;
ex vivo data;
contrived samples;
data from similar IVDs;
research-use-only products.
Where high-quality non-clinical data provide strong support for safety, performance and expected clinical benefit, they may reduce the amount of pre-market clinical performance evidence required.
Clinical Performance Evaluation Remains Mandatory
The general IVDR principles for performance evaluation still apply.
Manufacturers must:
identify relevant clinical performance data;
assess their quality and scientific validity;
analyse results and conclusions;
determine what evidence gaps remain.
Potential evidence sources can include scientific literature, disease registries, biobanks, previous clinical performance studies, legacy device use, derogations and experience from other jurisdictions.
Clinical Performance Studies May Not Always Be Feasible
IVDR Article 56(4) requires clinical performance studies unless reliance on other clinical performance data can be justified.
For orphan IVDs, MDCG recognises that prospective studies may sometimes be impractical because of the rarity of the target population.
Alternative evidence-generation approaches may therefore be appropriate.
Where studies are conducted, manufacturers should involve suitable experts such as:
geneticists;
epidemiologists;
statisticians.
Multi-centre collaboration may also be appropriate to increase specimen availability and improve the robustness of results.
PMPF Becomes Critical
MDCG places particular emphasis on Post-Market Performance Follow-up (PMPF).
Where pre-market evidence limitations are accepted, manufacturers must have a detailed and structured PMPF plan capable of addressing those limitations after market access.
The plan should define:
identified evidence gaps;
how each gap will be addressed;
the type of post-market data required;
expected specimen availability;
milestones;
timelines;
periodic analysis of data.
Real-World Data May Support Clinical Performance
Post-market evidence may come from:
PMPF studies;
registries;
routine clinical use;
real-world data;
data from other established regulatory systems.
This may be particularly useful where EU data remain limited due to the rarity of the population.
Benefit-Risk Assessment Must Continue Over the Lifecycle
MDCG stresses that PMPF data should support continuous reassessment of the benefit-risk profile.
Manufacturers should maintain a risk-management approach adapted to:
the orphan indication;
the intended use;
limitations in pre-market evidence;
emerging post-market findings.
Where new safety or performance concerns arise, appropriate action should be taken.
Notified Bodies Have an Important Role
Notified bodies should verify orphan status as early as possible in the conformity assessment process.
They should review:
the manufacturer’s justification for orphan status;
limitations in clinical performance evidence;
the performance evaluation;
PMS plans;
PMPF plans.
The technical documentation is assessed using the same underlying IVDR principles as for non-orphan IVDs, but with the specific considerations in MDCG 2026-6 taken into account.
Certificates May Include Specific Conditions
MDCG confirms that notified bodies may issue certificates containing specific conditions or provisions.
For example, certification may require manufacturers to complete defined PMPF or PMS activities within a specified timeframe to generate additional clinical evidence.
If those conditions are not met, the notified body may ultimately consider suspension or withdrawal of the certificate.
Expert Panel Advice Is Available
Manufacturers and notified bodies may voluntarily seek advice from expert panels concerning:
orphan IVD status;
clinical performance evaluation;
evidence limitations;
proposed PMPF activities.
The guidance distinguishes between early-stage and late-stage consultation.
Early Expert Advice Is Preferred
Manufacturers may approach the expert panel before the clinical performance evaluation or study.
This early-stage consultation can address:
whether the device qualifies as an orphan IVD;
the proposed clinical development strategy;
clinical performance study design;
PMPF planning.
The table on page 17 of the guidance shows the different possible consultation scenarios and explicitly identifies early manufacturer consultation as preferable to late-stage advice.
Expert Panel Timelines
Where advice relates only to orphan status, the expert panel will aim to respond within 60 days.
Where advice covers both orphan status and clinical performance evidence, the panel will aim to provide simple advice within 90 days.
For class D orphan IVDs, this consultation may interact with the Performance Evaluation Consultation Procedure (PECP) under IVDR Article 48(6).
Extrapolation of Clinical Performance Data
MDCG provides a dedicated framework for extrapolating clinical performance data from non-orphan populations to orphan indications.
Both partial extrapolation and, less commonly, full extrapolation may be possible.
The decision depends on:
relevance of the existing data;
similarity between populations;
data quality;
disease characteristics;
sample characteristics;
expected impact on safety and performance.
The decision tree on pages 27–28 provides a structured pathway for determining whether data are suitable for full extrapolation, partial extrapolation or should not be extrapolated.
Performance Evaluation Report Requirements
The Performance Evaluation Report (PER) should include orphan-specific information such as:
justification of orphan status;
evidence limitations;
residual risks;
benefit-risk justification;
non-clinical evidence;
clinical performance evidence;
PMPF plans;
expert panel interaction.
Post-market PER updates should also track:
continuing orphan status;
EU and global sales;
changes in available alternatives;
new clinical evidence;
benefit-risk updates;
PMPF progress.
Clinical Study Design Can Be More Flexible
Annex 4 provides specific considerations for clinical performance studies involving orphan IVDs.
Potential approaches include:
prospective studies;
retrospective biobank studies;
adaptive designs;
sequential designs;
Bayesian methods;
hybrid Bayesian approaches;
external historical controls.
MDCG recognises that conventional statistical approaches may be difficult in very small patient populations.
Bayesian Approaches May Be Appropriate
The guidance specifically notes that frequentist statistical methods may be impractical for some orphan IVD studies.
In such cases, descriptive statistics or Bayesian approaches may be more suitable.
Bayesian approaches can combine:
newly observed data;
historical data;
registries;
expert knowledge.
However, manufacturers must rigorously justify prior information and avoid methods that could increase the risk of misleading conclusions.
Impact on Manufacturers
For manufacturers developing orphan IVDs, MDCG 2026-6 creates a clearer regulatory pathway.
Key actions include:
confirming whether the device meets orphan criteria;
substantiating epidemiological thresholds;
documenting unmet need and clinical benefit;
identifying all available clinical and non-clinical evidence;
defining and justifying evidence limitations;
preparing a detailed PMPF strategy;
considering early expert panel consultation;
discussing orphan status with the notified body early;
documenting orphan-specific information in the PER.
Impact on Notified Bodies
Notified bodies will need to apply a more tailored assessment approach to orphan IVDs.
They should consider whether:
the claimed orphan status is justified;
limited pre-market evidence is acceptable;
PMPF adequately addresses remaining gaps;
certificate conditions are appropriate;
expert panel advice should be sought.
The guidance therefore reinforces the importance of structured dialogue between manufacturers and notified bodies throughout conformity assessment and post-market follow-up.
A More Proportionate IVDR Approach for Rare Diagnostics
MDCG 2026-6 represents an important step toward a more proportionate application of IVDR clinical evidence requirements to rare diagnostics.
The guidance does not remove the need to demonstrate safety, performance or clinical benefit.
Instead, it recognises that for genuine orphan IVDs, some clinical evidence may need to be generated progressively across the device lifecycle rather than entirely before market access.
This approach places greater importance on:
scientific justification;
non-clinical evidence;
targeted clinical data;
PMPF;
PMS;
notified body oversight;
expert panel involvement.
