New guidance provides definition for orphan device, offers alternative trial designs

Quick background on clinical evaluation and investigation requirements under the European medical device regulation

• The E.U. medical device (MDR; Regulation (EU) 2017/745) and IVD regulations (IVDR; Regulation (EU) 2017/746) established more robust requirements for clinical evidence than were required under the previous device and diagnostics directives (MDD, IVDD). All medical devices and diagnostics need to have sufficient evidence, clinical and otherwise, to demonstrate conformance with the general safety and performance requirements (GSPRs) outlined in Annex I of both regulations.
• Clinical investigations: Sponsors need to conduct prospective clinical investigations when the clinical evaluation – a review of existing clinical evidence according to MDR Annex XIV – shows there isn’t sufficient evidence to support device safety and performance requirements. Requirements for clinical investigations under the MDR are outlined in MDR Articles 62 – 80 and Annex XV. The study outcomes should establish clinical benefits and safety and verify device performance under normal conditions of use. Annex XV describes the requirements for clinical investigations and the information needed for the clinical application.
• Guidance issued by the Medical Device Coordination Group (MDCG) builds out and operationalizes the requirements for clinical evaluations and investigations. MDCG 2020-5 describes when equivalence with another device can be used to demonstrate sufficient clinical evidence, rather than needing to conduct a new clinical investigation. MDCG 2020-6 provides guidance on what would be considered sufficient clinical evidence for devices with valid certificates issued under the MDD. A question-and-answer document answers common questions on clinical investigation (read AgencyIQ’s analysis of MDCG 2021-6 here), and a Commission guidance (2023/C 163/06) outlines the content and structure of the clinical investigation report summary. For high-risk medical devices, MDCG 2023-7 describes the exemptions from performing a prospective clinical investigation and clarifies what would be sufficient levels of access to information from a competitor. [ Read AgencyIQ’s analysis of those exemptions here.] MDCG 2020-10 provides guidance on safety reporting during clinical investigations. Finally, MDCG 2024-3 outlines the expected content for a clinical investigation plan and MDCG 2024-5 describes the content of the investigator’s brochure. [Read AgencyIQ’s analyses of the content for a clinical investigation plan here and the content of the investigator brochure here.] In the post-market space, the group offers guidance on creating a post-market clinical follow-up (PMCF) plan, which confirms product safety and performance and identifies emergent risks (MDCG 2020-7).

This week, the MDCG issued a guidance document to help manufacturers of orphan devices navigate MDR clinical data requirements

• Quick background: The Commission organized an orphan device task force (ODTF) in late 2022 to tackle the unique clinical challenges for this device type. As written, the MDR does not offer special concessions or flexibilities for orphan devices used in only small populations. This has added complexity for manufacturers of these devices, who have been flagging concerns for some time. In April 2023, the first update ( link is a direct download) from the ODTF indicated that it was working to develop a definition for orphan device. The working definition offered at that meeting focused on devices intended to treat or diagnose patients for diseases or conditions affecting no more than 1 in 37,000 Europeans per year. Other work packages for the ODTF include information about clinical evidence for this device type, conditional certification, and the use of registries to support conformity assessment.
• The CORE-MD project contributed significantly to what clinical evidence for orphan and pediatric devices should look like. See here for an in-depth analysis of those recommendations, but in short, CORE-MD presented findings from research about the impact of the MDR on certain high-risk medical devices. Part of the project focused on the concerns about orphan device manufacturers’ ability to comply with the MDR. The report cited challenges given the absence of a population large enough to support the gold standard of randomized controlled trials (RCTs), and the fact that there is no one-size-fits-all trial design. For orphan devices in particular, CORE-MD noted that conditional approval could be important, given the limited patient populations and available patients. Other trial designs, lower on the clinical evidence hierarchy, may need to be employed. [See Appendix III of MDCG 2020-6 for the suggested hierarchy of clinical evidence.]
• The new MDCG guidance, MDCG 2024-10, offers makers of orphan devices a strategy for their clinical evaluations. The document is organized into 10 sections, with the first four encompassing abbreviations and terminology, introduction, scope, and orphan device status. Sections 5 – 9 are labeled as Part A and cover clinical evaluation considerations. Specifically, the guidance discusses opportunities for limited pre-market clinical data, what role non-clinical data may play, an overview of the clinical evaluation process, generating pre-market clinical data, and conducting post-market surveillance and PMCF studies. Sections 10 and 11 (Part B) of the guidance discuss procedural considerations and how Notified Bodies and expert panels are involved in the process. Three appendices cover the clinical evaluation report, considerations on orphan device clinical investigations and extrapolating clinical data for orphan indications.
• Out of scope are diagnostic devices, custom-made devices, in-house devices and devices with no intended medical purpose as described in MDR Annex XVI.
• Document-specific definition of “orphan device” (section 4.1): While the MDCG has been promising a formal definition of orphan device for some time, an attachment to meeting minutes from October 2023 (direct download) noted that the orphan device guidance would include a definition for orphan device. However, the new guidance, MDCG 2024-10, provides criteria “for the purpose of this guidance.” Those criteria are that the device is intended to benefit patients with a disease or condition present in 12,000 or fewer people in the E.U. per year, AND that there either are no available alternative options, or the device has a better expected clinical benefit as compared to the alternatives or state of the art option (including when considering patient population-specific factors). The guidance makes the point that orphan device status doesn’t confer any market exclusivity, and one device receiving this status does not preclude other devices from also receiving the designation.
• The need to document how and why a device qualifies as an orphan device (section 4.2) should be part of the documentation submitted to Notified Bodies and/or expert panels for the purpose of formalizing orphan device status. The justification should have an epidemiologic basis that the disease or condition either: (1) affects 12,000 or fewer EU citizens per year; or (2) affects a clinically valid patient sub-population within a disease or condition experienced by over 12,000 people per year, defined in this guidance as an orphan sub-population. These data should be scientifically based on authoritative references, and the guidance gives some examples of acceptable references. “Arbitrary limitations of use to only a subpopulation of patients to meet the incidents criteria will not be considered sufficient,” it cautions.
• The device description is part of qualifying as an orphan device, which could also include specific indications within the intended use. The device description should include information about the current state of the art treatment options and any alternative device choices. To support a manufacturer’s justification of expected clinical benefit from the device, the manufacturer can use consensus statements from professional societies, as well as any supporting non-clinical or preliminary clinical data. Where the orphan indication is part of a larger intended purpose, the intended purpose in the orphan population or subpopulation should be “sufficiently different” from the other intended purpose, and the clinical evidence for the non-orphan purpose should not be applicable (section 4.3). In order to extrapolate clinical data from the non-orphan population, appropriateness depends on the similarity between the two populations, the quality of the clinical data, and whether the extrapolated evidence can be considered valid scientific evidence.

Part A of the guidance helps orphan device manufacturers address limitations in their pre-market clinical data

• What are considered “acceptable limitations” in pre-market clinical data (section 5): “Orphan devices may be granted market access with acceptable limitations in the amount and quality of pre-market clinical data, provided that appropriate measures are implemented, as described in this document,” which would then be augmented by an “adequate” PMCF plan. However, the guidance goes on to note that “there must be sufficient clinical evidence to demonstrate conformity.” The only cases where limited pre-market clinical data are considered acceptable are when all of the available non-clinical and clinical data have been evaluated, any limitations in the clinical data have been identified, the existing data (non-clinical and limited clinical data) are sufficient to meet the GSPRs, the benefit-risk ratio is acceptable, and “it is not feasible or proportionate to generate further clinical data within an acceptable time frame in the pre-market setting.” The manufacturer also needs to have a PMCF plan in place to address the remaining limitations in the clinical data and inform users of the device’s orphan status.
• Other data that can support limited pre-market data: Section 6 contains a list of non-clinical data that can fulfill high-quality evidence expectations for orphan device safety and performance, which can be used with a “clear explanation on their relevance” to the orphan device. Some of these are laboratory and animal tests, cadaveric studies and data from similar devices.
• The new guidance summarizes the requirements for performing a clinical evaluation for any medical device, which also apply to orphan devices (section 7). These are laid out in MDR Article 61 and Annex XIV and include creating a clinical evaluation plan; finding, appraising and analyzing the clinical data; generating new data to address gaps; creating a clinical evaluation report; and creating a post-market clinical follow-up plan to update and augment the initial clinical evaluation.
• Factors that help determine acceptable limitations in the pre-market clinical data: For orphan devices where there may be limitations in generating sufficient pre-market clinical data, both disease- and device-specific factors can help determine what the acceptable limitations in those data would look like (section 7.1). Disease information may include epidemiologic information supporting orphan device status, disease severity, and the current state of the art, which should include potential treatment alternatives. Device-specific factors include summaries of the data supporting orphan device status, the pre-clinical evaluation, all non-clinical data, and a justification for why the limitations in the pre-market data are acceptable. When the manufacturer understands the limitations in clinical data, it can generate more data in a focused manner to specifically address those limitations and existing gaps. Per the guidance, “It may be acceptable for some limitations in clinical data to be addressed through specific PMCF activities.”
• The special case of orphan legacy devices (section 7.3): Legacy devices are those devices that still have valid certificates under the medical device directives. Legacy devices have their own clinical evidence requirements, described in guidance document MDCG 2020-6 on sufficient clinical evidence for legacy devices, and also in MDCG 2023-7 on exemptions from clinical investigations for high-risk and implanted device. Pre-market clinical data requirements for legacy devices can, in some cases, be satisfied with data collected under the directives, including clinical data and data from PMCF and post-market surveillance, as long as the manufacturer can demonstrate that the data meet MDR requirements. There are special requirements for demonstrating equivalence to other devices according to MDCG guidance MDCG 2020-5, especially where those may no longer be on the market. Support may also come from off-label use for an orphan indication, where a device has been used off-label for many years to the extent is it now considered best practice, as long as these data are of sufficient quantity and quality.
• Pre-market clinical data are still needed for orphan devices (section 8): In the case of class III and implanted devices, there are few exemptions to the need to carry out a prospective clinical investigation – see MDR Article 61(4) and this AgencyIQ analysis. In creating the clinical investigation plan for orphan devices, manufacturers need to involve clinical experts in appropriate study design, as well as considering engaging with patients and patient associations. To bolster the numbers, studies should aim to include multiple centers. Appendix A.2 outlines considerations for orphan device clinical investigation designs. There may be cases where extrapolating the data is appropriate – see Appendix A.3.
• Post-market data and conditional certification: Post-market data comes from post-market surveillance (PMS) and post-market clinical follow-up, which is especially important for orphan devices where pre-market clinical data may be limited (section 9). The PMCF plan needs to describe the limitations of the pre-market data and how the PMCF will address those limitations. Data can come from the PMCF investigation, registries or other post-market information, including real-world data. Where the Notified Body has reviewed the limitations and the PMCF plan, it may “be appropriate for specific PMCF activities and milestones to be required by the notified body as specific provisions of certification of the device.” Because timeframes may need to be adjusted because of the nature of the orphan device patient populations, the manufacturer and Notified Body may need to engage in ongoing structured dialogs in order to discuss challenges in completion of the PMCF plan.
• Benefit-risk determination, PMCF investigations and use of registries (sections 9.1, 9.2, 9.3): Orphan devices need detailed risk management plans, which the PMCF data will feed into. The plan should discuss monitoring and assessing risks, and when the manufacturer will take action based on new concerns arising from the data. The PMCF plan needs to address any conditions imposed by the Notified Body and any limitations in the pre-market clinical evidence. Where the preclinical data may not have addressed long-term exposure to the device, the PMCF plan needs to plan for long-term follow-up studies, to identify any safety and durability issues with ongoing use. The PMCF should include use of registries, developed by the manufacturer or, preferably, by national bodies and specialty medical associations, whose suitability the manufacturer should justify.
• Data outside the PMCF (section 9.4) generally come from real-world data generated through routine use of the device. Other data come from the post-market surveillance system (PMS), described in MDR Articles 83 – 91. These data may help detect rare complications.

Part B of the guidance offers recommendations on interacting with Notified Bodies, Notified Body responsibilities and what kind of advice and assistance the expert panels can offer

• The Notified Body is tasked with verifying orphan status against the technical documentation. The Notified Body first verifies the orphan device status, generally as structured dialog before or during conformity assessment; it may also request an expert panel opinion. The Notified Body reviews the technical documentation against Annex I, II and III in the MDR – GSPRs, product technical documentation and post-market documentation. Part of this is evaluating the clinical evaluation report (CER) and the acceptability of any limitations in the clinical data, measured against the PMCF plan.
• Orphan devices with acceptable limitations in clinical data can be issued conditional certificates. Per section 10.2, if the evidence is sufficient, the Notified Body can issue conditions to be fulfilled after issuing the certificate. These may be actions like completing certain PMS or PMCF actions in a specific time period and informing users of the device orphan status, limitations in clinical data, and specific instructions on how to report incidents and complaints. When conducting surveillance, Notified Bodies will verify the ongoing acceptability of the risk-benefit profile against the PMS and PMCF data and verify updates to the CER and compliance with the conditions of certification. Where conditions aren’t met, the Notified Body can consider suspending or withdrawing the certificate.
• Expert panels can offer advice on orphan device status and what clinical evidence should be collected, to the Notified Body or (rarely) directly to the manufacturer (section 11). This consultation is optional and independent of the clinical evaluation consultation process (CECP) for high-risk medical devices described in MDR Article 54. Manufacturers of high-risk devices – class III and class IIb devices that administer or remove a medicinal product – can and should seek scientific advice from the expert panels on the orphan device status and the clinical program, per the guidance; the level of clinical evidence will be affected by the orphan device status. Where the clinical program is already underway, the manufacturer can consult the expert panel in exceptional cases. Manufacturers’ direct consultation of the expert panel is an extraordinary measure allowed only during the MDR transition period, ending in December 2028 at the latest. The manufacturer should take care that expert panel advice doesn’t interfere with Notified Body assessments. This would entail review of the CER and orphan device status.
• Are the review timelines 30 days, 60 days, 90 days or 120 days? Per section 11.2, the expert panel has 60 days to respond to orphan device status requests and 90 days for combined orphan status and clinical program review requests. The guidance goes on to note that the panel can offer the advice in two steps, in which case the panel has 60 days for the orphan device status decision and another 60 days on the clinical evaluation.
• Appendix A.1: Orphan device-specific information to include in the CER: The CER should include a summary of how the device meets the orphan device criteria, identified limitations in clinical data and how they were identified, and any residual risks. The manufacturer needs to show that the limitations are acceptable, to include evaluation of all device data (clinical and non-clinical), evidence that the available data supports the device meeting the GSPRs, a statement that it’s not feasible or proportionate to collect more data in the pre-market space, and notifying users on the status of the orphan device and how to report incidents and complaints.
• The PMCF plan should be clear, stringent and detailed, and should include a summary of the risk management plan and description of the data needed to complete and fulfill the limited data collected in the pre-market space. This should include a timeline for collection of the data, projection of the number of patients per year, and where the data will be collected from (e.g., PMCF investigation, registries). Updates to the CER should include continued updates on how the device meets the orphan device criteria, total product sales in E.U. and worldwide, updates to state-of-the-art and the benefit-risk ratio, a summary report of progress on the PMCF activities, and how the studies are addressing the initial limitations in pre-market data.
• Appendix A.2 offers considerations for conducting clinical investigations of orphan devices, including proposed statistical treatments. Objectives may focus on short- and medium-term benefits, leaving the PMCF to address the long-term endpoints. Endpoint selection and study design may deviate from such canonical clinical trial designs as cross-over, adaptive and sequential designs. Other study design types that may be suitable for pre-market investigations include prospective observational studies, unblinded and open-label RCTs, and registry based RCTs, among other choices.
• Alternative statistical approaches may also be needed due to small population sizes. The appendix discusses different approaches including Bayesian designs, and also flags error types that may need to be considered based on the statistical approach. The choice of comparator and control may also vary from standard trials, including no control or comparator. The guidance notes that all approaches should be justified.
• Annex A.3 discusses the appropriateness of extrapolating data for orphan indications, an approach that can be used when the manufacturer has a device used in both orphan and non-orphan populations; whether extrapolation is appropriate, though, needs to be decided on a case-by-case basis. Combining extrapolated data with other clinical data is partial extrapolation; using only the extrapolated data is full extrapolation. Which approach a manufacturer uses needs to be fully justified and will depend on how relevant the extrapolated data are for the orphan population, as well as the quality and suitability of the data. Annex A.3 offers flowcharts to determine whether extrapolation is suitable and whether the manufacturer can use full or partial extrapolation.

Analysis and what’s next

• The new guidance is likely to be an important one for manufacturers of orphan devices, offering alternatives to full RCTs – with justification. Given the cost and effort to get devices certified under the MDR, special considerations are needed for devices that only apply to small populations of patients. The proposed alternate study designs have likely been informed by the CORE-MD work on alternate strategies for pediatric high-risk devices, which talked about the importance of conditional approvals that could be followed up in the post-market space with the use of registries. The document outlines the criteria for determining orphan device status, and how to document compliance with those criteria. It specifies what constitute acceptable limitations in pre-market data and how to fill in those gaps with the PMCF and other post-market data. Finally, it describes alternative clinical trial designs where RCTs aren’t feasible, and what statistics can be used to evaluate the data with minimal bias.
• Does this guidance offer the formal definition of “orphan device” we’ve been waiting for? The new guidance notes the definition of orphan device “for the purpose of this guidance” (section 4.1), but MDCG meetings late last year promised that the orphan device clinical guidance document would also include a formal definition for orphan device. Presumably, this does constitute a definition suitable for the MDR and not just this document. Still, the definition doesn’t quite match the ones proposed the ODTF in 2023 (1 or fewer in 37,000 people; see above) or by the CORE-MD project in August 2023, of a condition of less than 1 in 2,000 E.U. citizens addressing an unmet medical need that doesn’t have a suitable equivalent alternative. The definition from this guidance for an orphan device is one used for a disease or condition present in 12,000 or fewer E.U. citizens per year, and there are either no available alternatives, or the device has better expected clinical benefit than the state of the art or identified alternatives.
• How are the clinical requirements for orphan devices different from non-orphan devices? The guidance stated more than once that the orphan device pre-market clinical data need to support the MDR general safety and performance requirements and need to be “sufficient”; this is no different from the clinical evidence requirements for any device, orphan or not. While the guidance does go into possible study designs and statistical treatments, nowhere does it lift the requirement for “sufficient” clinical evidence, and any alternative strategies need agreement from the reviewing Notified Body and likely an expert panel. Certainly, though, the guidance presents the possibility of deferring the longer-term effects to post-market data collection.
• This is the first document to provide an example of what conditional certification might look like. Something the Commission has been promising since August 2022 with the introduction of its 19-point plan to free up Notified Body capacity, this is the first concrete example of what would qualify for conditional certification, conceived as limited but sufficient pre-market clinical evidence that would be completed by post-market clinical commitments within a promised timeframe.
• Is this a response or rebuttal to Parliament’s proposed MDR amendments? AgencyIQ dove into PETER LIESE’s proposal to amend the MDR earlier this week, and it proposed some of the same items this document supplies. These include a formal definition of orphan devices, though Parliament’s proposal suggested the criteria should be a disease or condition frequency of not more than 1 in 37,000 E.U. citizens per year or lack of sufficient alternatives with the same clinical benefit. The proposal also suggested adding legislation on conditional authorizations in the face of an incomplete clinical evaluation, where the manufacturer would be obligated to complete or undertake clinical studies to confirm the benefit-risk ratio.
• Last word: It is uncommon for a medical device guidance to hit the spotlight page of the Commission Public Health website, likely signaling the importance of this guidance to the European Commission as a whole.

To contact the author of this item, please email Corey Jaseph ( cjaseph@agencyiq.com).
To contact the editor of this item, please email Laura DiAngelo ( ldiangelo@agencyiq.com) or Kari Oakes ( koakes@agencyiq.com).

Key Documents and Dates

• News announcement – MDCG 2024-10 – Clinical evaluation of orphan medical devices – June 2024, published June 25, 2024
• MDCG 2024-10: Clinical evaluation of orphan medical devices
• E-News: New guidance on the clinical evaluation of orphan medical devices published, dated June 25, 2024