FDA Acceptance of Out-of-US Real-World Evidence for De Novo Classifications

By Rhizome Team

The FDA's De Novo pathway provides a route to market for novel, low-to-moderate risk medical devices that lack a predicate device. As the medical device landscape becomes increasingly global, manufacturers often seek to leverage real-world evidence (RWE) generated outside the United States to support their De Novo submissions.

Understanding FDA's acceptance of non-US RWE data is critical for manufacturers planning international clinical development strategies. The agency has shown willingness to consider foreign data when it meets specific quality standards and relevance criteria, potentially reducing development timelines and costs for device sponsors.

Here we examine documented cases where the FDA has accepted out-of-US real-world evidence to support De Novo classifications. This analysis provides practical insights into the types of foreign data the agency has deemed acceptable and the conditions under which such data can strengthen a De Novo submission.

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when has the FDA accepted out of US RWE data for a de novo?

Answer

Short Answer

Based on FDA De Novo decision summaries and guidance reviewed, the FDA has accepted OUS real-world evidence (RWE) in multiple De Novo decisions spanning 2012–2020. Clear, device-specific examples include:

  • 2012: NuCLEUS/NuCLEUS‑X BAV Catheters (NuMED, Inc.) — FDA relied on “a very large amount of worldwide clinical experience,” including an observational cohort from Waikato Hospital, New Zealand, as part of the evidentiary basis for the De Novo decision 25262729.
  • 2016: IlluminOss Bone Stabilization System — FDA accepted data from an EU Registry in Germany and The Netherlands (132 subjects) as part of the clinical evidence supporting the De Novo request 7980.
  • 2017: FETAL PILLOW — FDA accepted OUS RWE from Scotland (75 patients, Wishaw Hospital) and a retrospective cohort from Brisbane, Australia (160 patients) to address differences in standard of care and support the totality of evidence 115116117120.
  • 2019: Comaneci Embolization Assist Device — FDA accepted a post‑market retrospective study (observational cohort) from two OUS sites in Liverpool, UK and Sofia, Bulgaria (63 patients), acknowledging limitations and requiring a US postmarket study to supplement generalizability 891071211.
  • 2020: EndoRotor Device — FDA accepted real‑world clinical data from 39 OUS sites (including Erasmus in The Netherlands) covering 108 subjects and 134 procedures; this RWE was supportive (especially for safety) alongside an IDE study used for primary effectiveness 285284286288283.

What Was Accepted and How It Was Used

Types of OUS RWE the FDA Considered

  • Patient registry data:
    • EU registry with prospectively collected, standard-of-care outcomes and follow-up to 2 years (Germany/The Netherlands) for IlluminOss Bone Stabilization System 7980.
  • Retrospective observational cohorts/case series (chart/record abstraction from routine care):
    • Scotland (75 patients) and Australia (160 patients) for FETAL PILLOW 115116117120.
    • UK and Bulgaria post‑market retrospective study (63 patients) for Comaneci 891071211.
    • Multi‑site OUS “real‑world clinical data” (39 sites; 108 subjects; 134 procedures) for EndoRotor 285284286288283.
  • Published observational experience from outside the US:
    • New Zealand cohort (60 patients) within “worldwide clinical experience” cited for NuCLEUS/NuCLEUS‑X 27262529.

How FDA Weighed the OUS RWE

  • As supportive evidence, particularly for safety and context:
    • EndoRotor: FDA emphasized the US IDE study for effectiveness and considered Erasmus (Netherlands) plus 39-site OUS RWE primarily supportive, noting the RWE was not collected under a formal, pre-specified study design 285286288.
    • FETAL PILLOW: OUS RWE helped address differences in standard of care and populations; FDA combined these data with reanalysis and imposed special controls and labeling to mitigate residual risk 115116117118.
  • With explicit acknowledgement of limitations and need for additional US data:
    • Comaneci: Retrospective design, small sample, and non-US sites raised generalizability concerns; FDA granted the De Novo but required a US postmarket study to address uncertainty under real-world US practice 8910712.
  • As part of the totality of evidence given extensive real-world experience:
    • NuCLEUS/NuCLEUS‑X: FDA cited “worldwide clinical experience” and specific OUS observational data as scientifically sound and sufficient in concert with nonclinical testing; animal testing was not required due to the breadth and nature of clinical in vivo experience 25262729.
  • Integrated into a broader evidence package from routine care registries:
    • IlluminOss: EU registry data captured standard-of-care outcomes and adverse device effects in Germany and The Netherlands; FDA incorporated these real-world observations into the De Novo assessment 7980.

Key Examples with Nuances and Timeframe

2012 — NuMED NuCLEUS/NuCLEUS‑X BAV Catheters

  • What FDA accepted: Extensive OUS observational experience, including a New Zealand cohort of TAVI patients using the catheter for balloon aortic valvuloplasty 27262529.
  • Significance: FDA explicitly relied on worldwide real-world clinical experience plus bench data to establish reasonable assurance; this shows early De Novo use of OUS RWE for devices with established global practice patterns 252629.

2016 — IlluminOss Bone Stabilization System (DEN160062)

  • What FDA accepted: EU Registry (Germany/The Netherlands) of 132 subjects with prospectively gathered, standard-of-care data and up to 2 years follow-up 7980.
  • Significance: Illustrates FDA’s willingness to leverage structured OUS registry RWE in a De Novo, when data collection aligns with clinical reality and includes meaningful follow-up.

2017 — FETAL PILLOW

  • What FDA accepted: OUS RWE from Scotland (75-patient study) and Australia (160-patient retrospective cohort). FDA also considered a clinical trial in India but positioned the observational cohorts as “real-world” complements 115116117.
  • How FDA handled differences: Required supplemental real-world data and reanalysis to address US-vs-OUS care differences; applied special controls and labeling to mitigate residual risks 115116117118.
  • Significance: Shows FDA using OUS RWE to bridge practice differences while using controls to address uncertainty.

2019 — Comaneci Embolization Assist Device

  • What FDA accepted: Post-market retrospective observational data from two OUS hospitals (Liverpool, UK; Sofia, Bulgaria; 63 patients), with independent US-based imaging and AE analyses 891071211.
  • FDA’s conditions: Acknowledged uncertainty due to retrospective, non-US nature and small size; required a US postmarket study to assess safety and training in US practice 97108.
  • Significance: Demonstrates acceptance of OUS RWE with explicit recognition of generalizability limits and the use of postmarket commitments to manage premarket uncertainty.

2020 — EndoRotor Device (DEN200016)

  • What FDA accepted: RWE from 39 OUS sites (134 procedures, 108 subjects) plus Erasmus (Netherlands) data; the OUS RWE comprised routinely recorded clinical information from real-world use for walled-off pancreatic necrosis 285284286288283.
  • FDA’s weighting: Treated OUS RWE as supportive (especially for safety); relied on a US IDE study with pre-specified endpoints for effectiveness. Noted limitations of the RWE due to lack of formal design and standardized endpoints 285286288.
  • Significance: Highlights how OUS RWE can materially inform safety and clinical context while primary effectiveness rests on more controlled data.

What This Means in Practice

  • FDA can and does accept OUS RWE in De Novo reviews when it is fit-for-purpose and relevant to the US regulatory question. Most often, the OUS RWE is used as supportive evidence within a “totality of evidence” framework, with FDA calling out limitations (retrospective design, small sample size, differences in care settings) and, where needed, requiring postmarket data collection in the US to address generalizability and residual uncertainty 2852862881151161171188910712798025262729.
  • Where registries are well-structured and aligned with standard of care (e.g., EU registry), FDA has incorporated those real-world data directly into its assessment, particularly for safety outcomes and longitudinal follow-up 7980.
  • In several cases, FDA explicitly discussed how OUS RWE informed the benefit-risk assessment while adding special controls, labeling, or postmarket study requirements to manage uncertainties tied to OUS data sources 1151161171188910712.

Guidance Context and Non-Examples

  • Guidance supports the principle that OUS data and RWE may be appropriate in De Novo decisions under least burdensome and valid scientific evidence standards, but explicit OUS RWE De Novo examples in guidance documents are limited. The 2023 draft RWE guidance includes a De Novo example of supplemental RWE via single-site chart review (not explicitly OUS) and an OUS registry example for a PMA, underscoring that geography per se is not disqualifying if data are fit-for-purpose 175178. The Least Burdensome guidance likewise recognizes alternative sources, including OUS data and RWE, when appropriate 323133.
  • Several De Novo submissions relied on prospective clinical trials (some conducted OUS) rather than RWE; these were not counted as OUS RWE acceptance (e.g., iTind and other trials described as prospective studies rather than real-world data collections) 199201204.

Bottom Line

From 2012 through 2020, the FDA accepted out-of-US RWE in multiple De Novo classifications, including devices such as NuCLEUS/NuCLEUS‑X BAV Catheters (2012) 25262729, IlluminOss Bone Stabilization System (2016) 7980, FETAL PILLOW (2017) 115116117120, Comaneci Embolization Assist Device (2019) 891071211, and EndoRotor Device (2020) 285284286288283. Across these examples, the OUS RWE frequently comprised registries or retrospective observational cohorts used as supportive evidence, with FDA acknowledging limitations and, when needed, requiring postmarket US data to address generalizability and maintain reasonable assurance of safety and effectiveness.