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From an industry perspective, there is a clear need to advocate for the effective utilization of real-world evidence (RWE) in the regulatory evaluation of medical devices. This practice necessitates a dialogue with regulatory agencies so industry reps can ask clarifying questions, provide pragmatic insights and relay evidence-based recommendations that can improve patient care.
A dialogue would have ideally followed the publication of FDA’s recent draft guidance: “Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices.” Companies that want to invest in RWE and seek clarity on the draft guidance should continue to advocate for equitable device evaluation.
Only a handful of orthopedic devices, one being a biologic, have successfully utilized the RWE approach. Accordingly, industry understands the strong need to foster diversity in clinical data and facilitate evidence-based decision-making processes within the development of medical devices.
These are clear RWE deliverables. In contrast, FDA guidance feels less clear on how it may serve devices in common scenarios, such as expanded label indications and what may constitute acceptable criteria or expectations.
Understanding the inherent value of RWE is admittedly nuanced. Industry feels there is a disconnect between unmet patient needs that it is trying to address and the perceived regulatory critique of its efforts. Let’s critically analyze the six challenges confronting industry stakeholders and FDA in effectively leveraging RWE. We also included questions we’d want to ask FDA representatives if given the opportunity to clarify key pathways in RWE utilization.
1. Addressing the Inherent Limitations
It is crucial to acknowledge that RWE possesses inherent limitations that distinguish it from traditional controlled studies, such as IDE trials. These limitations include variability in data collection methods, potential biases in data acquisition and challenges in controlling confounding variables. Unlike IDE studies, the best of which are meticulously designed and controlled, RWE reflects the complexities and nuances of real-world clinical practice, making it inherently less standardized. For example, the flaws of registry data are well recognized.
Can FDA recognize these limitations? In the alternative, will the agency define circumstances in which allowances can and will be made?
2. Reconciling Standards
Given the fundamental differences between RWE and IDE studies, it is unreasonable to hold real-world data (RWD) to the same stringent standards as controlled clinical trials. Attempting to do so would overlook the intrinsic strengths of RWE and undermine its relevance and applicability in capturing real-world patient experiences and outcomes. Therefore, it is imperative to recognize and rationalize the limitations of RWE in comparison to IDE studies and develop appropriate standards that reflect the unique nature of RWD.
Can FDA set clear and efficient criteria for which it rejects RWE on the grounds of failed relevance and reliability, so that industry stakeholders can make the appropriate assessments of their data before submission or in the design of their data collection leading to submission? Alternatively, could FDA acknowledge that RWE will not be held to the same standard as IDE data?
3. Addressing the Regulatory Gap
The existing regulatory framework primarily focuses on the evaluation of medical devices based on data derived from controlled clinical trials, such as IDE studies. While these studies provide valuable insights into device safety and efficacy, they often lack the diversity and breadth of real-world clinical experiences captured by RWE. Consequently, there exists a significant regulatory gap in leveraging RWE for device evaluation and assessing post-market performance.
Can FDA acknowledge that RWE is a suitable tool for addressing the diversity gap in clinical data?
4. Bridging the Regulatory Gap
To bridge this regulatory gap and harness the full potential of RWE in device evaluation, it is essential to develop alternative approaches that accommodate the unique characteristics of RWD. This may involve establishing specific criteria for the collection and analysis of RWD, incorporating innovative statistical methodologies to account for inherent biases and confounders, and implementing robust postmarket surveillance mechanisms to continuously monitor device safety and performance in real-world clinical settings.
Would FDA accept that any one of the above methodologies would offer a practical way to close the regulatory gap and allow for the acceptance of RWE so as not to stifle innovation and benefit patient care? Alternatively, can FDA clarify what methodologies they deem acceptable to close categories of data gaps evident from prior failed applications?
5. Showing Relevance and Reliability
While RWE may not adhere to the same standards as IDE studies, it offers the potential for unparalleled insights into real-world clinical practice and patient outcomes, thereby enhancing the diversity and comprehensiveness of the evidentiary base for device evaluation. By demonstrating the relevance and reliability of RWE through rigorous data validation processes, transparent methodologies and comprehensive risk mitigation strategies, industry stakeholders can build confidence in the use of RWD for regulatory purposes.
Can FDA recognize the benefits of RWE in addressing gaps in clinical data? Alternatively, if certain gaps are deemed non-addressable through RWE, can the agency clarify ways to effectively mitigate these gaps and indicate which gaps remain unsuitable for closure through RWE?
6. Collaborative Efforts to Establish Best Practices
Leveraging RWE for device evaluation is complex and challenging, so it is essential to foster collaboration among industry stakeholders, regulatory agencies, healthcare providers and patient advocacy groups to establish best practices and guidelines for the collection, analysis and utilization of RWD. Through collaborative efforts, we can develop standardized methodologies, data quality standards and validation protocols that ensure the integrity and reliability of RWE while promoting patient safety and advancing public health objectives.
Can FDA commit to working transparently and efficiently with industry stakeholders to address developing complexities not captured by prior submissions?
By acknowledging and rationalizing the limitations of RWE, we can bridge the regulatory gap and harness its full potential to promote safe innovation, improve patient outcomes and advance public health objectives.
For balance, one must consider that the FDA guidance is intentionally or necessarily open to interpretation. Industry ought to be careful on what it wishes for. A poignant perspective is one that appreciates the perspicacity of FDA’s intentionality to run as a harmonic check and balance.
This counters the understandable eagerness of industry. Rather than being frustrated by the litmus-like approach, the draft lends itself to flexibility. It arguably allows organizations to make their case for RWE and structure a package of data that fits the requirements of “relevance and reliability.”
Being open to interpretation when attempting to regulate such a complex landscape is important. Afterall, the primary criticism of the EU MDR was that it overburdened regulatory processes, which simultaneously drove up costs and stifled innovation.
Dr. Erturan is the Medical Director – Global Lead Medical Affairs and Xavier Sarabia is Senior Director Global Regulatory Affairs & Compliance at Orthofix/SeaSpine.
