When Published Clinical Evidence Can Support an Expanded Intended Use

A Case Study

Expanding the intended use of a medical device does not always require a prospective clinical trial. In a previous post we outlined some key principles and best practices for using published clinical literature to support regulatory decision-making. In some cases, a manufacturer may be able to support a new or more specific indication using published real-world evidence.

A clinical evaluation is a systematic and planned process for continuously generating, collecting, analyzing, and assessing clinical data related to a medical device to verify its safety and performance, including clinical benefits, when used as intended by the manufacturer. Under the EU framework, the clinical evaluation must consider the current state of the art and demonstrate that the available clinical evidence supports the intended purpose, clinical benefits and performance claims, benefit-risk determination, risk controls, and labeling. If the existing clinical evidence is insufficient to support the proposed expansion, additional clinical data must be generated.

In the United States, the pathway depends on device type and submission context. For Class III devices, a Premarket Approval (PMA) supplement is required for changes affecting safety or effectiveness, including new indications for use and labeling changes. The FDA guidance for Class III device supplements recognizes that published literature may support PMA, Product Development Protocol (PDP), or Humanitarian Device Exemption (HDE) supplements (and may even serve as the sole basis for approval of the supplement) when the literature is “sufficient, detailed, objective, and directly applicable to the subject device.” FDA also cautions that “isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence to show safety or effectiveness.” For lower risk 510(k) devices, FDA’s substantial equivalence framework considers whether differences in indications or technology raise different questions of safety and effectiveness, and FDA’s draft guidance on clinical data in 510(k) submissions provides additional context for when clinical data may be necessary.

For manufacturers, the quality of the literature strategy can determine whether published evidence accelerates or complicates the regulatory pathway. A well-designed literature strategy can shorten the path to authorization when the intended use expansion is clinically and technically well supported. A poorly designed literature review, however, can create deficiencies, delay review, and undermine the credibility of an otherwise promising regulatory submission. Herein we present a case study illustrating how a targeted, regulatory-grade literature strategy helped transform a promising evidence base into a defensible case for an expanded intended use.

Case Presentation: when promising real-world evidence was not yet regulatory-grade

Consider a manufacturer of an established therapeutic medical device platform that sought to expand its labeling from an existing use to a more focused indication for a defined patient population. The proposed expansion was attractive because the core technology, procedural principles, and trained specialist users were already familiar; the manufacturer had also identified published clinical experience describing real-world use of the subject device and similar systems for the proposed indication.

However, the agency’s review found that the initial evidence package did not adequately define the proposed indication or demonstrate that the literature supported each clinically meaningful subgroup within the intended population. The indication had been described too broadly, and some cited articles addressed clinical conditions, anatomical targets, or patient groups outside the proposed use. Geographic differences introduced an additional challenge. Much of the published evidence originated outside the proposed market, requiring consideration of whether the study populations were sufficiently representative of the target population in the new region. Differences in patient demographics, disease presentation, diagnostic criteria, referral pathways, treatment patterns, practitioner training, procedural technique, concomitant therapies, and standards of follow-up could affect the transferability of reported safety and effectiveness outcomes. Accordingly, the evidence assessment needed to distinguish differences that were unlikely to affect clinical applicability from those that could limit generalizability or require additional justification, labeling considerations, training, or region-specific evidence. The issue was not that published evidence could never support the expansion; rather, the initial review did not yet connect the most relevant evidence to the specific proposed claim.

The agency also questioned whether the systematic review methods were sufficiently transparent and reproducible. The initial submission did not clearly define the population and outcomes of interest, provide complete search strategies and execution dates for each database, or present a robust, stepwise study-selection process. Concerns also arose regarding the inclusion of inappropriate article types, inconsistent handling of observational evidence, the absence of transparent search documentation, unclear reviewer roles, and use of risk-of-bias methods that were not appropriate for every study design. The practical effect was predictable: although the literature package contained some relevant information, it remained vulnerable because it did not demonstrate, in a traceable manner, how the published real-world evidence supported the proposed use, whether the data were applicable to the subject device or a justified equivalent configuration, or whether the foreseeable risks were adequately addressed through labeling, training, device-selection guidance, and follow-up recommendations.

Although this case arose in the context of a US FDA submission, the underlying evidence principles are also relevant to clinical evaluation under the EU MDR. Article 61 and Annex XIV, Part A require the clinical evaluation to be planned, conducted, documented, and updated throughout the device lifecycle, with sufficient clinical evidence to support the device’s intended purpose, clinical benefits, safety, performance, benefit-risk determination, and risk management conclusions. Accordingly, an EU MDR clinical evaluation supporting an expanded intended purpose would similarly need to establish that the literature is applicable to the specific device, indication, patient population, and claims, not merely relevant to the general technology or clinical field. These shared principles provide the foundation for the more focused and traceable evidence strategy described below.

What MED changed: from article collection to a defensible evidence argument

MED’s systematic literature review was designed to address the agency’s central concerns by rebuilding the evidence package around a focused indication involving use of an established therapeutic device in a defined adult patient population. The revised scope separated two related but distinct questions: what constitutes the current state of the art for managing the target clinical condition, and what published clinical evidence supports the safety and effectiveness of the subject device for the proposed indications?

For the state-of-the-art review, MED defined the population as adults meeting specified diagnostic and clinical criteria, the intervention as use of the relevant therapeutic technology under defined procedural conditions, and the outcomes as measures of clinical response, symptom improvement, functional status where relevant, adverse events, expected side effects, retreatment, and other clinically meaningful endpoints. MED searched recognized biomedical databases and medical society sources; documented the search terms, limits, search dates, and selection process; and evaluated the resulting literature to establish current clinical practice, benchmark performance outcomes, adverse events, expected side effects, user-training considerations, procedural factors, and long-term follow-up needs.

For the device-specific review, MED used a separate search strategy tailored to the subject device and its potentially equivalent configurations. Published clinical evidence was included only when the device could be adequately identified, the clinical procedure matched the proposed use, the study population was appropriate, and performance or safety outcomes were reported in sufficient detail to support evaluation. MED also documented why studies were excluded, including nonclinical research, indications outside the proposed scope, populations not covered by the proposed labeling, other manufacturers’ systems, mixed data sets that could not be separated, insufficient device identification, or inadequate safety and performance information.

The final evidence base included a substantial body of published clinical literature representing a large number of patients treated with the subject device. Importantly, MED did not simply count favorable studies. Each publication was appraised using a structured framework that considered device applicability, intended-use alignment, patient population, study design, follow-up, statistical analysis, outcome relevance, sample size, device configurations, indication coverage, user expertise, conflicts of interest, and level of evidence. This transformed the literature review from a narrative bibliography into a weighted, reviewer-facing evidence table.

MED then linked the evidence directly to the specific deficiencies. The revised review clearly distinguished the target condition and patient population from related but clinically distinct uses that fell outside the proposed indication. It described the diagnostic and eligibility criteria needed to confirm appropriate patient selection; summarized relevant procedural considerations, user qualifications, device-selection factors, and measures for protecting adjacent structures; and addressed foreseeable short- and long-term risks, the potential need for retreatment, and recommended follow-up. The review also placed adoption and training considerations into context, including the user learning curve, geographical differences, and the need for appropriately experienced practitioners.

Most importantly, MED showed how the clinical evidence compared with state-of-the-art benchmarks. Published data for the subject device demonstrated clinically meaningful improvements in the principal effectiveness outcomes at rates generally comparable with the broader literature. Safety outcomes were evaluated against benchmark rates for adverse events and device- or procedure-related complications, with transparent discussion of small-study variability and areas for which no established benchmark was available. The conclusion was appropriately calibrated: the published evidence supported a reasonable assurance of safety and effectiveness for the proposed expanded use when the device was used in the defined adult population and within the boundaries of appropriate patient selection, user training, procedural technique, labeling, and follow-up.

How MED helps clients expand product lines using published evidence

This case demonstrates how MED can help manufacturers determine whether an intended-use expansion can be supported by published evidence alone. For clients seeking to expand a product line, this support can be especially valuable when the available evidence comes from published real-world use, equivalent device configurations, heterogeneous patient populations, or a field with evolving clinical practice. MED can help determine which literature is directly supportive, which literature is useful only for clinical context, which studies should be excluded, and which evidence gaps must be acknowledged or addressed through labeling, post-market follow-up, or additional analysis.

The result is a clinical evidence package that tells the reviewer exactly what matters: what claim is being supported, which data support it, how the data were found, why the studies were included or excluded, how each study was weighted, how outcomes compare with current benchmarks, how risks are mitigated, and where any residual uncertainty remains. This level of traceability can help clients use published evidence efficiently while reducing the risk of preventable deficiencies. Published clinical evidence can be a powerful tool for expanding a medical device’s intended use or product line, but the evidence must do more than just exist. It must be systematically identified, objectively appraised, clinically relevant, technically applicable, and explicitly connected to the proposed labeling, benefit-risk profile, and risk controls.

Need support determining whether published evidence can support an expanded intended use? MED Institute can help; our cross-functional Scientific-Communications team draws from our Regulatory and Clinical service areas and is well equipped to help evaluate sufficiency of evidence, design and execute systematic literature reviews, address evidence gaps, and translate published real-world evidence into a defensible regulatory strategy. Our support can be tailored to the applicable market and submission pathway, including US FDA submissions and deficiency responses, as well as EU MDR clinical evaluation plans (CEPs), clinical evaluation reports (CERs), state-of-the-art assessments, and related lifecycle updates. Contact us to discuss an evidence strategy that supports your product and regulatory objectives.

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