Combination Product Industry News & Guidance

In a recent review exercise, Swissmedic, the Swiss national health authority examined a small set of Notified Body Opinions (NBOps) submitted in support of medicinal products with integral medical device components. What they found should make any combination product sponsor uncomfortable: despite these opinions being formally issued by designated Notified Bodies, many were incomplete, ambiguous, or of limited value for regulatory decision-making. 

This scenario is not hypothetical. It reflects a pattern our Suttons Creek team has increasingly observed across global programs, where sponsors assume that a Notified Body Opinion represents a definitive regulatory green light, only to discover late in the process that authorities interpret those same documents very differently. 

Why the Notified Body Opinion Matters More Than Ever

Under EU MDR Article 117, a Notified Body Opinion is a critical component of a marketing authorization application for medicinal products that incorporate a medical device element and lack a standalone CE certificate. The intent is clear: competent medical device experts assess whether the device component conforms to the General Safety and Performance Requirements (GSPRs) of Annex I of the MDR, and medicinal product authorities rely on that assessment rather than re-reviewing the full technical file. 

In practice, this creates a delicate dependency. Regulatory authorities are explicitly basing their assessment on what is written (and not written) in the NBOp. When the opinion is vague, poorly scoped, or unsupported by credible data summaries, the burden shifts back to the applicant, often during active review. 

What Regulators Are Actually Seeing

The reviewed NBOps showed substantial variability in both format and substance. While the competence of the Notified Bodies themselves was not questioned, the outputs were inconsistent enough to undermine their regulatory utility. Several recurring deficiencies stood out: 

Unclear scope of assessment Authorities struggled to determine exactly which components were covered. For example, it was not always evident whether an opinion for an injection system included the full fluid path, container, or needle components. This lack of clarity becomes critical when GSPRs related to system integration or combination use are assessed. 

Incorrect or missing classification and codes Errors in device classification—such as mislabeling active systems as non-active, or omission of required codes (e.g., for sterile products) raised immediate red flags. These are foundational elements that set the context for the entire conformity assessment. 

Incomplete or inconsistent GSPR coverage In some cases, applicable GSPRs were missing entirely, inconsistently applied, or declared met despite evident data gaps. Justifications for non-applicability were often weak or absent. From a regulator’s perspective, this undermines confidence that the full lifecycle risks of the device component have been adequately addressed. 

Reliance on outdated standards Several opinions referenced superseded standards for risk management, usability engineering, or biocompatibility. Even when the underlying testing may have been sound, the use of outdated standards signals misalignment with current regulatory expectations. 

Insufficient verification and validation summaries Authorities noted missing or incomplete summaries for biocompatibility, usability, transport simulation, and aging. In other cases, the data referenced did not clearly apply to the final, submitted version of the device component, creating uncertainty about relevance and transferability. 

Passing unresolved data gaps to authorities Perhaps most concerning, some NBOps appeared to defer unresolved issues to the medicinal product authority, even when those gaps fell squarely within the Notified Body’s remit. This defeats the purpose of Article 117 and introduces avoidable review friction. 

The Core Misconception: “No Comment” Does Not Mean “Approved” 

A recurring theme in sponsor interactions, mirrored in both EU and U.S. regulatory engagements, is the assumption that silence equals acceptance. If a specific design choice, test strategy, or omission was included in a submission package and not explicitly challenged, teams may conclude it has been endorsed. 

From our experience, this is one of the most common and costly misconceptions in combination product development. Unless a question is explicitly asked and explicitly answered, there is no regulatory position to rely on. This applies equally to FDA meetings and to interactions with Notified Bodies under the MDR. 

What Authorities Expect Instead

Regulators have been clear about what constitutes a high-quality Notified Body Opinion. At a minimum, they expect: 

• A clear description of the device component(s) assessed and their relationship to the medicinal product 

• Accurate classification, applicable MDR codes, and stated intended use 

• Comprehensive identification of applicable GSPRs, with data-backed confirmation of conformity 

• Plausible, well-justified rationale for any GSPRs deemed non-applicable 

• A list of applied standards, including versions 

• Concise but substantive summaries of reviewed verification and validation data 

• Transparent identification of any remaining data gaps, limited to areas within the authority’s responsibility 

• A clear, unambiguous conclusion on conformity 

Crucially, authorities have emphasized that it is the applicant’s responsibility to critically assess the NBOp before submission. An unclear or incomplete opinion is not a Notified Body problem once it reaches the authority, it becomes a sponsor problem. 

Strategic Implications for Combination Product Sponsors

For organizations developing combination products, especially those newer to the MDR framework, the implications are significant: 

• A Notified Body Opinion is not a commodity deliverable. Its quality can directly influence review timelines and approval outcomes. 

• Variability across Notified Bodies is real. With dozens of designated bodies operating under a high-level regulation, differences in interpretation and rigor are inevitable. 

• Late discovery of deficiencies is expensive. Gaps identified during authority review often require rapid remediation under intense time pressure. 

From a Suttons Creek perspective, one of the advantages of working across multiple programs and regulatory pathways is visibility into these recurring patterns. Many of the issues regulators flag are avoidable with earlier, more critical engagement around scope, data applicability, and regulatory intent. And, these are all issues that can be addressed during the Notified Body Opinion review process prior to its conclusion, assuming proper expertise and experience are available to push in the right direction. 

Final Thought

Notified Body Opinions were intended to streamline the review of integral combination products, not to introduce another layer of uncertainty. When treated as a strategic regulatory artifact rather than a box-checking exercise, they can do exactly that. 

For sponsors, the message is clear: if an NBOp cannot stand on its own as a robust, transparent, and defensible assessment, it may ultimately slow the very approval it was meant to support. 

These are the kinds of challenges we routinely see across programs, and they are rarely caused by lack of effort. More often, they stem from misunderstandings about how regulators actually use the information provided to them. 

AUTHOR

Bryan Bobo, Associate Technical Director, Suttons Creek –With over 9 years of experience in the pharmaceutical industry, Bryan has extensive knowledge of combination product development and what it takes to launch products on the market. He has practical and hands-on experience in various types of drug delivery systems from his years as both a Device Development Engineer as well as project and program management positions. In addition to his direct product development experience, Bryan engages with the global combination product community through his participation on various international standards committees as well as other various industry forums.