Misuse and Off-label Use: Challenges and Strategies for Medical Device Manufacturers

For manufacturers of medical devices, ensuring the safety of their products is always a top priority. To identify potential risks early and minimize negative consequences, manufacturers must continuously monitor how their products are used, including identifying instances of misuse.

This obligation is critical not only for patient safety but also for compliance with the regulatory requirements of the Medical Device Regulation (EU) 2017/745 (MDR) concerning post-market clinical follow-up (PMCF).

This article examines the challenges associated with detecting misuse and highlights how post-market surveillance (PMS) data can assist in meeting these requirements.

Defining Misuse of Medical Devices

The MDR places stringent requirements on post-market surveillance for medical devices. A core obligation in post-market clinical follow-up (PMCF) is to identify potential systematic misuse or off-label use of the product to assess whether its intended purpose remains appropriate.

Systematic misuse refers to repetitive misuse, which is not a one-off occurrence but demonstrates a certain regularity attributable to various factors.

Off-label use involves using a product beyond its approved indications.

Although the terms misuse and off-label use are crucial in the regulatory context, they are not explicitly defined in the MDR itself. The position paper of the European Association of Medical Devices Notified Bodies (Team-NB) on "Data Generated from 'Off-Label' Use of a Product Under the EU Medical Device Regulation 2017/745" also does not make a clear distinction between these terms.

However, the term misuse appears in the context of risk management systems, specifically as reasonably foreseeable misuse (Annex I – Chapter I General Requirements). This term refers to incorrect application of a product that does not align with the manufacturer's instructions.

In EN ISO 14971:2019+A11:2021 (Application of Risk Management to Medical Devices), reasonably foreseeable misuse is further defined as the "use of a product or system in a way not intended by the manufacturer, but which can result from readily predictable human behavior."

Attention should be paid to the second comment on the term, which includes both intentional and unintentional misuse. Both intentional misuse (e.g. deliberate non-compliance with the instructions for use) and unintentional misuse (e.g. misunderstandings in the instructions for use) also include off-label use. An off-label use can therefore be understood as a subset of misuse. The following therefore focuses on intentional and unintentional misuse, which can also include off-label use in addition to misuse.

Manufacturers must be active throughout the entire product life cycle in order to identify misuse of their products. As described in ISO/TR 24971:2020-06 (Medical devices - Guidance on the application of ISO 14971), chapter 5.2, this is possible, for example, via the usability process. Unintentional misuse in particular should be part of the risk analysis and should also be addressed in the usability assessment. The relationship between usability and risk is clarified in the usability standard IEC 62366-1. When identifying hazard-relevant application scenarios, manufacturers should not only examine the tasks that the user intends to perform, but also those that are not intended but could foreseeably occur. This forward-looking approach helps to minimize misuse and increase safety. However, it is also possible to identify misuse with the help of PMS after the product has been placed on the market.

Post-Market Surveillance as a Tool for Detecting Misuse

As described in Article 83 (2) of the MDR, the PMS system serves to actively and systematically collect relevant data on the quality, performance and safety of a device throughout its entire life cycle. This also includes possible misuse. To identify these, various methods can be used to collect and analyze PMS data.

Introduction to PMS and PMCF

Post-market surveillance (PMS) and post-market clinical follow-up (PMCF) are essential tools for the continuous monitoring and assurance of the safety and effectiveness of medical devices after they have entered the market.

PMCF, as part of PMS, focuses on the clinical data of post-market surveillance. The collection of clinical data aims, among other things, to identify systematic misuse or off-label use, which is a stated objective of PMCF (see Annex XIV, Part B of the MDR).

Data Sources for PMS in Identifying Misuse

The effectiveness of PMS largely depends on the quality and diversity of the data sources used. To detect misuse, various data sources from both PMCF and PMS should be utilized. It is therefore important to clearly distinguish how these different datasets are collected and used to meet regulatory requirements.

Reactive data is crucial for identifying misuse. This data includes information on adverse events, customer complaints and technical errors that can be indicators of misuse. An increase in the number of complaints, especially if the complaints relate to application problems that are not covered in the instructions for use, can be an indication of this. However, an accumulation of feedback, e.g. from a specific customer, is also an indication that there may be misuse. By analyzing and categorizing this data, manufacturers can identify patterns and take measures to reduce risk. Regular evaluation of this data helps to ensure the safety of the product and identify potential misuse at an early stage.

Market feedback in the sense of direct feedback from users (e.g. via sales) can also provide valuable insights into the actual use of a product. This direct exchange can also capture scenarios that do not appear in formal claims or complaints, such as unconventional applications in the sense of intentional misuse. In addition, market feedback offers the opportunity to obtain more detailed and contextualized information that contributes more specifically to product improvement and the detection of misuse. Here, the manufacturer can also take proactive measures to ensure that the product is used as intended, rather than only reacting when formal complaints are received.

PMCF activities in the sense of PMCF studies provide valuable and, above all, evidence-based informationon the safety and efficacy of a product but are less suitable for identifying misuse. This is due to the fact that PMCF studies follow a fixed study protocol and prescribe the use of the product within clearly defined framework conditions, so that cases of use o
utside the approved intended purpose are legally excluded here. It should also be noted that a PMCF study serves exclusively to monitor the actual use of the product within its approved intended purpose and not to collect data to expand the indication of the product. According to Article 74 (2) MDR, a clinical investigation is required instead if a CE-marked device is to be used outside its intended purpose. PMCF studies thus serve to monitor use in a real-life environment, but exclusively within the approved area of application.

In contrast, proactive user surveys as a PMCF dataset also offer the opportunity to obtain specific information on misuse by asking targeted questions. These surveys are particularly useful for determining whether there is systematic misuse, for example. A user survey can also provide support if a pattern has already been identified and further details are required to improve product safety. The decisive factor here is the design of this user survey in order to achieve the desired objectives of the survey. (We at Metecon are happy to support you in this strategy development).

Another valuable approach to identifying misuse, in addition to literature research on your own products, is to examine data on similar products on the market. Valuable insights can be gained through FSCA and literature research, even if this information does not necessarily represent misuse of the competitor's product. However, due to the similarity of the products, an impression can be gained as to which applications could possibly be relevant for your own product and would therefore also represent a use or misuse of your own product that exceeds the approval. In this way, you as a manufacturer can react to possible risks at an early stage and adapt your own risk analysis accordingly. By utilizing these data sources, manufacturers can better understand and mitigate the risks associated with misuse.

With the help of these data sources, manufacturers can not only identify misuse, but also better assess the associated risks. But how do you deal with this once you have identified such applications?

Measures for Risk Mitigation

According to EN ISO 14971:2019+A11:2021, manufacturers must take appropriate measures to minimize risks for foreseeable misuse in order to ensure patient safety. However, misuses that are not classified as “reasonably foreseeable” should also be carefully documented and evaluated. The fact that a misuse is currently classified as unforeseeable does not mean that this will always be the case. If similar scenarios occur more frequently, a pattern could develop that makes the misuse appear predictable in the future.

The possible measures are varied and depend on the product, the current status in the product life cycle and the scenario at hand. We have compiled a selection of measures that can be used to minimize reasonably foreseeable misuse after the product has been placed on the market:

• Product modifications: Targeted adaptations or improvements to the product design can significantly reduce the risk of misuse in certain circumstances. This could be done, for example, through mechanical or software-based changes that make it difficult or impossible to use the product outside the approved indications.
• Training: Providing specialized training to users can be a critical factor in promoting the correct use of the product. Training provides users with comprehensive information on the permitted areas of application within the scope of the intended use and draws attention to possible risks of improper use.
• Revision of the instructions for use: Precise and comprehensive wording of the instructions for use can prevent misunderstandings and misuse even before the product is placed on the market. The risk of unintentional misuse in particular can be reduced by revising and, if necessary, expanding the instructions for use after the product has been placed on the market. Please note that this may require a field safety corrective action (FSCA).
• Proactive information: The publication of targeted formal information (e.g. by the legal department or product management) serves to inform users at an early stage about possible risks associated with misuse. This proactive communication can highlight potential hazards and raise awareness of the correct use of the product. However, it should be seen as a complementary strategy for raising user awareness rather than a primary risk reduction measure in the risk analysis.

With these measures, manufacturers can not only contribute to the safety and efficacy of their products, but also ensure that they comply with the regulatory requirements of the MDR.

Conclusion

Even if the MDR does not directly define misuse, manufacturers of medical devices are faced with the challenge of recognizing it as part of PMS and PMCF. PMS and PMCF activities offer indispensable tools for identifying these intentional and unintentional misuses at an early stage and taking the necessary measures. A well-structured PMS system is therefore crucial not only to meet regulatory requirements, but also to improve patient safety in the long term.

Does your PMS system still have gaps in the detection of misuse? Or have you already identified cases and are unsure how best to deal with them? We will be happy to help you optimize your PMS system! We are also happy to support you in the areas of risk management and usability so that you are optimally equipped for all aspects relating to misuse.