We are all familiar with the listings of side-effects in the package insert of medicines and we often take them for granted. A side-effect is some potentially negative outcome from the use of these medicines and we accept that there is a chance that it happens to us. The use of a medical device can also be associated with side-effects. A user should be able to make their own judgment on whether the benefits of using the device outweigh the risks, and so the manufacturer of the device must provide information on side-effects to help them make that decision. The authorities, tasked with protecting public health, have made an evaluation of risks and acceptability of side-effects core to the conformity assessment of medical devices. Yet when we dive into the details of the regulations, this seemingly obvious topic can be confusing.
For starters, the EU Medical Devices Regulation (MDR) 2017/745 does not provide a definition of side-effect. Yet throughout the text the term appears 14 times: once in the context of the definition of “Incident”; 2 times in the context of the General Safety and Performance Requirements (GSPRs); 1 time in the context of clinical evaluation; 2 times in the context of a clinical investigation; 2 times in the context of instructions for use; 3 times in the context of post-market surveillance and post-market clinical follow-up (PMS/PMCF) and 3 times in the context of incident/trend reporting.
The MDR tells us that the event of an undesirable side effect is a type of incident (Article 2 ), that the risk of side effects shall be minimized and be acceptable when weighed against the benefits to the patient (Annex I, section 8) and that the information in this regard shall be provided in the instructions for use (Annex I, section 23.4g,t). The MDR requires the industry to evaluate side effects through clinical evaluation (Article 61; Annex XIV, section 1a). Clinical investigations may be carried out to “determine any undesirable side-effects, under normal conditions of use of the device, and assess whether they constitute acceptable risks when weighed against the benefits to be achieved by the device” (Article 62.1). Known side effects must be monitored and efforts must be made to identify previously unknown side-effects through PMS (Annex III, section 1.1a) and PMCF (Annex XIV, section 6.1b). Expected side effects are not reportable to the relevant competent authorities unless there is a statistically significant increase in the frequency or severity of the side-effect that could have a significant impact on the benefit-risk analysis (Article 87 and 88).
The Venn diagrams below demonstrate the relationship between residual risks and side effects.
Perfect world view ->
This might be sufficient level of detail for most discussions.
Other possibilities depending on completeness of product development, failure modes and effects analysis (FMEA), risk management report (RMR), clinical evaluation report (CER) and specifics of product. It would seem that some or all of the un-anticipated side effects might be outside of the known residual risks.
But then the appropriate documentation should be updated to include them. The anticipated events within the residual risks would grow and the un-anticipated events should decrease with updates to FMEA and RMR
For most products there might never be any un-anticipated side effects, but when they do occur they will either be part of the residual risks or not. Either way the appropriate documentation will need to updated which leads things back to the perfect world view.
All other things being equal, it would seem that a well-established technology (WET) product would be more likely to have worked through most of the un-anticipated side events whereas a new technology with an unproven track record would have a larger chance of having un-anticipated event.
In the setting of clinical investigations (both pre-market and as part of PMCF), side-effects play a special role. One of the goals of a clinical investigation can be to gather additional information on the known side-effects and to identify previously unknown side-effects. The clinical investigation plan (CIP), investigators brochure (IB) and the applications for regulatory approval and ethics approval of the clinical investigation must contain information regarding known foreseeable risks and undesirable side-effects (ISO14155:2011/AC2011 and MDR Annex XV). During a clinical investigation the safety and performance of a device are closely observed. All adverse events (AEs) are recorded. An adverse event is defined as “any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device” (Article 2 ). When an AE is related to the investigational device it is categorised as an adverse device effect (ADE) (ISO14155:2011/AC2011 Section 3.1).
ADEs can be further classified based on their severity and whether they were anticipated or unanticipated. ADEs are unanticipated when they were not identified in the current risk management. When they fall in the category of serious adverse events, they must be reported to the authorities of the countries where the study takes place (MDR and guidance MDCG 2020-10/1 “Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745”). The occurrence of unanticipated serious device effects (USADEs) could suggest that the clinical investigation places subjects at increased risk of harm relative to what was expected beforehand and may have consequences for the continuation of the study (MDCG 2020-10 and ISO14155:2011/AC2011). This is why you want to include a comprehensive list of identified side-effects in the clinical study documentation. The study data will feed back into your clinical evaluation and, if applicable, the risk management for the device. The study data on adverse events can thus be used to substantiate the evidence on the nature, incidence or severity of side-effects associated with the use of the device.
We advise our clients to follow a risk management approach and to assess the information from adverse event reports from clinical investigations or post-market clinical follow-up. Consider side effects being a form of patient harm (e.g. having an allergic reaction when exposed to a device) and that the risk of such harm is inherent to the use of the device (i.e. the risk remains after taking design risk mitigation measures) and cannot be reduced through protective measures or information for safety (the probability of occurrence of harm and the severity of harm are invariable). Any such clinical residual risk should be pointed out in the risk management file and added to the list of side effects in the information materials accompanying the device.
“A side-effect could be viewed as an undesired adverse effect associated with the use of the device under normal conditions of use and it is part of the residual risks for the device.”
“When not considered in the risk analysis, a device-related adverse event should be considered unanticipated”