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Paragraph 64 of the European Medical Device Regulations (Regulation (EU) 2017/745) states that clinical investigations should follow “well-established international guidance in this field, such as the international standard ISO 14155:2020 on good clinical practice for clinical investigations of medical devices for human subjects.”
The ISO 14155:2020 standard outlines the general principles of Good Clinical Practice (GCP) and provides specific guidelines for ethical considerations, as well as planning, conducting, and terminating clinical investigations. It also clarifies the responsibilities of the sponsor and the principal investigator as part of a medical device clinical investigation.
For medical device companies in Europe, complying with the EU MDR means complying with the GCP standard during your clinical investigation activities.
In this short guide, we’re taking a closer look at one key aspect of ISO 14155:2020 compliance in medical device clinical investigations: tracking Serious Adverse Events (SAEs).
You’ll discover how serious adverse events and other unintended events are defined in the ISO 14155:2020 GCP standard, the GCP compliance requirements for reporting serious adverse events, and the best ways to track SAEs in medical device clinical investigations.
Under the ISO 14155:2020 GCP standard, an Adverse Event (AE) is defined as:
An untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device and whether anticipated or unanticipated.
A Serious Adverse Event (SAE) is defined in the standard as an Adverse Event with any of the following outcomes:
Serious deterioration in the health of the subject, users, or other persons as defined by one or more of the following:
a life-threatening illness or injury, or
a permanent impairment of a body structure or a body function including chronic diseases, or
in-patient or prolonged hospitalization, or
medical or surgical intervention to prevent life-threatening illness or injury, or permanent impairment to a body structure or a body function,
Fetal distress, fetal death, a congenital abnormality, or birth defect including physical or mental impairment.
An Adverse Device Effect (ADE) is defined as an Adverse Event related to the use of an investigational medical device.
According to ISO 14155:2020, the definition of an ADE includes:
A Serious Adverse Device Effect (SADE) is defined as an ADE that has led to any of the outcomes that characterize an SAE (e.g. death, life-threatening illness, birth defect, etc.). A SADE may be further categorized as either an Anticipated serious adverse device effect (ASADE) or an Unanticipated serious adverse device effect (USADE) depending on whether the effect has previously been identified in the current risk assessment for the device.
SAEs and SADEs are both adverse events with serious consequences for the subject. The real difference between these two AE classifications is what they communicate about the cause of the event.
When an event is classified as an SAE, the implication is that the event was not related to the investigational medical device. But when an event is classified as a SADE, the implication is that the event was directly related or caused by the operation of the medical device.
This distinction is vitally important in clinical investigations where the goal is to prove the safety and effectiveness of a medical device for its intended use. If an adverse event occurs with serious consequences for the subject, stakeholders (e.g. sponsors, ethics committees, regulatory authorities, etc.) need to determine whether the event was related to the operation of the medical device.
ISO 14155:2020 defines a device deficiency as the inadequacy of a medical device with respect to its identity, quality, durability, reliability, usability, safety, or performance. The standard notes that malfunctions, use errors, incorrect instructions, and improper labeling of medical devices are all considered deficiencies.
The ISO 14155:2020 GCP standard establishes detailed requirements for documenting, classifying, and reporting on adverse events that occur during clinical investigations.
Section 7.4 of the ISO 14155:2020 standard deals with clinical investigation conduct surrounding adverse events and device deficiencies.
Section 7.4.2 requires that “all adverse events and any new information concerning these events shall be documented in a timely manner throughout the clinical investigation and shall be reported as specified in Sections 9.2.5 and 10.8.”
Section 7.4.3 says that device deficiencies must be documented throughout the clinical investigation and that sponsors should take corrective and preventive actions as appropriate to protect the safety of clinical subjects and other users. Device deficiencies that did not lead to an AE, but could have led to a SADE, must be reported as required in sections 9.2.5 and 10.8.
Section 9.2.5 of ISO 14155:2020 establishes safety evaluation and reporting requirements for clinical trial sponsors as part of conducting a clinical investigation. This section indicates that “the sponsor is responsible for the classification of adverse events and ongoing safety evaluation of the clinical investigation”.
In addition to carefully reviewing investigator assessments of AEs, classifying AEs, and evaluating reported device deficiencies, sponsors must:
Report or ensure the reporting, to the EC by the principal investigator(s), of all serious adverse events and device deficiencies that could have led to a serious adverse device effect,
Report to regulatory authorities, within the required time period, all serious adverse events and device deficiencies that could have led to a serious adverse device effect, and
Report all relevant safety information to the DMC, if established, according to written procedures.
Section 10.8 of ISO 14155:2020 establishes safety reporting requirements for principal investigators in medical device clinical studies. Under this section, principal investigators must:
Record, assess, and categorize every adverse event that takes place during the clinical investigation,
Report to the sponsor all SAEs and device deficiencies that could have led to a SADE, and follow up with written reports as required by the clinical investigation plan (CIP).
Report to the ethics committee on SAEs or device deficiencies that could have led to a SADE.
Report to regulatory authorities on SAEs and device deficiencies that could have led to a SADE.
Supply sponsors as needed with additional information related to the safety reporting of an AE.
Annex F of ISO 14155:2020 is also important for SAE safety reporting. This section includes a table of adverse event categories, along with decision-making flow charts that principal investigators and trial sponsors can use to accurately and consistently categorize AEs and device deficiencies.
Principal investigators are required to document and categorize every adverse event that takes place as part of a medical device clinical investigation or post-market clinical follow-up (PMCF) study. In our experience, most clinical staff members are highly aware and prepared to comply with these basic documentation requirements.
However, principal investigators running GCP-compliant studies are also required to document any medical device deficiencies that could have led to a SADE, even in cases where the SADE never materialized, and report them to the trial sponsor, ethics committee, or regulatory authorities as required by the CIP.
That means documenting any bugs, glitches, device malfunctions, improper labeling, incorrect instructions, or other device deficiencies that appear during the investigation, and linking the device deficiency with a potential SADE.
Clinical staff often aren’t aware of these reporting requirements, so it’s important for sponsors to provide adequate training on what’s required.
Greenlight Guru Clinical is the first and only Electronic Data Capture (EDC) software made specifically for medical devices and diagnostics. If you're already using an EDC system but are not sure whether it can support your clinical workflow, read our 10 tips on how to choose the right EDC system for you!
Our Adverse Event and Serious Adverse Event reporting modules make it easy for clinical investigation teams to document, categorize, and report on AEs, SAEs, and medical device deficiencies in clinical investigations.
While traditional EDC solutions require users to create a separate form or eCRF for reporting an AE/SAE, Greenlight Guru Clinical gives investigators access to ready-to-use AE form templates that reduce set-up time and eliminate duplicate documentation.
Investigators can create a new AE/SAE report during Event Reporting that includes the general information of the event, then complete the form by classifying the event as an AE, SAE, ADE, or SADE.
Principal investigators can also document medical device deficiencies using the AE reporting module. To help ensure GCP compliance, trial sponsors can add a yes/no question to the eCRF asking whether a reported device deficiency did or could have led to a SADE. If so, principal investigators can create a simple “DD SADE” report with their assessment and link it to the DD report form to achieve compliance with ISO 14155:2020 reporting guidelines.
More than 91% of studies conducted with Greenlight Guru Clinical use the AE reporting module to document, categorize, and report on device AEs.
Greenlight Guru Clinical is a software electronic data capture (EDC) system purpose-built to help clinical trial sponsors and principal investigators comply with the AE documentation, classification, and reporting requirements of the EU MDR and ISO 14155:2020 good clinical practices standard.
Greenlight Guru Clinical’s AE module offers straightforward GCP-compliant reporting and customizable forms to fit the needs of any study, with flexible access and permissions, real-time event progress tracking, and AE-specific data export.
Ready to Learn More? Contact us for a customized demo.
Jón Ingi Bergsteinsson, M.Sc. in Biomedical Engineering, is the co-founder of Greenlight Guru Clinical (formerly SMART-TRIAL). He was also the technical founder of Greenlight Guru Clinical where he paved the way for the platform’s quality standards, data security, and compliance.