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Under the EU MDR, both pre- and post-market clinical investigations shall follow the latest requirements for Good Clinical Practice (ISO 14155:2020). Recording and reporting of adverse events (AE) and serious adverse events (SAE) in compliance with the regulatory requirements is a key aspect of a successful clinical investigation.
In this blog you will learn how to facilitate compliant AE/SAE reporting in clinical investigations under the EU MDR.
One of the biggest hurdles for sponsors is to minimize the time from adverse event occurrence to the reporting of the event to competent authorities (CA). With fewer studies relying on outdated data capture technology, this hurdle is becoming easier to overcome.
However, technological development of electronic data capture (EDC) must continue, to ensure timely and compliant AE reporting, particularly with the increasingly stringent regulations being implemented with the EU MDR – a trend we will likely see in the rest of the world as well.
Delays in AE reporting is a hot topic, when discussing safety tracking in clinical investigations. But study sponsors need to improve several other key areas as well to ensure an optimal and compliant AE reporting process.
In this blog, we will discuss some of these key areas that are often missed when planning a clinical investigation. This will include:
Adverse Event Reporting Requirements and Device Deficiencies That Could Lead to a Serious Adverse Event
Who is “responsible” for reporting Adverse Events to the authorities in Clinical Investigations?
Are There Differences in Reporting AEs in Clinical Investigations and PMCF Investigations Under the EU MDR?
Coding of Adverse Events for Medical Devices
Reporting Adverse Events in the absence of EUDAMED
How Greenlight Guru Clinical Facilitates Adverse Event Reporting
The requirements for clinical investigations with medical devices have drastically increased with the implementation of the EU Medical Device Regulation (MDR), and the reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) have not been left out of that equation.
AE and SAE reporting have always been an important task under very strict regulatory control. This trend will continue with the new medical device regulations. The reporting and registration of safety events is now governed by Article 80 of the (EU) 2017/745 –Medical Device Regulation (MDR).
Adverse event definition in the MDR:
“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. (MDR Article 2(57))”
The ISO14155:2020 (Clinical investigation of medical devices for human subjects – Good clinical practice) further lays out the GCP requirements for reporting and classifying AEs. Compliance with the ISO standard is also a requirement from ethical committees and competent authorities in the union.
All adverse events and any information concerning these events shall be recorded in a timely manner throughout the clinical investigation. The standard for how to record and report AEs are outlined in section 9.2.5 and 10.8 in the ISO 14155:2020. Furthermore, the categorization of AEs is also crucial.
The sponsor must be able to specify which category the AE belongs to according to those requirements – which means that the documentation standard in the eCRF or the EDC must support that decision making.
All device deficiencies that could have led to a serious adverse device effect if either:
Suitable action had not been taken
Intervention had not been made
Circumstances had been less fortunate
shall be reported as specified in 9.2.5 and 10.8 in the ISO 14155:2020. This requirement means that the sponsor must be able to document possible SADEs as well – even though they did not happen.
This requirement alone means that people responsible for documenting and reporting the device event, must be informed of the possible SADE to be documented – which can be tricky.
It’s also important to note that only adverse events that have been identified in the Clinical Investigational Protocol (CIP) as critical to the evaluation of the results of the clinical investigation, shall be documented.
AEs related to users or other persons can be documented separately from adverse events associated with the patients – but must also take data privacy regulations into account.
Although the clinical responsibility for identifying and treating adverse events lies with investigators, the regulatory responsibility lies with the Sponsor.
Therefore, the Sponsor must appropriately and timely report all AEs. The sponsor shall as such fully record the AEs in accordance with the Clinical Investigation Plan (CIP). Furthermore, in the case of Serious Adverse Events (SAEs), the sponsor shall without delay report to all European Member States which the clinical investigation is carried out in.
Additionally, the urgency or period of reporting shall take the severity of the event into account (serious events should be reported faster than non-serious events).
The short answer is Yes!
However, the requirements depend on whether the PMCF investigation is carried out on a CE marked device under its intended use or not. In the case where a device is CE marked and the investigation is observing outcomes under its intended use, the requirements for safety reporting are governed by MDR Article 80(5) and 80(6).
This effectively means that the provisions on vigilance laid down in Articles 87 to 90 of the MDR shall apply instead of those laid out in Article 80(1) to 80(4).
But what does that mean? This means that manufacturers only need to notify competent authorities of serious incidents that have not been thoroughly documented (known side-effects clearly described in the product documentation) prior to introducing the device to a market in the European Union.
Furthermore, device companies are required to report on safety corrective actions on devices used in third countries if the same device and configuration is in use in the EU.
All adverse events shall be reported in an interim or final report of a clinical investigation, so whether the investigation is conducted pre- or post-market – the requirements of documentation are the same.
However, certain national regulations can apply to reporting of adverse events during post-market clinical investigations. Medical device manufacturers must observe the requirements in each country.
Visit our Practical PMCF Guide to learn more about PMCF compliance under EU MDR.
Although MedDRA coding is universally accepted for coding safety events in drug trials, it is often mistakenly believed to be the standard for classifying Medical Device safety events.
There is a better solution for devices which is fully harmonized with the requirements of FDA and competent authorities in the EU. The International Medical Device Regulators Forum (IMDRF) Adverse Event Reporting terminology was developed to improve, harmonize, and where necessary expand the terminology and systems being used to code information relating to medical device adverse events.
In addition, establish IMDRF adverse event terminology composed of the following three parts: terms for medical device malfunction, terms for patient/user outcome, and terms for part/component of a medical device.
This is somewhat lacking in other existing coding standards, such as MedDRA.
Furthermore, under the EU MDR, the IMDRF AE coding standard is highly encouraged by the Medical Device Coordination Group guidelines to track and report AEs in pre- and post-market vigilance activities.
The benefits of using the IMDRF terminologies are clear, faster, and higher quality reporting of safety events.
EUDAMED is the IT system developed by the European Commission to implement Regulation (EU) 2017/745 on medical devices and Regulation (EU) 2017/746 on in vitro diagnosis medical devices. The goal with EUDAMED is to provide an overall improvement in the transparency of information regarding the medical devices available on the EU market (EUDAMED definition by European Commission).
The EUDAMED database is still under construction so while some information (such as Actor registration) can already be registered there, the information on AEs cannot.
From May 26th, 2021, and until EUDAMED is available, the template provided by MDCG 2020-10/1 (Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745) shall be used. After that period, the provisions of the MDR on EUDAMED shall be followed.
To keep track of the EUDAMED status, you can access the European Commission’s official website here.
Modern Electronic Data Capture (EDC) tools can help with managing the increased activities required to maintain medical devices on the European market.
In the context of clinical investigations, Greenlight Guru Clinical was the first and only EDC to offer a Dedicated Adverse Reporting module, which complies with the ISO 14155:2020 requirements for documenting AEs.
The AE module can help site staff and sponsors to collaborate effectively on the correct documentation of AEs. It is imperative to have a straightforward and intuitive AE/SAE reporting process to avoid underreporting or delayed reporting. Making the reporting as easy as possible for the investigator will minimize these risks and improve the overall data quality.
Furthermore, Greenlight Guru Clinical helps manufacturers (Sponsors) to comply with the reporting requirements laid out by the CA, by offering AE templates. Greenlight Guru Clinical provides an out-of-the-box AE form template that facilitates documentation of adverse events, serious adverse events, and serious adverse device effects.
With the template, study coordinators, investigators, and sponsors are guided through the documentation process with intelligent show rules, validation checks, and automatic email notifications. This is especially crucial when reporting SAEs and SADEs.
Although the AE reporting of clinical investigations is somewhat structured, this is not the case for PMCF Investigations. Even though the PMCF investigations resemble the clinical investigations the tools available for manufacturers are not always a good fit.
A common eCRF can in theory be used to manage data collection and reporting. However, this method is extremely expensive which has led manufacturers to seek other methods for establishing an active method to follow-up on the clinical safety and performance outcomes for their devices.
Greenlight Guru Clinical is the first EDC software to introduce dedicated tools for ad-hoc reporting of Real-World Evidence, safety events, and clinical data.
Greenlight Guru Clinical Cases was created to facilitate proactive collection of clinical outcomes and vigilance reporting in a post-market setting. This enables manufacturers to get notified in a timely manner if an unknown side-effect is reported in the market.
The combination of both pre- and post-market data collection tools for AE and vigilance reporting enables manufacturers to use Greenlight Guru Clinical for clinical operations throughout the medical device lifecycle – in compliance with the EU MDR and other industry regulations.
You're always welcome to contact us in case you need advice on your AE reporting process or want to hear more about how Greenlight Guru Clinical can facilitate your reporting.
Páll Jóhannesson, M.Sc. in Medical Market Access, is the founder and Managing Director of Greenlight Guru Clinical (formerly SMART-TRIAL). Páll was previously the CEO of Greenlight Guru Clinical where he led the team to create the only EDC specifically made for medical devices.