Adverse Events
Within the course of a clinical investigation, what are the regulatory reporting requirements for adverse events?
1. OBJECTIVE
This guidance defines Serious Adverse Event (SAE) reporting modalities and includes a summary tabulation reporting format1. Its objective is to contribute to the notification of SAEs to all concerned National Competent Authorities (NCAs2) in the context of clinical investigations in line with the requirements of Annex 7 of Directive 90/385/EEC and Annex X of Directive 93/42/EEC, as amended by Directive 2007/47/EC.
According to annex 7 of Directive 90/385/EEC and to annex X of Directive 93/42/EEC:
“All serious adverse events must be fully recorded and immediately notified to all competent authorities of the Member States in which the clinical investigation is being performed.”
2. SCOPE
The reporting modalities and format set out in this guidance apply to pre-market clinical investigations conducted with:
a) Non-CE marked devices,
b) CE marked devices used outside the intended use(s) covered by the CE marking.
The tabular format featured in the Appendix needs to be updated for each reportable event or for new findings/updates to already reported events. It shall be transmitted to all NCAs where the clinical investigation is being performed.
3. DEFINITIONS (from ISO/FDIS 14155)
Adverse Device Effect (ADE)
Adverse event related to the use of an investigational medical device.
This includes any adverse event resulting from insufficiencies or inadequacies in the instructions for use, the deployment, the implantation, the installation, the operation, or any malfunction of the investigational medical device.
This includes any event that is a result of a use error or intentional misuse.
Adverse Event (AE)
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other persons whether or not related to the investigational medical device.
This includes events related to the investigational device or the comparator.
This includes events related to the procedures involved (any procedure in the clinical investigation plan).
For users or other persons this is restricted to events related to the investigational medical device.
Device deficiency
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or performance, such as malfunction, misuse or use error and inadequate labeling.
Investigational medical device
Medical device being assessed for safety or performance in a clinical investigation.
This includes medical devices already on the market that are being evaluated for new intended uses, new populations, new materials or design changes.
Serious Adverse Device Effect (SADE)
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event.
Serious Adverse Event (SAE)
Adverse event that:
a) led to a death,
b) led to a serious deterioration in health that either:
- resulted in a life-threatening illness or injury, or
- resulted in a permanent impairment of a body structure or a body function, or
- required in-patient hospitalization or prolongation of existing hospitalization, or
- resulted in medical or surgical intervention to prevent life threatening illness or injury or permanent impairment to a body structure or a body function.
c) led to fetal distress, fetal death or a congenital abnormality or birth defect.
This includes device deficiencies that might have led to a serious adverse event if a) suitable action had not been taken or b) intervention had not been made or c) if circumstances had been less fortunate. These are handled under the SAE reporting system.
A planned hospitalization for pre-existing condition, or a procedure required by the Clinical Investigation Plan, without a serious deterioration in health, is not considered to be a serious adverse event.
Unanticipated Serious Adverse Device Effect (USADE)
Serious adverse device effect which by its nature, incidence, severity or outcome has not been identified in the current version of the risk analysis report.
Anticipated: an effect which by its nature, incidence, severity or outcome has been previously identified in the risk analysis report
4. REPORTABLE EVENTS UNDER ANNEX 7 AND ANNEX X OF DIRECTIVES 90/385/EEC AND 93/42/EEC RESPECTIVELY.
For the purpose of this guidance and based on the definitions above, the following events are considered reportable events in accordance with Annex 7, section 2.3.5 and Annex X, section 2.3.5 of the above mentioned Directives:
- any SAE,
- any Investigational Medical Device Deficiency that might have led to a SAE if
-
a) suitable action had not been taken or
-
b) intervention had not been made or
-
c) if circumstances had been less fortunate
- new findings/updates in relation to already reported events.
Reportable events occurring in Third Countries in which a clinical investigation is performed under the same clinical investigation plan, have to be reported in accordance with this guidance.
5. REPORT BY WHOM.
Reportable events have to be reported by the sponsor of the clinical investigation, which could be the manufacturer (MFR), the authorized representative (AR) or another person or entity.
6. REPORT TO WHOM.
Reportable events must be reported at the same time to all NCAs where the clinical investigation has commenced using the summary tabulation featured in the Appendix. A list of clinical investigation contact points within the NCAs is published at the Commission’s homepage.
7. REPORTING TIMELINES
7.1 Report by sponsor to NCAs.
The sponsor must report to the NCAs where the clinical investigation has commenced:
- a SAE which indicates an imminent risk of death, serious injury, or serious illness and that requires prompt remedial action for other patients/subjects, users or other persons or a new finding to it: immediately, but not later than 2 calendar days after awareness by sponsor of a new reportable event or of new information in relation with an already reported event.
- any other reportable events as described in section 4 or a new finding/update to it: immediately, but not later than 7 calendar days following the date of awareness by the sponsor of the new reportable event or of new information in relation with an already reported event.
7.2 Report by the investigator to the sponsor
The sponsor shall implement and maintain a system to ensure that the reporting of the reportable events will be provided by the investigator to the sponsor in acceptable timely conditions, but not later than within 3 calendar days after the occurrence of the event.
In some cases, a different periodicity or different modalities12 may be agreed by the participating NCAs according to the investigational design and to the pathology under clinical investigation. This would allow adequate provision for clinical investigations (e.g. palliative oncology…) in which SAE frequency is expected to be high due to progression of the disease. This needs to be agreed between the sponsor and relevant NCAs.
8. REPORTING FORM
The reporting form template for the summary SAE tabulation is given in the Appendix of this document.
The table gives a cumulative overview of the reportable events per clinical investigation and will be updated and transmitted to participating NCAs each time a new reportable event or a new finding to an already reported event is to be reported. More detailed information has to be provided on request of an NCA.
The sponsor shall identify the new/updated information in the status column of the tabular form featured in the Appendix as:
a = added = new reportable event;
m = modified = new finding/update to an already reported event;
u = unchanged.
Changes in a line should be highlighted in bold and/or color in the respective column.
The reporting form is study specific and covers only a given clinical investigation, defined by a distinct clinical investigation plan. English is the recommended language for the reporting form. The report should be sent by email preferably in Excel or equivalent format to the participating NCAs.