Drug Evaluation Committee 2022-47 Clinical Trial-Specific Handling of Serious Adverse Events
Related classification: Adverse drug reaction reports
First published: Apr 2023
Question
The protocol of a clinical trial stipulates that certain endpoint events, such as hospitalization due to myocardial infarction or heart failure, are not considered adverse events or serious adverse events, but are entered as endpoint events in the eCRF and are not subject to emergency reporting.
On the other hand, our SOP stipulates that the investigator must promptly report to the head of the site and the sponsor if a serious adverse event occurs during the conduct of a clinical trial, but the SOP also stipulates that the investigator must report to the head of the site and the sponsor if an endpoint event is not considered an adverse event or serious adverse event as stipulated in the clinical trial protocol. However, the protocol does not specify how to handle cases in which the endpoint event is an adverse event or an event that is not considered a serious adverse event.
If an endpoint event hospitalization (hospitalization due to myocardial infarction or heart failure) occurs, even if there is no detailed description in the SOP, is it acceptable for the investigator not to report it as a serious adverse event to the head of the institution and the sponsor in accordance with the protocol?
In our opinion, referring to Article 273 of the Enforcement Regulations of the Act, it is desirable to report any hospitalization related to treatment to the head of the site and the clinical trial review committee in consideration of safety reporting, even if it is stipulated in the protocol. The current situation is that investigators report such events as serious adverse events to the head of the site and the clinical trial review committee reviews the reports.
As stated in Guidance 2, Article 1 of GCP, clinical trials are to be conducted in principle in compliance with the protocol approved in advance by the investigational review committee. Is there any problem if we don't treat them as serious adverse events even if they are not listed in the SOP?
Opinion of the Pharmaceutical Manufacturers Association of Japan (PMAJ)
As you pointed out, a clinical trial must be conducted in compliance with the protocol approved in advance by the investigational review committee (GCP Article 1 Guidance 2 (6)). In addition, the investigator must immediately report all serious adverse events to the sponsor, except in cases where the protocol and the investigational new drug summary and other documents stipulate that urgent reporting is not required (GCP Article 48, Paragraph 2/3, Guidance 3).
In the case of your question, the study protocol stipulates that the specific endpoint event is not considered a serious adverse event, so the event does not need to be treated as an adverse event and does not need to be reported to the sponsor or the head of the investigational site. However, if the head of the site determines that understanding the occurrence of the event is necessary to determine whether or not to continue the clinical trial, the investigator should report the event to the head of the site for review by the Clinical Trial Review Committee (GCP Article 31, Paragraph 2, Guidance 3).