Drug Evaluation Committee 2009-31 Timing of Determination of Causality of Adverse Events
Related classification: Adverse drug reaction reports
Initial release date: January 2010
Revised publication date: March 2021
Question
An adverse event has occurred in a clinical trial for which I am currently in charge.
These events occurred after the administration of the investigational drug, and they have already disappeared, and the investigational drug is still being administered without discontinuation.
When we asked the doctor about the causal relationship with the investigational drug, he replied, "Although the symptoms have subsided, as long as the investigational drug is being administered, we do not know when they may occur again. Therefore, we cannot determine the causal relationship at this point. We cannot make a judgment until we look at how the symptoms were experienced throughout the entire period of the study and how frequently the same symptoms are occurring nationwide, and look at these factors in a comprehensive manner. The doctor's opinion was that "we cannot make a judgment until we see the totality of these factors.
Certainly, the doctor's view is understandable. If similar events occur frequently in the future, a causal relationship with the investigational drug cannot be denied. However, if we follow this line of thinking, all adverse events cannot be denied to have a causal relationship with the investigational drug. The sponsor also needs to have an opinion on each and every adverse event at this point, regardless of what kind of adverse events may occur in the future. If not all adverse events can be ruled out as causally related, the possibility cannot be denied that the development of a drug may be discontinued, no matter how excellent it is.
I am sure that the doctors will be able to make a final decision, but since this is a long-term study, I think it would be unwise to delay the decision to that extent. I explained this to the doctor, but he was not convinced. Are there any strict rules on when to judge an adverse event? Is it when the event disappears or throughout the entire process?
Opinion of the Pharmaceutical Manufacturers Association of Japan (PMAJ)
GCP Article 2 Guidance 18 (10) states that an adverse reaction is "a reaction for which there is at least a reasonable possibility of a causal relationship between the investigational drug in question and the adverse event, and a causal relationship cannot be ruled out. In determining causality, the following conditions must be met: the adverse reaction must disappear after discontinuation of treatment; the adverse reaction must recur after resumption of treatment; a causal relationship must have been established with the investigational drug or a similar drug; there must be no confounding risk factors; the exposure dose and duration must be consistent; the involvement of the investigational drug must be almost certainly explainable with accurate medical history support; and the adverse reaction must have been caused by a drug that has been used for a long time and has been used in the past. The following factors can be used as references: the absence of confounding risk factors, consistency with the dose and duration of exposure, and no reasonable likelihood that concomitant therapy was the cause. The definition of "causal relationship" is as follows.
There is no stipulation in GCP regarding the timing for determining the causal relationship of adverse events that occur. However, Article 273 of the Ordinance for Enforcement of the Pharmaceutical Affairs Law stipulates that the reporting deadline for individual case reports is 7 or 15 days after the sponsor becomes aware of the event.
However, if there is a provision in the protocol, it is necessary to report to the sponsor in accordance with the provision. There is no problem if the judgment of causal relationship can be changed with appropriate reasons based on information obtained later.
Reason for revision of opinion
In accordance with the issuance of the GCP Guidance (No. 0831-15 issued by the Pharmaceutical Affairs Agency on August 31, 2020) and the enforcement of the Pharmaceutical Affairs Act (December 14, 2019), minor changes have been made to the description of the GCP Guidance.