7 keys to know about serious adverse events
Following the Rennes incident last January, the Ministry of Health issued a circular reminding the obligations to promoters (and to their CRO representative) regarding the reporting of hospitalizations in the clinical trials on healthy volunteers. This circular provides an understanding of what happened in this trial Phase I. However, as part of clinical trials from phase II to IV, the risk is real.
Investigators should be careful when during the participation of patients; the CRAs and the CSCs must remain vigilant! We will give you some tips on the topic of SAEs, whether you are CRA or CSC. Indeed, the promoter of the study should be informed as soon as possible to decide whether to continue the study or to stop it prematurely.
Let’s talk about practice…
SAE Rule n°1: Declare immediately SAE monitoring as well as the initial SAEs
When a center receives information, even basic on a SAE already declared, it is critical to transmit immediately the monitoring of this SAE! Indeed, it is important to keep in mind that tracking SAE is as important as the initial declaration of SAE. Some information that might seem banal can become very important for Pharmacovigilance services. So please, report the monitoring of SAE and that, within 24 hours (this is the deadline in the vast majority of clinical trial protocols) as well as the initial SAEs.
SAE Rule n°2: Do not wait for the signature of the investigator if you know that it is a SAE
You are CRA, you find an undeclared SAE in a folder and you have not met the investigator to discuss it?
You are CSC and your investigator is absent?
You can still report the SAE without waiting to the Pharmacovigilance. If changes must be made later or if the SAE must be canceled by your investigator, they will be afterwards!
A SAE must be reported without delay within 24 hours of followed its finding (by the investigator or by a member of the investigative team)
You do not have SAE forms right now? Send an email to the Pharmacovigilance 🙂
SAE Rule n°3: Report your SAE if it happens on weekends or Friday night!
Don’t wait for the following Monday to report it. Indeed, important things can happen during the weekend and in addition, if the declaration is not made in time, it will be a violation of the GCP. Your principal investigator and co-investigators must be aware that they must make the declaration within 24 hours mandatory, even during the weekend. The fact that you are not there is not a reason. Spread the message!
If you do not have the proper form, you can declare a SAE with a minimum of information and this by email. Indicate in:
- N° protocol
- Center number / name of the principal investigator
- Patient initials (if allowed by the protocol) / patient number
- Name of the SAE or symptoms
SAE Rule n°4: Declare your SAE even if your patient is hospitalized in another hospital and that you do not have reports!
Same, you can complete your SAE form with the information available. You need at minimum a SAE title (e.g. “Symptoms”).
SAE Rule n°5: The AEs of grade 4 are potential SAEs
The definition of grade 4 according to the NCI-CTCAE version 4.03 is: “put into play the vital prognosis, emergency response indicated.”
As a reminder, the definition of an adverse event is:
“According to 1 ° of Article R. 1123-39 of the Code of Public Health, any untoward medical occurrence that occurs in a person who consents to biomedical research, that this occurrence is related or not to the research or product on which this research is done.”
Clearly, an “adverse event” does not necessarily imply a causal relationship with the product studied. It may be a sign, a symptom or condition that appears or worsens during the observation period.
As a reminder, the definition of a serious adverse event is:
“In accordance with Article 6 of R. 1123-39 of the Code of Public Health, any event or adverse reaction which results in death, threatens the life of the person consenting to the research, requires hospitalization or prolongation of hospitalization, causes an incapacity or a significant or lasting disability, or results in an anomaly or birth defect, regardless of the dose administered.”
This can also be an important medical event (e.g. a spontaneous or induced abortion).
The threat of vital prognosis is one of the criteria of a SAE. Therefore, pay attention to AEs of grade 4 (e.g. in Oncology: Platelets, neutrophils, hemoglobin) that must be reported as SAEs. Get information from your investigator and medical monitor whether they consider that there is a real threat of vital prognosis. It is possible that it may be recognized as an important medical event. Ask and document the answer in your report and in your follow-up letter. Ask the investigator to do the same in his medical records.
SAE Rule n° 6: Gravity and causality
For AEs as for SAEs, the investigator must document in the medical record the gravity and causality.
- Gravity: that is to say the grade 1, 2, 3, 4 (e.g.in Oncology) or “light”, “Moderate” and “Severe” (for other pathologies).
- Causality: that is to say to what it is related: to the treatment? To the study? Or to something else? And this by “probable”, “possible”, “unlikely”, “not connected”?
This information should be in the medical record accurately and not only in the CRF. The absence of this information in the medical record can be annoying in case of audit or inspection. As CRA or CSC, you must make sure that what is noted in the CRF is present in the source folder.
SAE Rule n° 7: Train your investigators and your co-investigators on the SAEs
Train investigators in the implementation, it is good. Throughout the study, it is even the better. One is never too careful. Some bases can be forgotten, especially when it does not happen often. Make sure that the co-investigators are well aware of how SAEs are reported and the definition of a SAE. Plan to train them in the middle of implementation presentation rather than at the end of implementation: it happens that some investigators want to shorten the presentation at the end of implementation as soon as you start talking about GCPs.
And you, do you have any recommendations regarding SAEs? Put your opinion in the comments below!
You will find the definition of a grade 4 according to the NCI-CTCAE version 4.03 herein: (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5×11.pdf
Circular of the Ministry of Health, trial of Phase I: