In clinical drug trials, the most important aspect of patient safety is Serious Adverse Events (SAEs) – death, life-threatening events, hospitalisation, prolongation of hospitalisation, permanent or persistent or significant disability, congenital anomaly, or birth defect. Internationally, the focus is on assessing the causal link between an investigational drug and SAE.
In India, compensation rules require that the investigator has to report whether the SAE was related to a clinical trial. Such an SAE could occur due to 1) an investigational drug product, comparator product, or concomitant treatment or 2) clinical trial procedure or 3) the violation of the approved protocol, scientific misconduct or negligence by the sponsor or the investigator.
Assessment of causal link between a drug and an SAE can be done by using World Health Organization – Uppsala Monitoring Centre scale, and by reviewing the investigator’s brochure or package insert. But if a drug causes an adverse reaction which could overlap with the underlying disease or its complications, it would be inappropriate to consider such an SAE as not related to the drug. In a clinical trial of bevacizumab, if a patient suffering from metastatic colorectal cancer develops gastrointestinal perforation, it would be difficult to decide whether the perforation is due to cancer or bevacizumab, as the drug is reported to cause gastrointestinal perforations.
If the SAE is not due to the drug, then the investigator should consider whether the SAE could be due to other non-drug related factors. This is extremely complex as it requires consideration of procedures used in the trial – both routine clinical practice and special procedures required by the clinical trial protocol.
In clinical practice, patient harm or adverse events (AE) defined as an unintended injury or complication resulting in prolonged hospital stay, disability at the time of discharge, or death, and caused by health-care management rather than by the patient’s underlying disease process, are not uncommon. A recent meta-analysis of 70 studies involving 337,025 patients (BMJ May 2019), showed 12% prevalence of patient harms. There are hardly any systematic studies of patient harms in India. However, considering the difference in the quality of care between developed countries and India, the prevalence of such AEs is likely to be higher.
Patient harm occurring in a clinical trial setting would make an assessment of the relationship between clinical trial and SAE extremely challenging. In a clinical trial of diabetes, if a patient suffers from thrombophlebitis due to poor phlebotomy technique during blood collection for safety lab investigations, it would be difficult to consider this as unrelated to the clinical trial procedure. In a leukaemia clinical trial, if a patient given blood transfusion as required by the protocol, dies due to wrong blood group transfusion, it would be wrong not to consider such an event related to the clinical trial.
The objective of the causality assessment SAE in a clinical trial is to ensure the right of participants to get compensation. Hence, in complex situations, it is the ethical responsibility of the investigator to consider all SAEs as related to the clinical trial.
Writer is a consultant on clinical research & development from Mumbai. email@example.com