Safety
Safety is a focus of all clinical trials, but a top priority in Phase I and early Phase II trials. In the US, the FDA’s regulations for IND details safety reporting in clinical trials and the definitions used (https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application, accessed June 15, 2020). Adverse Events (AE) are any untoward medical occurrence associated with the use of a drug in humans, whether or not if it is considered to be drug related [IND Application 21 CFR § 312.32 (2020)]. This can be any unfavorable and unintended sign, symptom, laboratory result, or disease that coincides with the use of a drug; there is no implication of causality. AEs are considered Serious AEs (SAE) when the outcome of the AE is death, life-threatening, hospitalization or prolongation of an existing hospitalization, a persistent or significant disability or incapacity, or a congenital abnormality or birth defect. SAEs are reported to the FDA within 7-15 calendar days. In CF clinical trials, hospitalizations are handled as SAEs, even though they occur frequently in people with CF who are not enrolled in clinical trials and changes in the rates or risk of hospitalizations may be used as an efficacy outcome measure in CF clinical trials. Because CF is a multiorgan disease with substantial comorbidities, AEs occur commonly in people with CF enrolled in extended duration clinical studies, e.g., 94% of subjects with CF in a 96-week interventional clinical trial had at least one AE;(18) contrasted with a 60-week study of severe asthma were about 45% of subjects had at least one AE(19).
AEs and SAEs are recorded without regards to the potential for causality. All need to be reported during the course of the study. However, the focus of reporting during clinical trials is on events that may not be anticipated, unless mounting evidence suggests causality. An Unexpected Adverse Drug Experience is any adverse drug experience that is not included in the prior pre-clinical and clinical trial experience. These may include adverse reactions that are more severe than have been reported previously, e.g., the development of hepatic necrosis would be considered unexpected if prior experience had only demonstrated mild elevation of hepatic enzymes. Suspected Adverse Reactions (SAR) include events where there is a reasonable possibility that the experience may have been caused by the drug. Suspected Unexpected Serious Adverse Reactions (SUSAR) are those events that may be related to the study drug and have not been previously recorded.
Safety monitoring is conducted through a combination of several mechanisms. Institutional review boards (IRB) or Ethics Committees are responsible for evaluating a trial to determine if risks to study participants are appropriate in comparison to the potential anticipated benefits (21 CFR 56.111(a)). Evaluation of the informed consent process is an important component of the responsibilities of the IRB. A medical monitor may work on behalf of the pharmaceutical company to closely monitor study participants. In this role, they evaluate and categorize potential AEs and ensure timely reporting to the sponsor and FDA. A data monitoring committee (DMC) is comprised of a group of individuals with relevant expertise that reviews accumulating data from ongoing clinical trials on a regular basis. The DMC advises the pharmaceutical company regarding the safety of trial participants who remain in the study, as well as future participants. The DMC may recommend that a study stop early for clear signal of benefit or risk.
In clinical trials where investigators are blinded to the treatment assignment (i.e., drug or placebo), unblinding may occur if knowledge of the treatment received is necessary for treating the subject medically or if it will provide critical safety information that could have implications for the ongoing conduct of the trial.