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.