Events around high-profile brands such as Vioxx or Baycol highlight the importance of timely and accurate assessments of safety
and tolerability. All medicinal products carry risks in addition to their possible benefits. A judicious decision on whether
and how to develop a new medicine can only be made if both benefits and risks are addressed. The purpose of this article is
to provide the nonspecialist an introduction on the methods, terminology, and thinking behind the clinical assessment of safety
and tolerability.
Conceptually, a clinical trial is a straightforward enterprise. A select group of individuals is given something one wishes
to learn more about, i.e., the investigational product. Another group is given something one knows enough about to use it
as a reference or comparator. Both groups are carefully watched or monitored. All other things being equal, differences between
the groups—if large enough not to be explained by chance—are attributed to the investigational product.
What sounds simple in principle, as many readers will be painfully aware, is not so simple in practice. This is particularly
true for assessments of safety and tolerability. Whereas in most cases efficacy assessments have a clear direction and focus,
safety and tolerability assessments resemble the proverbial search for a needle in a haystack.
Basis of a clinical risk assessment
What AE Reports Tell Us
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The corner stone of a clinical risk assessment is the adverse event (AE). Put simply, an AE is any change in health status
other than the hoped for treatment benefit. Not showing a positive effect is not considered an AE in a clinical trial since
it is the purpose of the trial to find out if there is a treatment benefit. Adverse events may pertain to: 1) clinical laboratory
abnormalities in body fluids (e.g., blood, urine) or other biological samples; 2) abnormalities detected during technical
investigations (.e.g., electrocardiogram, X-ray); 3) signs identified during a physical examination (e.g., depressed tendon
reflexes); 4) symptoms recorded from a patient history (e.g., nausea, weakness, difficulty in thinking). AEs are not always
"bad" and may: 1) provide evidence of a compounds absorption; 2) provide a parameter against which to titrate a dose; 3) allow
identification of new indications (e.g., minoxidil and hair growth); or 4) provide leads for the development of new compounds
(e.g., sulfonamides and sulfonylureas).
Recording of adverse events frequently begins with the signing of consent forms and ends at a certain lag period after ending
participation in the trial. Depending on the nature and number of subjects enrolled in a clinical trial, hundreds or thousands
of AEs may be recorded and reported. Many of these will be purely coincidental or related to the underlying illness. Thus
investigators are usually asked to assess whether they believe the AE is related to the medicine under study or not. An AE
believed to be causally related to a medicinal product is referred to as an adverse drug reaction (ADR).
