Evolution of biological agents: how established drugs can become less safe

Biologicals change over time

Changes to the manufacturing of biologicals are surprisingly common, although healthcare professionals and patients are often unaware of them. For example, infliximab has undergone more than 35 alterations in its clinical lifetime of nearly 20 years.4 Most of these changes will have been relatively minor, and the manufacturer will have demonstrated to the regulator that the biological was unchanged at a physicochemical level.3 But not all changes are trivial, and some are introduced with the explicit intention of improving clinical parameters. Even if clinical trials are required after substantial alterations, they are typically short and rarely powered to detect adverse events that are uncommon or rare and serious.

“Biological evolution” describes how sequential manufacturing changes can cause the properties of a biological to diverge from the original (fig 1).5 For example, a recombinant protein might undergo sequential alterations to three key components—the active biological substance, the stabiliser, and the packaging—leading to a biological drug where all the main components have been changed. So does the drug retain the safety and efficacy profile of the original? Whether an object retains it …