Biological drugs are complex molecules produced in multistep manufacturing processes involving living cells. Processing changes may affect a biological’s safety profile. The report describes how biological manufacturing changes are common and sequential manufacturing changes can lead to ‘biological evolution’, whereby the biological becomes divergent from that was originally approved. In such cases, the authors voice concern over the safety profile of the evolved biological can deteriorate compare with the original. They demonstrate this through the case of recombinant erythropoietin used to treat anaemia. Here, an evolved preparation of erythropoietin-α demonstrated sustained increase in incidence of pure red cell aplasia in Europe.

Process changes go unnoticed
When altering processes, manufacturers are only required to demonstrate that minor process changes do not cause any physiochemical changes to the biological drug. However, some changes made to processing are more substantial and aim to improve clinical parameters. In such cases, additional short-term clinical trials are required by regulation to detect any potential adverse events. The authors highlight that some changes to manufacturing processes of established brands, and the evolution of a biological, can affect their safety profile and this is often overlooked. In many cases, healthcare professionals and patients will be unaware of changes made to an established product and the potential for any negative effects that this may have.

Improve knowledge and pharmacovigilance
The authors stress that all healthcare professionals who prescribe and monitor biologicals should be aware of biological evolution. They should be educated to understand the consequences of sequential process changes and also maintain vigilance in reporting adverse events throughout the lifetime of a drug. In general, the pharmacovigilance model of spontaneous reporting is adopted but in the case of evolved biologicals, it may be fundamentally limited in its ability to detect dynamic changes. As such, the authors highlight a need for additional active surveillance systems.

In conclusion, the authors highlight that biological registries are emerging as a means to evaluate risk of adverse events through actively reporting them, together with the tracking of manufacturing changes. They suggest that, as biologicals continue to become increasingly complex, individual medical specialities should look into developing their safety and monitoring frameworks. Overall, more research is required to understand the long-term safety implications of biological evolution.

A summary of the inadequacies of short-term clinical trials as described in this report is presented in another article.

Conflict of interest
The authors of the research paper [1] declared that there were no conflicts of interest.

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Reference
1. Casadevall N, Flossmann O, Hunt D. Evolution of biological agents: how established drugs can become less safe. BMJ. 2017;357. doi:https://doi.org/10.1136/bmj.j1707

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