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Assays in clinical trials and pharmacovigilance

Assays are crucial during pre-clinical and clinical trials, and for pharmacovigilance. By this stage, the molecule has already been fully profiled with a mechanism of action, and efficacy and safety are now being assessed in vivo.

Dr John Chappell, Director of Large Biomolecule Analysis at LGC, Fordham UK, works on developing analytical methods for measuring biologics to support clinical trials. Dr Chappell and his team work on a whole range of assays for monoclonal antibodies, fusion proteins and antibody/drug conjugates. We chatted to him about his work.

The use of assays 

In the later phases of biologic and biosimilar drug development, immunoassays are used, in preference to LC-MS which is more commonly used for small molecules. More recently LC-MS/immunoassay fusions are used, where antibodies are used to affinity purify the target molecule from samples prior to detection with MS.

Functional assays are crucial to assess antibody formation against the biologics and biosimilars, such as antibody neutralising assays, which is a big concern for new treatments. As well as blocking the drug mechanism of action, some patient antibody responses can affect the half-life of the drug and other antibodies may bind to and prevent other events, such as complement activation.

Reduction of efficacy

The main concern with monoclonal antibody immunogenicity is reduction of efficacy over time. With many biologics, antibodies tend to appear with persistent use over long periods. There is a now a drive for comprehensive pharmacovigilance on biopharmaceuticals, in particular biosimilars, because, although you can study efficacy during clinical trials, this is only with a limited number of subjects. Only when something is in routine use among the general population, in post-marketing, can you have an accurate assessment of immunogenicity.

Working with biosimilars

My team and I specialise in developing assays to monitor biosimilars in later phases of development. With biosimilars, it is the opportunity to work on the same compounds with different clients. Often you have a lot of experience with the molecules already, which means you can develop the required assays very quickly. The assays are key for developing biosimilars through to post-marketing.

It’s not like with small molecule generics, where you can simply manufacture the drug and then show bioequivalence. Biosimilars require complex manufacturing, such as cell-culture techniques, so developers must reverse engineer the product itself first, and then make their own version of it which will have structural differences to the originator. It is not the same molecule and the only way to assess that it is fit for purpose is with assays.

Initially, assays are required to show that the new product has the same or similar functionality to the originator; there is a lot of CMC characterisation that goes into biosimilars such as in vitro assays in order to establish functionality. Then in clinical trials you need the PK profiles of both the originator and the biosimilar – they have to be shown to be very similar; finally, immunogenicity is a very important safety assessment. Though with the originator being produced from older manufacturing techniques there is a lot of cases where immunogenicity has been improved in the new generation of biosimilars.

Conclusion 

Undeniably, biologics and biosimilars are providing very real and exciting new drug therapies for patients across many therapeutic areas. The key challenge is establishing and maintaining quality throughout the drug development process and beyond regulatory approval, and well-designed, well-executed assays provide the solution.

View the agenda for the 4th Biologics and Biosimilars Congress: Europe. 

 

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