The first International Standard for Adalimumab (NIBSC product code 17/236) was established by the World Health Organization (WHO) Expert Committee on Biological Standardization in October 2019.

It is intended to help characterise, calibrate and validate in vitro assays for bioactivity determination and for therapeutic drug monitoring (TDM).

This is the third International Standard in the anti-TNF product class following the previous establishment of Etanercept (NIBSC product code 13/204and Infliximab (NIBSC product code 16/170) International Standards.

The world’s top-selling drug faces new competition

Adalimumab is a monoclonal antibody used in the treatment of several autoimmune and inflammatory disorders including rheumatoid arthritis, Crohn’s disease and plaque psoriasis. It blocks the action of TNF-alpha, a cytokine involved in the development of these diseases.

Initially approved in 2002, adalimumab, sold under the brand name Humira®, has topped the list of the world’s best-selling drugs having generated approximately $20 billion in sales in 2018. This commercial success combined with EU patent expiry in 2018 and the upcoming USA patent expiry in 2023 has sparked the rapid development of biosimilars.

Currently there are 8 adalimumab biosimilars approved in Europe and 4 in the USA with several others either in clinical development or under regulatory review.The introduction of these biosimilars on to the market has driven down prices enabling healthcare providers to make substantial savings. In England, for example, the NHS is expected to save a record £300 million by 2021 by prescribing biosimilar versions of Humira®

A benchmark for harmonising bioactivity and for product consistency

This new adalimumab International Standard was developed by NIBSC following the WHO’s recognition of the global need to standardise monoclonal antibodies to ensure their quality, efficacy and safety. 

The manufacture and quality of monoclonal antibody products is strictly regulated. A product’s bioactivity must be evaluated relative to a specific reference standard throughout product development, prior to product release and for the comparability exercise required following changes to manufacturing processes and during biosimilar development. 

An extensive collaborative study involving 26 participants from 13 countries showed that the use of a common standard improved the consistency of bioactivity results between different laboratories in different in vitro bioassays (e.g., TNF neutralization, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity) and binding assays. The standard was also found to be highly stable over time.

A tool for therapeutic drug monitoring

Therapeutic drug monitoring is being considered for adalimumab treatment as some patients have been reported to lose response, possibly due to the development of antibodies against the drug. However, the current lack of standardisation of analytical testing methods has been recognised by clinicians as a barrier to implementation of TDM in routine clinical practice.

In a separate collaborative study designed to assess the suitability of the adalimumab International Standard for calibrating internal or kit standards in therapeutic drug monitoring tests, there was excellent agreement between different laboratories when reporting the adalimumab content of test samples relative to the International Standard.

The availability of this standard will therefore facilitate the harmonisation of therapeutic monitoring tests and ultimately help to guide personalised dose optimisation for improved patient benefit.

Dr Meenu Wadhwa, Section Leader from the Division of biotherapeutics at NIBSC comments that:

“The adalimumab international standard is a major step towards harmonising adalimumab bioactivity across products given that adalimumab is the most prolific drug target for biosimilar development. It will help patients access quality medicines that are effective and affordable. 

It will help patients access quality medicines that are effective and affordable.”

Dr Meenu Wadhwa, NIBSC Section Leader for Cytokines and Growth Factors

From a clinical perspective, the use of TDM will help to identify patients eligible for dose optimization, treatment cessation or switching to other therapies within or out-of-class. The international standard fulfils demands from clinicians and NICE for standardisation of drug monitoring assays allowing rational clinical decision-making aimed towards better patient outcomes.”

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Please note that this international standard cannot be used as a replacement for the reference medicinal product which is critical for biosimilarity assessments.