While every biologics manufacturer has its own standards against which it measures a product’s consistency over time, there is an increasing need for harmonization of these in-house standards with a public standard that can serve as a benchmark for the reference product and all biosimilars. This, explained Meenu Wadhwa, PhD, is where World Health Organization (WHO) international standards come in.
Substitutability of biosimilars and the potential for immunogenicity are both hot topics among physicians who are concerned about switching patients to biosimilars. To help address some of these concerns, the World Health Organization (WHO) is undertaking an effort to harmonize standards for biosimilars worldwide. Meenu Wadhwa, PhD, head of cytokines and growth factors in the biotherapeutics group at the United Kingdom’s National Institute for Biological Standards and Control (NIBSC), presented on the WHO’s activities during the SMi 9th annual conference on Biosimilars and Biobetters, held September 26-27 in London, United Kingdom.
First, said Wadhwa, the reason that many physicians still have concerns about whether biosimilars can be treated as interchangeable—in essence, whether they may be substituted for one another—arises from what she called misleading terminology in the medical literature. Some products that are produced and used in less regulated territories would be better termed “copy products,” but are instead called “biosimilars” in the literature. Use of some of these products has resulted in the production of neutralizing antibodies, giving rise to concerns about biosimilars' immunogenicity. This is particularly the case in Thailand, said Wadhwa, where there are 26 erythropoietin products on the market.
It is also the case that postapproval manufacturing changes in highly regulated markets can potentially result in shifts in quality over time; the reference infliximab, Remicade, has gone through approximately 50 such changes since approval, Wadhwa noted. Furthermore, as multiple biosimilars of a given reference product enter the marketplace, these individual products will all undergo their own changes, and could experience drift from the originator product.
While every product’s manufacturer has its own reference standards (a term not to be confused with reference product) against which it measures a product’s consistency over time, there is an increasing need for harmonization of these in-house standards with a public standard that can serve as a benchmark for the reference product and all biosimilars. “This,” said Wadhwa, “is where the WHO international standards come in.”
The international standards, developed by entities such as NIBSC, the center of the UK Medicines and Healthcare Products Regulatory Agency that is responsible for the testing of biologic medicines, serve as higher-order standards that allow in-house assays and potency assessments to be properly calibrated. They also harmonize globally the dosages of products given to patients, and enable consistent quality. Wadhwa explained that it takes 2 to 3 years to develop a WHO international standard using a stepwise approach. Materials for development of the standard are typically provided by the manufacturers of both reference and biosimilar versions of a molecule, which are then formulated to ensure that there is a stable standard.
When the first wave of biosimilar products was implemented, said Wadhwa, there were already standards for some drugs, like epoetin alfa. However, during the second wave, when biosimilars of products like infliximab or rituximab arrived, retrospective standardization had to be applied.
The first such standardization, undertaken in 2014, was for pegfilgrastim. Prior to development of a standard, biosimilar developers were using reference standards for the short-acting granulocyte-colony stimulating factor (G-CSF) filgrastim. However, filgrastim and its pegylated form have different activities, so using such a standard, was illogical, and risked clinical misunderstanding, said Wadhwa.
“Some of the assays that the participants were using could not distinguish between the 2 forms of G-CSF—the modified form and the nonmodified form,” she explained.
The second biosimilar to receive an international standard was etanercept, which is a complex product that is prone to misfolding. Using the reference and a biosimilar, they established the first standard for etanercept to use in bioassay performance. Next, they developed standards for rituximab and infliximab, and are currently working on standards for adalimumab, trastuzumab, and bevacizumab. A standard for darbepoetin, also a molecule of interest, may be developed as early as next year.
Because immunogenicity is also of interest with biosimilars, and because there have not historically been universally accepted standards for assays to detect antibodies, the WHO is now also developing standards for immunogenicity assays of products with biosimilars. The first, established in 2015, is an epoetin reference panel.
In developing the standard, said Wadhwa, investigators found that there was platform-based disparity; some antidrug antibody screening methods were missing low-affinity antibodies. According to Wadhwa, it is very likely there is underreporting of antibodies on a global level due to unsuitable assays.
Having established the epoetin immunogenicity reference, the WHO will next work on infliximab, adalimumab, and rituximab standards.
To Wadhwa, the WHO’s work in this area is key to ensuring the sustainability of the biosimilar landscape over time; “Only with the application of an international standard can you actually monitor product bioactivity” over time, and the WHO’s standards will help to minimize product drift and ensure the continued utility of these therapies for the future.