This article first appeared as a contribution to the 'Key Opinion Leader' series produced by Panacee Conseil.

My journey with biosimilars started when I became director of science & education at the European Association of Hospital Pharmacists in 2002, and soon thereafter assumed responsibility for the association's journal, European Journal of Hospital Pharmacy (EJHP). It was at that time that patents of key biological medicines like growth hormone, epoetin, and filgrastim were due to expire and became available for copying.

Around the same time, Johnson & Johnson reformulated its epoetin product Eprex, which some time later was linked to an increased occurrence of PRCA (pure red cell aplasia), a rare formation of antibodies to erythropoietin. The medical community was alarmed that a change in the formulation of a biological medicine might actually result in a detrimental side effect in patients. What could be the consequences if reverse-engineered copies were to be used in patients?

During that period, most healthcare professionals who followed these developments—and I was one of them—were very skeptical about the risks involved in the use of candidate biosimilars. And as editor-in-chief of EJHP, I devoted space in the journal to professionals who wished to express such concerns.  

2006 - The First Class of Biosimilars: Substitution Products  

What followed was a series of papers dealing with the difficulties of making copies of biological medicines. Copy products of epoetin from Asia and South America showed a large variation in composition and potency, and indeed an increase in serious complications like PRCA was observed. It was against this backdrop that the first products were licensed by the European Medicines Agency (EMA), in 2006 (somatropin), 2007 (epoetin), and 2008 (filgrastim). By 2010, EMA had licensed 12 biosimilars, and hospital pharmacists needed guidance on how to select the best product for their specific situations.

In 2007, Professor Irene Krämer from Mainz developed the first set of criteria to evaluate biopharmaceuticals, and they were published in the German journal Krankenhauspharmazie. For the European Journal of Hospital Pharmacy, Irene Krämer and I worked together with Dr. Roger Tredree from London to produce a European edition of the German paper that was made available to all hospital pharmacists. By 2008 we had published so much material that we bundled it into a book entitled Biopharmaceuticals for European Hospital Pharmacists.

It was Sandoz that stepped up to the plate to take full responsibility for informing hospital pharmacists about the proposed information format for their biosimilar epoetin (Binocrit®). This was a change in culture. Not just glossy promotional material, but real scientific background was provided, so pharmacists could look at the details of the licensed products beyond the package insert.

EMA did a formidable job: With all the licensed biosimilars, not a single serious event had occurred that was different from the innovator products. Proof had been delivered that safe re-engineering of these proteins was achievable, and could deliver significant cost savings for patients and healthcare systems.

In 2013, this was confirmed by an official publication of the European Commission claiming the remarkable success of biosimilars. The first class of biosimilars—substitution products—had landed safely in European healthcare systems. Nonetheless, uptake of these products in Europe varied considerably, reflecting the conservative attitude of physicians, at that time predominantly hematologists and nephrologists.  

2012 - The Second Class of Biosimilars: Proteins with a Distinct Pharmacological Action

In spring 2012, EMA accepted the first dossier for a biosimilar monoclonal antibody for assessment: CT-P13 (infliximab) from Korean drug developer Celltrion/Hospira, which received marketing authorization in September 2013. The arrival of this product led to vigorous discussion among a new group of specialists, specifically rheumatologists, dermatologists, and gastroenterologists. With the first class of biosimilars, there was not that much discussion on the extrapolation of indications, but that changed with Flixabi/Remsima (biosimilar infliximab). The clinical development program only addressed rheumatological diseases, but the product was also approved for inflammatory bowel disease. The new drug development paradigm puzzled many physicians, and considerable education was needed to address their concerns. For this reason, we published another update on how to select a biosimilar in EJHP in 2013.

The Korean biosimilar developers Celltrion and Samsung were real game changers in the field of biosimilars. Until then, relatively little had been published in the open scientific literature on biosimilars under development. The Korean companies understood only too well that, in the hospital drug market, published evidence carries considerable weight in the decision-making process. As a result, both the preclinical and clinical data (PK/PD, pivotal trials, extended trials) were published, mostly in open access publications. This new transparency in drug development has gone a long way to achieving acceptance of these new medicines.

But two important questions remained:

1. Do we need separate trials for uninvestigated (extrapolated) indications?

2. Are the biosimilars sufficiently equal to allow transition to a biosimilar in patients who are stable on an innovator product?

It was the Norwegian government that supported the NorSwitch-trial, a 500-plus patient trial across different indications, comparing head-to-head continued treatment with the reference product and biosimilar infliximab. The results were unequivocal: there was no difference in the final outcome.

In the meantime, several studies were undertaken to investigate cross-reactivity, and again, no differences were found. All in all, these studies showed that producing an almost perfect copy, indistinguishable in patients, was feasible. As a result, most professional medical and pharmaceutical societies in Europe threw their support behind biosimilars, including the transitioning of patients who were stable on the (expensive) innovator product. Across the board, a 40% to 60% discount appeared feasible in this market, leading to impressive savings for both patients and the healthcare system.  

2017 - The Third Class of Biosimilars: Targeted Biosimilar Medicines in Oncology and Hematology

The rituximab and trastuzumab patents had already expired in Europe in 2014–2015, but biosimilars were not yet ready. In oncology, there is no clear relationship between treatment and patient outcomes. These drugs provide an increased chance of survival at some point in time in the future. This was a considerable challenge for the biosimilar development paradigm: Which type of relatively short comparative trials would provide sufficient proof of similar safety and efficacy, predicting the long-term outcome?

Eventually, this was resolved by EMA in numerous scientific consultation sessions, and in 2017 the first rituximab biosimilars—from Celltrion and Sandoz—received marketing authorization in Europe. Several trastuzumab and rituximab biosimilars have now been approved by EMA and are used every day to treat patients.

Conclusions

Biosimilars are distinct from generic medicines in many aspects. They have a more complicated development and assessment trajectory, which may be confusing for those who do not have detailed knowledge of the subject. Thanks to EMA’s high and strict standards, not a single serious incident has occurred with any of the biosimilars it has approved. From this perspective, EMA’s approach to the similarity exercise has been highly successful. Uptake in the market is still variable, as patients and many healthcare professionals are still reluctant to accept this new drug development model as an alternative to traditional drug development, with much more uncertainty but at a much lower price.

Initially, I admit I was quite skeptical about biosimilars: Can these products be trusted? Over the years, I have learned that pharmaceutical companies take their responsibility seriously, can produce biosimilars at least equal to their innovator equivalents, and can be fully trusted after scrutiny by the European Medicines Agency. Due to the major financial savings possible with biosimilars that deliver the same quality of care at significantly lower costs, I have become a proponent of the use of biosimilars as they will drive competition in the market, lowering treatment costs and increasing access for patients.