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European Biopharmaceutical Review

Gaining Ground

Attitudes towards biosimilars are starting to shift, as a growing number of countries have begun to recognise their importance in healthcare systems and to patients. Even though biologics inevitably play an important role in providing lifesaving treatments for many patients, the cost can be prohibitive to healthcare budgets and put biologic therapy out of reach.

Increasingly, payers are acknowledging the cost savings that biosimilars represent, together with the opportunity to provide more patients with safe and efficacious treatments. Furthermore, biosimilars are crucial to keeping innovation alive; without them, healthcare systems would be unable to pay for improved therapeutics, the result of which would be no real incentive for pharmaceutical innovation – and new investment would move in other directions.

The research and development of biosimilars also presents the opportunity to develop biobetters, which are products that are superior to the originator – whether in the area of structural changes or bifunctional targeting, or improved formulation resulting in safety and/or efficacy improvement. Those superior elements have the potential to further develop the market for lifesaving therapies, as well as commercial potential for companies, because a biobetter that gains marketing authorisation could lead to market exclusivity.

The main challenges to the industry are:
  • To explain to physicians and payers what biosimilars are
  • To communicate to those physicians and payers the benefits of biosimilars
  • To detail why biosimilars represent an opportunity for all
  • To offer reassurance about the safety profiles of biosimilars through data
The fact is that biosimilars have already been on the market in Europe for 10 years and in that time, no significant problems have been discovered, thereby providing greater assurance about their safety profiles.

Changing Attitudes

While Europe was one of the first major markets to adopt biosimilars, several others have shown themselves to be open to the opportunities this class of products presents. Biosimilars have been approved in Japan since 2009, and in South Korea since 2010. In Thailand, the first biosimilar of an erythropoiesis-stimulating agent (ESA) – epoetin alfa – became available as early as 1997. The one major market that has been slower to adopt biosimilars is the US, which did not approve its first biosimilar until 2015.

As the differences in biosimilar approval dates demonstrate, progress towards biosimilar adoption has been highly regionalised and much still must be done by the industry and regulators to alter opinion. Even in Europe, biosimilar usage has differed from one country to the next. Biosimilar uptake was far quicker in Germany than Italy, for example, because of different approaches taken to encourage adoption: Germany used quotas and educational outreach to promote biosimilars, and German reference price rules enabled erythropoietin biosimilars to have a cost advantage for more than three years. Italy’s attempt to combat biosimilar resistance with pro-uptake policies, however, was met with mixed results.

But there is evidence that the tide is turning. Reports show that more and more countries in Europe support the switch to biosimilars. Italy and Spain are now catching up with an increased uptake of biosimilars in these regions. In France, pharmacies have been permitted to switch prescriptions from originator biopharmaceuticals to biosimilars since 2014. A recent move by the National Agency for the Safety of Medicines and Health Products shows the French authority is further relaxing its stance on biosimilars, to say its former objection to interchanging medicines during the course of treatment is no longer justified given the growing knowledge about the safety and efficacy of biosimilars. In 2015, the Finnish regulatory agency recommended physicians switch to biosimilars – and beyond Europe, Australia also recommended pharmacies offer a switch to biosimilars in 2015.

One of the clearest examples of the cost and patient benefits created by biosimilars is the impact that Remsima – Celltrion’s biosimilar form of rheumatoid arthritis and inflammatory bowel disease tumour-necrosis-factor (TNF) inhibitor Remicade – had in the Norwegian market. By the end of 2015, Remsima had almost totally replaced Remicade in Norway. In 2016, the cost of treatment with TNF inhibitors is expected to decline for the first time in 10 years – and more patients will be treated.

Although the attitude physicians have towards biosimilars varies by region and is influenced by lingering misperceptions, this is starting to change. A survey of US physicians in five speciality areas shows that almost half are inclined to embrace biosimilars and recognise their value in reducing patient therapy costs (1). According to a 2016 InCrowd survey, 17% of respondents said they believe biosimilars will become the norm or replace innovator biologic products within three years.

Demonstrating Safety

As copies of authorised biologics, biosimilars have been thoroughly compared to licenced reference products with regard to safety and efficacy. Unlike generic versions of chemical entities, it is not possible to explicitly establish the structure of large protein biopharmaceuticals. However, although biologics and biosimilars are not identical, any differences from reference products are not permitted to be of clinical relevance, which means the safety, purity and potency of the two versions must be the same.

Clinical data represents only a fraction of the information needed for establishing biosimilarity, and it cannot be considered in isolation from physicochemical, biological and other nonclinical data. To determine biosimilarity, sourcing of the reference product is critical. Pharmacokinetic/pharmacodynamic data, too, is pivotal in the creation of a biosimilar product, and data from patients does not override pharmacokinetic/pharmacodynamic results if equivalence cannot be established.

Recent results of Phase 3 comparability clinical trials comparing biosimilars with their reference products – and the approval of biosimilar infliximab by several regulatory agencies – demonstrate the growing importance of biosimilars in inflammatory diseases. The safety profiles of biosimilars developed according to regulatory guidelines appear to be highly similar to their reference products, and post-marketing pharmacovigilance programmes are in place. Regardless of whether we refer to biosimilars or reference products, biopharmaceuticals have unique safety profiles and may, therefore, require a specific approach to pharmacovigilance, guided by a deep understanding of the intended mechanism of action of the product, and by particular attention to their immunogenicity.

Indeed, safety studies suggest that adverse drug reactions to biopharmaceuticals are only the result of biopharmaceuticals’ pharmacological actions and immunogenicities. The priority must therefore be to develop a thorough understanding of the product’s intended mechanism of action, in order to guide pharmacovigilance activities. It is also important to acknowledge that even when strategies have been put in place to lessen the risks of unwanted biopharmaceutical immunogenicity, subtle changes in a product that cause unwelcome immune responses may not be identified before a drug is administered to large numbers of patients. In the case of biosimilars – wherein small differences from reference products are possible whether they occur during the production, packaging, storing or distribution process – concerns could potentially be raised. For example, a 2011 paper explored an incident in Thailand with ESA biosimilars wherein an alarming rise in the prevalence of pure red cell aplasia (PRCA) was found in 23 of 30 subjects referred due to loss of ESA efficacy in patients being treated for chronic kidney disease (2). The Thai regulatory authorities responded quickly by implementing an immunogenicity surveillance registry of ESAs to estimate the incidence of PRCA and evaluate the safety of ESAs in the country (3).

In its guideline on the evaluation of monoclonal antibodies as similar biotherapeutic products, or biosimilars, the WHO states the potential for immunogenicity and suggests for each biosimilar monoclonal antibody a tailored approach that includes assessment based on prior knowledge of the immunogenicity of the reference product, as well as a riskbased immunogenicity assessment programme that involves testing of patient samples pre-treatment, during treatment and post-treatment in a relevant set of assays. The WHO also recommends comparative immunogenicity testing with the reference product (4).

When it comes to assessment of risk, insight by observant physicians and researchers is mandatory, especially because when there is uncertainty about the causal relationship between an adverse event and a biopharmaceutical, spontaneous reports may be the only sources for regulatory action.

Gathering Knowledge

Despite questions arising about immunogenicity, and even though continued studies remain essential, the evidence shows that safety profiles of biosimilars are on a par with those of reference products (5). The challenge will be to sway the opinions of a larger number of healthcare practitioners. Winning physicians’ trust will require both payers and biosimilar experts to do more to address residual uncertainties that exist largely because of misinformation or lack of knowledge about biosimilar products. Addressing those uncertainties can best be achieved through education.

The goal of physicians is to provide good care for patients – but because their busy clinical practices demand most of their attention, few of them have the time it takes to study the safety profiles of biosimilars. Experts can help by providing physicians such tools as scientific literature to show that patients are not at risk, and by explaining that these medicines are under the same supervision by health authorities and regulatory agencies as any other medicines are.

Finally, physicians’ reservations about biosimilars can be addressed by pointing out that the new biosimilar medicines are much less expensive, which means important cost savings to healthcare systems and monies that can be redirected towards investment in other breakthrough medicines or other healthcare improvements.


1. “Nearly half of US physicians say they will prescribe more biosimilars, according to new data from InCrowd,” 3 March 2016. Visit:
2. Praditpornsilpa K et al, Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies, Kidney Int 80(1): pp88-92, July 2011
3. Wish JB, Erythropoiesis-stimulating agents and pure red-cell aplasia: You can’t fool Mother Nature, Kidney Int 80(1): pp11-13, July 2011
4. World Health Organization, Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs), 1 March 2016
5. Reinisch W and Smolen J, Biosimilar safety factors in clinical practice, Semin Arthritis Rheum 44(6 Suppl): S9-S15, June 2015

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Barbara Testa is Associate Director at ProductLife Group, providing management and support to the medical affairs team and strategic support to clients, as well as contributing to the development of the business. Barbara has more than 20 years of experience at CROs and in biopharmaceutical R&D in multiple therapeutic areas. She has broad experience in drug metabolism, pharmacokinetics and in preclinical development of macromolecules, and has developed new biological entities from clinical candidate through new drug application. She has a Master’s degree in Biological Science and a postdoctorate in Toxicology from the University of Turin.
Barbara Testa
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