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Biosimilars Gaining Traction as Regulator Confidence Grows


Biosimilars are gaining more support among payers and physicians, but more needs to be done to explain their benefits as well as their safety and efficacy profiles, writes Barbara Testa.

Biosimilars are coming increasingly into the spotlight amid growing support by regulatory authorities in recognition of their importance in the broader healthcare context and amid increased understanding about their production and safety profiles. Barbara Testa reports.

Biosimilars have the potential to provide patients with access to life-saving and life-changing medications while lowering healthcare costs. According to the IMS Institute for Healthcare Informatics, the use of biosimilars could result in collective savings for the five major European Union (EU) markets and the US of €50 million to €100 million in the next five years.[i]

More than 20 biosimilars have been granted central marketing authorization by the European Medicines Agency (EMA) in the past 10 years-many of them for multiple indications.[ii] The US has been slower to follow suit on biosimilars. However, in 2015, FDA finalized regulations for the biosimilar approval pathway and in the same year approved Sandoz’s biosimilar Zarxio (filgrastim). That was followed in April 2016 with approval of the first monoclonal antibody biosimilar in the US: Celltrion’s Inflectra (infliximab-dyyb). Since then, the FDA’s pace of biosimilar approvals has started to pick up. In July 2016, Amgen received approval for its biosimilar version of Humira for the treatment of inflammatory conditions such as rheumatoid arthritis, plaque psoriasis, and Crohn’s disease.

There are various reasons to produce and promote biosimilars, not least because their expected lower development costs translate to greater affordability for patients and to increased access to medicines. Drawing on knowledge from the originator product, an enhanced CMC (chemistry, manufacturing, and control) package reduces the amount of nonclinical and clinical development effort required. From a manufacturing point of view, more current methods can be used, which would result in improved efficiency and less-expensive production. In addition, biotherapeutics that come off patent open the door to more biosimilars.

Today a growing number of companies are targeting and developing biosimilars as the regulatory authorities become more adept and comfortable with these products. For example, Samsung’s biosimilar version of Remicade (infliximab) is under review, representing an important step in the electronic giant’s endeavour to enter the US drug market. Almost 50 distinct biosimilars are currently in development and will likely generate a highly competitive marketplace in the next five years, according to the IMS.

The commitment to biosimilars has led to some strong alliances. For example, to demonstrate in Canada the growing commitment of the broader industry to biosimilar development, an alliance of eight life sciences companies-Amgen, Boehringer Ingelheim, Coherus BioSciences, EMD Serono, Merck, Pfizer, Sandoz, and Teva-formed the Canadian Biosimilars Forum in order to lobby policy makers to support greater access to biosimilars.

Evaluating a biosimilar candidate

Regulatory authorities grant approval to biosimilars based on a totality of evidence: that a product has demonstrated similarity in terms of physiochemical properties, efficacy, and safety after extensive comparability studies. Because of the complexities involved in developing biopharmaceutical products in general compared with small molecules, a tailored approach to safety may be necessary.

Biosimilar developers are required to demonstrate understanding of the characteristics of innovator products and to design thorough studies involving analytic and biological assessments performed by way of nonclinical and clinical trials.

Differences between biosimilars and originators are most likely to emerge during production, such as the use of different cell lines and different growth conditions. Those differences have the potential to affect immunogenicity profiles, wherein an antigen induces an immune reaction-typically antidrug antibodies-that can increase the risk of adverse reactions. Comparative immunogenicity studies are therefore required. The EMA says “analytical assays should be performed with both the reference and biosimilar molecule in parallel (in a blinded fashion) to measure the immune response against the product that was received by each patient.”[iii]

Scientific tools and processes are available to detect immunogenicity-for example, by using the most-sensitive assays possible to uncover the best opportunities for detecting antibodies in patient samples[iv] and for testing immunogenicity in sensitive patients by using subcutaneous rather than intravenous administration and lower or less-frequent doses.

Biosimilars also produce challenges for regulatory affairs departments, which must adapt to new regulatory requirements and product differences. But certain general themes are consistent with global regulatory guidances regarding assessment of similarity, beginning with a strong analytic (CMC) package; one area that is less consistent is the need for nonclinical in vivo studies. The EMA appears less likely to request in vivo studies if the analytic package supports similarity, and even though the United States appears to be getting closer to the EMA in terms of requirements, other countries continue to request at least one in vivo toxicity study, even when clinical data are available from the proposed biosimilar.[v]

Next stage in biosimilars

The active ingredients in biosimilars are described as “highly similar” to their reference products. Biosimilars are different from generics, whose active ingredients are chemically identical to their branded counterparts.

For the market, an important next step could be the introduction of interchangeable biosimilars, which is a US–specific designation. As yet, the FDA has not issued final guidance on what will be required to achieve such a designation, and it remains uncertain whether the industry would consider investment in additional studies for such products worthwhile.

There is also debate about what the impact of interchangeability will be. When a biosimilar receives marketing authorization, it does not imply interchangeability or substitutability with the reference product.

At a Generic Pharmaceutical Association meeting in September 2016, Momenta CEO Craig Wheeler said interchangeability presents opportunities, but it’s not an absolute necessity for biosimilar success. At the same meeting, analyst Ronny Gal warned that confusion about the quality and safety of a standard biosimilar compared with an interchangeable biosimilar could negatively affect the former.

There are also concerns that substitution could complicate effective pharmacovigilance, and therefore it’s imperative that (1) control over prescribing remain with physicians and (2) so that any adverse events get attributed to the correct product, physicians be properly informed when substitutions are made.

Changing opinions

Biosimilars are gaining more and more support among payers and physicians, but more remains to be done to explain their benefits as well as their safety and efficacy profiles. An October 2015 survey of physicians in France, Spain, and the UK that was conducted by pharmaphorum found that less than 25% of physicians reported that they prescribed biosimilars, though almost half said they expect to do so in the future.

In its report, the IMS Institute for Healthcare Informatics said regulatory bodies, payers, and product manufacturers will have to reassure physicians about the science behind the data on biosimilar safety and efficacy. “Doctors need to trust that by driving the uptake of biosimilars, they are helping deliver savings for the health system as a whole and are helping improve patients’ access to much-needed treatments,” the report’s authors state.

In their article titled “Biosimilars: what clinicians should know,” Weise et al. say, “A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients.”[vi] Communication between physicians, biosimilars experts in academia and beyond, and regulators will be a priority.

Norway has taken the lead in striving to demonstrate the safety of biosimilars to physicians through the NOR-SWITCH study, wherein 23% of study patients were switched to a biosimilar infliximab from the reference infliximab.[vii] The study found comparable efficacy and safety in the patients switched to the biosimilar, thereby providing greater assurance for physicians.

As the science surrounding biosimilars advances, insurers and health-care systems will increasingly find ways to encourage biosimilars uptake, and physicians will become more comfortable with prescribing them or switching patients to biosimilars.

Seeking consistency

The value biosimilars provide for broader healthcare needs, for reducing costs, and even for advancing product pipelines is clear. Biosimilars create a competitive biologicals market, which is essential for healthcare systems and for the sustainability of innovative therapies while maintaining efficacy, safety, and quality for patients. And despite the continuing need for education to improve the physician and patient confidence, biosimilars are starting to gain real traction globally.


[i] Delivering on the Potential of Biosimilar Medicines: The Role of Functioning Competitive Markets, IMS Institute for Health Informatics, March 2016, https://www.imshealth.com/files/web/IMSH%20Institute/Healthcare%20Briefs/Documents/IMS_Institute_Biosimilar_Brief_March_2016.pdf.

[ii] European public assessment reports, European Medicines Agency, http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=WC0b01ac058001d124&searchTab=searchByAuthType&alreadyLoaded=true&isNewQuery=true&status=Authorised&keyword=Enter+keywords&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=biosimilars&genericsKeywordSearch=Submit.

[iii] Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins (draft), September 24, 2015, European Medicines Agency, http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/10/WC500194507.pdf.

[iv] Thomas B. May, Biosimilar Industry Perspective on Draft Guideline on Immunogenicity Assessment of Monoclonal Antibodies, Medicines for Europe Annual Biosimilar Medicines Group Conference, London, October 24, 2011, http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2012/06/WC500128725.pdf.

[v] K. Chapman et al., Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges. MAbs 2016, 8(3):427-35.

[vi] M. Weise et al., Biosimilars: what clinicians should know. Blood December 20, 2012,120(26):5111-7. doi: 10.1182/blood- 2012-04-425744.

[vii] The NOR-SWITCH Study, https://clinicaltrials.gov/ct2/show/NCT02148640.


About the author

Barbara Testa (btesta@productlife-group.com) is associate director at ProductLife Group (www.productlifegroup.com)





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