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Summarized from a Working Group session at the 2013 Annual Meeting of the American College of Rheumatology. Text amended and approved by the presenters: Arvind Chopra MD, Director and Consulting Rheumatologist, Center for Rheumatic Diseases, Pune, India; Thomas DÃ¶rner MD, Professor of Rheumatology and Clinical Immunology at CharitÃ© University Hospitals, Berlin; Jonathan Kay MD, Professor, Division of Rheumatology, University of Massachusetts Medical School; and Morton Scheinberg MD, Scientific Director of the Research Clinic at the Hospital Abreu Sodre Pesquisa and Professor of Immunology at the University of SÃ£o Paulo, Brazil.
1. Biosimilars are not the same as “me too” or “follow-on” drugs.
• Follow-on drugs are the result of chemical modifications of first-in-class drugs that have the same mechanism of action (for instance Zantac, approved in 1983, following the chemically similar Tagamet, approved in 1977).
• Biosimilars are produced in a different context or production system than the original “innovator” or “reference” drug, but are intended to be as similar as possible in structure, biophysical characteristics, efficacy, and safety. (They are sometimes classed as generally similar, highly similar, or in the case of some peptides precisely similar to the drug they emulate.) Most biosimilars intended for use in rheumatology are considered to be “highly similar,” being monoclonal antibodies against the same target as the reference drug, but produced in different cell lines.
2. Over their lifetimes, many drugs approved in the US and EU have slowly become “biosimilars” of themselves, due to a “natural drift” in drug properties caused by changes in production such as using different batches of medium or manufacture at different sites. These modifications may result in biological effects. For instance:
• Chemical characterization of different commercial lots of rituximab(Drug information on rituximab) and etanercept(Drug information on etanercept) produced between 2006 and 2011 revealed variations in C-terminal lysine content and glycosylation1
• A change in packaging resulted in the stimulation of antibodies to Eprex (synthetic erythropoietin(Drug information on erythropoietin)) that caused 127 cases of red cell aplasia. It took 16 years to recognize and resolve the problem.2
The FDA and the European Medicines Agency (EMA) are aware of this phenomenon, but do not generally require new clinical trials after small changes in the manufacturing process.
3. Although no biosimilars have yet been approved in the United States using the new abbreviated biologics license application process outlined in the Affordable Care Act, a biosimilar infliximab(Drug information on infliximab) was recently approved in Europe, based on the EMA/CHMP guidelines. Several “copy biologics” have been used widely for several years in India and South America, but have not undergone a formal regulatory approval process for biosimilars. Many biosimilars of biologicals used in rheumatology are in clinical testing worldwide.3
• According to a recent report, 25 biosimilars have been approved worldwide, and there are 276 now in the pipeline from 139 key biosimilar developers.4
• The first biosimilars in Europe (forms of epoetin alfa(Drug information on epoetin alfa) and somatotropin) were authorized by the EMA in 2006. The number of requests to EMA for approval of monoclonal antibody biosimilars increased rapidly beginning in 2009; the first one, a biosimilar to infliximab called CTP-13 marketed under the brand names Remsima (Celltrion) or Inflectra (Hospira), was approved in Europe earlier this year, based on randomized, comparative effectiveness clinical trials that demonstrated pharmacokinetic and pharmacodynamics similarity, efficacy ,and safety compared to the reference drug.5
• An Indian firm, Dr. Reddy's Laboratories, produces a rituximab copy called Reditux, which is has been used in India, Bolivia, Chile, and Peru for several years. A Chinese pharmaceutical firm manufactures a copy of etanercept that is marketed in China, Colombia, India, and Mexico. Sandoz has launched a clinical trial of its own biosimilar for etanercept, one of 7 biosimilars in its pipeline.6
• In South America, levels of regulation vary considerably across the nations, generally being less restrictive in smaller countries. In Brazil, where biosimilars are regulated according to standards based upon those of the WHO, companies are developing biosimilars for infliximab, rituximab, adalimumab(Drug information on adalimumab), and etanercept in response to financial incentives to manufacture the drugs locally. In contrast, there are no legal restrictions on the sale of biosimilars in Colombia, and a copy of etanercept manufactured in China has been used there by approximately 1200 patients.
4. Biosimilars may be less expensive than the “innovator” or “reference” drugs they emulate, but it is not clear that the price difference will be substantial. One published estimate has suggested a price reduction on the order of 30%,7 but in some South American countries the reported cost difference ranges from as much as 45% to no better than 5%.
5. Countries with medical systems affluent enough to support expensive reference drugs face a unique (theoretical) risk relating to biosimilars: possible immunological adverse effects due to switching between reference drugs and biosimilars.
• If a biosimilar is deemed to be “interchangeable” with the reference drug, pharmacists would be able to make substitutions without the authorization of the prescribing physician. Repeated interchanges between biosimilars and reference drugs might bring about an immune response to the biological agent that could compromise the efficacy and safety of both drugs, with the risk that the patient could never again take either the biosimilar or the reference product.
• A study of the infliximab biosimilar CT-P13 (Inflectra, Remsima) presented at the 2013 Annual Meeting of the American College of Rheumatology described comparable efficacy and tolerability of infliximab and the biosimilar among patients with ankylosing spondylitis, and claimed no noteworthy adverse effects up to 102 weeks despite a single switch between the reference product and the biosimilar.5The bottom line:Will a biosimilar be as effective as the originally licensed biopharmaceutical? Yes, in well-regulated markets.
Will it be as safe? We anticipate that it will, subject to the presence of vigorous pharmacovigilance when the biosimilar will be already in practice. In Europe, it will be in the hands of national agencies to implement mechanisms to track the manufacturers of certain biosimilars. However, we need to see how these look-back mechanisms will work.
If a pharmacist substitutes a biosimilar for an innovator/reference drug without the prescriber’s assent, will the patient suffer? We don't know, but it appears unlikely that “interchangeability” will ever be demonstrable. Thus, this likely will never take place.
Will this reduce the high cost of biological therapies for our patients? Not clear by how much. One article has estimated a 30% reduction in cost.
1. Schiestl M, Stangler T, Torella C et al.Acceptable changes in quality attributes of glycosylated biopharmaceuticalsNature Biotechnology (2011) 29: 310–312 doi:10.1038/nbt.1839
2. Boven K, Stryker S, Knight J et al.The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Intl (2005) 67:2346-53
3. Scheinberg MA and Kay J. The advent of biosimilar therapies in rheumatology-“O Brave New World”.Nat Rev Rheumatol (2012) 8:430-436.
BioWorld Data (Thompson Media Group) 2013. Accessed 11/20/13 at http://www.bioworld.com/sites/default/files/img/biosimilars_2013-toc_w-sample_0.pdf
5. Park W, Hrycaj P, Jeka S, et al.A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study.Ann Rheum Dis. (2013) 72:1605-1612. doi: 10.1136/annrheumdis-2012-203091. Epub 2013 May 16.
6. Sandoz launches Phase III clinical trial for biosimilar etanercept. Novartis press release. June 24, 2013. Accessed 11/20/13 at http://www.novartis.com/newsroom/media-releases/en/2013/1711249.shtml
7. Regulators pave way for 'biosimilar' drug breakthrough. Reuters. (2013) June 28 Accessed 12/5/13 at http://www.reuters.com/article/2013/06/28/us-celltrion-europe-arthritis-idUSBRE95R0GK20130628