Summary
In contrast to most drugs which are chemically synthesized and have a known structure, biological drugs are derived from living organisms or their products. Biologicals are structurally more complex and unique from chemically synthesized small drug molecules because of their larger size and intricate manufacturing process. Secondary to their protein structure, they are also more prone to acute and chronic immune responses. Biosimilars are intended to offer comparable safety and efficacy relative to reference brand biologicals, yet they are not generic alternatives to the original compounds and so are currently not considered interchangeable. Given their structural complexity, multifaceted manufacturing processes and risk for immunogenicity, biosimilars require class-specific regulatory approval pathways. Here we seek to provide a general overview of clinical trial design in the era of biosimilar drug development. This will include a review of the regulatory requirements for clinical trials in Europe and the United States, followed by a review of two biosimilars that have recently reported results of randomized trials against branded biologicals.
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References
Dranitsaris G, Amir E, Dorward K (2011) Biosimilars of protein based drug therapies: regulatory, clinical and commercial considerations. Drugs 71:1527–36
Insulin synthesis and secretion. July 25, 2012. (http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html) Accessed July 25, 2010.
Product monograph: Neupogen. (http://www.amgen.ca/Neupogen_PM.pdf). Accessed July 25, 2010.
Infliximab for injection. (http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/103772s5234lbl.pdf). Accessed July 25, 2010.
Mellstedt H, Niederwieser D, Ludwig H (2008) The challenge of biosimilars. Ann Oncol 19:411–9
Woodcock J, Griffin J, Behrman R et al (2007) The FDA’s assessment of follow on protein products: a historical perspective. Nat Rev Drug Discovery 6:437–42
Beck A (2009) European medicines workshop on biosimilars monoclonal antibodies: Perspective from the EU. MAbs 1:406–410
Kueppers E (2010) Follow on biologics: how to develop a competitive advantage. Business Development and Licensing Journal 12:17–18
Zacks Investment Research. Biosimilars: The next big thing. January 13, 2012. (http://www.dailymarkets.com/stock/2012/01/13/biosimilars-the-next-big-thing/). Accessed July 25, 2012.
Van De Werf F, Adgey J, Ardissino D et al (1999) Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomized trial. Lancet 354:716–22
Blackwelder WC (1982) Proving the null hypothesis in clinical trials. Control Clin Trials 3:345–53
Ware JH, Antman EM (1997) Equivalence trials. N Engl J Med 16(337):1159–61
Anonymous (1993) An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 329:673–82
Schumi J, Wittes JT (2011) Through the looking glass: understanding non-inferiority. Trials 12:106
Rothmann M, Li N, Chen G, Chi GY, Temple R, Tsou HH (2003) Design and analysis of non-inferiority mortality trials in oncology. Stat Med 22:239–64
Fox A (2010) Biosimilar medicines-new challenges for a new class of medicine. J Biopharm Stat 20:3–9
Dunnett CW (1996) An alternative to the use of two sided tests in clinical trials. Stat Med 15:1729–38
Christensen E (2007) Methodology of superiority vs. equivalence trials and non-inferiority trials. J Hepatol 46:947–54
Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ (2006) Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 295:1152–60
European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies. November 18, 2010. (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdf), Accessed July 25, 2012.
US Food and Drug Administration. Feb 9, 2012. (http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm291232.htm). Accessed July 25, 2012.
Yoo D, Miranda P, Piotrowski M, et al. A randomized double blind phase 3 study demonstrates clinical equivalence of CT-P13 to infliximab when co-administered with methotrexate in patients with active rheumatoid arthritis. Abstract FR10143. (http://www.gabionline.net/Biosimilars/Research/Biosimilar-infliximab-equivalence-proven-in-phase-III-trial)
Haydock I (2012) First approval for biosimilar infliximab, in South Korea. July 25, 2012. (http://www.scripintelligence.com/home/First-approval-for-biosimilar-infliximab-in-South-Korea-update) Accessed July 27, 2012
Gladkov O, Moiseyenko V, Bondarenko N et al (2011) A randomized, noninferiority study of recombinant human G-CSF/human serum albumin fusion (CG-10639) and pegfilgrastim in breast cancer patients receiving myelosuppressive therapy. J Clin Oncol 29:2011 (suppl: abstr 9086)
Volovat C, Gladkov OA, Bondarenko IM et al (2012) Efficacy and safety of balugrastim compared with pegfilgrastim in patients with breast cancer who are receiving chemotherapy. Support Care Cancer 20 (Suppl 1):S235 (abstract 986)
Teva Announces FDA Grants Approval for Tbo-filgrastim for the Treatment of Chemotherapy-Induced Neutropenia. August 30, 2012. (http://www.businesswire.com/news/home/20120830005436/en/Teva-Announces-FDA-Grants-Approval-Tbo-filgrastim-Treatment). Accessed October 30, 2012
Authors contributions
G. Dranitsaris: wrote manuscript, literature review
K. Dorward: literature review, edited manuscript
E. Hatzimichael: literature review, edited manuscript
E. Amir: literature review, edited manuscript
Declaration of competing interests
None of the authors have competing interests to declare. This review did not receive any funding.
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Dranitsaris, G., Dorward, K., Hatzimichael, E. et al. Clinical trial design in biosimilar drug development. Invest New Drugs 31, 479–487 (2013). https://doi.org/10.1007/s10637-012-9899-2
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DOI: https://doi.org/10.1007/s10637-012-9899-2