Abstract
Biologics are innovative, complex large molecule drugs that have brought life-changing improvements to patients in various disease areas like cancer, diabetes, or psoriasis. Biosimilars are copies of innovative biologics. Their development is currently a focus of attention because the patents of several important biologics have expired, making it possible for competing companies to produce their own biosimilar version of the drug. Although, at first sight, there seems to be some similarity with the development of generics, which are copies of simple small molecule drugs, there is an important distinction because of the complexity and the variability inherent in the development of biologics. This chapter introduces the studies and analyses required to obtain regulatory approval for marketing a biosimilar and reviews several important regulatory concepts. In addition, several important statistical challenges are highlighted and discussed.
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References
Arato T (2016) Japanese regulation of biosimilar products: past experience and current challenges. Br J Clin Pharmacol 82(1):30–40
Barlas S (2017) FDA guidance on biosimilar interchangeability elicits diverse views: current and potential marketers complain about too-high hurdles. Pharm Ther 42(8):509
Benucci M, Gobbi FL, Bandinelli F, Damiani A, Infantino M, Grossi V, Manfredi M, Parisi S, Fusaro E, Batticciotto A et al (2017) Safety, efficacy and immunogenicity of switching from innovator to biosimilar infliximab in patients with spondyloarthritis: a 6-month real-life observational study. Immunol Res 65(1):419–422
Berkowitz SA (2017) Analytical characterization: structural assessment of biosimilarity, Chap 2. In: Endrenyi L, Declerck P, Chow SC (eds) Biosimilar drug product development. CRC Press, Boca Raton, pp 15–82
Bewesdorff M (2016) Biosimilars in the U.S. – the long way to their first approval. Master of drug regulatory affairs, Rheinischen Friedrich-Wilhelms-Universitat Bonn
Blackstone E, Fuhr JP Jr (2017) Biosimilars and biologics. The prospect for competition, Chap 16. In: Endrenyi L, Declerck P, Chow SC (eds) Biosimilar drug product development. CRC Press, Boca Raton, pp 413–438
Brennan Z (2016) FDA to hold one advisory committee for each initial biosimilar. https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/9/fda-to-hold-one-advisory-committee-for-each-initial-biosimilar. Accessed 07 June 2018
Cazap E, Jacobs I, McBride A, Popovian R, Sikora K (2018) Global acceptance of biosimilars: importance of regulatory consistency, education, and trust. Oncologist 23:1188
CHMP (2005) Guideline on the choice of non-inferiority margins. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003636.pdf. Accessed 07 June 2018
CHMP (2008) Zarzio: EPAR public assessment report. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000917/WC500046528.pdf. Accessed 26 Oct 2015
CHMP (2014a) Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (revision 1). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf. Accessed 22 Feb 2018
CHMP (2014b) Guideline on similar biological medicinal products (revision 1). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf. Accessed 22 Feb 2018
CHMP (2016) Benepali: EPAR – public assessment report. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004007/WC500200380.pdf. Accessed 07 June 2018
CHMP (2017) Amgevita: EPAR – public assessment report. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004212/WC500225231.pdf. Accessed 07 June 2018
Chow SC, Hsieh TC, Chi E, Yang J (2009) A comparison of moment-based and probability-based criteria for assessment of follow-on biologics. J Biopharm Stat 20(1):31–45
Christl LA (2018) From our perspective: interchangeable biological products. https://www.fda.gov/Drugs/NewsEvents/ucm536528.htm. Accessed 22 Feb 2018
Christl LA, Woodcock J, Kozlowski S (2017) Biosimilars: the US regulatory framework. Annu Rev Med 68(1):243–254
Cohen H, Beydoun D, Chien D, Lessor T, McCabe D, Muenzberg M, Popovian R, Uy J (2016) Awareness, knowledge, and perceptions of biosimilars among specialty physicians. Adv Ther 33(12):2160–2172
Combest A, Wang S, Healey B, Reitsma DJ (2014) Alternative statistical strategies for biosimilar drug development. GaBI J 3(1):13–20
Crommelin D, Bermejo T, Bissig M, Damiaans J, Krämer I, Rambourg P, Scroccaro G, Strukelj B, Tredree R (2005) Pharmaceutical evaluation of biosimilars: important differences from generic low-molecularweight pharmaceuticals. Eur J Hosp Pharm Sci 11(1):11–17
EMA (2012) Questions and answers on biosimilar medicines (similar biological medicinal products). http://www.medicinesforeurope.com/2012/09/27/ema-questions-and-answers-on-biosimilar-medicines-similar-biological-medicinal. Accessed 22 Feb 2018
FDA (2009) Biologics price competition and innovation act. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ucm216146.pdf. Accessed 22 Feb 2018
FDA (2015a) Sandoz briefing book for application to market zarxio. https://patentdocs.typepad.com/files/briefing-document.pdf. Accessed 11 Jan 2019
FDA (2015b) Scientific considerations in demonstrating biosimilarity to a reference product. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed 05 June 2018
FDA (2016) Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf. Accessed 05 June 2018
FDA (2017a) Biological product definitions. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM581282.pdf. Accessed 05 June 2018
FDA (2017b) Considerations in demonstrating interchangeability with a reference product. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed 22 Feb 2018
FDA (2018) FDA withdraws draft guidance for industry: statistical approaches to evaluate analytical similarity. https://www.fda.gov/Drugs/DrugSafety/ucm611398.htm. Accessed 17 Jul 2018
Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B, Furst D, Goldsmith C, Kieszak S, Lightfoot R et al (1993) The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheumatol 36(6):729–740
Finckh A, Bansback N, Marra CA, Anis AH, Michaud K, Lubin S, White M, Sizto S, Liang MH (2009) Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis. Ann Intern Med 151(9):612–621
Health Affairs Health Policy Brief (2013) Biosimilars. https://www.healthaffairs.org/do/10.1377/hpb20131010.6409/full/. Accessed 05 June 2018
Holzmann J, Balser S, Windisch J (2016) Totality of the evidence at work: the first U.S. biosimilar. Expert Opin Biol Ther 16(2):137–142
Hsieh TC, Chow SC, Yang LY, Chi E (2013) The evaluation of biosimilarity index based on reproducibility probability for assessing follow-on biologics. Stat Med 32(3):406–414
Hsu JC, Hwang JTG, Liu HK, Ruberg SJ (1994) Confidence intervals associated with tests for bioequivalence. Biometrika 81(1):103–114
Hung A, Vu Q, Mostovoy L (2017) A systematic review of US biosimilar approvals: what evidence does the FDA require and how are manufacturers responding? J Manag Care Spec Pharm 23(12):1234–1244
ICH (2004) Comparability of biotechnological/biological products subject to changes in their manufacturing process, Q5E
Jacobs I, Singh E, Sewell KL, Al-Sabbagh A, Shane LG (2016) Patient attitudes and understanding about biosimilars: an international cross-sectional survey. Patient Prefer Adherence 10:937–948
Jones B, Kenward M (2014) Design and analysis of cross-over trials, 3rd edn. Chapman & Hall/CRC monographs on statistics & applied probability. Taylor & Francis. https://books.google.ch/books?id=tuisBAAAQBAJ
Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, Lundin KE, Mørk C, Jahnsen J, Kvien TK et al (2017) Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, noninferiority trial. Lancet 389(10086):2304–2316
Li J, Chow SC (2017) Statistical evaluation of the scaled criterion for drug interchangeability. J Biopharm Stat 27(2):282–292
Messori A, Trippoli S, Marinai C (2017) Network meta-analysis as a tool for improving the effectiveness assessment of biosimilars based on both direct and indirect evidence: application to infliximab in rheumatoid arthritis. Eur J Clin Pharmacol 73(4):513. https://doi.org/10.1007/s00228-016-2177-z
Mielke J, Jilma B, Koenig F, Jones B (2016) Clinical trials for authorized biosimilars in the European Union: a systematic review. Br Clin Pharmacol 82(6):1444–1457
Mielke J, Jilma B, Jones B, Koenig F (2018a) An update on the clinical evidence that supports biosimilar approvals in Europe. Br Clin Pharmacol 84(7):1415–1431
Mielke J, Jones B, Jilma B, König F (2018b) Sample size for multiple hypothesis testing in biosimilar development. Stat Biopharm Res 10(1):39–49
Mielke J, Schmidli H, Jones B (2018c) Incorporating historical information in biosimilar trials: challenges and a hybrid Bayesian-frequentist approach. Biom J 60(3):564–582
Mielke J, Woehling H, Jones B (2018d) Longitudinal assessment of the impact of multiple switches between a biosimilar and its reference product on efficacy parameters. Pharm Stat 17(3):231–247
Mielke J, Innerbichler F, Schiestl M, Ballarini NM, Jones B (2019) The assessment of quality attributes for biosimilars: a statistical perspective on current practice and a proposal. AAPS J 21:7
Moorkens E, Vulto AG, Huys I, Dylst P, Godman B, Keuerleber S, Claus B, Dimitrova M, Petrova G, Sović-Brkičić L et al (2017) Policies for biosimilar uptake in Europe: an overview. PLoS One 12(12):e0190147
Pan H, Yuan Y, Xia J (2017) A calibrated power prior approach to borrow information from historical data with application to biosimilar clinical trials. J R Stat Soc Ser C Appl Stat 66(5):979–996
Schellekens H, Moors E (2015) Biosimilars or semi-similars? Nat Biotechnol 33(1):19–20
Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R (2011) Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol 29:310–312
Schiestl M, Li J, Abas A, Vallin A, Millband J, Gao K, Joung J, Pluschkell S, Go T, Kang HN (2014) The role of the quality assessment in the determination of overall biosimilarity: a simulated case study exercise. Biologicals 42(2):128–132
Schoergenhofer C, Schwameis M, Firbas C, Bartko J, Derhaschnig U, Mader RM, Plaßmann RS, Jilma-Stohlawetz P, Desai K, Misra P et al (2018) Single, very low rituximab doses in healthy volunteers-a pilot and a randomized trial: implications for dosing and biosimilarity testing. Sci Rep 8(1):124
Schuirmann DJ (1987) A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 15(6):657–680
Tsong Y, Dong X, Shen M (2017) Development of statistical methods for analytical similarity assessment. J Biopharm Stat 27(2):197–205
Tsou HH, Chang WJ, Hwang WS, Lai YH (2013) A consistency approach for evaluation of biosimilar products. J Biopharm Stat 23(5):1054–1066
van Rosmalen J, Dejardin D, van Norden Y, Lwenberg B, Lesaffre E (2017) Including historical data in the analysis of clinical trials: is it worth the effort? Statistical methods in medical research. https://www.ncbi.nlm.nih.gov/pubmed/28322129
Webster CJ, Woollett GR (2017) A ‘global reference’ comparator for biosimilar development. BioDrugs 31(4):279–286
Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK (2014) Biosimilars: the science of extrapolation. Blood 124(22):3191–3196
Wellek S (2010) Testing statistical hypotheses of equivalence and noninferiority, 2nd edn. CRC Press, London
Weschler B (2016) Biosimilar trials differ notably from innovator studies. Appl Clin Trials. http://www.appliedclinicaltrialsonline.com/biosimilar-trials-differ-notably-innovator-studies
Acknowledgements
The authors gratefully acknowledge the funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 633567 and from the Swiss State Secretariat for Education, Research and Innovation (SERI) under contract number 999754557. The opinions expressed and arguments employed herein do not necessarily reflect the official views of the Swiss Government.
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Mielke, J., Jones, B. (2020). Biosimilar Drug Development. In: Piantadosi, S., Meinert, C. (eds) Principles and Practice of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-52677-5_272-1
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DOI: https://doi.org/10.1007/978-3-319-52677-5_272-1
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