Advertisement

Biosimilar Drug Development

  • Johanna Mielke
  • Byron JonesEmail author
Living reference work entry
  • 12 Downloads

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.

Keywords

Follow-on biologics Equivalence testing Totality of the evidence Biosimilarity Extrapolation Biologics Comparability Analytics Switchability Historical information 

Notes

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.

References

  1. Arato T (2016) Japanese regulation of biosimilar products: past experience and current challenges. Br J Clin Pharmacol 82(1):30–40CrossRefGoogle Scholar
  2. Barlas S (2017) FDA guidance on biosimilar interchangeability elicits diverse views: current and potential marketers complain about too-high hurdles. Pharm Ther 42(8):509Google Scholar
  3. 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):419–422CrossRefGoogle Scholar
  4. 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 15–82CrossRefGoogle Scholar
  5. Bewesdorff M (2016) Biosimilars in the U.S. – the long way to their first approval. Master of drug regulatory affairs, Rheinischen Friedrich-Wilhelms-Universitat BonnGoogle Scholar
  6. 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 413–438CrossRefGoogle Scholar
  7. 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
  8. Cazap E, Jacobs I, McBride A, Popovian R, Sikora K (2018) Global acceptance of biosimilars: importance of regulatory consistency, education, and trust. Oncologist 23:1188CrossRefGoogle Scholar
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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):31–45MathSciNetCrossRefGoogle Scholar
  15. Christl LA (2018) From our perspective: interchangeable biological products. https://www.fda.gov/Drugs/NewsEvents/ucm536528.htm. Accessed 22 Feb 2018
  16. Christl LA, Woodcock J, Kozlowski S (2017) Biosimilars: the US regulatory framework. Annu Rev Med 68(1):243–254CrossRefGoogle Scholar
  17. 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):2160–2172CrossRefGoogle Scholar
  18. Combest A, Wang S, Healey B, Reitsma DJ (2014) Alternative statistical strategies for biosimilar drug development. GaBI J 3(1):13–20CrossRefGoogle Scholar
  19. 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):11–17Google Scholar
  20. 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
  21. FDA (2009) Biologics price competition and innovation act. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ucm216146.pdf. Accessed 22 Feb 2018
  22. FDA (2015a) Sandoz briefing book for application to market zarxio. https://patentdocs.typepad.com/files/briefing-document.pdf. Accessed 11 Jan 2019
  23. 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
  24. 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
  25. FDA (2017b) Considerations in demonstrating interchangeability with a reference product. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed 22 Feb 2018
  26. 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
  27. 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):729–740CrossRefGoogle Scholar
  28. 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):612–621CrossRefGoogle Scholar
  29. Health Affairs Health Policy Brief (2013) Biosimilars. https://www.healthaffairs.org/do/10.1377/hpb20131010.6409/full/. Accessed 05 June 2018
  30. Holzmann J, Balser S, Windisch J (2016) Totality of the evidence at work: the first U.S. biosimilar. Expert Opin Biol Ther 16(2):137–142CrossRefGoogle Scholar
  31. 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):406–414MathSciNetCrossRefGoogle Scholar
  32. Hsu JC, Hwang JTG, Liu HK, Ruberg SJ (1994) Confidence intervals associated with tests for bioequivalence. Biometrika 81(1):103–114MathSciNetCrossRefGoogle Scholar
  33. 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):1234–1244Google Scholar
  34. ICH (2004) Comparability of biotechnological/biological products subject to changes in their manufacturing process, Q5EGoogle Scholar
  35. 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 10:937–948CrossRefGoogle Scholar
  36. 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
  37. 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):2304–2316CrossRefGoogle Scholar
  38. Li J, Chow SC (2017) Statistical evaluation of the scaled criterion for drug interchangeability. J Biopharm Stat 27(2):282–292CrossRefGoogle Scholar
  39. 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-zCrossRefGoogle Scholar
  40. 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):1444–1457CrossRefGoogle Scholar
  41. 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):1415–1431CrossRefGoogle Scholar
  42. Mielke J, Jones B, Jilma B, König F (2018b) Sample size for multiple hypothesis testing in biosimilar development. Stat Biopharm Res 10(1):39–49CrossRefGoogle Scholar
  43. Mielke J, Schmidli H, Jones B (2018c) Incorporating historical information in biosimilar trials: challenges and a hybrid Bayesian-frequentist approach. Biom J 60(3):564–582MathSciNetCrossRefGoogle Scholar
  44. 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):231–247CrossRefGoogle Scholar
  45. 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 21:7CrossRefGoogle Scholar
  46. 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):e0190147CrossRefGoogle Scholar
  47. 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):979–996MathSciNetCrossRefGoogle Scholar
  48. Schellekens H, Moors E (2015) Biosimilars or semi-similars? Nat Biotechnol 33(1):19–20CrossRefGoogle Scholar
  49. Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R (2011) Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol 29:310–312CrossRefGoogle Scholar
  50. 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):128–132CrossRefGoogle Scholar
  51. 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):124CrossRefGoogle Scholar
  52. 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):657–680CrossRefGoogle Scholar
  53. Tsong Y, Dong X, Shen M (2017) Development of statistical methods for analytical similarity assessment. J Biopharm Stat 27(2):197–205CrossRefGoogle Scholar
  54. Tsou HH, Chang WJ, Hwang WS, Lai YH (2013) A consistency approach for evaluation of biosimilar products. J Biopharm Stat 23(5):1054–1066MathSciNetCrossRefGoogle Scholar
  55. 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
  56. Webster CJ, Woollett GR (2017) A ‘global reference’ comparator for biosimilar development. BioDrugs 31(4):279–286CrossRefGoogle Scholar
  57. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK (2014) Biosimilars: the science of extrapolation. Blood 124(22):3191–3196CrossRefGoogle Scholar
  58. Wellek S (2010) Testing statistical hypotheses of equivalence and noninferiority, 2nd edn. CRC Press, LondonCrossRefGoogle Scholar
  59. Weschler B (2016) Biosimilar trials differ notably from innovator studies. Appl Clin Trials. http://www.appliedclinicaltrialsonline.com/biosimilar-trials-differ-notably-innovator-studies

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Novartis Pharma AGBaselSwitzerland

Section editors and affiliations

  • Babak Choodari-Oskooei
    • 1
  • Mahesh Parmar
    • 2
  1. 1.Statistician, MRC Clinical Trials Unit at UCLInstitute of Clinical Trials and MethodologyLondonUK
  2. 2.MRC Clinical Trials Unit and Institute of Clinical Trials and MethodologyUniversity College of LondonLondonEngland

Personalised recommendations