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Drug Res (Stuttg) 2016; 66(01): 1-6
DOI: 10.1055/s-0035-1548911
Review
© Georg Thieme Verlag KG Stuttgart · New York

From Bioequivalence to Biosimilarity: The Rise of a Novel Regulatory Framework

V. D. Karalis
1   Laboratory of Biopharmaceutics – Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
› Author Affiliations
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Publication History

received 13 February 2015

accepted 26 March 2015

Publication Date:
20 April 2015 (online)

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Abstract

One of the most crucial issues in pharmacotherapy is to address the query if a patient can be switched from one product to another of the same active substance. For the conventional small-molecule drugs, there is a consensus on the required bioequivalence criteria. However, proving equivalence in the field of biologicals is an issue with no clear harmony. The aim of this review is to highlight the differences between the biologicals and the conventional chemical drugs, as well as, to present the different regulatory requirements for the placement of biosimilars on the market.

Biologicals are substantially larger than chemical compounds, their manufacturing process is very complex, and their protein structure may trigger immune reactions. For this reason, the conventional bioequivalence approach is not adequate, but further emphasis should be placed on the quality of the manufacturing process and the risks of immunogenicity. The assessment procedure of biosimilars should encompass their comparison with the innovator product using all available evidence derived from the development process. The latter includes analytical and animal studies, pharmacokinetic and pharmacodynamic data, as well as, clinical trials focusing on immunogenicity. The US FDA has established a step-wise approach to demonstrate biosimilarity, while the EMA has already issued many guidelines referring either to all biosimilars or to specific products/classes. Overall, a case-by-case assessment procedure is considered by the regulatory authorities. In any case the placement of a biosimilar on the market does not necessarily imply interchangeability with the innovator drug.

Key words

follow on biologics - drug regulation - generics
 

  • References

  • 1 Noaiseh G, Moreland L. Current and future biosimilars: potential practical applications in rheumatology. Biosimilars 2013; 3: 27-33
    PubMedGoogle Scholar
  • 2 Klingel R, Heibges A, Fassbender C. Neurologic diseases of the central nervous system with pathophysiologically relevant autoantibodies – perspectives for immunoadsorption. Atheroscler Suppl 2013; 14: 161-165
    CrossrefPubMedGoogle Scholar
  • 3 Milo R. The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis. Ther Adv Neurol Disord 2014; 7: 7-21
    CrossrefPubMedGoogle Scholar
  • 4 Erickson BE. Untangling Biosimilars. Chem Eng News 2010; 88: 25-27
    PubMedGoogle Scholar
  • 5 Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies: regulatory, clinical and commercial considerations. Drugs 2011; 71: 1527-1536
    CrossrefPubMedGoogle Scholar
  • 6 Berkowitz SA, Engen JR, Mazzeo JR et al. Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars. Nat Rev Drug Discov 2012; 11: 527-540
    CrossrefPubMedGoogle Scholar
  • 7 Mellstedt H. Anti-neoplastic biosimilars – the same rules as for cytotoxic generics cannot be applied. Ann Oncol Suppl 2013; 5: v23-v28
    PubMedGoogle Scholar
  • 8 Dranitsaris G, Dorward K, Hatzimichael E et al. Clinical trial design in biosimilar drug development. Invest New Drugs 2013; 31: 479-487
    CrossrefPubMedGoogle Scholar
  • 9 Roger SD. Biosimilars: current status and future directions. Expert Opin Biol Ther 2010; 10: 1011-1018
    CrossrefPubMedGoogle Scholar
  • 10 Braido F, Holgate S, Canonica GW. From ‘blockbusters’ to ‘biosimilars’: An opportunity for patients, medical specialists and health care providers. Pulm Pharmacol Ther 2012; 25: 483-486
    CrossrefPubMedGoogle Scholar
  • 11 Food and Drug Administration . U.S. Department of Health and Human Services. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products, General Considerations. Rockville, MD: March 2003
    Google Scholar
  • 12 European Medicines Agency . Committee for medicinal products for human use. Guideline on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev.1/Corr** London: January 2010
    Google Scholar
  • 13 Van Peer A. Variability and impact on design of bioequivalence studies. Basic Clin Pharmacol Toxicol 2010; 106: 146-153
    CrossrefPubMedGoogle Scholar
  • 14 Karalis V, Macheras P. Current regulatory approaches of bioequivalence testing. Expert Opin Drug Metab Toxicol 2012; 8: 929-942
    CrossrefPubMedGoogle Scholar
  • 15 Bois FY, Tozer TN, Hauck WW et al. Bioequivalence: Performance of several measures of extent of absorption. Pharm Res 1993; 11: 715-722
    PubMedGoogle Scholar
  • 16 Chen ML, Lesko LJ, Williams RL. Measures of exposure versus measures of rate and extent of absorption. Clin Pharmacokinet 2001; 40: 565-572
    CrossrefPubMedGoogle Scholar
  • 17 Declerck P, Simoens S. A European perspective on the market accessibility of biosimilars. Biosimilars 2012; 2: 33-40
    PubMedGoogle Scholar
  • 18 Lee Ventola C. Biosimilars Part 1: Proposed Regulatory Criteria for FDA Approval. P.T. 2013; 38: 270-274
    PubMedGoogle Scholar
  • 19 Kueppers E. Follow on biologics: how to develop a competitive advantage. Bus Dev Licens J 2010; 12: 17-18
    PubMedGoogle Scholar
  • 20 Farfan-Portet MI, Gerkens S, Lepage-Nefkens I et al. Are biosimilars the next tool to guarantee cost-containment for pharmaceutical expenditures?. Eur J Health Econ 2014; 15: 223-228
    CrossrefPubMedGoogle Scholar
  • 21 Crommelin DJ, Bermejo T, Bissig M et al. Pharmaceutical evaluation of biosimilars: important differences from generic low molecular weight pharmaceuticals. Eur J Hosp Pharm Sci 2005; 11: 11-17
    PubMedGoogle Scholar
  • 22 Schellekens H. Follow-on biologics: challenges of the “next generation”. Nephrol Dial Transplant 2005; 20: 31-36
    PubMedGoogle Scholar
  • 23 Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: Implications for health-system pharmacists. Am J Health Syst Pharm 2013; 15 70: 2004-2017
    CrossrefPubMedGoogle Scholar
  • 24 Sekhon BS, Saluja V. Biosimilars: an overview. Biosimilars 2011; 1: 1-11
    PubMedGoogle Scholar
  • 25 Chow SC, Wang J, Endrenyi L et al. Scientific considerations for assessing biosimilar products. Stat Med 2013; 32: 370-381
    CrossrefPubMedGoogle Scholar
  • 26 Food and Drug Administration . U.S. Department of Health and Human Services. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (draft guidance). Rockville (MD): February 2012
    Google Scholar
  • 27 Food and Drug Administration . U.S. Department of Health and Human Services. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (draft guidance). Rockville (MD): February 2012
    Google Scholar
  • 28 Zelenetz AD, Ahmed I, Braud EL et al. NCCN biosimilars white paper: regulatory, scientific, and patient safety perspectives. J Natl Compr Canc Netw 2011; 9: S1-S22
    PubMedGoogle Scholar
  • 29 Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov 2002; 1: 457-462
    CrossrefPubMedGoogle Scholar
  • 30 Schellekens H. Biosimilar therapeutic agents: issues with bioequivalence and immunogenicity. Eur J Clin Invest 2004; 34: 797-799
    CrossrefPubMedGoogle Scholar
  • 31 Roger SD, Mikhail A. Biosimilars: opportunity or cause for concern?. J Pharm Sci 2007; 10: 405-410
    PubMedGoogle Scholar
  • 32 Perez Ruixo JJ, Ma P, Chow AT. The utility of modeling and simulation approaches to evaluate immunogenicity effect on the therapeutic protein pharmacokinetics. AAPS J 2013; 15: 172-182
    CrossrefPubMedGoogle Scholar
  • 33 European Medicines Agency . Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. London: October 2005
    Google Scholar
  • 34 Weise M, Bielsky MC, De Smet K et al. Biosimilars: what clinicians should know. Blood 2012; 120: 5111-5117
    CrossrefPubMedGoogle Scholar
  • 35 Ebbers HC, Crow SA, Vulto AG et al. Interchangeability, immunogenicity and biosimilars. Nat Biotechnol 2012; 30: 1186-1190
    CrossrefPubMedGoogle Scholar
  • 36 Chow SC, Endrenyi L, Lachenbruch PA et al. Scientific factors for assessing biosimilarity and drug interchangeability of follow-on biologics. Biosimilars 2011; 1: 13-26
    PubMedGoogle Scholar
  • 37 Zhang N, Yang J, Chow SC et al. Impact of variability on the choice of biosimilarity limits in assessing follow-on biologics. Stat Med 2013; 32: 424-433
    CrossrefPubMedGoogle Scholar
  • 38 Endrenyi L, Chang C, Chow SC et al. On the interchangeability of biologic drug products. Stat Med 2013; 32: 434-441
    CrossrefPubMedGoogle Scholar
  • 39 Chow SC, Endrenyi L, Lachenbruch PA. Comments on the FDA draft guidance on biosimilar products. Stat Med 2013; 32: 364-369
    CrossrefPubMedGoogle Scholar
  • 40 Tóthfalusi L, Endrényi L, Chow SC. Statistical and regulatory considerations in assessments of interchangeability of biological drug products. Eur J Health Econ 2014; S1: 5-11
    PubMedGoogle Scholar
  • 41 Chen X, Hickling T, Kraynov E et al. A mathematical model of the effect of immunogenicity on therapeutic protein pharmacokinetics. AAPS J 2013; 15: 1141-1154
    CrossrefPubMedGoogle Scholar
  • 42 Driscoll RO, Zhou L, Moxness M et al. Statistical and bioanalytical considerations for establishing a depletion criterion for specificity testing during immunogenicity assessment of a biotherapeutic. AAPS J 2013; 15: 1160-1167
    CrossrefPubMedGoogle Scholar
  • 43 Boone N, van der Kuy H, Scott M et al. How to select a biosimilar. Eur J Hosp Pharm 2013; 20: 275-286
    CrossrefPubMedGoogle Scholar
  • 44 Gwaza L, Gordon J, Welink J et al. Statistical approaches to indirectly compare bioequivalence between generics: a comparison of methodologies employing artemether/lumefantrine 20/120 mg tablets as prequalified by WHO. Eur J Clin Pharmacol 2012; 68: 1611-1618
    CrossrefPubMedGoogle Scholar
  • 45 Karalis V, Bialer M, Macheras P. Quantitative assessment of the switchability of generic products. Eur J Pharm Sci 2013; 50: 476-483
    CrossrefPubMedGoogle Scholar
  • 46 Karalis V, Macheras P, Bialer M. Generic products of antiepileptic drugs: a perspective on bioequivalence, bioavailability, and formulation switches using Monte Carlo simulations. CNS Drugs 2014; 28: 69-77
    CrossrefPubMedGoogle Scholar
  • 47 García-Arieta A, Gordon J. Bioequivalence requirements in the European Union: critical discussion. AAPS J 2012; 14: 738-748
    CrossrefPubMedGoogle Scholar
  • 48 Crommelin DJ, de Vlieger JS, Weinstein V et al. Different pharmaceutical products need similar terminology. AAPS J 2014; 16: 11-14
    CrossrefPubMedGoogle Scholar
  • 49 Schellekens H, Klinger E, Mühlebach S et al. The therapeutic equivalence of complex drugs. Reg Toxicol Pharmacol 2011; 59: 176-183
    CrossrefPubMedGoogle Scholar
  • 50 BPCI Act Biologics Price Competition and Innovation Act of 2009. Federal Register, 2010; HR 3590-686-702
    PubMed
  • 51 Lee Ventola C. Biosimilars Part 2: Potential Concerns and Challenges for P&T Committees. P.T. 2013; 38: 329-335
    PubMedGoogle Scholar
  • 52 Schellekens H, Stegemann S, Weinstein V et al. How to regulate non-biological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J 2014; 16: 15-21
    CrossrefPubMedGoogle Scholar