title: Scientific factors and current issues in biosimilar studies.
abstract: Biological drugs are much more complicated than chemically synthesized, small-molecule drugs; for instance, their size is much larger, their structure is more complicated, they can be sensitive to environmental conditions such as temperature or pressure, and they may expose patients to immunogen reactions. Consequently, the assessment of biosimilarity calls for greater circumspection than the evaluation of bioequivalence. The present communication discusses scientific factors and some current issues related to biosimilarity and the interchangeability of drug products. The scientific factors include questions involving endpoint selection, the one-size-fits-all criterion, and the need for a more flexible approach, e.g., evaluation of the degree of similarity (i.e., responding to the question of "how similar is similar?"; a review of study designs that are useful for the assessment of biosimilarity and drug interchangeability; and tests for the comparability of critical quality attributes at various stages of the manufacturing process). Current issues include the choice of reference standards and the relevant study designs; criteria for biosimilarity, as well as for interchangeability and for comparability; the determination of the noninferiority margin; and the concepts of the stepwise approach to biosimilarity studies and of their assessment by the totality of the evidence. The calculation of sample sizes is discussed for crossover (including some higher-order schemes) and parallel designs.
authors.affiliation: a Department of Biostatistics and Bioinformatics , School of Medicine, Duke University , Durham , North Carolina , USA.
authors.forename: Shein-Chung
authors.initials: SC
authors.lastname: Chow
authors.forename: Laszlo
authors.initials: L
authors.lastname: Endrenyi
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lachenbruch
authors.forename: France
authors.initials: F
authors.lastname: Mentré
mesh_terms: D059451:Biosimilar Pharmaceuticals / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods*; D017277:Drug Approval; D055808:Drug Discovery / Q000379:methods*; D023381:Endpoint Determination; D006801:Humans; D012015:Reference Standards; D012107:Research Design; D018401:Sample Size
chemical_list: D059451:Biosimilar Pharmaceuticals
keywords: Bioequivalence; Biosimilarity; Biosimilarity index; Moment-based approach; Probability-based approach; Totality of the evidence