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Keywords:

  • biomarkers;
  • EMA;
  • FDA;
  • Hatch-Waxman;
  • inhalers;
  • pharmacokinetics

The effectiveness and safety of generic drugs are backed by sound physicochemical control and regulatory bioequivalence acceptance criteria. Statistical testing of bioequivalence, comparing the pharmacokinetic profiles of the test and reference products, was made possible by modern drug assays. When the pharmacokinetic profile correlates with the dose, such comparisons show assay sensitivity and readily detect differences in dose. For large biological molecules, different manufactured batches cannot be validated using pharmacokinetic data alone. For these biosimilars, there is a three-stage assessment of pharmaceutical quality, laboratory testing and clinical data. This approach has also been applied to certain chemical products, termed ‘chemisimilars’, which have variable or complex synthesis of the active substance, or complex formulation, or a complex delivery device. Although there may be no detectable difference between the test and reference on clinical testing, many of the outcome measures are insensitive to even large differences in dose. For testing to be fit for purpose it should distinguish important dose differences, but many clinical tests of chemisimilars and biosimilars do not. As pharmacokinetic and pharmacodynamic technology advances, the trend of replacing dose-insensitive clinical trial data with equivalence tests that show assay sensitivity can be expected to continue.