- Volume 24 Issue 3
When a patent of an innovative (brand-name) small-molecule drug expires, generic copies of the innovative drug may be marketed if their therapeutic equivalence to the innovative drug has been shown. The small-molecule drugs are considered therapeutically equivalent and can be used interchangeably if two drugs are shown to be pharmaceutically equivalent with identical active substance and bioequivalent with comparable pharmacokinetics in a crossover clinical trial. However, the therapeutic equivalence paradigm cannot be applied to biosimilars since the active ingredients of biosimilars are huge molecules with complex and heterogeneous structures, and these molecules are difficult to replicate in every detail. The European Medicine Agency(EMEA) has introduced a regulatory biosimilar pathway which mandates clinical trials to show therapeutic equivalence. In this paper, we discuss statistical considerations in the design and analysis of biosimilar cancer clinical trials.
- Berger, R. L. and Hsu, J. C. (1996). Bioequivalence trials, intersection-union tests and equivalence confidence sets, Statistical Science, 11, 283-319. https://doi.org/10.1214/ss/1032280304
- Brown, L. D., Hwang, J. T. and Munk, A. (1997). An unbiased test for the bioequivalence problem, The annals of Statistics, 25, 2345-2367. https://doi.org/10.1214/aos/1030741076
- Bruno, R., Washington, C. B., Lu, J., Lieberman, G., Banken, L. and Klein, P. (2005). Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer, Cancer Chemother Pharmacol, 56, 361-369. https://doi.org/10.1007/s00280-005-1026-z
- Elashoff, J. D. (2007). nQuery Advisor. Version 7.0 User Guide, Statistical Solutions, Los Angeles.
- EMEA Committee for Medicinal Products for Human Use. (2010). Guideline on the Investigation of Bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1. London.
- Gatzemeier, U., Ciuleanu, T., Dediu, M., Ganea-Motan, E., Lubenau, H. and Del Giglio, A. (2009). XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy, Journal of Thoracic Oncology, 4, 736-740. https://doi.org/10.1097/JTO.0b013e3181a52964
- Hauschke, D., Steinijas, V. and Pigeot, I. (2007). Bioequivalence Studies in Drug Development: Methods and Applications, John Wiley & Sons, New York.
- Lubenau, H., Bias, P., Maly, A., Siegler, K. E. and Mehltretter, K. (2009). Pharmacokinetic and pharmacodynamic profile of new biosimilar filgrastim XM02 equivalent to marketed filgrastim neupogen: Single-blind, randomized, crossover trial, Biodrugs, 23, 43-51. https://doi.org/10.2165/00063030-200923010-00005
- Newcombe, R. G. (1988). Interval estimation for the difference between independent proportions: Comparison of eleven methods, Statistics in Medicine, 17, 873-890.
- Patterson, S. and Jones, B. (2006). Bioequivalence and Statistics in Clinical Pharmacology, Chapman & Hall/CRC, London.
- Schellekens, H. (2004). How similar do 'biosimilars' need to be?, Nature Biotechnology, 22, 1357-1359. https://doi.org/10.1038/nbt1104-1357
- Schuirmann, D. J. (1987). A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailabilty, Journal of Pharmacokinetics and Biophamaceutics, 15, 657-680. https://doi.org/10.1007/BF01068419
- Steinijans, V. W., Sauter, R., Jonkman, J. H., Schulz, H., Stricker, H. and Blume, H. (1989). Bioequivalence studies: Single vs multiple dose, International Journal of Clinical Pharmacology, Therapy and Toxicology, 27, 261-266.
- Waller, C. F., Bronchud, M., Mair, S. and Challand, R. (2010a). Pharmacokinetic profiles of a biosimilar filgrastim and Amgen filgrastim: Results from a randomized, phase I trial, Annals of Hematology, 89, 927-933. https://doi.org/10.1007/s00277-010-0961-x
- Waller, C. F., Bronchud, M., Mair, S. and Challand, R. (2010b). Comparison of the pharmacodynamic profiles of a biosimilar filgrastim and Amgen filgrastim: Results from a randomized, phase I trial, Annals of Hematology, 89, 971-978. https://doi.org/10.1007/s00277-010-0973-6
- Waller, C. F., Semiglazov, V. F., Tjulandin, S., Bentsion, D., Chan, S. and Challand, R. (2010c). A phase III randomized equivalence study of biosimilar filgrastim versus Amgen filgrastim in patients receiving myelosuppressive chemotherapy for breast cancer, Onkologie, 33, 504-511.
- Wellek, S. (2003). Testing Statistical Hypotheses of Equivalence, Chapman & Hall/CRC, London.
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research (2003). Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations. Office of Training and Communications, Division of Communications Management, Drug Information Branch, HFD-210, Rockville MD 20857.
- A calibrated power prior approach to borrow information from historical data with application to biosimilar clinical trials 2016, https://doi.org/10.1111/rssc.12204