Tyrosine kinase inhibitors becoming generic drugs – risks and chances from a regulatory perspective

摘要

Author byline as per print journal:?Niels Eckstein, PhD;?Lea R?per, BSc;?Bodo Haas, PhD;?Henrike Potthast, PhD;?Ulrike Hermes, PhD;?Christoph Unkrig, MD;?Frauke Naumann-Winter, PhD;?Harald Enzmann, MDAim: To provide a systematic overview on: i) safety profiles; ii) pharmacokinetic parameters; and iii) regulatory framework of anti-cancer tyrosine kinase inhibitors (TKI).Methodology: Recherché of pharmakokinetic (PK)-parameter: i) Germany’s federal drug database (public domain part) was accessed in November 2013. Section 5.2 (PK) of Summary of Product Characteristics systematically was searched for available PK-parameters, and ii) A search in PubMed/Medline was performed also in November 2013 using the international non-proprietary name of the respective medicinal product combined with the term ‘early phase’ or ‘dose escalation’. PubMed recherché was restricted by searching only in clinical trials.Safety profile assessment: On 11 November 2013, Summary of Product Characteristics of currently marketed medicinal products was accessed. Side effects were categorized as mentioned in the table’s legend by frequency for each preferred term of the systems organ class system. Source: Summary of Product Characteristics published on the Heads of Medicines Agencies homepage: http://mri.medagencies.org/HumanResults: PK-parameters and safety profiles are presented in the respective tables. Throughout the text, clinical meaning, orphan drug status and current discussion on narrow therapeutic index (NTID)-status by European committees and working parties is discussed.Conclusion: Tyrosine kinase inhibitors are a valuable addition of the therapeutic armamentarium. Especially in certain haematologic diseases, i.e. chronic myeloid leukaemia (CML)-therapy, TKI have revolutionized pharmacotherapy with survival rates not significantly different from healthy matched population. However, as their safety profile differs substantially from conventional cytostatic drugs, new side effects impact on patient’s quality of life. About ten years after first substances were authorized, patent protection will end within the next years. Thus, product specific guidance is needed to accurately perform bioequivalence studies and file marketing authorization applications for registration of TKI-generics.Submitted: 7 February 2014; Revised: 13 March 2014; Accepted: 13 March 2014; Published online first: 26 March 2014IntroductionInitially, great expectations were associated with these drugs; some were met, others not. Tyrosine kinase inhibitors (TKIs) are a very worthy additional option for physicians in clinical management of certain types and lines of treatment of cancer, see Table 1 for a tabular overview. In haemato-oncology, they are contributing to the tendency of chronificating rather than curing the disease. In contrast, the expectation of a new era of cancer-therapy without or at least substantially less side effects were not fulfilled, TKI have numerous, partly severe side effects eventually entailed with fatal outcome, see Table 2. On the other hand, after evolving of resistance to conventional (cytotoxic) or targeted anti-cancer therapy, TKI serve as additional therapy options in second, third and/or fourth-line therapy regimes according to their approved indications. For instance, Sunitinib is approved after Imatinib resistance formation in gastrointestinal stromal tumours (GIST), and Lapatinib after non-responding to antracycline- or taxane-based chemotherapy in combination with Trastuzumab in HER-2 positive breast cancer. Taken together, TKI are a valuable extension of the cancer drug armamentarium [1, 2].Challenges of generic TKI drugs in cancer therapyAccording to their European birth date during the past decade, these substances successively will be running off-patent within the next years, see Table 1. From a regulatory point of view, this raises the question how marketing authorization applications (MAA) should be filed and especially, how therapeutic