Response to the case report by Mattar: Generic Imatinib (Imatib, Cipla) in a patient with chronic myeloid leukemia in chronic phase

Abstract

This is in response to the case report published in the January issue of this journal [1]. The published case report suggests that a difference between the clinical efficacies of the 2 Imatinib products could be due to the two products containing different polymorphs, the alpha crystalline and the beta crystalline forms. It is of grave concern that such a case report has been published which has inaccuracies and without ascertaining several facts. There are a number of points we would like to bring to your attention. First of all, a single case report does not provide any grounds for even making a claim about a difference between the efficacies of 2 products. Further, the duration of treatment is inadequate (only 12 weeks) which we believe is not sufficient to reach such a conclusion. Cipla’s Imatinib Mesylate (Imatib) is an alpha polymorphic form, where as the polymorphic form in the marketed innovator product is a Beta form. The US FDA Guidance for Industry ANDAs [2]: Pharmaceutical Solid Polymorphism states ‘‘Polymorphic forms of a drug substance differ in internal solid-state structure, but not in chemical structure. Differences in drug substance polymorphic forms do not render drug substances different active ingredients for the purposes of ANDA approvals within the meaning of the Act and FDA regulation’’. Various drug regulatory bodies consider different forms of an active substance to be the same active substance in case of generic medicinal products. The alpha form of Imatinib was invented by the same drug manufacturer and it has been reported that the only difference between the 2 forms is that the beta form is more stable. No literature states that the beta form is more efficacious than the alpha form. Cipla has conducted detailed pharmaceutical studies on its product and found both the active pharmaceutical ingredient (API) and the formulation to be stable. The terminology ‘‘Mesylate ester of methane sulphonic acid’’ mentioned in the paper is scientifically incorrect, and it should be ‘‘alkyl ester of methane sulphonic acid’’. Cipla has evaluated its own API and finished product for this impurity and a degradation product called D-6 compound (N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine (IMT-2 compound), which is reported by the innovator as a genotoxic impurity with safety limit of not more than (NMT) 20 ppm. Cipla has also confirmed that these impurities are well below the acceptable limits. The word ‘copy’ is incorrect and we believe that Cipla’s Imatib is a generic version of Glivec. It has the same active substance, is the same dosage form, and has the same route of administration and a similar aqueous solubility. The author has erroneously mentioned about the inequivalence of the 2 products. In fact, Cipla has completed a bioequivalence study comparing the two products and found them to be bioequivalent, which is a marker of therapeutic equivalence. We do accept that the results of this study were not available to the author of the original paper at the time of submission. Furthermore, a clinical study has recently been conducted in Egypt to evaluate safety and efficacy of Cipla’s Imatib in patients with newly diagnosed Philadelphia chromosome positive Chronic Myeloid Leukemia in the chronic phase and in patients with resected localized or metastatic primary KIT positive gastrointestinal stromal tumors (GIST). In the study, 60% of all the patients who received 400 mg/day of Imatib for a period of up to 6 months showed a complete response while 40% showed This letter to the editor refers to the case report at doi:10.1007/s12185-009-0431-1.