| Ortho-Biotech has asked FDA to adopt bioequivalence requirements including clinical trials to govern approval of any ANDA or 505(b)(2) application for a generic form of its Doxil (doxorubicin HCl liposome injection). A 5/6 company citizen petition asks that FDA require that applicants for generic Doxil (1) have pharmacokinetic properties equivalent to Doxil’s; (2) have the same physicochemical properties as Doxil’s; and (3) have comparable effectiveness and safety to Doxil as demonstrated in the clinical and other studies recommended in the petition. Ortho contends that the usual method of determining bioequivalence by pharmacokinetic profiles of two products is not appropriate in the case of liposomal doxorubicin products for a number of reasons. First, it says, there are a number of identifiable physicochemical factors that appear to affect drug release and delivery in the case of liposomal doxorubicin products and as a threshold matter, FDA should require a generic product to be the same as Doxil in these respects. Sameness of physicochemical characteristics is not sufficient to demonstrate the bioequivalence of liposomal doxorubicin products, the petition says, because the available tests for physicochemical sameness of liposomal doxorubicin products generally measure only an average and do not measure distributional differences around the average value. But such differences can affect how a product performs clinically, it says. Since physicochenical sameness is not sufficient to ensure bioequivalence, a generic product manufacturer should be required to show equivalence through clinical study data, Ortho says. “We are not suggesting that the generic product applicant should be required to conduct clinical studies of the quantity and scope required for approval of a full new drug application,” the petition says. “The generic product applicant should, however, be required to submit scientifically sufficient clinical study data demonstrating that ovarian cancer patients treated with the generic product will achieve a clinical benefit similar to the results from treatment with Doxil. The clinical benefit should be assessed based on efficacy and safety endpoints. In addition, the generic product should demonstrate comparability to Doxil on a key safety parameter – risk of myocardial damage. FDA’s approval of Doxil was based in part on a clinical study of resting left ventricular ejection fraction (LVEF). Cardiotoxicity was defined as a decrease of more than 20% from baseline LVEF if LVEF remained in the normal range, or a decrease of more than 10% if the LVEF became abnormal. The same criteria should be applied in the study of the generic product, and the product should not be approved if it demonstrates cardiotoxicity greater than Doxil.” Ortho also says that although pharmacokinetic studies cannot properly serve as the basis for determining whether a generic product and Doxil are bioequivalent, pharmacokinetic studies should still be required since a generic product with a different pharmacokinetic profile is likely to have different clinical effects. The need for equivalent systemic levels is important in the case of generic versions of Doxil, which circulates systemically, because, as discussed above, doxorubicin has serious known side effects, including cardiotoxicity, it says. |
