Regulatory filing strategy for generic mesalazine modified release formulations

Abstract

Sir, Mesalazine, also known as mesalamine or 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug used to treat ulcerative colitis and Crohn's disease. The efficacy of mesalazine formulations in ulcerative colitis seem to depend on the pH at which they release the drug. If the drug is released at pH ≥ 7, it is effective in cases involving the terminal ileum and colon. If the affected site is ileal, release at pH ≥ 6 might be more effective. The oral mesalazine formulations use various coatings or protective characteristics that release the drug under specific conditions, targeting the distal gastrointestinal tract. These preparations exhibit different and individual in vitro release characteristics, resulting in different availabilities of the drug at different sites in the gastrointestinal tract, and hence, different pharmacokinetic parameters. Due to the different profiles of these modified release products, it is currently recommended that the available mesalazine formulations should not be used interchangeably, and should be prescribed by their proprietary name.[1–3] The regulatory approval of generic mesalazine formulations has been a knotty issue and the relevance of the comparative pharmacokinetic and clinical endpoint studies has been debated for long. In view of the above, current recommendations for the regulatory filing of the generic oral modified release mesalazine products are discussed herewith. To ensure that any new mesalazine product is pharmaceutically equivalent to an already marketed formulation, based on the available evidence, it would be necessary to establish comparable in vitro dissolution. The US FDA (Food and Drug Administration) states that in vitro dissolution testing should be conducted over a range of pHs, reflective of the expected conditions in the GI (gastrointestinal) tract.[1] The US FDA has recently recommended that if the pharmacokinetic data are analyzed using other metrics in lieu of or in addition to AUC and Cmax , then it is possible to detect significant differences, if any, between the mesalazine release profiles of the test and reference products, at the site of action. Pharmacokinetic profiles, specifically, can be analyzed over defined time intervals using partial AUC or other profile comparison tools (including, but not limited to, mean residence time and a steady state Cmax). Using these tools, the US FDA can analyze systemic mesalazine concentrations, over specified time intervals, to determine whether mesalazine from the test and reference products is absorbed at the same rate and to the same extent at the colon and rectum. In addition to this, if the products have equivalent in vitro dissolution characteristics, the agency can further conclude that drug availability at those sites of action is the same.[4,5] On account of the intended topical and targeted nature of mesalazine, it was argued that new mesalazine products should meet a more stringent set of clinical requirements than merely relying on systemic bioequivalence data. Hence, earlier it was suggested that a comparative clinical trial should be conducted to determine the therapeutic equivalence, in addition to in vitro dissolution and in vivo bioequivalence data.[1,2] However, in a recent development, the US FDA has continued to recommend in vitro dissolution testing, but now recommends comparative pharmacokinetic studies rather than clinical endpoint studies to show the bioequivalence of mesalazine products. The agency has further stated that comparative clinical endpoint studies will be less sensitive, accurate, and reproducible than pharmacokinetic studies.[5] The development of generic mesalazine preparations with non-identical delivery systems can be seen as a special case, as substitution will inevitably not create an identical effect, even though the principal active agent is the same. On account of the intended topical and targeted nature of mesalazine, it was earlier suggested that the new mesalazine products should meet a more stringent set of clinical requirements than merely relying on systemic bioequivalence data. However, in a recent development, the US FDA has recommended in vitro dissolution testing in addition to comparative pharmacokinetic studies, rather than clinical endpoint studies, to show the bioequivalence of these products. The US FDA believes that pharmacokinetic studies will better detect the significant differences, if any, in the drug release patterns of the test and reference formulations of mesalazine at the sites of drug action.