Earlier this month, FDA denied a Citizen Petition filed by Watson Laboratories Inc. (now part of Actavis, Inc. or "Actavis") on May 10, 2013, requesting that FDA deny any abbreviated new drug applications ("ANDAs") it receives for a generic version of Rapaflo® (silodosin) Capsules unless the applicant demonstrates bioequivalence for both silodosin and its metabolite KMD-3213G. Watson requested that bioequivalence for both the drug and its metabolite be measured using a strict statistical evaluation of the standard pharmacokinetic measures of area under the plasma concentration-time curve ("AUC") and peak drug concentration ("Cmax"). Watson further requested that FDA revise its draft guidance on bioequivalence testing for silodosin capsules to require a demonstration of bioequivalence for both silodosin and KMD-3213G.
On October 8, 2008, FDA approved Watson's new drug application ("NDA") for Rapaflo®, 4 mg and 8 mg, indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia ("BPH"). BPH is a noncancerous enlargement of the prostate that makes urination difficult and uncomfortable. Sandoz Inc. ("Sandoz") recently filed an ANDA for generic Rapaflo®.
Silodosin is an alpha-1 adrenergic receptor antagonist and undergoes extensive metabolism. Its main metabolite is a glucuronide conjugate, KMD-3213G, which has been shown in vitro to be active. KMD-3213G has an extended half-life (approximately 24 hours) and reaches plasma exposure approximately four times greater than that of silodosin.
An ANDA applicant must demonstrate its proposed generic is bioequivalent to the listed drug it references. On April 8, 2013, FDA issued draft bioequivalence guidance for silodosin capsules. The draft guidance recommends that ANDA applicants conduct two single-dose, two-way crossover in vivo studies with the 4 mg strength in normal, healthy males--one under fasting conditions and the other under fed conditions. According to the draft guidance, applicants should show bioequivalence to silodosin based on a 90% confidence interval for AUC and Cmax. Applicants were also advised to submit AUC and Cmax measurements for KMD-3213 as supportive evidence of comparable therapeutic outcome.
Watson provided three reasons for its request that FDA require a showing of bioequivalence for KDM-3213G. First, Watson reasoned that bioequivalence for the active metabolite was necessary because it contributed meaningfully to the overall therapeutic benefit, safety, and effectiveness of silodosin, citing FDA guidance published in March 2003 entitled, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products--General Considerations ("BA/BE Guidance").
FDA disagreed. As stated in the BA/BE Guidance, FDA generally recommended that the parent drug be measured for bioequivalence. The BA/BE Guidance also stated that when a metabolite is formed as a result of presystemic metabolism and contributed meaningfully to safety and/or efficacy, metabolite data can be used to provide supportive evidence of comparable therapeutic outcome. While FDA agreed that KMD-3213G formed as a result of presystemic metabolism and contributed meaningfully to the efficacy of silodosin, no analysis of the metabolite data for bioequivalence was required according to the BA/BE Guidance. According to FDA, no metabolite bioequivalence is required because the parent drug can be reliably measured and the concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite.
Watson asserted that bioequivalence for the active metabolite was necessary, because the metabolite functions as the major active ingredient once in systemic circulation during the latter half of the concentration-time profile. FDA disagreed, because there was insufficient evidence to support this assertion. FDA continued by stating that even if evidence demonstrated this assertion, FDA would not require a showing of bioequivalence for the metabolite. FDA reasoned that the pharmacologic activity of KMD-3213G during the latter half of the dosing period did not have a significant impact on safety or efficacy, since most of the absorption and pharmacologic activity of silodosin and KMD-3213G occurred in the first half of the dosing period and bioequivalence is generally based on the parent drug.
Finally, Watson asserted that bioequivalence for KMD-3213G was necessary to ensure that patients were not over- or under-dosed with the metabolite for safety reasons. FDA disagreed, because Watson did not demonstrate a safety concern. FDA also asserted that they will analyze the data presented by ANDA filers related to KMD-3213G to determine whether the data support a finding of bioequivalence.
Actavis sued Sandoz in Delaware federal district court in June 2013 for filing an ANDA to market 4 mg and 8 mg silodosin tablets before the expiration of the patent for Rapaflo®, U.S. Patent No. 5,387,603 issued February 1995.