FDA Proposes to Depart From Conventional Bioequivalence Metrics; Draft Guidance Proposes Partial AUC for Generic RITALIN LA

By Kurt R. Karst –      

In what appears to be the second guidance of its kind, FDA proposed in a draft bioequivalence guidance document issued earlier this week that companies seeking approval to market generic versions of RITALIN LA (methylphenidate HCl) Extended-Release Capsules must, in addition to demonstrating bioequivalence using the traditional metrics of area under the plasma concentration versus time curve (“AUC”) and maximum (i.e., “peak”) drug concentration (“Cmax”), demonstrate bioequivalence using certain partial AUC (“pAUC”) metrics.  FDA’s proposal follows an April 2010 meeting of FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee at which FDA discussed, among other things, the use of pAUC for the evaluation of ANDAs for products with complex pharmacokinetic profiles. 

RITALIN LA, which is approved under NDA No. 021284, is a multiphasic modified-release formulation designed to release a bolus of methylphenidate followed by slower delivery later in the day.  Other multiphasic methylphenidate drug products include METADATE CD (methylphenidate HCl) Extended-Release Capsules (NDA No. 021259) and CONCERTA (methylphenidate HCl) Extended-Release Tablets (NDA No. 021121).  FDA’s proposal for generic RITALIN LA is to require three studies – one study under fed conditions and two studies under fasting conditions (in one of which the contents of the drug are sprinkled over a spoonful of applesauce).  For the fed study, FDA says that “[t]he partial AUCs, AUC0-4 and AUC4-t, have been determined to be the most appropriate parameters for evaluation of the drug bioavailability responsible for the quick onset and sustained maintenance of the clinical response throughout the 24 hr dosing period,” and, along with other bioequivalence measures, “will ensure that the pharmacokinetic profiles and clinical effects of test and reference products are sufficiently similar.”  With respect to both of the fasting studies, FDA says that the pAUCs of AUC0-3 and AUC3-t are most appropriate, and, along with other bioequivalence measures, “will ensure that the pharmacokinetic profiles and clinical effects of test and reference products are sufficiently similar.”  The proposed 3- and 4-hour pAUCs are consistent with FDA’s proposals at the April 2010 advisory committee meeting.

FDA’s proposal to require pAUC measurements for purposes of approving ANDAs for generic versions of RITALIN LA appears to be the second instance in which FDA has issued drug product-specific bioequivalence guidance seeking such information.  In a guidance finalized in October 2011 for generic versions of AMBIEN CR (zolpidem tartrate) Extended Release Tablets (NDA No. 021774), FDA established the pAUCs of AUC0-1.5, AUC1.5-t in the required fasting study.  The finalization of the zolpidem bioequivalence guidance was preceded by an October 2010 response to a June 2007 citizen petition (Docket No. FDA-2007-P-0182).  In its response, FDA agreed that AUC and Cmax are not adequate to demonstrate bioequivalence and discussed what were at that time the proposed pAUCs for generic AMBIEN CR.

Notably absent from FDA’s announcement earlier this week of the availability of new draft bioequivalence guidances, including RITALIN LA, were draft bioequivalence guidances for generic METADATE CD and CONCERTA.  After all, all three of the multiphasic methylphenidate drug products – RITALIN LA, METADATE CD and CONCERTA – were up for discussion at the April 2010 advisory committee meeting.  Their absence, however, may be explained by the existence of long-pending citizen petitions submitted in March 2004 for CONCERTA (Docket No. FDA-2004-P-0151) and in May 2004 for METADATE CD (Docket No. FDA-2004-P-0290).  Both of the citizen petitions request that FDA require certain pAUC measures in connection with ANDA approvals.  FDA may have delayed issuing product-specific guidances for these two drugs until the Agency has wrapped up responses to the citizen petitions and is poised to make ANDA approval decisions.