FDA Once Again Departs From Conventional Bioequivalence Metrics and Sets Partial AUC Parameters for Generic ADDERALL XR

By Kurt R. Karst –      

Nearly seven years after having received a citizen petition (FDA Docket No. FDA-2005-P-0120) requesting that FDA apply more stringent and unconventional bioequivalence requirements (and twice supplemented – here and here – along the way) before approving generic versions of ADDERALL XR (dextroamphetamine mixed salts of a single-entity amphetamine product) 5mg, 10mg, 15mg, 20mg, 25mg, and 30mg Capsules, FDA finally issued a decision to Shire Pharmaceuticals Group, plc (“Shire”) late last Friday granting in part and denying in part the October 17, 2005 petition.  On the same day, FDA also approved Actavis’ ANDA No. 077302 for generic ADDERALL XR. 

In responding to Shire’s petition, FDA, for only the third time, determined that generic applicants must, in addition to demonstrating bioequivalence using the traditional metrics of area under the plasma concentration versus time curve (“AUC”) – calculated to both the last measured concentration time (“AUC0-t”) and AUC extrapolated to infinity (“AUC0-inf”) – and maximum (i.e., “peak”) drug concentration (“Cmax”), demonstrate bioequivalence using certain partial AUC (“pAUC”) metrics.  As we previously reported, FDA has set out pAUC requirements for generic versions of RITALIN LA (methylphenidate HCl) Extended-Release Capsules and AMBIEN CR (zolpidem tartrate) Extended Release Tablets.  (Still pending are decisions on two 2004 citizen petitions requesting that FDA apply pAUC bioequivalence metrics to generic versions of METADATE CD (methylphenidate HCl) Extended-Release Capsules and CONCERTA (methylphenidate HCl) Extended-Release Tablets.)

FDA approved ADDERALL XR, a dopamine agonist amphedamine, on October 11, 2001 under NDA No. 021303 for the treatment of Attention Deficit Hyperactivity Disorder (“ADHD”) in children ages 6-12 years).  FDA later approved NDA supplements for ADDERALL XR the treatment of adult ADHD (August 11, 2004) and for the treatment of adolescent ADHD (July 21, 2005).  ADDERALL XR contains the neutral sulfate salts of dextroamphetamine (d-amphetamine) and amphetamine with the dextro isomer of amphetamine saccharate and d,levo (l)-amphetamine aspartate monohydrate in two types of drug-containing beads – immediate-release (“IR”) and delayed-release (“DR”) – designed to prolong the release of amphetamine from the drug product.  ADDERALL XR is listed in FDA’s Orange Book with four unexpired patents – U.S. Patent Nos. 6,322,819 (“the ‘819 patent), 6,605,300 (“the ‘300 patent”), RE41,148 (“the ‘148 patent”), and RE42,096 (“the ‘096 patent”) – that are all scheduled to expire on October 21, 2018, but that are each subject to a period of pediatric exclusivity that expires on April 21, 2019. 

Shire’s October 2005 citizen petition made several requests, including that FDA establish certain therapeutic equivalence requirements, such as AUCpR (i.e., area under concentration-time curve truncated at the population median “Tmax”, which is the time to reach peak concentration) in addition to traditional pharmacokinetic parameters, and pAUC measurements for each time point up to 4 hours (AUC0-l, AUC1-2, AUC2-3, and AUC3-4).  A recent petition supplement also requests that FDA apply a pAUC metric of 1.5 hours, or, alternatively, a pAUC metric of 3 hours, and that the pAUC metric be applied in bioequivalence testing under fasting, sprinkled, and fed conditions with appropriate adjustments to the pAUC intervals. 

FDA, in the Agency’s petition response, acknowledged that “it is important to use parial AUC for some specialized dosage forms, because our current acceptance criteria . . . may not be adequate for certain drugs formulated as multiphasic [modified-release] products.”  Moreover, wrote FDA, “because the mixed amphetamine salts [modified-release] dosage form (1) contains IR and DR components; (2) is designed to achieve both rapid onset of activity and sustained activity throughout the day; and (3) does not show unusual accumulation at steady state, the additional metrics may be appropriate to ensure that generic versions are therapeutically equivalent to the reference product.”  FDA was unwilling, however, to accept Shire’s proposed pAUC parameters.  Instead, FDA found:

that using two partial AUCs, AUC0-5h and AUC5h-t, would be sufficiently sensitive to determine the bioequivalence of generic mixed amphetamine [modified-release] formulations.  We would require these two partial AUC metrics, in addition to Cmax, and AUCo-inf, for both d- and l- amphetamines in fasting, fasting sprinkle-in-applesauce, and fed bioequivalence studies of generic mixed amphetamine salts [modified-release] products referencing Adderall XR.

FDA also denied other requests made by Shire in the company’s petition and supplements, including that FDA require generic versions of ADDERALL XR to have identical or superimposable plasma concentration-time profies, that ANDA sponsors perform a deconvolution study, that FDA seek the advice of an advisory committee regarding the pAUC metrics for generic ADDERALL XR, that ANDA sponsors bioequivalence in the pediatric population, and that FDA require ANDA  applicants to conduct clinical effcacy studies if they have not demonstrated an identical plasma concentration-time profile.

Still unclear is how FDA resolved another round of 180-day generic drug marketing exclusivity for generic ADDERALL XR.  180-day exclusivity for generic ADDERALL XR is governed by the pre-Medicare Modernization Act version of the FDC Act where exclusivity is patent-by-patent and product-by-product.  Exclusivity with respect to the ‘819 and the ‘300 patents (for all strengths) was apparently triggered for another ANDA sponsor with the marketing of an authorized generic (see here).  In April 2010, Actavis submitted a citizen petition (Docket No. FDA-2010-P-0188) to FDA requesting the Agency’s determination that Actavis is entitled to 180-day exclusivity with respect to the ‘148 patent.  We understand that the petition was withdrawn.  (The ‘096 patent, which issued on February 1, 2011, first appeared in the February 2011 Orange Book Cumulative Supplement, and presumably triggered a certification from sponsors with pending ANDAs.)