Astellas Sues FDA After the Agency Substantially Denies PROGRAF Citizen Petition and Approves Generic

August 12, 2009

By Kurt R. Karst –   

Earlier this week, Astellas Pharma US, Inc. (“Astellas”) filed a Complaint and an accompanying Memorandum of Points and Authorities in the U.S. District Court for the District of Columbia requesting declaratory and injunctive relief in connection with FDA’s response to a citizen petition and approval of an ANDA for a generic version of Astellas’ PROGRAF (tacrolimus).  Astellas had previously announced in a company press release that it planned to sue FDA over the petition decision.

FDA’s August 10, 2009 decision substantially denied a September 21, 2007 citizen petition submitted by Astellas requesting that the Agency take certain actions related to orally administered immunosuppressants used in the transplant population – and in particular, PROGRAF.  Specifically, the Astellas petition requested that FDA, with respect to orally administered immunosuppressants “characterized by a narrow therapeutic index”:

(1) Require bioequivalence studies in healthy subjects be supplemented by studies performed in the transplant patient population.  (FDA’s draft guidance document for bioequivalence testing of tacrolimus recommends that bioequivalence be demonstrated in two single-dose studies in healthy volunteers.);

(2) Require additional warnings and precautions in drug product labeling that physicians must be notified whenever a substituted oral formulation is about to be provided to a transplant patient;

(3) Add to the Orange Book Preface (§ 1.8 – Description of Special Situations) a discussion of narrow therapeutic index immunosuppressive drugs for use in transplant patients that highlights the “particular risks associated with switching patients among different oral formulations of immunosuppressants, such as tacrolimus;” and

(4) Require manufacturers of substitute oral formulations to “differentiate between strengths by color of capsule and container closure, to provide prominent dosage strength information, and to clearly differentiate between sources so that patients, physicians and pharmacists know when the sourcing has changed” in order to “reduce the potential for medication errors associated with confusion regarding strengths and sourcing of different formulations.”

FDA’s August 10th petition decision substantially denied Astellas’ requests.  FDA ruled that bioequivalence studies in the transplant patient population are not justified, and that with respect to tacrolimus, “there is insufficient scientific evidence to suggest that the use of specific patient population(s) in bioequivalence studies would detect differences in formulation that might have clinical significance and that would not be detected by bioequivalence studies in healthy subjects.”  (Also, concerning Astellas’ claim that tacromilus is characterized by a narrow therapeutic index – i.e., a product with a narrow margin of safety between doses that are therapeutic and doses that are toxic – FDA notes that “[w]hile tacrolimus is a drug product that requires careful dosage titration and monitoring of patient blood levels, FDA has not made a determination whether to characterize tacrolimus as a narrow therapeutic range drug product,” but that the Agency “is confident that it has established suffcient criteria to determine bioequivalence for tacrolimus whether or not the agency subsequently decides to characterize tacrolimus as a narrow therapeutic range drug product.”)

FDA also denied Astellas’ request for labeling changes, stating that they are not needed and that “[t]he current review process for ANDAs is adequate to assure the interchangeability of generic versions of immunosuppressant drugs such as tacrolimus with their branded counterparts.”  In addition, FDA disagreed that the Orange Book Preface should be amended, and that manufacturers should be required to differentiate between product source.  FDA did agree, however, that “it is important to differentiate between strengths for immunosuppressants,” and said that the Agency “will ensure that different strengths of a generic version of these drug products are differentiated by appropriate means (e.g., the use of unique color and/or adequate documentation of dosage strength information in the labeling).” 

Astellas’ complaint challenges FDA’s decisions concerning bioequivalence study requirements, product labeling, and source differentiation, as well as FDA’s decision to approve an ANDA for a generic version of PROGRAF.  The complaint alleges that FDA’s petition denial and and generic approval decision violate the Administrative Procedure Act, the FDC Act, and FDA’s regulations, by “failing to require bioequivalence testing in transplanted patients because meeting the FDA-established bioequivalence standards in studies with only healthy volunteers will not sufficiently predict the pharmacokinetics observedwhen tacrolimus is administered to trransplant patients,” and by “failing to require that the label of Prograf and any approved generic alert physicians and patients to the risks associated with substituting formulations of tacrolimus and to any change in the source of manufacturing.”  The company requests declaratory and injunctive relief requiring FDA to revoke ANDA approval. 


  • On August 12, FDA filed its opposition memorandum, and the court issued an Order denying Astellas' TRO/PI motion.  A memorandum opinion will soon follow.  An Astellas press release issued after the court's order states that the company is evaluating its options.
  • The district court's Memorandum Opinion was issued on August 17th and is available here.

Categories: Hatch-Waxman