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Astellas Pharma US, Inc. v. Food and Drug Administration

August 17, 2009


The opinion of the court was delivered by: Ricardo M. Urbina United States District Judge

Re Document No.: 3




This matter is before the court on the plaintiff's motion for a temporary restraining order and preliminary injunction requiring the Food and Drug Administration ("FDA") to withdraw its approval of any generic version of the immunosuppressant tacrolimus. The plaintiff, which pioneered the development of tacrolimus and markets it under the brand name Prograf(r), contends that the FDA acted in an arbitrary and capricious manner in approving a generic version of the drug for distribution in the U.S. market. Because the plaintiff has failed to demonstrate a likelihood of success on the merits, has not demonstrated that it will suffer irreparable harm absent interim injunctive relief and has failed to show that the public interest favors withdrawing the FDA's approval of the generic drug, the court denies the plaintiff's motion.


A. Framework Governing the Approval of New Drugs

The Food, Drug, and Cosmetic Act ("FDCA") provides that before any new drug can be introduced into the U.S. market, the FDA must determine that it is safe and effective. 21 U.S.C. § 355(a). The first, or "pioneer," applicant for a given drug must submit to the FDA a new drug application ("NDA"), containing, among other things, "full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use . . . a full list of the articles used as components of such drug . . . [and] a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drugs." Id. § 355(b). Once approved, the pioneer drug is referred to as a "listed" drug. Id.

Recognizing that the NDA process is costly and time-consuming, Congress amended the FDCA in 1984 pursuant to the "Hatch-Waxman Amendments." Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1316 (D.C. Cir. 1998) (citing H.R. Rep. No. 98-857, pt. 1 at 14 (1984)). In an effort "to make available more low cost drugs," id., the amended FDCA permits the manufacturer of a generic version of a listed drug to obtain FDA approval through a far simpler, abbreviated new drug application ("ANDA") containing a more limited set of information than that required for an NDA. 21 U.S.C. § 355(j). Rather than requiring the applicant to make an independent showing that the proposed generic is itself safe and effective, the amended statute requires a showing that the proposed generic operates in the same manner as the pioneer drug on which it is based -- its reference listed drug ("RLD"). Thus, the FDA's approval of a new generic drug relies on its prior determination that the RLD is safe and effective. See id.

Specifically, the FDCA provides that an ANDA must contain "information to show that the new drug is bioequivalent" to the RLD.*fn1 Id. § 355(j)(2)(A)(iv); 21 C.F.R. § 314.127(a)(6)(i) (stating that the FDA will refuse approval of an ANDA if the information submitted "is insufficient to show that the drug product is bioequivalent to the listed drug referred to in the abbreviated new drug application"). The FDA must approve an ANDA unless the information submitted in the ANDA is insufficient to meet the statutory requirements. 21 U.S.C. § 355(j)(4).

The FDCA further provides that a generic drug is considered to be "bioequivalent" to an RLD if "the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses." Id. § 355(j)(8)(B)(i); see also 21 C.F.R. § 320.1(e). The applicable regulations identify several methodologies for testing bioequivalency, including comparative clinical trials, in vitro studies and "any other approach deemed adequate by FDA to measure bioavailability or establish bioequivalence." 21 C.F.R. § 320.24(b).

B. Approval of Prograf(r) and Generic Tacrolimus

In April 1994, the FDA approved the plaintiff's NDA for the immunosuppressant tacrolimus, which it markets under the brand name Prograf(r). Pl.'s Mot. at 8. Prograf(r) is indicated for the prophylaxis of organ rejection in patients receiving liver, kidney and heart transplants. Id. Typically, the drug is administered orally. Id. The plaintiff states that in fiscal year 2008, sales of Prograf(r) constituted roughly half of the plaintiff's total U.S. revenues of $884 million. Id. at 9, 26.

The plaintiff notes that tacrolimus is characterized as a narrow therapeutic index ("NTI") drug, meaning that it is the type of drug for which "small changes in concentration in the body can lead to significant difference in pharmacodynamic and clinical response." Id. at 3. The plaintiff also asserts that tacrolimus is a "critical dose" drug, meaning that "small changes in concentration in the body can lead to acute rejection, toxicities, or even death of the patient." Id. As a result, "careful therapeutic monitoring of blood levels and clinical monitoring of each patient is necessary." Id.

In 2006, the FDA published draft guidelines for establishing the bioequivalency of generic tacrolimus. Id., Ex. L (Letter from Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research, Department of Health & Human Services) ("Woodcock Letter") at 3-4. The FDA recommended the following studies to establish bioequivalency: (1) a single-dose, two-treatment in vivo study of individuals in a fasting state and (2) a single-dose, two-treatment in vivo study of individuals in a fed state. Id.

The plaintiff states that over the past decade, the FDA has acknowledged the limitations of its existing bioequivalency guidelines for NTI drugs like tacrolimus. Id. at 6. The plaintiff asserts that on multiple occasions, the FDA has considered amending its bioequivalency guidelines for NTI drugs but, inexplicably, has never implemented those changes. Id. at 6-7.

In September 2007, the plaintiff submitted a "Citizen Petition" to the FDA. Id. at 10. In the petition, the plaintiff requested that the FDA (1) require that bioequivalence studies be performed in transplant populations (rather than solely in healthy populations) for orally administered NTI immunosuppressants like tacrolimus and (2) revise labeling requirements for all orally administered NTI immunosuppressants to add warnings notifying physicians about the substitution of the generic for the name brand. Id. In support of its petition, the plaintiff offered a letter authored by Dr. David C. Cronin, a transplant surgeon and pharmacist, stating that due to the significant intrapatient variability in the pharmacokinetics of tacrolimus, the FDA's existing bioequivalency standards would not sufficiently predict the effects of the generic when administered to individual patients. Id. at 11. Cronin also supported the plaintiff's petition for revising the label requirement, asserting that where tacrolimus formulations have been switched, physicians must be particularly vigilant in monitoring their patients to avoid serious adverse effects. Id. at 12. The plaintiff also submitted a white paper from the National Kidney Foundation and a meeting report from the American Society of Transplantation, both of which expressed concerns about the general application of the FDA's current bioequivalence standards to special populations such as transplant recipients. Id. at 13.

On August 10, 2009, the FDA denied the plaintiff's Citizen Petition in all relevant respects. Id. at 13; Woodcock Letter at 6-15. The FDA concluded that additional bioequivalence studies ...

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