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October 17, 2002


The opinion of the court was delivered by: Henry H. Kennedy, United States District Judge.


Plaintiffs, Association of American Physicians and Surgeons ("AAPS"), Competitive Enterprise Institute ("CEI"), and Consumer Alert, bring this lawsuit to challenge the authority of the United States Food and Drug Administration ("FDA") to promulgate "Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients" ("Pediatric Rule"), 21 C.F.R. § 201, 312, 314, 601, 63 Fed. Reg. 66, 632 (Dec. 2, 1998). Plaintiffs claim that the Pediatric Rule exceeds the FDA's statutory authority and that the Rule's promulgation was arbitrary and capricious. Plaintiffs thus petition this court for relief pursuant to the Administrative Procedure Act ("APA"), 5 U.S.C. § 701 et seq.

Before this court are the parties' cross-motions for summary judgment. Upon consideration of the parties' submissions and the summary-judgment record,*fn1 the court concludes that defendants' motion for summary judgment must be denied and plaintiffs' motion for summary judgment must be granted.


The Federal Food Drug and Cosmetic Act ("FDCA"), 21 U.S.C. § 321 et seq., provides a systematic scheme for the approval of new drugs and new drug formulations intended to be marketed for use in interstate commerce. Under the FDCA, a new drug product cannot be marketed unless the FDA approves the product and determines that it is safe and effective for its intended use. See 21 U.S.C. § 355(a). When the FDA approves a drug, it approves the drug only for the particular use for which it was tested, but after the drug is approved for a particular use, the FDCA does not regulate how the drug may be prescribed. Thus, a drug that has been tested and approved for adult use only can be prescribed by a physician for her pediatric patients.

Because of the expense and difficulty in finding substantial pediatric populations to undergo tests, along with the ethical complications associated with testing new drugs on children, many drugs are tested for safety and effectiveness in adults only. As a result, even though there are many diseases and ailments that are common to both children and adults, physicians with pediatric patients*fn2 often find their treatment options limited. Some physicians, forced "to choose between prescribing drugs without well-founded dosing and safety information or utilizing other, potentially less effective, therapy" respond by prescribing adult-approved drugs to children, but in a smaller dose. See Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, 62 Fed. Reg. 43, 900 (Aug. 15, 1997).

Prescribing adult-approved drugs to children is often referred to as going "off-label." An off-label use is the prescription of a drug by a doctor for a condition not indicated on the label or for a dosing regimen or patient population not specified on the label. Off-label use of pharmaceuticals appears to be "generally accepted" in the medical community. See Washington Legal Found. v. Friedman, 13 F. Supp.2d 51, 56 (D.D.C. 1998) vacated in part on other grounds, 202 F.3d 331 (D.C. Cir. 2000) (observing that "off-label use of FDA-approved drugs by physicians is an established aspect of the modem practice of medicine"); Buckman Co. v. Plaintiffs' Legal Comm., No. 98-1768, 2001 WL 167647, at *5 (U.S. Feb. 21, 2001).

While it is a common practice for physicians to prescribe to children pharmaceuticals only approved for adult use, by doing so, they can expose children to various hazards. Children may be given an ineffective dose or an overdose, and they face an increased risk of side effects. See 62 Fed. Reg. 43, 900, 43, 901. This happens because:

Correct pediatric dosing cannot necessarily be extrapolated from adult dosing information using an equivalence based either on weight . . . or body surface area. . . . Potentially significant differences in pharmacokinetics may alter a drug's effect in pediatric patients. The effects of growth and maturation of various organs, maturation of the immune system, alterations in metabolism throughout infancy and childhood, changes in body proportions, and other developmental changes may result in significant differences in the doses needed by pediatric patients and adults.

62 Fed. Reg. at 43, 901.

In the face of insufficient information about a new medication, pediatricians do not merely prescribe inexact doses, however. Physicians sometimes prescribe for their young patients older, less effective, but well-tested medication — as opposed to newer, more effective, medication that has not been subjected to rigorous study on pediatric populations. This practice keeps children from benefitting from state-of-the-art medication. See 63 Fed. Reg. at 66, 632.

In response to these concerns, in 1994, the FDA issued a regulation requiring manufacturers of marketed drugs to survey existing data and determine whether the data was sufficient to support pediatric use information on the drug's labeling. If so, the FDA required manufacturers to submit a supplemental new drug application seeking the FDA's approval of the labeling change. If the drug had not been sufficiently tested on children, the rule required the manufacturer to include in the product's labeling a statement to read: "Safety and effectiveness in pediatric patients have not been established." 21 C.F.R. § 201.57(f)(9)(vi).

Also in an effort to encourage pediatric testing, in 1997, Congress passed the Food and Drug Administration Modernization Act ("FDAMA"), Pub. L. No. 105-115, 111 Stat. 2296 (1997). This Act established a five-year experimental program to encourage pediatric drug testing. Under this Act, the FDA could request (but never require) manufacturers of new drugs to conduct studies on pediatric patients. Drug manufacturers that agreed to conduct these pediatric tests could receive six months of market exclusivity for their products. See 21 U.S.C. § 355a(a). Similarly, for already-marketed drugs, Congress required the FDA to publish a "list of approved drugs for which additional pediatric information may produce health benefits." § 355a(b). The statute also contained a requirement that the FDA report to Congress on the effectiveness and adequacy of this provision by January 1, 2001.*fn3

Finding that the voluntary incentive provisions of FDAMA did not increase pediatric testing as much as the FDA had hoped, after proper notice-and-comment, the FDA issued the "Pediatric Rule" in 1998.*fn4 See 63 Fed. Reg. at 66, 632; see also id. at 66, 639 (providing it "does not believe . . . that incentives alone will result in pediatric studies of some of the drugs and biologics where the need is greatest."); Letter from Hubbard to Rein, 11/1/2000 at 1 (hereafter "HHS Denial") ("the voluntary nature of the pediatric exclusivity incentive is likely to leave many drugs, age groups, and indications unstudied"); id. at 7 ("data indicate that voluntary efforts had not, by 1997, substantially increased the number of products entering the marketplace with adequate pediatric labeling"). This Rule's legitimacy is challenged here.

The FDA presumes that sponsors will study all new drugs in pediatric patients unless the applicant can show that waiver is appropriate. Waivers are granted if: (1) necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed; or (2) there is evidence strongly suggesting that the product would be ineffective or unsafe in all pediatric age groups.*fn6 21 C.F.R. § 314.55(c)(2), 601.27(c)(2). In addition, an applicant may request a partial waiver of the above testing and development requirements if the applicant certifies that the product: (1) does not represent a meaningful therapeutic benefit for pediatric patients over existing treatments; and (2) is not likely to be used in a substantial number of pediatric patients. §§ 314.55(c)(2), 601.27(c)(2); 63 Fed. Reg. at 66,634. Partial waiver may also be available if a manufacturer can demonstrate that reasonable attempts to produce a pediatric formulation necessary for a particular age group have failed. See 21 C.F.R. § 314.55(c)(3), 601.27(c)(3).

For already-marketed drugs, the Pediatric Rule still applies, but it has a more narrow sweep. For such drugs, the FDA may still require a manufacturer to submit an application containing adequate evidence to support dosage and administration in some or all pediatric subpopulations, and the FDA may also still require an applicant to develop a pediatric drug formulation. 21 C.F.R. § 201.23(a). In this context, however, the burden is on the FDA show that such testing and analysis is required. See id. The FDA satisfies this burden only if the absence of adequate labeling could pose significant risks to pediatric patients; and either (1) the drug is "used in a substantial number of pediatric patients for the labeled indications;" or (2) there is "reason to believe that the drug product would represent a meaningful therapeutic benefit over existing treatments for pediatric patients for one or more of the claimed indications." 21 C.F.R. § 201.23(b).

This Rule's application, for both new and existing drugs, is limited in three other respects as well. First, the Rule does not require a manufacturer to study its product for unapproved or unclaimed indications, even if the product is widely used in pediatric patients for those indications. See 63 Fed Reg. 66, 658; FDA Denial at 7. This means that a drug marketed as a cure for one disease in adults does not need to be tested for its ability to cure an entirely different disease in children. Second, the Pediatric Rule allows drug manufacturers to defer pediatric testing until after the FDA has approved the product for adult use. See 21 C.F.R. § 314.55(b); 63 Fed. Reg. at 66, 634, 66, 642-44.*fn7 Third, the Rule only requires testing of new "innovator" drugs. The Rule does not apply to generic copies of previously-approved drugs or for suitability petitions for a change in dosage strength.*fn8

When the Pediatric Rule does apply, however, it has real teeth to force compliance. If a manufacturer refuses to submit an application containing indications for pediatric use or fails to submit a requested pediatric formulation, the FDA may seek a federal court injunction to declare that the product is "misbranded or an unapproved new drug or unlicensed biologic." § 201.23(d); 63 Fed. Reg. at 66, 636. The FDA may also request that the court impose fines or subject the manufacturer to contempt proceedings. Id. In addition, in rare cases, the FDA may withdraw approval of the drug or biological product. Id.

In 1999, plaintiffs filed a citizen petition with the FDA, challenging the Pediatric Rule's wisdom and legal authority. The FDA denied the petition in 2000, advancing essentially the same defenses it advances here. This suit, brought under the judicial review provisions of the Administrative Procedure Act ("APA"), 5 U.S.C. § 701 et seq., followed.

Since the filing of this lawsuit, Congress has passed, and the President has signed into law, the "Best Pharmaceuticals for Children Act, " Public Law No. 107-109, 115 Stat. 1408 (2002) ("BPCA"). This Act reauthorized and expanded the pediatric testing incentives set forth in FDAMA. The BPCA endorses the goal of increasing the number of drugs studied in pediatric populations but does not authorize FDA to require manufacturers to conduct pediatric testing. Instead, the Act establishes a legislative framework to encourage voluntary testing. Under the Act, a manufacturer receives an additional six months of market exclusivity on a new or marketed drug if: (1) FDA determines that pediatric testing of the drug "may produce health benefits in that population;" (2) FDA makes a written request to the manufacturer to conduct such testing; (3) the manufacturer agrees to test the drug within an appropriate time-frame; (4) the manufacturer conducts the tests and submits reports of these tests to the FDA; and (5) the FDA accepts the testing reports. See 21 U.S.C. § 355a(a), (c).

In addition, when the FDA determines that more information about a particular drug is needed, the BPCA establishes two ways third parties may be paid to generate this information. First, the FDA may "refer the drug to the Foundation for the National Institutes of Health" ("the Foundation"), a non-profit organization, and the FDA may authorize the Foundation to collect funds for pediatric pharmacologic research and drug testing. See 42 U.S.C. § 284m(a). The Foundation may then award a research grant to a third party who will conduct the necessary studies and provide the FDA with its final report and supporting data. § 284m(b)(6)(A). Alternatively, if the Foundation has insufficient funds to pay for the pediatric testing, the BPCA establishes a public fund of $200 million for fiscal year 2002 and "such sums as are necessary for each of the five succeeding fiscal years" that FDA may use to pay a third party to conduct the relevant tests. § 284m(d).

If relevant new information is discovered as a result of this third-party pediatric testing, the BPCA establishes a multi-step process by which the FDA may seek product reformulations and labeling changes. If the third-party's results indicate that a formulation change is necessary and the FDA agrees, FDA will send a "nonbinding" letter of recommendation regarding that formulation change to the drug's manufacturer.*fn9 See § 284m(c)(12). Alternatively, if the FDA determines that a labeling change is necessary, the FDA must first attempt to reach agreement with the manufacturer. See 42 U.S.C. § 284m(c)(7). If the FDA and drug manufacturer are unable to agree on the proposed change, the FDA "shall refer the request" to a Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee ("Subcommittee"), which will make a labeling recommendation within ninety days. The FDA will then review the Subcommittee's recommendation and, if appropriate, request that the manufacturer change its label accordingly. § 284m(c)(9). If ...

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