Opinion ID: 2780871
Heading Depth: 2
Heading Rank: 1

Heading: FDA's Drug Approval Process

Text: The FDA drug approval process is onerous and lengthy. Mut. Pharm. Co., Inc. v. Bartlett, 133 S.Ct. 2466, 2471 (2013). The FDCA requires that drug manufacturers gain FDA approval prior to marketing or selling a drug in interstate commerce. See 21 U.S.C. § 355(a). To gain FDA approval, a drug manufacturer must submit either a new-drug application (NDA), for a new drug, or a supplemental new-drug application (sNDA), for a new treatment. See 21 C.F.R. § 314.1 et seq. NDAs and sNDAs are subject to the same approval requirements. See id. The NDA or sNDA must include full reports of [all clinical] investigations which have been made to show whether . . . such drug is effective in use. 21 U.S.C. § 355(b)(1)(A). The FDA may only approve the drug if the NDA or sNDA provides substantial evidence that the drug will have the effect it . . . is represented to have. Id. § 355(d)(5). As part of its showing that it has provided such substantial evidence, a manufacturer submits the results of adequate and well-controlled -3- investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved. Id. § 355(d)(7). In its evaluation of an NDA or sNDA, the FDA has discretion to determine that data from one adequate and wellcontrolled clinical investigation, along with other confirmatory evidence, are sufficient to establish effectiveness. Id.; see 21 C.F.R. § 314.105(c) ([The] FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet the statutory standards.) The FDA will not approve a drug if the NDA or sNDA lacks substantial evidence that the drug will have the effect it purports or is represented to have. 21 U.S.C. § 355(d)(5). The drug manufacturer must also submit the labeling proposed to be used for such drug. Id. § 355(b)(1)(F); 21 C.F.R. § 314.50(c)(2)(i). The application must include the proposed label's text with annotations to the information in the [drug application] that support the inclusion of each statement [on the label]. 21 C.F.R. § 314.50(c)(2)(i). In order to approve an NDA or sNDA, the FDA must determine, based on a fair evaluation of all material facts, that the proposed label is not false or misleading in any particular. 21 U.S.C. § 355(d)(7); 21 C.F.R. § 314.125(b)(6). After approval, the manufacturer may distribute -4- the drug without violating federal law as long as it uses the FDAapproved label. See 21 U.S.C. §§ 331(c), 333(a), & 352(a), (c). In an effort to secure FDA approval to sell Lexapro for the treatment of major depressive disorder in adolescents, Forest submitted to the FDA the results of four studies: Celexa Study 94404, Celexa Study 18, Lexapro Study 15, and Lexapro Study 32. Celexa Study 94404 and Lexapro Study 15 showed no efficacy. Celexa Study 18 and Lexapro Study 32 found positive efficacy that was statistically significant, but only barely so. In March 2009, the FDA nevertheless approved the sale of Lexapro to treat major depressive disorder in adolescents based on a finding that substantial evidence supported the efficacy of that use. In making this finding, the FDA extrapolate[d] on the basis of a previously reviewed positive study with [Celexa], along with the positive statistical efficacy results from Lexapro Study 32. As required by the FDCA, in approving the sNDA, the FDA made a specific finding that Lexapro's label was not false or misleading in any particular. 21 U.S.C. § 355(d)(7); 21 C.F.R. § 314.125(b)(6). That approved label included the following: Clinical Studies, Major Depressive Disorder -- Adolescents The efficacy of Lexapro as an acute treatment for major depressive disorder in adolescent patients was established in an 8-week, flexible-dose, placebo-controlled study that compared Lexapro 10-20 mg/day to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive -5- disorder. The primary outcome was change from baseline to endpoint in the Children's Depression Rating Scale -- Revised (CDRS-R). In this study, Lexapro showed statistically significant greater mean improvement compared to placebo on the CDRS-R. The efficacy of Lexapro in the acute treatment of major depressive disorder in adolescents was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram [i.e., Celexa] 20-40 mg/day. In this outpatient study in children and adolescents 7 to 17 years of age who met DSM- IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the adolescent subgroup. Two additional flexible-dose, placebo- controlled MDD studies (one Lexapro study in patients ages 7 to 17 and one citalopram [Celexa] study in adolescents) did not demonstrate efficacy. Although maintenance efficacy in adolescent patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients.