Health Law Daily FDA followed law when denying NDA based on false and misleading label
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Monday, May 4, 2020

FDA followed law when denying NDA based on false and misleading label

By Jeffrey H. Brochin, J.D.

The FDA did not act contrary to the law when denying a pharmaceutical company’s NDA based solely on its finding that the proposed labeling was false or misleading.

A federal appeals court in the District of Columbia has denied a petition for administrative review of an FDA denial of an NDA for a new opioid drug. The Petitioner, Pharmaceutical Manufacturing Research Services (PMRS) sought approval to market a prescription opioid drug that it claimed would be less prone to abuse by patients. However, the FDA acted consistent with the law in finding that the NDA’s accompanying draft label was false and misleading because there was no evidence that the drug in fact possessed abuse deterrent properties. The agency also acted within its discretion in denying PMRS a hearing after determining that there was no genuine and substantial issue of fact surrounding the label content (Pharmaceutical Manufacturing and Research Services, Inc. v. FDA, May 1, 2020, Rao, N.).

FDA evidentiary standards. A manufacturer seeking FDA approval to market a prescription opioid with a label describing the drug as "abuse deterrent" must establish, among other things, substantial evidence that the drug will have the effect it purports to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling. Furthermore, the proposed label may not be false or misleading. "Substantial evidence" is defined in the FDC Act as "adequate and well-controlled investigations, including clinical investigations, by experts on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have in the proposed labeling."

Applicant’s proposed label. PMRS is a privately owned pharmaceutical company that produces a range of oral solid and liquid drugs, and, in January 2017, submitted an NDA seeking FDA approval for an immediate-release formulation of oxycodone that PMRS claimed would have abuse-deterrent properties. In its application, PMRS proposed to include "ADF," short for "Abuse Deterrent Formulation," in the product name, and to include various statements in the label describing the drug’s abuse deterrent chemical and physical properties. However, its proposed labelling also stated: "There is no clinical evidence that TRADENAME has a reduced abuse liability compared to immediate-release oxycodone." And, "Abuse of TRADENAME by injection, as well as by the oral and nasal routes, is still possible."

FDA NDA denial. In November 2017, the FDA sent PMRS a response letter explaining that its NDA could not be approved in its current form, and included in the reasons was that the FDA could not conclude based on the evidence that PMRS’s drug possessed the abuse-deterrent properties described in the proposed label. The agency also found that PMRS had failed to submit evidence supporting its hypothesis that the inclusion of dye in the formulation would deter intravenous abuse, and, that studies showed that PMRS’s drug was "easily manipulated" to create a solution suitable for abuse by the intravenous route. The FDA recommended that PMRS address these deficiencies by reformulating its product.

FDA hearing denial. Rather than attempt to remedy these deficiencies and resubmit its NDA, PMRS requested a hearing regarding approval of its application, and it asserted that its proposed label reflected a novel approach to reducing opioid abuse potential by focusing on product indication and recommended dosing more than the hypothetical abuse-deterrent properties of the drug’s formulation. PMRS did not submit additional evidence to support the label’s statements concerning the drug’s physical and chemical properties, and the FDA denied its request for a hearing. PMRS’s suit for administrative review followed.

Conflicting statutory provisions. The court reviewed the text of the FDC Act provisions granting the FDA authority to deny an NDA, and determined that a conflict existed within the statute: The opening provisions indicated that any of the seven grounds for denial specified in subsection (d) was a basis on which the agency must deny an application, but if none of those grounds applied, the application must be approved. However, the sentence following the seven grounds complicated matters because it stated that if the FDA "finds that clauses (1) through (6)do not apply, [the agency] shall issue an order approving the application." That sentence would suggest that subsection (d)(7)—the false or misleading labeling provision—does not furnish a sufficient basis

Congressional scrivener’s error. Although the statute did not explain the internal inconsistency, the FDA argued that the inconsistency in the text reflected a scrivener’s error resulting from a 1984 amendment to the FDC Act that added a seventh ground for denying a new drug application. In the pre-1984 version of the statute, the false or misleading label provision appeared at subsection (d)(6) and was followed by the same reference to "clauses (1) through (6)" that appears in the current version. Accordingly, under the prior iteration of Section 355(d), a false or misleading label was a sufficient ground for denying an application. Congress amended the statute by inserting a new ground for denial at subsection (d)(6) and moving the false or misleading labeling clause to (d)(7)—but it left unchanged the reference to "clauses (1) through (6)" in the sentence that followed.

The court agreed with the FDA, finding that the only plausible reading of the statute was that a false or misleading label is a sufficient ground for denial. Accordingly, the court ruled that the FDA acted consistent with the law, as now interpreted, in denying the NDA based on a false or misleading label.

The case is No. 18-1335.

Attorneys: Elizabeth Petrela Papez (Gibson, Dunn & Crutcher LLP) for Pharmaceutical Manufacturing Research Services, Inc. Sarah Carroll, U.S. Department of Justice, for Food & Drug Administration.

Companies: Pharmaceutical Manufacturing Research Services, Inc.; Food & Drug Administration

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