Pharm. Mfg. Research Servs., Inc. v. Food & Drug Admin.

Citation957 F.3d 254
Decision Date01 May 2020
Docket NumberNo. 18-1335,18-1335
Parties PHARMACEUTICAL MANUFACTURING RESEARCH SERVICES, INC., Petitioner v. FOOD & DRUG ADMINISTRATION, et al., Respondents
CourtUnited States Courts of Appeals. United States Court of Appeals (District of Columbia)

Elizabeth P. Papez argued the cause and filed the briefs for petitioner.

Sarah Carroll, Attorney, U.S. Department of Justice, argued the cause for respondents. With her on the brief were Scott R. McIntosh, Attorney, Robert P. Charrow, General Counsel, U.S. Department of Health and Human Services, and AnnaMarie Kempic, Deputy Chief Counsel, Litigation.

Before: Henderson, Wilkins, and Rao, Circuit Judges.

Rao, Circuit Judge:

Before bringing a new drug to the market, a pharmaceutical manufacturer must demonstrate to the Food and Drug Administration that the drug is safe, effective, and works as described. Here, petitioner Pharmaceutical Manufacturing Research Services ("PMRS") sought approval to market a prescription opioid drug that PMRS claims will be less prone to abuse by patients. The FDA denied the application, finding that PMRS's draft label was false and misleading because there was no evidence that the drug in fact possessed abuse deterrent properties. The agency also denied PMRS's request for a hearing regarding approval of its application. PMRS challenges both determinations under the Administrative Procedure Act. We conclude that the FDA's decision to deny the application was reasonable and consistent with law and that its decision to deny PMRS's request for a hearing was not an abuse of discretion. We therefore deny the petition for review.

I.

In recent years, as the prescription opioid crisis gripping the United States has worsened, the pharmaceutical industry has placed increasing emphasis on developing new formulations of opioid medications designed to deter abuse. Such "abuse-deterrent formulations" possess physical or chemical properties that are intended to make it more difficult for patients to take advantage of "the known or expected routes of [opioid] abuse, such as crushing in order to snort or dissolving in order to inject." FDA, Abuse-Deterrent Opioid Analgesics (last updated June 11, 2019), https://go.usa.gov/xyKd7.

As for any new drug, 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 thereof," 21 U.S.C. § 355(d)(5), and that the proposed label is not "false or misleading in any particular," id. § 355(d)(7). "Substantial evidence" is defined in the Food, Drug, and Cosmetic Act ("FDCA") 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 thereof." Id. § 355(d).

With respect to abuse deterrent opioids, the FDA has elaborated on the FDCA's general evidentiary standards for new drugs. In 2015, the agency published a guidance document that purports to "explain[ ] FDA's current thinking" about the types of clinical studies "that should be conducted to demonstrate that a given formulation [of an opioid] has abuse-deterrent properties," "how those studies should be performed and evaluated[,] ... and their implications in product labeling." FDA, Abuse-Deterrent Opioids—Evaluation and Labeling: Guidance for Industry 1 (Apr. 2015) ("2015 Guidance"), https://www.fda.gov/media/84819/download. The 2015 Guidance sets out three categories of "premarket studies" that the FDA states will be "appropriate" "[i]n most cases ... to obtain a full and scientifically rigorous understanding of the impact of a technology or technologies on a product's abuse potential." Id. at 5.

Petitioner PMRS is a privately owned pharmaceutical company that produces a range of oral solid and liquid drugs. In January 2017, PMRS submitted a new drug application ("NDA") seeking FDA approval for an immediate-release formulation of oxycodone that PMRS claimed to 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. The proposed label read in relevant part:

TRADENAME is formulated with inactive ingredients that make the capsule more difficult to manipulate for misuse and abuse. ...
In vitro physical and chemical manipulation studies ... demonstrated that TRADENAME capsules ... have increased resistance to physical and chemical extraction [relative to a previously approved opioid, Roxicodone

].

There is no clinical evidence that TRADENAME has a reduced abuse liability compared to immediate-release oxycodone.

Abuse of TRADENAME by injection, as well as by the oral and nasal routes, is still possible.

J.A. 66–67. The label's claim regarding "inactive ingredients" referred in part to the inclusion of a dye blend that was intended to give a solution prepared from the drug a "dark, opaque," "contaminated" appearance. J.A. 412. PMRS claimed this would "create a visual deterrent to abuse" by intravenous injection

. J.A. 412.

In November 2017, the FDA sent PMRS a complete response letter explaining that its NDA could not be approved in its current form. See 21 C.F.R. § 314.110(a) (describing FDA process for complete response letters). The letter identified numerous deficiencies in the NDA that would bar approval under governing law. Most relevant to this appeal, the FDA stated it could not conclude based on the evidence that PMRS's drug possessed the abuse deterrent properties described in the proposed label. Among other things, the agency found that PMRS had failed to submit evidence supporting its hypothesis that the inclusion of dye in the formulation would deter intravenous abuse. Moreover, studies showed that PMRS's drug was "easily manipulated to create a solution suitable for abuse by the [intravenous] route." J.A. 54. The FDA recommended that PMRS address these deficiencies by reformulating its product with properties expected to deter intravenous and nasal1 abuse and by conducting Category 1, 2, and 3 studies (as defined in the 2015 Guidance) to support the abuse deterrent labeling claims.2

Rather than attempt to remedy these deficiencies and resubmit its NDA, PMRS requested a hearing regarding approval of its application. In a series of submissions to the FDA over the ensuing months, PMRS 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." J.A. 890. In other words, PMRS did not submit additional evidence to support the label's statements concerning the drug's physical and chemical properties. Instead, the company insisted that its product carried less potential for abuse because it would be indicated only for acute, rather than long-term, pain management, and because the label would recommend a maximum daily dosage that was lower than similar opioids already on the market. According to PMRS, the acute pain indication coupled with lower dosing recommendations would make its drug "the safest labeled opioid" on the market. J.A. 575. PMRS also argued that the FDA's approach to abuse deterrence, as laid out in the 2015 Guidance, was "misleading, unscientific, and dangerous," J.A. 575, and that a hearing was needed to address the flaws in the agency's approach.

In June 2018, the FDA sent PMRS a draft order proposing denial of PMRS's application and hearing request. The draft order reiterated the deficiencies identified in the complete response letter and explained that PMRS had failed to identify a genuine factual issue that would justify a hearing. The agency described numerous statutory grounds on which to deny the NDA, including that PMRS's proposed label was false and misleading given the lack of scientific support for the label's statements about abuse deterrence.

Two months after receiving the proposed order, PMRS filed a response in which it suggested modifying the draft label to read, as relevant here:

Oxycodone

HC1 IR ADF capsule is formulated with inactive ingredients intended to make the capsule more difficult

to manipulate for misuse and/or abuse. Postmarketing epidemiology evidence is required to demonstrate meaningful abuse-deterrent properties. Oxycodone

HC1 IR ADF capsules should be prescribed knowing meaningful abuse-deterrent properties have not been proven.

J.A. 893 (emphasis in original).

The FDA issued a final order denying PMRS's request for a hearing and refusing to approve its NDA in October 2018. See 83 Fed. Reg. 54,598 (Oct. 30, 2018) ("Denial Order"). The agency's decision rested exclusively on its finding that PMRS's proposed label was false or misleading under the FDCA. Id. at 54,601 –02 (citing 21 U.S.C. § 355(d)(7) ). As the FDA explained, PMRS failed to provide evidence supporting its claim that the drug "has properties that make it more difficult to manipulate for purposes of abuse and misuse than a conventional formulation." Id. at 54,600. Given the complete "lack of sufficient, reliable evidence supporting PMRS's proposed labeling for abuse-deterrent properties," the FDA found that a hearing was not required because there was no "genuine and substantial issue of fact" as to whether the NDA was approvable in its present form. Id. (capitalization altered). The FDA declined to address additional statutory deficiencies in the NDA because "even if resolved in PMRS's favor, PMRS's NDA would still be refused approval in its present form" due to the false and misleading label. Id. at...

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