`
`
`
`PUBLISHED
`
`UNITED STATES COURT OF APPEALS
`FOR THE FOURTH CIRCUIT
`
`
`No. 21-2077
`
`
`AVAIL VAPOR, LLC; BLACKSHIP TECHNOLOGIES DEVELOPMENT, LLC;
`BLACKBRIAR REGULATORY SERVICES, LLC,
`
` Petitioners,
`
`v.
`
`UNITED STATES FOOD AND DRUG ADMINISTRATION,
`
` Respondent.
`
`------------------------------
`
`INC.; AMERICAN VAPOR
`AMERICAN VAPING ASSOCIATION,
`MANUFACTURERS ASSOCIATION, INC.; CONSUMER ADVOCATES FOR
`SMOKE-FREE ALTERNATIVES ASSOCIATION,
`INC.; SMOKE-FREE
`ALTERNATIVES TRADE ASSOCIATION,
`INC.; UNITED VAPERS
`ALLIANCE, INC.; ARIZONA SMOKE FREE BUSINESS ALLIANCE, INC.;
`BREATHE EASY ALLIANCE OF ALABAMA; CONNECTICUT CHAPTER OF
`SMOKE FREE ALTERNATIVES TRADE ASSOCIATION; FLORIDA SMOKE
`FREE ASSOCIATION, INC.; GEORGIA SMOKE FREE ASSOCIATION, INC.;
`HAWAII CHAPTER OF SMOKE FREE ALTERNATIVES TRADE
`ASSOCIATION; KANSAS SMOKE FREE ASSOCIATION; KENTUCKY
`VAPING RETAILERS ASSOCIATION, INC., d/b/a Kentucky Smoke Free
`Association; INDIANA SMOKE FREE ALLIANCE, INC.; IOWANS FOR
`ALTERNATIVES TO SMOKE AND TOBACCO, INC.; IOWA VAPE
`ASSOCIATION,
`INC.; LOUISIANA VAPE ASSOCIATION,
`INC.;
`MARYLAND VAPOR ALLIANCE; MICHIGAN VAPE SHOP OWNERS, INC.;
`MIDWEST VAPE COALITION,
`INC.; MINNESOTA SMOKE FREE
`ALLIANCE; MISSOURI SMOKE FREE, INC.; MONTANA SMOKE FREE
`ASSOCIATION, INC.; NEBRASKA VAPE VENDORS ASSOCIATION, INC.;
`
`

`

`NEVADA VAPING ASSOCIATION, INC.; NEW MEXICO SMOKE FREE
`ALLIANCE, INC.; NEW YORK STATE VAPOR ASSOCIATION, INC.;
`NORTH CAROLINA VAPING COUNCIL, INC.; OHIO VAPOR TRADE
`ASSOCIATION, INC.; ROCKY MOUNTAIN SMOKE FREE ASSOCIATION,
`INC.; RHODE ISLAND CHAPTER OF SMOKE FREE ALTERNATIVES
`TRADE ASSOCIATION; SMOKE FREE ALTERNATIVES COALITION OF
`ILLINOIS, INC.; SOUTH CAROLINA VAPOR ASSOCIATION, INC.; TEXAS
`CHAPTER OF SMOKE FREE ALTERNATIVES TRADE ASSOCIATION;
`TENNESSEE SMOKE FREE ASSOCIATION, INC.; VIRGINIA SMOKE FREE
`ASSOCIATION, INC.; WASHINGTON SMOKE FREE ASSOCIATION, INC.;
`WEST VIRGINIA SMOKE FREE ASSOCIATION, INC.; DR. DAVID B.
`ABRAMS; CLIVE D. BATES; PROFESSOR DAVID T. SWEANOR, J.D.,
`
` Amici Supporting Petitioners,
`
`MEDICAL AND PUBLIC HEALTH GROUPS,
`
` Amici Supporting Respondent.
`
`
`On Petition for Review of an Order of the Food & Drug Administration. (PM0001233)
`
`
`
`
`
`
`Argued: October 25, 2022
`
`Decided: December 12, 2022
`
`
`
`Before WILKINSON and DIAZ, Circuit Judges, and MOTZ, Senior Circuit Judge.
`
`
`Petition denied by published opinion. Judge Wilkinson wrote the opinion, in which Judge
`Diaz and Senior Judge Motz joined.
`
`
`
`
`
`
`ARGUED: Eric Nathan Heyer, THOMPSON HINE LLP, Washington, D.C., for
`Petitioners. Antonia Marie Konkoly, UNITED STATES DEPARTMENT OF JUSTICE,
`Washington, D.C., for Respondent. ON BRIEF: Joseph A. Smith, Jessica Tierney,
`THOMPSON HINE LLP, Washington, D.C., for Petitioners. Brian M. Boynton, Principal
`Deputy Assistant Attorney General, Eric B. Beckenhauer, Assistant Branch Director,
`Cormac A. Early, Federal Programs Branch, UNITED STATES DEPARTMENT OF
`JUSTICE, Washington, D.C.; Daniel J. Barry, Acting General Counsel, UNITED STATES
`DEPARTMENT OF HEALTH AND HUMAN SERVICES, Washington, D.C.; Wendy S.
`Vicente, Acting Deputy Chief Counsel for Litigation, Seth I. Heller, Associate Chief
`Counsel, Office of the Chief Counsel, UNITED STATES FOOD AND DRUG
`
`
`
`2
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`

`

`ADMINISTRATION, Washington, D.C., for Respondent. J. Gregory Troutman,
`TROUTMAN LAW OFFICE, PLLC, Louisville, Kentucky, for Amici 38 National and
`State Electronic Nicotine Delivery System Product Advocacy Associations. Mary G.
`Bielaska, ZANICORN LEGAL PLLC, New York, New York, for Amici Dr. David B.
`Abrams, Clive D. Bates, and Professor David T. Sweanor, J.D. William B. Schultz,
`Andrew N. Goldfarb, ZUCKERMAN SPAEDER LLP, Washington, D.C.; Dennis A.
`Henigan, Connor Fuchs, CAMPAIGN FOR TOBACCO-FREE KIDS, Washington, D.C.,
`for Amici Medical and Public Health Groups.
`
`
`
`
`
`
`
`3
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`

`

`WILKINSON, Circuit Judge:
`
`
`
`The Family Smoking Prevention and Tobacco Control Act requires manufacturers
`
`of new tobacco products to obtain authorization from the United States Food & Drug
`
`Administration (FDA) prior to marketing their products. See Pub. L. 111-31, § 910, 123
`
`Stat. 1776, 1807–12 (2009) (codified at 21 U.S.C. § 387j(a)). In reviewing a
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`manufacturer’s Premarket Tobacco Product Application, FDA must determine that the
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`marketing of the product is “appropriate for the protection of the public health.”
`
`§ 910(c)(4), 123 Stat. at 1810. The agency denied Avail Vapor LLC’s application for its
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`flavored electronic cigarettes, chiefly on the grounds that its products posed a serious risk
`
`to youth without enough offsetting benefits to adults. We now uphold that decision and
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`deny Avail’s petition for review.
`
`I.
`
`A.
`
`
`
`Congress enacted the Tobacco Control Act (TCA) in 2009. It found that “[t]he use
`
`of tobacco products by the Nation’s children” was “a pediatric disease of considerable
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`proportions that result[ed] in new generations of tobacco-dependent children and adults.”
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`§ 2(1), 123 Stat. at 1777. Further, “[v]irtually all new users of tobacco products are under
`
`the minimum legal age to purchase such products,” and “[t]obacco advertising and
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`marketing contribute significantly to the use of nicotine-containing tobacco products by
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`adolescents.” §§ 2(4), 2(5), 123 Stat. at 1777. Congress’s previous attempts to curb
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`adolescent tobacco use had failed, and thus the TCA sought “to address comprehensively
`
`the public health and societal problems caused by the use of tobacco products.” § 2(7), 123
`4
`
`
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`

`

`Stat. at 1777. Congress entrusted the FDA with this important task, finding that it
`
`“possesses the scientific expertise needed to implement effectively all provisions of the
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`[TCA].” § 2(45), 123 Stat. at 1781.
`
`The TCA authorizes the FDA to regulate tobacco products including “cigarettes,
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`cigarette tobacco, roll-your-own tobacco, and smokeless tobacco,” as well as “any other
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`tobacco products that the [FDA] by regulation deems to be subject” to the TCA. § 901(b),
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`123 Stat. at 1786. Relevant here, the TCA requires manufacturers of “new tobacco
`
`products” to submit Premarket Tobacco Product Applications (PMTAs) and receive
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`authorization from the FDA prior to releasing their products on the market. See
`
`§ 910(a)(2)(A), 123 Stat. at 1807. A “new tobacco product” is any tobacco product that
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`was not “commercially marketed in the United States as of February 15, 2007.”
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`§ 910(a)(1)(A), 123 Stat. at 1807.
`
`The FDA must deny a PMTA if it finds that “there is a lack of showing that
`
`permitting such tobacco product to be marketed would be appropriate for the protection of
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`the public health.” § 910(c)(2)(A), 123 Stat. at 1809. Whether a product is “appropriate for
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`the protection of the public health” is “determined with respect to the risks and benefits to
`
`the population as a whole, including users and nonusers of the tobacco product.”
`
`§ 910(c)(4), 123 Stat. at 1810. As part of this inquiry, the TCA explicitly requires the FDA
`
`to consider “the increased or decreased likelihood that existing users of tobacco products
`
`will stop using such products” and “the increased or decreased likelihood that those who
`
`do not use tobacco products will start using such products.” § 910(c)(4)(A)–(B), 123 Stat.
`
`
`
`5
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`

`

`at 1810. Thus, the FDA is required to weigh the benefits of “cessation” associated with a
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`new tobacco product against the risks of “initiation.”
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`Finally, the TCA states that “whether permitting a tobacco product to be marketed
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`would be appropriate for the protection of the public health shall, when appropriate, be
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`determined on the basis of well-controlled investigations.” § 910(c)(5)(A), 123 Stat. at
`
`1810. However, if FDA “determines that there exists valid scientific evidence” other than
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`well-controlled investigations “which is sufficient to evaluate the tobacco product,” FDA
`
`may issue a marketing order based on that evidence. § 910(c)(5)(B), 123 Stat. at 1810.
`
`B.
`
`
`
`The petition before us involves the public health debate surrounding the novel use
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`of an ancient product. Electronic nicotine delivery systems (ENDS), also known as e-
`
`cigarettes, were introduced widely in the United States since Congress passed the TCA. In
`
`contrast to traditional cigarettes, ENDS heat a liquid that includes nicotine, chemicals, and
`
`flavors until it generates an aerosol or vapor, which can then be inhaled by the user. See
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`Nicopure Labs, LLC v. FDA, 944 F.3d 267, 270 (D.C. Cir. 2019). These products have the
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`potential to benefit adult smokers if used as a complete substitute for combustible tobacco
`
`smoking, i.e., if adult smokers “switch” to ENDS products, as they are less likely to cause
`
`disease and death. See U.S. Dep’t of Health and Hum. Servs., E-Cigarette Use Among
`
`Youth and Young Adults: A Report of the Surgeon General 186 (2016). These products still
`
`contain nicotine, however, which is an addictive substance known to harm the developing
`
`brain. Id. at 100–07.
`
`
`
`6
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`

`

`Two of the most common ENDS systems have “pods” or “cartridges” that hold
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`nicotine-containing liquid known as “e-liquid.” “Closed systems,” or cartridge-based
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`systems, use pods or cartridges that are sold pre-filled with e-liquid. Those cartridges are
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`discarded and replaced after the e-liquid within them runs out. “Open systems” have
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`cartridges that can be refilled with e-liquid by the user. Thus, the open system user mostly
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`buys e-liquid bottles to refill his product.
`
`
`
`Although the TCA banned the sale of cigarettes with a characterizing flavor (e.g.,
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`fruit), see § 907(a)(1)(A), 123 Stat. at 1799, this ban did not apply to ENDS products.
`
`Therefore, ENDS products not only came in traditional flavors reminiscent of a
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`combustible cigarette, like tobacco and menthol, but also had other flavors derived from
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`fruit, candy, dessert, and other sweets. This distinction between “tobacco-flavored” and
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`other “flavored” products is important for this petition, as the FDA has found that other
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`flavored ENDS products appeal to youth more than traditional tobacco-flavored ENDS
`
`products. See J.A. 27. This is commonsensical: young people have an age-old proclivity
`
`toward sweets.
`
`
`
`Sales of e-cigarettes in the United States rose rapidly from 2007 onward. See Report
`
`of the Surgeon General, supra, at 10. After 2010, there was a marked increase in e-cigarette
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`use by both adults and youth. In 2011, an estimated 1.5% of high school students were e-
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`cigarette users. Id. By 2015, 16% of high school students used ENDS, surpassing the rate
`
`of combustible cigarette use. Id. These trends led to substantial concern among public
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`health communities. Id. Unlike combustible cigarettes, however, ENDS products had
`
`
`
`7
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`

`

`limited regulatory oversight, as the TCA did not give the FDA immediate jurisdiction over
`
`these products. Id. at 15.
`
`To close this gap, FDA asserted regulatory jurisdiction over ENDS products in May
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`2016 in accordance with its authority to “deem” new products subject to the strictures of
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`the TCA. See 21 U.S.C. § 387a(b); 81 Fed. Reg. 28,974 (May 10, 2016) (“Deeming Rule”).
`
`It noted that the Deeming Rule was necessary in substantial part due to “the continued
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`dramatic rise in youth and young adult use of tobacco products such as e-cigarettes.” Id. at
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`29,894. However, the FDA also recognized that this new rule meant that most ENDS
`
`products were already on the market without manufacturers having submitted a PMTA, a
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`violation of the TCA. Thus, the FDA decided not to act on a product’s lack of premarket
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`authorization for two to three years while manufacturers prepared, and FDA reviewed,
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`marketing applications. Id. at 28,977–78. After the Deeming Rule, FDA made a series of
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`public announcements relevant to the matter at hand, which we examine below.
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`In the summer of 2017, FDA announced that it did not intend to initiate enforcement
`
`regarding PMTAs for newly regulated ENDS products for five years, i.e., until 2022. J.A.
`
`94. The extension reflected nationally representative data that suggested youth use of e-
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`cigarettes had declined beginning in 2016. Id. The decline, however, did not last long.
`
`Whereas the downward trend in youth e-cigarette use in 2016 moved FDA toward more
`
`lenient regulation of the ENDS industry, new information caused the FDA to change
`
`course. By late 2017, FDA started to see an explosion in complaints about ENDS products,
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`and new data indicated an alarming increase in the use of ENDS products by middle and
`
`high school students. J.A. 94–95. Between 2017 and 2018, studies showed that e-cigarette
`8
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`

`

`use had increased by 78% in high school students and 48% in middle school students. J.A.
`
`97. Considering this new data, FDA’s then-Commissioner characterized the situation as a
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`“youth vaping epidemic” in 2018. J.A. 75. The FDA began to use its enforcement
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`discretion, issuing over 6,000 warning letters to manufacturers and more than 1,000 civil
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`monetary complaints to retailers for the marketing and sale of ENDS products to minors.
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`J.A. 97.
`
`C.
`
`While FDA was reckoning with the new and evolving information on youth ENDS
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`use, it also issued guidance on PMTAs for ENDS manufacturers. FDA, Premarket Tobacco
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`Product Applications for Electronic Nicotine Delivery Systems, Guidance for Industry
`
`(June 12, 2019) (“2019 Final PMTA Guidance”); see J.A. 220–74. The final compliance
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`date was simultaneously moved up from 2022 to September 9, 2020, in response to a suit
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`initiated by a group of pediatric physicians. See Am. Acad. of Pediatrics v. Food & Drug
`
`Admin., 379 F. Supp. 3d 461(D. Md. 2019); J.A. 94–95. FDA stated that in reviewing
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`PMTAs, it “weighs all of the potential benefits and risks from the information contained in
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`[a] PMTA to make an overall determination of whether the product should be authorized
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`for marketing.” J.A. 234. Further, the FDA stated that while “[n]onclinical studies alone
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`are generally not sufficient to support a determination that permitting the marketing of a
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`tobacco product would be appropriate for the protection of the public health,” there are
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`some cases where it “may be possible to support a marketing order for an ENDS product
`
`without conducting new nonclinical or clinical studies,” such as when there was “an
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`established body of evidence regarding the health impact . . . of [a manufacturer’s] product
`9
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`or a similar product that can be adequately bridged to [the manufacturer’s] product.” J.A.
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`234, 268.
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`Rapidly accumulating evidence about the danger of ENDS products to youth again
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`shifted FDA’s priorities. After the agency issued the 2019 Final PMTA Guidance, two
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`national surveys measuring tobacco habits among youth found that e-cigarette use hit the
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`highest levels ever recorded, underscoring the magnitude of the problem. J.A. 97. In
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`response, in April 2020, FDA issued a final enforcement guidance with the changing
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`landscape in mind. FDA, Enforcement Priorities for Electronic Nicotine Delivery System
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`(ENDS) and Other Deemed Products on the Market Without Premarket Authorization,
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`Guidance for Industry (Apr. 29, 2020) (“2020 Enforcement Guidance”); see J.A. 89–140.
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`In a departure from its previous policy of deferring enforcement until manufacturers
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`submitted PMTAs, FDA decided to immediately exercise its enforcement authorities with
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`respect to certain products that attracted youth. J.A. 98. At the head of its list were flavored
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`cartridge-based ENDS products, as evidence showed that youth were particularly attracted
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`to these devices. J.A. 108. FDA also intended to prioritize enforcement against all other
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`ENDS products either marketed to youth or for which the manufacturer had failed to take
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`adequate steps to prevent youth access. J.A. 107.
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`Notwithstanding these specific priorities, FDA made clear that it would “make
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`enforcement decisions on a case-by-case basis” and that it “is continuously evaluating new
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`information and adjusting its enforcement priorities in light of the best available data[.]”
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`J.A. 92, 100. Importantly, FDA found that “evidence continues to accumulate, further
`
`confirming that youth are particularly attracted to flavored ENDS products.” J.A. 103. New
`10
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`

`

`studies showed that flavors drove both initiation and continued regular use by youth. Id.
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`Further, FDA noted that its previous attempts at restricting youth access to ENDS products
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`had fallen flat, finding that “youth have continued access to these products in the face of
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`legal prohibitions and even after voluntary actions by some manufacturers.” J.A. 110. As
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`for marketing access restrictions, FDA told manufacturers that it “believes that age
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`verification alone is not sufficient to address this issue, given the most recent data that
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`youth use of ENDS products continues to increase.” J.A. 133.
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`
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`After FDA implemented its 2020 Enforcement Guidance, the percentage of youth
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`using e-cigarettes decreased. J.A. 29. But despite this decline, ENDS remained the most
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`popular tobacco product among youth, “with youth use at levels comparable to what
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`originally led FDA to declare a youth vaping epidemic in 2018.” Id. Moreover, there was
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`a substantial rise in youth use of yet another type of flavored e-cigarettes, this time a system
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`designed to be discarded after a single use. Id. These products were largely excluded from
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`the 2020 Enforcement Guidance, and thus they remained on the market as a flavored
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`option. Id. This fast product switching underscored the important role that flavors have in
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`driving youth use, in whatever form or device the flavored e-cigarette is available. Up to
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`and through the PMTA deadline, FDA received applications for over 6 million vaping
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`products. See FDA, Deemed Product Review: A Conversation with the Center for Tobacco
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`Products Office of Science (June 11, 2021). While the regulatory path may be a winding
`
`one, its constants are the persistence of youth use of flavored ENDS products and the
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`obligation of FDA to incorporate new public health data into an evolving regulatory
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`framework.
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`11
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`D.
`
`
`
`Avail Vapor is a Richmond, Virginia company which sells, researches, and
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`contracts for ENDS products. Avail submitted its PMTAs to the FDA for approval on
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`September 8, 2020, right before the court-imposed deadline. Avail’s PMTAs focused on
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`various fruit- and dessert-flavored e-liquids. These included flavors like “Aphrodite X,” a
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`blend of “perfectly ripened strawberries bursting with natural flavor, a touch of juicy melon
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`to add contrast, and just a hint of pillowy marshmallow to balance out the tartness of the
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`strawberry.” Gov’t Response Br. at 15–16. Avail also included an application for “Golden
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`Dawn,” which is a “deliciously balanced dessert vape” featuring “the taste of crunchy,
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`savory waffle cone.” Id. at 16.
`
`
`
`Avail included the results of four behavioral studies to support its PMTAs: 1) a two-
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`week online diary study that assessed vaping habits and attitudes associated with Avail’s
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`e-liquids; 2) data from a series of focus groups with a total of 39 participants, which
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`evaluated perceptions and experiences with e-cigarettes and vaping in general; 3) a national
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`survey of adults that measured attitudes towards, and intentions to use tobacco products;
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`and 4) a “human factors summative protocol,” which surveyed 18 adults about the usability
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`and safety of one of Avail’s e-liquid flavors in four nicotine strengths.
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`Avail also filed its marketing plan with its PMTAs, which outlined measures
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`designed to prevent underage use. Such measures consisted of naming its flavored e-liquids
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`with “non-descriptive and non-characterizing names” that do not identify the product flavor
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`to prevent appealing to youth. See J.A. 293. Avail believed its age-gated brick-and-mortar
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`stores and independent age-verification services in Avail’s point-of-sale system would
`12
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`

`

`prevent youth access to its products. See J.A. 295–97. Avail also required its distributors
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`to submit a written policy on their age-verification procedures and a record of compliance
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`with these policies. J.A. 314. While some other ENDS manufacturers were exploring
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`innovative “access restriction” technology, whereby, for example, an ENDS product is tied
`
`to the thumb print of the purchaser, Avail’s marketing plan included only garden variety
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`restrictions that the FDA had previously found wholly inadequate in preventing youth use.
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`Oral Arg. at 34:09; see 2020 Enforcement Guidance, J.A. 131–36.
`
`
`
`On September 15, 2021, the FDA rejected Avail’s PMTAs and issued a marketing
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`denial order for its products. See J.A. 11–16. It listed the following as the “key basis” for
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`the denial:
`
`All of your PMTAs lack sufficient evidence demonstrating that your flavored ENDS
`will provide a benefit to adult users that would be adequate to outweigh the risks to
`youth. In light of the known risks to youth of marketing flavored ENDS, robust and
`reliable evidence is needed regarding the magnitude of the potential benefit to adult
`smokers. This evidence could have been provided using a randomized controlled
`trial and/or longitudinal cohort study that demonstrated the benefit of your flavored
`ENDS products over an appropriate comparator tobacco-flavored ENDS.
`
`Alternatively, FDA would consider other evidence but only if it reliably and
`robustly evaluated the impact of the new flavored vs. tobacco-flavored products on
`adult smokers’ switching or cigarette reduction over time. Although your PMTAs
`contained four protocols for [randomized controlled trials]….to address the new
`products’ abuse liability, the study reports were not submitted…; therefore, this
`evidence is not sufficiently strong to support the benefit to adult smokers of using
`these flavored ENDS because it does not evaluate the specific products in the
`application(s). . . .
`
`Without this information, FDA concludes that your application is insufficient to
`demonstrate that these products would provide an added benefit that is adequate to
`outweigh the risks to youth and, therefore, cannot find that permitting the marketing
`of your new tobacco products would be appropriate for the protection of the public
`health.
`
`
`
`
`13
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`

`

`J.A. 11–12. The FDA also provided Avail with a separate Technical Project Lead Review
`
`explaining its reasoning for the denial. See J.A. 25–45.
`
`Avail administratively appealed this order, requesting that FDA re-review its
`
`applications and rescind the marketing denial order. FDA agreed and granted an
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`administrative stay, allowing Avail’s products to remain on the market during the re-review
`
`process. On February 23, 2022, FDA concluded that recission was not warranted,
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`reiterating its determination that petitioners’ evidence did not “demonstrate a sufficient
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`potential benefit to adult smokers” when weighed against the known risk to youth. J.A. 56.
`
`In the re-review, FDA looked to each of the four behavioral studies submitted by Avail as
`
`part of its PMTAs. See J.A. 46–60. The evidence from each behavioral study was found
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`lacking because it did not “demonstrat[e] the benefit to adult users of the applicant’s
`
`flavored ENDS over an appropriate comparator tobacco-flavored ENDS in terms of
`
`switching from or reducing cigarettes.” J.A. 56.
`
`E.
`
`
`
`Avail timely petitioned this court for review of FDA’s marketing denial order. This
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`court has jurisdiction over Avail’s petition pursuant to the TCA. See 21 U.S.C.
`
`§ 387l(a)(1)(B) (providing jurisdiction for federal court review of a marketing denial order
`
`for the circuit in which a company has its “principal place of business”).
`
`Avail raises a flurry of objections to the FDA’s marketing denial order. Avail’s chief
`
`complaint is that the FDA arbitrarily imposed a new “comparative efficacy” standard,
`
`which asked applicants to demonstrate through certain long-term studies that their fruit-
`
`and dessert-flavored products better promote smoking cessation than tobacco-flavored
`14
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`

`

`products. This standard, Avail complains, was adopted with no explanation to applicants
`
`and without consideration of their reliance interests. Avail also raises a substantive
`
`objection, arguing that FDA’s imposition of this comparative efficacy standard exceeded
`
`its statutory authority under the TCA.
`
`
`
`All of Avail’s objections founder on common ground. First, Avail attempts to tie
`
`the hands of the FDA to certain forms of evidence and kinds of studies in what is a rapidly
`
`evolving field. Second, in focusing upon procedural points, Avail encourages us to neglect
`
`the forest for the trees. Avail essentially argues that “the FDA’s willingness to consider
`
`some forms of evidence, explicitly phrased as such, required the FDA to accept that
`
`evidence as meeting a statutory requirement even where the FDA found the evidence
`
`unsatisfactory.” Breeze Smoke, LLC v. U.S. Food & Drug Admin., 18 F.4th 499, 507 (6th
`
`Cir. 2021) (denying a judicial stay from a substantially similar marketing denial order).
`
`Avail’s proposed restrictions simply run counter to FDA’s broad statutory mandate to
`
`determine from the totality of the evidence before it whether marketing of new tobacco
`
`products is “appropriate for the protection of the public health.” Tobacco Control Act, §
`
`910(c)(2)(A), 123 Stat. at 1809.
`
`II.
`
`
`
`We proceed in accord with well-settled principles of administrative law. The TCA
`
`incorporates by reference the customary Administrative Procedure Act standard of review.
`
`See 21 U.S.C. § 387l(b) (citing 5 U.S.C. § 706(2)(A)). Under this standard, we are
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`instructed to “hold unlawful and set aside agency action, findings, and conclusions found
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`to be . . . arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with
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`law.” 5 U.S.C. § 706(2)(A). Agency action is arbitrary and capricious “if the agency has
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`relied on factors which Congress has not intended it to consider, entirely failed to consider
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`an important aspect of the problem, offered an explanation for its decision that runs counter
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`to the evidence before the agency, or is so implausible that it could not be ascribed to a
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`difference in view or the product of agency expertise.” Motor Vehicle Mfrs. Ass’n of U.S.
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`v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 43 (1983).
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`Arbitrary and capricious review, however, comes “with a presumption in favor of
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`finding the agency action valid.” Ohio Valley Env’t Coal. v. Aracoma Coal Co., 556 F.3d
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`177, 192 (4th Cir. 2009). Further, in reviewing agency action, “due account shall be taken
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`of the rule of prejudicial error,” 5 U.S.C. § 706, which is an administrative law “harmless
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`error rule.” Shinseki v. Sanders, 556 U.S. 396, 406 (2009) (internal quotations omitted).
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`Avail carries the burden of showing that any procedural error by the FDA is harmful. Id.
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`at 409.
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`A.
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`We shall first set forth why the agency did what it did. We shall then discuss Avail’s
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`challenges to its actions.
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`We must initially review the evidence FDA considered in making its determination
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`that allowing Avail to market its products would not be “appropriate for the protection of
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`the public health.” Tobacco Control Act, § 910(c)(2)(A), 123 Stat. at 1809. The TCA
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`requires FDA to make this inquiry by weighing the risk of tobacco product initiation by
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`nonsmokers, including youth, against the benefit of cessation by current smokers.
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`§ 910(c)(4), 123 Stat. at 1810.
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`FDA straightforwardly applied that statutory mandate in reviewing the PMTAs, and
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`it found Avail’s applications wanting against that standard. In short, FDA “examined the
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`relevant data and provided an explanation of its decision that includes a rational connection
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`between the facts found and the choice made.” Aracoma, 556 F.3d at 192 (internal
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`quotations omitted). The care taken by the agency in this review undermines any argument
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`by Avail that FDA acted arbitrarily and capriciously.
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`In reviewing Avail’s PMTAs, FDA began with the same concern that motivated
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`Congress’s passage of the TCA: “use of tobacco products, no matter what type, is almost
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`always started and established during adolescence when the developing brain is most
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`vulnerable to nicotine addiction.” J.A. 29–30. FDA then reviewed a litany of scientific
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`evidence definitively showing the relationship between flavors and youth use of ENDS
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`products. To start, ENDS products are the most used tobacco product among youth, and
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`“[t]he majority of youth who use ENDS report using a flavored ENDS product, and the use
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`of flavored ENDS has increased over time.” J.A. 30. Further, youth ENDS users were
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`more likely to use flavored products than adult ENDS users. Id.
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`FDA next examined studies which showed that flavors drove youth initiation of
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`ENDS use, with most users reporting that their first experience with ENDS was with a
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`flavored product. Id. And beyond initiation, flavors promoted regular ENDS use: nationally
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`representative studies indicated that youth users consistently cited the availability of
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`desirable flavors as the reason behind their use. J.A. 31. Further, “[r]esearch show[ed] that
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`flavored ENDS are rated as more satisfying than tobacco-flavored ENDS, such that
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`participants will work harder for and take more puffs of flavored ENDS compared to non-
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`flavored ENDS.” Id. Evidence also indicated that flavors can actually increase nicotine
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`exposure by “potentially influencing the rate of nicotine absorption through pH effects and
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`by promoting the reward of ENDS use.” Id. Thus “this evidence suggests flavored ENDS
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`may pose greater addiction risk relative to tobacco-flavored ENDS, which increases
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`concerns of addiction in youth[.]” J.A. 31.
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`Particularly striking, FDA found that although “there is variability in the popularity
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`of device types among youth,” the role of flavor is consistent across all of them. Id. Across
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`all device types, “fruit was the most commonly used flavor type among youth.” Id. Further,
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`“the preference for device types and popularity of certain styles is likely fluid and affected
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`by the marketplace.” J.A. 32. Ergo, where flavors were only available in certain device
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`types, youth tended to gravitate toward them. Id. This was illustrated by the substantial
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`migration of youth towards single-use ENDS, which remained on the market as a flavored
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`option after the 2020 Enforcement Guidance cracked down on other flavored products
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`popular with youth. Id.
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`To FDA, the crux of the issue was that youth use of ENDS products was driving
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`nicotine dependency, a matter of substantial public health concern. Id. “[N]icotine
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`exposure during adolescence enhances the rewarding and reinforcing effects of nicotine in
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`adulthood, and can induce short and long-term deficits in attention, learning, and memory.”
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`Id. The agency, having been tasked by Congress with preventing youth use of tobacco
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`products that “are inherently dangerous and cause cancer, heart disease, and other serious
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`adverse health effects,” see Tobacco Control Act, § 2(2), 123 Stat. at 1777, noted that
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`“there is a growing body of evidence showing a link between ENDS use and subsequent
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`smoking among youth.” J.A. 33. Other studies showed as well that there is an association
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`between ENDS use and respiratory issues in young adults. Id.
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`Notwithstanding the substantial risks of youthful addiction and associated health
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`issues, FDA considered the possibility that flavored ENDS may help promote smoking
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`cessation or switching to a less detrimental product as required by the statute. FDA noted
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`scientific evidence that ENDS are healthier for tobacco users than combustible cigarettes.
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`J.A. 34. But “whether this is true for any particular new ENDS product, and the
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`implications for health risks from a particular product, are considered on a case-by-case
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`basis.” Id. For flavored ENDS, which pose a massive risk of addicting a new generation to
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`nicotine, “the magnitude of the likely benefit would have to be substantial enough to
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`overcome the significant risk . . . .” Id.
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`In contrast to the role that flavors play in promoting ENDS use by youth, FDA found
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`that “the evidence regarding the role of flavors in promoting switching among adult
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`smokers is far from conclusive.” J.A. 36. The literature was conflicting and inconclusive
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`on whether flavors actually promoted switching or