Liquid Labs LLC v. FDA ( 2022 )

PRECEDENTIAL
UNITED STATES COURT OF APPEALS
FOR THE THIRD CIRCUIT
______________
No. 21-2883
______________
LIQUID LABS LLC,
Petitioner
v.
UNITED STATES FOOD AND DRUG
ADMINISTRATION
______________
On Petition for Review of a Final Marketing Denial Order
By the United States Food and Drug Administration
(Agency Nos. PM0003412 & PM0000984)
______________
Submitted Under Third Circuit L.A.R. 34.1(a)
October 3, 2022
______________
Before: CHAGARES, Chief Judge, SHWARTZ and
SCIRICA, Circuit Judges.
(Filed: October 27, 2022)
Kevin T. Duffy, Jr.
Duffy & Staab
165 West Putnam Avenue
Suite 2B
Greenwich, CT 06903
Gary G. Staab
Duffy & Staab
2 William Street
The Kennedy Building
Suite 302
White Plains, NY 10601
Counsel for Petitioner
Arun G. Rao
Gustav W. Eyler
Hilary K. Perkins
Jonathan E. Amgott
United States Department of Justice
Consumer Protection Branch
450 5th Street, N.W.
Suite 6400 South
Washington, DC 20001
Brian M. Boynton
Joshua Koppel
United States Department of Justice
Civil Division
950 Pennsylvania Avenue, N.W.
Room 7212
Washington, DC 20530
Daniel J. Barry
United States Department of Health & Human Services
200 Independence Avenue, S.W.
2
Washington, DC 20201
Wendy S. Vicente
Marci B. Norton
Food and Drug Administration
Office of the Chief Counsel
10903 New Hampshire Ave.
Silver Spring, MD 20993
Counsel for Respondent
James G. Troutman
Troutman Law Office
4205 Springhurst Boulevard
Suite 201
Louisville, KY 40241
Counsel for Amicus Petitioners 38 National and
State Electronic Nicotine Delivery System Product
Advocacy Associations
Mary G. Bielaska
Zanicorn Legal
845 Third Avenue
6th Floor
New York, NY 10022
Counsel for Amicus Petitioners Dr. David B.
Abrams,Clive D. Bates, and Professor David T.
Sweanor, J.D.
William B. Schultz
Zuckerman Spaeder
1800 M Street, N.W.
Suite 1000
Washington, DC 20036
3
Counsel for Amicus Respondents Medical and
Public Health Groups
______________
OPINION OF THE COURT
______________
SHWARTZ, Circuit Judge.
Liquid Labs LLC (“Liquid Labs”) sought permission
from the Food and Drug Administration (“FDA”) to market
products used in e-cigarettes. The FDA denied the request, and
Liquid Labs petitions for review. Because the FDA’s order
was within its statutory authorities and the Administrative
Procedure Act (“APA”), we will deny the petition.
I
A
E-cigarettes are electronic nicotine delivery systems
(“ENDS”) that vaporize e-liquids and allow for inhalation. 1
1
Some e-cigarettes are disposable, while others are
reusable. Within the reusable group, some e-cigarettes have
“open systems,” meaning they are “refillable” and “include[] a
reservoir that a user can refill with an e-liquid of their
choosing,” JA 210; some have “closed systems,” meaning, for
example, they “use[] e-liquid contained in replaceable
cartridges or pods that are not intended to be refillable,” JA 210
4
See, e.g., Big Time Vapes, Inc. v. FDA, 963 F.3d 436, 439 n.11
(5th Cir. 2020), cert. denied, 141 S. Ct. 2746 (2021). Liquid
Labs manufactures and sells e-liquids that generally contain
nicotine and flavoring.
Liquid Labs’ e-liquids qualify as “new tobacco
product[s]” under the Family Smoking Prevention and
Tobacco Control Act (the “Act”). See 21 U.S.C. §§ 387-387u.
The Act applies to “all cigarettes, cigarette tobacco, roll-your-
own tobacco, and smokeless tobacco and to any other tobacco
products that the Secretary by regulation deems to be subject
to” the Act. 21 U.S.C. § 387a(b); see also 21 U.S.C.
§ 387j(a)(1)(A) (defining “a new tobacco product,” as relevant
here, to be “any tobacco product . . . that was not commercially
marketed in the United States as of February 15, 2007”). In
2016, the FDA “deem[ed]” e-cigarettes and related
components (such as Liquid Labs’ e-liquids) to be subject to
the Act’s requirements. See Deeming Tobacco Products To Be
Subject to the Federal Food, Drug, and Cosmetic Act, 81 Fed.
Reg. 28,974, 29,028 (May 10, 2016); see also Big Time Vapes,
963 F.3d at 440.
Because Liquid Labs’ e-liquids qualify as new tobacco
products, they may not be introduced into interstate commerce
without the FDA’s authorization. See 21 U.S.C. § 387j(a)(2).
One way to obtain authorization is by submitting a premarket
tobacco product application (“PMTA”). See, e.g., Big Time
Vapes, 963 F.3d at 439; see also 21 U.S.C. § 387j(b)-(c).
and some have “mod[ifiable] system[s]” that allow the user to
adjust various aspects of the e-cigarette, see, e.g., JA 135.
Liquid Labs’ e-liquids are used in connection with open
systems.
5
Under the Act, the FDA “shall deny” a PMTA if the
applicant fails to “show[] that permitting such tobacco product
to be marketed would be appropriate for the protection of
public health.” 21 U.S.C. § 387j(c)(2)(A). “[T]he finding as
to whether the marketing of a tobacco product . . . is
appropriate for 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.” 21 U.S.C. § 387j(c)(4). On this subject, the
Act directs the FDA to “tak[e] into account” both “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.” 21 U.S.C.
§ 387j(c)(4)(A)-(B).
In addition to the Act and the deeming regulation, the
FDA took several related regulatory steps. For example, the
FDA issued guidance in June 2019 (“June 2019 Guidance”)
and April 2020 (“April 2020 Guidance”) that “help[ed]
manufacturers prepare [PMTA] applications ahead of the
[discretionarily delayed submission] deadline,” and “set[] out
the agency’s enforcement priorities,” respectively. Prohibition
Juice Co. v. U.S. Food & Drug Admin., 45 F.4th 8, 13-15 (D.C.
Cir. 2022). Among other things, these documents highlighted
that flavored e-liquids’ had a “disproportionate appeal to
children,” id. at 13, and “noted the types of rigorous scientific
evidence [the FDA] would accept in support of applications to
market such products,” id. at 15.
6
B
Liquid Labs submitted two PMTAs on September 4,
2020, covering twenty e-liquid products. The products
spanned ten flavors, two of which are described as being
tobacco flavored, and eighteen of which are described as
having a “characterizing flavor” other than tobacco or menthol
with names such as “OG Island Fusion,” “Berry Au Lait, “OG
Summer Blue,” and “Shake.”
In connection with the applications, Liquid Labs
submitted evidence from a variety of sources, including an
abuse liability study, a cross-sectional perception and intention
study, a population modeling analysis, a clinical literature
review, and “well-controlled non-clinical analyses of Liquid
Labs’ Products.” Pet. Br. at 20. Liquid Labs also submitted a
marketing plan setting forth, among other things, various
measures Liquid Labs planned to take to discourage youths
from using its products.
In September 2021, the FDA denied Liquid Labs’
PMTAs. 2 In connection with its denials, the FDA sent Liquid
Labs several documents, including a Marketing Denial Order,
a document titled “Technical Project Lead (TPL) Review of
PMTAs,” JA 62, and two documents titled “Review for
Flavored ENDS PMTAs,” JA 52, 57.
2
The denial order did not list Liquid Labs’ tobacco-
flavored e-liquids as products “lack[ing] sufficient evidence to
demonstrate that the marketing of th[e] products is appropriate
for the protection of public health.” JA 10. Liquid Labs
represents that approval for its tobacco-flavored e-liquids has
been neither granted nor denied.
7
The Marketing Denial Order briefly explained why the
applications “lack[ed] sufficient evidence to demonstrate that
the marketing of the[] products [wa]s appropriate for the
protection of public health.” JA 1. It noted, for example, that
“[i]n light of the known risks to youth of marketing flavored
ENDS, robust and reliable evidence” was “needed regarding
the magnitude of the potential benefit to adult smokers,” and
such evidence could have been provided through “randomized
controlled trial[s] and/or longitudinal cohort stud[ies],” as well
as through “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.” JA 1. The FDA found that Liquid Labs’ cross-
sectional survey was “not sufficient” because “it d[id] not
evaluate product switching or cigarette reduction resulting
from use of these products over time or evaluate these
outcomes based on flavor type to enable comparisons between
tobacco and other flavors.” JA 1-2.
The Technical Project Lead Review further discussed
the FDA’s rationale for denying Liquid Labs’ applications.
For example, it set forth the FDA’s concern about youth use of
flavored ENDS and regulatory actions the FDA has taken to
address the issue. It also explained, among other things, (1)
why the FDA focused “on the risk to youth nonusers as well as
the potential benefit to adult smokers as current users,” (2) why
“only the strongest types of evidence” would be sufficient to
show an adequate benefit to adult smokers, (3) why the FDA
looked for “acceptably strong evidence that the flavored
products have an added benefit relative to that of tobacco-
flavored ENDS in facilitating smokers completely switching
away from or significantly reducing their smoking,” and (4)
8
how it concluded that although Liquid Labs’ applications
“contain other evidence regarding the potential benefit to adult
users,” the “other evidence [wa]s not adequate.” JA 64.
The Technical Project Lead Review explained that
Liquid Labs’ “internet-based cross-sectional survey” evidence
“[wa]s not sufficiently strong to support the benefit to adult
smokers of using these flavored ENDS because it d[id] not
evaluate product switching or cigarette reduction resulting
from use of these products over time or evaluate these
outcomes based on flavor type to enable comparisons between
tobacco and other flavors.” JA 75. Accordingly, the FDA
concluded that Liquid Labs had not shown that the benefits of
the products sufficiently outweighed the risks they posed to
youths.
In the Reviews for Flavored ENDS PMTAs, the FDA
examined Liquid Labs’ submissions to see if they “contain[ed]
evidence from a randomized controlled trial, longitudinal
cohort study, and/or other evidence regarding the impact of the
new ENDS on switching or cigarette reduction that could
potentially demonstrate the benefit of [its] flavored ENDS over
an appropriate comparator tobacco-flavored ENDS.” JA 53,
58. The reviews noted that the PMTAs lacked both
randomized controlled trials related to new product use and
smoking behavior and longitudinal cohort studies on new
product use and smoking behavior and one review specified
that the “[o]ther evidence” submitted was “not sufficient to
support the benefit to adult smokers of using these flavored
ENDS . . . .” JA 54; see also JA 57 (noting “[e]vidence is
absent in PMTAs”).
9
Liquid Labs petitions for review. 3
II 4
A5
3
Liquid Labs also sought re-review from the FDA.
After completing its re-review, the FDA again concluded that
Liquid Labs’ evidence did not “demonstrate a sufficient
potential benefit to adult smokers to warrant rescission” of its
prior denial. JA 317.
4
This Court has jurisdiction pursuant to 21 U.S.C.
§ 387l(a)(1)(B).
5
We review the FDA’s order denying the PMTAs under
the standards set forth in the APA, see 21 U.S.C. § 387l(b)
(noting a “regulation or denial” “shall be reviewed in
accordance with section 706(2)(A)” of the APA), and, thus,
may hold it “unlawful and set [it] aside” if “arbitrary,
capricious, an abuse of discretion, or otherwise not in
accordance with law,” 5 U.S.C. § 706(2)(A). An agency acts
arbitrarily or capriciously if, for example, it “entirely fail[s] to
consider an important aspect of the problem,” Motor Vehicle
Mfrs. Ass’n of U.S., Inc. v. State Farm Mut. Auto. Ins. Co.,
463 U.S. 29, 43 (1983), “offer[s] only a ‘conclusory statement’
which ‘fail[s] to articulate a rational basis for its conclusion,’”
or “cit[es] no data whatsoever in support of its decision,” Sierra
Club v. U.S. Env’t Prot. Agency, 972 F.3d 290, 298 (3d Cir.
2020) (first quoting W.R. Grace & Co. v. E.P.A., 261 F.3d 330,
342 (3d Cir. 2001), then quoting Natural Res. Def. Council,
Inc. v. E.P.A., 790 F.2d 289, 309 (3d Cir. 1986)).
When conducting this analysis, we “review the whole
record or those parts of it cited by a party, and [give] due
account . . . [to] the rule of prejudicial error.” 5 U.S.C. § 706;
10
Liquid Labs contends that the FDA acted arbitrarily and
capriciously in a number of respects. For the reasons below,
we reject each of Liquid Labs’ arguments.
1
Liquid Labs first argues that the FDA acted arbitrarily
and capriciously by “pull[ing] a surprise switcheroo” by
“requir[ing]” certain evidence it previously indicated would
not be necessary and rejecting evidence it led Liquid Labs to
believe would be sufficient. 6 Pet. Br. at 39. In doing so, the
see also Nat’l Ass’n of Home Builders v. Defs. of Wildlife, 551
U.S. 644, 659 (2007); Shinseki v. Sanders, 556 U.S. 396, 409
(2009) (explaining that the “burden of showing that an error is
harmful normally falls upon the party attacking the agency’s
determination”). Concomitantly, we “judge the agency’s
decision ‘solely by the grounds [it] invoked.’” Rad v. Att’y
Gen., 983 F.3d 651, 656 (3d Cir. 2020) (quoting SEC v.
Chenery Corp., 332 U.S. 194, 196 (1947)) (alteration in
original).
To the extent the issue pertains to an agency’s
interpretation of the statutes it administers, we follow the
“familiar Chevron framework,” first “giv[ing] effect to
Congress’ unambiguous intent” “if the statute is clear,” and,
second, “defer[ring] to an implementing agency’s reasonable
interpretation of that statute” “if the statute is silent or
ambiguous with respect to a specific issue.” Contreras Aybar
v. Sec’y U.S. Dep’t of Homeland Sec., 916 F.3d 270, 273 (3d
Cir. 2019) (quoting De Leon-Ochoa v. Att’y Gen., 622 F.3d
341, 348 (3d Cir. 2010)).
6
Specifically, Liquid Labs claims that the FDA
unexpectedly required it to provide (1) randomized controlled
11
FDA, according to Liquid Labs, provided inadequate notice,
upset its reliance expectations, and acted arbitrarily and
capriciously.
Liquid Labs relies on several documents the FDA
issued between June of 2019 and September 2021. The first is
the FDA’s June 2019 Guidance “intended to assist persons
submitting . . . PMTAs.” JA 205. The June 2019 Guidance
explained, among other things, that although the Food, Drug,
and Cosmetic Act “states that the finding of whether permitting
the marketing of a product would be [appropriate for the
protection of public health] will be determined, when
appropriate, on the basis of well-controlled investigations,” the
FDA was also permitted to consider “other ‘valid scientific
evidence’ if found sufficient to evaluate the tobacco product.”
JA 216; see also JA 250 (“FDA believes that in some cases, it
may be possible to support a marketing order for an ENDS
product without conducting new nonclinical or clinical studies.
. . . In cases where a product has not yet been sufficiently
reviewed, new nonclinical and clinical studies may be
necessary to support a marketing order.”). It further stated that
“[n]onclinical studies alone are generally not sufficient to
trials and/or longitudinal cohort studies, (2) studies occurring
“over time” and/or “long-term studies,” and (3) studies
comparing the “efficacy between different ENDS products.”
Reply Br. at 5, 7, 10.
Liquid Labs adds new arguments in its reply brief
regarding a “net benefit” requirement and the FDA’s “refusal
to request additional evidence before issuing denial.” See
Reply at 12, 14. We decline to “reach arguments raised for the
first time in a reply brief.” Barna v. Bd. of Sch. Dirs. of Panther
Valley Sch. Dist., 877 F.3d 136, 146 (3d Cir. 2017).
12
support a determination that permitting the marketing of a
tobacco product would be appropriate for the protection of
public health.” JA 216. “Nonetheless,” the document
continued, the FDA “in general,” did not “expect that
applicants w[ould] need to conduct long-term studies to
support an application.” JA 217. The Guidance also
“recommend[ed that] an applicant compare the health risk of
its product to both products within the same category and
subcategory, as well as products in different categories as
appropriate.” JA 217.
According to Liquid Labs, the June 2019 guidance
“encourag[ed] submission of the very evidence FDA
[ultimately] reject[ed],” and “induced” the shortcomings
highlighted in the FDA’s denial of Liquid Labs’ PMTA. Pet.
Br. at 38. The second item that Liquid Labs relies on is a July
2021 internal FDA memorandum, which explained, among
other things, that the “[t]he absence of” “a randomized
controlled trial” and/or “a longitudinal cohort study”
constituted “a fatal flaw, meaning any application lacking
[such] evidence w[ould] likely receive a marketing denial
order,” JA 273-74, and an August 2021 internal memorandum
that Liquid Labs asserts “justified” the July 2021
memorandum, Pet. Br. at 26. 7
7
Liquid Labs relies heavily on the FDA’s July
statements and its August justification that the absence of
certain studies would constitute a “fatal flaw” in a PMTA
application, but this ignores the fact that the memoranda that
made this comment were rescinded either expressly or
implicitly.
13
We join our sister circuit courts who have rejected these
“surprise switcheroo” arguments. See Prohibition Juice, 45
F.4th at 20-21; Wages & White Lion Invs., LLC v. FDA, 41
F.4th 427, 438-39 (5th Cir. 2022) 8; Breeze Smoke, LLC v. U.S.
Food & Drug Admin., 18 F.4th 499, 506-07 (6th Cir. 2021),
cert. denied, 142 S. Ct. 638 (2021).
With respect to the claim that the FDA surprisingly
required randomized controlled trials and/or longitudinal
cohort studies, “[t]he text of the FDA’s [June] 2019 Guidance
makes . . . clear” that “the FDA did not reverse course.”
Prohibition Juice, 45 F.4th at 21. Put simply, the FDA did not
newly require those specific types of studies but instead found
that Liquid Labs’ other evidence was inadequate. The 2019
Guidance “said that [such studies] would not be necessary if
applicants submitted similarly rigorous ‘valid scientific
evidence,’” but “nowhere guaranteed that unspecified other
forms of evidence would necessarily be sufficient—only that
they might be, so the FDA would consider them.” Id.; accord
Wages & White Lion, 41 F.4th at 438-39; Breeze Smoke, 18
F.4th at 506-07; Gripum, LLC v. United States Food & Drug
Admin., 47 F.4th 553, 559-60 (7th Cir. 2022). Further, the July
2021 memorandum “did not necessarily foreclose reliance on
other forms of rigorous evidence,” and the August
memorandum “expressly required the agency to consider other
8
Liquid Labs relies heavily on an earlier opinion from
the Court of Appeals for the Fifth Circuit granting a stay
pending merits review. See Wages & White Lion Invs., LLC
v. U.S. Food & Drug Admin., 16 F.4th 1130 (5th Cir. 2021).
The merits panel, however, denied the petition for review. See
Wages & White Lion Invs., 41 F.4th 427.
14
forms of evidence if sufficiently robust.” Prohibition Juice, 45
F.4th at 22.
Further, in denying Liquid Labs’ applications, the FDA
acted in conformity with the June 2019 Guidance. Nothing in
the Marketing Denial Order, the Technical Project Lead
Review, and the two Reviews for Flavored ENDS PMTAs
“required” Liquid Labs to include “product-specific
[randomized controlled trials]/longitudinal cohort studies.”
Reply Br. at 5. 9 Each document states that the FDA would—
and indicates that it in fact did—consider other evidence.
Liquid Labs’ studies, however, did not produce the kind of
evidence the FDA consistently sought. For example, the June
2019 Guidance recommends that “PMTAs for flavored
products [ ] examine [both] the impact of the flavoring on
consumer perception . . . especially given the attractiveness of
flavors to youth and young adults,” and the “adult appeal of
9
Liquid Labs also contends that an FDA press release
“announced that it [would] require[] the very studies it
originally expected it didn’t need.” Pet. Br. at 39. The press
release does not reveal that the FDA changed its requirements.
Indeed, it specifically states that “the agency [was] not
foreclos[ing] the possibility that other types of evidence”—i.e.,
other than randomized controlled trials and longitudinal cohort
studies—“could be adequate if sufficiently robust and
reliable.” See Press Release, FDA Denies Marketing
Applications for About 55,000 Flavored E-Cigarette Products
for Failing to Provide Evidence They Appropriately Protect
Public Health (Aug. 26, 2021), https://www.fda.gov/news-
events/press-announcements/fda-denies-marketing-
applications-about-55000-flavored-e-cigarette-products-
failing-provide-evidence .
15
such flavors in their decisions to initiate use, cease use of more
harmful products, or dual use.” JA 246; see JA 241-42
(recommending “considering” “[p]ublished literature or
applicant-initiated studies evaluating the effects of the ENDS
on users, including effects on initiation, switching behavior,
cessation, and dual use; and on nonusers’ initiation of the
product.”). Further, the Guidance recommends that “an
applicant compare the health risks of its products to both
products within the same category and subcategory, as well as
products in different categories as appropriate.” JA 217; see
also JA 244. Liquid Labs’ abuse liability study compares its
“OG Blue” flavor e-liquid with cigarettes and nicotine gum but
not with its “Bacco” flavor or other tobacco-flavored e-liquid.
Similarly, the cross-sectional survey neither shows a benefit to
flavoring nor provides meaningful information regarding
actual switching or reduction, and both Liquid Labs’ literature
review and a third-party literature review indicate uncertainty
regarding the role of flavors in smoking cessation. Thus, the
FDA did not deny Liquid Labs’ applications solely because
they lacked randomized controlled trials or longitudinal cohort
studies. Rather, the record indicates that the FDA properly
denied them because the other evidence Liquid Labs submitted
was insufficient.
Accordingly, the FDA did not “reverse course” and
newly require randomized controlled trials and/or longitudinal
cohort studies, and therefore did not upset Liquid Labs’
reliance interests, provide inadequate notice, or act arbitrarily
and capriciously.
Contrary to Liquid Labs’ assertion, the FDA also did
not arbitrarily and capriciously mandate “over time/long-term
16
studies.” Reply at 7. 10 The Marketing Denial Order, Reviews
for Flavored ENDS PMTAs, and Technical Project Lead
Review all demonstrate that the FDA wanted reliable evidence
that Liquid Labs’ flavored e-liquids, among other things,
helped adult smokers cut down on their cigarette use or switch
to using ENDS products only. So did the FDA’s June 2019
Guidance. See, e.g., JA 217. Reliable evidence of these
behavioral changes is more likely to come from a study
conducted over time because data collected over a short period
may not show whether a particular change is temporary or
long-lasting. To this end, the FDA stated that “it might accept
evidence other than long-term studies, if that evidence had
sufficient scientific underpinnings to meet the [Act]’s statutory
mandate of demonstrating that flavored ENDS devices are
appropriate for the protection of public health.” Breeze
Smoke, 18 F.4th at 506-07 (emphasis omitted). Thus, the FDA
does not require PMTA applicants to conduct long-term
studies. 11
10
Liquid Labs conflates “long-term” studies with
studies examining behavior “over time.” First, the FDA
materials show that the phrase “long-term study” measures the
duration of a study. For example, the FDA describes “long-
term studies” as lasting six months or more. Studies that
measure behavior over time, however, can last shorter periods.
In fact, the Technical Project Lead Review indicates that
studies occurring “over time” could be shorter than six months.
Second, although a study concerning behavioral changes over
time could be the focus of a “long-term” study, such a study
may not be necessary to secure the information sought.
11
That said, to the extent Liquid Labs is claiming “the
FDA’s statement that it would consider evidence other than
long-term studies” “announc[ed]” that “‘long-term studies
17
Moreover, the FDA did not require “long-term studies”
from Liquid Labs. Both the Marketing Denial Order and the
Technical Project Lead Review refer to studies analyzing
behavior “over time,” JA 1-2, 73-74 & n.xxiii, but, as
explained above, that does not mean that a long-term study is
required. Rather, “the FDA has all along required ‘valid
scientific evidence,’ and its denial orders explained how the
. . . data petitioners submitted fell short of the mark.”
Prohibition Juice, 45 F.4th at 23. Accordingly, Liquid Labs’
“over time/long-term studies” argument is also unavailing.
2
We also join our sister circuits in concluding that the
FDA permissibly “required a comparison of a manufacturer’s
‘flavored products’ with ‘tobacco-flavored ENDS’ products in
their ability . . . to assist adult smokers to quit or switch.” Reply
Br. at 10 (emphasis omitted); see Wages & White Lion, 41
F.4th at 434; Prohibition Juice, 45 F.4th at 19-20, 23-24. “The
governing statute expressly asks for evidence concerning
whether an applicant’s ‘tobacco product presents less risk than
other tobacco products,’ . . . and the FDA’s [June] 2019
were likely unnecessary,’” they are “over-read[ing]” it.
Prohibition Juice, 45 F.4th at 22-23 (quoting Wages & White
Lion, 16 F.4th at 1140-41). In its June 2019 Guidance, the
FDA “broadened the types of evidence it would consider,”
meaning “[i]nstead of limiting applicants to the two types of
evidence it usually requires, the agency allowed manufacturers
to submit evidence in other forms.” Id. at 21. “But at the same
time the agency made clear it would not relax the scientific
rigor of the requisite public health demonstration.” Id.
18
Guidance told manufacturers that the agency would look for
comparisons between the proposed product and ‘tobacco
products in the same category or subcategory.’” Prohibition
Juice, 45 F.4th at 23 (first quoting 21 U.S.C. § 387j(b)(1)(A),
then quoting June 2019 Guidance at 13). The “FDA is then
required to consider ‘the information submitted to the
Secretary as part of the application,’ which necessarily
includes the comparative efficacy reports that applicants must
provide.” Wages & White Lion Invs., 41 F.4th at 434 (quoting
21 U.S.C. § 387j(c)(2)) (emphasis omitted). The FDA is also
required to “consider ‘the increased or decreased likelihood
that existing users of tobacco products will stop using such
products,’” which “necessarily implies a comparative
analysis.” Id. (quoting 21 U.S.C. § 387j(c)(4)(A)). 12 Thus, the
statute and June 2019 Guidance are clear about comparative
analysis. 13 Accordingly, “[b]ecause the [June] 2019 Guidance
gave fair notice of the analysis the agency would perform and
12
Additionally, even if such express authority were
lacking, the “FDA certainly has implied authority”—for the
reasons the Court of Appeals for the Fifth Circuit explained—
to consider comparative risk as it did here. Wages & White
Lion, 41 F.4th at 435.
13
Liquid Labs also contends that it was misled because
the June 2019 Guidance “focuses exclusively on the
physiological health risks associated with the compared
products, not behavioral impacts.” Reply Br. at 10-11; see also
id. at 25. As the Wages & White Lion court explained,
however, “[i]nitiation and cessation behaviors are
physiological health risks.” 41 F.4th at 434 (emphasis
omitted); see also Prohibition Juice, 45 F.4th at 19-20 (“The
degree to which a harmful product entices and addicts new
users is inarguably a component of the ‘health risk’ it poses.”).
19
the purpose of those comparisons, . . . the agency did not create
unfair surprise by focusing on comparisons between otherwise
similar flavored and nonflavored products.” 14 Prohibition
Juice, 45 F.4th at 24. 15
14
Liquid Labs’ related argument that the FDA, in effect,
engaged in the modified risk tobacco products inquiry or the
required proof akin to that necessary for drugs is also
unpersuasive. As discussed herein, the FDA did not impose
“entirely different (and far more stringent) requirements,” Pet.
Br at 52, than those contemplated by the governing statute, see
also 21 U.S.C. §§ 355(b)(1)(A), 387k. “Moreover, the fact that
the FDA has other authorities through which it can approve
other products . . . does not release the FDA from following its
statutory mandate here to approve only tobacco products the
sale of which it determines ‘would be appropriate for the
protection of the public health,’” and Liquid Labs has given us
“no persuasive reason to think that those other authorities
somehow limit the inquiry the FDA may make in reaching” its
“determination.” Prohibition Juice, 45 F.4th at 20 (quoting 21
U.S.C. § 387j(c)(2)); see also Gripum, LLC, 47 F.4th at 559.
15
Liquid Labs claims that it provided evidence aligning
with the FDA’s June 2019 Guidance. Liquid Labs has not
shown, however, that the FDA erred in concluding that the
evidence was insufficient. Wages & White Lion, 41 F.4th at
439; see also Breeze Smoke, 18 F.4th at 507 (“declin[ing] to
embrace” petitioner’s claim “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”).
20
For these reasons, the FDA did not apply unannounced
or changed standards for PMTAs.
3
The FDA’s decision to decline to review Liquid Labs’
marketing plan does not change the result because there is no
indication the plan would have made up for the deficiencies the
FDA identified in Liquid Labs’ applications. See Delaware
Riverkeeper Network v. Sec’y Pa Dep’t of Env’t Prot., 833
F.3d 360, 377 (3d Cir. 2016) (“[M]istakes that have no bearing
on the substantive decision of an agency do not prejudice a
party.”); see also, e.g., Prohibition Juice, 45 F.4th at 25
(concluding petitioner failed to show that the FDA’s failure to
consider its marketing plan “could have changed the agency’s
decision on their applications”); Wages & White Lion, 41 F.4th
at 442 (concluding that even if the FDA inadequately reviewed
petitioners’ marketing plans, the error was harmless because
petitioners failed to “show that they would have received
authorization had [the] FDA considered the[] plans”). 16 For
16
In a divided opinion, the Court of Appeals for the
Eleventh Circuit remanded after concluding the FDA’s failure
to review the petitioners’ marketing plans was both arbitrary
and capricious and harmful. See Bidi Vapor LLC v. U.S. Food
& Drug Admin., 47 F.4th 1191 (11th Cir. 2022). Among other
things, the Bidi Court distinguished Prohibition Juice on the
grounds of “concessions . . . made . . . at oral argument” before
the Court of Appeals for the District of Columbia Circuit. Id.
at 1208. The purported concessions echoed the Prohibition
Juice petitioners’ briefing, which did not “identify how they
were harmed from the FDA’s failure to consider essentially the
same [marketing] measures it had previously rejected.”
21
example, to address youth use, Liquid Labs’ marketing plan
lists, among other things, “age verification measures,” a
“mystery shopper” program, Pet. Br. at 12, and a prohibition
on marketing material “that could be perceived to be targeting
individuals below the legal vaping age,” JA 322-23, but these
are similar, if not identical, to the kinds of approaches the FDA
found did not address this serious problem, see, e.g., JA 89-91,
125-27 (April 2020 Guidance); see also Prohibition Juice, 45
F.4th at 25 (explaining that “self-verification of age at the point
of sale and . . . less vibrant marketing unappealing to youth”
“track measures the FDA in its 2020 guidance deemed
inadequate”); Wages & White Lion, 41 F.4th at 442
(explaining the “FDA had already explained,” for example,
that “products . . . [being] only sold in age-gated vape and
specialty tobacco shops and through age-gated online sales”
“do not work”) (emphasis omitted). Liquid Labs has not
explained how the approaches in its plan differ from ones
previously found insufficient or how its marketing plans would
have cured other noted deficiencies in its applications,
particularly given the FDA’s earlier conclusion that “focusing
on how the product was sold would not be sufficient to address
youth use of [flavored cartridge-based] products.” 17 JA 125.
Prohibition Juice, 45 F.4th at 25 (“In response to questioning .
. . at oral argument, the manufactures again did not identify
. . . .”). Liquid Labs also did not provide such an explanation,
so it is like Prohibition Juice and thus different from Bidi.
17
Liquid Labs tried to distinguish its marketing plan
from “many” other companies’, but it fails to explain how its
purportedly distinctive features—e.g., selling via online third-
party distributors rather than selling through its own website—
make a meaningful difference or address the concerns about
youth usage.
22
Because Liquid Labs has not shown that its marketing
plans differ from those previously rejected or that its plans
would have rectified the scientific deficiencies, the marketing
plans would not change the result. Accordingly, even
assuming the FDA erred in declining to review Liquid Labs’
marketing plans, the error was harmless. See Shinseki v.
Sanders, 556 U.S. 396, 411 (2009) (stating one of “the factors
that inform[s] a reviewing court’s ‘harmless-error’
determination” is “an estimation of the likelihood that the
result would have been different”).
4
Contrary to Liquid Labs’ claim, the FDA did not ignore
that Liquid Labs sought approval for “bottled e-liquids
intended for use with open-systems devices.” Pet Br. at 45-46.
The FDA acknowledged that “there may be differential appeal
of certain product styles,” but pointed to evidence where “the
removal of one flavored product option prompted youth to
migrate to another ENDS type that offered the desired flavor
options” as “underscoring the . . . role of flavor in driving
appeal,” and explained, based on the evidence it reviewed, that
“the role of flavor is consistent” “across . . . different device
types.” JA 68-69. Because these observations and
conclusions are backed “with substantial evidence, . . . we have
no basis to second-guess [them].” Prohibition Juice, 45 F.4th
at 26; Wages & White Lion, 41 F.4th at 437-38. We therefore
reject Liquid Labs’ argument that the FDA ignored the specific
characteristics of its products.
Finally, Liquid Labs argues that the FDA erred by
failing to consider all segments of the population, including
23
adults currently using flavored ENDS who may lose their
ability to access them and who may turn to the “illicit market”
as a result. Pet. Br. at 51. 18
Liquid Labs’ argument lacks merit. As an initial matter,
all non-tobacco and/or menthol flavored ENDS are not banned,
and thus, there is no reason for the FDA to examine Liquid
Labs’ speculative “entire[] eliminat[ion]” claim. Pet Br. at 50.
In any event, the FDA explained that: (1) the relevant statutory
authorities required it to account for “the risks and benefits to
the population as a whole,” JA 64 n.ii; (2) its “review [wa]s
focused on the risk to youth nonusers as well as the potential
benefit to adult smokers as current users, as they are the group
through which the potential benefit to public health is most
substantial and could overcome the known risk to youth,” JA
64 n.ii; see JA 65 n.vii; and (3) it considered, among other
things, (a) “the likelihood that an authorization will increase or
decrease the number of tobacco users in the overall
population,” JA 65 n.vii, (b) “the degree of benefit to a flavored
ENDS product over a tobacco-flavored variety in facilitating
18
Liquid Labs also argues that the FDA did not consider
“less disruptive alternatives” to issuing the denial order. Pet.
Br. at 51 (quoting Wages & White Lion, 16 F.4th at 1139). The
FDA, however, “was not required to consider alternative
regulatory approaches before denying the manufacturers’
applications for premarket approval.” Prohibition Juice, 45
F.4th at 26. Further, the portion of the Wages & White Lion
opinion that Liquid Labs cites discusses alternatives in the
context of its conclusion that the FDA “chang[ed] from its no-
long-term-studies-necessary policy to its apparent long-term-
studies-required policy.” 16 F.4th at 1139. We have already
concluded, however, that no such change occurred.
24
smokers completely switching or significantly reducing their
smoking,” JA 72, and (c) the lack of conclusive evidence
“regarding the role of flavors in prompting switching among
adult smokers,” JA 72; see also JA 64 n.vi (“[I]n the absence
of strong evidence generated by directly observing the
behavioral impacts of using a flavored product vs. a tobacco-
flavored product over time, we are unable to reach a conclusion
that the benefit outweighs the clear risks to youth.”). Thus, the
record shows that the FDA considered whether Liquid Labs’
products were appropriate for the protection of public health
from several vantage points, provided evidence for its
particular focus, and concluded that the evidence Liquid Labs
submitted came up short.
B
In light of the foregoing, Liquid Labs’ additional
arguments lack merit. The FDA reviewed Liquid Labs’
application in conformity with, among other things, its
statutory authorities and publicly issued guidance, and thus did
not act ultra vires. Likewise, because the FDA did not adopt a
“new secret standard” or otherwise change course, it also did
not violate the Act or APA and had no obligation to proceed
through notice-and-comment rulemaking.
III
For the foregoing reasons, we will deny the Petition for
Review.
25