Vanda Pharmaceuticals, Inc. v. United States Food and Drug Administration

United States Court of Appeals
FOR THE DISTRICT OF COLUMBIA CIRCUIT
Argued January 15, 2025 Decided August 15, 2025
No. 24-1049
VANDA PHARMACEUTICALS, INC.,
PETITIONER
v.
UNITED STATES FOOD AND DRUG ADMINISTRATION, ET AL.,
RESPONDENTS
On Petition for Review of an Order
of the Food & Drug Administration
Paul W. Hughes argued the cause for petitioner. With him
on the briefs were Sarah P. Hogarth, Charles Seidell, and
Nicole Wittstein.
Lewis Yelin, Attorney, U.S. Department of Justice, argued
the cause for respondents. With him on the brief were Brian
M. Boynton, Principal Deputy Assistant Attorney General, at
the time the brief was filed, Daniel Tenny, Attorney, Samuel R.
Bagenstos, General Counsel, U.S. Department of Health &
Human Services, at the time the brief was filed, and Kwabena
Akowuah, Associate Chief Counsel, U.S. Food & Drug
Administration.

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Before: PAN and GARCIA, Circuit Judges, and EDWARDS,
Senior Circuit Judge.
Opinion for the Court filed by Circuit Judge GARCIA.
GARCIA, Circuit Judge: Vanda Pharmaceuticals, Inc.
applied for Food and Drug Administration approval to market
the drug tasimelteon as a treatment for jet lag. FDA denied
Vanda’s application without first holding a hearing. Vanda
petitioned our court for review. Vanda argues that FDA was
required by statute to hold a hearing before denying Vanda’s
application. Alternatively, Vanda argues that the record here
presented material factual disputes requiring a hearing, and that
the agency’s reasons for denying the application were arbitrary
and capricious. We agree with Vanda in part. FDA can deny
a new drug approval application without holding a hearing if
no material facts are genuinely disputed. On this record,
however, FDA’s refusal to hold an evidentiary hearing must be
set aside.
I
A
The Food, Drug, and Cosmetic Act (FDCA) requires that
drug manufacturers apply to FDA for approval before
marketing a new drug (or an existing drug for a new purpose).
See 21 U.S.C. § 355(a). FDA may approve the application only
if, among other things, the manufacturer offers “substantial
evidence” that the drug is safe and effective for its proposed
use. Id. § 355(d). The Act defines “substantial evidence” as
“adequate and well-controlled investigations, including
clinical investigations, by experts” from which “it could fairly

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and responsibly be concluded by such experts that the drug will
have the effect it . . . is represented to have.” Id.
After reviewing an application, FDA “shall either . . .
approve the application,” or if it cannot do so, “give the
applicant notice of an opportunity for a hearing . . . on the
question whether such application is approvable.” Id.
§ 355(c)(1). Per agency regulations, if FDA does not approve
an application on first pass, it will notify the applicant of its
determination by issuing a “complete response letter”
explaining the application’s defects and suggesting steps to
remedy those defects. 21 C.F.R. § 314.110(a); see also id.
§ 314.125(a). The applicant may then withdraw or resubmit its
application, or may request “an opportunity for a hearing.” Id.
§ 314.110(b)(3).
If the applicant requests an opportunity for a hearing, FDA
can “either approve the application . . . or refuse to approve the
application” and issue “the applicant written notice of an
opportunity for a hearing” (known as an NOOH). Id.; see also
id. § 314.200(a). Upon receiving an NOOH, an applicant may
request a hearing and submit additional materials to support
that request. See id. § 314.200(c)(1). FDA will hold a hearing,
however, only “if the material submitted shows” that there “is
a genuine and substantial issue of fact for resolution.” Id.
§ 12.24(b)(1). If it instead “conclusively appears from the face
of the” record that there is no such issue for resolution, FDA
will “enter summary judgment” denying the application. Id.
§ 314.200(g)(1).
B
In 2018, Vanda applied to FDA for approval to market
tasimelteon—a drug previously approved as a treatment for a
rare sleep disorder—as a treatment for jet lag. As part of its
submission to FDA, Vanda offered the results from five clinical
trials, three of which form the core of its application.

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Vanda’s three trials sought to assess tasimelteon’s effect
on jet lag and its symptoms. The trials measured both
“[p]rimary endpoints” (measurements “typically selected to
address the main clinical question”) and “secondary endpoints”
(which may “be used to support the claim of efficacy,”
including “by demonstrating additional effects”). J.A. 246 ¶ 29
(citation modified). The trials’ “primary endpoints” related to
the ease with which subjects fell asleep and stayed asleep.
These primary endpoints were evaluated objectively, using
measures of subjects’ brain activity. The “secondary
endpoints” related to patients’ perceived alertness, and were
assessed using subjective tools including the Karolinska
Sleepiness Scale (KSS) and the Visual Analog Scale (VAS).
In 2019, FDA’s Center for Drug Evaluation and Research
(CDER) issued a complete response letter, signaling its intent
to deny Vanda’s application. CDER refused approval in part
because it was unpersuaded that Vanda’s trials satisfied the
“substantial evidence” burden. CDER explained that it was
“not clear how [the] primary endpoints assess the fundamental
sleep disturbances associated with jet lag disorder.” J.A. 35.
The letter described that “[o]ther important aspects of the
disorder,” beyond sleepiness, were not measured. Id. And it
concluded that at least one of the subjective tools used to
measure the secondary endpoints, the KSS, was “not fit-for-
purpose.” Id.
After receiving CDER’s response letter, Vanda repeatedly
met with FDA and submitted two formal dispute-resolution
requests. Vanda argued that tasimelteon should be approved
for the use (or “indication”) that Vanda had initially requested:
treatment of jet lag as a whole. In the alternative, Vanda argued
that, even accepting CDER’s critiques, tasimelteon could at
least be approved for a narrower indication: treatment of the
insomnia symptoms associated with jet lag.

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Both of Vanda’s dispute requests were denied. The
reviewing officers agreed with the initial conclusion that Vanda
had not sufficiently demonstrated that tasimelteon could treat
the distinct symptoms of jet lag. And they concluded that a
request for a narrower indication was outside the scope of the
dispute-resolution request, as Vanda had not asked for a
narrower indication before CDER issued the complete
response letter.
In June 2022, Vanda requested an opportunity for
hearing. Two months later, FDA issued an NOOH, repeating
its skepticism that Vanda’s studies measured the relevant
symptoms of jet lag. FDA explained that demonstrating a
drug’s efficacy in treating jet lag required showing
improvement on two categories of symptoms: (1) “insomnia or
excessive daytime sleepiness, accompanied by a reduction of
total sleep time, associated with transmeridian jet travel across
at least two time zones” and (2) the “associated impairment of
daytime function, general malaise, or somatic symptoms within
one to two days after travel.” J.A. 134. FDA concluded that
Vanda’s studies did not provide substantial evidence that
tasimelteon improved either symptom—much less that
tasimelteon improved both symptoms, as would be required for
approval. FDA found that Vanda’s primary endpoints at best
measured only sleepiness symptoms. It further found that the
tools Vanda used to evaluate its secondary endpoints did not
measure next-day impairment, were internally flawed, and
suffered from statistical error.
In November 2022, Vanda requested a hearing, arguing in
part that the FDCA mandated one. To support its request,
Vanda would eventually submit five expert declarations. The
declarations responded to each of FDA’s objections, explained
the experts’ views that Vanda’s three clinical studies
constituted substantial evidence of tasimelteon’s efficacy for

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treating jet lag, and argued that a hearing was required to
resolve factual disputes over the adequacy of the clinical trials.
On February 29, 2024, FDA issued a final decision
denying Vanda’s application and its hearing request. The
agency’s Principal Deputy Commissioner found there was “no
genuine and substantial issue of fact justifying a hearing.” J.A.
1987. She again defined jet lag as encompassing both insomnia
symptoms and next-day impairment. J.A. 1988–89. And she
reiterated that Vanda’s studies were statistically flawed and,
even if sound, failed to demonstrate that tasimelteon impacted
next-day impairment. See J.A. 2026–30.
Vanda petitioned our court for review of FDA’s final
decision and hearing denial. We have jurisdiction under 21
U.S.C. § 355(h).
II
Vanda lodges three primary challenges to FDA’s order.
First, Vanda argues that FDA unlawfully denied its request for
a hearing—either because the FDCA requires FDA to conduct
a hearing whenever an applicant requests one, or because
Vanda raised a material factual dispute precluding summary
judgment. Next, Vanda contends that FDA acted
inconsistently, and therefore arbitrarily and capriciously, both
by refusing to grant Vanda a narrower indication and by
demanding that Vanda offer evidence of jet lag’s second
symptom. Finally, Vanda claims that the Principal Deputy
Commissioner’s issuance of FDA’s final decision violated the
Appointments Clause.
We disagree with each of Vanda’s arguments, save one:
Though the FDCA does not mandate that FDA must hold a
hearing before denying any new drug application, in this case,
FDA’s decision denying Vanda a hearing was arbitrary and

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capricious. We therefore remand to FDA for further
proceedings.
A
Vanda’s primary challenge is to FDA’s denial of its
hearing request. As noted, it argues both that FDA was
statutorily required to hold a hearing, and that summary
judgment was inappropriate here regardless. We consider each
argument in turn.
1
The FDCA does not require FDA to hold a hearing before
denying any new drug approval application that it receives.
Sections 355(c) and (d) of Title 21 outline hearing
procedures for new drug applications. Section 355(d) specifies
that an application will be approved if “the Secretary finds,
after due notice to the applicant . . . and giving him an
opportunity for a hearing,” that certain criteria are met,
including that the applicant provided substantial evidence of
the drug’s efficacy. 21 U.S.C. § 355(d). Section 355(c)
commands that the HHS Secretary has 180 days to “(A)
approve [an] application” or “(B) give the applicant notice of
an opportunity for a hearing . . . on the question whether such
application is approvable.” Id. § 355(c)(1). It then describes
the timeline on which a “hearing shall commence.” Id.
For decades, FDA regulations implementing those
provisions have subjected new drug applications to
summary judgment procedures. See Hearing Regulations and
Regulations Describing Scientific Content of Adequate and
Well-Controlled Clinical Investigations, 35 Fed. Reg. 7250,
7252 (May 8, 1970). Pursuant to those procedures, FDA can,
in specified circumstances, deny an application on its merits
without holding a hearing. Vanda argues that those regulations
are invalid because Section 355(c) requires FDA to hold a

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hearing for every application it intends to deny, regardless of
the application’s merit. We have never directly considered that
issue. Cf. Pharm. Mfg. Rsch. Servs., Inc. v. FDA, 957 F.3d
254, 266 (D.C. Cir. 2020) (applying FDA’s summary judgment
procedures without explicitly considering their conformity
with the statute). But we do not write on a blank slate.
In Weinberger v. Hyson, Westcott & Dunning, Inc., 412
U.S. 609 (1973), the Supreme Court interpreted the very
similar text of Section 355(e) of the FDCA—which governs
FDA’s withdrawal of prior drug approvals—to permit FDA’s
use of summary judgment procedures. Id. at 620–23. The
Weinberger Court reached that holding even though the “Act
require[d] FDA to give ‘due notice and opportunity for hearing
to the applicant’ before [withdrawing] its approval.” Id. at 620
(quoting 21 U.S.C. § 355(e)). The Court explained that the
provision’s text did not “preclude” an agency “from
particularizing statutory standards through the rulemaking
process and barring at the threshold those who [do not] measure
up to them.” Id. (quotation omitted). The Court added that it
could not “impute to Congress the design of requiring, nor [did]
due process demand, a hearing when it appears conclusively
from the applicant’s ‘pleadings’ that the application cannot
succeed.” Id. at 621.
Weinberger’s interpretation of Section 355(e) guides our
interpretation of Sections 355(c) and (d). Most centrally,
Weinberger informs our reading of the plain text. It holds that
FDA may use summary judgment procedures to deny a hearing
when no material facts are genuinely disputed, despite Section
355(e)’s requirement that the Secretary provide “notice and
opportunity for hearing.” Like Section 355(e), Section 355(d)
states that the Secretary “shall issue an order refusing to
approve the application” after “due notice to the applicant . . .
and giving him an opportunity for a hearing.” 21 U.S.C.
§ 355(d). And Section 355(c) similarly requires the Secretary

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to “give the applicant notice of an opportunity for a hearing.”
Id. § 355(c)(1)(B). Given the comparable phrasing across
these provisions, it stands to reason that if Section 355(e) does
not preclude summary judgment procedures, then Sections
355(c) and (d) do not either. After all, we generally “give . . .
consistent meaning” to the same or similar terms when they are
used “throughout [an] Act.” Gustafson v. Alloyd Co., 513 U.S.
561, 568 (1995). That interpretive principle applies with even
greater force where, as here, the provisions are next to one
another, within the same section of a statute, and pertain to
parallel processes. See Nat’l Credit Union Admin. v. First
Nat’l Bank & Tr. Co., 522 U.S. 479, 501 (1998) (describing
“the established canon of construction that similar language
contained within the same section of a statute must be accorded
a consistent meaning”).
Weinberger also rests on a practical rationale that applies
to new drug approvals as much as to withdrawals. Weinberger
reasoned that requiring FDA “automatically to hold a hearing
for each product whose efficacy was questioned . . . even
though many hearings would be an exercise in futility” would
preclude FDA from “fulfill[ing] its statutory mandate to
remove from the market all those drugs which do not meet the
effectiveness requirements of the Act.” 412 U.S. at 621.
So too if FDA were required to hold a hearing for every new
drug approval application it planned to deny. After all,
addressing applications for new drug approval is also a
“massive regulatory task.” SmithKline Corp. v. FDA, 587 F.2d
1107, 1116 (D.C. Cir. 1978). In the approval context, then,
we also “cannot impute to Congress” a meaning that
strains logic, imposing a requirement that FDA expend
resources even “when it appears conclusively from the
applicant’s ‘pleadings’ that the application cannot succeed.”
Weinberger, 412 U.S. at 621.

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Vanda would have us distinguish Weinberger by fixating
on one phrase that appears in Section 355(c) but not in Section
355(e). Subsection (c) states that, absent agreement between
FDA and the applicant, a hearing “shall commence” within 120
days of an NOOH’s issuance “[i]f the applicant elects to accept
the opportunity for hearing.” 21 U.S.C. § 355(c) (emphasis
added). Vanda contends that this language is “unambiguous”
and “command[s]” that FDA conduct every hearing that a party
requests. Petitioner’s Brief 18.
That language, however, must be read in context.
Subsection (c) is, at least primarily, a timing provision. It is
entitled “Period for approval of application; period for, notice,
and expedition of hearing; period for issuance of order.” 21
U.S.C. § 355(c). And it describes the pace at which various
actions take place: Subsection (c)(1) specifies that the
Secretary must either approve an application or issue an NOOH
within 180 days of receiving an application. Id. at § 355 (c)(1).
Subsection (c)(2) describes the time by which “the holder of
[an] approved application” must “file with the Secretary”
relevant patent information. Id. § 355(c)(2). And subsection
(c)(3) establishes a timetable for when applications including
certain certifications become effective. Id. § 355(c)(3).
Moreover, it is Section 355(d)—and not Section 355(c)—
that governs the substantive contours of the hearing process.
Subsection (d) is entitled “Grounds for refusing application;
approval of application; ‘substantial evidence’ defined.” Id.
§ 355(d). And it recounts the substantive considerations that
FDA must weigh, including the requirement that the applicant
offer substantial evidence. See id. Even the text of subsection
(c) itself suggests that subsection (d) governs substance;
subsection (c) says that “the Secretary shall . . . give the
applicant notice of an opportunity for a hearing before the
Secretary under subsection (d) on the question whether such
application is approvable.” Id. § 355(c)(1)(B) (emphasis

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added). No similar mandate that a hearing “shall commence”
appears in the substantive instructions that Section 355(d)
outlines.
Read against that statutory context, subsection (c)’s “shall
commence” language does not create an unconditional right to
a hearing. Instead, it fits within the following statutory scheme:
FDA can, consistent with Weinberger, establish by regulation
that an “opportunity for a hearing” exists only if there is a
material factual dispute. If a material factual dispute exists and
an opportunity for a hearing arises, FDA must “give the
applicant notice” of that opportunity and the applicant may
“elect[] to accept the opportunity.” Id. And if the applicant
does so, “such hearing shall commence” within 120 days of
such notice. Id. In short, the “shall commence” language—
like the balance of subsection (c)—simply sets a timing
requirement, providing that any hearings that do occur “shall
commence not more than ninety days after the expiration of . . .
thirty days” from when notice is given. Id. (emphasis added).
In sum, Vanda’s argument assigns too much weight to
Section 355(c)’s “shall commence” language. The Supreme
Court has authoritatively construed Section 355(e) to permit
summary judgment procedures despite similar language
requiring “notice and opportunity for a hearing.” The same
reasoning applies here. We therefore find that FDA’s summary
judgment procedures comport with the statute.
2
Vanda next argues that, even if the FDCA does not always
mandate a hearing, Vanda was entitled to one here. Vanda
submits that FDA’s contrary decision was “arbitrary,
capricious, . . . or otherwise not in accordance with law.” 5
U.S.C. § 706(2)(A). “[O]ur review focuses on whether the
agency’s decision was reasonable and reasonably explained.”
Pharm. Mfg., 957 F.3d at 262 (citation modified). We agree

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with Vanda that FDA’s order must be set aside under that
standard.
FDA may deny a request for a hearing unless “the
applicant . . . identif[ies] a material issue of fact.” Am.
Cyanamid Co. v. FDA, 606 F.2d 1307, 1314 (D.C. Cir. 1979);
see also 21 C.F.R. § 12.24(b). To survive summary judgment,
then, an applicant must raise a dispute that concerns factual
issues, rather than “issues of policy and law,” Pharm. Mfg., 957
F.3d at 266 (quoting 21 C.F.R. § 12.24(b)(1)), and that is
material because it “might affect the outcome . . . under the
governing law,” John D. Copanos & Sons, Inc. v. FDA, 854
F.2d 510, 523 (D.C. Cir. 1988) (quoting Anderson v. Liberty
Lobby, Inc., 477 U.S. 242, 248 (1986)).
When FDA denies an applicant a hearing, we review that
denial to determine “whether the agency has given adequate
consideration to all relevant evidence in the record.” Pharm.
Mfg., 957 F.3d at 266 (citation modified). In so doing, “we
give a high level of deference to the agency’s scientific analysis
of the evidence before it.” Id. at 262 (citation modified). Our
review is particularly deferential where FDA identifies a
“precise” regulatory standard that forms the basis for its denial.
See SmithKline, 587 F.2d at 1117–18; Copanos, 854 F.2d at
522. Our review becomes somewhat more searching, however,
where the agency’s denial is premised solely on a more general
standard that provides less precise guidance. See SmithKline,
587 F.2d at 1117–18; Copanos, 854 F.2d at 522; see also Am.
Cyanamid, 606 F.2d at 1312–13. In that case, we consider
whether the applicant “manifest[ly]” failed to comply with the
“general statutory or regulatory provisions.” Copanos, 854
F.2d at 522 (citation modified). Put otherwise, we ask if FDA
has demonstrated that the applicant’s evidence was
“conclusively deficient.” Am. Cyanamid, 606 F.2d at 1319.

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Here, FDA denied Vanda a hearing on the ground that no
factual dispute existed that, if resolved in Vanda’s favor, could
establish “substantial evidence” supporting its application. See
21 U.S.C. § 355(d)(5). Recall that the statute defines
“substantial evidence” in relevant part as “evidence consisting
of adequate and well-controlled investigations, including
clinical investigations, by experts qualified by scientific
training and experience to evaluate the effectiveness of the
drug involved.” Id. § 355(d). Under our precedents, that is
ordinarily a more “general,” rather than “specific,” standard (as
no party squarely disputes). See SmithKline Corp, 587 F.2d at
1117–18; Am. Cyanamid, 606 F.2d at 1312–13. We therefore
review FDA’s denial to determine whether FDA has shown
that Vanda’s experts’ studies and testimony are “conclusively
deficient.” Am. Cyanamid, 606 F.2d at 1319.
FDA’s primary argument is that it properly denied Vanda
a hearing “in light of the company’s complete failure to
establish that tasimelteon improved impairment in next-day
functioning,” the second symptom of jet lag. Respondents’
Brief 41. On FDA’s view, Vanda’s clinical studies could never
demonstrate that tasimelteon effectively treated next-day
impairment because they did not measure that symptom. At
most, FDA found, the studies evaluated only subjective
impressions of sleepiness and alertness—primarily using
the KSS and VAS tools—and those tools are not proven to
measure the distinct symptom of next-day impairment. The
“link” between next-day impairment and the sleepiness
measured by the KSS and VAS tools, FDA said, “cannot be
assumed.” J.A. 2028.
That rationale could carry the day if it were a reasonable
description of the record evidence, as FDA would then have
“identified at least one conclusive deficiency in” Vanda’s
evidence. Am. Cyanamid, 606 F.2d at 1314. But it is not an
accurate description of the evidence submitted here. Vanda did

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not merely assume that these tools measured next-day
impairment. Nor did it enlist experts who merely submitted
“general and unsupported” assertions to that effect. Copanos,
854 F.2d at 526. Vanda instead offered pages of expert
testimony describing that improvement on the KSS and VAS
corresponded to improvement in next-day functioning. And
here, FDA primarily dismissed Vanda’s arguments as
assumptions without adequately explaining any flaws in
Vanda’s evidence. As a result, on this record, FDA
has not shown that the testimony is “conclusively deficient,”
and so a material factual dispute remains. Am. Cyanamid,
606 F.2d at 1319.
Examples of Vanda’s testimony and FDA’s responses
demonstrate the point. To start, Vanda submitted expert
testimony from Dr. Daniel Combs concluding that both the
KSS and VAS could measure the next-day impairment relevant
to jet lag. J.A. 490–93 ¶¶ 207–19. Dr. Combs supported that
conclusion with reasoning and with citations to relevant
literature. He first explained that “next-day alertness
was measured by VAS” in one of Vanda’s trials; that in that
trial “it was shown that patients treated with tasimelteon had
reduced next-day symptoms as evidenced by significantly
higher alertness compared to the placebo”; and thus that those
findings “show[ed] that next-day daytime functioning
impairment is lessened with tasimelteon use because higher
alertness and less exhaustion results in better daytime
functioning.” J.A. 490 ¶ 207. Dr. Combs then described that
Vanda’s studies demonstrated similar results on the KSS. J.A.
491 ¶ 208. And Dr. Combs noted that “[t]he KSS has been
demonstrated to correlate closely with measures of cognitive
function,” citing a study to support that claim. J.A. 491 ¶ 209.
He directly disputed CDER’s conclusion that the KSS was not
“fit-for-purpose.” J.A. 491 ¶ 211 (citation modified); J.A.
492 ¶ 214; J.A. 493 ¶ 219.

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Dr. Combs also explained that, contrary to FDA’s claims,
“[t]he KSS is a validated instrument for measuring sleepiness
and has been found to highly correlate to behavioral variables
and brain functioning.” J.A. 491–92 ¶ 213. He added that “the
validity of the KSS as a measure of sleepiness and indicator of
impaired waking function has been recognized by the scientific
community,” citing multiple studies. Id. And sleep, he
explained, “is essential for cognitive performance, as reported
next-day sleepiness and low alertness directly affect next-day
functioning when travelers are engaging in tasks such as
driving or working.” J.A. 492–93 ¶ 217 (footnote omitted).
Dr. Combs then cited studies in which sleep deprivation has
been linked to dangerous errors that stem from functional
impairment. J.A. 492–93 ¶ 217 & n.8.
Vanda provided further testimony from Dr. Thomas Roth,
who similarly concluded that each subjective tool Vanda used
could measure the next-day impairment relevant to jet lag. See
J.A. 1506–13 ¶¶ 89–105. Dr. Roth described that “KSS scores
and VAS scores all correlate strongly with daytime function.”
J.A. 292 ¶ 175. He also cited three studies for the proposition
that it “is common within the sleep research community to use
[the] VAS to measure aspects of sleep and daytime functioning
and the effects of therapeutic interventions on them.” J.A. 249
¶ 41 (quotation omitted). To rebut FDA’s claims that the KSS
does not measure the impairment that accompanies jet lag, he
explained that the KSS has previously been used in studies
measuring jet lag disorder, citing five examples. J.A. 321–22
¶ 266. He also explained why the KSS would adequately
measure the next-day impairment associated with jet lag:
“[D]aytime sleepiness is an aspect of daytime function” and so
“relates to impaired next-day function,” as illustrated by a
cited study linking sleepiness to impairment of functioning.
J.A. 1513–14 ¶ 107.

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FDA did not (and likely could not) dispute either of these
experts’ credentials. Instead, FDA principally argued that the
experts’ claims were merely conclusory—that “Vanda ha[d]
not specifically identified reliable evidence to support [its]
assertions,” J.A. 2068, and had simply “assumed” a link
between what the KSS and VAS measured and impaired
daytime function, J.A. 2028. Those statements, though,
mischaracterize the evidence before FDA. As the above
excerpts show, these experts fully explained their reasons for
concluding that the KSS and VAS could measure next-day
impairment, then cited studies from their field to support that
position. The experts’ views were thus specific, reasoned,
and rooted in evidence. Their declarations are unlike
the “general and unsupported” attestations that we have
found insufficient to create a genuine dispute of material fact.
Copanos, 854 F.2d at 526.
In the alternative, FDA disputes these experts’ claims by
questioning the validity and applicability of the particular
studies on which they rely. See J.A. 2030–35. That iteration
of FDA’s argument, though, only helps to prove Vanda’s point:
Vanda provided evidence that created a genuine dispute over
the strength of the scientific evidence supporting the link
between the KSS and VAS tools and next-day impairment.
Had FDA pointed to some “conclusive” flaw in the experts’
rationale or the studies they rely on—the sort of flaw, for
instance, that renders those studies facially irrelevant—then
FDA might nonetheless have demonstrated that no dispute
existed, despite the evidence Vanda provided. See Am.
Cyanamid, 606 F.2d at 1314. But FDA has not made any such
showing here. Instead, its treatment of Vanda’s evidence is
cursory (and was barely mentioned in FDA’s brief, see
Respondents’ Brief 38–39).
Insofar as FDA addresses Vanda’s evidence at all, the
agency mostly dwells on minor and seemingly irrelevant

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disagreements with the cited studies’ analysis. For example,
FDA claimed that two studies Vanda identified as using the
KSS to assess jet-lag-related topics were irrelevant because
they studied Swedish or Chinese volunteers, and not U.S.
populations. See J.A. 2031–33. Similarly, FDA noted that a
third study did not label the response options in its version of
the KSS in precisely the same way as Vanda’s studies did. J.A.
2032. Dr. Roth responded that those distinctions were
immaterial to whether the KSS is a viable measure of next-day
functioning for purposes of jet lag disorder, which was what
Vanda had relied on the KSS studies to show. J.A. 1515 ¶ 111.
Even according deference to FDA’s scientific judgments, the
issues FDA identified do not establish a conclusive deficiency
in Vanda’s evidence. See Am. Cyanamid, 606 F.2d at 1314–16
(finding applicant raised material issue of fact where parties’
experts disagreed over scientific meaning of clinical trials’
results); see also SmithKline, 587 F.2d at 1119.
3
In addition to its core claim that Vanda did not offer
evidence measuring next-day impairment, FDA also notes an
array of other problems with Vanda’s evidence that might
foreclose taismelteon’s approval and make a hearing
unnecessary. But none of FDA’s other arguments show that
Vanda “manifest[ly]” failed to carry its substantial evidence
burden. Copanos, 854 F.2d at 522 (quotation omitted).
To start, FDA argues that the KSS and VAS tools are
improperly designed, and so cannot accurately evaluate even
the subjective “sleepiness” and “alertness” they were created
to measure. FDA offers little scientific substantiation for its
arguments, and some of its claims appear facially implausible.
(FDA claims without support, for example, that trial subjects
would be unable to understand that “rather alert” indicates a
degree of alertness lower than “alert,” even when the terms are

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ordered and labeled on a numeric scale. J.A. 2027.) Moreover,
Vanda’s experts explained why those concerns with the KSS
and VAS tools were not merited, pointing to numerous other
sleep studies where the KSS and VAS tools were deployed.
See, e.g., J.A. 321–22 ¶¶ 264–68; J.A. 491–92 ¶¶ 212–15; J.A.
1504–06 ¶¶ 83–88; J.A. 2235–37 ¶¶ 83–88; J.A. 1511–13 ¶¶
102–05; J.A. 2247–48 ¶¶ 102–05. At the very least, that
evidence created a genuine factual dispute over the validity of
these tools.
FDA next argues that, in their measurement of secondary
endpoints, Vanda’s studies failed to control for the risk of
“Type I error”—or false indications that the treatment has a
statistically significant affect. “The overarching statistical
defect,” FDA explains, was that “Vanda failed to prespecify the
statistical analysis to be conducted after collecting data
concerning certain secondary study outcomes.” Respondents’
Brief 33 (citation modified). And without such
prespecification, “the likelihood of false positive outcomes
increases.” Id.
The presence of Type I error, if fully explained by FDA
and left meaningfully unanswered by Vanda, might also be the
sort of flaw that establishes a conclusive deficiency in a party’s
evidence. Here, however, a nonconclusory declaration from
Dr. Platt described why Vanda’s trial design would not result
in Type I error in this instance, even if prespecification is
ordinarily a best practice. See J.A. 1563 ¶¶ 29–30; J.A.
1567 ¶ 47. Dr. Platt’s declaration included a meta-analysis of
the three clinical studies Vanda submitted. And it articulated,
based on that analysis, why the risk of Type I error was
negligible here. Id.
In turn, neither FDA’s final decision nor its brief on appeal
directly acknowledges Dr. Platt’s analysis. FDA responded to
a related argument in Dr. Roth’s declaration, see J.A. 2039–40

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& n.187, but did not directly respond to Dr. Platt’s more-
developed assessment. It would thus be quite difficult for us to
conclude, on this record, that FDA reasonably explained why
Dr. Platt’s analysis did not raise a material dispute of fact as to
the reliability of Vanda’s studies. Ultimately, although
“[m]any of FDA’s reservations about [the statistical rigor of
Vanda’s] stud[ies] may be valid,” our court’s “function is
not to choose among expert opinions but to determine whether
FDA’s evaluation of the study conclusively establishes”
its invalidity. Am. Cyanamid, 606 F.2d at 1315. Given Dr.
Platt’s thorough declaration, we cannot agree that FDA has
made that showing.1
Finally, FDA contested Vanda’s ability to demonstrate
taismelteon’s efficacy in treating the first symptom of jet lag,
sleep disturbance. Vanda, however, clearly offered meaningful
evidence of tasimelteon’s efficacy in improving sleep
disturbance. Its three clinical trials were each designed to
primarily measure improvement on one of two sleep-focused
metrics. And each trial showed statistically significant
improvement on the primary endpoint measured. See J.A. 721;
J.A. 843; J.A. 266–67 ¶ 96.
1 FDA’s decision below (though, again, not its brief to us) does
refer in a footnote to a portion of a CDER submission that engages
with Dr. Platt’s analysis. See J.A. 2040 & n.189. Even if FDA is
fairly treated as adopting CDER’s response as part of its final
decision, on our review, CDER’s explanation does not describe any
conclusive deficiency in Dr. Platt’s analysis; CDER instead
disagrees with Dr. Platt over a specific scientific question that he
addresses at length. See J.A. 2449–53. Ultimately, at this stage, the
dispute remains a battle of experts who offer conflicting and
nonconclusory views—and that is exactly the type of dispute our
precedent says is inappropriate for resolution without a hearing. See
Am. Cyanamid, 606 F.2d at 1315–16.

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FDA challenged Vanda’s reliance on those three trials by
questioning the relevance of the two primary endpoints Vanda
selected—endpoints that respectively focused on how quickly
subjects achieved persistent sleep and how well they slept
during the first two-thirds of the night.2 See Respondents’
Brief 15. But Vanda provided a reasonable answer to FDA’s
concerns. Vanda offered experts who attested that those
measurements were relevant to jet-lag-related sleep
disturbance. And these experts again provided sufficiently
detailed support for their view to raise a factual dispute. For
example, Dr. Roth and Dr. Combs identified other sleep-drug
studies and jet lag studies that similarly relied on measures of
patients’ time to fall asleep. See J.A. 300–02 ¶¶ 198, 204; J.A.
486 ¶ 186. They named multiple other sleep drugs that FDA
has approved based on studies measuring that endpoint. See
J.A. 486 ¶ 187; see also J.A. 300 ¶¶ 198–99. And while
insomnia studies typically measure total sleep time, Dr. Roth
explained (with cited support) that “jet lag disorder is most
likely to have a sleep-disturbing effect during the first two
thirds of a person’s total sleep time” and that it therefore
2 In its final decision, FDA also quibbled with broader study
design choices, arguing these choices invalidated Vanda’s
measurements even of its primary endpoints. FDA contended, for
instance, that too few participants were used in one study. See J.A.
1983–84. And it contested the fact that the two other studies were
conducted in a laboratory (and so did not require participants to
undergo transmeridian travel) and did not screen subjects for prior
symptoms of sleep disturbance. See J.A. 2044–45. Those issues are
not squarely raised in FDA’s brief. But cf. Respondents’ Brief 8, 11,
15. And even to the extent they were properly presented to our court,
they primarily involve a scientific assessment of the adequacy of the
evidence, on which Vanda’s experts offered thoroughly explained
contrary views. See, e.g., J.A. 297–98 ¶¶ 187–89; J.A. 1470–71 ¶ 12;
J.A. 1501 ¶¶ 73, 75–76; J.A. 1525 ¶ 14. These concerns, then, also
raise factual disputes and so would not foreclose approvability.

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“makes sense that jet lag disorder studies focus on [sleep time]
during the first two thirds of a night.” J.A. 302 ¶ 207. Dr.
Combs described why that is true: “By the last third of the
night, individuals would have reached their circadian night and
would be expected to have better sleep compared to the first
two-thirds of the night, when they would be expected to still be
in their circadian day.” J.A. 485 ¶ 185.
Even affording substantial deference to FDA’s expertise,
we cannot say on this record that FDA has reasonably
articulated any conclusive flaw in Vanda’s evidence that
forecloses approval without requiring the resolution of material
factual disputes. Instead, it again casts Vanda’s evidence on
this issue as “conclusory” when it plainly was not. J.A. 2006.
Thus, FDA could not properly deny Vanda’s application on
that basis without holding a hearing.
B
Vanda also raises several arbitrary-and-capricious
challenges to the reasoning in FDA’s denial. We generally
decline to reach those challenges, given that FDA will be
required to conduct further proceedings on remand.
Nonetheless, we address two arguments that relate to the
reasoning above and that bear on the proper scope of those
further proceedings.
First, Vanda contests its obligation to prove the second
symptom of jet lag, next-day impairment. Vanda argues that
tasimelteon should be considered an effective treatment for jet
lag even if Vanda’s evidence shows only that tasimelteon can
remedy sleep-disturbance symptoms. FDA reasonably
disagreed.
FDA defined jet lag disorder as encompassing both sleep
disturbance and next-day impairment. To arrive at that
definition, FDA looked to the International Classification of

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Sleep Disorders (ICSD-3) published by the American
Academy of Sleep Medicine. As Vanda does not dispute, the
ICSD-3 is the “internationally recognized standard for
diagnosing jet lag disorder.” J.A. 1989.
The ICSD-3 describes jet lag as characterized by three
diagnostic criteria: “A. There is a complaint of insomnia or
excessive daytime sleepiness”; “B. There is associated
impairment of daytime function, general malaise, or somatic
symptoms”; and “C. The sleep disturbance is not better
explained by another current sleep disorder . . . or . . .
medication.” J.A. 1263. It also explains the “[e]ssential
[f]eatures” of the disorder: “Jet lag disorder is characterized by
a temporary mismatch between the timing of the [internal]
sleep and wake cycle . . . and . . . [the external] sleep and wake
pattern required by a change in time zone. Individuals
complain of disturbed sleep, sleepiness and fatigue, and
impaired daytime function.” Id. Based on those materials,
FDA concluded that jet lag’s symptoms consisted—as the
ICSD-3 described—of both sleep disturbance and next-day
impairment. See J.A. 1988–90.
Vanda argues that, when approving other sleep-disorder
drugs, FDA has not required manufacturers to prove “Criterion
B” symptoms—those symptoms categorized by the letter “B”
in the ICSD-3’s diagnostic criteria list. On Vanda’s view, it is
therefore inconsistent to require proof of a Criterion B
symptom—next-day impairment—only for jet lag. And FDA,
Vanda insists, has not adequately explained its choice to hold
Vanda to a new and different standard.
But FDA did explain why it looked at a Criterion B
symptom in defining jet lag, even if it has not always done so
for other sleep disorders. Here, next-day impairment was not
only listed in Criterion B but was also described as one of the
“essential features” of jet leg. J.A. 1989–90; J.A. 2013–15.

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Other sections of the ICSD-3 also describe how jet lag works
in greater detail. And they explain that “[t]he symptoms of jet
lag disorder are due to both desynchronization of endogenous
circadian rhythms with local time and sleep disturbance.” J.A.
1265 (emphasis added). Thus, by looking to the whole of the
ICSD-3—and particularly the “essential features” portion of
the definition—FDA reasonably concluded that “jet lag
disorder necessarily encompasses more than sleep disturbance
alone.” J.A. 1989; see also J.A. 2014–15.3
Second, Vanda challenges FDA’s refusal to consider a
“narrower indication” and approve tasimelteon as a treatment
only for insomnia related to jet lag (rather than as a treatment
for jet lag as a whole). Vanda again claims that FDA acted
inconsistently. Vanda contends that FDA ordinarily considers
narrower indications that companies propose and cites a list of
other drugs where narrower indications were approved. See
Petitioner’s Brief 35–37.
FDA does not dispute that it commonly considers requests
to narrow proposed indications. See Respondents’ Brief 49–
50; J.A. 2061. Here, however, Vanda requested a narrower
3 In its reply brief, Vanda suggests that FDA’s explanation that
next-day impairment is an essential feature is also inconsistent and
arbitrary; in other cases, Vanda claims, FDA has not required
applicants to prove Criterion B symptoms even when those
symptoms are listed as essential features. Reply Brief 11–12. Vanda
forfeited that argument, however, by failing to raise it in its opening
brief without justification. See Johnston v. SEC, 49 F.4th 569, 578
n.3 (D.C. Cir. 2022). The argument also appears meritless. In the
examples Vanda points to, the ICSD-3 definitions do not characterize
any Criterion B symptom as an “essential feature” of the disorder; to
the contrary, the “essential features” section of the ICSD-3 explicitly
labels only a Criterion A symptom as the “essential feature” of the
disorder and notes that Criterion B symptoms merely “accompan[y]”
that single “essential feature.” See J.A. 2085–87; J.A. 2105–07.

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indication only after FDA had issued its complete response
letter. FDA explained that it does not consider requests for
narrower indications raised after issuance of a complete
response letter. J.A. 61; J.A. 2062–63. And Vanda never
claims that, in any of the cases it identified, FDA considered
narrower indications that, like Vanda’s, were proposed at that
late stage.4 Indeed, contrary to Vanda’s argument, our court
recently found that FDA reasonably refused to consider a
narrower indication for another drug for much the same reason.
See Pharm. Mfg., 957 F.3d at 263–64, 266.
FDA did not act arbitrarily and capriciously either in
defining jet lag to include next-day impairment or in refusing
to consider Vanda’s narrower proposed indication.
C
Finally, Vanda argues that the Principal Deputy
Commissioner’s issuance of FDA’s final decision violated the
Constitution’s Appointments Clause. Vanda, however,
forfeited its Appointments Clause challenge by failing to raise
it before the agency.
The FDCA provides that “[n]o objection to the order of
the Secretary shall be considered by the court unless such
4 In response, Vanda suggests that it had earlier informally
raised the idea of pursuing a narrower indication but was dissuaded
from doing so, as FDA represented that the narrower indication
likely would not be approved. See, e.g., Petitioner’s Brief 34. That
answer, though, is nonresponsive. It matters little whether FDA
earlier signaled it was unpersuaded that a narrower indication was
approvable; Vanda still itself chose not to pursue the narrower
indication until after the complete response letter was issued. And
Vanda offers no argument as to why FDA acted inconsistently
in refusing to consider the narrower indication due to that
procedural failing.

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objection shall have been urged before” the agency, or “there
were reasonable grounds for [the] failure so to do.” 21 U.S.C.
§ 355(h). The statute’s text provides no carveout for
constitutional arguments. See id. And our court has applied
similar statutory exhaustion requirements to constitutional
claims. See Fleming v. USDA, 987 F.3d 1093, 1098 (D.C. Cir.
2021) (finding challenge to for-cause removal protections
forfeited where not raised before the agency because that
“argument is subject to a mandatory, non-excusable, issue-
exhaustion requirement imposed by statute”).
Vanda argues that it did raise its Appointments Clause
challenge to the FDA by repeatedly requesting a “hearing
before the Commissioner.” Reply Brief 23–24 (emphasis in
original). But Vanda identifies no place in its agency filings
where it explicitly argued that the Commissioner must
personally conduct the hearing. Nor does Vanda claim to have
mentioned the Appointments Clause—or even the
Constitution—in requesting a hearing before the
Commissioner. Because Vanda did not provide FDA a
meaningful “opportunity to pass on [the] issue,” the argument
is forfeited. Fleming, 987 F.3d at 1100 (citation modified).
Vanda next claims it had reasonable grounds to excuse its
forfeiture. Vanda explains that before FDA issued its final
decision, Vanda “had no occasion to suspect that anyone but
the Commissioner would issue the order,” or that any
Appointments Clause violation might occur. Reply Brief 24
(emphasis in original). Vanda’s claim is unpersuasive. Many
final decisions publicly available in the Federal Register are
signed by officials other than the Commissioner. See, e.g.,
Final Decision on the Proposal to Refuse to Approve a New
Drug Application for ITCA 650, Docket No. FDA-2021-N-
0874 (Aug. 23, 2024) (signed only by the Principal Deputy
Commissioner); Final Decision on the Proposal to Withdraw
Approval of Pepaxto (melphalan flufenamide) for Injection,

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Docket No. FDA-2023-N-3167 (Feb. 23, 2024) (signed by
Director of FDA’s Center for Biologics Evaluation and
Research). Vanda is a sophisticated repeat player before the
FDA; we are not persuaded that it could not reasonably have
anticipated that someone other than the Commissioner would
issue the decision.
Finally, Vanda argues that we retain the discretion to
entertain a forfeited Appointments Clause challenge. Cf., e.g.,
Freytag v. Comm’r of Internal Revenue, 501 U.S. 868, 878–79
(1991). Even if we possess such discretion where, as here, the
petitioner’s claim is subject to a mandatory statutory
exhaustion requirement, cf. Fleming, 987 F.3d at 1098, we
decline to exercise any such discretion in this case. The
complexity of the questions Vanda belatedly seeks to raise and
the weakness of its explanation for not complying with the
statute suggest this is not one of the “rare cases” where we
should overlook Vanda’s forfeiture. Freytag, 501 U.S. at 879.
III
The petition for review is granted in part, and the case is
remanded to FDA for future proceedings not inconsistent with
this opinion.
So ordered.

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