Vanda Pharmaceuticals, Inc. v. FDA

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.

2

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

3

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.

4

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.

5

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

6

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

7

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

8

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

9

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.

10

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

11

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

12

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.

13

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

14

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.

15

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.

16

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

17

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

18

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

19

& 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.

20

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.

21

“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

22

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.

23

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.

24

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.

25

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,

26

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.