Pharmaceutical Manufacturing Research Services, Inc. v. FDA ( 2020 )

United States Court of Appeals
FOR THE DISTRICT OF COLUMBIA CIRCUIT
Argued December 3, 2019 Decided May 1, 2020
No. 18-1335
PHARMACEUTICAL MANUFACTURING RESEARCH SERVICES,
INC.,
PETITIONER
v.
FOOD & DRUG ADMINISTRATION, ET AL.,
RESPONDENTS
On Petition for Review of a Final Order
of the United States Food & Drug Administration
Elizabeth P. Papez argued the cause and filed the briefs
for petitioner.
Sarah Carroll, Attorney, U.S. Department of Justice,
argued the cause for respondents. With her on the brief were
Scott R. McIntosh, Attorney, Robert P. Charrow, General
Counsel, U.S. Department of Health and Human Services, and
AnnaMarie Kempic, Deputy Chief Counsel, Litigation.
Before: HENDERSON, WILKINS, and RAO, Circuit Judges.
Opinion for the Court filed by Circuit Judge RAO.
2
RAO, Circuit Judge: Before bringing a new drug to the
market, a pharmaceutical manufacturer must demonstrate to
the Food and Drug Administration that the drug is safe,
effective, and works as described. Here, petitioner
Pharmaceutical Manufacturing Research Services (“PMRS”)
sought approval to market a prescription opioid drug that
PMRS claims will be less prone to abuse by patients. The
FDA denied the application, finding that PMRS’s draft label
was false and misleading because there was no evidence that
the drug in fact possessed abuse deterrent properties. The
agency also denied PMRS’s request for a hearing regarding
approval of its application. PMRS challenges both
determinations under the Administrative Procedure Act. We
conclude that the FDA’s decision to deny the application was
reasonable and consistent with law and that its decision to
deny PMRS’s request for a hearing was not an abuse of
discretion. We therefore deny the petition for review.
I.
In recent years, as the prescription opioid crisis gripping
the United States has worsened, the pharmaceutical industry
has placed increasing emphasis on developing new
formulations of opioid medications designed to deter abuse.
Such “abuse-deterrent formulations” possess physical or
chemical properties that are intended to make it more difficult
for patients to take advantage of “the known or expected
routes of [opioid] abuse, such as crushing in order to snort or
dissolving in order to inject.” FDA, Abuse-Deterrent Opioid
Analgesics (last updated June 11, 2019),
https://go.usa.gov/xyKd7.
As for any new drug, a manufacturer seeking FDA
approval to market a prescription opioid with a label
describing the drug as “abuse deterrent” must establish,
3
among other things, “substantial evidence that the drug will
have the effect it purports … to have under the conditions of
use prescribed, recommended, or suggested in the proposed
labeling thereof,” 21 U.S.C. § 355(d)(5), and that the
proposed label is not “false or misleading in any particular,”
id. § 355(d)(7). “Substantial evidence” is defined in the Food,
Drug, and Cosmetic Act (“FDCA”) as “adequate and well-
controlled investigations, including clinical investigations, by
experts …, on the basis of which it could fairly and
responsibly be concluded by such experts that the drug will
have the effect it purports or is represented to have … in the
… proposed labeling thereof.” Id. § 355(d).
With respect to abuse deterrent opioids, the FDA has
elaborated on the FDCA’s general evidentiary standards for
new drugs. In 2015, the agency published a guidance
document that purports to “explain[] FDA’s current thinking”
about the types of clinical studies “that should be conducted
to demonstrate that a given formulation [of an opioid] has
abuse-deterrent properties,” “how those studies should be
performed and evaluated[,] … and their implications in
product labeling.” FDA, Abuse-Deterrent Opioids—
Evaluation and Labeling: Guidance for Industry 1 (Apr.
2015) (“2015 Guidance”), https://www.fda.gov/media/84819/
download. The 2015 Guidance sets out three categories of
“premarket studies” that the FDA states will be “appropriate”
“[i]n most cases … to obtain a full and scientifically rigorous
understanding of the impact of a technology or technologies
on a product’s abuse potential.” Id. at 5.
Petitioner PMRS is a privately owned pharmaceutical
company that produces a range of oral solid and liquid drugs.
In January 2017, PMRS submitted a new drug application
(“NDA”) seeking FDA approval for an immediate-release
formulation of oxycodone that PMRS claimed to have abuse
4
deterrent properties. In its application, PMRS proposed to
include “ADF,” short for “Abuse Deterrent Formulation,” in
the product name and to include various statements in the
label describing the drug’s abuse deterrent chemical and
physical properties. The proposed label read in relevant part:
TRADENAME is formulated with inactive
ingredients that make the capsule more
difficult to manipulate for misuse and
abuse. …
In vitro physical and chemical manipulation
studies … demonstrated that
TRADENAME capsules … have increased
resistance to physical and chemical
extraction [relative to a previously approved
opioid, Roxicodone].
There is no clinical evidence that
TRADENAME has a reduced abuse
liability compared to immediate-release
oxycodone.
Abuse of TRADENAME by injection, as
well as by the oral and nasal routes, is still
possible.
J.A. 66–67. The label’s claim regarding “inactive ingredients”
referred in part to the inclusion of a dye blend that was
intended to give a solution prepared from the drug a “dark,
opaque,” “contaminated” appearance. J.A. 412. PMRS
claimed this would “create a visual deterrent to abuse” by
intravenous injection. J.A. 412.
In November 2017, the FDA sent PMRS a complete
response letter explaining that its NDA could not be approved
in its current form. See 21 C.F.R. § 314.110(a) (describing
5
FDA process for complete response letters). The letter
identified numerous deficiencies in the NDA that would bar
approval under governing law. Most relevant to this appeal,
the FDA stated it could not conclude based on the evidence
that PMRS’s drug possessed the abuse deterrent properties
described in the proposed label. Among other things, the
agency found that PMRS had failed to submit evidence
supporting its hypothesis that the inclusion of dye in the
formulation would deter intravenous abuse. Moreover, studies
showed that PMRS’s drug was “easily manipulated to create a
solution suitable for abuse by the [intravenous] route.” J.A.
54. The FDA recommended that PMRS address these
deficiencies by reformulating its product with properties
expected to deter intravenous and nasal1 abuse and by
conducting Category 1, 2, and 3 studies (as defined in the
2015 Guidance) to support the abuse deterrent labeling
claims.2
Rather than attempt to remedy these deficiencies and
resubmit its NDA, PMRS requested a hearing regarding
approval of its application. In a series of submissions to the
FDA over the ensuing months, PMRS asserted that its
1
PMRS initially claimed that its product possessed properties
expected to deter nasal abuse, but later abandoned that claim,
conceding that there was insufficient evidence to support it.
2
The complete response letter also identified several other statutory
grounds on which to deny the application, including that PMRS had
not provided sufficient data to show that the drug’s formulation was
safe, see 21 U.S.C. § 355(d)(1), or that “the methods used in, and
the facilities and controls used for, the manufacture, processing, and
packing of such drug are [adequate] to preserve its identity,
strength, quality, and purity,” id. § 355(d)(3). The FDA
recommended steps PMRS could take to address those deficiencies.
6
proposed label reflected a “novel approach to reducing
[opioid] abuse potential” by focusing on product “indication
and recommended dosing [more] than the hypothetical abuse-
deterrent properties of [the drug’s] formulation.” J.A. 890. In
other words, PMRS did not submit additional evidence to
support the label’s statements concerning the drug’s physical
and chemical properties. Instead, the company insisted that its
product carried less potential for abuse because it would be
indicated only for acute, rather than long-term, pain
management, and because the label would recommend a
maximum daily dosage that was lower than similar opioids
already on the market. According to PMRS, the acute pain
indication coupled with lower dosing recommendations would
make its drug “the safest labeled opioid” on the market. J.A.
575. PMRS also argued that the FDA’s approach to abuse
deterrence, as laid out in the 2015 Guidance, was “misleading,
unscientific, and dangerous,” J.A. 575, and that a hearing was
needed to address the flaws in the agency’s approach.
In June 2018, the FDA sent PMRS a draft order
proposing denial of PMRS’s application and hearing request.
The draft order reiterated the deficiencies identified in the
complete response letter and explained that PMRS had failed
to identify a genuine factual issue that would justify a hearing.
The agency described numerous statutory grounds on which
to deny the NDA, including that PMRS’s proposed label was
false and misleading given the lack of scientific support for
the label’s statements about abuse deterrence.
Two months after receiving the proposed order, PMRS
filed a response in which it suggested modifying the draft
label to read, as relevant here:
Oxycodone HC1 IR ADF capsule is
formulated with inactive ingredients
7
intended to make the capsule more difficult
to manipulate for misuse and/or abuse.
Postmarketing epidemiology evidence is
required to demonstrate meaningful abuse-
deterrent properties. Oxycodone HC1 IR
ADF capsules should be prescribed
knowing meaningful abuse-deterrent
properties have not been proven.
J.A. 893 (emphasis in original).
The FDA issued a final order denying PMRS’s request
for a hearing and refusing to approve its NDA in October
2018. See 83 Fed. Reg. 54,598 (Oct. 30, 2018) (“Denial
Order”). The agency’s decision rested exclusively on its
finding that PMRS’s proposed label was false or misleading
under the FDCA. Id. at 54,601–02 (citing 21 U.S.C.
§ 355(d)(7)). As the FDA explained, PMRS failed to provide
evidence supporting its claim that the drug “has properties
that make it more difficult to manipulate for purposes of
abuse and misuse than a conventional formulation.” Id. at
54,600. Given the complete “lack of sufficient, reliable
evidence supporting PMRS’s proposed labeling for abuse-
deterrent properties,” the FDA found that a hearing was not
required because there was no “genuine and substantial issue
of fact” as to whether the NDA was approvable in its present
form. Id. (capitalization altered). The FDA declined to
address additional statutory deficiencies in the NDA because
“even if resolved in PMRS’s favor, PMRS’s NDA would still
be refused approval in its present form” due to the false and
misleading label. Id. at 54,603.
The FDA acknowledged that PMRS had recently
proposed modifying the label to state that “meaningful abuse-
deterrent properties have not been proven,” but refused to
8
consider revisions to the NDA made months after PMRS
requested a hearing. Id. at 54,600 n.9. The agency also noted
that in any event the proposed revisions did not appear to
address its concerns about the false or misleading label, as
PMRS still sought to include “ADF” in the product name,
conveying that the product had an “abuse deterrent
formulation.” Id. Similarly, the FDA declined to address other
arguments raised by PMRS that did not relate to the specific
concerns about the label cited in the complete response
letter—including PMRS’s claim that its product would deter
abuse because it would “only be labeled for management of
acute [rather than chronic] pain.” Id. at 54,602 n.20.
Finally, the FDA concluded a hearing was not needed to
address PMRS’s “legal and policy objections to FDA’s
approach to evaluating, labeling, and approving opioids.” Id.
at 54,602. The FDA explained that these issues had no
bearing on the approvability of PMRS’s application, and that
the agency had determined a hearing was not otherwise in the
public interest, see 21 C.F.R. § 314.200(g)(6), because a
hearing on a specific new drug application was not the
appropriate forum to address broader concerns about the
agency’s approach to the opioid epidemic. 83 Fed. Reg. at
54,602–03.
PMRS timely filed a petition for review pursuant to 21
U.S.C. § 355(h), which permits applicants to appeal an FDA
order denying approval of a new drug application to this
court.
II.
PMRS challenges the denial of the NDA on two grounds:
first, that a false or misleading label is not a sufficient
statutory ground on which to deny a new drug application;
and second, that denying the application based on the draft
9
label was arbitrary and capricious and contrary to law. We
explain in turn why each APA challenge fails.
A.
As a preliminary matter, PMRS asserts that the FDA’s
refusal to approve its application was contrary to law because
the FDCA does not permit the agency to deny an NDA solely
on the basis of a false or misleading label.
As with all questions of statutory interpretation, we start
with the text. See, e.g., Ross v. Blake, 136 S. Ct. 1850, 1856
(2016). The FDCA provides first that the FDA “shall …
approve [a new drug] application if [the agency] finds that
none of the grounds for denying approval specified in
subsection (d) applies.” 21 U.S.C. § 355(c)(1)(A) (emphasis
added). Subsection (d), in turn, provides that the FDA “shall
issue an order refusing to approve [an] application” if it finds
that one of seven grounds—enumerated in subsections (d)(1)
through (d)(7)—exists. Id. § 355(d) (emphasis added).
Subsection (d)(7) covers situations in which the FDA
concludes, “based on a fair evaluation of all material facts,”
that the applicant’s proposed labeling “is false or misleading
in any particular.” Id. § 355(d)(7). Together, these provisions
indicate that any of the seven grounds for denial specified in
subsection (d) is a basis on which the agency must deny an
application; if none of these grounds applies, the application
must be approved.
The sentence following the seven grounds for denial,
however, complicates matters. It states that if the FDA “finds
that clauses (1) through (6) do not apply, [the agency] shall
issue an order approving the application.” Id. § 355(d)
(emphasis added). Read in isolation, this sentence would
suggest that subsection (d)(7)—the false or misleading
labeling provision—does not furnish a sufficient basis,
10
standing alone, to deny an application. Yet this clause is in
direct conflict with the language in Section 355(c) and (d)
discussed above, which requires the agency to deny an
application on any of the seven grounds, including false or
misleading labeling. The statute does not explain this internal
inconsistency, and there is no other language in Section 355
suggesting that subsection (d)(7) should be treated differently
from the other six grounds for denial.
PMRS contends that the reference to “clauses (1) through
(6)” in Section 355(d) means the FDA cannot refuse to
approve an NDA based solely on a false or misleading label.
Here, the agency relied exclusively on subsection (d)(7) in
denying PMRS’s application. PMRS argues that the Denial
Order therefore contravened the plain text of the FDCA and
was contrary to law within the meaning of the APA. See 5
U.S.C. § 706(2)(A).
The FDA responds that this inconsistency in the text
reflects a scrivener’s error resulting from a 1984 amendment
to the FDCA that added a seventh ground for denying a new
drug application. In the pre-1984 version of the statute, the
false or misleading label provision appeared at subsection
(d)(6) and was followed by the same reference to “clauses (1)
through (6)” that appears in the current version. In other
words, under the prior iteration of Section 355(d), a false or
misleading label was a sufficient ground for denying an
application. Congress amended the statute by inserting a new
ground for denial at subsection (d)(6) and moving the false or
misleading labeling clause to (d)(7)—but it left unchanged the
reference to “clauses (1) through (6)” in the sentence that
follows. Compare 21 U.S.C. § 355(d) (1982), with 21 U.S.C.
§ 355(d) (1988). The FDA maintains that nothing in the
current statute indicates that Congress intended this
renumbering to alter the longstanding statutory scheme by
11
permitting the FDA, for the first time, to approve an
application that proposes false or misleading labeling. Indeed,
the remainder of Section 355 directly contradicts that
interpretation. Thus, the FDA maintains the only plausible
reading is that Congress simply neglected to update one
clause of Section 355(d) to include the renumbered ground
(7).
We agree with the FDA that a false or misleading label is
a sufficient ground for denial. As written, Section 355 states
an irreconcilable contradiction—two provisions indicate that
the agency can deny an application based only on false or
misleading labeling, but another suggests it cannot. While we
cannot “judicially amend[] a statute ‘to provide for what [we]
might think … is the preferred result,’” this case represents a
rare situation where “there is no plausible reading of the plain
text absent recognizing and correcting for the error.” United
States v. Palmer, 854 F.3d 39, 52–53 (D.C. Cir. 2017)
(quoting Lamie v. U.S. Tr., 540 U.S. 526, 542 (2004)). Under
such circumstances, “it is not contrary to sound principles of
interpretation … to give the totality of context precedence
over a single word”—or, in this instance, a single number.
Antonin Scalia, Common-Law Courts in a Civil-Law System:
The Role of United States Federal Courts in Interpreting the
Constitution and Laws, in A Matter of Interpretation: Federal
Courts and the Law 3, 20–21 (Amy Gutmann ed., 1997).
Here, the totality of statutory context confirms that the
FDA must deny an application if the label is false or
misleading, consistent with the text in Section 355(c)(1)(A)
and the beginning of Section 355(d). Section 355(e), for
example, provides that the FDA may withdraw its prior
approval of a new drug if “new information” reveals that the
drug’s label is “false or misleading in any particular.” 21
U.S.C. § 355(e). It would be incoherent to allow the FDA to
12
withdraw approval of a drug for false or misleading labeling,
but not to allow the FDA to deny approval on the same
grounds. Similarly, neighboring sections of the FDCA that
govern approvals of medical devices and animal drugs
unambiguously direct the FDA to deny any application that
proposes false or misleading labeling. See id. § 360e(d)(2)(D);
id. § 360b(d)(1)(H). The language and structure of these
provisions is substantially identical to Section 355(d), aside
from Section 355(d)’s contradictory reference to “clauses (1)
through (6).”3 Thus, throughout the statute, Congress
consistently prohibited the FDA from allowing drugs, medical
devices, and other regulated products to reach the market with
false or misleading labels. This context bolsters our
conclusion that the 1984 amendments did not establish a
novel standard for new drug applications that disrupts the
broader statutory scheme. Cf. Garcia-Carias v. Holder, 697
F.3d 257, 263 (5th Cir. 2012) (“[A] statutory provision cannot
be read in isolation, but necessarily derives meaning from the
context provided by the surrounding provisions, as well as the
broader context of the statute as a whole.” (citation and
quotation marks omitted)).
For similar reasons, the statutory history of Section
355(d) reinforces our interpretation. Before 1984, Section 355
unequivocally required the FDA to deny a new drug
application based on false or misleading labeling. See 21
U.S.C. § 355(d) (1982). The 1984 amendments inserted a new
subsection (d)(6), addressing patent information, but did not
3
A separate chapter of the FDCA, addressing regulation of tobacco
products, also directs the FDA to deny an application to market a
tobacco product if the agency finds, “based on a fair evaluation of
all material facts, the proposed labeling is false or misleading in any
particular.” 21 U.S.C. § 387j(c)(2)(C).
13
change the false or misleading labeling provision aside from
moving it to subsection (d)(7). See 21 U.S.C. § 355(d) (1988).
Construing the reference to “clauses (1) through (6)” to
effectively read “clauses (1) through (7)” does the “least
violence to the text.” Green v. Bock Laundry Mach. Co., 490
U.S. 504, 529 (1989) (Scalia, J., concurring in the judgment);
see also Lacson v. U.S. Dep’t of Homeland Sec., 726 F.3d
170, 173 n.2 (D.C. Cir. 2013) (“Because there is no indication
that Congress intended this technical change to affect the
scope of [the statutory provision], we agree with both parties
that the failure to replace the words ‘subsection … (s)’ with
‘subsection … (r)’ was a scrivener’s error.”).
PMRS asserts that we could “harmonize” the conflicting
statutory provisions by reading them to require the FDA to
approve an application that includes false or misleading
proposed labeling “subject to revision of the label.” Reply Br.
23. This interpretation, however, has absolutely no basis in
the text and would require us to “rewrit[e] the statute rather
than correct[] a technical mistake.” United States v. X-
Citement Video, Inc., 513 U.S. 64, 82 (1994) (Scalia, J.,
dissenting).
True scrivener’s errors are unusual and we should not
lightly assume that Congress has made one. Here, however,
reading the text of Section 355 in light of the broader context
and structure of the statute demonstrates that the lingering
reference to “clauses (1) through (6)” is best understood as an
error. We will not privilege one contradictory numbered
reference over the rest of the statutory text, context, and
structure. Accordingly, we conclude the FDA did not act
contrary to law in denying PMRS’s NDA based solely on its
finding that the proposed labeling was false or misleading.
14
B.
We next consider PMRS’s claim that the FDA’s decision
to deny approval of PMRS’s NDA was “arbitrary, capricious,
… or otherwise not in accordance with law.” 5 U.S.C.
§ 706(2)(A). As with all such claims, our review focuses on
whether the agency’s decision was “reasonable and
reasonably explained,” and “based on ‘consideration of the
relevant factors.’” Nat’l Tel. Co-op. Ass’n. v. FCC, 563 F.3d
536, 540 (D.C. Cir. 2009) (quoting Motor Vehicle Mfrs.
Ass’n, Inc. v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 43
(1983)). In the context of a challenge to the FDA’s
decisionmaking, we “give[] a high level of deference” to the
agency’s scientific analysis of the evidence before it, Rempfer
v. Sharfstein, 583 F.3d 860, 867 (D.C. Cir. 2009) (quotation
marks omitted), and must avoid “unduly second-guess[ing]
[those] scientific judgments,” Cytori Therapeutics, Inc. v.
FDA, 715 F.3d 922, 923 (D.C. Cir. 2013). Applying these
standards to the present case, we conclude the FDA acted
reasonably and in accordance with applicable law in finding
that PMRS’s proposed label was false and misleading and in
denying the NDA on that basis.
The FDA examined the evidence presented by PMRS and
reasonably concluded that it did not support the specific
statements included in PMRS’s proposed labeling. PMRS’s
draft label and proposed product name represented that its
drug possessed physical and chemical abuse deterrent
properties. Yet the FDA found that PMRS failed to present
substantial and reliable evidence showing that its
“formulation … actually possess[es] those properties.” 83
Fed. Reg. at 54,603. The reasons for this finding were
explained in detail in the Denial Order, as well as in the
FDA’s earlier responses to PMRS. As an initial matter, the
FDA emphasized that PMRS provided no evidence indicating
15
that the inclusion of a dye that would make an injectable
solution derived from the drug “dark, opaque, [and]
‘contaminated-looking’” would actually deter abuse. Id. at
54,598. The agency found this hypothesis particularly
problematic given that people who abuse opioids “routinely
take extraordinary risks in connection with their opioid
abuse.” Id. at 54,601. While PMRS criticizes the FDA for
“focus[ing] myopically on the dye in denying the
application,” Reply Br. 4, PMRS does not point to any other
scientific support for the label’s statements about the drug’s
“inactive ingredients” that the FDA overlooked.
Similarly, the FDA found no support for the draft label’s
statement that the drug had “increased resistance to physical
and chemical extraction” as compared to a previously
approved opioid, Roxicodone. In the Denial Order, the FDA
noted that this labeling claim “appear[ed] to rest on a
misunderstanding of how th[e] term [‘extraction’] is used in
the context of abuse-deterrent opioids,” because PMRS’s data
in fact showed that oxycodone could be easily extracted from
its product to create a solution suitable for injection. 83 Fed.
Reg. at 54,598 n.1. On appeal, PMRS argues that the FDA
erred in its “cursory dismissal of PMRS’s evidence on
‘solubility’ and ‘extraction,’” but never explains precisely
what the FDA is supposed to have gotten wrong. PMRS Br.
31.
The FDA also noted that PMRS had failed to submit any
evidence indicating that its drug would “deter abuse by
snorting,” 83 Fed. Reg. at 54,601, but acknowledged that
PMRS had “conceded … that the formulation should not be
considered to have this property,” id. at 54,598 n.2. PMRS
argues that the agency should not have “relie[d] heavily” on
the absence of such evidence since PMRS had abandoned its
original claim that the drug would deter nasal abuse. PMRS
16
Br. 30. While the FDA’s discussion on this point admittedly is
not a model of clarity, it does not undermine the validity of
the agency’s overall decisionmaking or its conclusion that
PMRS provided no evidence that its formulation had abuse
deterrent properties of any kind.
The FDA next considered the disclaimers PMRS
included in its draft label—stating there was “no clinical
evidence” that its product “has a reduced abuse liability
compared to immediate-release oxycodone,” and that abuse of
its product is “still possible”—and concluded that they did not
make the label accurate. 83 Fed. Reg. at 54,602 n.17.
Juxtaposed with the label’s other statements about abuse
deterrence, the FDA found the disclaimers conveyed that
PMRS’s drug had abuse deterrent properties, even if it was
not “abuse-proof.” Id.4
Finally, the FDA articulated a rational explanation for its
refusal to consider the revisions to the draft label that PMRS
submitted after its hearing request. According to the Denial
Order, by requesting a hearing, PMRS asked the FDA to
determine whether its existing application could be approved,
not to opine on whether PMRS could at some point formulate
a different NDA that “might address some of the deficiencies”
identified by the FDA. Id. at 54,600 n.9. We find this position
to be consistent with the FDA’s regulations, which require
applicants to choose between resubmitting an application and
4
In its reply brief, PMRS claims that the FDA “[did] not identify
any of this text as affirmatively false or misleading,” but does not
engage with the FDA’s actual analysis. Reply Br. 9. We will not
consider such a cursory argument raised for the first time on reply.
Dodge of Naperville, Inc. v. NLRB, 796 F.3d 31, 41 (D.C. Cir.
2015).
17
requesting a hearing. See 21 C.F.R. § 314.110(b).5 In any
event, the FDA explained that even the proposed revisions
would not address the FDA’s central concern “that PMRS’s
labeling represents that its product possesses abuse-deterrent
properties when the presence of such properties is not
supported by substantial and reliable evidence,” because
PMRS still proposed to include “ADF” in the product name.
83 Fed. Reg. at 54,600 n.9.
PMRS contends that the FDA departed from its precedent
by refusing to consider these proposed revisions. But it fails
to identify any examples of the FDA approving an NDA on
the basis of significant labeling revisions proposed after a
hearing request, particularly where there was no evidence
showing the formulation had any abuse deterrent properties.
Indeed, in the only arguably analogous example PMRS points
to, the FDA approved an opioid formulation with an amended
label describing the drug’s abuse deterrent properties only
after finding that the applicant “provided sufficient data to
demonstrate that the … formulation appears to provide an
incremental decrease in” persistent nasal abuse. See FDA, Ctr.
for Drug Eval. & Research, App. No. 202080Orig1s000,
Summary Review, at 18 (June 17, 2011). The FDA found no
comparable evidence here.
PMRS’s remaining arguments all rest on the same
premise: The FDA should have accepted PMRS’s alternative,
5
The regulation provides that after receiving a complete response
letter, an applicant “must take one of” three actions: (1) “Resubmit
the application …, addressing all deficiencies identified in the
complete response letter”; (2) “[w]ithdraw the application”; or (3)
“[a]sk the agency to provide the applicant an opportunity for a
hearing on the question of whether there are [statutory] grounds for
denying approval of the application.” 21 C.F.R. § 314.110(b).
18
superior approach to opioid abuse deterrence and approved
the NDA notwithstanding the lack of evidence for the label’s
assertions about the drug’s abuse deterrent formulation. Yet
the simple fact is that even if the FDA were willing to
consider PMRS’s alternative evidence of abuse deterrence,
such evidence would do nothing to fix the inaccuracies in the
label PMRS proposed.
First, PMRS argues the FDA disregarded the statutory
requirement to consider the accuracy of a drug’s labeling in
light of “all material facts,” 21 U.S.C. § 355(d)(7), which,
according to PMRS, includes the “conditions of use
prescribed, recommended, or suggested in the proposed
labeling,” id. § 355(d)(5). Here, PMRS proposed labeling its
drug with an indication for acute, rather than chronic, pain
management, and following the Center for Disease Control’s
dosing recommendations for immediate-release opioids.
According to PMRS, the FDA’s refusal to consider those
“conditions of use” in assessing the accuracy of the draft label
rendered the Denial Order contrary to law.
Next, PMRS argues that the agency failed to consider an
important aspect of the problem when it arbitrarily refused to
“‘even consider the possibility’ that PMRS’s indications and
studies could support an abuse deterrent label.” PMRS Br. 43
(emphasis omitted) (quoting State Farm, 463 U.S. at 48).
PMRS maintains that the FDA’s approach to abuse
deterrence, as set out in the 2015 Guidance, is scientifically
unsound, and that PMRS’s purportedly novel focus on
duration and dosing indications is more likely to deter abuse.
In effect, PMRS seeks to enlist the court in its preferred
approach to abuse deterrence. Whatever the validity of its
broader claims, PMRS’s proposal to label its product for acute
pain management and to recommend lower daily dosing—
19
features that have nothing do with a drug’s physical or
chemical properties—has no bearing on the accuracy of its
labeling claims about the product’s abuse deterrent
formulation. While PMRS contends on appeal that its
proposed label “described the product, not just its
‘formulation,’” Reply Br. 4, the words of the proposed label
belie that contention. PMRS sought to designate its drug as an
“abuse deterrent formulation,” not an abuse deterrent product.
The bottom line, as the FDA pointed out, is that PMRS
provided “no evidence establish[ing] … that this formulation
has the abuse-deterrent properties PMRS propose[d] to
include in its product labeling.” 83 Fed. Reg. at 54,601.6
Because both the product name and the draft label focused on
6
For this reason, PMRS’s separate claim that the FDA improperly
treated the 2015 Guidance as binding law also fails. It is well
established that “[o]nly ‘legislative rules’” promulgated through
public notice and comment “have the force and effect of law.”
Appalachian Power Co. v. EPA, 208 F.3d 1015, 1020 (D.C. Cir.
2000). PMRS contends that the FDA treats the 2015 Guidance as
requiring applicants seeking labeling for abuse deterrence to
present evidence from Category 1, 2, and 3 studies, without having
put those evidentiary guidelines through notice and comment
rulemaking. The problem for PMRS is that the FDA did not
premise its denial solely on the absence of Category 1, 2, and 3
studies—it denied the NDA due to the absence of any evidence
supporting PMRS’s labeling claims. The FDCA requires applicants
to support a proposed label with “substantial evidence.” 21 U.S.C.
§ 355(d). Because PMRS failed to provide substantial evidence of
any kind—Guidance-compliant or otherwise—it could not have
met the statutory standard. On these facts, we see no basis to
conclude that the FDA applied the 2015 Guidance “as if it were
binding.” Nat’l Mining Ass’n v. McCarthy, 758 F.3d 243, 253 (D.C.
Cir. 2014).
20
unproven abuse deterrent physical and chemical properties of
PMRS’s drug, they were false and misleading regardless of
whether PMRS is correct that there are other, more effective
ways of reducing opioid abuse. In other words, there was no
reason for the FDA to separately consider the particular
“conditions prescribed, recommended, or suggested in
[PMRS’s] proposed labeling” once it had found that the label
would be false and misleading regardless of those conditions.
See 21 U.S.C. 355(d).
The FDCA requires the FDA to determine whether a
proposed label is false or misleading “based on a fair
evaluation of all material facts.” Id. § 355(d)(7) (emphasis
added). For the reasons already stated, PMRS’s evidence
regarding alternative approaches to abuse deterrence was
immaterial to the agency’s assessment of the specific claims
in PMRS’s proposed label. In the absence of countervailing
evidence, we have no basis to question the agency’s
conclusion that the operative version of PMRS’s proposed
label created the false and misleading impression that the drug
possessed abuse deterrent physical and chemical properties.
See Rempfer, 583 F.3d at 867 (according heightened
deference to FDA where “there [was] no scientific evidence
in the administrative record to contradict [its] judgment”).
Meaningful review of the agency’s actions does not require us
to step into the FDA’s shoes and reassess its scientific
judgments—a role that we are “ill-equipped” to play “under
the guise of the APA’s arbitrary and capricious standard.”
Cytori Therapeutics, 715 F.3d at 927. Here, the FDA
examined the material factors, considered the record as a
whole, and provided a reasonable explanation for its decision
to deny PMRS’s application. Am. Wild Horse Pres. Campaign
v. Perdue, 873 F.3d 914, 923 (D.C. Cir. 2017). The APA
requires no more.
21
III.
Lastly, we consider whether the FDA properly exercised
its discretion in refusing to grant PMRS’s request for a
hearing on its application. See 21 U.S.C. § 355(c)(1) (after
reviewing an NDA, the agency must either approve the
application or “give the applicant notice of an opportunity for
a hearing … on the question whether such application is
approvable”); accord 21 C.F.R. § 314.200. Our review of an
agency’s decision to grant or deny a hearing is “necessarily
deferential,” and is “limited to an evaluation of whether [the
agency] has given adequate consideration to all relevant
evidence in the record.” Nat’l Corn Growers Ass’n v. EPA,
613 F.3d 266, 271–72 (D.C. Cir. 2010) (citation and quotation
marks omitted). To warrant a hearing, a party’s submission
must raise a genuine and substantial issue of fact “that might
affect the outcome … under the governing law.” John D.
Copanos & Sons, Inc. v. FDA, 854 F.2d 510, 522–23 (D.C.
Cir. 1988) (citation omitted); see also 21 C.F.R. §12.24(b)(4)
(“A hearing will not be granted on factual issues that are not
determinative with respect to the action requested.”). For
many of the reasons discussed in Part II.B, we find the FDA
acted within its discretion in denying PMRS’s hearing
request.
As already explained, the FDA considered PMRS’s
application and reasonably determined that there was no
evidence to support PMRS’s claim that its product had an
abuse deterrent “formulation.” PMRS’s evidence regarding
duration and dosing therefore could not remedy the false and
misleading nature of its draft label, which focused on the
product’s chemical and physical properties. This meant that
PMRS’s alternative evidence, even if considered, necessarily
could not create a “genuine and substantial issue of fact” that,
if resolved in PMRS’s favor, would justify approval of
22
PMRS’s application. 21 C.F.R. § 12.24(b). In other words,
because PMRS’s proffered evidence created no relevant
factual dispute, it did not provide a basis on which to grant a
hearing. See Copanos, 854 F.3d at 523.
Nor can we conclude that PMRS’s eleventh hour attempt
to modify its proposed label created a genuine issue of fact
requiring a hearing. PMRS submitted a proposed revision to
its draft label in August 2018—many months after receiving
the complete response letter and electing to request a hearing
rather than revise and resubmit its application. As already
noted, we find the FDA’s explanation for its refusal to
consider revisions at this late stage to be reasonable. See
supra at 16–17.
Finally, we do not believe the FDA exceeded its
discretion in refusing to grant PMRS’s request for a hearing
on broader policy issues related to the problem of opioid
abuse deterrence. PMRS might be dissatisfied with the
agency’s overall approach, but the FDA’s regulations make
clear that “a hearing will not be granted on issues of policy
and law.” See 21 C.F.R. § 12.24(b)(1). Particularly in light of
our “necessarily deferential” review of agency hearing
requests, Nat’l Corn Growers Ass’n, 613 F.3d at 271, we will
not lightly overrule an agency’s determination that a hearing
is not “otherwise in the public interest.” See 83 Fed. Reg. at
54,603 (citing 21 C.F.R. § 314.200(g)(6)). In the Denial
Order, the FDA described the numerous fronts on which it is
working to tackle the pervasive crisis of prescription opioid
addiction and abuse. Id. The FDA chose to set such policies in
publicly available guidance documents, thereby providing
notice and predictability to regulated entities. We find no
abuse of discretion in the FDA’s determination that a hearing
on one manufacturer’s new drug application is not the
23
appropriate forum to address these important public health
issues.
* * *
The FDA reasonably concluded that PMRS’s proposed
labeling was false and misleading under 21 U.S.C.
§ 355(d)(7). On that basis, it denied PMRS’s request for a
hearing and refused to approve its NDA. Because the FDA
complied with applicable law, examined the evidence
provided by PMRS, and explained its reasoning, we uphold
the agency’s action. The petition for review is denied.
So ordered.