Nostrum Pharmaceuticals LLC v. FDA

United States Court of Appeals
FOR THE DISTRICT OF COLUMBIA CIRCUIT
Submitted March 2, 2022 Decided June 3, 2022
No. 20-1525
NOSTRUM PHARMACEUTICALS, LLC,
PETITIONER
v.
UNITED STATES FOOD AND DRUG ADMINISTRATION,
RESPONDENT
On Petition for Review of Orders
of the Food and Drug Administration
Shashank Upadhye was on the briefs for petitioner.
Douglas B. Farquhar entered an appearance.
Brian M. Boynton, Acting Assistant Attorney General at
the time the brief was filed, U.S. Department of Justice, Scott
McIntosh and Joshua Dos Santos, Attorneys, Daniel J. Barry,
Acting General Counsel, U.S. Department of Health and
Human Services, Wendy Vicente, Acting Deputy Chief
Counsel for Litigation, and Leslie Cohen, Associate Chief
Counsel, were on the brief for respondent.
2
Before: TATEL* and MILLETT, Circuit Judges, and
EDWARDS, Senior Circuit Judge. †
Opinion for the Court filed by Circuit Judge MILLETT.
MILLETT, Circuit Judge: Nostrum Pharmaceuticals, LLC
is a drug manufacturer seeking to market various strengths and
formulations of generic theophylline, a drug used to treat
asthma and other respiratory conditions. To that end, Nostrum
submitted a supplemental abbreviated new drug application to
the Food and Drug Administration (“FDA”). This application
remains pending. As part of the FDA’s review process, an
agency division sent Nostrum a so-called “complete response
letter” that flagged deficiencies in the application and
explained how Nostrum could remedy them. Nostrum sought
reconsideration of only a portion of the complete response
letter, which the division denied. Nostrum now petitions for
review of the complete response letter and the denial of
reconsideration. Because neither agency action constitutes a
final rejection of the application, we lack jurisdiction to hear
Nostrum’s petition and therefore dismiss it.
I
A
Under the Food, Drug, and Cosmetic Act, a drug
manufacturer seeking to market a generic drug must submit an
abbreviated new drug application to the FDA showing that the
*
Judge Tatel assumed senior status after this case was argued
and before the date of this opinion.
†
This petition was considered on the record from the Food and
Drug Administration and on the briefs filed by the parties. See FED.
R. APP. P. 34(a)(2); D.C. CIR. R. 34(j).
3
new drug is “bioequivalent” to a drug that has already been
approved, which is known as the “listed drug.” 21 U.S.C.
§ 355(j)(2)(A)(iv). The FDA considers two drugs
bioequivalent if there is no “significant difference in the rate
and extent to which” their active ingredients become “available
at the site of drug action[,]” typically in the blood. 21 C.F.R.
§ 314.3. The FDA’s regulations include guidelines on how to
conduct bioequivalence studies. See, e.g., 21 C.F.R. §§ 320.26,
320.29. Additionally, if a manufacturer wishes to make a
“major manufacturing change” to the production of its already
approved generic drug, it must submit a supplemental
application to the FDA. 21 U.S.C. § 356a(c)(1); 21 C.F.R.
§§ 314.70(b)(1), 314.97.
Once a drug manufacturer submits an application to the
FDA, a multi-step review process begins. The FDA may refuse
to approve an application for a number of reasons, including a
lack of data sufficient to show that the proposed generic drug
is bioequivalent to the reference drug. 21 C.F.R.
§ 314.127(a)(6)(i). If, in the course of reviewing an
application, the FDA or one of its divisions concludes that an
application has a defect that could potentially cause the agency
to reject the application, it issues a “complete response
letter[.]” Id. § 314.110(a).
A complete response letter “will describe all of the specific
deficiencies” that the agency identified in the application and,
“[w]hen possible,” will “recommend actions that the applicant
might take to place the application * * * in condition for
approval.” 21 C.F.R. § 314.110(a)(1), (4). If the applicant’s
responses would “require extensive assessment[,]” the agency
categorizes them as “major” amendments. CENTER FOR D RUG
EVALUATION & RESEARCH, U.S. FOOD & DRUG ADMIN.,
ANDA SUBMISSIONS—AMENDMENTS TO ABBREVIATED NEW
DRUG APPLICATIONS UNDER GDUFA: GUIDANCE FOR
4
INDUSTRY 4 (July 2018) [hereinafter AMENDMENTS TO
ABBREVIATED NEW DRUG APPLICATIONS].
An applicant who receives a complete response letter has
several options for proceeding. First, it may “[r]esubmit the
application * * *, addressing all deficiencies identified in the
complete response letter.” 21 C.F.R. § 314.110(b)(1). Second,
it may “[w]ithdraw the application * * * without prejudice to a
subsequent submission.” Id. § 314.110(b)(2). Third, it may
decline to revise its application and request a hearing “on the
question of whether there are grounds for denying approval of
the application[.]” Id. § 314.110(b)(3). Additionally, FDA
draft guidance permits applicants to seek reconsideration of a
complete response letter by the division that issued the letter.
See CENTER FOR DRUG EVALUATION & RESEARCH, U.S. FOOD
& DRUG ADMIN ., REQUESTS FOR RECONSIDERATION AT THE
DIVISION LEVEL UNDER GDUFA: GUIDANCE FOR INDUSTRY
3–6 (Oct. 2017) [hereinafter “RECONSIDERATION GUIDANCE
FOR INDUSTRY”]. If the applicant does nothing for a full year
after the complete response letter is issued, the FDA may, after
some additional steps, deem the application withdrawn without
prejudice to resubmission. 21 C.F.R. § 314.110(c).
If an applicant does not want to make the proposed
changes, it may choose the third option and ask for a hearing.
At that point, the FDA may go ahead and approve the
application as is. 21 C.F.R. § 314.110(b)(3). Or it could
propose to “refuse to approve the application * * * and give the
applicant written notice of an opportunity for a hearing * * *
on the question of whether there are grounds for denying
approval of the application[.]” Id.; see id. § 314.200(a)
(describing this stage of the agency decisionmaking process as
a “proposal to refuse to approve an application”) (emphasis
added). The FDA regulations governing such hearings allow
for the submission of evidence and arguments. Id.
5
§ 314.200(c)–(e). The Commissioner of Food and Drugs may
then either enter summary judgment, id. § 314.200(g)(1)–(4),
or hold a hearing “if there exists a genuine and substantial issue
of fact or if [he] concludes that a hearing would otherwise be
in the public interest[,]” id. § 314.200(g)(6). If, after all this,
the Commissioner issues an “order * * * refusing * * *
approval of an application[,]” that order is subject to judicial
review. 21 U.S.C. § 355(h); see also id. § 355(j)(5)(E).
B
Nostrum manufactures generic theophylline extended-
release tablets. Theophylline is used to treat a number of
chronic lung diseases such as asthma, emphysema, and
bronchitis. When theophylline is administered at the
appropriate blood concentration, it can be effective. The
challenge is that, for theophylline, “[t]here is little separation
between effective concentrations and concentrations associated
with serious toxicity[,]” and “[s]ub-optimal concentrations lead
to severe therapeutic failure.” OFFICE OF GENERIC DRUGS, U.S.
FOOD & DRUG ADMIN., A SSESSMENT OF THEOPHYLLINE AS A
NARROW THERAPEUTIC INDEX D RUG 1 (Jan. 12, 2017). In other
words, small variations in theophylline’s dosage can have
serious adverse health consequences for patients. For that
reason, the FDA has classified theophylline as a “narrow
therapeutic index” drug.
Bioequivalence is commonly shown through a “two-way
study” in which subjects are administered one dose each of the
test drug and the listed drug, and the rate and extent of
absorption of the two drugs is compared. But in light of the
unique safety concerns that narrow therapeutic index drugs
pose, the FDA advises that drug manufacturers submit more
rigorous bioequivalence studies for generic narrow therapeutic
index drugs than for other generics. Specifically, the FDA’s
6
preferred method of demonstrating a narrow therapeutic index
drug’s bioequivalence is a “fully replicated crossover design”
study. See, e.g., CENTER FOR D RUG EVALUATION & RESEARCH,
U.S. FOOD & DRUG ADMIN ., SUMMARY MINUTES OF THE
ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE AND
CLINICAL PHARMACOLOGY 5 (July 26, 2011). A fully
replicated crossover design study requires that subjects be
given two doses each of the test and the listed drug so that
researchers can measure the difference in rate and extent of
absorption as between two doses of the same drug administered
at different times to the same subject. Basically, this study
design is meant to confirm that the generic drug is as reliable
as the listed drug in being absorbed by the same person in a
consistent manner across multiple doses.
C
In 2020, Nostrum submitted a supplemental abbreviated
new drug application seeking, among other things, approval to
market a 450 milligram strength of its theophylline extended-
release tablets and to reformulate its previously approved 100,
200, and 300 milligram strengths. Nostrum sought to
demonstrate the 450 milligram strength’s bioequivalence by
submitting two-way studies. Nostrum also asked for a waiver
of the requirement to show bioequivalence for its reformulated
strength tablets.
On July 21, 2020, a division within the Office of Generic
Drugs issued a complete response letter notifying Nostrum that
its supplemental abbreviated new drug application could not be
approved “in its present form.” Joint Appendix (“J.A.”) 611.
The letter advised that “[t]he Agency has recently determined
that theophylline is a narrow therapeutic index * * * drug[,]”
and so Nostrum’s two-way studies “were insufficient to
demonstrate” bioequivalence. J.A. 612. The division asked
7
Nostrum to conduct bioequivalence studies “using a fully
replicated crossover design[,]” which it identified as “the most
accurate, sensitive, and reproducible approach” to
bioequivalence testing. J.A. 612 (citing 21 C.F.R.
§ 320.24(a)). It also denied Nostrum’s request for a waiver of
bioequivalence studies for its lower-strength formulations.
The letter identified other issues for Nostrum to address, such
as dissolution testing and labeling.
The division categorized the gaps in Nostrum’s application
as “major[,]” and it advised Nostrum that it could respond by
taking one of the actions available under 21 C.F.R.
§ 314.110(b)—namely, make the requested changes, withdraw
its application, or request a hearing before the Commissioner.
J.A. 615.
Nostrum twice requested reconsideration from the
division. In August 2020, it asked the division to reclassify the
defects in its application as “minor” rather than “major” so that
it could avoid the case-processing consequences of a major
classification. See J.A. 619 (Nostrum’s reconsideration
request); AMENDMENTS TO ABBREVIATED NEW DRUG
APPLICATIONS 3–5 (discussing the distinctions between major
and minor amendments). A month later, the division denied
that request. In September 2020, Nostrum requested that the
division reconsider several of the other issues raised by the
complete response letter. The status of that request is under
seal.
D
On December 30, 2020, with its second reconsideration
request still pending, Nostrum petitioned this court for review
of the complete response letter and the denial of its first request
for reconsideration, arguing that the FDA acted arbitrarily and
8
capriciously in requiring Nostrum to demonstrate
bioequivalence using a fully replicated study.
The FDA moved to dismiss the petition on the ground that
neither the complete response letter nor the reconsideration
denial were reviewable final agency actions.
In March 2021, while that motion to dismiss was pending,
Nostrum sent the FDA a “major” “resubmission” of its
supplemental abbreviated new drug application, with the stated
goal of maintaining the pendency of its application before the
agency. Nostrum Mot. to Govern Further Proceedings 5–6
(“Nostrum submitted the * * * Letter to FDA in an effort to
stave off an automatic withdrawal[.]”). In the main, Nostrum
vigorously disputed the complete response letter’s
bioequivalence conclusions and the need to conduct new
studies. Id. At the same time, the resubmitted application did
“respond[] to all the other issues detailed in the Complete
Response Letter” in the hope that providing “satisfactory
answers to FDA’s other concerns” would “protect” its
application. Id. at 9–10.1
II
As relevant here, we have jurisdiction to review only “an
order of the Secretary refusing * * * an application under this
section.” 21 U.S.C. § 355(h). Consequently, our review is
limited to final rejections of drug applications, not interim
decisions or nonbinding statements subject to further review or
change. See Pharmaceutical Mfg. Rsch. Servs., Inc. v. FDA,
1
The court’s motion panel referred to this panel the FDA’s
motion to dismiss the petition, and a separate motion filed by
Nostrum to supplement the administrative record with certain
communications sent by Nostrum staff to FDA officials and
materials relating to past abbreviated new drug applications.
9
957 F.3d 254, 259 (D.C. Cir. 2020) (Section 355(h) “permits
applicants to appeal an FDA order denying approval of a new
drug application[.]”) (emphasis added).
A
We hold that courts lack jurisdiction to review a complete
response letter issued by an FDA division because it is not an
“order of the Secretary” that “refus[es] * * * approval of an
application[.]” 21 U.S.C. § 355(h). Rather, a complete
response letter is an interim step in the FDA’s consideration of
an application. More must happen before the FDA’s final
determination on the application is made. Cf. Bennett v. Spear,
520 U.S. 154, 178 (1997) (decisions “of a merely tentative or
interlocutory nature” are not final agency action).
The FDA’s regulations are explicit that complete response
letters simply afford applicants the opportunity to provide
additional information before the agency makes a final decision
on the application. Cf. California Cmtys. Against Toxics v.
EPA, 934 F.3d 627, 631 (D.C. Cir. 2019) (“[W]hen assessing
the nature of an agency action (including whether it is final),
* * * courts should take as their NorthStar the unique
constellation of statutes and regulations that govern the action
at issue.”). That is why a complete response letter “will
describe all of the specific deficiencies that the agency has
identified in an application[.]” 21 C.F.R. § 314.110(a)(1). It
will also identify any shortcomings in the data an applicant has
submitted. Id. § 314.110(a)(3). And the letter will, when
possible, “recommend actions that the applicant might take to
place the application or abbreviated application in condition for
approval.” Id. § 314.110(a)(4). In other words, a complete
response letter “inform[s] sponsors of changes that must be
made before an application can be approved, with no
implication as to the ultimate approvability of the application.”
10
Applications for Approval to Market a New Drug; Complete
Response Letter; Amendments to Unapproved Applications,
73 Fed. Reg. 39,588, 39,589 (July 10, 2008).
So rather than end the agency process, a complete response
letter opens multiple doors for further processing of an
application. After receiving a letter, the applicant may choose
to withdraw its application without prejudice, 21 C.F.R.
§ 314.110(b)(2), revise its application, id. § 314.110(b)(1),
stand on its application by requesting an opportunity for a
hearing, id. § 314.110(b)(3), or seek reconsideration at the
division level, RECONSIDERATION GUIDANCE FOR INDUSTRY
3 –6.
If an applicant requests an opportunity for a hearing, the
FDA may decide to approve the application as is. 21 C.F.R.
§ 314.110(b)(3). If it does not, the applicant may make its case
to senior FDA leadership. First, the Director of the Center for
Drug Evaluation and Research “will prepare an analysis of the
request and a proposed order ruling on the matter.” Id.§ 314.200(f). Then, the Commissioner of Food and Drugs
will consider the matter. Id. § 314.200(f)–(g). If the
Commissioner rejects an application, either on summary
judgment or after a hearing, he will enter an “order * * *
refusing * * * approval” that is appealable to a court of appeals
under 21 U.S.C. § 355(h). See also 21 U.S.C. § 355(j)(5)(E);
Pharmaceutical Mfg., 957 F.3d at 259.
All of that is to say that complete response letters are only
a preliminary step in the agency’s scientific review process.
The recipient of a complete response letter “still enjoys an
opportunity to convince the agency to change its mind[,]”
MediNatura, Inc. v. FDA, 998 F.3d 931, 939 (D.C. Cir. 2021)
(citation omitted), by persuading senior FDA leadership. As a
matter of agency process and decisionmaking, the issuance of
11
a complete response letter is multiple steps removed from the
conclusive “order * * * refusing * * * approval of an
application[,]” 21 U.S.C. § 355(h), that is a prerequisite to our
jurisdiction.
The facts of this case underscore the unfinished nature of
the agency process at the complete-response-letter stage. Since
petitioning this court for review, Nostrum has continued to
press for approval of its still-pending application before the
agency. In March 2021, Nostrum sent the FDA a letter
disputing the complete response letter’s bioequivalence
conclusions, while also “responding to all the other issues” that
the division had raised. Mot. to Govern 5–6, 9–10. Nostrum
sent this letter for the express purpose of “stav[ing] off” an end
to agency proceedings. Id. at 5; see 21 C.F.R. § 314.110(c)(1)
(inaction by an applicant for a year after the issuance of a
complete response letter may be construed as a “request by the
applicant to withdraw the application”). Those measures
would make no sense if the FDA had already issued an order
“refusing * * * approval of [the] application[.]” 21 U.S.C.
§ 355(h).
Nostrum argues that the continued pendency of its
application is no obstacle to our review because it remains at
loggerheads with the FDA on the central question of how it can
demonstrate its products’ bioequivalence. Mot. to Govern 4,
12. The short answer is that Congress has conditioned our
jurisdiction on the actual rejection of Nostrum’s application,
not the mere existence of disagreement over a scientific issue
in the course of the agency’s consideration.
Beyond that, the disagreement does not seem to be
cemented. In motions for extensions of briefing deadlines,
Nostrum advised this court that it continued to push the FDA
for relief and saw at least some prospect that it would be
12
successful, explaining that if the FDA “respond[ed] favorably”
to the points raised in Nostrum’s March letter, that would cause
“Nostrum’s request for review * * * [to] become moot[.]”
Nostrum Mot. to Extend Deadline for Filing Brs. 2; accord
Nostrum Emergency Mot. to Extend Deadlines for Filing Brs.
2 (“FDA’s anticipated response [to the March letter] may moot
this case[.]”). That Nostrum has been pursuing relief
simultaneously before the agency and this court shows that the
complete response letter was not a conclusive rejection of its
(concededly still-pending) application. Cf. Bellsouth Corp. v.
FCC, 17 F.3d 1487, 1489 (D.C. Cir. 1994) (“[A]n agency
action cannot be considered nonfinal for one purpose and final
for another.”).
Nostrum’s additional arguments cannot overcome the
plain statutory barrier to our review.
First, Nostrum argues that, after a complete response letter
issues, there is “nothing else for the agency to do.” Nostrum
Reply Br. 26. That is wrong. Unless the applicant voluntarily
withdraws its application, the FDA will either need to consider
a resubmitted application, 21 C.F.R. § 314.110(b)(1), or, if the
applicant chooses not to make the suggested changes and seeks
a hearing, decide on the application as it stands, id.§§ 314.110(b)(3); 314.200.
Second, Nostrum contends that, because it “will not
voluntarily make the changes” called for in the complete
response letter, the FDA “has effectively determined that the
application cannot be approved” and further proceedings
would be futile. Nostrum Reply Br. 27; see id. at 30. Not so.
The regulations expressly provide that the applicant can seek a
hearing at this juncture and that the FDA could then approve
the application as is, without Nostrum making any changes. 21
C.F.R. § 314.110(b)(3). Or Nostrum could go forward with a
13
hearing, which could lead to a final FDA decision approving or
rejecting the application in its current form. See id.; id.§ 314.200.
Finally, Nostrum observes that the Act does not require it
to request a hearing before seeking judicial review. True
enough. But it does condition judicial review on the issuance
of an order rejecting an application. 21 U.S.C. § 355(h). That
has not happened yet.
B
For similar reasons, the FDA’s denial of Nostrum’s
reconsideration request is not properly before us. Nostrum
asked the division to reclassify the defects in its application as
“minor” rather than “major[.]” J.A. 619. The denial of that
request certainly is not an “order of the Secretary refusing * * *
approval of an application[.]” 21 U.S.C. § 355(h).
III
Nostrum’s petition for review is dismissed. Nostrum’s
motion to supplement the record and the FDA’s separate
motion to dismiss the petition are denied as moot.
So ordered.