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 DRUG 

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 extendedrelease 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., ASSESSMENT OF THEOPHYLLINE AS A 

NARROW THERAPEUTIC INDEX DRUG 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 DRUG 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 extendedrelease 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.