Cumberland Pharmaceuticals Inc. v. Food and Drug Administration

UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF COLUMBIA
____________________________________
)
CUMBERLAND )
PHARMACEUTICALS INC., )
)
Plaintiff, )
)
v. ) Civil Action No. 12-01842 (RBW)
) UNDER SEAL
FOOD & DRUG )
ADMINISTRATION, et al., )
)
Defendants. )
____________________________________ )
MEMORANDUM OPINION
Plaintiff Cumberland Pharmaceuticals Inc. (“Cumberland”) brings suit against the Food
& Drug Administration (“FDA”), FDA Commissioner Margaret A. Hamburg, and Department of
Health and Human Services Secretary Kathleen Sebelius (collectively “FDA”), alleging that the
FDA’s denial of Cumberland’s May 18, 2012 citizen petition and simultaneous approval of
InnoPharma, Inc.’s (“InnoPharma”) abbreviated new drug application for acetylcysteine
injection was arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with
law in violation of the Administrative Procedure Act (“APA”), 5 U.S.C. § 706(2)(A) (2012).
Complaint (“Compl.”) ¶¶ 32–38. The FDA’s Motion to Dismiss Or, In the Alternative, for
Summary Judgment (“Defs.’ Mot.”) and Cumberland’s Cross-Motion for Summary Judgment
(“Pl.’s Mot.”) are currently before the Court. After careful consideration of the parties’
submissions and the administrative record (“A.R.”), 1 the Court concludes that it must grant
summary judgment to the FDA.
1
In addition to the filings already referenced, the Court considered the following documents in rendering its
decision: (1) the Defendants’ Memorandum in Support of Motion to Dismiss Or, In the Alternative, for Summary
Judgment (“Defs.’ Mem.”); (2) the Memorandum of Points and Authorities in Opposition to Defendants’ Motion to
Dismiss and In Support of Plaintiff’s Cross-Motion for Summary Judgment (“Pl.’s Mem.”); (3) the Federal
(continued . . . )
I. STATUTORY AND REGULATORY BACKGROUND
The Food, Drug, and Cosmetic Act (“FDCA”) provides that “[n]o person shall introduce
or deliver for introduction into interstate commerce any new drug, unless an approval of an
application filed pursuant to . . . this section is effective with respect to such drug.” 21 U.S.C. §
355(a) (2012). In order to obtain approval, a new drug application (“NDA”) must include,
among other things, “full reports of investigations which have been made to show whether or not
[the] drug is safe for use and whether [the] drug is effective in use.” Id. § 355(b)(1)(A). Because
this process is “costly and time[-]consuming,” Congress amended the FDCA in 1984 to “permit[]
a manufacturer of a generic alternative to a pioneer drug to seek FDA approval by submitting an
abbreviated new drug application (“ANDA”),” Serono Labs., Inc. v. Shalala, 158 F.3d 1313,
1316 (D.C. Cir. 1998), which references and relies on the prior approval of the pioneer drug,
Astellas Pharma US, Inc. v. FDA, 642 F. Supp. 2d 10, 13–14 (D.D.C. 2009). So “[r]ather than
requiring the [ANDA] applicant to make an independent showing that the proposed generic is
itself safe and effective, the amended statute requires a showing that the proposed generic
operates in the same manner as the pioneer drug on which it is based.” Id.To that end, FDA regulations require that an ANDA include information comparing,
among other things, the proposed drug’s active ingredients, route of administration, dosage form,
and strength to the “reference listed drug.” 21 C.F.R. §§ 314.94(a)(5), (6) (2012). For injectable
ANDA drugs in particular, there are additional regulations regarding the inactive ingredients in
the drug, which require that the proposed drug “[g]enerally . . . contain the same inactive
ingredients and in the same concentration as the reference listed drug.” Id. § 314.94(a)(9)(iii).
(. . . continued)
Defendants’ Reply Memorandum in Support of Motion to Dismiss Or, In the Alternative, for Summary Judgment
and Opposition to Plaintiff’s Cross-Motion for Summary Judgment (“Defs.’ Reply”); and (4) the Reply
Memorandum in Support of Plaintiff’s Cross-Motion for Summary Judgment (“Pl.’s Reply”).
2
Nonetheless, “an applicant may seek approval of a drug product that differs from the reference
listed drug in preservative, buffer, or antioxidant provided that the applicant identifies and
characterizes the differences and provides information demonstrating that the differences do not
affect the safety or efficacy of the proposed drug product.” Id. An ANDA applicant may also
ask the FDA to waive any regulatory requirement governing the submission of ANDAs. Id. §
314.99(b). The FDCA unequivocally prohibits the FDA from approving an ANDA, however, if
information submitted in the application or any other information available to the
Secretary shows that (i) the inactive ingredients of the drug are unsafe for use
under the conditions prescribed, recommended, or suggested in the labeling
proposed for the drug, or (ii) the composition of the drug is unsafe under such
conditions because of the type or quantity of inactive ingredients included or the
manner in which the inactive ingredients are included.
21 U.S.C. § 355(j)(4)(H).
If an ANDA applicant wishes to rely on a reference listed drug that has been voluntarily
withdrawn from the market in the United States, the applicant must include with its application a
petition “seeking a determination whether the listed drug was withdrawn for safety or
effectiveness reasons . . . and must contain all evidence available to the petitioner concerning the
reasons for the withdrawal from sale.” 21 C.F.R. § 314.122(a). The petition may be in the form
of a “citizen petition” under 21 C.F.R. § 10.30 or another petition form specified in FDA
regulations. Id. The FDA “consider[s] the evidence in the petition and any other evidence
before the agency” to determine whether the reference listed drug was withdrawn for safety or
effectiveness reasons. Id. § 314.122(b).
In conducting this inquiry, the FDA “rel[ies] upon circumstantial evidence and logical
inference to determine the actual intent of those who decided to withdraw the product from the
market” and “focus[es] on whether there were sufficient concerns about safety and effectiveness
to make a withdrawal from sale likely and reasonable.” 54 Fed. Reg. 28,872-01, 28,907 (July
3
10, 1989). While the FDA considers a manufacturer’s stated reasons for withdrawing a product,
it does “not consider the NDA holder’s stated reasons for withdrawing a drug to be determinative
because such remarks could be biased.” 57 Fed. Reg. 17,950-01, 17,971 (Apr. 28, 1992).
Recognizing that a drug manufacturer may have business reasons to disclaim concerns about the
safety or effectiveness of a withdrawn product, the FDA employs a rebuttable presumption that a
withdrawal was for safety or effectiveness reasons “[i]f a drug manufacturer withdraws a drug
from the market which accounted for significant sales to that manufacturer, and there is no
evidence to the contrary.” 54 Fed. Reg. 28,872-01 at 28,907. To determine whether a
withdrawal was for reasons of safety or effectiveness, the FDA also considers “other factors . . .
such as increases in the number of adverse drug reactions reported on the drug and published or
unpublished studies of the drug questioning its safety or effectiveness.” Id. If it concludes that
the reference listed drug was withdrawn from sale for safety or effectiveness reasons, the FDA
must disapprove the ANDA referencing the withdrawn drug. See 21 C.F.R. §§ 314.93(e)(1)(v),
314.127(a)(11).
II. FACTUAL BACKGROUND
Acetylcysteine injection, marketed by Cumberland under the brand name Acetadote, is an
intravenous drug administered to treat acetaminophen overdose. A.R. at 000456. Cumberland
first submitted an NDA for Acetadote to the FDA on June 27, 2002. See A.R. at 001723. The
original formulation of Acetadote contained the inactive ingredient disodium edetate (“edetate”),
which Cumberland believed to be necessary to stabilize the drug. A.R. at 000282. In a letter
dated December 30, 2002, the FDA informed Cumberland that it found the information
submitted in the NDA to be inadequate to approve Acetadote, and identified a number of
deficiencies for Cumberland to address in an amendment to its application if it wished to
continue seeking approval for Acetadote. See A.R. at 001723–27. Among other things, the FDA
4
requested that Cumberland provide “scientific and regulatory justification for the inclusion of
[e]detate as a component of the drug product” and “a description of the pharmacological
properties for [e]detate in this drug product.” A.R. at 001724.
Following additional submissions by Cumberland, the FDA approved Acetadote on
January 23, 2004. A.R. at 001540–43. In its approval letter, the FDA noted that Cumberland
had agreed, at the FDA’s request, to conduct postmarketing studies to “further evaluate the
incidence of anaphylactoid[2] reactions after administration of Acetadote” and to “evaluate the
potential benefit of [e]detate disodium on the stability of the drug product,” including “a
comparison of the current concentration of [e]detate to a formulation with a lower concentration
and no concentration of [e]detate.” A.R. at 001541. Cumberland completed its commitment to
evaluate the inclusion of edetate, A.R. at 000932–33, finding that edetate was not, in fact,
necessary to ensure the stability of Acetadote, A.R. at 001355. Cumberland sent its final report
on the inclusion of edetate to the FDA on August 13, 2008, A.R. at 001349–61, and then in
September 2010, sought approval to market a new formulation of Acetadote that did not contain
edetate, A.R. at 001147–56. The FDA approved the application supplement containing the new
formulation, A.R. at 001081–82, and Cumberland withdrew the original formulation from the
market ten days thereafter, A.R. at 000282. Cumberland issued a press release announcing the
new formulation and the withdrawal of the prior version of Acetadote, stating that the new
formulation was the result of a postmarketing commitment to the FDA, under which Cumberland
“initiated a program to develop the new formulation and determined that it could be prepared and
scaled in a commercial manufacturing setting without compromising the potency, solubility or
2
Anaphylaxis is “[a]n immediate (and often unpleasant) hypersensitivity reaction produced by the body’s . . .
antibodies to a foreign substance” in which “the affected tissues release histamine which causes local or systemic
attack.” Black’s Medical Dictionary 31 (Gordon Macpherson ed., 40th ed. 2004). In rare cases, anaphylaxis may
cause shock and lead to death unless the individual receives medical attention. Id.5
stability of the product.” A.R. at 000006. Neither the FDA nor Cumberland initiated a recall of
the original formulation of Acetadote that was already on the market after the new formulation
was approved. See A.R. at 000519.
Several months after the introduction of the new formulation of Acetadote, the FDA
received a citizen petition from the law firm Leydig, Voit & Mayer, Ltd. (“Leydig”) on behalf of
an unnamed client, seeking a determination that the edetate-containing formulation was not
withdrawn for safety and effectiveness reasons. A.R. at 000001–03. Cumberland then submitted
a citizen petition to the FDA requesting that the agency not approve any ANDA based on the
edetate-containing formulation of Acetadote as the reference listed drug. A.R. at 000280–89.
During this same time period, an ANDA using the edetate-containing formulation that had been
initially filed in 2009 by InnoPharma remained pending before the FDA. See A.R. at 001851.
Following receipt of Leydig’s citizen petition, FDA’s Office of Regulatory Policy
requested the opinion of FDA’s Division of Gastroenterology and Inborn Errors Products (“the
Gastroenterology Division” or “the Division”) on the issues raised by the petition. A.R. at
000563. The Division issued a four-page opinion on July 1, 2011. See A.R. at 000563–66. The
opinion noted that the amount of edetate in the original formulation of Acetadote was
comparable to that contained in “[o]ther injectable acetylcysteine products used worldwide,”
discussed two studies “showing that [edetate] is associated with allergic reactions when used in
other drug product formulations,” and compared the amount of edetate in Acetadote to the
amount of the substance in another drug, Leukine, which was withdrawn from the market by the
manufacturer due to an increase in the number of adverse reactions following the addition of
edetate to the drug’s formula. See A.R. at 000564. In response to the Office of Regulatory
Policy’s question regarding why the FDA originally requested a postmarketing study from
Cumberland concerning edetate, the Division determined without further discussion that
6
“[a]lthough early documentation concerning the postmarketing commitment is sparse, it is clear
from subsequent discussions with the company that the FDA had concerns about allergic
reactions and syncope.” A.R. at 000565. It therefore recommended that the agency “not accept
ANDAs for acetylcysteine injection based on the discontinued formulation.” Id.The Office of Regulatory Policy subsequently asked the Office of Surveillance and
Epidemiology (“Surveillance Office”) for its opinion regarding the safety of Acetadote
containing edetate. See A.R. at 000664. The Surveillance Office conducted a search of the
Adverse Event Reporting System, but concluded that “safety concerns regarding the use of the
preservative [edetate] in Acetadote[] cannot be reliably ascertained using available [adverse
event report] data” because “[t]he lack of control prevents the attribution of the adverse events in
question to either of the co-present ingredients.” A.R. at 000665. The Surveillance Office
offered a similar opinion concerning reports of adverse events involving other drug products
containing edetate. See A.R. at 000665–66.
After the Surveillance Office issued its report, individuals from various divisions within
the FDA met twice to discuss the ongoing review of the safety of Acetadote containing edetate.
See A.R. at 000515. During the initial meeting, findings regarding edetate in another drug
product, Diprivan, were also discussed. Id. At the conclusion of this meeting, the individuals
representing the Gastroenterology Division “agreed to reassess, in light of additional
information, whether they [should] conclude that Acetadote with [edetate] was discontinued for
reasons of safety or effectiveness.” Id. During the second meeting, representatives from the
FDA’s Office of Generic Drugs and Office of New Drugs raised concerns that the
Gastroenterology Division’s initial opinion “appears inconsistent with Agency precedent and
potentially unsupportable” because (1) there was no recall of the original formulation, (2) the
amount of edetate in Acetadote is comparable to that in approved and currently-marketed
7
propofol products, (3) the FDA allows both propofol products that contain and do not contain
edetate, (4) there are a number of other products containing edetate in various amounts on the
market, and (5) “[t]here are concerns about drug shortages and the potential problems of having a
single supplier of this product.” Id. Based on these concerns, the Gastroenterology Division
“was asked to reconsider its position taking into account these concerns.” A.R. at 000516.
The Gastroenterology Division ultimately issued a twenty-eight page report reconsidering
its initial opinion. A.R. at 000513–40. First, with respect to the motivation for the FDA’s
request for a postmarketing commitment to study the benefit of edetate on the stability of the
drug, the Division concluded that, “[o]n re-examination of the electronic records of letters and
reviews for this NDA, there is no definitive evidence that this [postmarketing commitment] was
prompted by specific safety concerns.” A.R. at 00516. The report reviewed the FDA’s internal
documentation regarding the postmarketing commitment, which focused primarily on whether it
was actually necessary to include edetate in the formulation. See A.R. at 000534–37. Second,
regarding whether the original formulation of Acetadote was withdrawn for safety reasons, the
Division ultimately concluded that while “[t]here are potential safety concerns . . . associated
with [edetate,] . . . none of these concerns rises to the level that would enable us to conclude that
the old formulation of Acetadote[] (with [edetate]) was withdrawn for reasons of safety.” A.R. at
000539–40. The report considered the chelation 3 potential of edetate, reports of adverse events
involving Acetadote, studies and safety information on other edetate-containing products, and
the FDA’s review of a propofol product that contains edetate. See A.R. at 000517–34. In
addition, the memorandum considered information submitted by InnoPharma supporting its
3
Edetate “is a molecule that functions as a chelator,” A.R. at 000514, which is a “compound[] that will render an ion
(usually a metal) biologically inactive,” thereby “ridding the body of toxic metals such as mercury,” Black’s
Medical Dictionary, supra, n.2, at 107. Edetate’s chelating ability is used to rid the body of an excess of elements
(continued . . . )
8
ANDA application. See A.R. at 000519, 000526, 000528–32. After reviewing the above
considerations and concluding that the original formulation of Acetadote was not withdrawn for
reasons of safety, the Division acknowledged that “exclusively marketing a non-[edetate]
containing product would be preferable because it would eliminate even the potential for risk
from [edetate],” but reasoned that “there is a risk to the U.S. population in having only a single
source of Acetadote[] available for treating [the] life[-]threatening condition of acetaminophen
poisoning (i.e., concerns about future drug shortages, which could be devastating in this case).”
A.R. at 000539–40.
On November 7, 2012, the FDA issued a joint decision on the citizen petitions submitted
by Leydig and Cumberland, finding that the formulation of Acetadote which contained edetate
was not discontinued for safety and effectiveness reasons and that the original formulation of
Acetadote is therefore an appropriate reference listed drug for an ANDA. A.R. at 000456–63. In
reaching this conclusion, Dr. Janet Woodcock, Director of the Center for Drug Evaluation and
Research, discussed the Gastroenterology Division’s findings regarding the chelation potential of
edetate, the Surveillance Office’s conclusions regarding adverse reports involving Acetadote, the
inclusion of edetate in comparable or higher amounts in other approved and currently-marketed
products, and the recent withdrawal of another edetate-containing drug, Leukine, for safety
reasons. A.R. at 000460–61. Dr. Woodcock determined that “[a]lthough there is a theoretical
safety concern with [edetate] in Acetadote based on its potential to contribute to anaphylactic
reactions, we have insufficient data to conclude that the original formulation was withdrawn for
reasons of safety.” A.R. at 000461.
(. . . continued)
such as lead and calcium, but can present a safety concern if the amount of edetate “would be expected to cause
major electrolyte changes” when edetate is not being used for its chelating abilities. A.R. at 000514.
9
Concerning the use of the edetate-containing formulation of Acetadote as the reference
listed drug in an ANDA, Dr. Woodcock first notes that pursuant to 21 C.F.R. § 314.99(b), the
FDA may waive the regulatory requirement that the inactive ingredients in an injectable drug
proposed in an ANDA be the same as those in the reference listed drug “as long as the statutory
requirement [of 21 U.S.C. § 355(j)(4)(H)] regarding safety of inactive ingredients has been met.”
A.R. at 000462. She then concludes that “experience with Cumberland’s original Acetadote
formulation and FDA’s recent analysis have not shown that the original [edetate]-containing
Acetadote formulation is unsafe,” and therefore, a waiver of the regulatory requirements to
permit ANDAs based on the original formulation of Acetadote is appropriate. A.R. at 000462.
The same day when Dr. Woodcock issued her decision, the FDA approved InnoPharma’s ANDA
using the edetate-containing version of Acetadote as its reference listed drug. A.R. at 001851–
55.
Cumberland subsequently commenced this litigation, alleging that both the FDA’s denial
of its citizen petition and its approval of InnoPharma’s ANDA violated the FDCA and its
regulations, and therefore was arbitrary, capricious, an abuse of discretion, or otherwise not in
accordance with the APA, 5 U.S.C. § 706(2)(A). See Compl. ¶¶ 32–38. In response, the FDA
has filed a motion to dismiss, or in the alternative, for summary judgment, and Cumberland then
cross-moved for summary judgment. Specifically, Cumberland argues that (1) the FDA’s
conclusion that the edetate-containing formulation of Acetadote was not withdrawn for safety
reasons relies in part on improper considerations and is not supported by the administrative
record and, (2) the FDA violated its own regulations by waiving the requirements that
InnoPharma’s generic drug contain the same inactive ingredients as the reference listed drug on
which its ANDA is based and that InnoPharma demonstrate that the inclusion of edetate in its
10
formulation does not render the drug less safe than the reference listed drug. See Pl.’s Mem. at
1–2.
III. STANDARD OF REVIEW
The FDA moves for dismissal under Federal Rule of Civil Procedure 12(b)(6), or, in the
alternative, for summary judgment under Federal Rule of Civil Procedure 56. Defs.’ Mot. at 1.
Because a claim under the APA presents only questions of law, the claim may be considered on
its merits pursuant to either a motion to dismiss under Rule 12(b)(6) or a motion for summary
judgment under Rule 56. Marshall Cnty. Health Care Auth. v. Shalala, 988 F.2d 1221, 1226
(D.C. Cir. 1993). While “there is no real distinction in this context between the question
presented on a 12(b)(6) motion and a motion for summary judgment,” id., “[i]t is probably the
better practice for a district court always to convert to summary judgment,” id. at 1226 n.5.
Accordingly, the Court will consider the parties’ motions under the summary judgment standard
of review.
“Summary judgment is the proper mechanism for deciding, as a matter of law, whether
an agency action is supported by the administrative record and consistent with the APA standard
of review.” Loma Linda Univ. Med. Ctr. v. Sebelius, 684 F. Supp. 2d 42, 52 (D.D.C. 2010)
(citing Stuttering Found. of Am. v. Springer, 498 F. Supp. 2d 203, 207 (D.D.C. 2007), aff’d, 408
F. App’x 383 (D.C. Cir. 2010)); see also Richards v. INS, 554 F.2d 1173, 1177 & n.28 (D.C. Cir.
1977). But due to the limited role of a court in reviewing the administrative record, the typical
summary judgment standards set forth in Federal Rule of Civil Procedure 56 are not applicable.
Stuttering, 498 F. Supp. 2d at 207. Rather, “[u]nder the APA, it is the role of the agency to
resolve factual issues to arrive at a decision that is supported by the administrative record,
whereas ‘the function of the district court is to determine whether or not as a matter of law the
evidence in the administrative record permitted the agency to make the decision it did.’” Id.
11
(quoting Occidental Eng’g Co. v. INS, 753 F.2d 766, 769–70 (9th Cir. 1985)). In other words,
“when a party seeks review of agency action under the APA, the district judge sits as an
appellate tribunal,” and “[t]he ‘entire case’ on review is a question of law.” Am. Bioscience, Inc.
v. Thompson, 269 F.3d 1077, 1083 (D.C. Cir. 2001) (footnote and citations omitted).
IV. ANALYSIS
The APA requires courts to “hold unlawful and set aside agency action, findings, and
conclusions found to be arbitrary, capricious, an abuse of discretion, or otherwise not in
accordance with law.” 5 U.S.C. § 706(2)(A). “The ‘arbitrary and capricious’ standard of review
as set forth in the APA is highly deferential,” and the Court must “presume the validity of agency
action.” Am. Horse Prot. Ass’n v. Yeutter, 917 F.2d 594, 596 (D.C. Cir. 1990). Nonetheless, a
reviewing court must ensure that the agency “examine[d] the relevant data and articulate[d] a
satisfactory explanation for its action including a rational connection between the facts found and
the choice made.” Motor Vehicle Mfrs. Ass’n v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29,
43 (1983) (citations and quotation marks omitted). An agency’s decision will be considered
arbitrary and capricious if
the agency has relied on factors which Congress has not intended for it to
consider, entirely failed to consider an important aspect of the problem, offered an
explanation for its decision that runs counter to the evidence before the agency, or
is so implausible that it could not be ascribed to a difference in view or the
product of agency expertise.
Id. However, a “court is not to substitute its judgment for that of the agency,” and will “uphold a
decision of less than ideal clarity if the agency’s path may reasonably be discerned.” Id.(citations and quotation marks omitted).
Moreover, when a court reviews an agency’s evaluation of “‘scientific data within its
technical expertise,’” the arbitrary and capricious standard of review is “‘extreme[ly]
deferential.’” Nuclear Energy Inst., Inc. v. EPA, 373 F.3d 1251, 1289 (D.C. Cir. 2004) (citation
12
omitted). This is because courts “review scientific judgments of the agency ‘not as the chemist,
biologist, or statistician that we are qualified neither by training nor experience to be, but as a
reviewing court exercising our narrowly defined duty of holding agencies to certain minimal
standards of rationality.’” Troy Corp. v. Browner, 120 F.3d 277, 283 (D.C. Cir. 1997) (citation
omitted). It is well-established that the FDA’s “judgments as to what is required to ascertain the
safety and efficacy of drugs fall squarely within the ambit of the FDA’s expertise and merit
deference.” Schering Corp. v. FDA, 51 F.3d 390, 399 (D.C. Cir. 1995).
A. Determination that Original Formulation of Acetadote Was Not Withdrawn for
Safety Reasons
The FDA’s decision in response to the Leydig and Cumberland citizen petitions easily
meets the minimum standards of rationality required by the APA. The decision responded point-
by-point to the arguments made in Cumberland’s citizen petition regarding edetate’s association
with adverse events, Bayer HealthCare Pharmaceuticals’ withdrawal of Leukine, the purported
inconsistency of the FDA’s requested postmarketing commitment on the removal of edetate, and
the FDA’s prior determinations concerning original formulations of drugs for which a safer
alternative was later developed. Compare A.R. at 000285–88 (Cumberland Citizen Petition),
with A.R. at 460–61, 460 n.11 (FDA Response to Leydig and Cumberland Citizen Petitions). In
addition, the FDA’s response also considered and relied on Cumberland’s stated reasons for
withdrawing the original formulation of Acetadote, a comment to Cumberland’s citizen petition
filed by the Rocky Mountain Poison and Drug Information Center and the Pittsburgh Poison
Center, additional safety concerns potentially associated with edetate, a comparison of the
warnings and precautions included in both the new and original formulations of Acetadote, and
the fact that other approved and currently-marketed drug products contain edetate, some at even
higher quantities than the original formulation of Acetadote. See A.R. at 460–61, 460 n.14, 461
13
n.15, 16, 17. In further support of its conclusion, the decision incorporated the independent
analyses conducted by the Surveillance Office and the Gastroenterology Division. See A.R. at
460–61.
None of Cumberland’s attacks on the reasoning of the FDA’s decision or the factors it
considered are persuasive. Cumberland contends that the agency’s consideration of other drugs
that include edetate was improper because “[t]he only issue for FDA to determine was whether
the original formulation of Acetadote was withdrawn for safety reasons,” and “not whether all
[edetate]-containing products are or are not safe.” Pl.’s Mem. at 17 (emphasis added). The
Court disagrees with Cumberland’s premise. That numerous other products containing edetate
are currently on the market, a fact which Cumberland was undoubtedly aware of when it decided
to withdraw the original formulation of Acetadote from the market, is clearly relevant to the
FDA’s determination regarding whether Cumberland discontinued edetate-containing Acetadote
for safety reasons. The FDA’s consideration of this fact does not convert its decision into an
exploration of the safety of all drugs containing edetate, but rather serves only as circumstantial
evidence from which to divine Cumberland’s reasons for withdrawing the original formulation of
Acetadote.
Cumberland also argues that the FDA improperly relied on “inconclusive data” regarding
adverse event reports involving Acetadote without “explain[ing] . . . why, if the data were
‘inconclusive,’ that would not lead to the opposite conclusion; that is, that the original
formulation was withdrawn for reasons of safety.” Pl.’s Mem. at 18–19. But Cumberland
mischaracterizes the FDA’s discussion of the adverse events data. After noting that the relevant
adverse event reports showed that “the original formulation of Acetadote, which contained
[edetate], was associated with allergic reactions, including anaphylaxis, in some patients,” the
FDA’s decision continues:
14
However, these data did not demonstrate that these adverse reactions were
attributable to the [edetate] in the formulation. These adverse events could
alternatively be attributed to the active ingredient, acetylcysteine, or to the
multisystem organ pathology associated with the underlying acetaminophen
overdose. Therefore, the [adverse event reports] data do not provide a reasonable
basis upon which to conclude that the original, [edetate]-containing formulation
of Acetadote was unsafe.
A.R. at 000460–61 (emphasis added). Accordingly, the data do not show that edetate caused the
adverse reactions, and therefore offer no support for the conclusion urged by Cumberland that
edetate-containing Acetadote is unsafe. Nor do the data support the conclusion that edetate-
containing Acetadote is safe. Cumberland attempts to undermine this conclusion by pointing out
that an opposite inference is appropriate because “the data indicated that the incidence of allergic
reactions in patients had decreased once the [edetate]-containing formulation had been
withdrawn.” Pl.’s Mem. at 18. The FDA’s reasoning here, however, is consistent with logic and
sufficiently explained. And, even if the data arguably supports an opposing inference, the FDA
does not rely solely on this data to explain its decision, 4 and so any deficiency in this single
aspect does not render the decision arbitrary and capricious. See Mail Order Ass’n of Am. v.
U.S. Postal Serv., 2 F.3d 408, 434 (D.C. Cir. 1993) (“When an agency relies on multiple grounds
for its decision, some of which are invalid, we may nonetheless sustain the decision as long as
one is valid and the agency would clearly have acted on that ground even if the other were
4
For this reason, Earth Island Institute v. Hogarth, 494 F.3d 757 (9th Cir. 2007), cited by Cumberland in support of
its argument regarding the adverse events data, Pl.’s Mem. at 19, is inapposite. In that case, the agency relied
primarily on inconclusive data to support its conclusion. See Earth Island Inst., 494 F.3d at 763–64 (“[B]ecause
most of the data the government relied upon was inconclusive, the district court correctly held that the [agency’s
final decision] was not rationally connected to the best available scientific evidence.” (emphasis added)). Here, the
FDA relied on several rationales as support for its decision, only one of which involved inconclusive data. See A.R.
at 000460–61. The other case cited by Cumberland in support of its argument on this point, Brower v. Evans, 257
F.3d 1058 (9th Cir. 2001), Pl.’s Mem. at 19, is also inapplicable. In Brower, the court rejected the agency’s claim
that there was insufficient data for it to make a determination that it was statutorily mandated to make. See Brower,
257 F.3d at 1071 (“[T]he Secretary cannot use insufficient evidence as an excuse for failing to comply with the
statutory requirement.”). There is no dispute here that the adverse event reports data is inconclusive, and the FDA
has not relied on its inconclusiveness to avoid making a determination.
15
unavailable.” (citation and quotation marks omitted)). The Court thus sees no flaw in the
decision on its face. 5
Cumberland’s chief argument in support of its claim that the FDA’s decision is arbitrary
and capricious is that the decision is not adequately supported by the evidence before the agency.
See Pl.’s Mem. at 12–17, 19–20. Cumberland contends that the FDA reversed its position
regarding the safety of edetate-containing Acetadote, pointing to the postmarketing commitment
the FDA elicited during the approval process for Acetadote and the July 1, 2011
Gastroenterology Division opinion as evidence that the agency “had, and continues to have,
safety concerns about the [edetate]-containing formulation of Acetadote.” See id. at 12–14, 19–
20.
The APA requires that a court reviewing agency action “shall review the whole record or
those parts of it cited by a party.” 5 U.S.C. § 706. Indeed, “[i]t is a widely accepted principle of
administrative law that the courts base their review of an agency’s actions on the materials that
were before the agency at the time its decision was made.” IMS, P.C. v. Alvarez, 129 F.3d 618,
5
Cumberland also asserts, for the first time in its reply brief, that the FDA’s decision is deficient because under
FDA regulations, the agency “presumes that a ‘pharmaceutical manufacturer would not cease distribution of a
profitable drug if safety or effectiveness concerns had not arisen,’” but does not address this presumption in its
decision, Pl.’s Reply at 2 n.1, and that the agency’s consideration of Cumberland’s stated reasons for withdrawing
the original formulation of Acetadote was inappropriate, Pl.’s Reply at 5. Because these arguments were raised for
the first time in Cumberland’s reply brief, thus depriving the FDA of the opportunity of responding to them, the
Court need not consider them. See, e.g., Natural Res. Def. Council v. U.S. EPA, 25 F.3d 1063, 1071 n.4 (D.C. Cir.
1994) (citations omitted). However, the Court notes that, with respect to both arguments, Cumberland’s quotations
from the FDA’s regulations are taken out of context. When each regulation is considered in its entirety, it is
apparent that neither of Cumberland’s belated arguments is persuasive. The rebuttable presumption that
Cumberland references applies if the withdrawn drug “accounted for significant sales to [the] manufacturer” and
“there is no evidence to the contrary” indicating that the drug was withdrawn for reasons other than safety or
effectiveness. See 54 Fed. Reg. 28,872-01 at 28,907. When the FDA’s presumption is considered in proper context,
it is evident that it is inapplicable in the circumstances here because there is evidence to the contrary which indicates
that the original formulation of Acetadote was withdrawn for reasons other than safety or effectiveness. Similarly,
while it is true that the FDA does not consider a drug manufacturer’s stated reasons for withdrawing a product to be
determinative, the regulation expressly states in the preceding sentence that the FDA will consider the
manufacturer’s stated reasons for withdrawing a product as one consideration among many when determining
whether a drug was withdrawn for safety or effectiveness reasons. The FDA’s consideration of Cumberland’s stated
reasons for withdrawing the original formulation of Acetadote, as one of a number of factors included in its
decision, was therefore in accordance with its regulations. See 57 Fed. Reg. 17,950-01 at 17,971.
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623 (D.C. Cir. 1997). This review must consider the record as a whole, rather than just isolated
portions of it. See Ethyl Corp. v. EPA, 541 F.2d 1, 37–38 (D.C. Cir. 1976) (“[A]fter considering
the inferences that can be drawn from the studies supporting the [agency decisionmaker], and
those opposing him, we must decide whether the cumulative effect of all this evidence, and not
the effect of any single bit of it, presents a rational basis for the low-lead regulations.” (emphasis
added)); see also Citizens to Preserve Overton Park, Inc. v. Volpe, 401 U.S. 402, 420 (1971)
(“[A court’s] review is to be based on the full administrative record that was before the Secretary
at the time he made his decision.” (emphasis added)). While the record must be considered in its
entirety, the agency’s decision may be upheld even though some information in the record
supports a different conclusion than that reached by the agency. See Am. Horse Prot. Ass’n, 917
F.2d at 598 (noting that conclusion that agency’s decision must be upheld “is not to suggest that
one could not locate facts in the record to support a contrary decision . . . but such a de novo
reweighing of the evidence presented to the Secretary is not proper when reviewing agency
action under an arbitrary and capricious test”); Ethyl Corp., 541 F.2d at 37. The proper inquiry
is not, then, whether there is sufficient evidence in the record to support the opposing conclusion,
but rather whether the choice made by the agency “has a rational basis in the evidence.” See id.The Court’s review of the administrative record shows that it supports the FDA’s
determination that the original formulation of Acetadote was not withdrawn for safety reasons.
Cumberland argues that “there was no reason for [the] FDA to have required [it] to do a
postmarketing study on the feasibility of reducing or eliminating of [edetate] from the
formulation other than that [the] FDA had safety concerns about the [edetate] in the
formulation,” and that it then “follows a fortiori that when Cumberland conducted that study,
found that it could remove the [edetate], and promptly withdrew the [edetate]-containing
formulation from the market, it did so for the same safety reasons that prompted the
17
postmarketing requirement in the first place.” Pl.’s Mem. at 13–14. The Court disagrees. The
FDA requested that Cumberland “[c]ommit to evaluate the potential benefit of [edetate] on the
stability of the drug product,” including specifically “a comparison of the current concentration
of [e]detate to a formulation with a lower concentration and no concentration of [e]detate.” A.R.
at 001541. The agency rejected Cumberland’s argument that this request was made for safety
reasons based on the plain language of the request, see A.R. at 000460, and evidence in the
record supports this conclusion. Internal memoranda regarding the postmarketing commitment
contemporaneous with the request focus on the necessity for including edetate, rather than
particular safety concerns, see A.R. at 000535–37.
Moreover, even if the FDA’s request for the postmarketing commitment was based on
safety concerns, such a motivation is not necessarily inconsistent with the challenged
determination here. Having concerns about the safety of an ingredient and even expressing a
preference for a formulation that does not contain it is not the same as definitively believing the
ingredient to be unsafe or requiring a manufacturer to remove an ingredient. See ISTA Pharms.,
Inc. v. FDA, 898 F. Supp. 2d 227, 233 (D.D.C. 2012) (upholding the FDA’s decision that
withdrawal of drug was not for reasons of safety even though the agency “has admittedly asked
some sponsors to voluntarily change their labeling to address these concerns, but has not
required any changes thus far”). And, as the FDA points out, it would not have approved
Cumberland’s NDA for edetate-containing Acetadote if it had significant concerns regarding the
product’s safety. Defs.’ Mem. at 23–24.
Cumberland’s singular emphasis on the Gastroenterology Division’s July 1, 2011
memorandum and the Division’s “about-face” is similarly misplaced. See Pl.’s Mem. at 14–17,
19–20. Because the Court’s inquiry here must consider the record in its entirety, the fact that a
single memo in the record recommended finding that Cumberland withdrew the original
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formulation of Acetadote for safety reasons is not dispositive. See Am. Horse Prot. Ass’n, 917
F.2d at 598. Admittedly, the Gastroenterology Division’s July 1, 2011 report is at odds with the
FDA’s final conclusion. Compare A.R. at 000563–66 (July 1, 2011 Gastroenterology Division
Memorandum), with A.R. at 000460–61 (FDA Response to Leydig and Cumberland Citizen
Petitions). However, disagreement among agency staff during the decisionmaking process does
not fatally undermine the agency’s final determination, nor does it alone justify according the
agency’s final decision less deference than usual. See Serono Labs., 158 F.3d at 1320–21; San
Luis Obispo Mothers For Peace v. U.S. Nuclear Regulatory Comm’n, 789 F.2d 26, 33 (D.C. Cir.
1986) (en banc) (“The position of an agency’s staff, taken before the agency itself decided the
point, does not invalidate the agency’s subsequent application and interpretation of its own
regulation.”); Graceway Pharms., Inc. v. Sebelius, 783 F. Supp. 2d 104, 113 (D.D.C. 2011)
(Walton, J.) (“The internal disagreement between the different divisions of the FDA is certainly
not irrelevant, but neither is it the dispositive proof of arbitrary and capricious action that the
plaintiff seems to believe it is.”).
This reasoning is particularly appropriate under the circumstances here. The
Gastroenterology Division’s initial opinion is a four-page report which gives somewhat cursory
treatment to the issues raised in the Leydig citizen petition, basing its conclusion on two studies
showing adverse allergic reactions to edetate-containing products and the voluntary withdrawal
of Leukine, another edetate-containing drug. See A.R. at 000563–64. Importantly, the report
rests its finding that the postmarketing commitment involving edetate was based on the FDA’s
safety concerns solely on what was related in “subsequent discussions with [Cumberland].” A.R.
at 000565 (emphasis added). In contrast, the Gastroenterology Division’s second opinion on the
subject is set forth in a detailed twenty-eight page memorandum that extensively reviews the
FDA’s internal documentation regarding the postmarketing commitment, numerous studies of
19
other edetate-containing drugs, adverse event reports for Acetadote, other edetate-containing
products and available safety information on them, the reasons for the withdrawal of Leukine,
and the FDA’s own analysis regarding safety concerns relating to chelation. See A.R. at
000513–40. And, contrary to Cumberland’s assertions, this is not a situation in which “the FDA
entirely ignored the opinion offered by” the Gastroenterology Division initially. See Pl.’s Mem.
at 19 (quoting Graceway Pharms., 783 F. Supp. 2d at 113). The later opinion by the
Gastroenterology Division reviews each reason given for the initial conclusion and refutes it.
See A.R. at 000534 (withdrawal of Leukine); A.R. at 000534–37 (rationale for postmarketing
commitment); A.R. at 000534 (studies cited in initial opinion). Consequently, the Court has no
difficulty finding that the FDA’s decision is supported by the record despite the July 1, 2011
Gastroenterology Division report.
Finally, Cumberland takes issue with two considerations included in the
Gastroenterology Division’s later opinion—the possibility of drug shortages if there is only one
drug manufacturer and the FDA’s failure to recall the original formulation of Acetadote. See
Pl.’s Mem. at 15–17. While this document is part of the administrative record used to assess
whether the FDA’s decision was arbitrary and capricious, when “there [is] a contemporaneous
explanation of the agency decision[,] . . . [t]he validity of the [agency’s] action must . . . stand or
fall on the propriety of that finding, judged, of course, by the appropriate standard of review,”
Camp v. Pitts, 411 U.S. 138, 143 (1973), and therefore the focus of this Court’s review of the
FDA’s decision must be on the reasons stated for the decision in Dr. Woodcock’s response to the
Leydig and Cumberland citizen petitions, not other reasons given by agency staff elsewhere in
the record, see Serono Labs., 158 F.3d at 1321 (“[D]eference is owed to the decisionmaker
authorized to speak on behalf of the agency, not to each individual agency employee.” (citation
omitted)); cf. Actavis Elizabeth LLC v. U.S. FDA, 689 F. Supp. 2d 174, 180 (D.D.C. 2010),
20
aff’d, 625 F.3d 760 (D.C. Cir. 2010) (rejecting the argument that the FDA’s decision was
arbitrary and capricious because a draft manual contradicted the approach taken in the agency’s
subsequent formal regulation). “[T]o hold otherwise . . . would effectively empower any
individual employee not just to veto the views of the agency head, but to preclude any deference
to the agency at all, since [the court] would have no basis for deciding to whose view we should
defer.” Serono Labs., 158 F.3d at 1321.
The Court is unconvinced by Cumberland’s attempts to discredit the FDA’s
determination that the original formulation of Acetadote was withdrawn for safety reasons.
Although the record contains some contrary evidence, the Court nonetheless finds that the FDA
has met its obligations under the APA with respect to this determination.
B. Waiver of Inactive Ingredient Regulatory Requirement
Having concluded that the Court must affirm the FDA’s determination that the edetate-
containing version of Acetadote was not withdrawn for reasons of safety, Cumberland’s
objection to the FDA’s grant of a waiver of the regulatory requirement that a proposed ANDA
drug contain identical inactive ingredients as the reference listed drug to InnoPharma must also
fail. In its response to the Leydig and Cumberland citizen petitions, the FDA noted that it may
waive the regulatory requirements for inactive ingredients in proposed ANDA drugs pursuant to
21 C.F.R. § 314.99(b), so long as it satisfied the FDCA’s directive not to approve any application
if “information submitted in the application or any other information available to the Secretary
shows that” the inactive ingredients are “unsafe for use under the conditions prescribed,
recommended, or suggested in the labeling proposed for the drug” or that the “type or quantity of
inactive ingredients” in the drug render the “composition of the drug . . . unsafe under such
conditions.” A.R. at 000462; 21 U.S.C. § 355(j)(4)(H). Citing solely to a single reference in the
Gastroenterology Division’s July 1, 2011 memorandum, Cumberland contends that the standard
21
applicable to InnoPharma’s ANDA is “whether the difference in inactive ingredients between the
proposed ANDA product and the reference-listed drug make the proposed ANDA product less
safe for use.” Pl.’s Mem. at 21. This proposition is incorrect.
The FDA noted in its final decision that edetate is not a preservative, buffer, or
antioxidant, and Cumberland has not challenged this determination. See A.R. at 000462. FDA
regulations require that if an inactive ingredient is a preservative, buffer, or antioxidant, an
ANDA applicant must “provide[] information demonstrating that the differences [in inactive
ingredients] do not affect the safety or efficacy of the proposed drug product.” 21 C.F.R. §
314.94(a)(9)(iii). Otherwise, neither the FDCA nor FDA regulations require a comparison of
whether a proposed product is more or less safe, but only a determination of whether it is unsafe.
See 21 U.S.C. § 355(j)(4)(H); 21 C.F.R. § 314.94(a)(9)(iii). The FDA concluded that edetate is
not a preservative, buffer, or antioxidant, and that the original formulation of Acetadote is not
unsafe, a determination which the Court has already upheld as consistent with the requirements
of the APA. Accordingly, the FDA’s decision to grant a waiver to InnoPharma in order to
permit its proposed ANDA drug to deviate from the inactive ingredients in the current
formulation of Acetadote was in accordance with the FDCA and the applicable FDA regulations.
Cumberland also argues that it was arbitrary and capricious “for [the] FDA to have
granted a waiver to InnoPharma to market an [edetate]-containing formulation when [the] FDA
has consistently preferred that Cumberland, if possible, reduce or remove [edetate] from its
product.” Pl.’s Mem. at 21. The Court does not find the agency’s actions inconsistent. On the
contrary, the FDA is allowing InnoPharma to market an edetate-containing generic version of
Acetadote, just as it permitted Cumberland to market an edetate-containing formulation of the
drug. Cumberland’s argument essentially rests on the premise that the FDA believes that an
edetate-containing version is unsafe and requested a postmarketing commitment from
22
Cumberland because of this belief, an argument that the Court has already considered and
rejected. Seeing no inconsistency in the agency’s treatment of Cumberland and InnoPharma, the
Court therefore finds that the FDA’s grant of a waiver to InnoPharma, allowing it to market an
edetate-containing formulation of Acetadote, was not arbitrary and capricious.
V. CONCLUSION
For the foregoing reasons, the Court concludes that the FDA’s determination in its
response to the Leydig and Cumberland citizen petitions that (1) Cumberland did not withdraw
the original formulation of Acetadote for safety reasons, and (2) the requirement that an ANDA
proposed drug contain the same inactive ingredients as the reference listed drug could be waived
to permit approval of InnoPharma’s ANDA based on Acetadote was not arbitrary and capricious,
an abuse of discretion, or otherwise not in accordance with law in violation of the APA.
Accordingly, the Court will grant the FDA’s motion for summary judgment and deny
Cumberland’s motion for summary judgment.
SO ORDERED this 30th day of September, 2013. 6
REGGIE B. WALTON
United States District Judge
6
An order consistent with this memorandum opinion shall be issued contemporaneously.
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