Zeneca, Inc. v. Shalala

PUBLISHED
UNITED STATES COURT OF APPEALS
FOR THE FOURTH CIRCUIT
ZENECA, INCORPORATED,
Plaintiff-Appellant,
v.
DONNA E. SHALALA, in her official
capacity as Secretary of Health and
Human Services; JANE HENNEY,
M.D., Commissioner of the Food No. 99-2329
and Drug Administration,
Defendant-Appellees,
v.
GENSIA SICOR PHARMACEUTICALS,
INCORPORATED,
Movant-Appellee.
Appeal from the United States District Court
for the District of Maryland, at Baltimore.
William M. Nickerson, District Judge.
(CA-99-307-WMN)
Argued: April 5, 2000
Decided: May 17, 2000
Before NIEMEYER, Circuit Judge,
HAMILTON, Senior Circuit Judge, and
Roger J. MINER, Senior Circuit Judge of the
United States Court of Appeals for the Second Circuit,
sitting by designation.
_________________________________________________________________
Affirmed by published opinion. Senior Judge Hamilton wrote the
opinion, in which Judge Niemeyer and Senior Judge Miner joined.
COUNSEL
Anthony Craig Roth, MORGAN, LEWIS & BOCKIUS, L.L.P.,
Washington, D.C., for Appellant. Gerald Cooper Kell, Senior Trial
Counsel, Office of Consumer Litigation, UNITED STATES
DEPARTMENT OF JUSTICE, Washington, D.C., for Appellees Sha-
lala and Henney; David Glenn Adams, VENABLE, BAETJER,
HOWARD & CIVILETTI, L.L.P., Washington, D.C., for Appellee
Gensia Sicor. ON BRIEF: Stephen P. Mahinka, MORGAN, LEWIS
& BOCKIUS, L.L.P., Washington, D.C., for Appellant. David W.
Ogden, Acting Assistant Attorney General, Office of Consumer Liti-
gation, UNITED STATES DEPARTMENT OF JUSTICE, Washing-
ton, D.C.; Barbara J. Stradling, Associate Chief Counsel for
Enforcement, FOOD AND DRUG ADMINISTRATION, Washing-
ton, D.C., for Appellees Shalala and Henney. James N. Czaban, VEN-
ABLE, BAETJER, HOWARD & CIVILETTI, L.L.P., Washington,
D.C., for Appellee Gensia Sicor.
_________________________________________________________________
OPINION
HAMILTON, Senior Circuit Judge:
This case involves a challenge by appellant Zeneca, Inc. (Zeneca),
the manufacturer of the prescription drug DIPRIVAN, to the Food
and Drug Administration's (the FDA) approval of a generic version
of DIPRIVAN manufactured by intervenor-appellee Gensia Sicor
Pharmaceuticals, Inc. (Gensia). The district court granted Gensia's
and the FDA's motions for summary judgment. Because we agree
with the district court that the FDA's approval of Gensia's generic
drug was in accordance with the Federal Food, Drug and Cosmetic
Act (the FFDCA), 21 U.S.C.A. §§ 301-397 (West 1999), and the
FDA's own regulations implementing the FFDCA, we affirm.
I
A
The FFDCA requires drug manufacturers to obtain FDA approval
prior to marketing new drugs. See id. § 355. To obtain FDA approval,
2
the first applicant to market a drug--the "pioneer"--must submit a
New Drug Application (NDA) to the FDA containing, among other
things, "full reports of investigations which have been made to show
whether or not such drug is safe for use and whether such drug is
effective in use," and "specimens of the labeling proposed to be used
for such drug." Id. § 355(b)(1). The FDA's primary role in the NDA
process is to ensure that the drug manufacturer has proven that its new
drug (the pioneer drug) is safe and effective prior to marketing. See
generally id. § 355(d).
Once the FDA has "listed" a pioneer drug as approved, the FFDCA
allows any person or entity desiring to market a generic copy of the
pioneer drug to seek FDA approval of its generic version through an
Abbreviated New Drug Application (ANDA). See id. § 355(j). The
ANDA procedure "permits generic drug applications to piggy-back
on clinical findings that [the] FDA has already embraced" in the
NDA, In re Barr Labs., Inc., 930 F.2d 72, 73 (D.C. Cir. 1991), and
thus, the ANDA applicant need not duplicate the clinical safety
studies that supported the pioneer drug's NDA. The ANDA process,
however, does not absolve the generic drug manufacturer from its
burden of establishing that its generic drug is the bioequivalent of the
pioneer drug, see 21 U.S.C.A. § 355 (j)(2)(A)(iv), (4)(F), and is safe
and effective, see id. § 355(j)(2)(A)(iv), (4)(H).1
In order to obtain approval of a generic drug, a manufacturer must
provide information sufficient to establish that, among other things:
(1) the generic drug is "bioequivalent" to the pioneer drug; (2) its
active ingredients, route of administration, strength and dosage form
are "the same as" those of the pioneer drug; and (3) the inactive ingre-
dients are not "unsafe for use under the conditions prescribed, recom-
mended, or suggested in the labeling proposed for the drug." Id.
§§ 355(j)(4)(C), (D), (H). With respect to the substitution of inactive
ingredients in a parenteral drug,2 the FDA's regulations require that
_________________________________________________________________
1 From the structure of § 355(j), it is evident that subsection 355(j)(2)
explicates the required information a would-be generic drug manufac-
turer must provide in its ANDA. Subsection 355(j)(4), on the other hand,
provides the parameters for the FDA's review of the information submit-
ted under subsection 355(j)(2) and its authority to deny an ANDA.
2 Parenteral means "[b]y some other means than through the gastroin-
testinal tract: referring particularly to the introduction of substances into
an organism by intravenous, subcutaneous, intramuscular, or intramedul-
lary injection." Stedman's Medical Dictionary 1316 (1999).
3
most of the generic drug's inactive ingredients be the same as the
inactive ingredients of the pioneer drug. Differences in inactive ingre-
dients that are preservatives, buffers, or antioxidants are permitted as
long as those differences do not affect the safety of the drug. See 21
C.F.R. §§ 314.94(a)(9)(iii), 314.127(a)(8)(ii)(B) (1999).
Manufacturers of generic drugs are also required to show that "the
labeling proposed for the new [generic] drug is the same as the label-
ing approved for the listed drug . . . except for changes required
. . . because the new drug and the listed drug are produced or distrib-
uted by different manufacturers." 21 U.S.C.A.§ 355(j)(2)(A)(v); see
also id. § 355(j)(4)(G). This "same labeling" requirement has been
interpreted by the FDA to require that
[l]abeling . . . proposed for the [generic] drug product must
be the same as the labeling approved for the reference listed
drug, except for changes required . . . because the drug prod-
uct and the reference listed drug are produced or distributed
by different manufacturers. Such differences between the
applicant's proposed labeling and labeling approved for the
referenced listed drug may include differences in expiration
date, formulation, bioavailability, or pharmacokinetics,
labeling revisions made to comply with current FDA label-
ing guidelines or other guidance, or omission of an indica-
tion or other aspect of labeling protected by patent or
accorded exclusivity under section 505(j)(4)(D) of the act.
21 C.F.R. § 314.94(a)(8)(iv) (emphasis added).
B
Zeneca manufactures the pioneer drug DIPRIVAN (a form of
propofol), which the FDA approved in 1989 based on Zeneca's sub-
mission of an NDA. DIPRIVAN is a parenteral drug used for induc-
ing and maintaining anesthesia and for support of mechanical
ventilation and sedation. DIPRIVAN has a pH range of 7.0 to 8.5.
Shortly after Zeneca introduced DIPRIVAN in the United States,
post-operative fevers and infections were documented and associated
with its use. These post-operative fevers and infections were deter-
mined to be the result of microbial contamination caused by mishan-
4
dling of the drug by medical personnel. With the FDA's
encouragement, Zeneca decided to reformulate DIPRIVAN by adding
the preservative disodium edetate (EDTA) in order to prevent micro-
bial contamination. Zeneca performed clinical studies on the safety of
the reformulated DIPRIVAN and, in return, was awarded three years
of exclusivity for the reformulated DIPRIVAN when it was approved
in 1996.
In March 1997, Gensia submitted an ANDA to the FDA for
approval of a generic propofol product with EDTA, the same compo-
sition as DIPRIVAN. In July 1997, Gensia informed the FDA that it
was evaluating the development of propofol using the preservative
sodium metabisulfite (Sulfite) instead of EDTA. 3 In its July 1997 let-
ter, Gensia provided preliminary data on a propofol product with Sul-
fite that would have a pH range of 6.0 to 7.5.4 Gensia asked the FDA
to review the preliminary data and consider, in particular, the pro-
posed lower pH of Gensia's formulation and the safety of Sulfite as
a preservative. The Office of Generic Drugs (the OGD) undertook a
review of the preliminary data.5 In addition, the FDA's Division of
Anesthetic, Critical Care and Addiction Products, the division that
reviewed and approved the NDA for DIPRIVAN, provided consulta-
tion to the OGD about the proposed propofol product containing Sul-
fite. On January 16, 1998, Gensia withdrew its ANDA for propofol
with EDTA and submitted an ANDA for propofol with Sulfite (Gen-
sia's ANDA for propofol with Sulfite) with a new proposed pH range
of 4.5 to 6.4.
On April 7, 1998, after learning that the FDA was considering an
ANDA for generic propofol, Zeneca filed an administrative petition
for a stay of action pursuant to 21 C.F.R. § 10.35 (1999). Zeneca's
petition requested, among other things, that the FDA decline to
approve any generic version of DIPRIVAN that "contains an antimi-
_________________________________________________________________
3 Sulfite is a preservative, which is an inactive ingredient under the
FFDCA. See 21 C.F.R. §§ 314.94(a)(9)(iii), 314.127(a)(8)(ii)(B).
4 To ensure that its propofol with Sulfite would achieve a microbial
growth retardation similar to DIPRIVAN, Gensia eventually had to
adjust the pH to the 4.5 to 6.4 range.
5 OGD is the office within the FDA that receives, reviews, and
approves ANDAs. See 21 C.F.R. § 5.80(c)(1)(i).
5
crobial additive other than [EDTA], the safety of which is not sup-
ported by preclinical, clinical, or other scientific investigative
studies." (J.A. 684). Zeneca contended that the substitution of Sulfite
for EDTA and the lower pH of Gensia's propofol with Sulfite raised
safety issues; specifically, issues of allergenicity, toxicity, antimicro-
bial effectiveness, and product stability. Further, Zeneca argued that
the addition of a Sulfite warning required by 21 C.F.R. § 201.22 to
the label of Gensia's propofol with Sulfite would violate the statutory
"same labeling" requirement for generic drugs.
On January 4, 1999, the FDA approved Gensia's ANDA for propo-
fol with Sulfite. On the same day, the FDA denied Zeneca's petition.
The FDA noted that it "did not require clinical studies to establish the
safety of [Gensia's] drug product; instead, the Agency found that suf-
ficient information was available both in the ANDA and before the
Agency to address whether changing the preservative to sodium meta-
bisulfite compromised the safety of the propofol injectable emulsion
product." (J.A. 689). The FDA concluded that it"had substantial data
to evaluate the possible effects of sodium metabisulfite in propofol
because sodium or potassium metabisulfite is present in concentra-
tions ranging from 0.1 mg/ml to 10 mg/ml in more than 50 approved
drug products." (J.A. 689-90). Based on the information in the admin-
istrative record and its scientific expertise, the FDA determined that
the presence of Sulfite in Gensia's propofol did not affect the safety
profile of the drug.
The FDA also concluded that Gensia's propofol with Sulfite was
safe and therapeutically equivalent to DIPRIVAN. Of particular note,
the FDA acknowledged that "patients with sulfite allergies should not
be administered a formulation of propofol with [Sulfite]. Appropriate
labeling, however, is sufficient to protect against improper use of the
product." (J.A. at 694). Accordingly, the FDA required Gensia's
propofol with Sulfite product to include a "statement in the insert
labeling informing practitioners of precautions related to the presence
of sulfites," and to "highlight prominently on the container label that
the product contains [Sulfite]."6 (J.A. 694). The FDA concluded that
_________________________________________________________________
6 The FDA's regulations require a warning statement to appear on
package inserts for prescription drugs containing sulfites because "sul-
6
these warnings "serve to alert practitioners of the potential for allergic
reactions and are adequate to ensure safe use of the drug." (J.A. 694).
Based on the addition of these warnings to the label of Gensia's
propofol with Sulfite, the FDA concluded that Gensia's propofol with
Sulfite was a safe generic drug when properly administered to the
majority of the population, which has no allergic reaction to Sulfites.
On February 5, 1999, Zeneca filed a complaint and a motion for
a preliminary injunction in the United States District Court for the
District of Maryland challenging the FDA's approval of Gensia's
ANDA for propofol with Sulfite as arbitrary and capricious under
§ 706(2)(A) of the Administrative Procedure Act (the APA),
5 U.S.C.A. § 706(2)(A) (West 1996).7 Zeneca primarily argued that
the substitution of Sulfite for EDTA in Gensia's propofol raised
safety concerns and required a label warning such that the drug could
not be lawfully approved through an ANDA. Gensia sought, and was
granted, permission to intervene as a defendant.
At a hearing on March 26, 1999, the district court, after hearing
oral arguments, denied Zeneca's motion for a preliminary injunction.
On April 15, 1999, Zeneca filed a motion for partial summary judg-
ment. The FDA and Gensia filed cross-motions for summary judg-
ment on the entire case on May 6 and 7, 1999, respectively. On
August 12, 1999, the district court granted the FDA's and Gensia's
motions for summary judgment. This timely appeal by Zeneca fol-
lowed.
_________________________________________________________________
fites may cause allergic-type reactions in certain susceptible persons,
especially asthmatics." 21 C.F.R. § 201.22(a) (1999). The FDA's
approval of Gensia's propofol with Sulfite also required the label to state
"Contains Sulfite" and list "SODIUM METABISULFITE" as an ingredi-
ent. Id. § 201.22(b).
7 The denial of Zeneca's administrative petition for a stay of action
filed pursuant to 21 C.F.R. § 10.35 constitutes final agency action for
purposes of judicial review under the APA, 5 U.S.C.A. §§ 701-706. See
21 C.F.R. § 10.45(d).
7
II
On appeal, Zeneca makes three substantive arguments in support
of its claim that the FDA's approval of Gensia's ANDA for propofol
with Sulfite was arbitrary and capricious, and must therefore, be
declared invalid and permanently enjoined. First, Zeneca argues that
the FDA's approval of Gensia's ANDA for propofol with Sulfite vio-
lated two FDA regulations prohibiting the FDA from approving an
ANDA for a generic drug with a different preservative than the pio-
neer drug where the information submitted by the generic drug manu-
facturer fails to show that the substitute preservative does not affect
the safety of the proposed generic drug. Second, Zeneca argues that
the FDA violated its own regulation requiring a generic drug's label-
ing to be the same, with some exceptions, as its pioneer counterpart.
Finally, Zeneca argues that the FDA approved Gensia's ANDA for
propofol with Sulfite based upon a flawed medical review of the
safety of Gensia's propofol with Sulfite.
We review the district court's grant of summary judgment de novo.
See Marshall v. Cuomo, 192 F.3d 473, 478 (4th Cir. 1999). Our
review of the underlying FDA approval of Gensia's ANDA for propo-
fol with Sulfite, however, is conducted pursuant to§ 706(2)(A) of the
APA, which provides in relevant part that a "reviewing court shall
. . . hold unlawful and set aside agency action, findings, and conclu-
sions found to be--(A) arbitrary, capricious, an abuse of discretion,
or otherwise not in accordance with law." 5 U.S.C.A. § 706(2)(A); see
Marshall, 192 F.3d at 478. In determining whether agency action vio-
lates § 706(2)(A) of the APA, "we perform``only the limited, albeit
important, task of reviewing agency action to determine whether the
agency conformed with controlling statutes,' and whether the agency
has committed ``a clear error of judgment.'" Maryland Dep't of
Human Resources v. USDA, 976 F.2d 1462, 1475 (4th Cir. 1992)
(quoting Baltimore Gas & Elec. Co. v. Natural Resources Defense
Council, Inc., 462 U.S. 87, 97 (1983), and Citizens to Preserve Over-
ton Park, Inc. v. Volpe, 401 U.S. 402, 416 (1971)). "[T]he ultimate
standard of review is a narrow one. The court is not empowered to
substitute its judgment for that of the agency." Citizens to Preserve
Overton Park, 401 U.S. at 416.
With these principles of the standard of review in mind, we now
turn to address each of Zeneca's three substantive arguments.
8
A
Zeneca first argues that the FDA violated 21 C.F.R.
§§ 314.94(a)(9)(iii) and 314.127(a)(8)(ii)(B) by approving Gensia's
ANDA for propofol with Sulfite without requiring Gensia to ade-
quately show that the substitution of Sulfite for EDTA as a preserva-
tive did not affect the safety of the drug formula based on
DIPRIVAN. Therefore, Zeneca argues, the FDA's approval was arbi-
trary and capricious. We conclude that Zeneca's argument is without
merit.
Section 314.94(a)(9)(iii) permits substitution of preservatives in
parenteral drugs "provided that the applicant identifies and character-
izes the differences and provides information demonstrating that the
differences do not affect the safety of the proposed drug product." 21
C.F.R. § 314.94(a)(9)(iii). Similarly, section 314.127(a)(8)(ii)(B) pro-
vides, in relevant part, that the FDA will not approve an ANDA for
a generic drug product "unless it contains the same inactive ingredi-
ents, other than preservatives . . . and, if it differs from the listed drug
in a preservative . . . the application contains sufficient information
to demonstrate that the difference does not affect the safety of the
drug product." Id. § 314.127(a)(8)(ii)(B). Collectively, these regula-
tory sections establish that prior to approving an ANDA for a generic
drug with a preservative that differs from the listed pioneer drug, the
FDA must determine that the preservative does not affect the safety
of the drug. In this case, the FDA concluded that the substitution of
Sulfite for EDTA as a preservative did not affect the safety of Gen-
sia's propofol because warnings on the product's container and label-
ing would "serve to alert practitioners of the potential for allergic
reactions and are adequate to ensure safe use of the drug." (J.A. 694).
As an initial matter, we note that the use of Sulfites in prescription
drugs is widespread. See Sulfiting Agents; Labeling in Drugs for
Human Use; Warning Statement, 50 Fed. Reg. 47,558, 47,558 (1985)
(proposed rule) (noting that, at that time, sulfites were present "in
more than 1,100 oxygen-sensitive prescription drug products"). More-
over, the "FDA has not found evidence in the available information
on sulfites in human drugs that demonstrates a significant health haz-
ard to the general population." Id. at 47,560. Zeneca does not chal-
lenge this finding nor does it contest the FDA's determination that
9
"sulfites serve a necessary public health function by maintaining the
potency of certain medications." Sulfiting Agents; Labeling in Drugs
for Human Use; Warning Statement, 51 Fed. Reg. 43,900, 43,903
(1986) (final rule). Accordingly, the issue before us is not whether
sulfites, in and of themselves, are safe. They are. Rather, the issue is
whether the substitution of Sulfite for EDTA in Gensia's propofol
with Sulfite affects the safety of Gensia's propofol with Sulfite. The
FDA concluded that the substitution of Sulfite for EDTA in Gensia's
propofol with Sulfite did not affect the safety of Gensia's propofol
with Sulfite because warning labels obviated any potential risks.
Zeneca argues that the FDA's reliance upon warnings on the prod-
uct's container and labeling in making its decision as to whether Gen-
sia's propofol with Sulfite is safe for use is prohibited under the plain
language of sections 314.94(a)(9)(iii) and 314.127(a)(8)(ii)(B). In
other words, Zeneca argues, under the plain language of these two
regulations, the FDA may not rely on an enhanced warning label to
obviate the safety concerns associated with different preservatives.
In response, the FDA contends that Zeneca's argument is without
merit, because it places an unreasonably narrow construction on the
regulations at issue, regulations promulgated by the FDA.8 In support
of its contention, the FDA points to the plain language of 21 U.S.C.
§ 355(j)(4)(H), the statute the two regulations at issue were promul-
gated to implement, which expressly provides that under the ANDA
process, the FDA's consideration of the safety of inactive ingredients
in generic drugs is dependent upon: (1) the "conditions prescribed,
recommended, or suggested in the labeling"; and (2) the "type or
quantity of inactive ingredients included or the manner in which the
inactive ingredients are included." 21 U.S.C.A.§ 355(j)(4)(H).
Zeneca's argument challenges the FDA's interpretation of its own
regulations, which interpretation "is entitled to``substantial deference'
and will be sustained unless it is plainly erroneous or inconsistent
with the regulation[s]." Clinchfield Coal Co. v. Harris, 149 F.3d 307,
309 (4th Cir. 1998). We find the FDA's interpretation of 21 C.F.R.
§§ 314.94(a)(9)(iii) and 314.127(a)(8)(ii)(B) to be consistent with the
_________________________________________________________________
8 Because the FDA and Gensia represent the same interests in this
appeal, we refer to them collectively as the FDA.
10
language of these regulations and not plainly erroneous. Specifically,
the language of sections 314.94(a)(9)(iii) and 314.127(a)(8)(ii)(B) is
broad enough to encompass the FDA's interpretation. Furthermore,
the FDA's interpretation is completely faithful to the statute that these
two regulations were promulgated to implement, 21 U.S.C.
§ 355(j)(4)(H).9 See Abbreviated New Drug Application Regulations,
57 Fed. Reg. 17,950, 17,957, 17,968-69 (1992) (final rule); Abbrevi-
ated New Drug Application Regulations, 54 Fed. Reg. 28,872, 28,884
(1989) (proposed rule). In sum, we conclude the FDA acted in accor-
dance with 21 C.F.R. §§ 314.94(a)(9)(iii) and 314.127(a)(8)(ii)(B)
and 21 U.S.C. § 355(j)(4)(H). Thus, the FDA's approval of Gensia's
ANDA for propofol with Sulfite was not arbitrary and capricious for
the first reason argued by Zeneca.
B
Next we address Zeneca's argument that the FDA violated its own
regulation requiring a generic drug's labeling to be the same as its
pioneer counterpart.
Section 355(j)(2)(A)(v) of the FFDCA allows labeling differences
that are necessary "because the new [generic] drug and the listed [pio-
neer] drug are produced or distributed by different manufacturers." 21
U.S.C.A. § 355(j)(2)(A)(v). The FDA has interpreted
§ 355(j)(2)(A)(v) to permit changes in labeling because of "differ-
ences in expiration date, formulation, bioavailability, or pharmaco-
kinetics, [or] labeling revisions made to comply with current FDA
labeling guidelines or other guidance." 21 C.F.R. § 314.94(a)(8)(iv)
(emphasis added). In this case, the FDA interpreted 21 C.F.R.
§ 314.94(a)(8)(iv) to find that the Sulfite warning for Gensia's propo-
fol with Sulfite fit squarely within the exceptions for (1) formulation
differences and (2) differences required to comply with the labeling
guidelines in the FDA's Sulfite warning regulation, see 21 C.F.R.
§ 201.22(b).
_________________________________________________________________
9 Section 355(j)(4)(H) is the only section in the FFDCA's new drug
approval process (both NDA and ANDA) that directly addresses the
FDA's review of inactive ingredients. See generally 21 U.S.C.A.
§ 355(j).
11
Zeneca agrees that under section 314.94(a)(8)(iv) a generic drug's
labeling may reflect differences in formulation but argues that the
generic drug's labeling may only reflect differences in the compo-
nents or ingredients of the drug and not safety risks associated with
the components or ingredients. Zeneca also agrees that under section
314.94(a)(8)(iv) a generic drug's labeling may reflect differences
required by the FDA's labeling guidelines but argues that, by its
terms, this exception only applies to situations in which such guide-
lines are issued "after approval of the[pioneer] drug but before
approval of the generic." (Appellant's Br. at 52).
Again, Zeneca's arguments challenge the FDA's interpretation of
its own regulation, which interpretation "is entitled to ``substantial def-
erence' and will be sustained unless it is plainly erroneous or incon-
sistent with the regulation." Clinchfield Coal Co., 149 F.3d at 309.
We find the FDA's interpretation of 21 C.F.R. § 314.94(a)(8)(iv) to
be consistent with the language of the regulation and not plainly erro-
neous. The Sulfite safety warning in Gensia's labeling is a direct
result of the difference in formulation between Gensia's propofol with
Sulfite and DIPRIVAN. Gensia was fully authorized to formulate its
generic drug with a different preservative than is contained in
DIPRIVAN. See 21 U.S.C.A. § 355(j)(4)(H); 21 C.F.R.
§ 314.94(a)(9)(iii) (providing that "an applicant may seek approval of
a [parenteral] drug product that differs from the reference listed drug
in preservative" (emphasis added)). Because a difference in preserva-
tive is a permitted variation in formulation, it is reasonable for the
FDA to interpret its own regulation to allow corresponding differ-
ences in labeling to identify the preservative and provide any appro-
priate warnings.
In addition to permitting labeling changes based on differences in
formulation, section 314.94(a)(8)(iv) permits changes in order "to
comply with current FDA labeling guidelines and guidance." 21
C.F.R. § 314.94(a)(8)(iv). Section 201.22(b) of the FDA's regulations
requires that prescription drugs containing sulfites
shall bear the warning statement "Contains (insert the name
of the sulfite, e.g., sodium metabisulfite), a sulfite that may
cause allergic-type reactions . . . in certain susceptible peo-
ple. The overall prevalence of sulfite sensitivity in the gen-
12
eral population is unknown and probably low. Sulfite
sensitivity is seen more frequently in asthmatic than in non-
asthmatic people."
21 C.F.R. § 201.22(b) (emphasis in the original). The FDA inter-
preted section 314.94(a)(8)(iv) to permit Gensia to include in its
labeling the "warning statement" required by section 201.22, a current
FDA labeling guideline. This interpretation is consistent with the lan-
guage of section 314.94(a)(8)(iv). Furthermore, we see no merit to
Zeneca's argument that the exception permitting revisions in labeling
to comply with the FDA's current labeling guidelines only applies in
situations in which the guidelines are issued after approval of the pio-
neer drug but before approval of the generic.
In sum, we conclude that the FDA's interpretation of 21 C.F.R.
§ 314.94(a)(8)(iv) to allow the label on Gensia's propofol with Sulfite
to reflect a warning against possible allergic reaction to Sulfite con-
tained in the drug is not plainly erroneous or inconsistent with the lan-
guage of the regulation. Accordingly, the FDA's approval of Gensia's
ANDA for propofol with Sulfite was not arbitrary and capricious for
the second reason argued by Zeneca.
C
Finally, Zeneca argues that the FDA's approval of Gensia's propo-
fol with Sulfite as a generic drug must be declared invalid and perma-
nently enjoined because in determining that Gensia's propofol with
Sulfite is safe the FDA relied upon safety evaluations that analyzed
the wrong pH range. In this regard, Zeneca contends that the FDA
conducted its safety evaluations of Gensia's propofol with Sulfite
based on the initially proposed pH range of 6.0-7.5 rather than the
lower pH range of 4.5-6.4 actually used in Gensia's ANDA for propo-
fol with Sulfite.
In considering Zeneca's argument, we are mindful 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 from us.'" A.L. Pharma, Inc. v. Shalala, 62 F.3d
1484, 1490 (D.C. Cir. 1995) (quoting Schering Corp. v. FDA, 51 F.3d
390, 399 (3d Cir. 1995)). Our review of the record reveals that Zene-
13
ca's argument, that the FDA relied upon the wrong pH range in deter-
mining that Gensia's propofol with Sulfite is safe, is without merit.
Specifically, the record contains: (1) repeated references to the correct
pH in Gensia's ANDA for propofol with Sulfite; (2) an agenda to a
teleconference call between Gensia and FDA officials on the subject
of the pH proposed in Gensia's ANDA for propofol with Sulfite; (3)
the FDA's participation in the teleconference call held on August 19,
1998 to discuss the pH proposed in Gensia's ANDA for propofol with
Sulfite; and (4) an assessment of the pH proposed in Gensia's ANDA
for propofol with Sulfite and a determination by Dr. Mary Fanning,
Associate Director of Medical Affairs for the OGD, that the proposed
pH raised no safety issues. This evidence demonstrates that the
FDA's safety determination regarding Gensia's propofol with Sulfite
included its assessment of the actual lower pH range used in Gensia's
final proposed version of propofol with Sulfite. 10
III
In sum, there is no basis in the record before us to hold that the
FDA acted arbitrarily and capriciously in approving Gensia's ANDA
for propofol with Sulfite. Accordingly, we affirm the district court's
grant of Gensia's and the FDA's motions for summary judgment.
AFFIRMED
_________________________________________________________________
10 We also note that the issue of Zeneca's standing was raised at oral
argument. We conclude that Zeneca has standing. See Mova Pharm.
Corp. v. Shalala, 140 F.3d 1060, 1074 (D.C. Cir. 1998) (noting that "nu-
merous cases have found that a firm has constitutional standing to chal-
lenge a competitor's entry into its market"); Schering Corp., 51 F.3d at
395 (noting that FDA did not contest "that Schering's potential loss of
monopoly profits upon FDA approval of a competitive generic substitute
is sufficient to meet the Article III injury-in-fact standing requirement");
see also MD Pharm., Inc. v. DEA, 133 F.3d 8, 11 (D.C. Cir. 1998) ("We
have previously held that ``increased competition represents a cognizable
Article III injury,' Liquid Carbonic Industries Corp. v. FERC, 29 F.3d
697 (D.C. Cir. 1994), and MD's competitive injury is fairly traceable to
DEA's decision to issue a certificate of registration to Mallinckrodt.").
14