Alpharma Inc v. Leavitt, Michael

United States Court of Appeals
FOR THE DISTRICT OF COLUMBIA CIRCUIT

Argued February 10, 2006 Decided August 11, 2006

No. 05-5137

ALPHARMA, INC.,
APPELLANT

v.

MICHAEL O. LEAVITT, SECRETARY, HEALTH AND HUMAN
SERVICES, ET AL.,
APPELLEES

Appeals from the United States District Court
for the District of Columbia
(No. 83cv01603)

Douglas J. Behr argued the cause for appellant. With him
on the briefs was John B. Dubeck.

Suzette A. Smikle, Attorney, U.S. Department of Justice,
argued the cause for appellees. With her on the brief were Peter
D. Keisler, Assistant Attorney General, Eugene M. Thirolf,
Director, and Drake Cutini, Attorney.

Before: GARLAND, Circuit Judge, and SILBERMAN and
WILLIAMS, Senior Circuit Judges.
 2

Opinion for the court filed by Circuit Judge GARLAND.

Opinion concurring in part and dissenting in part filed by
Senior Circuit Judge WILLIAMS.

GARLAND, Circuit Judge: This is the second time we have
heard an appeal in this matter. In our first opinion, we
concluded that the Food and Drug Administration (FDA) had
failed to adequately explain why it granted Philips Roxane,
Inc.’s “new animal drug application” for bacitracin zinc.1 See
A.L. Pharma, Inc. v. Shalala, 62 F.3d 1484, 1486 (D.C. Cir.
1995). In this opinion, we conclude that the explanation the
FDA offered on remand adequately addressed the questions
raised in our first opinion. Nonetheless, we agree with appellant
Alpharma, Inc.2 that the FDA’s explanation raises new problems
and apparent contradictions that, unfortunately, require yet
another remand.

I

The “tortured story” of this case is recounted at length in
our previous opinion, A.L. Pharma, 62 F.3d at 1486, and in two
district court opinions, A.L. Pharma, Inc. v. Thompson, No.
83-1603, Mem. Op. (D.D.C. Feb. 4, 2005), and A.L. Labs. v.
Shalala, No. 83-1603, 1993 U.S. Dist. LEXIS 21357 (D.D.C.
Dec. 21, 1993). We retell it only briefly here.

1
The parties alternatively refer to the drug as “bacitracin zinc”
and “zinc bacitracin.” We follow the convention established in our
previous opinion, A.L. Pharma, 62 F.3d at 1486, and use “bacitracin
zinc.”
2
Alpharma brought suit in the district court under the names of its
predecessors, A.L. Laboratories, Inc. and A.L. Pharma, Inc. This
opinion refers to petitioner by its current name.
 3

Under the Food, Drug, and Cosmetic Act (the “Act”), a
manufacturer must apply to the FDA for approval to market a
new animal drug. 21 U.S.C. § 360b. To gain approval, a
manufacturer must submit a “new animal drug application”
(NADA) demonstrating that the drug is both safe and effective
under the conditions “prescribed, recommended, or suggested in
the proposed labeling.” 21 U.S.C. § 360b(d)(1)(A) & (E); see
id. § 360b(a)(1) & (b)(1); 21 C.F.R. § 514.1.

In the early 1970s, the Animal Health Institute, an industry
trade association, coordinated a safety study on bacitracin zinc.
There is no dispute that the study provided an adequate basis for
the FDA’s subsequent conclusion that Philips Roxane’s
bacitracin zinc product met the Act’s safety requirements. See
A.L. Pharma, 62 F.3d at 1486. The study did not, however,
address the statute’s efficacy requirement.

The FDA has allowed manufacturers of certain classes of
drugs to establish a drug’s efficacy by using a “regulatory
shortcut” known as “bioequivalency.” A.L. Pharma, 62 F.3d at
1488. The agency determined that, for those classes, applicants
did not need to conduct their own field studies to prove that their
products were effective. Instead, an applicant could establish a
generic drug’s efficacy by demonstrating that it was
“bioequivalent” to a “benchmark” drug that the FDA had
already found to be effective for the same intended uses. See id.
at 1487; see also Tri-Bio Lab., Inc. v. United States, 836 F.2d
135, 138-39 (3d Cir. 1987).

In July 1970, the FDA found that bacitracin zinc products
were effective for increased rate of weight gain and improved
feed efficiency in poultry. See Bacitracin With or Without
Penicillin; Drugs for Veterinary Use; Drug Efficacy Study
Implementation, 35 Fed. Reg. 11,531 (July 17, 1970). Based on
that finding, the FDA permitted applicants submitting NADAs
 4

for bacitracin zinc intended for those uses to establish the
efficacy of their products by showing they were “bioequivalent”
to the benchmark drugs upon which the FDA had based its
initial finding. See New Animal Drugs for Use in Animal
Feeds; Bacitracin Zinc; NAS/NRC Update, 46 Fed. Reg. 37,043,
37,044 (July 17, 1981) (codified at 21 C.F.R. § 558.78).

On May 28, 1981, Philips Roxane submitted an application
to the FDA for approval of its generic version of bacitracin zinc.
To establish bioequivalence, Philips Roxane’s application,
which the FDA designated as NADA 128-550, relied on a 1978
study conducted by Dr. John Prescott of the University of
Guelph in Ontario, Canada (“Prescott Study”). Prescott tested
the Philips Roxane product alongside a benchmark drug
produced by International Minerals & Chemical Corp. The
study was designed to determine whether the two were equally
effective in treating experimentally-induced necrotic enteritis in
a population of chickens when administered at a single dosage.
See New Animal Drugs for Use in Animal Feeds; Bacitracin
Zinc, 47 Fed. Reg. 35,187 (August 13, 1982); see also Prescott
Aff. ¶ 4 (J.A. 98). Prescott concluded that the two drugs were
equally effective for that purpose. See Prescott Aff. ¶ 4.

On August 13, 1982, the FDA approved NADA 128-550.
Based on the Animal Health Institute study, the agency
determined that Philips Roxane’s bacitracin zinc product was
safe. See A.L. Pharma, 62 F.3d at 1486. Based on the Prescott
Study, it found that Philips Roxane’s product was bioequivalent
to the International Minerals benchmark. See 47 Fed. Reg. at
35,187. And based on the finding of bioequivalence, the agency
concluded that Philips Roxane’s bacitracin zinc was effective for
increasing weight gain and improving feed efficiency in broiler
chickens. Id.
 5

Appellant Alpharma manufactures an approved bacitracin
zinc product that is similar to the product covered by NADA
128-550. After Philips Roxane’s application was granted,
Alpharma filed four “citizen petitions” asking the FDA to
revoke its approval of NADA 128-550.3 The agency rejected all
four petitions. On June 6, 1983, Alpharma brought suit in the
United States District Court for the District of Columbia under
the Administrative Procedure Act (APA), 5 U.S.C. § 701 et seq.,
challenging the FDA’s approval of NADA 128-550. The district
court granted the FDA’s motion for summary judgment on
December 21, 1993, and Alpharma appealed.

Alpharma’s appeal disputed the FDA’s conclusion that the
Prescott Study established bioequivalence between the Philips
Roxane product and the benchmark drug.4 Alpharma relied on
affidavits and letters submitted by sixteen “highly credentialed
scientists, all of whom questioned the bioequivalency
conclusion.” A.L. Pharma, 62 F.3d at 1488; see id. at 1490.
Alpharma asserted that the “unanimous views of these experts
conclusively establish[ed] that the FDA acted arbitrarily and
thus illegally when it refused to rescind its approval of the
NADA.” A.L. Pharma, 62 F.3d at 1490. Alpharma offered two
principal criticisms of the Prescott Study.

3
FDA regulations permit any “interested person” to “petition the
Commissioner to issue, amend, or revoke a regulation or order, or to
take or refrain from taking any other form of administrative action.”
21 C.F.R. § 10.25(a); see 21 C.F.R. § 10.30.
4
Alpharma also contended that the FDA had failed to follow its
regulations with respect to the use of certain safety data in Philips
Roxane’s application. We resolved that issue in the FDA’s favor, A.L.
Pharma, 62 F.3d at 1490, and it is not at issue on this appeal.
 6

Alpharma’s first contention was that a comparison of the
two products’ relative effectiveness for the purpose of fighting
a disease (necrotic enteritis) was not a proper measure of
bioequivalence for the purpose of promoting growth rates and
feed efficiency -- the product’s intended use. The FDA
responded that it had already determined the benchmark
product’s efficacy for the latter purpose; hence, the function of
a bioequivalence study was not to determine the new product’s
efficacy for that purpose, but rather to determine “whether the
drug’s delivery mechanism operates similarly to that of the
benchmark product.” Id. at 1491. The FDA noted that the usual
method of establishing bioequivalence, measuring levels of the
drug in blood, was not possible for bacitracin zinc. And it
further noted that, because “the expected differences [between
the performance of drugs in the necrotic enteritis study] are
much greater than those for growth experiments,” a comparison
of “the drugs’ abilities to fight disease was perhaps even a better
measure of the similarities of their delivery mechanisms than a
direct comparison of [their] effects on growth promotion.” Id.
(internal citation and quotation marks omitted). Concluding that
this “position reflect[ed] a scientific determination within the
scope of the FDA’s expertise,” we deferred to it. Id.

We were unwilling, however, to accept the agency’s
response to Alpharma’s second criticism. Alpharma’s experts
argued that the Prescott Study could not prove that the two drugs
“were equivalent for the purpose of fighting necrotic enteritis,
because the two drugs were tested at a single dosage.” Id. at
1490. To reach the conclusion that the drugs were equivalent,
they maintained, “different dosages would have to be tested and
dose-response curves for the two products constructed and
compared.” Id. Without the benefit of multi-dosage testing,
“there [was] no way to rule out the possibility that one of the
drugs barely reached effectiveness at the dosage tested while the
other would have been effective against the disease at a fraction
 7

of the dose.” Id. The FDA’s response to this second critique
was brief: It “‘d[id] not believe that it [was] necessary to test
different levels of the drugs and compare dose-response curves’
in order to show ‘that the biological activity of the two drugs
against a known disease organism was not significantly
different.’” Id. (citing Citizen Pet. Denial at 2).

Finding this response “conclusory,” we held that the FDA
had “made no attempt to ‘cogently explain’” why Alpharma was
mistaken in claiming “that a single-dosage study cannot prove
bioequivalency.” Id. at 1492 (quoting Motor Vehicle Mfr’s
Ass’n. v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 48
(1983)). In light of that failure, we set aside the district court’s
grant of summary judgment (but not the FDA’s approval itself),
and remanded the case “so that the FDA may explain what
bioequivalency entails in the animal drug context and how the
Prescott Study satisfied that standard.” Id.

The FDA’s response to our remand came in the form of an
October 27, 1995 letter from Ronald Chesemore, Associate
Commissioner for Regulatory Affairs, to counsel for Alpharma.
J.A. 208 (“Chesemore Letter”). The FDA advised Alpharma
that, “[u]pon review, the agency determined the Prescott study
was an appropriate means for evaluating the bioequivalence of
the zinc bacitracin product covered by NADA 128-550.”
Chesemore Letter at 1. In so doing, the FDA reaffirmed its
original decision to deny Alpharma’s citizen petitions and to
approve NADA 128-550. The details of the FDA’s explanation
are discussed in Parts III and IV below.

On February 4, 2005, the district court held that the
Chesemore Letter complied with the terms of our remand,
concluding that “the FDA provided an adequate justification for
its conclusion that the two drugs are bioequivalent.” A.L.
Pharma, No. 83-1603, Mem. Op. at 5. This appeal followed.
 8

II

We review the district court’s grant of summary judgment
de novo, “applying the same standards as those that govern the
district court’s determination.” Troy Corp. v. Browner, 120 F.3d
277, 281 (D.C. Cir. 1997). We may set aside the FDA’s
approval of NADA 128-550 only if it was “arbitrary, capricious,
an abuse of discretion, or otherwise not in accordance with law.”
5 U.S.C. § 706(2)(A). That standard requires an agency to
“examine the relevant data and articulate a satisfactory
explanation for its action including a ‘rational connection
between the facts found and the choice made.’” State Farm, 463
U.S. at 43 (quoting Burlington Truck Lines, Inc. v. United
States, 371 U.S. 156, 168 (1962)). The “agency must cogently
explain why it has exercised its discretion in a given manner,”
id. at 48, and that explanation must be “sufficient to enable us to
conclude that the agency’s action was the product of reasoned
decisionmaking,” id. at 52.

We are met at the outset with Alpharma’s contention that
the Chesemore Letter cannot provide a “satisfactory
explanation” because it is a “post-h[o]c rationalization”
generated “thirteen years after the relevant decision.” Alpharma
Br. 24. As Alpharma notes, in Citizens to Preserve Overton
Park, Inc. v. Volpe, the Supreme Court held that post hoc
rationalizations “have traditionally been found to be an
inadequate basis for review” of agency decisions. 401 U.S. 402,
419 (1971). Nonetheless, in Overton Park itself, the Court
approved the procedure of remanding so that an agency can
provide an explanation for an inadequately articulated decision.
Id. at 420. Needless to say, if it is appropriate for a court to
remand for further explanation, it is incumbent upon the court to
consider that explanation when it arrives. And also needless to
 9

say, a letter produced in response to our 1995 remand would
have to be “post hoc” as measured against an agency decision
issued in 1982. See id. at 419 (noting, in remanding for an
explanation, that “[s]uch an explanation will, to some extent, be
a ‘post hoc rationalization’”).

Thirty years ago, we rejected the identical argument that
Alpharma raises here. In Local 814, Int’l Bhd. of Teamsters v.
NLRB, we concluded that we had the authority to consider a
supplemental explanation that the NLRB provided in response
to our remand. 546 F.2d 989, 992 (D.C. Cir. 1976). We
explained the meaning of the “post hoc rationalization” rule as
follows:

[The] rule is not a time barrier which freezes an
agency’s exercise of its judgment after an initial
decision has been made and bars it from further
articulation of its reasoning. It is a rule directed at
reviewing courts which forbids judges to uphold
agency action on the basis of rationales offered by
anyone other than the proper decisionmakers. Thus the
rule applies to rationalizations offered for the first time
in litigation affidavits and arguments of counsel. The
policy of the post hoc rationalization rule does not
prohibit [an agency] from submitting an amplified
articulation of the distinctions it sees. . . . Moreover,
the logic of the rule requires it. If a reviewing court
finds the record inadequate to support a finding of
reasoned analysis by an agency and the court is barred
from considering rationales urged by others, only the
agency itself can provide the required clarification.

Id. (internal citations omitted).
 10

There is no question that Associate Commissioner
Chesemore is a “proper decisionmaker[,]” id., and that his letter
represents the considered views of the agency itself. See
Chesemore Letter at 1 (“Upon review, the agency has
determined that the Prescott study was an appropriate means for
evaluating the bioequivalence of the zinc bacitracin product
covered by NADA 128-550.”) (emphasis added). The letter is
neither a mere “litigation affidavit[,]” nor an “argument[] of
counsel.” Local 814, 546 F.2d at 992. Accordingly, an
examination of its contents is perfectly appropriate. In Part III,
we consider whether the agency’s explanation satisfactorily
answered the two questions we posed in our remand order. In
Part IV, we address the new problems that arise out of the
explanation that the FDA offered.

III

Our remand order instructed the FDA to “explain what
bioequivalency entails in the animal drug context and how the
Prescott Study satisfied that standard.” A.L. Pharma, 62 F.3d at
1492. That instruction involved two questions, each of which
the FDA addressed in the Chesemore Letter.

A

To paraphrase another (and more famous) poultry case:
The first issue is, what is bioequivalence? Cf. Frigaliment
Importing Co. v. B. N. S. Int’l Sales Corp., 190 F. Supp. 116,
117 (S.D.N.Y. 1960) (Friendly, J.) (“The issue is, what is
chicken?”). More precisely, the question we asked on remand
was “what characteristics . . . two drugs must share in order to
be deemed bioequivalent.” A.L. Pharma, 62 F.3d at 1491.
 11

The Chesemore Letter set forth, as representing the meaning
of bioequivalence during the 1981-82 period in which NADA
128-550 was considered, the following definition:

A demonstration of bioequivalence involves
establishing that two comparable drug formulations,
which cannot be presumed to be identical based on
chemical equivalence, perform in a similar way in a
chosen test system.

Chesemore Letter at 1. Alpharma objects that the FDA’s
definition is too vague, because it does not clearly explain what
it means for two drugs “to perform in a similar way in a chosen
test system.” Alpharma Br. 34. In context, however, we
understand the “chosen test system” to mean experimentally-
induced necrotic enteritis, and we understand “perform in a
similar way” to mean similarly effective in treating that disease.
See Chesemore Letter at 3 (“[T]he study demonstrated that [the
NADA 128-550] product and the innovator zinc bacitracin
product perform in a similar way in the chosen test system (i.e.,
in the treatment of necrotic enteritis).”). Performance, in turn,
was evaluated under the pre-established criteria of mortality,
lesions, and weight gain. See Memorandum from Dr. Thomas
V. Raines to Drs. Malcolm Thomas and Lonnie Luther 1 (Aug.
25, 1981) (describing the evaluation parameters of the Prescott
Study) (J.A. 43) (“Raines Memorandum”).

In our initial opinion, we acknowledged that “there may be
more than one reasonable definition of bioequivalency,” and that
the FDA was entitled to “latitude in its construction of the term.”
A.L. Pharma, 62 F.3d at 1491-92. Bacitracin zinc is a drug for
which “conventional blood level study is not appropriate”
because it “does not produce blood levels.” Raines
Memorandum at 1. As we suggested in our initial opinion,
where blood levels could not be used to measure bioequivalence,
 12

it was not unreasonable for the FDA to define bioequivalence in
terms of performance -- here, the treatment of a specific disease.
See A.L. Pharma, 62 F. 3d at 1491 (deferring to the FDA’s
judgment that a comparison of “the drugs’ abilities to fight
disease was perhaps even a better measure of the similarities of
their delivery mechanisms than a direct comparison of [their]
effects on growth promotion”).

We also note -- as did the Chesemore Letter -- that the
FDA’s “description of bioequivalence is consistent with what
Congress later codified in the Generic Animal Drug and Patent
Restoration Act of 1988,” Pub. L. 100-670, 102 Stat. 3971
(1988)). Chesemore Letter at 1 n.1.5 Six years after the FDA
approved NADA 128-550, Congress provided a statutory
definition of bioequivalence for situations (like this one) in
which “the Secretary determines that the measurement of the
rate and extent of absorption or excretion of the new animal
drug in biological fluids is inappropriate or impractical.” 21
U.S.C. § 360b(c)(2)(H)(ii)(III). In such circumstances, a new
animal drug “shall be considered to be bioequivalent to” an
approved new animal drug (i.e., a benchmark drug) if

an appropriate acute pharmacological effects test or
other test of the new animal drug and . . . of the
approved new animal drug . . . in the species to be
tested . . . does not show a significant difference
between the new animal drug and such approved new
animal drug when administered at the same dose under
similar experimental conditions.

Id. Although Congress’ subsequent enactment of a similar
bioequivalency standard does not in itself validate the FDA’s

5
At oral argument, counsel for Alpharma conceded that the 1988
Act could be read as the FDA reads it. Oral Arg. Tape at 50:44.
 13

definition, it does suggest that the concern that prompted our
first remand question may not recur.

B

The second issue posed by our remand was “how the
Prescott Study satisfied” the FDA’s bioequivalency standard.
Id. at 1492. Specifically, we asked why the FDA viewed a
single-dose rather than multiple-dose study as appropriate for
establishing bioequivalence. Id.

In response, the Chesemore Letter explained that
“[b]ioequivalence testing of generic veterinary drugs has
historically been conducted using a single dose level; this was
the accepted approach at the time NADA 128-550 was
approved.” Chesemore Letter at 2. “Testing at more than one
dosage level,” the FDA said, “is necessary only where the drug
at issue is a sustained release product or in the rare instance in
which the drug has demonstrated nonlinear kinetics.” Id.6
Because “neither circumstance existed with zinc bacitracin,” the
FDA concluded that “a single dose bioequivalence study is
sufficient.” Id.

The FDA’s description of its historical practice is entitled
to deference in light of the agency’s experience and expertise in
these matters. See Fed. Power Comm’n v. Fla. Power & Light
Co., 404 U.S. 453, 463 (1972). To be sure, that description
would have been more persuasive had it been accompanied by

6
See FDA Br. 13 n.5 (“Sustained release drugs are drugs that are
manufactured to release a certain amount of an active ingredient in
uniform doses at regular intervals over a given period of time.
Nonlinear kinetics exists where absorption, distribution, and
elimination of a drug cannot be defined by rate constants that are
concentration-independent.”).
 14

citations. But the plaintiff has not cited anything to contradict
the agency’s representation, and at oral argument plaintiff’s
counsel conceded that he did not know of any contrary
examples. Oral Arg. Tape 50:01-50:20.

The Chesemore Letter then went on to explain why
multiple-dose studies had not historically been required to
establish bioequivalence:

A bioequivalency study is not designed to demonstrate
or affirm the efficacy of the product at issue for a given
use; instead, . . . its purpose is to demonstrate that two
comparable formulations perform similarly in a chosen
test system. In contrast, a dose response study is
conducted in order to isolate from the range of doses
being tested the optimally effective dose of a product
for a particular condition or use.

Chesemore Letter at 2.7 Since the purpose of the Prescott Study
was not to determine “the optimally effective dose,” Chesemore
Letter at 2, but only to determine whether the two drugs would
perform in a similar way with respect to necrotic enteritis, the
agency’s explanation for not employing a multiple-dose study
was reasonable. Such a “judgment[] as to what is required to
ascertain the safety and efficacy of drugs falls squarely within
the ambit of the FDA’s expertise and merit[s] deference from
us.” A.L. Pharma, 62 F.3d at 1490 (internal quotation marks
omitted); see Schering Corp. v. FDA, 51 F.3d 390, 399-400 (3d

7
As we noted above, see supra Part I, a bioequivalency study is
not designed to demonstrate efficacy because the FDA has already
determined the benchmark product’s efficacy for the given use; the
function of a bioequivalency study is only to determine whether the
generic “drug’s delivery mechanism operates similarly to that of the
benchmark product.” A.L. Pharma, 62 F.3d at 1491.
 15

Cir. 1995) (holding, in the human drug context, that the FDA
has “discretion to determine what tests or studies would provide
it with appropriate information from which to determine
bioequivalence”).

In sum, we conclude that the Chesemore Letter adequately
responded to the questions we raised in our remand order.
Those responses provide a satisfactory explanation both of what
“bioequivalency entails in the animal drug context,” and of how
the single-dose Prescott Study “satisfied that standard.” A.L.
Pharma, 62 F.3d at 1492.

IV

We would like nothing better than to end this “tortured
story” right here. Id. at 1486. But the FDA has not made that
possible. As Alpharma correctly argues, in the course of
responding to our remand, the FDA made new, seemingly
contradictory statements that require further clarification before
we can conclude that the agency acted reasonably.

The FDA insists that Alpharma’s arguments are not
properly before us because the company did not raise them on
the first appeal. But the arguments that Alpharma asserts here
all involve statements that the FDA made for the first time after
that appeal, in the Chesemore Letter. Therefore, because they
are not arguments that “could have been raised on an initial
appeal,” it is not “inappropriate to consider [them] on a second
appeal following remand.” Northwestern Ind. Tel. Co. v. FCC,
872 F.2d 465, 470 (D.C. Cir. 1989).

As discussed in Part III, we are satisfied with the FDA’s
explanation for concluding that “a single dose bioequivalence
study is sufficient” for evaluating bacitracin zinc. Chesemore
Letter at 2. As Alpharma points out, however, two additional
 16

problems arise out of the agency’s further declaration that “a
dose of 100 grams/ton of feed” -- the single dose used in the
Prescott Study -- “was the appropriate zinc bacitracin dose for
control of necrotic enteritis.” Id. We consider those problems
below.

A

The first problem involves an apparent contradiction
between the Chesemore Letter’s conclusion that 100 grams/ton
was the appropriate dose, and its statement that “[h]istorically,
the FDA has recommended that, as a general rule, a
bioequivalence study be conducted using the highest approved
dose.” Id. As Alpharma notes, 100 grams/ton was not the
highest approved dose in the two sources that the Chesemore
Letter cites in support of the proposition that 100 grams/ton was
the appropriate dose for the Prescott Study. Id. One of those
sources listed “the approved dose for the water soluble powder
form of zinc bacitracin.” Id. (citing Certifiable Peptide
Antibiotic Drugs for Animal Use; Zinc Soluble Powder, 47 Fed.
Reg. 24,693, 24,694 (June 8, 1982)). That source fixed the
highest approved water-soluble dose for control of necrotic
enteritis in chickens at 400 milliliters/gallon, see 47 Fed. Reg. at
24,694, which is comparable to 200 grams/ton of feed8 -- double
the dose used in the Prescott Study. The other cited source was
for “the approved dose of a related form of bacitracin, bacitracin
methylene disalicylate,” for use in feed to control necrotic
enteritis. Chesemore Letter at 2 (citing 21 C.F.R. § 558.76
(1982)). The highest approved dose for that drug was 200
grams/ton, see Animal Drugs, Feeds, and Related Products;
Bacitracin Methylene Disalicylate, 47 Fed. Reg. 21,748, 21,749

8
See Alpharma Br. 32. The FDA has not disputed Alpharma’s
translation of water-soluble doses into feed doses.
 17

(Apr. 14, 1981) (codified at 21 C.F.R. § 558.76) -- again double
that used by Prescott.

There is another inconsistency lurking here as well. The
Chesemore Letter stated that 100 grams/ton of feed was the
appropriate dose for the “control” of necrotic enteritis.
Chesemore Letter at 2. But it is not clear from the agency’s own
description whether Prescott studied the control or the
prevention of necrotic enteritis. As Alpharma points out, the
FDA has “described the Prescott Study at times as studying
prevention while at other times studying control.” Alpharma Br.
at 29.9 This is significant because the two sources cited in the
Chesemore Letter listed highest approved doses that were
different for prevention than for control -- and that were also
different from the 100 grams/ton used in the Prescott Study.
Indeed, if the focus of the study was prevention, then the highest
approved doses for that purpose were half the 100 grams/ton that
Prescott used. See 47 Fed. Reg. at 24,694 (listing 100
milliliters/gal, comparable to 50 grams/ton of feed, as the
highest approved dose of water-soluble bacitracin zinc for
prevention); 47 Fed. Reg. at 21,749 (listing 50 grams/ton of feed
as the highest approved dose of bacitracin methylene disalicylate
for prevention).

Finally, we note that all of these comparisons of highest
approved doses are something of a fiction given the FDA’s
acknowledgment that, at the time of the Prescott Study, there

9
See, e.g., Briefing Memorandum on Approval for a New Drug
Application 2 (June 30, 1992) (J.A. 66) (describing the Prescott Study
as comparing the drugs’ “ability to prevent necrotic enteritis in broiler
chickens”) (emphasis added); see also Prescott Aff. ¶ 4 (“The study
results demonstrated that the two different sources of bacitracin zinc
were equally efficacious at the levels used in preventing
experimentally induced necrotic enteritis.”) (emphasis added).
 18

was no approved dose of bacitracin zinc for the control of
necrotic enteritis. See Chesemore Letter at 3 n.4 (“The agency
acknowledges that at the time of the approval of NADA-128-
550, zinc bacitracin was not approved for use in feed for the
control of necrotic enteritis.”). The two sources cited by the
FDA were for approvals issued well after the Prescott Study was
concluded. Yet nothing in the Chesemore Letter explains how
Prescott could have appropriately relied on approvals that had
not yet been made. Nor does it explain why it was appropriate
for him to use a dose different from (either higher or lower than,
depending on whether Prescott studied prevention or control) the
highest approved dose -- as the FDA had historically
recommended.

B

The second problem identified by Alpharma centers around
the Chesemore Letter’s declaration that 100 grams/ton was the
“appropriate zinc bacitracin dose” because it was the “optimally
effective dose for controlling necrotic enteritis.” Chesemore
Letter at 3 n.4. The Letter offers no support for the latter
proposition, and, this time, Alpharma points to contradictory
indicators. Compare supra Part III.B (accepting the FDA’s
description of its historical practice regarding single-dose
studies where plaintiff cited nothing to contradict it).

As Alpharma points out, and as we noted above, the
Chesemore Letter concedes that at the time of the approval of
NADA 128-550, bacitracin zinc had not been approved for the
control of necrotic enteritis at any level, let alone at an optimally
effective dose. See Chesemore Letter at 3 n.4.10 Moreover,

10
See also FDA Br. 23 (acknowledging that “Alpharma correctly
states that FDA had not approved zinc bacitracin to control necrotic
enteritis at the 100 grams/ton dose level at the time of the Prescott
 19

neither of the two sources discussed in the Chesemore Letter
established an optimally effective dose for the control of
necrotic enteritis. While 100 grams/ton fell within the range of
approved doses for both water-soluble bacitracin zinc and
bacitracin methylene disalicylate, neither approval referred to an
optimally effective dose. See 47 Fed. Reg. at 24,694; 47 Fed.
Reg. at 21,749.

The Chesemore Letter flatly declares that “the agency had
a clear rationale for its determination that 100 grams/ton would
be the optimally effective dose for controlling necrotic
enteritis.” Chesemore Letter at 3 n.4. The problem is that the
letter offers no hint of what that “clear rationale” might have
been. Accordingly, we are unable to determine whether it was
reasonable.11

V

For the reasons discussed in Part III, we conclude that the
FDA adequately responded to our initial remand. For the
reasons discussed in Part IV, however, we conclude that the
agency’s response raises questions that leave us unable to
conclude that the decision to approve Philips Roxane’s new
animal drug application “was the product of reasoned
decisionmaking.” State Farm, 463 U.S. at 43. We therefore set

study”).
11
The FDA’s appellate brief proposes a number of reasons why
the agency might have accepted the 100 grams/ton dose as
appropriate, and why it deviated from its general rule that a
bioequivalency study should use the highest approved dose. FDA Br.
22-28. These, however, truly are “post hoc” rationalizations “offered
for the first time in litigation affidavits and arguments of counsel,” and
we are “barred from considering” them. Local 814, 546 F.2d at 992
(D.C. Cir. 1976) (citations omitted); see supra Part II.
 20

aside the district court’s grant of summary judgment and remand
the case.

Alpharma cannot start counting its chickens just yet.
Notwithstanding the problems of the Chesemore Letter, the
FDA may still “be able to explain why it reasonably determined
that the Prescott Study demonstrated bioequivalence.” A.L.
Pharma, 62 F.3d at 1492. For that reason, and “because no
significant harm would result from allowing the approval to
remain in effect pending the agency’s further explanation,”12 we
leave the approval in place. Id. (citing, inter alia, Allied-Signal,
Inc. v. NRC, 988 F.2d 146, 151 (D.C. Cir. 1993)). The district
court is instructed to remand the matter to the FDA for an
adequate explanation of its conclusion that a dose of 100
grams/ton was the appropriate bacitracin zinc dose for use in the
Prescott bioequivalency study. That explanation must resolve
the problems and apparent contradictions highlighted in Part IV.

So ordered.

12
Indeed, the parties advised us that the Philips Roxane drug has
never been marketed. See Oral Arg. Tape 21:53, 42:23. Perhaps that
explains why neither side appears concerned about the length of time
it has taken to litigate this case, which was first filed in 1983.
 WILLIAMS, Senior Circuit Judge: I concur in the court’s
opinion except Part III.B. I’m not convinced that the FDA
adequately explained how a single-dose study satisfied its
bioequivalency standard.

In the first appeal of this case, we remanded precisely on
this issue, finding that the FDA’s “conclusory response to
[Alpharma] that it ‘does not believe that it is necessary to test
different levels of the drugs and compare dose-response
curves’ [is not] sufficient.” A.L. Pharma, Inc. v. Shalala, 62
F.3d 1484, 1492 (D.C. Cir. 1995). We based this ruling on a
record containing affidavits and letters of 16 experts arguing,
in essence, that a single-dose study was weak support for an
inference that the new drug was truly bioequivalent to the
benchmark drug. See, e.g., Johnson Aff. ¶ 8 (concluding that
“several levels at equally spaced intervals of the drug should
be tested and a dose response curve constructed” because
“[u]sing a single dose level and finding 100% success only
indicates that the drugs are effective at the stated level”).
Most of the rest make essentially this point. In response, the
FDA’s Chesemore Letter offers two substantive reasons that
persuade the majority, but I find each defective. (I do not
discuss the FDA’s historical practice, as practice alone would
not constitute an adequate explanation in the face of a serious
substantive challenge.)

First, the FDA asserts that multiple dosages are only
necessary for sustained release drugs and drugs exhibiting
nonlinear kinetics (“SRNK” drugs). But nowhere does the
FDA provide an explanation of why only SRNK drugs should
be tested this way. Nothing in the record establishes that if
the benchmark and new drug exhibit linear kinetics and have
the same effects at one dose, they will have the same effect at
all doses (or, more pertinently, at all doses likely to be
lawfully prescribed in the event of approval).
 2

Indeed, nonlinear kinetics appear to be a complete red
herring. We are told by the FDA on brief that “nonlinear
kinetics exists where absorption, distribution, and elimination
of a drug cannot be defined by rate constants that are
concentration-independent.” FDA Br. 13 n.5. But the
absorption, distribution, and elimination of a drug appear to
refer to attributes of a blood level study, not a pharmacologic
endpoint study, which the Prescott Study was. Compare
Center for Veterinary Medicine, Bioequivalency Guideline 5-
8 (April 12, 1990) (discussing how blood level studies
“encompass . . . absorption and depletion (elimination) phases
of the drug concentration profiles” and that “a single dose
study at the highest approved dose will generally be adequate
for the demonstration of bioequivalence”); with id. 13-15
(noting that “[w]here the direct measurement of the rate and
extent of absorption . . . is inappropriate or impractical, the
evaluation of an appropriate pharmacologic endpoint will be
acceptable” and that “[d]osage(s) approved for the pioneer
product should be used in the study”). Moreover, as with
nonlinear kinetics, the FDA provides no discussion of
sustained release drugs. The FDA’s terse incantation of
SRNK drugs thereby provides no basis for an adequate
explanation.

Second, the FDA asserts that dose-response studies are
designed to choose optimally effective doses. But the fact that
multiple-dose testing is required to determine the optimal dose
tells us nothing about whether such testing is sensible to show
bioequivalence. Moreover, as Alpharma argues, the assertion
begs the question of what it means to “perform similarly in a
chosen test system,” see Chesemore Letter at 2, failing to
provide an explanation of how bioequivalence can be
established without testing in the ranges that are plausible for
the drugs’ uses.
 3

The FDA might, though it seems implausible, show that
multiple-dose testing affords no material increase in
confidence in the bioequivalence of the two drugs. More
likely, it might offer some reason to believe that although
multiple-dose testing was more accurate, the gain in accuracy
wasn’t worth the time and cost. Barring some statutory
problem, we would properly defer to such a view.
Alternatively, of course, the FDA may find that multiple-dose
testing is sound as a matter of both science and policy.

In short, the FDA’s response to our remand seems
completely unilluminating. As the court remands for the FDA
to straighten out its explanation of what (single) dose to use,
perhaps the agency will seize the occasion to explain its
single-dose policy. Users of new drugs would surely find
relief in a real explanation.