Source: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-caDC-05-05137/USCOURTS-caDC-05-05137-0/pdf.json

Nature of Suit Code: 890
Nature of Suit: Other Statutory Actions
Cause of Action: 

---

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.

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 1 of 23
2

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. 

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.

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 2 of 23
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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 3 of 23
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. 

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 4 of 23
5

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.

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. 

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 5 of 23
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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 6 of 23
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. 

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 7 of 23
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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 8 of 23
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). 

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 9 of 23
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. 

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 10 of 23
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 experimentallyinduced 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,

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 11 of 23
12

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.

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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 12 of 23
13

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.”).

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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 13 of 23
14

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. 

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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 14 of 23
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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 15 of 23
16

8

See Alpharma Br. 32. The FDA has not disputed Alpharma’s

translation of water-soluble doses into feed doses.

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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 16 of 23
17

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).

(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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 17 of 23
18

10See 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

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,

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 18 of 23
19

study”). 

11The 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.

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

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 19 of 23
20

12Indeed, 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. 

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.

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 20 of 23
 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). 

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 21 of 23
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. 

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 22 of 23
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. 

USCA Case #05-5137 Document #985560 Filed: 08/11/2006 Page 23 of 23