Bartlett v. Mutual Pharmaceutical

2009 DNH 144

• Court: District Court, D. New Hampshire
• Decided: September 30, 2009
• Docket: CV-08-358-JL
• Status: Published

Opinion

Bartlett v . Mutual Pharmaceutical CV-08-358-JL 09/30/09 P UNITED STATES DISTRICT COURT DISTRICT OF NEW HAMPSHIRE

Karen L. Bartlett and Gregory S . Bartlett

v. Civil N o . 08-cv-358-JL Opinion N o . 2009 DNH 144 Mutual Pharmaceutical Company, Inc. et al.

O R D E R

This case presents a question currently pending before three

different federal courts of appeal: whether state-law tort

claims alleging the defective labeling of generic drugs are pre-

empted by federal law. See Morris v . Wyeth, Inc., N o . 09-5509

(6th Cir. Apr. 2 7 , 2009); Demahy v . Wyeth, Inc., N o . 08-31204

(5th Cir. Dec. 1 6 , 2008); Mensing v . Wyeth, Inc., N o . 08-3850

(8th Cir. Dec. 1 0 , 2008). The defendants, Mutual Pharmaceutical

Company, Inc. and United Research Laboratories, Inc., move for

judgment on the pleadings, see Fed. R. Civ. P. 12(c), on claims

by the plaintiffs, Karen L . and Gregory S . Bartlett, alleging

that Karen suffered serious injuries from Sulindac, a generic

drug manufactured by the defendants. The defendants argue that

all of the plaintiffs’ state-law causes of action are pre-empted

by Title I of the Drug Price Competition and Patent Term Restoration Act of 1984, 1 part of the Hatch-Waxman Amendments to

the Federal Food, Drug, and Cosmetic Act (“FDCA”). 2 This court

has subject-matter jurisdiction under 28 U.S.C. § 1332(a)(1)

(diversity).

After considering the parties’ extensive briefing and oral

argument, the court denies the defendants’ motion for judgment on

the pleadings. The Bartletts’ claims do not present an obstacle

to the accomplishment and execution of the full purposes and

objectives of Congress in the Hatch-Waxman Amendments, nor does

complying with the state law underlying those claims make it

impossible to comply with the Hatch-Waxman Amendments or any

other federal law identified by the defendants. The Supreme

Court’s recent decision on the pre-emptive effect of federal drug

regulation on state tort law in Wyeth v . Levine, 129 S . C t . 1187

(2009), makes that result clear. Accordingly, the Bartletts’

claims are not pre-empted.

I. Applicable legal standard

Federal “preemption is an affirmative defense on which [the]

defendant bears the burden of proof.” Cambridge Literary Props.,

1 Pub. L . 98-417, tit. I , 98 Stat. 1985, codified as amended at 21 U.S.C. § 355(j) (1999 & supp. 2009). 2 Ch. 675, 52 Stat. 1040 (1938), codified as amended at 21 U.S.C. §§ 301 et seq. (1999 & supp. 2009).

2 Ltd. v . W . Goebel Porzellanfabrik G.m.b.H. & C o . KG, 510 F.3d 7 7 ,

102 (1st Cir. 2007), cert. denied, 129 S . C t . 58 (2008); see also

Wyeth, 129 S . C t . at 1193 (characterizing a manufacturer’s

argument that federal drug law pre-empted the plaintiff’s claims

as a defense). While an affirmative defense can support a Rule

12(c) motion for judgment on the pleadings, it can do so “only

where it is (1) definitively ascertainable from the complaint and

other sources of information that are reviewable at [the

pleadings] stage, and (2) [these] facts establish the affirmative

defense with certitude.” Citibank Global Mkts., Inc. v .

Rodriguez Santana, 573 F.3d 1 7 , 23 (1st Cir. 2009).

II. Background

A. The Bartletts’ allegations

For purposes of the defendants’ motion for judgment on the

pleadings, the court accepts the following allegations of the

Bartletts’ complaint as true. See Gray v . Evercore Restructuring

L.L.C., 544 F.3d 3 2 0 , 324 (1st Cir. 2008). In December 2004,

Karen Bartlett’s physician prescribed her Sulindac, a non-

steroidal anti-inflammatory drug manufactured by the defendants,

for pain in her right shoulder. Within weeks of filling the

prescription, she went to a local emergency room complaining of

“pimple like bumps, spots or blisters on her face, a fever, eye

irritation,” and other symptoms. She was soon diagnosed with

3 Stevens-Johnson syndrome progressing to toxic epidermal

necrolysis, a serious and potentially fatal condition

characterized by large areas of lesions on and necrosis of the

skin and mucous membranes. See Dorland’s Illustrated Medical

Dictionary 1872 (31st ed. 2007). She spent approximately three

months in the hospital recovering, including two months in a

medically induced coma, and emerged with permanent injuries.

Sulindac is the generic version of a drug originally

approved by the FDA in 1978; the generic version at issue here

was approved in 1991. The Bartletts allege that, following this

approval, the defendants “had an ongoing duty to conduct

postmarketing safety surveillance for any reports of serious

adverse events associated with Sulindac including any such report

in the medical literature” and that, had they done s o , they would

have uncovered information compelling them “to warn physicians

about the dangers” of the drug, including associations with

Stevens-Johnson syndrome and toxic epidermal necrolysis.

The Bartletts’ complaint asserts seven counts:

• strict product liability--failure to warn (count 1 ) ;

• strict product liability--defective in design or manufacture (count 2 ) ;

• fraud, in the sense that the defendants “made misrepresentations of material facts . . . and omitted and/or concealed material facts” about the risks of Sulindac (count 3 ) ;

4 breach of implied warranty that Sulindac was “of merchantable quality and safe and fit for [its intended] use” (count 4 ) ;

breach of express warranty that Sulindac “was safe and well accepted by patients and was safe for long-term use” (count 5 ) ;

negligence in failing “to use reasonable care in designing, testing, labeling, marketing, supplying, distribution [sic] and selling” Sulindac (count 6 ) ;

gross negligence based on the same omissions (count 7 ) .

B. The statutory and regulatory scheme

1. Overview of the FDA approval process

The FDCA prohibits the “introduction into interstate

commerce [of] any new drug, unless an approval of an application

filed pursuant to subsection (b) or (j) of this section is

effective with respect to such drug.”3 21 U.S.C. § 355(a). As

discussed in detail below, those two subsections provide two

different procedures for obtaining the requisite approval from

the Secretary of Health and Human Services to distribute a new

drug. The Secretary oversees the Food and Drug Agency in

carrying out these procedures. See id. § 393(b)(2)(A).

3 The FDCA defines “new drug,” in relevant part, as “[a]ny drug . . . the composition of which is such that such drug is not generally recognized among experts qualified by scientific training and experience to evaluate the safety of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof.” 21 U.S.C. § 321(p)(1).

5 Subsection (b) authorizes a new drug application (“NDA”)

containing certain specified data, e.g., “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 for use,”

“a full list of the articles used as components of such drug,”

and “specimens of the labeling proposed to be used for such

drug.” Id. § 355(b)(1). The Secretary shall approve such an

application absent specified grounds for denial. See id.

§ 355(c)(1)(A). These grounds include, e.g., that the required

investigations “do not include adequate tests . . . to show

whether or not such drug is safe for use under the conditions

prescribed, recommended, or suggested in the proposed labeling

thereof,” that “results of such tests show that such drug is

unsafe for use under such conditions,” and that “based on a fair

evaluation of all material facts, such labeling is unsafe or

misleading in any particular.” Id. § 355(d).

Subsection ( j ) , the Hatch-Waxman Amendments, sets forth a

process under which “[a]ny person may file with the Secretary [of

HHS] an abbreviated application for the approval of a new drug.”

Id. § 355(j)(1) (emphasis added). Rather than the data required

of a full-blown NDA by subsection ( b ) , an abbreviated application

(“ANDA”) must show that “the conditions of use prescribed,

recommended, or suggested in the labeling have been previously

approved for . . . a listed drug,” id. §§ 355(j)(2)(A)(i)

6 (internal quotation marks and parentheses omitted), and that each

of a number of specified characteristics of the new drug is “the

same as that of the listed drug.” Id. §§ 355(j)(2)(A)(ii)-(v).

These characteristics include the drug’s active ingredient, route

of administration, dosage form, strength, and labeling. See id.

A “listed drug” is a “drug which has been approved for

safety and effectiveness under subsection (c) of this section,”

id. § 355(j)(7)(A)(i)(I), which, as just discussed, governs the

approval of applications submitted under subsection ( b ) . The

Secretary must approve an ANDA absent certain specified grounds,

e.g., “information submitted with the application is insufficient

to show that each of the proposed conditions of use have been

previously approved for the listed drug,” id. § 355(j)(4)(B), or

“information submitted in the application is insufficient to show

that the labeling proposed for the drug is the same as the

labeling approved for the listed drug,”4 id. § 355(j)(4)(G).

The Hatch-Waxman Amendments, then, authorize the approval of

a new drug without demanding the information that would otherwise

be required in an application under subsection ( b ) , i.e., the

reports of safety and effectiveness investigations and the like,

4 There is an exception to this requirement “for changes required because of differences approved under a petition filed under [21 U.S.C. § 355(j)(2)(C)] or because the new drug and the listed drug are produced or distributed by different manufacturers.” 21 U.S.C. § 355(j)(2)(A)(v). That exception is not at issue in this case.

7 provided the same drug has been previously approved for the same

conditions under that more rigorous process. As one committee

report on the Amendments noted, their “focus . . . is to provide

the Food and Drug Administration with sufficient information to

assure that the generic drug is the same as the listed drug that

has previously been determined to be safe and effective.” H.R.

Rep. N o . 98-857, p t . 1 , at 21 (1984), reprinted in 1984

U.S.C.C.A.N. 2647, 2654 (footnote and parenthetical omitted).

The term “generic drug,” in this context, refers to a “listed

drug” not covered by a patent, whether because that patent has

expired or otherwise. See 21 U.S.C. § 355(j)(2)(A)(vii).

2. ANDA procedures before Hatch-Waxman

As this committee report also noted, the FDA had, at that

point, already been approving ANDAs for generic drugs, but only

insofar as such a drug was “the same as [a] pioneer [i.e., non-

generic] drug” approved prior to 1962. H.R. Rep. N o . 98-857, p t .

1 , at 1 6 , 1984 U.S.C.C.A.N. at 2649; see also Abbreviated New

Drug Applications, 48 Fed. Reg. 2751, 2755 (Jan. 2 1 , 1983) (later

codified at 21 C.F.R. § 314.2 (1984)). This temporal limitation

had its origins in the Drug Amendments of 1962, which “required

that all drugs, both generic and pioneer, . . . be approved as

safe and effective [by the FDA] prior to marketing”; before those

amendments, the FDA had approved drugs on the basis of safety

8 alone. H.R. Rep. N o . 98-857, p t . 1 , at 1 6 , 1984 U.S.C.C.A.N. at

2649; see also Drug Amendments of 1962 §§ 102(d) (codified as

amended at 21 U.S.C. § 355(d)).

To carry out the mandate of the Drug Amendments, the FDA

“created the drug efficacy study (DESI) to determine if all pre-

1962 [approved] drugs were effective.” H.R. Rep. N o . 98-857, p t .

1 , at 1 6 , 1984 U.S.C.C.A.N. 2647, 2649. The FDA later concluded

that the reports generated in that study, together with other

available data, “constituted a body of information sufficient, in

the case of most DESI drugs determined to be effective, to

conclude that the same drug product produced by another

manufacturer would also be safe and effective if properly

manufactured and used under the same conditions.” Abbreviated

Drug Applications, 43 Fed. Reg. 39126, 39127 (proposed Sept. 1 ,

1978). Thus, the FDA promulgated a rule allowing an ANDA for a

particular new drug upon a finding that such an approach was

“sufficient.” Abbreviated Applications, 35 Fed. Reg. 6574, 6575

(Apr. 2 4 , 1970) (later codified at 21 C.F.R. § 130.4 (1971)).

This rule required, in relevant part, that an ANDA contain

“[l]abeling that is in accord with the labeling conditions

described in the finding.” Id. (later codified at 21 C.F.R.

§ 130.4(f)(2) (1971)).

After receiving ANDAs for new drugs varying from ones

approved through the DESI program in ways that “pose[d]

9 significant questions of safety or effectiveness,” however, the

FDA proposed a new rule limiting the ANDA process. 43 Fed. Reg.

at 39127. This rule, promulgated in 1983, permitted an ANDA only

upon a finding that a drug product “covered by [DESI] may be

approved for marketing without the submission of additional

evidence of preclinical and clinical studies to show safety and

effectiveness.” 48 Fed. Reg. at 2755 (parenthetical omitted)

(later codified at 21 C.F.R. § 314.2(a) (1984)).

The new rule also provided that such a finding, i.e., “that

an [ANDA] is suitable for a drug product[,] applies only to a

product that is the same in active ingredient, dosage form and

strength, route of administration, and conditions of use as the

drug product that was the subject of the finding.” Id. (later

codified at 21 C.F.R. § 314.2(b)(2)). This amendment did not

alter the requirement that an ANDA contain “[l]abeling that is in

accord with the labeling conditions described in the finding that

an [ANDA] is sufficient.” Id. at 2756 (later codified at 21

C.F.R. § 314.2(f)(2)).

At the time it proposed this rule, the FDA announced its

“inten[t] to extend the ANDA concept at a later time to post-1962

drug products by publishing criteria for making a determination

about these drugs,” noting that the rationale for the ANDA

concept covered drugs approved before 1962 only--since only they

had been subjected to the rigors of the DESI process. 43 Fed.

10 Reg. at 39128. The FDA never did act on its own to make the ANDA

process available for drugs approved after 1962, H.R. Rep. N o .

98-857, p t . 1 , at 1 6 , 1984 U.S.C.C.A.N. at 2649, so Congress

acted through the Hatch-Waxman Amendments, “generally extend[ing]

the procedures used to approve generic copies of pre-62 drugs to

post-62 drugs,” id., at 1 4 , 1984 U.S.C.C.A.N. at 2647.

Doing s o , the committee report recognized, would allow the

FDA to approve such drugs without requiring human clinical

trials, “retesting” which the FDA saw as “unnecessary and

wasteful”--as well as “unethical”--“because the drug has already

been determined to be safe and effective.” Id. at 1 6 , 1984

U.S.C.C.A.N. at 2649. The committee report also noted that the

“approximately 150 drugs approved after 1962 that [were] off

patent and for which there [was] no generic equivalent” at that

time “could be approved in generic form if there was [an ANDA]

procedure,” resulting in significant cost savings. Id. at 1 7 ,

1984 U.S.S.C.A.N. at 2650.

3. ANDA procedures after Hatch-Waxman

The FDA later proposed amending its regulations to implement

the ANDA procedure set forth in the Hatch-Waxman Amendments. See

Abbreviated New Drug Application Regulations, 54 Fed. Reg. 28872

(proposed July 1 0 , 1989). In relevant part, the FDA proposed “to

add a new requirement with respect to the submission of labeling

11 as part of an ANDA” to effect Hatch-Waxman’s rule that an ANDA

“show that the proposed labeling for its drug product is the same

as that of the reference listed drug.” Id. at 28884 (emphasis

added). The FDA then promulgated rules specifying that an ANDA

must include “[a] statement that the applicant’s proposed

labeling is the same as the labeling of the reference listed drug

except for” enumerated differences not relevant here.

Abbreviated New Drug Application Regulations, 57 Fed. Reg. 17950,

17985-86 (Apr. 2 8 , 1992) (later codified at 21 C.F.R.

§§ 314.94(a)(8)(iii)-(iv) (1993)).

These rules also stated that the FDA would deny an ANDA if

it was “insufficient to show that the labeling proposed for the

drug is the same as the labeling approved for the listed drug,”

id. at 17992 (later codified at 21 C.F.R. § 314.127(a)(7)

(1993)), and that the FDA “may” begin proceedings to withdraw its

approval of an ANDA if it found “[t]hat the labeling for the drug

product that is the subject of the [ANDA] is no longer consistent

with that for the listed drug,” id. at 17993-94 (later codified

at 21 C.F.R. § 314.150(b)(10) (1993)) (emphasis added), both with

exceptions not relevant here.5

5 Though the FDA has since made slight modifications to § 314.94, see Prescription Drug Product Labeling; Medication Guide Requirements, 63 Fed. Reg. 66378-01, 66397 (Dec. 1 , 1998 these are in relevant part the same regulations that were in effect at the time Karen Bartlett was prescribed and ingested Sulindac, and that remain in effect today. See 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7), 314.150(b)(10) (2008).

12 During the notice-and-comment period on these rules, the FDA

received feedback that “the labeling provisions should be revised

to permit ANDA applicants to deviate from the labeling for the

reference listed drug to add contraindications, warnings,

precautions, adverse reactions, and other safety-related

information.” Id. at 17961. The FDA noted that it “disagree[d]

. . . . [T]he ANDA’s product labeling must be the same as the

listed drug’s product labeling because the listed drug product is

the basis for ANDA approval.” Id. But the FDA also noted that

Consistent labeling will assure physicians, health professionals, and consumers that a generic drug is as safe and effective as its brand-name counterpart. If an ANDA applicant believes new safety information should be added to a product’s labeling, it should contact FDA, and FDA will determine whether the labeling for the generic and listed drugs should be revised. After approval of an ANDA, if an ANDA holder believes that new safety information should be added, it should provide adequate supporting information to FDA, and FDA will determine whether the labeling for the generic and listed drugs should be revised.

Id. (emphasis added).

Further, in response to a comment that “FDA should create a

mechanism to compel ANDA holders to revise their labeling to

conform to the listed drug product once the ANDA is approved,”

the FDA observed that 21 U.S.C. § 355(e)(2)

authorizes the withdrawal of approval of an application if ‘there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or

13 suggested in the labeling thereof.’ This provision applies to both ANDA and NDA drug products. Because an ANDA must have labeling that is the same as the reference listed drug under [21 U.S.C. § 355(j)(2)(A)(v)], FDA believes that a generic drug product approved on the basis of studies conducted on the listed drug and whose labeling is inconsistent with the listed drug’s labeling might not be considered safe and effective for use under the conditions prescribed, suggested, or recommended in the listed drug’s labeling. FDA, therefore, has revised § 314.150 to permit the agency to withdraw approval of the ANDA if the applicant fails to maintain labeling in compliance with the requirements of the Act.

Id. at 17968(emphases added). In explaining this revision, the

FDA noted its agreement with comments that it “should create a

new provision authorizing the agency to withdraw an [ANDA] if the

[ANDA] holder failed to modify its labeling to match labeling

changes in the reference listed drug.”6 Id. at 17970. Thus, the

FDA explained, “§ 314.150(b)(10) states that the ANDA applicant’s

failure to maintain drug labeling that is consistent with that of

the listed drug may be grounds for withdrawing approval of the

[ANDA].” Id. (emphasis added).

6 The FDA had initially proposed to “retain its current regulations under § 314.150 stating the grounds for the withdrawal of approval of applications and abbreviated applications for drugs under [21 U.S.C. § 355(e)],” while adding regulations “to describe additional circumstances under which the agency will suspend or withdraw ANDA approval under [21 U.S.C.] § 355(j)(5)].” 54 Fed. Reg. at 28904. Section 355(j)(5 in essence, directs the Secretary to withdraw or suspend an ANDA upon the withdrawal or suspension of its listed drug’s application; those were the “additional circumstances” described in the added regulations. 54 Fed. Reg. at 17993 (codified at 21 C.F.R. §§ 314.151, 314.153 (2008)).

14 4. Revisions to drug labeling

Revisions to drug labeling are covered under another FDA

regulation, 21 C.F.R. § 314.70, “Supplements and other changes to

an approved application.” Under this rule, before making

“[c]hanges in labeling,” id. § 314.70(b)(2)(v)(A), the applicant

must submit, and the FDA must approve, a “supplement” describing

the change, id. §§ 314.70(a)(1)(i), (b)(1). The rule has

exceptions, however, see id. § 314.70(b)(2)(v)(A), one of which

is for “[c]hanges in the labeling . . . [t]o add or strengthen a

contraindication, warning, precaution, or adverse reaction,” id.

§ 314.70(c)(6)(iii)(A). In such a case, “the holder of an

approved application may commence distribution of the drug

product involved upon receipt by the agency of a supplement for

the change,” rather than waiting for the FDA to approve i t . Id.

§ 314.70(c)(6)(iii). This is known as a “changes being effected”

or “CBE” supplement. Id. § 314.70(c)(3). As with other changes

in labeling, the FDA may ultimately disapprove a change made

through the CBE process, in which case “it may order the

manufacturer to cease distribution of the drug product(s) made

with the . . . change.” Id. § 314.70(c)(7).

This version of the rule was promulgated in 2004, following

the passage of Food and Drug Administration Modernization Act of

15 1997 (“FDAMA”). 7 Supplements and Other Changes to an Approved

Application, 69 Fed. Reg. 18728, 18764-65 (Apr. 8 , 2004). 8 The

Modernization Act provided that, “[w]ith respect to a drug for

which there is in effect an approved application under section

355 . . . , a change from the manufacturing process approved

pursuant to such an application . . . may be made, and the drug

as made with the change may be distributed.” 21 U.S.C.

§ 356a(a). The Act authorized the Secretary to “designate a

category of . . . changes for the purpose of providing that . . .

the holder involved may commence distribution of the drug

involved upon the receipt by the Secretary of a supplemental

application for the change,” rather than wait for approval. Id.

§ 356a(d)(3)(B)(ii).

S o , by opening the CBE process to labeling changes that

added or strengthened warnings and the like under 21 C.F.R.

§ 314.70(c)(6)(iii)(A), the Secretary created “a category of

changes” that could be implemented upon receipt of a supplemental

application effecting them. In substance, however, a rule like

§ 314.70(c)(6)(iii)(A) had been in effect since 1965, when the

Secretary promulgated a rule that, if a supplemental application

7 Pub. L . 105-115, § 116(a), 111 Stat. 2296, 2313 (codified at 21 U.S.C. § 356a (1999)). 8 The rule was subsequently revised in ways not relevant here. Requirements on Content and Format of Labeling for Human Prescription Drugs and Biological Products, 71 Fed. Reg. 3922, 3997 (Jan. 2 4 , 2006).

16 proposed “additional warning, contraindication, side-effect, [or]

precaution information” to package labeling, that change “should

be placed in effect at the earliest possible time.” Supplemental

New-Drug Applications. 30 Fed. Reg. 9 1 1 , 993 (Jan. 3 0 , 1965)

(later codified at 21 C.F.R. § 130.9(d)(1) (1965)). To effect

this goal, the FDA announced in the rule a policy “to take no

action against a drug or applicant solely because changes of

[this] kind . . . are placed in effect by the applicant prior to

his receipt of a written notice of approval.” Id. at 994 (later

codified at 21 C.F.R. § 130.9(e)).

Despite some renumbering, see 39 Fed. Reg. 11680, 117123

(Mar. 2 9 , 1974) (recodifying § 130.9 as § 314.8), the relevant

substance of this rule remained the same until 1985, when the

rule took its current form. See New Drug and Antibiotic

Regulations, 50 Fed. Reg. 7452, 7498-99 (Feb. 2 2 , 1985) (later

codified at 21 C.F.R. § 314.70 (1985)). Though the Hatch-Waxman

Amendments had already become law at that point, the FDA had yet

to promulgate the regulations implementing them; when the agency

did s o , however, the only change it made to the rule on

supplemental applications, § 314.70, was to add a paragraph

directing that “[t]he applicant shall comply with the patent

information requirements under section 505(c)(2) of the act.”9

9 When FDA amended the rule again in response to the Modernization Act, its only substantive edit to the CBE

17 Abbreviated New Drug Applications, 57 Fed. Reg. at 17983

(codified at 21 C.F.R. § 314.70(f)).

But later, in a 2008 proposal to amend 21 C.F.R. § 314.70(c)

“to reaffirm that a CBE supplement is appropriate to amend the

labeling for an approved product only to reflect newly acquired

information,” the FDA stated in a footnote that “CBE changes are

not available for generic drugs approved under an [ANDA] under 21

U.S.C. [§] 355(j). To the contrary, a generic drug manufacturer

is required to conform to the approved labeling for the listed

drug.” Supplemental Applications Proposing Labeling Changes for

Approved Drugs, Biologics, and Medical Devices, 73 Fed. Reg.

2848-01, 2849 n.1. (proposed Jan. 1 6 , 2008). The footnote cited

21 C.F.R. § 314.150(b)(10)--which provides, again, that the FDA

may attempt to revoke its approval of an ANDA if its labeling is

not “consistent with” that of the listed drug--as well as the

FDA’s comments on ANDA applicants’ labels, quoted above.

The FDA did not, however, propose to amend any of its

regulations to clarify that an ANDA holder could not avail itself

of a CBE supplement. See id. Nor did its final version of the

proposed rule contain any such provision. See Supplemental

provision, § 314.70(c)(6), was to allow distribution of the revised drug product “upon receipt by the agency of the supplement for the change,” rather than “promptly” as under the former rule. Compare 69 Fed. at 18764-65 with 50 Fed. Reg. at 7498-99.

18 Applications Proposing Labeling Changes for Approved Drugs,

Biologics, and Medical Devices, 73 Fed. Reg. 49603-01 (Aug. 2 2 ,

2008). And the footnote in the proposal did not acknowledge

that, when the FDA promulgated its new rule on ANDA applications

following Hatch-Waxman, it included a provision that “[t]he

applicant shall comply with the requirements of §§ 314.70 and

314.71 regarding the submission of supplemental applications to

an approved abbreviated application.”10 57 Fed. Reg. at 17987

(codified at 21 C.F.R. § 314.97).

5. Generic manufacturers’ reporting obligations

The ANDA regulations promulgated after Hatch-Waxman require

that “each applicant having an [ANDA] . . . shall comply with the

requirements of § 314.80 regarding the reporting and

recordkeeping of adverse drug experiences.” Id. at 17983

(codified as amended at 21 C.F.R. § 314.98(a)). Section 314.80

requires an applicant to report (A) “each adverse drug experience

that is both serious and unexpected . . . as soon as possible but

in no case later than 15 calendar days of the initial receipt of

the information by the applicant,” 21 C.F.R. § 314.80(c)(1)(i),

and (B) every other “adverse drug experience . . . at quarterly

intervals, for 3 years from the date of approval . . . and then

10 21 C.F.R. § 314.71 sets forth the procedures for submitting a supplement to an application.

19 at annual intervals,” id. § 314.80(c)(2)(i).11 Furthermore, an

applicant “shall also develop written procedures for the

surveillance, receipt, evaluation, and reporting of postmarketing

adverse drug experiences to FDA.” Id. § 314.80(b).

Congress also addressed the ongoing responsibilities of

generic drug manufacturers in the Food and Drug Administration

Amendments Act of 2007.12 This law requires the Secretary to

“promptly notify the responsible person”--defined as the holder

of an application for a prescription drug approved under

subsection ( b ) , see 21 U.S.C. § 355(o)(2)--“or, if the same drug

approved under subsection (b) of this section is not currently

marketed, the holder of an approved application under subsection

(j),” “if the Secretary becomes aware of new safety information

that the Secretary believes should be included in the labeling of

the drug.” 21 U.S.C. § 355(o)(4). The holder of the ANDA

approval must, in response, either “submit a supplement proposing

changes to the approved labeling to reflect the new safety

information” or explain “why such a change is not warranted.”

Id. §§ 355(o)(4)(B)(i), ( i i ) .

11 Periodic reporting “does not apply to adverse drug experience information obtained from postmarketing studies,” 21 C.F.R. § 314.80(c)(2)(iii), nor need such information be included in a “15-day Alert report . . . unless the applicant concludes there is a reasonable possibility that the drug caused the adverse experience,” id. § 314.80(e)(1). 12 Pub. L . 110-85 § 1 0 7 , 121 Stat. 823, 841.

20 Paragraph (4) of subsection (o) also contains a “Rule of

construction” that it “shall not be construed to affect the

responsibility of . . . the holder of the approved application

under [21 U.S.C. § 355(j)] to maintain its label in accordance

with existing requirements, including subpart B of part 201 and

section[] 314.70 . . . of Title 2 1 , Code of Federal Regulations

(or any successor regulations).” Id. § 355(o)(4)(I). Subpart B

of part 201 imposes labeling requirements on prescription drugs,

including that “[t]he labeling shall be revised to include a

warning as soon as there is reasonable evidence of a serious

hazard with a drug; a causal relationship need not have been

proved.”13 21 C.F.R. § 201.80(e) (2008).

13 As the result of a 2006 amendment to these rules, “[p]rescription drug products for which a new drug application (NDA), biologics license application (BLA), or efficacy supplement was approved . . . between June 3 0 , 2001 and June 3 0 , 2006,” or which was pending or submitted on or after that date, are subject to “Labeling requirements for new and more recently approved prescription drug products” set forth at 21 C.F.R. §§ 201.56(d) and 201.57. Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, 71 Fed. Reg. 3922, 3986-87 (Jan. 2 4 , 2006) (codified at 21 C.F.R. §§ 201.56(b)(1), (d) (2008)). But “[p]rescription drug products not described in paragraph (b)(1) of this section”--i.e., other than for which an NDA, BLA, or efficacy supplement was approved after June 3 0 , 2001--“are subject to the labeling requirements” set forth at 21 C.F.R. §§ 201.56(e) and 201.80. Id. at 3987 (codified at 21 C.F.R. § 201.56(b)(2) (2008)). The version of these rules previously in effect, including when Karen Bartlett was prescribed and ingested Sulindac, contained the same requirement as the 2008 version of § 210.80(e). See Labeling and Prescription Drug Advertising; Content and Format for Labeling for Prescription Human Drugs, 44 Fed. Reg. 37434, 37463 (June 2 6 , 1979) (later codified at 21 C.F.R. § 210.57(e) (1980)). As the FDA explained in enacting the 2008 version of the labeling rules,

21 II. Analysis

The defendants argue that all of the Bartletts’ claims are

pre-empted by the Hatch-Waxman Amendments to the FDCA or the ANDA

regulations that followed i t . “A fundamental tenet of our

federalist system is that constitutionally enacted federal law is

supreme to state law. See U.S. Const. Art. V I . c l . 2 . As a

result, federal law sometimes preempts state law either expressly

or by implication.” N.H. Motor Transp. Ass’n v . Rowe, 448 F.3d

6 6 , 74 (1st Cir. 2006), aff’d, 128 S . C t . 989 (2008).

The defendants make no express preemption argument here;

indeed, nothing in the Hatch-Waxman Amendments expressly preempts

state law.14 Instead, the defendants argue for implicit

“older drugs not subject to the revised labeling content and format requirements in § 201.57 remain subject to labeling requirements at former § 201.57, which is redesignated as § 201.80.” 71 Fed. Reg. at 3965. 14 As the Bartletts point out, when Congress previously amended the FDCA, in 1962, it included a provision that “[n]othing in the amendments . . . shall be construed as invalidating any provision of State law which would be valid in the absence of such amendments unless there is a direct and positive conflict between such amendments and such provision of State law.” Drug Amendments of 1962, Pub. L . 87-781, § 2 0 1 , 76 Stat. 7 8 0 , 793. But this provision, by its terms, applies only to the 1962 amendments (none of which is at issue here) and therefore does not on its face limit the pre-emptive effect--if any--of other provisions of the FDCA, such as the Hatch-Waxman Amendments. Nevertheless, the Supreme Court has viewed this provision as one indicator among many that “Congress took care to preserve state law” while enlarging federal oversight of prescription drugs. Wyeth, 129 S . C t . at 1195-96 (citing Riegel v . Medtronic, Inc., 128 S . C t . 999, 1017 (2008) (Ginsburg, J., dissenting)). As discussed infra, that observation does bear upon the pre-emption question here, as it did in Wyeth.

22 preemption of the Bartletts’ state-law claims. “[F]ederal law

can preempt state law by implication in two ways,” as the court

of appeals has explained:

First, Congress may indicate an intent to occupy an entire field to the exclusion of state law. Second, even if Congress has not occupied the field, state law is nevertheless pre-empted to the extent it actually conflicts with federal law, that i s , when compliance with both state and federal law is impossible, or when the state law stands as an obstacle to the accomplishment and execution of the full purposes and objectives of Congress.

Good v . Altria Group, Inc., 501 F.3d 2 9 , 47 (1st Cir. 2007)

(internal quotation marks and citations omitted), aff’d, 129 S .

C t . 538 (2008). The defendants also make no “field preemption

argument,” relying solely on “conflict preemption” instead.

The defendants invoke both kinds of conflict pre-emption,

though: that complying with the state law underlying the

Bartletts’ claims (1) would be impossible in light o f , and

(2) would frustrate the goals o f , the Hatch-Waxman Amendments and

the subsequent ANDA regulations. Specifically, the defendants

argue that, having obtained FDA approval for their generic

version of Sulindac under the ANDA procedure envisioned by Hatch-

Waxman, they could not change Sulindac’s design, or the warnings

included in the drug’s labeling, without running afoul of federal

law (impossibility pre-emption). They further argue that, even

if the FDA could approve such a change, it could come only after

“substantial expense to obtain the scientific substantiation

23 necessary to support [it],” frustrating Hatch-Waxman’s goal to

“increase the availability of low-cost generic drugs” by opening

the ANDA process to them (frustration-of-purpose pre-emption).

As the Supreme Court reaffirmed in Wyeth, “‘the purpose of

Congress is the ultimate touchstone in every pre-emption case.’”

129 S . C t . at 1194 (quoting Medtronic, Inc. v . Lohr, 518 U.S.

470, 485 (1996) (further internal quotation marks omitted by the

Court)). The Court also reaffirmed in Wyeth that “‘[i]n all pre-

emption cases, and particularly in those in which Congress has

legislated . . . in a field which the States have traditionally

occupied,’ we start with the assumption that the historic police

powers of the States were not to be superseded by the Federal Act

unless that was the clear and manifest purpose of Congress.’”

Id. at 1194-95 (quoting Lohr, 518 U.S. at 485) (further internal

quotation marks omitted).

Prior to the Court’s decision in Wyeth, the continued

validity of this so-called “presumption against pre-emption” had

been in some doubt, see, e.g., Rowe, 448 F.3d at 74 n.10; for

that reason, perhaps, the parties here have not even mentioned

the presumption in their briefing. Wyeth, however, clarified not

only that the presumption applies against claims of implied pre-

emption, but that it applies in this case, given “the historic

presence of state law” in the field of drug labeling. 129 S . C t .

at 1194-95 & n.3; see also id. at 1229 n.14 (Alito, J.,

24 dissenting) (observing that it “remained an open question--before

[Wyeth]--whether [the] presumption applied in conflict pre-

emption cases”). Thus, this court must evaluate the defendants’

preemption arguments in light of the assumption “that ‘Congress

does not cavalierly pre-empt state-law causes of action.’” Id.

at 1195 n . 3 (quoting Lohr, 518 U.S. at 4 8 5 ) . The defendants’

arguments do not withstand that level of scrutiny.

A. The plaintiffs’ non-failure-to-warn claims

As an initial matter, the court notes that the defendants’

arguments are directed almost entirely at the failure-to-warn

aspects of the Bartletts’ claims. In addition to those claims,

however, the Bartletts also allege that the defendants

defectively designed or manufactured Sulindac; that they breached

their express and implied warranties that Sulindac was safe and

fit for its intended use; and that they negligently failed to

design or test Sulindac.15 The defendants suggest, without fully

15 As discussed supra, the complaint also makes claims for failure to warn, fraud, and breach of implied warranty. Based on the allegations underlying those claims, the court has treated them as dependent, at least in part, on the defendants’ alleged failure to warn; similarly, the court has treated the Bartletts’ express warranty claim as independent of any statements in Sulindac’s labeling. Ultimately, however, the proper characterization of these various claims makes no difference to the outcome of the pending motion, because the court rules that federal law does not pre-empt even those claims that are based on allegedly inadequate warnings.

25 explaining, that the Hatch-Waxman Amendments still pre-empt these

claims because they depend on state law mandating “a generic

drug’s design to differ from that of the branded on which it is

based,” which is not permitted under the Hatch-Waxman Amendments.

Assuming, without deciding, that either the letter or spirit

of the amendments would prevent the defendants from changing

Sulindac’s design, that would not conflict with the state law

underlying the Bartletts’ non-failure-to-warn claims. Those

claims allege that the defendants violated state law by

distributing a product that was defectively designed or

manufactured, that was not fit for its intended use, and without

using due care in designing or testing i t . While one way to

avoid violating state law in this way would be to redesign

Sulindac to remove the alleged defect before distributing the

drug (or otherwise to meet the standard of care), another way to

do so would be to refrain from distributing it at all.16

The defendants have not offered an explanation of how state

law requiring them to do so would conflict with Hatch-Waxman or

16 And a third way to do it would be to distribute the drug only with the allegedly necessary warnings, s o , if this were the only theory encompassed by the Bartletts’ defective design or manufacture, warranty, and negligence claims, then the defendants’ pre-emption arguments would at least be implicated. See Good, 501 F.3d at 36-37 (conducting pre-emption analysis by considering “how [a] particular theory--as opposed to a more generalized claim” set forth as cause of action--implicates federal l a w ) . The lack of adequate warnings, however, is not the only omission alleged in support of these claims.

26 any other federal law.17 At the outset, then, the defendants’

motion must be denied as to the Bartletts’ claims for defective

design or manufacture, breach of express or implied warranties,

and negligence. See Kellogg v . Wyeth, 612 F. Supp. 2d 4 2 1 , 427-

28 (D. V t . 2008) (ruling that negligence, strict products

liability, and express and implied warranty claims were “not

exclusively based on failure to add to or strengthen the warnings

in FDA-approved labeling for” a generic drug and therefore not

pre-empted); Masterson v . Apotex Corp., N o . 07-61665, 2008 WL

3262690, at *5 (S.D. Fla. Aug. 7 , 2008) (“compliance with a state

law duty to warn would conflict with the federal statutory scheme

. . . [but] preemption does not extend to manufacturing defect

claims that arise separate and apart from [that] claim.”) 18 .

17 As the Bartletts point out, the FDA regulations do require that “[a]n applicant who is the sole manufacturer of an approved drug product” give the agency at least six months’ notice “prior to discontinuing manufacture,” but only for drugs that are “life supporting, life sustaining, or intended for use in the prevention of a serious disease or condition” and “not originally derived from human tissue and replaced by a recombinant product.” 21 C.F.R. § 314.81(b)(3)(iii)(a) (2008). There is no suggestion that Sulindac fits this narrow category. 18 Bolin ex rel. Bolin v . SmithKline Beecham Corp., N o . 08- 60523, 2008 WL 3286973 (S.D. Fla. Aug. 7 , 2008) and Valerio ex rel. Valerio v . SmithKline Beecham Corp., N o . 08-60522 (S.D. Fla. Aug. 7 , 2008) reached the same conclusion; both were decided by the same judge, on the same day, as Masterson.

27 B. The plaintiffs’ failure-to-warn claims

The defendants do argue, at length, that the Hatch-Waxman

Amendments and their implementing regulations pre-empt the

Bartletts’ claims insofar as they arise out of the defendants’

alleged failure to warn of Sulindac’s potential to cause severe

adverse reactions. This argument rests on the premise that,

because the FDA approved Sulindac under a process that required

the drug’s labeling to be “the same as” that of its listed

predecessor, they could not have changed the labeling--to add or

strengthen a warning about such a reaction, or otherwise--without

breaking, or at least standing in the way o f , the federal law

creating that process, the Hatch-Waxman Amendments.

1. Impossibility pre-emption

To succeed with their impossibility pre-emption argument,

the defendants must show “that it would have been impossible for

[them] to comply with the state-law duty to modify [Sulindac’s]

labeling without violating federal law,” Wyeth, 129 S . C t . at

1193, i.e., that “‘compliance with both federal and state [law]

is a physical impossibility.’” Fid. Fed. Sav. & Loan Ass’n v . de

la Cuesta, 458 U.S. 1 4 1 , 153 (1982) (quoting Fla. Lime & Avocado

Growers, Inc. v . Paul, 373 U.S. 1 3 2 , 142-43 (1963)). As this

standard suggests, “[i]mpossibility pre-emption is a demanding

28 defense,” Wyeth, 129 S . C t . at 1193. The defendants have not

satisfied those demands here.

a. The Hatch-Waxman Amendments

Again, the Hatch-Waxman Amendments require that an ANDA

contain “information to show that the labeling proposed for the

new drug is the same as the labeling approved for the listed

drug,” 21 U.S.C. § 355(j)(2)(A)(v), and direct the Secretary to

approve an ANDA absent a finding that “information submitted in

the application is insufficient” to make such a showing, id.

§ 355(j)(4)(G), both with exceptions not relevant here. There is

no dispute here that, absent these exceptions, Hatch-Waxman thus

prevents the approval of an ANDA for a generic drug with labeling

that is not “the same as” that of the listed drug; the Bartletts

acknowledge as much. But the Bartletts do not seek to hold the

defendants liable under state law because they failed to submit

an ANDA for their generic Sulindac with labeling that was “the

same as” the labeling for the pioneer version.

Rather, as noted in Part II.A, supra, the Bartletts allege

that, after securing approval of the ANDA for generic Sulindac

with the same labeling as its listed predecessor’s, the

defendants failed to change the label to warn adequately of the

risks of Stevens Johnson-Syndrome and toxic epidermal necrolysis,

despite actual or constructive knowledge of these risks. Nothing

29 in the text of 21 U.S.C. §§ 355(j)(2)(A)(v) or (4)(G), as just

quoted, prohibited the defendants from doing so.19 The

defendants point out that, likewise, “there is no provision in

the FDCA permitting either a branded or generic manufacturer,

following product approval, to change the product’s labeling”

(emphasis added). But that point is both irrelevant (at least as

to the impossibility pre-emption analysis) and incorrect.

Impossibility pre-emption arises where federal and state law

“impose directly conflicting duties,” e.g., “if the federal law

said, ‘you must sell insurance,’ while the state law said, ‘you

may not.’” Barnett Bank of Marion County, N.A. v . Nelson, 517

U.S. 2 5 , 31 (1996). To fit their claimed predicament into this

framework, the defendants would need to show a federal law saying

“You may not change your label” to conflict with the state law

underlying the Bartletts’ failure-to-warn claims, i.e., “You must

change your label.” So the defendants’ assertion that the FDCA

does not say one way or the other whether they can change their

label is insufficient.

19 For this reason, the defendants are not helped by the FDA’s statement in a guidance document that “[a]ll labeling changes for ANDA drug products must be consistent with section 505(j) of the Act.” FDA, Guidance for Industry: Changes to an Approved NDA or ANDA 1 (2004), available at http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances 2 4 . Section 505(j) as the Act, as just discussed, requires sameness of labeling as a condition of ANDA approval; it does not restrict what happens to the label afterwards.

30 It is also incorrect, because, as discussed in part II.B.4,

supra, the FDAMA allows, “[w]ith respect to a drug for which

there is in effect an approved application under section 355

. . . , a change from the manufacturing process approved pursuant

to such application.” 21 U.S.C. § 356a(a)(1). Both NDAs and

ANDAs, of course, are approved under section 355. The FDAMA did

restrict such changes: insofar as they qualify as “major

manufacturing changes,” they must await the Secretary’s approval

of a supplemental application. Id. § 356a(c)(1). But Congress

did not classify labeling changes as “major manufacturing

changes” per s e , see id. § 356a(c)(2), and, as the CBE regulation

demonstrates, neither has the FDA in exercising its authority to

further define that term. See 21 C.F.R. § 314.70(c)(6)(iii).

Because 21 U.S.C. § 356a expressly authorizes a

manufacturer’s changes to an application approved under § 355 of

the Act--whether under subsection ( b ) , as in the case of an NDA,

or under subsection ( j ) , as in the case of an ANDA--the

defendants are incorrect that nothing in the Act permits a

manufacturer to change its label post-approval. As another court

has noted, while “Congress intended for ANDA applicants to submit

identical labeling to the FDA when seeking ANDA approval, the

statute is silent as to the manufacturer’s obligation after the

ANDA is granted.” Stacel v . Teva Pharms., USA, 620 F. Supp. 2d

899, 907 (N.D. Ill. 2009) (citation omitted); but see Mensing v .

31 Wyeth, Inc., 562 F. Supp. 2d 1056, 1064 (D. Minn. 2008) (not

discussing FDAMA amendments, and holding that “under the federal

statutory scheme, the labeling for generic drugs must always

remain the ‘same as’ that of the name brand drug.”), appeal

docketed, N o . 08-3850 (8th Cir. Dec. 1 0 , 2008); Masterson, 2008

WL 3262690, at *4-*5 (same); Colacicco v . Apotex, Inc., 432 F.

Supp. 2d 5 1 4 , 537-38 (E.D. P a . 2006) (similar), aff’d on other

grounds, 521 F.3d 253 (3d Cir. 2008), vacated, 129 S . C t . 1578

(2009). 20 Nothing in the “statutory scheme,” then, makes it

impossible for a manufacturer to change the labeling of an ANDA-

approved drug--or to comply with a state-law requirement that it

do s o .

b. FDA labeling regulations

The analysis of the defendants’ impossibility argument does

not end there, because “state laws can be pre-empted by federal

regulations as well as by federal statutes.” Hillsborough

County, Fla. v . Automated Med. Labs., Inc., 471 U.S. 7 0 7 , 713

(1985). At the outset, the court notes that some of the

regulations on which the defendants rely, like the provisions of

20 In Colacicco, the Court of Appeals for the Third Circuit expressly did not decide “whether actions against generic drug manufacturers are preempted on the basis of their obligations under the Hatch-Waxman Amendments.” 521 F.3d at 271 (footnote omitted).

32 the Hatch-Waxman Amendments which those regulations implement, do

not purport to restrict changes to the label of a generic drug

following its approval. See 21 C.F.R. §§ 314.94(a)(8),

314.127(a)(7) (quoted in Part II.B.3, supra). Instead, those

rules expressly require the generic drug’s proposed label to be

the same as that of the listed drug, and provide that an ANDA

will be denied for failing to demonstrate that. See id.

These regulations, then, do not prevent post-approval

changes to the label of an ANDA-approved drug any more than the

Hatch-Waxman Act does, as a number of courts have recognized.21

See Demahy v . Wyeth, Inc., 586 F. Supp. 2d 6 4 2 , 649-52 (E.D. L a .

2008), appeal docketed, N o . 08-31204 (5th Cir. Dec. 1 6 , 2008);

Laisure-Radke v . Par Pharm., Inc., 2006 WL 901657, at *3-*5 (W.D.

Wash. Mar. 2 9 , 2006); Bell v . Lollar, 791 N.E.2d 849, 854 (Ind.

C t . App. 2003); see also Barnhill v . Teva Pharms. USA, Inc., N o .

06-282, 2007 U.S. Dist. LEXIS 44718, at *13 (S.D. Ala. Apr. 2 4 ,

2007) (reasoning that the comments to the regulations “address

labeling requirements necessary for initial approval, not changes

to labels for approved ANDA’s”) (footnote omitted); but see

21 The same is true of the FDA’s remarks in proposing and promulgating these regulations. See Demahy, 586 F. Supp. 2d at 649-52; Barnhill, 2007 U.S. Dist. LEXIS 44718, at * 1 3 . As the quotation of one of those remarks in Part II.B.3, supra, illustrates, they refer to the requirement that the applicant propose the same labeling as that of the listed drug; they do not speak to what happens post-approval. See also 57 Fed. Reg. at 17953; 54 Fed. Reg. at 28884.

33 Morris v . Wyeth, Inc., 582 F. Supp. 2d 8 6 1 , 868 (W.D. Ky. 2008),

appeal docketed, N o . 09-5509 (6th Cir. Apr. 2 7 , 2009). 22

This is not to say that generic drug manufacturers--or any

drug manufacturers, for that matter--have carte blanche to make

whatever alterations they want to their labels. FDA regulations

classify most “labeling changes” as “major changes,” see 21

C.F.R. § 314.70(b)(2)(v), meaning that § 356a prohibits a

manufacturer from making them without the FDA’s prior approval,

see 21 U.S.C. § 356a(c)(1). As the Supreme Court observed in

Wyeth, “[g]enerally speaking, a manufacturer may only change a

drug label after the FDA approves a supplemental application.”

129 S . C t . at 1196. But, as Wyeth also noted, the FDA does have

a “regulation that permits a manufacturer to make certain changes

to its label before receiving the agency’s approval”--namely, 21

C.F.R. § 314.70(c)(iii), establishing the “CBE” supplement

process. Id. Under this process, as discussed in Part II.B.4,

supra, “if a manufacturer is changing a label to ‘add or

strengthen a contraindication, warning, precaution, or adverse

reaction,’ . . . it may make the labeling change upon filing its

22 Wilson v . PLIVA, Inc., N o . 07-378, 2008 WL 2677049 (W.D. Ky. June 3 0 , 2008), appeal docketed, N o . 09-5466 (6th Cir. Apr. 2 0 , 2009), and Smith v . Wyeth, Inc., N o . 07-18, 2008 WL 4697002 (W.D. Ky. Oct. 2 4 , 2008), appeal docketed, N o . 09-5460 (6th Cir. Apr. 1 6 , 2009), reached the same conclusion as Morris, and were decided by the same court on the same day as that case.

34 supplemental application with the FDA; it need not wait for FDA

approval.” Id. (quoting 21 C.F.R. § 314.70(c)(6)(iii)(A)).

The Court in Wyeth relied on this regulation in rejecting a

manufacturer’s argument that state-law failure-to-warn claims

were “pre-empted because it is impossible for it to comply with

both the state-law duties underlying those claims and its federal

labeling duties.” Id. at 1196. The Court ruled that, once the

risk of the adverse reaction experienced by the plaintiff had

become “apparent,” triggering a state-law duty to warn of i t ,

“the CBE regulation permitted [the manufacturer] to provide such

a warning before receiving the FDA’s approval.” Id. at 1198.

While the Court acknowledged that “the FDA retains authority to

reject labeling changes made pursuant to the CBE regulation in

its review of the manufacturer’s supplemental application,” the

Court declined to “conclude that it was impossible for [the

manufacturer to comply with both federal and state requirements”

without “clear evidence that the FDA would not have approved a

change” to effect the warning at issue. Id. The defendants here

have not presented any such evidence, i.e., that the FDA would

not have approved a change to their labeling to Sulindac to

strengthen the warning as allegedly required by state law.

In a supplemental memorandum (Wyeth, again, was decided

after the parties here had already fully briefed the motion for

judgment on the pleadings), the defendants nevertheless maintain

35 that the Court’s decision does not foreclose their pre-emption

defense. They principally argue that, because Sulindac is a

generic drug approved through an ANDA, its labeling cannot be

changed through the CBE process, which applies only to NDA-

approved drugs; therefore, the defendants conclude, it would be

impossible for them to comply with both the federal labeling

scheme and the state law underlying the Bartletts’ failure-to-

warn claims.23 This court rejects with both the premise and the

conclusion of that argument.

i. FDA regulations do not forbid adding or strengthening warnings to the labeling of an ANDA-approved drug through the CBE process

a. The regulations and their commentary

Just as nothing in the text of the Hatch-Waxman Amendments

forbids a generic manufacturer from changing its drug’s label

from the listed version’s post-approval, nothing in the text of

23 This argument assumes, of course, that the defendants could not have satisfied their state-law duty to warn by proposing to change Sulindac’s label to correct the allegedly inadequate warning, obtaining the FDA’s approval of that change, then making i t . C f . Perry v . Novartis Pharm. Corp.. 456 F. Supp. 2d 6 7 8 , 685 (E.D. P a . 2006) (ruling that, in the case of a branded drug, “state law may require a manufacturer to at least seek FDA approval for the addition of a new warning” without being pre-empted). The defendants do not expressly argue that, as ANDA holders, they are foreclosed from making a labeling change with the FDA’s prior approval, but neither do the Bartletts allege that the defendants would have obtained such approval had they sought i t . So the court need not consider this point here.

36 the CBE regulation forbids a generic manufacturer from using the

CBE process to do s o . As discussed in Part II.B.4, supra, the

CBE regulation represents the FDA’s use of its authority, under

the FDAMA, to designate labeling changes that add or strengthen

warnings and such as “manufacturing changes that are not major

manufacturing changes,” 21 U.S.C. § 356a(d)(1), and that

therefore can be made without prior FDA approval, see id.

§§ 356a(d)(1)(B), (3)(B)(ii); the FDAMA, again, does not restrict

this process to NDA-approved drugs. The regulation itself also

imposes no such restriction: “the holder of an approved

application”--not just an approved new drug application under

subsection (b)--“may commence distribution of the drug product

involved upon receipt by the agency of a supplement for the

change.” 21 C.F.R. § 314.70(c)(6).

“Determining a regulation’s meaning requires application of

the same principles that imbue exercises in statutory

construction.” Morales v . Sociedad Española de Auxilio Mutuo y

Beneficencia, 524 F.3d 5 4 , 57 (1st Cir. 2008), cert. denied, 129

S . C t . 898 (2009). These principles include, first and foremost,

“the plain meaning rule, stating that if the language of a . . .

regulation has a plain and ordinary meaning, courts need look no

further and should apply the regulation as it is written.”

Textron, Inc. v . Comm’r, 336 F.3d 2 6 , 31 (1st Cir. 2003) (citing,

inter alia, Comm’r v . Soliman, 506 U.S. 1 5 8 , 174 (1993)).

37 Because, as just discussed, nothing in the text of the CBE

regulation declares its process for labeling changes off-limits

to ANDA-approved drugs, it would seem “the interpretive odyssey

is at an end,” Morales, 524 F.3d at 5 7 ; like other ANDA holders,

the defendants could have availed themselves of the CBE process

to add or strengthen the warnings on Sulindac’s labeling.24

To support their view that the CBE process is nevertheless

unavailable to ANDA-approved drugs, the defendants rely on the

FDA’s remark explaining its revision to § 314.70 following the

Hatch-Waxman Amendments. That remark states, in its entirety,

FDA received no comments on this provision, but has amended the provision to adopt references to statutory, rather than regulatory, provisions to explain what information should be provided. However, the agency wishes to remind ANDA applicants that, as noted in paragraph 4 above, the labeling for an ANDA product

24 In their opening brief, the defendants claimed that the FDA has permitted CBE supplements seeking to add or strengthen warnings “only where the NDA holder becomes aware of newly discovered safety information” and “there is sufficient evidence of a causal association with the drug.” While the publication the defendants purport to quote for this language says nothing of the sort, see Supplemental New-Drug Applications, 30 Fed. Reg. 993 (Jan. 3 0 , 1965), the FDA did amend § 314.70(c)(6)(iii) in 2008--after Karen Bartlett was prescribed and took Sulindac--to limit it to “[c]hanges in the labeling to reflect newly acquired information.” 73 Fed. Reg. at 49609. The Court in Wyeth did not “decide whether the 2008 CBE regulation is consistent with the FDCA and the previous version of the regulation,” ruling that the manufacturer there “could have revised [the allegedly deficient] label even in accordance with the amended regulation.” 129 S . C t . at 1196. This court can take much the same tack here. The defendants do not argue that they could not have used the CBE supplement process to revise Sulindac’s label because they lacked “newly acquired information,” but only because the drug was approved on an ANDA instead of a NDA.

38 must, with few exceptions, correspond to that for the reference listed drug.

57 Fed. Reg. at 17955. But for the reference to “paragraph 4,”

this remark might provide some arguable (if atextual) support for

the defendants’ view: the remark, unlike others they cite,

speaks of “the labeling for an ANDA product,” rather than the

“labeling proposed” for i t , and thus might be read to require the

labeling to remain the same beyond the approval process.

“Paragraph 4,” though, rejects a comment that the FDA

“accept ANDA’s with warnings or precautions in addition to those

on the reference listed drug’s label,” pointing out that “section

505(j)(2)(A)(v) and (j)(3)(G) of the act requires [sic] that the

applicant’s proposed labeling be the same as that of the listed

reference drug” with exceptions not relevant here. Id. at 17953.

Those provisions, again, dictate the content of the drug’s

labeling at the times the ANDA is submitted and approved, not

afterwards. In light of the reference to “paragraph 4"--and, in

turn, that paragraph’s references to 21 U.S.C. § 305(j)--the

FDA’s comment to § 314.70 cannot be fairly read to extend the

mandate that “the labeling proposed for the drug [be] the same as

the labeling approved for the listed drug,” 21 U.S.C. §

355(j)(4)(G), into the post-proposal, or post-approval, period.

Moreover, the only change the FDA made to the existing

version of § 314.70 through the post Hatch-Waxman ANDA

39 regulations was to add a paragraph requiring the applicant to

“comply with the patent information requirements under [21 U.S.C.

§ 355(c)(2)].” Id. at 17983 (later codified at 21 C.F.R. §

314.70(e) (1993)). It is hard to believe that, in remarking upon

this minor revision to the rule, the FDA was in fact expressing

the view that the CBE procedures of § 314.70(c)(6)(iii)--which

were not being changed, and were not mentioned anywhere in the

remark--are off-limits to ANDA-approved drugs.

Indeed, as discussed in Part II.B.4, supra, the FDA had been

letting manufacturers make labeling changes to approved drugs

that added or strengthened warnings and the like, without prior

agency approval, for nearly 20 years prior to Hatch-Waxman, and

for more than 27 years prior to the FDA’s post-Hatch-Waxman ANDA

rules. See 30 Fed. Reg. at 993-94. And, as discussed in Part

II.B.2, supra, the FDA had been accepting ANDAs for much of that

period. I f , in spite of this history, the FDA had intended to

place the CBE process for labeling changes off-limits to ANDA-

approved drugs in the wake of Hatch-Waxman, the agency might have

been expected to do so explicitly by amending § 314.70(c)(6)(iii)

to that effect--rather than by making a comment, which might or

might not be read that way, while amending the rule in a

different way entirely.25

25 By the same reasoning, as well as that set forth in note 21 and the accompanying text, supra, the FDA’s remarks in revising its rules on the content and format of drug labeling say

40 What the FDA actually did was in fact markedly to the

contrary: it promulgated 21 C.F.R. § 314.97, entitled

“Supplements and other changes to an approved abbreviated

application.” 57 Fed. Reg. at 17987. The FDA enacted this

provision as part of its overhaul of the ANDA rules following

Hatch-Waxman, and received--and made--no comments on i t . See id.

at 17964. This rule, as mentioned in Part II.B.4, supra,

provides: “The applicant shall comply with the requirements of

§§ 314.70 and 314.71 regarding the submission of supplemental

applications and other changes to an approved abbreviated

application.” The “requirements of § 314.70” referred to by §

314.97 include, of course, the CBE provision.

Had the FDA intended that, notwithstanding the clear

language of § 314.97, the CBE provision was nevertheless

inapplicable to drugs approved via ANDAs, one would have expected

little if anything about a manufacturer’s power to change its labeling after the ANDA is approved. Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, 71 Fed. Reg. 3922, 3929 (Jan. 2 4 , 2006) (“the labeling of a drug product submitted for approval under an ANDA must be the same as the labeling of the listed drug referenced in an ANDA,” referring to 21 C.F.R. § 314.94(a)(8)(iv)) (emphasis added), 3963 (making the same statement in explaining that “the requirement to revise the labeling of a reference listed drug in the new format does not have any impact on the duration of exclusivity for the drug and, therefore, does not prevent a manufacturer of a generic product from using the revised labeling of the reference listed drug”). And the defendants point to nothing in the content and format rules themselves affecting a generic manufacturer’s ability to add or strengthen a warning post-approval. See 21 C.F.R. §§ 201.56-57.

41 § 314.97--or the CBE provision itself--to contain language to

that effect o r , at least, for the FDA to have clearly explained,

in enacting those provisions, that a generic manufacturer could

not use the CBE process to change its labels. But the FDA did

none of these things. So the defendants are essentially asking

this court to rewrite § 314.97 by tacking the words “except for

§ 314.70(c)(6)(iii)” onto the end.

This court, like almost all of those to have considered the

availability of the CBE procedure to ANDA-approved drugs in light

of § 314.97, declines to do s o . See Stacel, 620 F. Supp. 2d at

907; Kellogg, 612 F. Supp. 2d at 435-36; Demahy, 586 F. Supp. 2d

at 649-52; Laisure-Radke, 2006 WL 901657, at *3-*5; accord Foster

v . Am. Home Prods. Corp., 29 F.3d 165, 170 (4th Cir. 1994)

(citing § 314.97 in recognizing that manufacturers of generic

drugs are “permitted to add or strengthen warnings and delete

misleading statements on labels, even without prior FDA

approval”); but see Morris v . Wyeth, Inc., N o . 07-176, 2009 WL

424590, at *6 (W.D. Ky. Feb. 2 0 , 2009); 26 Mensing, 562 F. Supp.

26 In Morris, the court denied the plaintiff’s motion to reconsider its earlier ruling that his state-law failure to warn claims were pre-empted in light o f , among other authorities, Demahy. The Morris court’s earlier ruling had not taken § 314.97 into account. See 582 F. Supp. 2d 861. On reconsideration, the court discussed

two possible interpretations of § 314.97. Either the Demahy court is correct that § 314.97 requires ANDA holders to utilize § 314.70, in which case whether or not an ANDA holder can unilaterally change its label is

42 2d at 1064.27 Where the language of a regulation is clear, “the

courts have no warrant to rewrite [it] in the guise of

‘interpretation.’” United States v . Charles George Trucking Co.,

823 F.2d 685, 689 (1st Cir. 1987).

an issue currently pending before the Supreme Court, or the Demahy court is incorrect and § 314.97 merely states that when a brand manufacturer utilizes § 314.70, then so too must the generic manufacturer make that same change to its corresponding drug’s label.

2009 WL 424590, at *6 (footnotes omitted).

But the court did not explain the second of these “possible interpretations” in light of either § 314.70 or § 314.97. As to the first interpretation, the court was referring to the Wyeth case, reasoning that “[s]hould the Court determine that brand manufacturers cannot unilaterally change their labels under § 314.70 . . . then neither can generic manufacturers.” See id. n.3. In Wyeth, again, the Court held that brand-name manufacturers could unilaterally change their labels under § 314.70(c)(iii)(A). 129 S . C t . at 1198. Because the contingency essential to the first “possible interpretation” of § 314.97 did not come to pass, and because the second “possible interpretation” was left unexplained, this court declines to follow Morris. The same is true of two other decisions which were issued by the same court on the same day and come to the same conclusion. Wilson v . PLIVA, Inc., N o . 07-378, 2009 WL 425027 (W.D. Ky. Feb. 2 0 , 2009); Smith v . Wyeth, Inc., N o . 07-18, 2009 WL 425032 (W.D. Ky. Feb. 2 0 , 2009). 27 In explaining away § 314.97, the court in Mensing relied solely on the FDA’s amicus brief to the Third Circuit in Colaccio, which itself stated simply that § 314.97 “does not modify the requirement that the drug label for a generic drug must be the same as the label for the approved innovator drug.” 562 F. Supp.2d 1064 (quotation formatting and emphasis omitted). Not only has that brief since been withdrawn, as noted infra Part III.B.1.b.i.b, but, in this circuit at least, courts “do not defer to [agency] views espoused only in the context of litigation,” including in amicus briefs. Rosenberg v . Merrill Lynch, Pierce, Fenner & Smith, Inc., 170 F.3d 1 , 12 (1st Cir. 1999). The court declines to follow Mensing.

43 That principle is particularly apt in light of what Congress

had to say when it recently spoke on the labeling duties of

generic drug manufacturers in the Food and Drug Amendments Act of

2007, as discussed in Part II.B.5, supra. Not only does that act

require an ANDA holder (provided the drug is no longer marketed

by its NDA holder) to submit a supplemental application proposing

labeling changes to reflect new safety information identified by

the Secretary, or to explain why no change was warranted, 21

U.S.C. §§ 355(o)(4)(B), it also provides that § 355(o)(4) “shall

not be construed to affect the responsibility of . . . the holder

of the approved application under [21 U.S.C. § 355(j)] to

maintain its label in accordance with existing requirements,

including subpart B of part 201 and section[] 314.70 . . . of

Title 2 1 , Code of Federal Regulations (or any successor

regulations).” Id. § 355(o)(4)(I).

As also discussed in Part II.B.5, supra, Title 2 1 , part 2 0 1 ,

subpart B of the Code of Federal Regulations requires that “[t]he

labeling shall be revised to include a warning as soon as there

is reasonable evidence of a serious hazard with a drug,” 21

C.F.R. § 201.80(e), at least for prescription drugs not approved

on an NDA, BLA, or efficacy supplement after June 3 0 , 2001. See

id. § 201.56(b). 28 The surest way to revise a label to include a

28 Despite the clear language of 21 C.F.R. § 201.56(b)(2) that “[p]rescription drug products not described in paragraph (b)(1) of this section”--i.e., other than for which an NDA, BLA,

44 warning “as soon as there is reasonable evidence,” of course, is

to make the revision through the CBE process.

I f , as the defendants posit, the portion of § 314.70 which

opens the CBE process to labeling changes adding or strengthening

warnings does not apply to generic manufacturers--if, in fact,

§§ 201.80(e) and 314.70(c)(6)(iii) impose no “responsibility” on

ANDA holder “to maintain its label”--then the court is left to

wonder, without an explanation, why Congress would have thought

it necessary to clarify that 21 U.S.C. § 355(o)(4) does not

affect that responsibility. The courts “assume that Congress is

aware of existing law when it passes legislation.” South Dakota

v . Yankton Sioux Tribe, 522 U.S. 329, 351 (1998). Yet the

defendants do not attempt to reconcile 21 U.S.C. § 355(o)(4) with

their view that neither § 201.80(e) nor § 314.70(c)(6)(iii)

applies to them.

In this void, it is reasonable to read the statute as

authorizing the FDA to notify an ANDA holder of necessary

labeling changes to reflect new safety information, while making

clear that an ANDA holder’s responsibility to make those changes

or efficacy supplement was approved after June 3 0 , 2001--“are subject to the labeling requirements” set forth at 21 C.F.R. § 201.80, see note 1 3 , supra, the defendants argue that the rule “does not mean ANDAs are subject to the requirements in § 201.80; it means that any NDA drug first-approved before June 2001 is subject to the regulation.” The defendants do not explain, though, how an ANDA-approved drug is anything other than a “[p]rescription drug product[] not described in paragraph (b)(1).” So the court rejects their interpretation.

45 on its own under 21 C.F.R. § 201.80(e), through the CBE process

set forth in 21 C.F.R. § 314.70(c)(6), remains. Indeed, as Wyeth

observed of 21 U.S.C. § 355(o)(4), “when Congress granted the FDA

this authority, it reaffirmed the manufacturer’s obligations and

referred specifically to the CBE regulation, which both reflects

the manufacturer’s ultimate responsibility for its label and

provides a mechanism for adding safety information to the label

prior to FDA approval.” 129 S . C t . at 1198.

The defendants also advance an argument that § 314.70(c)(6)

applies only to drugs approved through the NDA process which

depends not on § 314.70(c)(6) itself, but on a different

provision of the ANDA regulations, 21 C.F.R. § 314.150(b)(10).

That regulation, as noted in Part II.B.3, supra, states:

FDA may notify the applicant, and, if appropriate, all other persons who manufacturer or distribute identical, related, or similar drug products, and for a new drug afford an opportunity for a hearing on a proposal to withdraw approval of the application or the [ANDA] under [21 U.S.C. § 355(e)] and under the procedure set forth in [21 C.F.R. § 314.200], if the agency finds:

(10) That the labeling for the drug product that is the subject of the [ANDA] is no longer consistent with that for the listed drug referred to in the [ANDA], except for differences approved in the ANDA . . . .

21 C.F.R. § 314.150(b) (emphasis added). The defendants argue

that this rule forbade them from using the CBE process to change

Sulindac’s label, because doing so would have resulted in an

46 ANDA-approved drug with labeling that was “no longer consistent

with that for the listed drug,” thus subjecting the ANDA to

revocation. The court cannot read § 314.150 that way.

Initially, unlike the admonition repeated throughout the

Hatch-Waxman Amendments, and elsewhere in the ANDA regulations,

that an ANDA must show “that the labeling proposed for the new

drug is the same as the labeling approved for the listed drug,”

see, e.g., 21 U.S.C. § 355(j)(2)(A)(v) (emphasis added), section

314.150(b)(10) of the regulations requires that the ANDA’s

labeling be “consistent with that of the listed drug” (emphasis

added). While “same” means “being one without addition, change,

or continuance,” Webster’s Third New International Dictionary

2007 (2002), the term “consistent,” in contrast, means “showing

no significant change, unevenness, or contradiction.” Id. at

484.

Where two provisions of the same rule “differ in that one

provision uses a term, but the other provision, where it would be

equally sensible to use that term if [the agency] desired it to

apply,” uses a different term instead, “it is generally assumed

that [the agency] acts intentionally and purposely in the

disparate” wording. United States v . Councilman, 418 F.3d 6 7 ,

73-74 (1st Cir. 2005). Here, as one court has noted, “the

discrepancy between the manifold use of the phrase ‘same as’ in

the FDA’s initial rulemaking on the pre-approval ANDA process is

47 curious in comparison to the use of the phrase ‘consistent with’

in the regulation governing post-approval processes,” suggesting

the terms are not equivalent. Demahy, 586 F. Supp. 2d at 649.

Labeling on an ANDA-approved drug that differs from that on the

listed version only in having stronger or additional warnings is

“consistent with,” if not “the same as,” that labeling, in that

the generic’s warning, contraindication, side-effect, and

precaution information completely overlaps the brand name’s.29

Indeed, the FDA enacted § 314.150 in response to a comment

that it “should create a new provision authorizing the agency to

withdraw an [ANDA] if the [ANDA] holder failed to modify its

labeling to match labeling changes in the reference listed drug.”

57 Fed. Reg. at 17970. The rule therefore “revised the rule

accordingly” to “state[] that the ANDA applicant’s failure to

maintain drug labeling that is consistent with that of the listed

drug may be grounds for withdrawing approval of the [ANDA].” Id.

And the FDA also invoked § 314.150 in response to another comment

that “FDA should create a mechanism to compel ANDA regulations to

29 In proposing the regulations, the FDA noted that it would “not accept ANDA’s for products with significant changes in labeling,” on the theory that those might be necessitated by other kinds of differences from the listed drug that would “jeopardize the safe or effective use of the product.” 54 Fed. Reg. at 28885 (emphasis added).

48 revise their labeling to conform to the listed drug product once

the ANDA is approved.” Id. at 17968.30

As these remarks suggest, then, “the purpose of [the]

regulation was not to prevent a generic manufacturer from

improving or strengthening its warnings. It was, instead, to

ensure that the FDA could require a generic manufacturer to

modify its labeling to match labeling changes in the reference

listed drug.” Barnhill, 2007 U.S. Dist. LEXIS 44718, at * 1 3 .

S o , according to the FDA’s own explanation for § 310.150(b)(10),

it was not intended to address the opposite situation--where the

ANDA holder wants to make labeling changes that have yet to be

made on the listed drug.31

If anything, the FDA’s remarks in promulgating its new ANDA

rules after Hatch-Waxman suggest that the agency expected ANDA

holders to do just that. In rejecting a comment that it allow

“ANDA applicants to deviate from the labeling for the reference

listed drug,” the FDA noted that, “[a]fter approval of an ANDA,

30 To like effect is the FDA’s remark, in response to a comment on 21 C.F.R. § 314.127(a)(7), that it had “revised § 314.150 to require ANDA holders to maintain current labeling.” 57 Fed. Reg. at 17968. 31 The remarks do note that § 314.150 “permit[s] the agency to withdraw approval of the ANDA if the applicant fails to maintain labeling in compliance with the requirements of the Act,” 57 Fed. Reg. at 17968 (emphasis added), but, as already discussed at length, there is nothing in “the Act” to prevent a generic drug maker from making changes to its labeling post- approval, provided that is done per the applicable procedures. See 21 U.S.C. § 356a.

49 if an ANDA holder believes that new safety information should be

added, it should provide adequate supporting information to FDA,

and FDA will determine whether the labeling for the generic and

listed drugs should be revised.” 57 Fed. Reg. at 17961 (emphasis

added). While at least one court has taken this statement to

“underscore the notion that the ANDA drug’s label must remain the

same as that of the listed drug,” Mensing, 562 F. Supp. 2d at

1062, this court sees it differently.

As the emphasized language suggests, the statement draws the

familiar distinction between the near-absolute ban on labeling

differences when a manufacturer proposes an ANDA and their

availability “after an ANDA is approved.” During that latter

period, “[t]he applicant shall comply with the requirements of

§§ 314.70 and 314.71 regarding the submission of supplemental

applications and other changes to an [ANDA],” 21 C.F.R. § 314.97,

o r , as this remark puts i t , “if an ANDA holder believes that new

safety information should be added, it should provide adequate

supporting information to FDA, and FDA will determine whether the

labeling for the generic and listed drugs should be revised.” 57

Fed. Reg. at 17961. That is precisely the process set forth by

21 C.F.R. § 314.70(c)(6)(iii).32

32 Again, as discussed in Part II.B.4, supra, the FDA must approve all labeling changes, even those subject to the CBE process; it is just that such changes, as opposed to their “major” counterparts, are not approved until after the manufacturer has already implemented them.

50 Accordingly, reading § 314.150 to allow revocation of an

ANDA if its holder fails to keep up with warnings added to the

listed drug’s labeling--rather than if the holder uses the CBE

process to add those warnings on its own--harmonizes that

regulation with the rest of the FDA’s ANDA rules, including

§§ 314.70 and 314.97. “Otherwise, the FDA permits a generic

manufacturer to strengthen or modify its labeling . . . , only to

suspend its approval because the new label does not conform to

the label for the listed drug.” Barnhill, 2007 U.S. Dist. LEXIS

44718, at * 1 3 . This court cannot read the ANDA regulations in

such a self-contradictory manner. See, e.g., Ricci v . DeStefano,

129 S . C t . 2658, 2699 (2009) (“Our task in interpreting separate

provisions of a single [enactment] is to give [it] the most

harmonious, comprehensive meaning possible.”).

b. The FDA’s contrary amicus briefs and footnote

As the defendants emphasize, the FDA has made statements

since it promulgated the current ANDA regulations to the effect

that a generic manufacturer cannot utilize the CBE process to

effect a labeling change. Some of these statements were in

amicus briefs the FDA filed in Colacicco, supra, first in the

district court and later in the Court of Appeals for the Third

Circuit. The brief to the Third Circuit, however, was recently

withdrawn, with the explanation that “the United States does not

51 take a position on whether plaintiffs-appellants’ claims in this

case are preempted. The [FDA] has not yet conducted an

examination of various preemption issues following the Supreme

Court’s decision in Wyeth that would be necessary to inform a

position of the United States in this case.” Letter from Sharon

Swingle, Appellate Staff, DOJ, to Marcia M . Waldron, Clerk, Court

of Appeals for the Third Circuit (Apr. 2 8 , 2009) (on file with

the Court of Appeals for the Third Circuit). 33

The defendants also rely on the footnote in the FDA’s

proposed 2008 revision to § 314.70(c) asserting that “CBE changes

are not available for generic drugs approved under an [ANDA]

under 21 U.S.C. § 355(j). To the contrary, a generic drug

manufacturer is required to conform to the approved labeling for

the listed drug.” 73 Fed. Reg. at 2849 n.1. But as discussed in

Part II.B.4, supra, the footnote does not accompany a proposal to

amend § 314.70 in any way that would call for a comment on the

availability of its procedures to generic drug manufacturers.34

Nor was the language of the footnote, in any form, included in

the final version of the revision. So “[t]he FDA essentially

33 And as discussed in note 2 7 , supra, an agency’s statements in amicus briefs receive no particular deference from the courts of this circuit anyway. See Rosenberg, 170 F.3d at 1 2 . 34 As discussed in Part II.B.4, supra, the proposed (and ultimately the final) rule was “to reaffirm that a CBE supplement is appropriate to amend the labeling for an approved product only to reflect newly acquired information.” 73 Fed. Reg. at 2849.

52 took the opportunity to make a significant statement on the

preemption of generic drug labeling claims in the relative

obscurity of a footnote in the introductory statement of a

document that has nothing at all to do with rules pertaining to

generic drugs or to the ANDA process.” Denahy, 586 F. Supp. 2d

at 654 (emphases deleted).

Based on these concerns, the court in Denahy refused to

accord the footnote “any significant level of deference” in

deciding whether generic manufacturers can avail themselves of

the CBE process for labeling changes. Id. This is consistent

with precedent from the court of appeals. An agency’s statements

that “are neither adjudicatory nor the product of notice-and

comment rulemaking . . . are . . . entitled to deference only to

the extent they have the power to persuade,” an approach known as

“Skidmore deference” after Skidmore v . Swift & Co., 323 U.S. 134

(1944). Noviello v City of Boston, 398 F.3d 7 6 , 90 n.3 (1st Cir.

2005) (citing Christensen v . Harris County, 529 U.S. 576, 587

(2000)). The FDA’s footnote in its 2008 proposed regulation,

which, again, was not incorporated into the final version of the

rule and therefore was not subjected to the notice-and-comment

procedure, fits this category. See Stacel, 620 F. Supp. 2d at

906; Kellogg, 612 F. Supp. 2d at 435.35 Thus, “the agency must

35 Kellogg also observed that “[t]here is no ambiguity in the regulations,” since § 314.97 “plainly instructs ANDA holders to comply with § 314.70,” and that no deference is therefore due the

53 ultimately depend on the persuasive power of its argument. The

simple fact that the agency has a position, in and of itself, is

of only marginal significance.” Mayburg v . Sec’y of HHS, 740

F.2d 1 0 0 , 106 (1st Cir. 1984) (Breyer, J . ) .

The FDA’s footnote-bound position that “CBE changes are not

available for generic drugs approved under an [ANDA] under 21

U.S.C. § 355(j)” is not persuasive, for the reasons just

explained at length in Part III.B.1.b.i.a, supra. First, the

footnote did not so much as acknowledge 21 C.F.R. § 314.97.

Second, while the footnote did cite § 314.150(b)(10), that rule,

as already discussed at length, provides only that the FDA may

attempt to withdraw its approval of an ANDA if “the labeling for

the drug product that is the subject of the [ANDA] is no longer

consistent with that for the listed drug”; it says nothing at all

about CBE changes, and cannot be read to prevent them in light of

the other provisions of the ANDA rules. Third, while the

footnote also cited certain of the agency’s comments in

promulgating the ANDA regulations, those comments, as also

already discussed at length, do not support excluding generic

manufacturers from the CBE process. Based on these deficiencies,

this court joins with those others that have refused to adopt the

footnote under Auer v . Robbins, 519 U.S. 452 (1997). This court agrees but, in any event, the defendants do not argue that the rule is ambiguous or that Auer deference applies.

54 view set forth in the FDA’s footnote. See Stacel, 620 F. Supp.

2d at 907; Kellogg, 612 F. Supp. 2d at 435; Denahy, 586 F. Supp.

2d at 655; but see Morris, 2009 WL 424590, at *6 (deferring to

the footnote without discussing the appropriate level of

deference as a matter of administrative l a w ) ; Mensing, 562 F.

Supp. 2d at 1064 (same). 36

The defendants nevertheless argue that because, “[i]n

codifying FDA’s procedures, Congress clearly required generic

drug labeling to be the ‘same as’ the pioneer drug,” the FDA’s

footnote interpreting its regulations to that effect “is not only

entitled to deference, but is ‘virtually conclusive.’” (quoting

Red Lion Broad. C o . v . FCC, 395 U.S. 3 6 7 , 380-81 (1969)). This

court again differs with the defendants’ view.

First, while Congress did indeed “generally extend[] the

procedures used to approve generic copies of pre-62 drugs to

post-62 drugs” through the Hatch-Waxman Amendments, H.R. Rep. N o .

98-857, p t . 1 , at 1 , 1984 U.S.C.C.A.N. at 2647, those Amendments,

as is clear by now, did not in fact require the generic drug’s

labeling to remain the same as the pioneer’s drug’s post-

approval; they required the labeling proposed in the ANDA to be

the same as the pioneer drug’s. See Part III.B.1.a, supra.

36 The district court’s opinion in Colacicco, supra, also deferred to the footnote, 432 F. Supp. 2d at 5 3 7 , but, as noted above, that decision, following its affirmance by the Third Circuit, was vacated by the Supreme Court for reconsideration in light of Wyeth. 129 S . C t . 1578.

55 Second, the defendants have pointed to nothing in the rules

the FDA had in place before Hatch-Waxman indicating that the

agency disallowed post-approval changes to the labeling of an

ANDA-approved drug. The relevant rules, both before and after

their amendment in 1983, required only that an ANDA contain

described in the finding that an [ANDA] is sufficient.” 48 Fed.

Reg. at 2756 (later codified at 21 C.F.R. § 314.2(f)(2) (1984))

(emphasis added); see also 35 Fed. Reg. at 6575 (later codified

at 21 C.F.R. § 130.4(f)(2) (1971)).

As discussed in Part II.B.2, supra, that “finding” was the

first step of the ANDA approval process prior to Hatch-Waxman,

and hinged on whether the drug, based on its approval through the

DESI process, could be approved in generic form without

additional clinical and pre-clinical studies--not on whether the

generic drug had the same labeling as its DESI-approved version.

See 48 Fed. Reg. at 2751 (later codified at 21 C.F.R. § 314.2(a)

(1984)); 35 Fed. Reg. at 6575 (later codified at 21 C.F.R.

§ 130.4(f)(2) (1971)). It was not until after that finding had

issued that the rules placed any restriction on labeling, and

even that restriction operated only to keep the labeling proposed

in the ANDA “in accord with the labeling conditions described in

the finding,” as opposed to with those of the pioneer drug.

56 Given that, as discussed in Part II.B.2, supra, the FDA

retained this precise language when it amended its ANDA rules in

1983, that amendment also imposed no such restriction. To the

contrary, the amendment simply limited a finding that an ANDA was

suitable “to a product that was the same in active ingredient,

dosage form and strength, and conditions of use as the drug

product that was the subject of the finding.” 48 Fed. Reg. at

2755 (later codified at 21 C.F.R. § 314.2(a) (1984)). This

amendment did not prevent the FDA from finding, in the first step

of the ANDA process, that an ANDA was suitable for a drug with

labeling that differed from its DESI-approved version.

So the defendants are incorrect that, in the years prior to

Hatch-Waxman, the FDA’s rules disallowed ANDAs proposing labels

for generic drugs that differed from those of their DESI-approved

versions; the rules merely disallowed ANDAs proposing labels not

“in accord with the labeling conditions described” in the

agency’s finding that an ANDA was suitable for that particular

drug. Indeed, had FDA rules during that time in fact done what

the defendants say, the agency would not have referred to its

post Hatch-Waxman rule that an ANDA show “that the proposed

labeling for its drug product is the same as that of the

reference listed drug” as “a new requirement.” 54 Fed. Reg. at

28884 (emphasis added). Even if the defendants were correct,

moreover, the most their assertion demonstrates is that, under

57 the FDA’s pre-Hatch-Waxman regime, an ANDA had to propose

labeling that was the same as the pioneer drug’s. As in the case

of the Hatch-Waxman Amendments themselves and the FDA’s

implementing regulations, it simply does not follow that the

labeling had to remain the same after the ANDA had been approved.

c. The presumption against pre-emption

As just discussed in exhaustive detail, that point is clear

from the text of the statute and the regulations. But even if

the defendants, through the footnote and certain other portions

of the FDA comments on its ANDA rules, were able to cast some

doubt on whether generic manufacturers can use the CBE process to

make labeling changes, that doubt could not be resolved in the

defendants’ favor. As Wyeth makes clear, a court must “start

with the assumption that the historic police powers of the States

were not to be superseded by the Federal Act unless that was the

clear and manifest purpose of Congress.” 129 S . C t . at 1194-95.

For the reasons just discussed at length--in particular, the

absence of any ban on labeling changes to an ANDA-approved drug

in either the Hatch-Waxman Amendments or their implementing

rules--that presumption cannot be overcome here.

This is not to say that Congress could not have passed

legislation to give the FDA, rather than state authorities or

juries, the final say-so on the content of generic drug labeling,

58 much as Congress has done in the case of medical devices. See

id. at 1200 (citing Riegel v . Medtronic, Inc., 128 S . C t . 999

(2008)). It is just that, without evidence of such a “clear and

manifest purpose” to pre-empt state law, this court must presume

that federal law is not to be read to that effect. The

defendants cannot overcome that presumption here, even if any and

all arguable inconsistencies in the FDA’s commentary are resolved

in the defendants’ favor. See Stacel, 620 F. Supp. 2d at 906-07;

Kellogg, 612 F. Supp. 2d at 436; but see Mensing, 562 F. Supp. 2d

at 1061 (declining to apply the presumption, pre-Wyeth).

ii. Even read as the defendants suggest, the regulations do not make compliance with state law impossible

Finally, even if the defendants were correct that they could

not use the CBE process to make unilateral changes adding or

strengthening warnings to their generic drug, it does not follow

that compliance with state law requiring such warnings is

impossible. In Wyeth, the Court rejected the drug manufacturer’s

argument that “if it had unilaterally added . . . a warning, it

would have violated federal law governing unauthorized

distribution and misbranding . . . on the assumption that this

labeling change would have rendered [its drug] a new drug lacking

an effective application.” 129 S . C t . at 1197.

59 The Court reasoned, first, “strengthening the warning would

not have rendered [the manufacturer’s drug] a new drug” (citing

21 U.S.C. § 321(p)(1) and 21 C.F.R. § 310.3(h)) and, second,

Nor would this warning have rendered [the drug] misbranded. The FDCA does not provide that a drug is misbranded simply because the manufacturer has altered an FDA-approved label; instead, the misbranding vision focuses on the substance of the label and, provision among other things, proscribes labels that fail to include ‘adequate warnings.’ 21 U.S.C. § 352(f). Moreover, because the statute contemplates that federal juries will resolve most misbranding claims, the FDA’s belief that a drug is misbranded is not conclusive.

The same reasoning applies with equal force here. Even if

§ 310.150(b)(10) forbids a generic manufacturer from using the

CBE procedure to strengthen its label, the FDA would have to

enforce that prohibition through proceedings to withdraw its

approval of the ANDA under 21 U.S.C. § 355(e). Like the

misbranding trials discussed by the Court in Wyeth, the outcome

of such a proceeding ultimately turns not on whether the label is

in fact “consistent with” that of the listed version, but on

whether “such drug is unsafe under the conditions of use upon the

basis of which the application was approved” or “there is lack of

substantial evidence that the drug will have the effect it

purports or is represented to have under the conditions of use

prescribed, recommended, or suggested in the labeling thereof.”

21 U.S.C. §§ 355(e)(1), ( 3 ) . S o , even if the defendants were

60 correct that § 314.150(b)(10) required them to keep the same

label on their generic Sulindac as that on the listed version, it

is hardly a foregone conclusion that breaking the rule by

strengthening a particular warning without prior FDA approval

would result in revocation of their ANDA for the drug.37

The upshot is that, at best, the defendants can show “a

hypothetical or potential conflict . . . insufficient to warrant

pre-emption.” Rice v . Norman Williams Co., 458 U.S. 6 5 4 , 659

(1982). The defendants have offered no reason to believe that

the FDA would begin revocation proceedings against them for

strengthening the warning, and no reason to believe that those

proceedings would actually lead to revocation under § 355(e).

They have not met the demands of impossibility pre-emption. See

Wyeth, 129 S . C t . at 1197-98; Kellogg, 612 F. Supp. 2d at 430.

37 There is also the Wyeth Court’s point that “the very idea that the FDA would bring an enforcement action for strengthening a warning pursuant to the CBE is difficult to accept--neither [the defendants] nor the United States has identified a case in which the FDA has done so.” 129 S . C t . at 1197. Thus, while non-enforcement of a prohibition does not necessarily have any legal consequence, the Court in Wyeth reasoned that the historical lack of a misbranding prosecution arising out of a strengthened warning at least tended to undermine the manufacturer’s impossibility argument.

61 2. Frustration-of-purpose pre-emption

The defendants also claim that the state law underlying the

plaintiffs’ failure-to-warn claims “stands as an obstacle to the

accomplishment and execution of the full purposes and objectives

of Congress” in the Hatch-Waxman Amendments. Good, 501 F.3d at

47. Specifically, the defendants argue that state-law

requirements that a manufacturer alter the warning on an ANDA-

approved drug post-approval will necessarily entail duplicative

clinical trials “necessary to generate the data that might put

generic companies on notice that label changes are warranted.”

This testing, the argument goes, will drive up the price of

generic drugs in contravention of one of Hatch-Waxman’s goal “to

make available more low cost generic drugs by establishing a

generic drug approval procedure for drugs approved after 1962.”

H.R. Rep. N o . 98-857, p t . 1 , at 1 4 , 1984 U.S.S.C.A.N. at 2647.

There are a number of serious problems with this argument.

At the outset, the defendants do not identify anything in

the statutory or regulatory provisions on manufacturing changes,

21 U.S.C. § 356a and 21 C.F.R. § 314.70, requiring that

manufacturers justify heightened warnings with the results of

their own clinical trials. Those provisions, in fact, contain no

such requirement. See 21 U.S.C. §§ 356a(d)(3)(A), 21 C.F.R.

§ 314.70(c)(3). And another FDA rule, as discussed in Part

II.B.5, supra, requires that “labeling shall be revised to

62 include a warning as soon as there is reasonable evidence of a

serious hazard with a drug; a causal relationship need not have

been proved.” 21 C.F.R. § 201.80(e). If anything, then, the

regulatory scheme actually contemplates that manufacturers add

warnings to their labels without conducting clinical trials; it

in no way makes those trials a prerequisite to such additions.

So the premise of the defendants’ argument is defective.

Furthermore, as also discussed in Part II.B.5, supra, FDA

rules enacted to carry out the Hatch-Waxman Amendments

specifically require ANDA holders to adhere to the agency’s rules

on “the reporting and recordkeeping of adverse drug experiences,”

21 C.F.R. § 314.98(a), which include, among other things, a

mandate for “written procedures for the surveillance, receipt,

evaluation, and reporting of postmarketing adverse drug

experiences to FDA,” id. § 314.80(b). These requirements

naturally impose costs on generic drug makers, driving up the

costs of their products. Yet the FDA has chosen to subject

generic manufacturers to its monitoring and reporting

requirements anyway. This strongly suggests that the similar

requirements of state products liability law do not stand as an

obstacle to Hatch-Waxman’s cost-cutting objectives.38

38 A different kind of state-law claim could theoretically have this effect: for example, a claim that a manufacturer of an ANDA-approved drug was negligent in failing to conduct clinical trials prior to its approval. But that is not this case, where the Bartletts allege that “reports of serious adverse events

63 As discussed in Parts II.B.1-2, supra, Congress pursued

those objectives through the Hatch-Waxman Amendments by relieving

generic drug manufacturers of the burdens of safety and

effectiveness testing as a condition of approval. The defendants

have pointed to nothing in the Amendments, their legislative

history, the FDA’s rules enforcing them, or the agency’s comments

in making those rules to indicate that Congress also sought to

relieve generic drug manufacturers of any of the burdens of state

products liability law. There is little doubt that doing so

would likewise reduce the cost of generic drugs, but it does not

follow that Congress intended that state laws having the opposite

effect should perish on the strength of Hatch-Waxman.39

associated with Sulindac . . . in the medical literature”--rather than independent testing--sufficed to put the defendants on notice that a stronger warning was appropriate.

39 The defendants’ reliance on Justice Breyer’s concurring opinion in Wyeth is therefore misplaced. He noted that “some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need” and that, in such a case, the FDA may determine that state tort law serves as “a hindrance to achieving the safe drug- related medical care that Congress sought.” 129 S . C t . at 1204. Thus, Justice Breyer observed, the FDA “may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect.” Id. The defendants, however, point to nothing to suggest that either Congress or the FDA determined that state tort law--as opposed to federal drug-approval requirements--was acting as a hindrance to “safe drug-related medical care” by driving up generic drug prices. Thus, whatever the proper reading of FDA rules as they govern labeling changes to ANDA-approved drugs, those rules do not “embody” any

64 As the court of appeals has instructed, “it is not the fact

of [federal] action on a particular subject alone--but the

reasons for the action--that control its preemptive effect.”

Good, 501 F.3d at 5 5 . Lacking any evidence that Congress passed

the Hatch-Waxman Amendments intending to displace state-law

labeling requirements on generic drugs, the defendants have

provided no basis for finding those requirements pre-empted by

the Amendments. Nor have the defendants overcome the assumption,

endorsed by the Wyeth Court, that “[i]f Congress thought that

state-law suits posed an obstacle to its objectives, it surely

would have enacted an express pre-emption provision” directed at

those suits as part of Hatch-Waxman. 129 S . C t . at 1199. Here,

as there, the fact that Congress did no such thing strongly

indicates that Congress meant to do no such thing. Again, “the

purpose of Congress is the ultimate touchstone in every pre-

emption case.” Id. at 1194 (internal quotation marks omitted).

In that vein, the defendants’ frustration-of-purpose

argument (and their impossibility argument, for that matter)

raises another serious difficulty: leaving those injured by

drugs unaccompanied by warnings deemed adequate by state law

without any remedy at all without any indication that Congress

desired, or even contemplated the possibility, of such a

determination to displace state tort law. So Justice Breyer’s observations are inapposite here.

65 result.40 While Congress could have thought this a necessary

consequence of lowering the costs of prescription drugs, “[i]f

Congress had intended to deprive injured parties of a long

available form of compensation, it surely would have expressed

that intent more clearly.” Bates v . Dow Agrosciences LLC, 544

U.S. 4 3 1 , 449 (2005).

But, as just discussed at length, Congress did not do s o .

Without such a clear expression of intent, this court refuses to

take that step on its own. This puts this court in line with

others to consider the issue. See Stacel, 620 F. Supp. 2d at

907; Kellogg, 612 F. Supp. 2d at 440-41; Schrock v . Wyeth, Inc.,

601 F. Supp. 2d 1262, 1265-66 (W.D. Okla. 2009); Laisure-Radke,

40 The vast majority of courts have rejected the notion that the manufacturer of the brand-name drug may be liable for defects in its generic equivalent on a theory of “innovator liability.” See, e.g., Foster, 29 F.3d at 171; Goldych v . Eli Lilly & Co., N o . 04-1477, 2006 WL 2038436, at *6 (N.D.N.Y. July 1 9 , 2006); Colaccio, 432 F. Supp. 2d at 543; Block v . Wyeth, Inc., N o . 02- 1077, 2003 WL 203067, at *2-*3 (N.D. Tex. Jan. 2 8 , 2003); Sharp v . Leichus, N o . 2004-0643, 2006 WL 515532, at *3-*5 (Fla. Cir. C t . Feb. 1 7 , 2006); Kelly v . Wyeth, N o . 2003-03314, 2005 WL 4056740, at *4 (Mass. Super. C t . May 6, 2005); but see Conte v . Wyeth, Inc., 85 Cal. Rptr. 3d 299, 318 (Cal. C t . App. 2008). While this court need not decide whether New Hampshire would recognize such a theory, its widespread rejection supports the view that, if failure-to-warn claims against generic drug makers are indeed pre-empted, those injured as a result of deficient warnings on those products have no recourse. The defendants did not dispute this point at oral argument, suggesting instead that consumers who opt for generic drugs over name-brand equivalents may have effectively lost their right to recompense for injuries suffered from inadequate warnings in the bargain. That suggestion is not only distasteful but also contrary to fundamental principles of tort law.

66 2006 WL 9 0 1 6 5 7 , at * 6 ; accord Foster, 29 F.3d at 170 (“The

statutory scheme governing premarketing approval for drugs simply

does not evidence Congressional intent to insulate generic drug

manufacturers from liability . . . or . . . to alter state

products liability l a w ” ) . The defendants have not shown that the

state-law requirements underlying the Bartletts’ failure-to-warn

claims present an obstacle to the accomplishment and execution of

the full purposes and objectives of Congress in the Hatch-Waxman

Amendments or their implementing regulations.

I I I . Conclusion

For the foregoing r e a s o n s , the defendants’ motion for

judgment on the pleadings i s DENIED.

SO ORDERED.

Jos ___ h N. ___ ap __ ante United States District Judge

Dated: September 3 0 , 2009

cc: Bryan Ballew, E s q . Keith M . Jensen, E s q . Christine M . C r a i g , E s q . Timothy P . Beaupre, E s q . Patrick J. O ’ N e a l , E s q . Paul J. Cosgrove, E s q . Jeffrey D . Geoppinger, E s q . Joseph P . T h o m a s , E s q . Linda E . M a i c h l , E s q . Stephen J. J u d g e , E s q .