Rodney Guilbeau v. Pfizer Inc. , 880 F.3d 304 ( 2018 )

In the
United States Court of Appeals
For the Seventh Circuit
____________________
No. 17-2056
RODNEY GUILBEAU, et al.,
Plaintiffs-Appellants,
v.
PFIZER INC. and PHARMACIA & UPJOHN COMPANY LLC,
Defendants-Appellees.
____________________
Appeal from the United States District Court for the
Northern District of Illinois, Eastern Division. MDL No. 2545
Master Docket Case No. 1:14-cv-1748 — Matthew F. Kennelly, Judge.
____________________
ARGUED OCTOBER 23, 2017 — DECIDED JANUARY 19, 2018
____________________
Before BAUER and HAMILTON, Circuit Judges, and DARROW,
District Judge.*
HAMILTON, Circuit Judge. In Wyeth v. Levine, the Supreme
Court held that claims against a manufacturer of a brand-
name prescription drug for failure to warn adequately of the
drug’s dangers were not preempted by federal law. 555 U.S.
* Of the Central District of Illinois, sitting by designation.
2 No. 17-2056
555, 581 (2009). In PLIVA, Inc. v. Mensing, the Supreme Court
held that such failure-to-warn claims against manufacturers
of generic drugs are preempted by federal law. The different
results, the Court explained in Mensing, are based on the dif-
ferent regulatory requirements and processes for approving
and labeling prescription drugs. 564 U.S. 604, 614, 618, 625
(2011).
This appeal arises from the district court presiding over
thousands of related claims against manufacturers of testos-
terone replacement therapy drugs. We must consider how to
apply Levine and Mensing to a manufacturer of a drug that
does not fit neatly into the colloquial dichotomy between
brand-name and generic drugs. We must look at the more pre-
cise legal and regulatory context underlying those terms, fo-
cusing on whether the U.S. Food and Drug Administration
(FDA) approved public sale of the drugs through the “new
drug application” or NDA process, or instead through the
“abbreviated new drug application” or ANDA process. We
have tried to minimize use of impenetrable acronyms, but
readers are warned that some are unavoidable.
Testosterone replacement drugs have been sold for more
than sixty years as prescription drugs with the approval of the
FDA. The drugs have long been used to treat low testosterone
production in younger men. In recent years, though, manu-
facturers have found a new market for these drugs to coun-
teract the effects of declining testosterone production in older
men. Older men experience a higher incidence of heart at-
tacks, strokes, and other cardiovascular events than younger
ones. Numerous lawsuits have been filed against testosterone
drug manufacturers alleging that the drugs increase these
No. 17-2056 3
health risks. One theory in such cases is that the drug manu-
facturers have failed to warn doctors and patients adequately
about the risks, a tort theory arising under state product-lia-
bility laws. Such cases pending in federal district courts have
been consolidated for discovery and pretrial proceedings in a
multi-district litigation (MDL) docket before Judge Kennelly
in the Northern District of Illinois. See 28 U.S.C. § 1407.
The district court granted a motion to dismiss brought by
the manufacturers of one testosterone replacement drug,
Depo-T, on the ground that failure-to-warn claims are
preempted by federal law. The district court found that Depo-
T’s manufacturers could not change their drug labels to add
additional warnings because FDA regulations prohibit them
from “making a unilateral labeling change.” In re Testosterone
Replacement Therapy Products Liability Litig., 142 F. Supp. 3d
747, 754, 755 (N.D. Ill. 2015). Plaintiffs appeal that decision, as
well as the district court’s related decision to deny further dis-
covery related to the preemption defense. We affirm both de-
cisions.
Part I explains the regulatory approval process for pre-
scription drugs and the particular historical context and pro-
cedural background needed to understand the issues in this
appeal. Part II analyzes the defendant drug-makers’ preemp-
tion defense. Part III reviews the district court’s decision to
deny further discovery on the preemption defense. 1
1 This single appeal covers more than one thousand individual cases
before the MDL transferee court. On appeal, it has become clear that com-
plete diversity of citizenship is lacking in forty of the cases covered by this
appeal. See App. Dkt. 15-1, at 5–7. By separate order today, we vacate the
dismissals on the merits in those forty cases despite our affirmance in all
the other cases where federal subject matter jurisdiction is secure. Those
4 No. 17-2056
I. Factual Background and Procedural History
A. Regulatory Background
Prescription drugs in the United States must be approved
by the Food and Drug Administration (FDA) before they can
be sold. 21 U.S.C. § 355(a). Prospective drugs can follow one
of two general paths to obtain FDA approval. A new drug that
has never been marketed before must be approved through
the new drug application (NDA) process. The NDA process
requires an extensive series of safety and effectiveness trials
before a new drug can be sold. See § 355(b)(1).
If the prospective drug is “the same as” an existing drug
already on the market, however, the maker can obtain ap-
proval through the shorter and less onerous abbreviated new
drug application (ANDA) process. See § 355(j)(2)(A). The
ANDA process requires proof that the drug in question has
the same active ingredients, effects, and labeling as a prede-
cessor drug that the FDA has already approved. Id.; 21 C.F.R.
§ 314.94(a) (2015). The predecessor drug that has already re-
ceived FDA approval is known as the reference listed drug
(RLD). 21 C.F.R. § 314.3(b). In many cases, the reference listed
drug is the original drug that pioneered a new active ingredi-
ent or a new treatment and gained FDA approval through the
new drug application process. If the original pioneer drug has
been discontinued, the FDA will typically designate the re-
maining market-leading drug to take its place as the reference
listed drug for that particular category of drugs. See below at
17.
forty cases must be remanded to the district court to resolve the jurisdic-
tional problems.
No. 17-2056 5
NDA-approved drugs are often referred to as “brand-
name” drugs and ANDA-approved drugs as “generic” drugs.
These colloquial terms are not quite precise enough for our
purposes in this case, though. The 1984 Hatch-Waxman Act
established the current drug approval processes and the asso-
ciated patent protection for truly new drugs. Drug Price Com-
petition and Patent Term Restoration (Hatch-Waxman) Act of
1984, Pub. L. 98-417, 98 Stat. 1585; H.R. Rep. No. 98-857, at 14–
15 (1984); Mensing, 564 U.S. at 612 & n.2. 2 Depo-T, the drug at
issue in this appeal, has a trademarked name and was ap-
proved long before the 1984 changes, but the FDA has classi-
fied Depo-T as an ANDA-approved drug (i.e., a “generic”)
under current law. See Supp. App. at 41, 55.
The approval process is central to both the preemption is-
sue here and the difference between the Supreme Court’s
preemption decisions in Levine and Mensing. Those decisions
turn on whether a drug-maker may or may not change its la-
bel to add a warning without prior approval from the FDA.
Levine held that if the drug-maker may make such unilateral
changes, then federal law does not preempt a state-law claim
based on an inadequate label. Federal law thus would not pre-
vent the drug-maker from complying with a state statute or
court decision requiring more cautious warnings than appear
2 For further background on the drug approval process, see FDA, Cen-
ter for Drug Evaluation and Research, Determining Whether To Submit
an ANDA or a 505(b)(2) Application: Guidance for Industry (Draft Guid-
ance) 1–5 (Oct. 2017); Suzanne M. Kirchhoff et al., Congressional Research
Service, Frequently Asked Questions About Prescription Drug Pricing
and Policy 2 & n.b (May 2017) (explaining “Generic Drug” and Hatch-
Waxman).
6 No. 17-2056
on the FDA-approved label. 555 U.S. at 573 (rejecting preemp-
tion defense for NDA-holder).
The issue is governed by an FDA regulation known as the
“changes-being-effected” (CBE) regulation, which permits
“changes in the labeling to reflect newly acquired infor-
mation” in advance of later FDA approval. 21 C.F.R.
§ 314.70(c)(6)(iii). The regulation allows a unilateral change
“to add or strengthen a contraindication, warning, precau-
tion, or adverse reaction for which the evidence of a causal
association” meets FDA standards. § 314.70(c)(6)(iii)(A). The
Supreme Court has interpreted the CBE regulation to be avail-
able only if the drug in question was approved through the
NDA process, but not if it was approved via the ANDA pro-
cess because ANDA-approved “generic” drugs may change
their labels only with the FDA’s approval or at the FDA’s re-
quest. See Mensing, 564 U.S. at 614–15, 623–26 (“We … con-
clude that the CBE process was not open to the [ANDA
holder] Manufacturers for the sort of change required by state
law.”). 3 The Mensing Court held that this difference in ap-
proval procedures is decisive for preemption:
We recognize that from the perspective of [plaintiffs]
Mensing and Demahy, finding pre-emption here but
not in Wyeth [v. Levine] makes little sense. Had Mensing
3 Perhaps for the sake of readability, the Mensing Court referred to
drugs approved pursuant to new drug applications (NDAs) as “brand-
name” drugs and those approved pursuant to abbreviated new drug ap-
plications (ANDAs) as “generic” drugs. When one reads Mensing together
with the cited regulations, see 564 U.S. at 612 n.2, 616–17, and the cited
passages from the FDA’s amicus brief in that case, see 564 U.S. at 614, it is
clear that Mensing used the terms brand-name and generic interchangea-
bly with the FDA terms NDA-approved and ANDA-approved.
No. 17-2056 7
and Demahy taken Reglan, the brand-name drug pre-
scribed by their doctors, Wyeth would control and their
lawsuits would not be pre-empted. But because phar-
macists, acting in full accord with state law, substituted
generic metoclopramide instead, federal law pre-
empts these lawsuits.
Id. at 625. The Mensing decision did not address the concept
of reference listed drugs (RLDs) in any meaningful detail. See
id. at 612, 614. With this background, we turn to the specific
drugs in this appeal. 4
B. FDA Approval of Depo-Testosterone
In 1953, the Food and Drug Administration approved a
new drug, Delatestryl, as a testosterone replacement injection.
Its original purpose, according to the new drug application
filed on its behalf, was to treat men whose bodies did not pro-
duce enough testosterone naturally. This NDA came before
many of today’s regulatory requirements, though Delatestryl
later passed effectiveness screening in the 1960s as required
under the then-new Drug Efficacy Study Implementation
program.
In 1979, the FDA approved the Upjohn Company’s abbre-
viated new drug application (ANDA) for Depo-Testosterone,
a testosterone injection similar to Delatestryl. Depo-T, as the
4 As in Mensing, we are concerned in this appeal only with the CBE
regulation’s availability to “add or strengthen a … warning” without prior
FDA action. 21 C.F.R. § 314.70(c)(6)(iii)(A). The CBE regulation might be
available to ANDA holders for other purposes not addressed in Mensing
and thus not relevant to this appeal. See, e.g., FDA, Generic Drug Labeling
Revisions Covered under Section 505(j)(10) of the Federal Food, Drug, and Cos-
metic Act, Manual of Policies and Procedures § 5230.3 (2013).
8 No. 17-2056
product is still called, produced safety and effectiveness re-
sults equivalent to those of Delatestryl. Under the drug ap-
proval process at the time, similar results sufficed for stream-
lined ANDA approval. But because of a slight difference in its
physical composition that made it not quite the same as De-
latestryl, after the 1984 statutory changes were implemented,
Depo-T became the reference listed drug (RLD) for its precise
kind of testosterone injection. This meant that any drugs seek-
ing to follow in Depo-T’s footsteps had to demonstrate bioe-
quivalence to (i.e., that they were the same as) Depo-T to qual-
ify for the streamlined approval process of an abbreviated
new drug application. See above at 4; see also 21 U.S.C.
§ 355(j)(2)(A)(iv); 21 C.F.R. § 314.3(b). When these lawsuits
were filed, defendant Pfizer had taken over production and
marketing of Depo-T, and the drug remained the reference
listed drug. More than half a dozen other testosterone drugs
have followed Depo-T’s lead since its approval in 1979.
C. Procedural History
Testosterone replacement drugs like Depo-T gained new
life in recent years as doctors began prescribing them to aging
men with health conditions possibly related to low testos-
terone levels (known in some marketing campaigns as “Low
T”). By 2014, however, a sizable number of men treated with
testosterone replacement drugs had filed suits against drug-
makers alleging that the drugs caused heart attacks, strokes,
and other cardiovascular problems. In June 2014, such cases
pending in federal courts were transferred to the Northern
District of Illinois for consolidated discovery and pretrial pro-
ceedings under the title In re: Testosterone Replacement Therapy
Products Liability Litigation (MDL 2545). See 28 U.S.C. § 1407.
No. 17-2056 9
The broader MDL against the makers of testosterone replace-
ment products continues, involving numerous products and
defendants and thousands of plaintiffs.
This appeal is limited to just one issue about one drug:
whether failure-to-warn claims under state law against Depo-
T’s maker are preempted by federal law. The plaintiffs allege
that the testosterone replacement drug-makers violated state
product-liability law when they failed to warn the plaintiffs
and their doctors adequately about the potential side effects
of the drugs. These warnings, the plaintiffs allege, should
have appeared in the drug’s labeling.
The district court decided that federal law preempted state
failure-to-warn claims for all drugs approved pursuant to an
abbreviated new drug application. The court granted a mo-
tion to dismiss all such claims, which covered claims against
Depo-T. 142 F. Supp. 3d 747, 754 (N.D. Ill. 2015). The court re-
jected plaintiffs’ effort to avoid preemption by emphasizing
that Depo-T was also the reference listed drug: “RLD ANDA
holders are prohibited under federal law from unilaterally
changing their drugs’ warning labels” just like any other
ANDA holder. Id. The district court also denied further dis-
covery into two instances from the 1990s where it seemed that
Depo-T’s label was changed through the changes-being-ef-
fected process for other reasons. Id. at 754–55. The district
court denied reconsideration. No. 14 C 1748, 2016 WL 861213
at *2 (N.D. Ill. Mar. 7, 2016). Plaintiffs have appealed both rul-
ings.
10 No. 17-2056
II. Preemption
A. Generic Drug Labeling and Preemption at the Supreme
Court
The district court granted a Rule 12(b)(6) motion to dis-
miss on preemption grounds, a legal determination that we
review de novo. Toney v. L’Oreal USA, Inc., 406 F.3d 905, 907–08
(7th Cir. 2005). Preemption comes in several forms, but in
these disputes over drug labels, conflict preemption takes
center stage. E.g., Mason v. Smithkline Beecham Corp., 596 F.3d
387, 390 (7th Cir. 2010). State-law tort claims alleging that a
drug label failed to warn consumers adequately of potential
dangers may be preempted because of the extensive labeling
requirements imposed by federal law. See id. at 391–96. In es-
sence, tort litigation can place a state-law duty on drug-mak-
ers to warn adequately of the material risks involved in using
their products. The FDA also imposes labeling duties under
federal law in the drug approval process. When these state
and federal duties create “an actual conflict between state and
federal law such that it is impossible for a person to obey
both,” federal law controls and the state-law tort claims must
be dismissed. See id. at 390.
As summarized above, a series of recent Supreme Court
decisions on federal preemption in failure-to-warn cases in-
volving prescription drugs has narrowed our task. In Wyeth v.
Levine, 555 U.S. 555, 568 (2009), the Supreme Court zeroed in
on whether the changes-being-effected regulation could al-
low a brand-name drug manufacturer to comply with both
federal law and state law requiring warnings that went be-
yond those on the FDA-approved label. The Court found that
the changes-being-effected regulation, 21 C.F.R. § 314.70(c),
No. 17-2056 11
permits label changes to “add or strengthen a contraindica-
tion, warning, precaution, or adverse reaction,” and—critical
to the preemption issue—changes by eligible application
holders “need not wait for FDA approval.” Levine, 555 U.S. at
568. The Levine Court concluded that the changes-being-ef-
fected regulation was available for “brand-name” drugs ap-
proved through NDAs, which covered the drug at issue there.
Because the changes-being-effected regulation “permitted
Wyeth to unilaterally strengthen its warning” and Wyeth
could not demonstrate that the FDA would have “prohibited
such a change,” the Vermont jury award stood. Id. at 573. Wy-
eth, in short, had “failed to demonstrate that it was impossible
for it to comply with both federal and state requirements” be-
cause the changes-being-effected regulation was available to
add new warnings without delay. Id.
In PLIVA, Inc. v. Mensing, the Supreme Court narrowed the
holding of Levine, limiting it to brand-name drugs approved
through NDAs. 564 U.S. 604 (2011). The issue in Mensing was
“whether, and to what extent, generic [drug] manufacturers
may change their labels after initial FDA approval” of an
ANDA. Id. at 613 (emphasis altered). The FDA explained in
an amicus brief that it had “consistently taken the position
that an ANDA holder”—i.e., a generic drug-maker—“may
not unilaterally change its approved labeling” using the
changes-being-effected regulation. Brief for the United States
as Amicus Curiae Supporting Respondents at 16, Mensing,
564 U.S. 604 (No. 09-993), 2011 WL 741927, at *16. The Mensing
Court accepted this reading of the changes-being-effected
regulation, extending deference to the agency’s interpretation
of its own regulations. 564 U.S. at 614–15. Given its approving
citation, see id. at 616–17, the Court seemed particularly con-
12 No. 17-2056
vinced by the 1992 explanation the FDA offered in its pream-
ble to the ANDA regulations. There the agency explained that
only the FDA—and not the ANDA holder—had the power to
decide whether new warnings were needed:
After approval of an ANDA, if an ANDA holder be-
lieves 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.
Abbreviated New Drug Application Regulations, 57 Fed. Reg.
17,950, 17,961 (Apr. 28, 1992). Accordingly, the preemption
defense was available to the ANDA holders in Mensing even
though it had not been available to the NDA holder in Levine.
Warnings could not have been added without FDA ap-
proval in Mensing because ANDA holders “have an ongoing
federal duty of ‘sameness.’” 564 U.S. at 613. At all times their
drugs’ labeling “must be the same as the listed drug product’s
labeling” that was the basis of the ANDA approval. Id., quot-
ing 57 Fed. Reg. at 17,961. Since the only thing left for ANDA
holders to do in that case was to petition the FDA to approve
a labeling change, the drug-makers could not “independently
satisfy [their] state duties for pre-emption purposes,” and the
state-law tort claims were preempted. Id. at 624; see also Mu-
tual Pharm. Co. v. Bartlett, 570 U.S. —, —, 133 S. Ct. 2466, 2480
(2013) (Mensing’s holding—that the availability of the
changes-being-effected regulation determines preemption—
turns what could otherwise be a complex impossibility anal-
ysis into a “straightforward application of pre-emption law”).
No. 17-2056 13
B. The MDL Plaintiffs’ Preemption Arguments
Plaintiffs here seek to avoid the preemption holding of
Mensing by pointing to a small but, they say, critical, factual
difference. Yes, Depo-T was approved through an ANDA, like
the generic drug in Mensing, but plaintiffs point out that
Depo-T is also the reference listed drug (RLD) for its family of
testosterone replacement drugs. Because the federal duty of
sameness attaches to the RLD’s labeling (which is not always
a drug approved via an NDA), and because Depo-T itself is
the RLD, plaintiffs believe that “Pfizer’s obligation is to main-
tain a label identical to the RLD – that is, identical to itself.”
Appellants’ Br. at 27. “Because the only label with which
Pfizer must maintain identity is the label for Depo-T itself,”
plaintiffs reason, “nothing in the FDA regulations precludes
Pfizer from using the CBE procedure to add warnings to the
Depo-T label.” Id. Any unilateral changes would not lead to
inconsistent labeling because Depo-T’s label would always
match its own and thus comply with federal law, or so this
theory goes.
Even if the RLD v. not-RLD distinction alone is insufficient
to avoid preemption, plaintiffs argue further, Depo-T’s age
and unusual timeline of approval should distinguish it from
the situation in Mensing. Depo-T is an RLD made by an
ANDA holder “for which there never was an NDA-holder.”
Id. As noted, Depo-T’s ANDA was approved in 1979 before
Congress established the current approval regime. Because of
this idiosyncrasy, plaintiffs suggest, none of the FDA interpre-
tations the Court found important in Mensing should bar
Pfizer from using the changes-being-effected regulation to
add new warnings required by state law, so preemption
should not apply to bar plaintiffs’ claims.
14 No. 17-2056
C. Availability of the Changes-Being-Effected Regulation
1. Summary
We disagree with the plaintiffs’ efforts to avoid applying
Mensing to Depo-T. We reach this conclusion for two princi-
pal reasons. First, we read Mensing to bar any use of the
changes-being-effected regulation to strengthen warnings by
any ANDA holder, whether it is the reference listed drug or
not. This is an interpretation drawn from the drug approval
statutes and regulations that apply to all ANDA drugs. Sec-
ond, we conclude that RLD ANDA holders are not under a
different duty of sameness. Like all other ANDA holders,
they must match the labeling for the RLD already approved by
the FDA, which in their case refers to their own prior ap-
proved labeling. These reasons accord with a decision of the
Sixth Circuit on this issue and show why the plaintiffs’ claims
are preempted by federal law despite Depo-T’s unusual his-
tory.
2. CBE Changes Are Not Available to ANDA Holders to
Add Warnings
Mensing instructs that no ANDA holder may use the CBE
regulation to add or strengthen a warning on its own. Mens-
ing, 564 U.S. at 614 (“CBE changes unilaterally made to
strengthen a generic drug’s warning label would violate the
[relevant] statutes and regulations”); see also above at 6–7.
That conclusion, drawn from the applicable drug labeling
statutes, regulations, and FDA interpretations, applies with
equal force to ANDA holders whose drugs are also RLDs.
First, despite potentially confusing references to brand-
name and generic drugs—recall that the relevant FDA terms
are NDA-approved and ANDA-approved, respectively—
No. 17-2056 15
Mensing itself unambiguously refers to the lines drawn in the
drug approval process as determining access to the CBE reg-
ulation. Mensing concludes that while NDA holders may use
the CBE regulation to add warnings, ANDA holders (like
Pfizer here) may not. Responding to the criticism that finding
pre-emption in Mensing but not in Levine made little sense, the
Mensing Court observed that “the federal statutes and regula-
tions that apply to brand-name drug manufacturers are
meaningfully different than those that apply to generic drug
manufacturers,” id. at 626.
Despite their occasional use of these terms, the Supreme
Court, Congress, and the FDA all agree that the meaningful
difference is found in approval process classifications, not
shorthand terms like brand-name and generic. Like the Mens-
ing Court, see 564 U.S. at 612 n.2, the FDA treats “brand-name
drug” as a synonym for a “drug approved in an NDA” and
“generic drug” as a term referring to the product of an ANDA
holder. See Supplemental Applications Proposing Labeling
Changes for Approved Drugs and Biological Products, 78
Fed. Reg. 67,985, 67,988, 67,998 (proposed Nov. 13, 2013) (to
be codified at 21 C.F.R. § 314.70). The distinction between
NDAs and ANDAs comes directly from statute. Compare 21
U.S.C. § 355(b)–(c) with 21 U.S.C. § 355(j). In addition, the clas-
sifications set forth in 21 C.F.R. § 314.50 et seq. (NDAs) and 21
C.F.R. § 314.92 et seq. (ANDAs) do not distinguish drugs on
the basis of whether they are used as RLDs for later applica-
tions. 5 As Depo-T itself demonstrates, having a registered
5 The parties dispute the significance of a recent change to these regu-
lations. See Abbreviated New Drug Applications and 505(b)(2) Applica-
tions, 81 Fed. Reg. 69,580 (Oct. 6, 2016). Mensing is based on the fact that
NDA holders and ANDA holders are subject to different rules. 564 U.S. at
16 No. 17-2056
trademark name and being designated as an RLD does not
change a drug’s approval process classification at FDA. See
Supp. App. at 41, 52.
One of the statutes cited in Mensing emphasizes another
key detail about what it means to be an RLD under the ANDA
approval process. Until the FDA acts, what matters to ANDA
holders in this context is not which drug is currently the RLD,
but rather which drug was the RLD when the ANDA was sub-
mitted. For initial approval, a maker of an ANDA-approved
drug must show that its labeling will be “the same as the la-
beling approved for the listed drug.” 21 U.S.C.
§ 355(j)(2)(A)(v); see also Mensing, 564 U.S. at 612–13 (citing
this language). Mensing clarifies that this is a continuing duty:
ANDA drug labeling “must always be the same” as labeling
for the “listed drug product” designated by the FDA. Id. at
613, quoting Abbreviated New Drug Application Regula-
tions, 57 Fed. Reg. 17,950, 17,961 (Apr. 28, 1992); see also Mens-
ing, 564 U.S. at 618 (defining an ANDA holder’s “federal law
duty to keep the label the same”). Unless and until the FDA
decides the labeling needs to change, ANDA holders must
625. One such rule is that NDA holders may use the CBE regulation to add
warnings unilaterally, without prior FDA approval, while ANDA holders
may not. This basic point is not affected by the recent rule update, which
was described as a set of “technical amendments … intended to promote
clarity and consistency.” 81 Fed. Reg. at 69,630. The specific update at is-
sue here was presented under the heading “Consistent Use of Defined
Terms.” See id. Nowhere in that 2016 rule change does FDA indicate that
it is departing from its 2013 position that ANDA holders may make CBE
labeling changes only “to conform with approved labeling for the RLD.” 78
Fed. Reg. at 67,988 (emphasis added); see also below at 18–19. If the 2016
rule change had been meant to alter this earlier understanding, it would
have said as much.
No. 17-2056 17
match the FDA-approved language for the RLD, not whatever
the RLD’s manufacturer currently thinks would be best. See
below at 20–23.
The ANDA regulations cited in Mensing further reinforce
this conclusion that approval-process status and RLD status
are separate. See 564 U.S. at 613, citing ANDA Regulations, 57
Fed. Reg. at 17,961. For example, when the sale of an RLD is
discontinued, to remain current the FDA must select a new
RLD for that type of drug from among those still on the mar-
ket. If no NDA-approved drug is left in circulation, the re-
placement RLD is selected on the basis of its market share.
This new RLD will remain designated as such even if its mar-
ket share later shrinks. 6 What actually matters in terms of
choosing an RLD, then, is simply that the FDA needs a new
RLD and the selected drug continues to be sold in the market.
Plaintiffs have not directed us to an authoritative FDA inter-
pretation that says taking on RLD status also confers new la-
6In implementing the current NDA and ANDA approval regime, the
FDA explained:
As stated above, FDA has revised the rule so that FDA will
designate all reference listed drugs. Generally, the reference
listed drug will be the NDA drug product for a single source
drug product. For multiple source NDA drug products or
multiple source drug products without an NDA, the reference
listed drug generally will be the market leader as determined by
FDA on the basis of commercial data. … Once FDA designates
that reference listed drug, that drug will continue to be the
reference standard even if the drug is later replaced as the
market leader.
ANDA Regulations, 57 Fed. Reg. at 17,958 (emphasis added).
18 No. 17-2056
beling abilities and responsibilities on that drug’s manufac-
turer. See Appellants’ Br. at 27–33. By itself, the RLD designa-
tion does not change the preemption analysis under Mensing.
For purposes of the changes-being-effected regulation, the
key distinction to both the Supreme Court and the FDA is the
approval process, not RLD status. The statutes, the regula-
tions, and the Mensing opinion do not draw the distinction
plaintiffs advocate: a difference in abilities and responsibili-
ties between RLD ANDA holders and other ANDA holders.
Second, the FDA has already interpreted Mensing as pro-
hibiting any ANDA holder, whether it is the RLD or not, from
using the changes-being-effected regulation to add a warning
without prior FDA approval. In November 2013, after Mens-
ing was decided, the agency proposed a rule change that for
the first time would “expressly provide that ANDA holders
may distribute revised labeling that differs from the RLD
upon submission of a [changes-being-effected] supplement to
FDA.” Labeling Changes for Approved Drugs, 78 Fed. Reg. at
67,989. 7 If adopted, this change “would create parity between
NDA holders and ANDA holders” with respect to adding
warnings using the CBE regulation. Id. This action, if final-
ized, “may eliminate the preemption of certain failure-to-
warn claims with respect to generic drugs,” id. at 67,989—a
prediction the FDA offered immediately after the agency dis-
cussed the Levine and Mensing decisions in detail. Id. at
67,988–89.
7 This proposed rule change has not received final approval. Compare
78 Fed. Reg. at 67,998 (proposing new paragraph (8) to be titled: “Equal
applicability to application holders and abbreviated application holders”)
with 21 C.F.R. § 314.70(c) (2017) (ending at paragraph (7)).
No. 17-2056 19
The FDA’s discussion of the issue did not signal any dif-
ference in abilities or responsibilities between RLD and non-
RLD ANDA holders. In fact, this proposed change would fur-
ther make clear that “the duty to maintain accurate product
labeling does not differ between an ANDA designated as the
reference standard for bioequivalence studies and other ap-
proved ANDAs.” Id. at 67,989. 8 The FDA explained that un-
less this rule change took effect, under Levine and Mensing,
“access to the courts is dependent on whether an individual
is dispensed a brand name or generic drug,” id. at 67,988, with
no reference to whether that dispensed drug was an RLD or
not.
This proposed rule change from 2013 thus indicates sev-
eral things. The FDA believes its current rules apply equally
to all ANDAs, whether they are RLDs or not. The FDA con-
sidered making a uniform preemption policy change that
would apply equally to all ANDA holders. And the FDA
thought this change “would create parity between NDA hold-
ers and ANDA holders,” indicating that these CBE changes
would have effect only prospectively and not retroactively. Id.
at 67,989. For now this remains only a proposed rule change,
but it sheds light on the FDA’s understanding of current law.
8 There is a slight difference between the terms “reference listed drug”
and “reference standard,” see 21 C.F.R. § 314.3(b), but the FDA gives no
indication that this distinction is material to preemption or that it matters
for the purposes of the proposed rule. See Labeling Changes for Approved
Drugs, 78 Fed. Reg. at 67,989; see also FDA, Center for Drug Evaluation
and Research, Draft Guidance: Referencing Approved Drug Products in
ANDA Submissions 6 (January 2017); 21 C.F.R. § 314.94(a)(3). Instead, this
illustration indicates that all ANDAs are treated alike for purposes of
preemption, in the eyes of the FDA.
20 No. 17-2056
Plaintiffs are asking us in effect to recognize a third cate-
gory in a highly regulated context where the relevant agency
and the Supreme Court have recognized only two. Rather
than basing preemption on the difference between an NDA
and an ANDA, as Levine and Mensing do, plaintiffs contend
we should put labeling claims against NDA holders and RLD
ANDA holders on one side (not preempted) and those against
all other ANDA holders on the other (preempted). This
change would enable a new category of plaintiffs to pursue
labeling claims against a subset of drug-makers in situations
that we recognize may involve “dreadful injuries” and “pas-
sionate responses.” Mutual Pharmaceutical Co. v. Bartlett, 570
U.S. —, —, 133 S. Ct. 2466, 2478 (2013). We do not see, how-
ever, a statutory or regulatory basis for drawing the line that
plaintiffs propose.
3. All ANDA Holders Share an Identical Duty of Sameness
The second principal reason plaintiffs’ claims are
preempted is that ANDA drugs that are also RLDs have a
duty of sameness indistinguishable from that of all other
ANDA drugs. As mentioned in Mensing, by statute, all AN-
DAs must show that “the labeling proposed for the new drug
is the same as the labeling approved for the listed drug” in a
side-by-side comparison. 21 U.S.C. § 355(j)(2)(A)(v) (emphasis
added); see also Mensing, 564 U.S. at 612–13 (citing statute and
establishing that this is a continuing duty of ANDA holders).
The statute uses the past tense (“approved”) to describe
the labeling that ANDA holders must match. This language
signals that all ANDAs must mirror the version of the RLD’s
labeling that was previously approved by the FDA. See FDA,
Center for Drug Evaluation and Research, Guidance for In-
dustry: Revising ANDA Labeling Following Revision of the
No. 17-2056 21
RLD Labeling 4 (2000) (explaining that “approved changes in
the RLD labeling generally necessitate changes in the labeling
of … ANDAs using the RLD”). Put another way, the duty of
sameness does not attach to whatever labeling the RLD is cur-
rently using but rather to the labeling the FDA has already
approved for the drug, whether the approval happened re-
cently or long ago. Pfizer may not unilaterally change the
FDA-approved language on Depo-T’s label. A lawsuit under
state law that seeks to recover damages for Pfizer’s failure to
do so is preempted by federal law. 9
Two examples help illustrate why this is the case. Consider
first what would happen if the label for a brand-name (NDA)
drug that is also an RLD were changed through the CBE pro-
9 The duty of sameness applies throughout the life of the ANDA-
approved drug since the definition of an ANDA includes “all amend-
ments and supplements to the application.” 21 C.F.R. § 314.3(b). Plaintiffs
contend that another regulation relieves the apparent statutory burden of
matching the FDA-approved version of the RLD’s label. FDA may with-
draw an ANDA’s approval after the drugs have hit the marketplace when
its label “is no longer consistent with that for the listed drug.” 21 C.F.R.
§ 314.150(b)(10). This says nothing about matching the approved version of
the RLD’s label, just that consistency with the listed drug is key. But one
could easily imagine a situation where it takes the FDA a few weeks or
months to conclude that a CBE change to a listed drug’s label should not
be approved. This disapproval may come even though the RLD’s new la-
bel has already hit the marketplace. It cannot be the case that ANDA hold-
ers must always and immediately match the contemporaneous RLD label
in the marketplace, since at the time of the CBE action, later FDA disap-
proval remains a possibility. The duty of sameness attaches to what the
FDA later approves. Cf. 78 Fed. Reg. at 67,986 (proposing to give all
ANDA holders 30 days to “submit a CBE–0 supplement with conforming
labeling changes after FDA approval of a revision to the labeling for the
RLD”) (emphasis added).
22 No. 17-2056
cess to add a new warning. (Levine explains why this is possi-
ble. 555 U.S. at 570–73.) This NDA RLD labeling change
would create a corollary matching duty for all ANDA holders
who used that drug as an RLD to obtain their own ANDA ap-
provals. Not updating would violate the duty of sameness
and perhaps also lead to state-law tort liability for inadequate
warnings. See Fulgenzi v. PLIVA, Inc., 711 F.3d 578, 586–87 (6th
Cir. 2013) (explaining how state-law liability for inadequate
warnings can be distinct from duties imposed by federal law).
But just when that potential liability might arise would not
be clear because of the inherent lag period. FDA approval may
not come until months after the CBE change has been made.
For liability purposes, would the ANDA holder’s ‘failure to
timely update’ occur as soon as the NDA holder made the
CBE change, or would it occur later when the FDA approved
that change? When and what must ANDA holders match?
The New Jersey Supreme Court has answered this question
persuasively.
What matters, that court explained, are the date and sub-
stance of FDA approval. In re Reglan Litigation, 142 A.3d 725
(N.J. 2016). In Reglan, the FDA had approved new warning la-
bels in 2004, id. at 729, but the plaintiffs alleged that the de-
fendant ANDA holders had not updated their labels to match
the FDA-approved warnings until 2009, long after those new
warnings were issued, id. at 730. This claim could proceed be-
cause federal law was no longer an obstacle: the FDA had al-
ready approved a proper label for the drug. By not acting, the
defendant ANDA holders had allegedly fallen below that es-
tablished standard. See id. at 742. At the same time, the Reglan
court also rejected the argument that the “defendant generic
manufacturers had a duty to provide warnings beyond those
No. 17-2056 23
that the FDA approved for the brand name.” Id. (emphasis
added). We agree with the Reglan analysis. The label ap-
proved by the FDA defines an ANDA holder’s duty of same-
ness and thus the lines of federal preemption as well.
Consider next what would happen if a drug-maker de-
cided to create a new generic drug by copying an existing
RLD product. Where would this new ANDA applicant obtain
the labeling it needs to submit to the FDA for comparison un-
der 28 U.S.C. § 355(j)? A bottle of the RLD at the nearest phar-
macy? No. The agency has made clear that the FDA itself is
the authoritative source of that information. Applicants must
facilitate the “side-by-side comparison of the applicant’s pro-
posed labeling with the approved labeling for the reference
listed drug,” which is made possible by the fact that the “cur-
rent approved labeling could be obtained under the Freedom
of Information Act” from FDA itself. ANDA Regulations, 57
Fed. Reg. at 17,960.10
D. Agreement with the Sixth Circuit in Darvocet
As a fallback position, plaintiffs contend that even if RLDs
with ANDAs approved after 1984’s Hatch-Waxman Act may
10 Approved drug labeling information is now available through a
regularly-updated FDA database. See Drug Safety Labeling Changes (SLC)
Quick Reference, U.S. Food & Drug Admin., https://www.fda.gov/Drugs/
DrugSafety/ucm518488.htm (last visited Jan. 18, 2018). Recent draft guid-
ance from the FDA says that applicants are responsible for “checking ap-
propriate sources in order to obtain the RLD labeling,” but the FDA also
suggests that an applicant may resort to the marketplace to find a substi-
tute for missing labeling only “for convenience initially.” FDA, Center for
Drug Evaluation and Research, Draft Guidance: Referencing Approved
Drug Products in ANDA Submissions 6 n.7 (January 2017). Thus, the FDA
itself is still the authoritative source for approved RLD labeling.
24 No. 17-2056
not take advantage of the changes-being-effected regulation,
the rule should be different for Depo-T because it was ap-
proved in 1979, before the current regime was put in place.
Plaintiffs argue that the intervening changes in statutes and
regulations in the 1980s and 1990s that created today’s ap-
proval process altered the status of pre-existing RLD ANDA
holders. See Appellants’ Br. at 33 n.6.
For the same reason, plaintiffs argue that we should part
company from the Sixth Circuit’s position on this preemption
issue. With respect to generic drugs approved under the cur-
rent regime, the Sixth Circuit concluded that “the status of an
ANDA holder’s product as the RLD for a given prescription
drug product does not alter the ANDA holder’s obligations”
or make available the CBE regulation to add a new warning
unilaterally. In re Darvocet, Darvon, & Propoxyphene Prods. Liab.
Litig., 756 F.3d 917, 923, 934 (6th Cir. 2014) (hereinafter Dar-
vocet); see also Morris v. PLIVA, Inc., 713 F.3d 774, 777–78 (5th
Cir. 2013) (per curiam) (similar observation). Darvocet found
preemption, and so did the district court here in applying
Darvocet. 142 F. Supp. 3d 747, 754 (N.D. Ill. 2015).
We agree with the Sixth Circuit and reject plaintiffs’ invi-
tation to draw a distinction where one is not clearly called for.
The FDA has noted that products approved prior to the 1984
Hatch-Waxman changes to federal drug laws are treated the
same as ANDA approvals that came after. See 21 C.F.R.
§ 314.94(b) (explaining that products stemming from Drug Ef-
ficacy Study Implementation approvals are subject to today’s
ANDA regulations). Depo-T falls under this provision. See
Appellants’ Br. at 7, 10. It thus makes no difference to the
preemption analysis that Depo-T was approved back in 1979.
No. 17-2056 25
E. Conclusion
In sum, the statutes, regulations, and FDA interpretations
that govern the labeling requirements for drugs approved
pursuant to an abbreviated new drug application (ANDA)
control the outcome of this case. Those authorities, and the
reading given to them by the Supreme Court in PLIVA, Inc. v.
Mensing, indicate that there is no meaningful difference for
preemption purposes between ANDA holders for reference
listed drugs and those for non-RLD drugs. There is also no
clear reason why the specific circumstances of the approval
history of this particular drug, Depo-T, should make the result
any different than in Mensing. Since unilateral changes to
Depo-T’s label were not possible, state-law claims alleging a
failure to take that action are preempted.
III. Plaintiffs’ Discovery Requests
Plaintiffs also appeal the district court’s denial of further
discovery into communications between the defendants and
the FDA about Depo-T. As a general rule, appellate courts
leave discovery to the sound discretion of the district court, so
we review this decision only for an abuse of discretion. Citi-
zens for Appropriate Rural Roads v. Foxx, 815 F.3d 1068, 1081 (7th
Cir. 2016). We find no abuse of discretion here.
Since “preemption is a legal question for determination by
courts,” see Watters v. Wachovia Bank, N.A., 550 U.S. 1, 20
(2007), discovery of facts may not be as vital to this inquiry as
it could be to others. If plaintiffs could show that the FDA had
issued an authoritative legal interpretation saying that the
CBE process is in fact available to the defendants to add or
strengthen a warning, that would defeat the preemption de-
fense here under the logic of Levine.
26 No. 17-2056
To support their request for discovery, plaintiffs offer two
batches of correspondence between the FDA and Upjohn in
the 1990s about the labeling for Depo-T. The first set of letters,
from April to July 1991, refers to Upjohn’s supplemental ap-
plication seeking to modify the labeling for Depo-T in light of
a change in federal law: the rules implementing the Anabolic
Steroids Control Act of 1990. See Supp. App. at 41–46; see also
Pub. L. No. 101-647, § 1901 et seq., 104 Stat. 4851 (1990); Sched-
ules of Controlled Substances; Anabolic Steroids, 56 Fed. Reg.
5753, 5754 (Feb. 13, 1991) (final rule promulgated by the Drug
Enforcement Administration requiring such labeling for tes-
tosterone by August 27, 1991). The second batch of letters,
stretching from 1994 to 1996, involves Upjohn’s attempts to
avoid confusion between the similar-looking cartons of Depo-
T and a contraceptive injection known as Depo-Provera. See
Supp. App. 52–67; Appellee App. 23 (a letter from the U.S.
Department of Health and Human Services requesting
Upjohn change its similar-looking drug cartons); see also 21
U.S.C. §§ 331(a), 331(b), 321(m), 352(a), and 352(f) (ANDA
holders’ duty to avoid misbranding and mislabeling their
products).
The most those letters show is that the CBE process might
have been used in the early 1990s to make Depo-T’s label con-
form with a change in federal law, and perhaps again to avoid
confusion at the request of a different federal agency. These
kinds of CBE changes are not relevant to our preemption anal-
ysis because they focus on using the regulation for reasons
other than adding additional warnings, the sole issue of con-
cern here. 11 In addition, though further discovery may reveal
11
This stands in contrast to the letter of another defendant in the un-
derlying MDL, Auxilium, that did engage the FDA on the issue of adding
No. 17-2056 27
more about the defendants’ view of the CBE regulation from
past decades, it would not be likely to uncover what the plain-
tiffs actually need: the FDA’s policy before Mensing was de-
cided in 2011 about whether ANDA holders like Upjohn
could have added warnings through the CBE process. The
plaintiffs already have available to them the process they
might need for that kind of discovery—the Freedom of Infor-
mation Act, 5 U.S.C. § 552 et seq. The district court did not
abuse its discretion by denying discovery on this point.
Conclusion
We AFFIRM the decisions of the district court challenged
in this appeal, apart from those vacated by the separate juris-
dictional order issued today.
warnings through the CBE process. See In re TRT, No. 14 C 1748, 2016 WL
861213, at *4 (N.D. Ill. Mar. 7, 2016); R. 1175 at 3-4. The resulting response
from the FDA, as described by the district court, further reinforces our
point above that “such changes require the agency’s advance approval”
and could not be made unilaterally by that ANDA holder through the CBE
process.