Rodney Guilbeau v. Pfizer Inc.
Opinion
In
Wyeth v. Levine,
the Supreme Court held that claims against a manufacturer of a brand-namé prescription drug for failure to warn adequately of the drug’s dangers were not preempted by federal law.
This appeal arises from the district court presiding over thousands of related claims against manufacturers of testosterone 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 precise legal and regulatory, context underlying those terms, focusing 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, manufacturers have found a new márket for these drugs to counteract the effects of declining testosterone production in older men. Older men experience a higher incidence of heart attacks, strokes, and other cardiovascular events than younger ones. Numerous lawsuits have been filed against testosterone drug manufacturers alleging that the drugs increase these health risks. One theory in such cases is that the drug
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manufacturers have failed to warn doctors and patients adequately about the risks, a tort theory arising under state product-liability 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
The district court granted a motion to dismiss brought by the manufacturers of one testosterone replacement drug, DepoT, 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.,
Part I explains the regulatory approval process for prescription drugs and the particular historical context and procedural background needed to understand the issues in this appeal. Part II analyzes the defendant drug-makers’ preemption defense. Part III reviews the district court’s decision to deny further discovery on the preemption defense. 1
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.
If the prospective drug is “the same as” an existing drug already on the market, however, the maker can obtain approval through thé 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 predecessor drug that the FDA has already approved.
Id.;
NDA-approved drugs are often referred to as “brand-name” drugs and ANDA-ap-proved drugs as “generic” drugs. These colloquial terms are not quite precise enough for our purposes in this case,
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though. The 1984 Hatch-Waxman Act established the current drug approval processes and the associated patent protection for truly new drugs. Drug Price Competition and Patent Term Restoration (Hatch-Waxman) Act of 1984, Pub. L. 98-417,
The approval process is central to both the preemption issue 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 label 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 prevent the drug-maker from complying with a state statute or court decision requiring more cautious warnings than appear on the FDA-approved label.
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 information” 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, precaution, 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 available only if the drug in question was approved through the NDA process, but not if it was approved via the ANDA process because ANDA-approved “generic” drugs may change their labels only with the FDA’s approval or at the FDA’s request. See
Mensing,
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 and Demahy taken Re-glan, the brand-name drug pre-scribed by their doctors, Wyeth would control and their lawsuits would not be pre *309 empted. But because pharmacists, acting in full accord with state law, substituted generic metoclopramide instead, federal law pre-empts these lawsuits.
B. FDA Approval of Depo-Testoster-one
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 produce 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 abbreviated new drug application (ANDA) for Depo-Testosterone, a testosterone injection similar to Delatestryl. Depo-T, as the product is still called, produced safety and effectiveness results equivalent to those of Delatestryl. Under the drug approval process at the time, similar results sufficed for streamlined ANDA approval. But because of a slight difference in its physical composition that made it not quite the same as Delatestryl, 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 seeking to follow in Depo-T’s footsteps had to demonstrate bioequivalence to (i.e., that they were the same as) Depo-T to qualify for the streamlined approval process of an abbreviated new drug application. See above at 4; see also -
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 testosterone 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 proceedings under the title
In re Testosterone Replacement Therapy Products Liability Litigation.
See
This appeal is limited to just one issue about one drug: whether failure-to-warn *310 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, shpuld 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 motion to dismiss all such claims, which covered claims against Depo-T.
II. Preemption
A. Generic Drug Labeling and Preemption at the Supreme Court
The district court granted a Rule 12(b)(6) motion to dismiss on preemption grounds, a legal determination that we review
de novo. Toney v. L’Oreal USA, Inc.,
As summarized above, a series of recent Supreme Court decisions on federal preemption in failure-to-warn cases involving prescription drugs has narrowed our task.
In Wyeth v. Levine,
In
PLIVA, Inc. v.
Mensing, the Supreme Court narrowed the holding of
Levine,
limiting it to brand-name drugs approved through NDAs.
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.
Abbreviated New Drug Application Regulations,
Warnings could not have been added without FDA approval in
Mensing
because ANDA holders “have an ongoing federal duty of ‘sameness.’ ”
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
Mens-ing,
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
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NDA), and because Depo-T itself is the RLD, plaintiffs believe that “Pfizer’s obligation is to maintain 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.”
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.”
C. Availability of the Changes-Being-Effected Regulation
1. Summary
Wé disagree with the plaintiffs’ efforts to avoid applying Mensing to Depo-T. We reach this conclusion for two principal 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. Second, 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 approved 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 history.
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.
Mensing,
First, despite potentially confusing references to brand-name and generic drugs—recall that the relevant FDA terms are NDA-approved and ANDA-approved,
respectively—Mensing
itself unambiguously refers to the lines drawn in the drug approval process as determining access to the CBE regulation.
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 regulations that apply to brand-name drug manufacturers are meaningfully different than those that
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apply to generic drug manufacturers,”
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
Mensing
Court, see
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 submitted. For initial approval, a maker of an ANDA-approved drug must show that its labeling will be “the same as the labeling approved for the listed drug.”
The ANDA regulations cited in
Mensing
further reinforce this conclusion that approval-process status and RLD status are separate. See
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 regulations, and the Mensing opinion do not draw the distinction plaintiffs advocate: a difference in abilities and responsibilities between RLD ANDA holders and other ANDA holders.
Second, the FDA has already interpreted
Mensing
as prohibiting any ANDA hblder, 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,
The FDA’s’ discussion of the issue did not signal any difference in abilities or responsibilities between RLD and non-RLD ANDA holders. In fact, this proposed change would further 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 approved ANDAs.”
This proposed rule change from 2013 thus indicates several things. The FDA believes its current rules apply equally to all ANDAs, whether they are RLDs or hot. The FDA considered 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 holders and ANDA holders,” indicating that these CBE changes would have effect only prospectively and not retroactively.
Plaintiffs are asking us in effect to recognize a third category 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 “passionate responses.”
Mutual Pharmaceutical Co. v. Bartlett,
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 ANDAs 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. .
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 Industry: Revising ANDA Labeling Following Revision of the 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 currently using but rather to the labeling the FDA has' already approved for the drug, whether the approval happened recently 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 *316 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 process to add a new warning.
(.Levine
explains why this is possible.
But just token 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,
Consider next what would happen if .a drug-maker decided 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 under 28 U.S.C. §. 355(j)? A bottle of the RLD at
*317
the nearest pharmacy? 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 proposed labeling with the approved labeling for the reference listed drug,” which is made possible by the fact that the “current approved labeling could be obtained under the Freedom of Information Act” from FDA itself. ANDA Regulations,
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 not take advantage of the changes-being-effected regulation, the rule should be different for Depo-T because it was approved 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 approval process altered the status of preexisting 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
current
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. Li-tig.,
We agree with the Sixth Circuit and reject plaintiffs’ invitation 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
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 pre *318 emption 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.
Citizens for Appropriate Rural Roads v. Foxx,
, Since “preemption is a legal question for determination by courts,” see
Watters v. Wachovia Bank, N.A.,
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 application 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.,
The most those letters show is that the CBE process'might have been used in the early 1990s to make .Depo-T’s label conform 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 analysis because they focus on using the regulation for reasons other than adding additional warnings, the sole issue of concern here.
11
In addition, though further discovery may reveal more about the
defendants’
view of
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the CBE regulation from past decades, it would not be likely to uncover what the plaintiffs actually need: the FDA’s policy before
Mensing
was decided 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 Information Act,
Conclusion
We AFFIRM the decisions of the district court challenged in this appeal, apart from those vacated by the separate jurisdictional order issued today.
. This single appeal covers more than one thousand individual cases before the MDL transferee court. On appeal, it has become clear that complete 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 forty cases must be remanded to the district court to resolve the jurisdictional problems.
. For further background on the drug approval process, see FDA, Center for Drug Evaluation and Research; Détermining Whether To Submit an ANDA or a 505(b)(2) Application: Guidance for Industry (Draft Guidance) 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-Wax-man).
. 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 applications (ANDAs) as "generic” drugs. When one reads
Mensing
together with the cited regulations, see
. 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.
. The parties dispute the significance of a recent change to these regulations. See Abbreviated New Drug Applications and 505(b)(2) Applications,
.In 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 hy 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,
. This proposed rule change has not received final approval. Compare
. There is a slight difference between the terms "reference listed drug” and "reference standard,” see
. , The duty of sameness applies throughout the life of the ANDA-approved drug since the definition of an ANDA includes "all amendments and supplements to the application.”
. 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/Drug Safety/ucm518488.htm (last visited Jan. 18, 2018). Recent draft guidance from the FDA says that applicants are responsible for “checking appropriate sources in order to obtain the RLD labeling,” but the FDA also suggests that an applicant may resort to the marketplace to 'find a substitute 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.
. This stands in contrast to the letter of another defendant in the underlying MDL, Auxilium, that did engage the, FDA on the issue of adding warnings through the CBE process. See
In re TRT,
No.
Reference
- Full Case Name
- Rodney GUILBEAU, Et Al., Plaintiffs-Appellants, v. PFIZER INC. and Pharmacia & Upjohn Company LLC, Defendants-Appellees
- Cited By
- 13 cases
- Status
- Published