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In re Fosamax (Alendronate Sodium) Products Liability Litigation

United States Court of Appeals, Third Circuit

March 22, 2017

IN RE: FOSAMAX (ALENDRONATE SODIUM) PRODUCTS LIABILITY LITIGATION

          Argued June 30, 2016

         On Appeal from the United States District Court for the District of New Jersey (D.C. Nos. 3:08-cv-00008-FLW et al., MDL No. 2243) District Judge: Honorable Joel A. Pisano

          David C. Frederick, Esq. [Argued] Kellogg Hansen Todd Figel & Frederick Edward Braniff, Esq. Michael E. Pederson, Esq. Weitz & Luxenberg Donald A. Ecklund, Esq. Carella Byrne Cecchi Olstein Brody & Agnello Counsel for Appellant

          John H. Beisner, Esq. [Argued] Jessica D. Miller, Esq. Geoffrey M. Wyatt, Esq. Skadden Arps Slate Meagher & Flom Andrew T. Bayman, Esq. Chilton D. Varner, Esq. King & Spalding Karen A. Confoy, Esq. Fox Rothschild Wilfred P. Coronato, Esq. Hughes Hubbard & Reed David J. Heubeck, Esq. Stephen E. Marshall, Esq. Paul F. Strain, Esq. Venable Counsel for Appellee

          Todd N. Hutchison, Esq. Alfred W. Putnam, Jr., Esq. Carol F. Trevey, Esq. Drinker Biddle & Reath Counsel for Amicus Curiae Pharmaceutical Research and Manufacturers of America

          Before: FUENTES, CHAGARES, and RESTREPO, Circuit Judges

          OPINION

          FUENTES, Circuit Judge.

         Beginning in 2010, hundreds of plaintiffs filed personal-injury suits against the drug manufacturer Merck Sharp & Dohme, alleging that the osteoporosis drug Fosamax caused them to suffer serious thigh bone fractures. Each Plaintiff brought a state-law tort claim alleging that Merck failed to add an adequate warning of the risk of thigh fractures to Fosamax's FDA-approved drug label. Many Plaintiffs also brought a variety of additional claims including defective design, negligence, and breach of warranty.

         Plaintiffs' suits were consolidated for pretrial administration in a multi-district litigation in the District of New Jersey. Following discovery and a bellwether trial, the District Court granted Merck's motion for summary judgment and dismissed all of Plaintiffs' claims on the ground that they were preempted by federal law. The District Court based its ruling on the Supreme Court's decision in Wyeth v. Levine, [1]which holds that state-law failure-to-warn claims are preempted when there is "clear evidence" that the FDA would not have approved the warning that a plaintiff claims was necessary.

         We will vacate and remand. Preemption is an affirmative defense, and Merck has not carried its burden to prove that it is entitled to that defense as a matter of law. The Wyeth "clear evidence" standard is demanding and fact-sensitive. It requires the factfinder to predict a highly probable outcome in a counterfactual world and, therefore, requires a court sitting in summary judgment to anticipate both the range of conclusions that a reasonable juror might reach and the certainty with which the juror would reach them. Here, Plaintiffs have produced sufficient evidence for a reasonable jury to conclude that the FDA would have approved a properly-worded warning about the risk of thigh fractures-or at the very least, to conclude that the odds of FDA rejection were less than highly probable. Under Wyeth and Rule 56, that is enough for Plaintiffs to defeat summary judgment and proceed to trial.

         I. BACKGROUND

         A. Fosamax and Atypical Femoral Fractures

         Fosamax is a drug manufactured by Merck that belongs to a class of drugs known as bisphosphonates. The Food and Drug Administration ("FDA") approved Fosamax in the 1990s for the treatment and prevention of osteoporosis in postmenopausal women.

         Fosamax treats osteoporosis by correcting an imbalance in the so-called "bone remodeling" process. Throughout a person's life, bones are continuously broken down through a process called resorption and then reformed by the creation of new bone cells. In postmenopausal women, the rate of bone resorption exceeds that of bone formation, thereby causing bone loss. If bone loss continues unchecked, a person may develop osteoporosis, "a disease characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture."[2] Bisphosphonates like Fosamax slow the resorption process, restoring the balance between resorption and formation and reducing the risk of osteoporotic fracture.

         Plaintiffs claim, however, that Fosamax can actually increase the risk of certain bone fractures. They allege that by slowing resorption, bisphosphonates inhibit bone repair. According to Plaintiffs, bones frequently develop so-called "microcracks, " which are ordinarily repaired through the resorption process. An accumulation of microcracks can lead to incomplete bone fractures called "stress fractures." The standalone term "stress fracture" typically connotes a fracture resulting from excessive loading of a normal bone, and is commonly seen in physically active individuals. A so-called "insufficiency stress fracture, " by contrast, is a fracture caused by normal loading of poor-quality bone. Plaintiffs claim that while stress fractures typically heal on their own, "some Fosamax users who develop insufficiency fractures have reduced bone toughness, and Fosamax prevents the normal repair of the fracture."[3] According to Plaintiffs, these patients may then go on to develop what are known as "atypical femoral fractures": severe, non-traumatic, low-energy complete fractures of the femur.

         Plaintiffs in this case are all Fosamax users who suffered atypical femoral fractures. They allege, among other things, that (1) Fosamax caused these atypical fractures by slowing the resorption process and allowing microcracks to accumulate, and (2) Merck was aware of the risk of such fractures but acted unlawfully by failing to warn doctors and patients of those dangers. They claim that Merck should have included a warning about atypical femoral fractures in the federally-mandated drug warnings that accompany prescription drugs. The interplay, and potential collision, between state-law warning duties and federal regulatory requirements is the subject of this appeal.

         B. Regulatory Framework

         The Food, Drug, and Cosmetic Act ("FDCA")[4]regulates the marketing and sale of prescription drugs in the United States. Under the FDCA, a manufacturer must obtain approval from the United States Food and Drug Administration ("FDA") before marketing a new drug.[5] As part of a new drug application, the manufacturer must submit a proposed package insert, commonly called the "drug label, " that sets out the drug's medical uses ("indications") and health risks.[6] "To obtain FDA approval, drug companies generally must submit evidence from clinical trials and other testing that evaluate the drug's risks and benefits and demonstrate that it is safe and effective for all of the indications 'prescribed, recommended, or suggested' on the drug's label."[7] The FDA's approval of a new drug application is conditioned on its approval of the exact text of the drug label.[8]

         Drug labels includes two sections relevant to this litigation: a "Warnings and Precautions" section and an "Adverse Reactions" section. The Warnings and Precautions section must describe "clinically significant adverse reactions, " including any that are "serious even if infrequent."[9] The Adverse Reactions section requires a description of "the overall adverse reaction profile of the drug based on the entire safety database, " including a list of all "undesirable effect[s], reasonably associated with use of a drug."[10]

         After a drug is approved, the FDA retains the authority to approve or require amendments to the drug's label.[11] The fundamental premise of the federal drug labeling scheme, however, is that "manufacturers, not the FDA, bear primary responsibility for their drug labeling at all times."[12] The manufacturer is charged not only "with crafting an adequate label" as an initial matter, but also "with ensuring that its warnings remain adequate as long as the drug is on the market."[13] A manufacturer can fulfill its responsibility to revise the warnings on a drug label in two ways.

         First, the "Changes Being Effected" ("CBE") regulation permits a manufacturer to unilaterally change a drug label to reflect "newly acquired information, " subject to later FDA review and approval.[14] Under the CBE regulation, the manufacturer may, upon filing a supplemental application with the FDA, change a label to "add or strengthen a contraindication, warning, precaution, or adverse reaction"; it need not wait for FDA approval.[15] To add a warning to the Warnings and Precautions section through a CBE submission, "there need only be 'reasonable' evidence of a causal association with the drug, a standard that could be met by a wide range of evidence."[16] Thus, a manufacturer can amend the label to address potential adverse effects even if the evidence for a causal connection would "not also support a higher evidentiary standard, such as a finding that there is a 'preponderance' of evidence that a product actually causes a particular kind of adverse event."[17]

         For purposes of the CBE regulation, "newly acquired information" includes "new analyses of previously submitted data."[18] This definition "accounts for the fact that risk information accumulates over time and that the same data may take on a different meaning in light of subsequent developments."[19] Thus, if a manufacturer were to "determine[ ] that existing warnings were insufficient based on . . . a new analysis of previously submitted data, [it] could still submit a CBE based on its new analysis of the previous data."[20] A manufacturer's ability to change a label via the CBE process is not absolute, however. The FDA reviews CBE submissions and retains the power to reject proposed changes that do not meet the regulatory standards.[21]

         Second, manufacturers can implement "major changes" to a label by filing a so-called "Prior Approval Supplement" ("PAS").[22] Unlike a CBE change, a PAS change requires prior FDA approval before it can be implemented.[23] The key distinction for present purposes is that a proposed label change that qualifies for a CBE supplement-including a proposal to "add or strengthen a contraindication, warning, precaution, or adverse reaction"- need not be submitted through the PAS process and does not require prior FDA approval.[24]

         It is important to recognize, however, that the FDA does not simply approve warnings out of an abundance of caution whenever the manufacturer posits a theoretical association between drug use and an adverse event. As the FDA has recognized, "[e]xaggeration of risk, or inclusion of speculative or hypothetical risks, could discourage appropriate use of a beneficial drug."[25] Moreover, "labeling that includes theoretical hazards not well-grounded in scientific evidence can cause meaningful risk information to lose its significance."[26] Accordingly, the FDA will reject a PAS application or CBE amendment if there is insufficient evidence of a causal link between drug use and the adverse event.[27]

         C. Fosamax Labeling History

         Both Merck and the FDA have long been aware that anti-resorptive drugs like Fosamax could theoretically increase the risk of atypical femoral fractures. The question that both Merck and the FDA faced in the years following the drug's approval was whether the developing evidence of a causal link between Fosamax and atypical fractures was strong enough to require adding a warning to the Fosamax drug label. As explained further in Section II of this opinion, the primary question in this appeal is whether, prior to September 2010, the FDA would have rejected an attempt by Merck to unilaterally amend the Fosamax label (via a CBE submission) to include a warning about the risk of atypical femoral fractures. The following evidence bears on that question.

         i. Early Studies Suggest a Possible Link Between Fosamax and Atypical Femoral Fractures

         During Fosamax's development, Merck scientists and third-party researchers discussed the possibility that anti-resorptive drugs could inhibit a bone's ability to repair microdamage, potentially leading to stress fractures. In 1992, prior to FDA approval, Merck informed the FDA that "antiresorptive agents may inhibit microdamage repair by preventing . . . bone resorption at the sites of microdamage."[28]Nonetheless, when the FDA approved Fosamax in 1995 for the treatment of osteoporosis in postmenopausal women, it did not require Merck to include a warning about bone fractures. Nor did it do so in 1997, when it approved Fosamax for the prevention of osteoporosis in postmenopausal women.

         Between 1995 and 2010, scores of case studies, reports, and articles were published documenting possible connections between long-term bisphosphonate use and atypical femoral fractures. Plaintiffs have directed our attention to six such studies from this period. None of these studies, however, concluded that Fosamax caused bone fractures, or even that Fosamax use was definitively associated with atypical fractures. Rather, they variously stated that Fosamax use "may . . . potentially" increase the risk of fracture[29] or "may be associated" with insufficiency fractures, [30] or that certain findings "raise[d] the possibility" that Fosamax use led to fractures.[31] Merck's assertion that the link between Fosamax and fracturing "remained hypothetical and unsubstantiated"[32] may be an understatement, but not even Plaintiffs suggest that there was definitive proof of a causal connection at this time.

          Merck kept the FDA informed of these and other studies suggesting a possible association between bisphosphonates and fractures, either citing or submitting them in communications with the agency. In March 2008, Merck submitted a periodic safety update to the FDA that included over 30 pages of information regarding atypical femur fractures and suppression of bone turnover. Merck reported that "recent publications" had "implicated a link between prolonged bisphosphonate therapy and atypical low-energy non-vertebral fractures."[33] It also stated "the reporters related these findings to severely suppressed bone turnover that may develop during long-term" use of Fosamax.[34]Later that month, Merck forwarded to the FDA a letter published in the New England Journal of Medicine describing a "potential link between [bisphosphonate] use and low-energy fractures of the femur."[35]

         In June 2008, the FDA informed Merck that it was "aware of reports regarding the occurrence of subtrochanteric hip fractures in patients using bisphosphonates."[36] It also stated that it was "concerned about this developing safety signal."[37] The FDA asked Merck to submit any investigations it had conducted or reports it had received regarding femoral fractures. Merck promptly complied.

         ii. Merck Attempts to Amend the Fosamax Label

         In September 2008, while the FDA was analyzing Merck's data, Merck submitted a PAS to the FDA. As discussed above, a PAS is a label-change request that, unlike a CBE submission, requires prior approval from the FDA.[38]In the PAS, Merck proposed to add language to both the Warnings & Precautions and the Adverse Reactions sections of the label to address atypical femoral fractures. Merck explained that "[i]t is not possible with the present data to establish whether treatment with" Fosamax "increases the risk of [these] . . . low-energy subtrochanteric and/or proximal shaft fractures."[39] But because of the temporal association between these fractures and Fosamax use, Merck believed that it was "important to include an appropriate statement about them in the product label" to "increase physicians' awareness of possible fractures in some osteoporotic patients at risk and allow early intervention, thereby possibly preventing the progression to complete fracture and/or other complications."[40] Merck proposed adding the following language to the Warnings and Precautions section of the label:

         Low-Energy Femoral Shaft Fracture

Low-energy fractures of the subtrochanteric and proximal femoral shaft have been reported in a small number of bisphosphonate-treated patients. Some were stress fractures (also known as insufficiency fractures) occurring in the absence of trauma. Some patients experienced prodromal pain in the affected area, often associated with imaging features of stress fracture, weeks to months before a complete fracture occurred. The number of reports of this condition is very low, and stress fractures with similar clinical features also have occurred in patients not treated with bisphosphonates. Patients with suspected stress fractures should be evaluated, including evaluation for known causes and risk factors (e.g., vitamin D deficiency, malabsorption, glucocorticoid use, previous stress fracture, lower extremity arthritis or fracture, extreme or increased exercise, diabetes mellitus, chronic alcohol abuse), and receive appropriate orthopedic care. Interruption of bisphosphonate therapy in patients with stress fractures should be considered, pending evaluation of the patient, based on individual benefit/risk assessment.[41]

         Merck also proposed adding "low-energy femoral shaft fracture" to the list of reported adverse reactions in the Adverse Reactions section of the label, [42] as well as the following statement to the Patient Package Insert: "Patients have experienced fracture in a specific part of the thigh bone. Call your doctor if you develop new or unusual pain in the hip or thigh."[43] In support of its PAS application, Merck included an analysis of femur fractures in Fosamax users and cited to nine articles reporting cases of low-energy femoral fractures in Fosamax users.

         In April 2009, Merck representatives held a telephone conversation with Dr. Scott Monroe of the FDA. According to Merck's internal notes, Dr. Monroe stated that the FDA could agree to add language in the Adverse Reactions section of the label, but that Merck's "elevation of this issue to a precaution in the labeling" was prolonging review.[44] The FDA wanted "to approach the issue of a precaution from the [perspective] of all bisphosphonates" and was "working with the Office of Safety and Epidemiology to do so."[45] Dr. Monroe also stated that because "the conflicting nature of the literature does not provide a clear path forward, . . . more time will be need[ed] for FDA to formulate a formal opinion on the issue of a precaution around these data."[46]

         Later in April 2009, an FDA liaison sent Merck an email stating that the FDA was not prepared to include language about low-energy femoral fractures in the Warnings and Precautions section of the label and would only approve a reference to atypical fractures in the "Adverse Reaction" section.[47] The FDA asked Merck to "hold off on the [Warnings and Precautions] language at this time" so that drug evaluators could "then work with [the FDA's Office of Surveillance and Epidemiology] and Merck to decide on language for a [Warnings and Precautions] atypical fracture language, if it is warranted."[48]

         In May 2009, the FDA sent Merck a "Complete Response" letter, authored by Dr. Monroe. In the Complete Response, the FDA approved the addition of "low energy femoral shaft and subtrochanteric fractures" to the Adverse Reactions section, but the FDA rejected Merck's proposed addition to the Warnings and Precautions section. Because the parties vigorously dispute the grounds for this rejection, it is worth excerpting the relevant portion of the FDA notice in full:

We have completed the review of your [PAS] applications, as amended, and have determined that we cannot approve these applications in their present form. We have described below our reasons for this action and our recommendation to address this issue.
1. While the Division agrees that atypical and subtrochanteric fractures should be added to the ADVERSE REACTIONS, Post-Marketing Experience subsections of the [Fosamax] labels, your justification for the proposed PRECAUTIONS section language is inadequate. Identification of "stress fractures" may not be clearly related to the atypical subtrochanteric fractures that have been reported in the literature. Discussion of the risk factors for stress fractures is not warranted and is not adequately supported by the available literature and post-marketing adverse event reporting.[49]

         The outcome of this case hinges in large part on how one reads (or really, on how a reasonable jury could read) this language in conjunction with the FDA's accompanying actions and communications. Plaintiffs claim that the FDA was objecting only to Merck's use of the imprecise and potentially misleading term "stress fractures, " and that the FDA would have approved a proposed warning that specifically discussed the risk of atypical femoral fractures while eliminating the general references to stress fractures. Merck claims that this letter, along with the FDA's other communications, demonstrates that the FDA simply did not believe there was sufficient evidence of a causal link between Fosamax use and atypical fractures, and would have rejected any proposed warning relating to such a risk.

         iii. The FDA Revises its Position on the Link Between Bisphosphonates and Atypical Femur Fractures

         In March 2010, after reviewing the data submitted by Merck and other manufacturers, the FDA stated publicly that the data reviewed to date had "not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures."[50] The FDA announced that it would work with an outside expert task force to gather additional information.

         In September 2010, the task force published a report finding that "there is evidence of a relationship between long-term [bisphosphonate] use and a specific type of subtrochanteric and femoral shaft fracture."[51] The report stated that although there was an association between long-term bisphosphonate use and atypical fractures, the association had not been proven to be causal. The FDA responded by issuing a Drug Safety Communication stating that, "[a]lthough it is not clear if bisphosphonates are the cause [of fractures], these unusual femur fractures have been identified in patients taking these drugs."[52] Regarding the task force's recommendation of a label change, the FDA stated that it "has assembled and is thoroughly reviewing all long term data available on the products, as well as all safety reports" and would be "considering label revisions."[53]

         In October 2010, the FDA announced that it would require all bisphosphonate manufacturers to add information regarding the risk of atypical femoral fractures to the Warnings and Precautions section of the drug labels, based on the FDA's conclusion that "these atypical fractures may be related to long-term . . . bisphosphonate use."[54] It reiterated that it was still "not clear if bisphosphonates are the cause, " but noted that "these unusual femur fractures have been predominantly reported in patients taking bisphosphonates."[55]In a conference call accompanying the announcement, the FDA's Deputy Director of the Office of New Drugs stated that the task force report made the FDA "confident" that atypical femur fractures are "potentially more closely related to" long-term use of bisphosphonates "than [the FDA] previously had evidence for."[56]

         The same day, the FDA wrote to Merck requesting that Merck add the following language to the Warnings and Precautions section of the Fosamax label:

         Atypical Subtrochanteric and Diaphyseal Femoral Fractures:

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
Atypical femur fractures most commonly occur with minimal or no impact to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.
Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out a femur fracture. Subjects presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.[57]

         Merck responded by proposing additional language that, according to Merck, was intended to make clear that doctors should attempt to rule out stress fractures. The proposal contained five specific references to "stress fractures." The FDA responded to this proposal by eliminating every instance of the phrase "stress fractures." In rejecting Merck's proposal, the FDA explained that "the term 'stress fracture' was considered and not accepted. The Division believes that for most practitioners, the term 'stress fracture' represents a minor fracture and this would contradict the seriousness of the atypical femoral fractures associated with bisphosphonate use."[58] The FDA subsequently approved language nearly identical to its original October 2010 proposal. That language was added to the Fosamax label in January 2011 and has remained there since.

         D. Procedural History

         After the label change, patients who had taken Fosamax and suffered atypical femur fractures filed lawsuits against Merck throughout the country. In May 2011, the Judicial Panel on Multidistrict Litigation consolidated these cases for pre-trial administration in a multi-district litigation ("MDL") in the District of New Jersey.[59] Since then, the MDL has been assigned to three different district judges[60] and has swelled to over 1, 000 cases, each involving a separate patient who allegedly suffered a femur fracture after taking Fosamax.

         Although no two complaints in the MDL are identical, all of the actions "share questions of fact arising from similar allegations that use of Fosamax . . . caused femur fractures or similar bone injuries."[61] The individual Plaintiffs in this appeal all allege that they were injured before September 14, 2010, the date the outside expert task force published its report documenting an association between bisphosphonate use and atypical femur fractures. According to Plaintiffs, [62]the complaints filed by this cohort generally include a state-law products liability claim for failure to warn, alleging that Fosamax was defective because Merck failed to warn Plaintiffs and their physicians about the risk of atypical femur fractures. Many complaints also claim that Fosamax was defectively designed because the risks of Fosamax exceeded the benefits, or because Fosamax was unreasonably dangerous or more dangerous than an ordinary consumer would expect. Many complaints also include claims for, among other causes of action, negligence, negligent misrepresentation, breach of express and implied warranties, unjust enrichment, punitive damages, and violations of state consumer fraud and deceptive trade practice statutes.[63]

         Merck has argued since the inception of the MDL that Plaintiffs' state-law failure-to-warn claims are preempted by FDA regulations. The District Court decided to address preemption after developing a full record in a bellwether trial, the so-called Glynn trial. Typical of all plaintiffs in this MDL, the lead plaintiff in Glynn claimed that she suffered an atypical femur fracture that was proximately caused by Merck's failure to include adequate fracture warnings on the Fosamax label.[64] Merck moved for judgment as a matter of law on preemption grounds before and during trial, but the District Court reserved judgment.[65] The jury returned a verdict for Merck on the merits, finding that Ms. Glynn failed to prove by a preponderance of the evidence that she experienced an atypical femur fracture.[66] Despite this verdict, the District Court announced that it would still decide whether the Glynns' claims were preempted.[67]

         In June 2013, the District Court issued an opinion concluding that the Glynns' failure-to-warn claim was preempted by federal law. Applying the Supreme Court's decision in Wyeth, the court stated that state-law failure-to-warn claims are preempted when "there is 'clear evidence that the FDA would not have approved a change' to the prescription drug's label."[68] The District Court concluded that the Glynns' claim was preempted because the FDA's May 2009 denial of Merck's request to add language about atypical femur fractures to the Warnings and Precautions section of the label was "clear evidence that the FDA would not have approved a label change to the Precautions section of the label prior to Ms. Glynn's injury."[69]

         Shortly after the Glynn decision, Merck moved for an order to show cause why all the cases in the MDL alleging injuries prior to the release of the September 2010 task force report should not be dismissed on preemption grounds. Plaintiffs opposed the motion on the ground that resolving their claims through a show-cause procedure would violate their due process right to individual trials. In August 2013, the District Court issued an Order to Show Cause why the pre-September 2010 claims should not be dismissed on preemption grounds, and the parties submitted briefing. Although both sides disputed the propriety of the show-cause procedure and the substance of Merck's preemption arguments, the parties and the District Court all agreed that Federal Rule of Civil Procedure 56 "provides the exclusive mechanism by which the Court can resolve the dispositive issues presented by Merck's preemption defense before trial(s)."[70]

         After briefing, the District Court granted summary judgment to Merck and ruled that all claims made by plaintiffs who were injured prior to September 14, 2010 were preempted under Wyeth. Specifically, the court ruled that: (1) Merck had met its initial burden of demonstrating that there was no genuine issue of material fact as to preemption in Glynn, and that Plaintiffs therefore bore the burden of producing a genuine issue for trial; (2) Plaintiffs had failed to create a genuine issue as to preemption; (3) it was proper to use a show-cause proceeding to apply the Glynn preemption ruling to other MDL cases; (4) Plaintiffs' design-defect and other non-warning claims were also preempted because they sounded in failure to warn; and (5) Plaintiffs' alternate theories that Merck should have added information about fractures to the Adverse Reactions section of the label prior to 2009 and should have warned that Fosamax's long-term benefits were limited should be dismissed.

         With respect to the failure-to-warn claims, the District Court reiterated its conclusion from Glynn that "the fact that the FDA never required [Merck] to submit new language or change the label demonstrates that the FDA did not think that the label should have been changed at that time."[71] This evidence "remain[ed] unchanged" and provided "clear evidence that the FDA would have rejected a stronger Precautions warning because the FDA did reject a stronger Precautions warning."[72] As to the non-failure-to-warn claims (including claims for design defect, negligence, fraud, breach of warranty, deceptive trade practice, and unjust enrichment), the District Court concluded that that these claims "are based entirely on the premise that Fosamax had risks which should have been disclosed to consumers" and therefore "ultimately hinge[ ] on the adequacy of Fosamax's warning."[73] Because these claims "rise and fall with a claim for failure to warn, " they too were preempted.[74] This appeal followed.[75]

          II. LEGAL BACKGROUND

         The primary issue in this case is whether Plaintiffs' state-law failure-to-warn claims are preempted by federal law under the Supreme Court's decision in Wyeth. This is not a straightforward determination. Wyeth says only that a claim is preempted when there is "clear evidence" that the FDA would not have approved a label change. This standard is cryptic and open-ended, and lower courts have struggled to make it readily administrable. This appeal, however, requires us to do so. To assess whether Merck is entitled to summary judgment on its affirmative preemption defense, we must answer two questions: What is "clear evidence"? And who should determine whether clear evidence exists?

          For the following reasons, we conclude that (1) the term "clear evidence" refers solely to the applicable standard of proof, and (2) the ultimate question of whether the FDA would have rejected a label change is a question of fact for the jury rather than for the court. By describing the ultimate question as one of fact for the jury, we do not mean to suggest that summary judgment is categorically unavailable to a manufacturer asserting a preemption defense. When there is no genuine issue of material fact-that is, when no reasonable jury applying the clear-evidence standard of proof could conclude that the FDA would have approved a label change- the manufacturer will be entitled to judgment as a matter of law. We simply hold that, at the summary judgment stage, the court cannot decide for itself whether the FDA would have rejected a change, but must instead ask whether a reasonable jury could find that the FDA would have approved the change.

         A. Federal Preemption Doctrine: Impossibility Preemption and the Supreme Court's Decision in Wyeth v. Levine i. Impossibility Preemption

         The Supremacy Clause establishes that federal law "shall be the supreme Law of the Land."[76] The Supremacy Clause, therefore, preempts "state laws that 'interfere with, or are contrary to, ' federal law."[77] There are several varieties of preemption; the one at issue here is called "conflict" or "impossibility" preemption. Impossibility preemption applies, and state law must give way, when "it is 'impossible for a private party to comply with both state and federal requirements.'"[78] "The question for 'impossibility' is whether the private party could independently do under federal law what state law requires of it."[79]

         In this case, Plaintiffs claim that state law obligated Merck to add a warning about atypical femur fractures to the Fosamax label. At issue is whether federal law-here, FDA regulations-prevented Merck from adding the type of warnings that Plaintiffs claim were required under state law. The Supreme Court confronted a similar question in Wyeth, and its opinion governs our analysis here.

         ii. The Wyeth Decision

         In Wyeth, the Supreme Court addressed whether and to what extent state-law failure-to-warn claims are preempted by the FDCA and federal drug-labeling regulations. The Court held that failure-to-warn claims against drug manufacturers generally are not preempted by FDA approval of the drug's warning label. But such a claim is preempted by federal law when there is "clear evidence" that the FDA would not have approved the warning that a plaintiff claims was necessary.

         The plaintiff in Wyeth developed gangrene when a physician's assistant injected her with the antinausea drug Phenergan. She brought a state-law failure-to-warn claim against Wyeth, the manufacturer of Phenergan, for failing to provide an adequate warning about the risks involved with various methods of administering the drug. A jury concluded that the plaintiff's injury was caused by Wyeth's inadequate warning label. Wyeth argued on appeal that the state-law failure-to-warn claims were preempted because it was impossible to comply with both state-law warning duties and federal labeling obligations.[80]

         The Supreme Court rejected Wyeth's argument. It began by citing the "central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times."[81] Under this rule, a manufacturer "is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market."[82] Thus, when the risks of a particular drug use become apparent, the manufacturer has "a duty to provide a warning that adequately describe[s] that risk."[83]

         In response to Wyeth's contention that federal law made it impossible to add the warnings the plaintiff claimed were necessary, the Court observed that drug manufacturers are allowed to strengthen an FDA-approved warning label without FDA approval through the CBE process.[84] Wyeth therefore could not establish impossibility preemption because the CBE regulation "permitted [Wyeth] to provide . . . a warning [of the risk of gangrene] before receiving the FDA's approval."[85]

         The Supreme Court cautioned, however, that the mere availability of a CBE label amendment would not always defeat a manufacturer's preemption defense, because the FDA "retains authority to reject labeling changes."[86] Thus, where there is "clear evidence that the FDA would not have approved a change" to the label, federal law preempts state-law claims premised on the manufacturer's failure to make that change.[87] Impossibility preemption applies in that instance because the manufacturer would be legally prevented by the FDA from taking the very action that state law ostensibly requires.[88]

         The manufacturer in Wyeth could not take advantage of the clear-evidence exception because it had "offered no such evidence" that the FDA would have rejected the warning sought by the plaintiff.[89] But the Supreme Court made it clear that if a manufacturer does present "clear evidence" that the FDA would reject a plaintiff's proposed warning, it would have a complete preemption defense to any state-law failure-to-warn claims.

         In this case, Merck claims that the FDA's 2009 rejection of its proposed label amendment is just such "clear evidence."

         B. Defining "Clear Evidence"

         Courts applying the Wyeth preemption rule confront an immediate question: what is "clear evidence that the FDA would not have approved a change"? The Wyeth Court did not define the "clear evidence" standard or explain how courts should apply it. The only guidance the Court offered was to call impossibility preemption a "demanding defense."[90] In the absence of explicit direction or a coherent doctrinal framework, lower courts have been understandably reluctant to articulate firm definitions of the standard or its requirements. For example, several of our sister circuits have decided preemption cases by simply treating the facts of Wyeth as a yardstick: if the evidence for FDA rejection in a given case is less compelling than the manufacturer's evidence in Wyeth, the thinking goes, then there is clear evidence that the FDA would not have approved a label change and the manufacturer's preemption defense fails.[91]Many district courts have adopted a similar, if more complex, approach of exhaustively surveying the post-Wyeth case law and then testing the facts of a particular case against prior decisions.[92] Both approaches produce valid outcomes in individual cases, but neither clarifies or builds out the doctrine. The result is an anomaly in our preemption jurisprudence: the number of cases applying the clear evidence standard continues to grow, yet "the clear evidence standard remains undefined."[93]

         Today, we hold that the Supreme Court intended to announce a standard of proof when it used the term "clear evidence" in Wyeth.

         The Wyeth Court articulated the "clear evidence" exception as follows: "[A]bsent clear evidence that the FDA would not have approved a change to Phenergan's label, we will not conclude that it was impossible for Wyeth to comply with both federal and state requirements."[94] This formula has three components: (1) a legal rule that defines the circumstances in which a manufacturer is absolved of state-law liability (it must be impossible for the manufacturer to comply with both federal and state requirements); (2) a factual showing that satisfies the legal rule (the FDA would not have approved the proposed label change); and (3) a standard of proof that specifies how convincing the factual showing must be (the manufacturer must show that the FDA would not have approved the proposed label change by "clear evidence"). The term "clear evidence" therefore does not refer directly to the type of facts that a manufacturer must show, or to the circumstances in which preemption will be appropriate. Rather, it specifies how difficult it will be for the manufacturer to convince the factfinder that the FDA would have rejected a proposed label change. The manufacturer must prove that the FDA would have rejected a warning not simply by a preponderance of the evidence, as in most civil cases, but by "clear evidence."

         Our conclusion that the Wyeth Court intended the term "clear evidence" to denote a standard of proof is supported by the Supreme Court's prior usage of the term. For example, the Court has consistently held that a complainant alleging official government misconduct must present "clear evidence" of unlawful behavior.[95] "Clear evidence" in this context is understood to be a standard of proof, rather than a condition on the type of facts that must be proven.[96] Similar examples are found in the bankruptcy and patent settings.[97]

         Nor must we look far to discern the meaning of "clear evidence, " as Supreme Court usage confirms that the term is synonymous with "clear and convincing evidence."[98] The latter is a well-recognized intermediate standard of proof- more demanding than preponderance of the evidence, but less demanding than proof beyond a reasonable doubt. Black's Law Dictionary defines clear and convincing evidence as "evidence indicating that the thing to be proved is highly probable or reasonably certain."[99] We adopt that definition here. It is consistent with both settled understanding and Wyeth's instruction that the clear-evidence test is a "demanding defense" meant to represent a longstanding "presumption against pre-emption."[100]

         We therefore conclude that for a defendant to establish a preemption defense under Wyeth, the factfinder must conclude that it is highly probable that the FDA would not have approved a change to the drug's label.

         C. Whether the FDA Would Have Rejected a Label Change is a Question of Fact for the Jury

         Once "clear evidence" is understood as a standard of proof rather than a condition on the type of facts to be proven, the Wyeth test narrows to a single inquiry: would the FDA have approved the label change that Plaintiffs argue was required?

         Oral argument in this case revealed a fundamental yet unexplored disagreement between the parties. Merck claimed that the Wyeth preemption test presents a pure question of law that must be decided by a court, not a jury. Plaintiffs argued that Wyeth preemption poses a mixed question of fact and law that may require jury factfinding in appropriate circumstances. The distinction is crucial in this case because it dictates the course of our summary judgment analysis. If the question of whether the FDA would have rejected Plaintiffs' proposed warning is a question of law for the court, then we may simply answer it ourselves; but if it is a question of fact for the jury, then we must instead attempt to anticipate the range of answers that could be given by reasonable jurors applying the clear evidence standard and then determine whether summary judgment is appropriate. Having reviewed the case law and the parties' supplemental briefing on the issue, we conclude that the question of whether the FDA would have rejected a proposed label change is a question of fact that must be answered by a jury.[101] The court's role at the summary judgment stage is therefore limited to determining whether there are genuine issues of material fact that preclude judgment as a matter of law.

         i. Conflict Preemption Can Require Fact Determinations by a Jury

         Merck makes two general, threshold arguments in favor of treating Wyeth preemption as a purely legal question to be answered by the court.

         First, Merck notes that the vast majority of courts applying Wyeth have assumed, either explicitly or implicitly, that Wyeth preemption presents a question of law. This observation is only somewhat accurate and wholly unpersuasive.

         Wyeth does not indicate whether the "clear evidence" test poses a legal or factual question. Nor is it possible to divine a clear answer from the Supreme Court's application of the test in Wyeth itself.[102] However, the Supreme Court did decide that the evidence presented in Wyeth was not sufficient to pass the clear evidence test. Therefore, in light of the Court's definitive holding that the evidence in Wyeth did not pass muster, the many federal courts that have applied the Wyeth preemption test have simply compared the evidence presented in their cases to the evidence presented in Wyeth. For example, in Mason v. Smithkline Beecham Corp., the Seventh Circuit walked through the record evidence and concluded that, "in light of the extensive showing required by [Wyeth], " the manufacturer "did not meet its burden of demonstrating by clear evidence that the FDA would have rejected a label change."[103] The Ninth Circuit took a similar approach in Gaeta v. Perrigo Pharmaceuticals Co., and explicitly stated that since "the only guidance this court has is that the evidence presented in [Wyeth] was insufficient to meet the clear evidence standard, " the manufacturer would not meet the clear evidence standard if the "evidence in this case [is] less compelling than [that] in [Wyeth]."[104] Many other circuits have followed this approach and have found no preemption because the evidence in those cases fell short of the record in Wyeth.[105]

         It is possible to characterize this approach as a tacit acknowledgment that the "clear evidence" test is a legal question to be answered directly by the court. Mason, for example, was an appeal of a grant of summary judgment, but the court did not engage in a Rule 56 disputed-facts analysis or consider whether a reasonable jury could reach a contrary conclusion. At the same time the court also did not explain why the Wyeth test should be resolved by the court in the first instance. We do not lightly discount the wisdom of our sister circuits and the district courts that have grappled with these issues. But there is a difference between rejecting another court's considered judgment, on the one hand, and taking up an issue that has not been thoroughly analyzed, on the other. Furthermore, the approach taken by our sister circuits would be entirely consistent with our decision that the "clear evidence" test is a fact question that is ultimately for a jury to decide. After all, by comparing the evidence presented in these cases with the evidence presented in Wyeth, these circuits are in fact engaging in a summary judgment analysis, even if they do not name it.

         Second, Merck asserts that conflict preemption always presents a pure question of law. To be sure, we have made numerous offhand statements that seem to support Merck's position.[106] And as Merck points out, several district courts relying on similar language have concluded, albeit without substantial analysis, that a manufacturer's entitlement to the Wyeth preemption defense is a question of law for the court rather than the jury.[107]

         The "rule" Merck cites, however, is one of thumb rather than law. It is true that most preemption cases present purely legal questions-for example, whether Congress intended to preempt state law, how to interpret the scope of an express preemption provision, or whether two regulatory schemes are facially incompatible. But it is equally clear that preemption can be, and sometimes must be, a fact question for the jury.

         The Supreme Court's opinion in Boyle v. United Technologies Corp.[108] illustrates the distinction. In Boyle, as in Wyeth, the Supreme Court defined the scope of conflict preemption in a particular setting and announced the factual showing that a defendant must make to prove the affirmative preemption defense. Specifically, the Court held that "[l]iability for design defects in military equipment cannot be imposed, pursuant to state law, when (1) the United States approved reasonably precise specifications; (2) the equipment conformed to those specifications; and (3) the supplier warned the United States about the dangers in the use of the equipment that were known to the supplier but not to the United States."[109] The Court clarified that "whether the facts establish the conditions for the defense is a question for the jury."[110] The proper question on summary judgment, therefore, was whether a "reasonable jury could, under the properly formulated defense, have found for the petitioner on the facts presented."[111] It would be error, the Court said, for a court to "assess[ ] on its own whether the defense had been established."[112]

         While our court has not gone so far as to declare that any one species of preemption defense categorically requires jury factfinding, we have acknowledged that the availability of the defense can turn on questions of fact. In MD Mall Associates, LLC v. CSX Transportation, Inc., [113] we determined that the question of whether state-law storm water trespass claims conflicted with federal railroad-safety regulations had to be addressed "under the circumstances of this particular case."[114] We therefore held that whether the defendant railroad could reasonably comply with federal drainage requirements while also complying with Pennsylvania law regarding storm water trespass "is a question of fact."[115] Having so concluded, we remanded for further development of the factual record.

         Boyle and MD Mall confirm that the availability of a conflict preemption defense is not automatically a question of law that must be kept from the jury. The question, therefore, is whether there are independent jurisprudential or practical reasons to conclude that Wyeth preemption, specifically, requires a legal or a factual determination.

         ii. Whether the FDA Would Have Approved a Label Change is a Factual Question Appropriate for the Jury

         There are no general, hard-and-fast rules that we can use to distinguish fact questions from legal ones.[116] The Supreme Court has candidly acknowledged that "the appropriate methodology for distinguishing questions of fact from questions of law has been, to say the least, elusive."[117]In the absence of a governing principle, we look to the fact/law distinctions drawn by our court in similar cases, practical considerations regarding the allocation of decision-making authority between judge and jury, and the text of Wyeth itself. What we discern from these sources is that the question at the heart of the Wyeth test-would the FDA have approved the label change plaintiffs argue was required?-is little different from the type of fact questions that are routinely given to a jury.

         At root, Wyeth requires the decisionmaker to use an existing fact record to predict the outcome of a hypothetical scenario. The question posed to the decisionmaker in this case is: based on the contemporaneous medical literature and the interactions between Merck and the FDA that actually did happen, what would have happened if Merck had proposed the warning plaintiffs say was required? We think this question is one of fact, for three reasons.

         First, we have recognized that an assessment of the probability of a future event should generally be categorized as a finding of fact, even if that finding automatically generates a legal consequence. In Kaplun v. Attorney General of the United States, [118] we held that a determination of the probability of future torture was a fact question subject to clear-error review. In so doing, we observed in general terms that "[a] present probability of a future event is something distinct from its legal effect that is made up of facts and actually exists but is not a tangible thing, or actual occurrence."[119] Even though the future event has not occurred, and even if the prediction as to that event's likelihood is dispositive of a legal issue, "the likelihood itself remains a factual finding that can be made ex ante the actual outcome."[120] The Kaplun panel cited a number of other non-immigration cases in which we or other circuits have held that inferences drawn from historical facts concerning the ...


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