The case before the Fifth Circuit addresses whether federal regulations concerning pharmaceuticals preempt state law failure-to-warn claims against generic drug manufacturers. Julie Demahy, who developed tardive dyskinesia allegedly from long-term use of the generic drug metoclopramide, filed personal injury claims against Actavis under the Louisiana Products Liability Act. Demahy contends that Actavis failed to adequately warn about the risks associated with prolonged use and did not seek necessary label revisions from the FDA, despite existing medical literature indicating increased risk.
Actavis moved to dismiss the claims, asserting that state law duties conflict with federal law, which would result in preemption. The district court denied this motion specifically for the failure-to-warn claims. The court noted that, following the Supreme Court's decision in Wyeth v. Levine, which determined that similar claims against name brand manufacturers are not preempted, it seems federal regulations also do not preempt such claims against generics.
The FDA approved Reglan in 1980, and Actavis began manufacturing its generic version thereafter. The label was updated in 1985 to include warnings about tardive dyskinesia risk, with Actavis aligning its label with that of Reglan. In February 2009, the FDA issued a new warning regarding long-term use. The case notes a split in lower courts on this issue, with one circuit ruling against preemption, and highlights a prior case, Colacicco v. Apotex, which found preemption but was later vacated following the Levine ruling. The FDA's approval process for new drugs requires extensive safety and efficacy documentation through a new drug application (NDA), as established by the 1962 FDCA.
New drug approval necessitates successful clinical trial results and accurate labeling reflecting the drug's benefits and risks. The FDA conducts a thorough review of proposed labeling before approving a New Drug Application (NDA) and will reject any labeling that is deemed false or misleading. In contrast, generic drug approvals follow a less stringent process due to the Hatch-Waxman Amendments of 1984, which allow a drug company to apply for a generic version of a drug through an Abbreviated New Drug Application (ANDA) after the pioneer drug's patent expires. ANDA drugs must match the brand drug in active ingredients, administration route, dosage form, strength, and labeling conditions but do not require repeating clinical trials; instead, they must demonstrate bioequivalence to the brand drug. This process fosters competition and innovation while saving consumers an estimated $8 billion to $10 billion annually, with generics making up 70% of prescriptions in the U.S. Generic manufacturers must confirm that their proposed labeling matches that of the reference drug, and failure to do so results in application denial. The Supreme Court's decision in Levine clarified that federal regulation does not preempt state-law failure-to-warn claims against brand drug manufacturers, emphasizing that brand manufacturers can unilaterally change their labeling through the "changes being effected" (CBE) process, unlike generic manufacturers, who must adhere to the original label. The Court acknowledged that once risks are identified, manufacturers can warn consumers under state law before FDA approval of label changes is obtained.
The FDA has the authority to reject labeling changes under the CBE regulation, but the Court did not find it impossible for manufacturers to comply with both federal and state laws without clear evidence of FDA disapproval for a warning change. Justice Breyer highlighted that the case did not address the preemptive effect of specific agency regulations and emphasized the FDA's role in determining how state tort law interacts with federal regulations intended to ensure safe drug-related medical care. The majority agreed that state law was not preempted in Levine, which has implications for Actavis's situation.
In preemption cases, the intent of Congress is crucial, which can be expressed in statutory language or implied through federal law's structure. Implied preemption can be field or conflict preemption. Field preemption occurs when federal law is comprehensive enough to leave no room for state law, while conflict preemption arises when state law directly contradicts federal law. Actavis argues that Louisiana state law imposes a heightened warning label requirement that conflicts with federal regulations governing generic drugs, creating an impossible compliance scenario.
The Court must assume that state police powers are not intended to be superseded by federal law unless Congress clearly expresses that intent. This presumption, which acknowledges states as independent sovereigns, influences how courts approach preemption, particularly in health and safety matters. A higher bar for finding preemption exists here because federal law does not remedy consumer injuries, and preempting state failure-to-warn claims would eliminate traditionally available remedies. Courts are generally cautious in finding preemption in health-related cases without clear congressional intent, especially since Congress has previously preempted state claims for some FDA-regulated products but chose not to do so for others, further arguing against preemption in this instance.
In Levine, the Court noted that Congress's express preemption for medical devices is significant, especially considering the historical coexistence of state tort remedies with federal drug regulation. The Supreme Court has emphasized that federal preemption is less justified when Congress acknowledges state law's role in a federally regulated field but chooses to maintain both frameworks. Actavis argues that it cannot comply with state law requiring modified product labeling without violating federal law, claiming a physical impossibility between the two. Actavis asserts that federal law mandates its label to remain identical to the brand name drug's label, precluding compliance with state law that may require additional warnings.
Demahy, the plaintiff, does not allege Actavis was liable for inadequate warnings at the time of initial approval but instead claims Actavis failed to update the label to reflect new risks associated with long-term use of metoclopramide. While federal law necessitates that a generic drug's label initially matches the brand's, it remains silent on the manufacturer's obligations post-approval. However, federal regulations do not prohibit generic labeling modifications after initial approval and require manufacturers to maintain adequate labels and warnings throughout the drug's market life. Demahy argues that Actavis did not fulfill its obligation to revise its label in light of new safety evidence. Actavis contends that such obligations rest solely with the brand manufacturer or are overridden by the requirement to conform to the brand's label. FDA commentary supports Demahy's claim that generic manufacturers should notify the FDA of any new safety hazards and provide information for potential label revisions post-approval.
Generic manufacturers are required to maintain the same record-keeping and reporting standards for adverse drug experiences as name brand manufacturers. The FDA mandates that Abbreviated New Drug Application (ANDA) applicants submit periodic reports of adverse drug experiences, regardless of whether they have received any reports or made labeling changes. Generic manufacturers are also expected to initiate their own label changes in addition to mirroring those of the brand-name drug.
Under 21 U.S.C. § 355(e), the FDA can withdraw approval of a drug application if it lacks substantial evidence of the drug's effectiveness as labeled. This provision applies to both generic and brand-name drugs. Furthermore, 21 C.F.R. § 314.150 states that the FDA may initiate withdrawal of a generic drug's approval if its labeling becomes inconsistent with that of the referenced listed drug, barring approved differences in the ANDA. Actavis interprets this regulation as preventing it from altering the label of its generic metoclopramide, fearing that any change could lead to withdrawal of approval.
The FDA's final version of 21 C.F.R. § 314.150 was influenced by public comments suggesting the need for a mechanism to ensure ANDA holders adjust their labeling to reflect changes in the reference listed drug post-approval. The FDA clarified that a generic drug must have labeling consistent with the listed drug to be deemed safe and effective.
The regulation aims to ensure that the FDA can compel generic manufacturers to update their labeling in accordance with changes to the reference drug, not to restrict them from enhancing warnings. The Supreme Court's decision in Levine indicated that the FDA would likely not penalize manufacturers for strengthening warnings. A drug is not considered misbranded solely for changes to an FDA-approved label; misbranding pertains to the label's accuracy and the adequacy of warnings, with federal juries expected to handle most claims.
However, drug manufacturers cannot freely make label changes; most require FDA approval through a major changes procedure. As noted in Levine, a manufacturer typically must receive approval for any modifications to a drug label.
A manufacturer can modify its drug label prior to FDA approval using the changes being effected (CBE) process under 21 C.F.R. 314.70(c)(iii). Demahy asserts that Actavis could comply with FDA regulations and state law through the CBE process, major changes procedure, or direct warnings to healthcare providers. A ruling of preemption would eliminate these options for generic manufacturers. The CBE process allows for labeling changes that add or strengthen warnings or contraindications based on new evidence, enabling manufacturers to act upon submitting a supplemental application without waiting for FDA approval. The district court examined the accessibility of the CBE process for generic manufacturers, noting that the Hatch-Waxman Amendments do not prohibit generics from altering their labels post-approval. The CBE regulation does not differentiate between generic and branded manufacturers in allowing unilateral label changes. The regulation requires that CBE supplements reflect newly acquired information and be supported by sufficient causal evidence. While FDA commentary appears to suggest generic labels should match the reference drug's post-approval label, a detailed review indicates the commentary primarily pertains to pre-approval labeling.
The FDA has rejected a proposal to allow Abbreviated New Drug Applications (ANDAs) to include warnings or precautions beyond those present on the reference listed drug's label, emphasizing that the labeling for a generic drug must match that of the reference drug, with limited exceptions. This establishes that during the ANDA approval process, generic drug labeling must conform strictly to the reference drug's labeling, while leaving unclear what happens post-approval. The document critiques Actavis's interpretation that this directive extends into the post-approval period, suggesting that such an interpretation would disrupt traditional state regulation.
Additionally, the FDA's amendments to the CBE regulations, which were the only changes made during the implementation of the Hatch-Waxman Amendments, introduced a requirement for applicants to adhere to patent information regulations. The regulation 21 C.F.R. 314.97 mandates ANDA applicants to comply with the requirements for submitting supplemental applications, including the CBE process, indicating that generic manufacturers do retain access to CBE procedures. The FDA did not clarify any denial of access to these procedures for generic manufacturers in the relevant regulations, implying that Actavis's position lacks plausibility. Actavis argues that the CBE process is only applicable for changes made by the brand name manufacturer, suggesting that ANDA holders should submit drug labeling at regular intervals to ensure it matches the reference drug's label. However, this interpretation misreads the regulatory framework established by the FDA.
The FDA deems the procedure for ANDA holders to independently change labeling unnecessary, asserting that existing reporting requirements under 21 C.F.R. 314.70, including the changes-being-effected (CBE) provision, adequately ensure timely communication of labeling changes. Post-approval changes related to exclusivity or patent expiration remain the ANDA holder's responsibility. Although the FDA encourages generic drug manufacturers to utilize the CBE process for FDA-endorsed changes, it does not allow them to diverge from the labeling of the reference listed drug. The FDA mandates that an ANDA product’s labeling must match that of the listed drug to maintain consistency and ensure safety and efficacy perceptions among healthcare professionals and consumers. Should an ANDA holder believe new safety information warrants labeling updates, they must submit supporting evidence to the FDA, which will then decide on necessary revisions. The FDA retains the final authority on all labeling changes, regardless of whether they originate from a pioneer or generic manufacturer, with all modifications requiring FDA approval based on a scientific evaluation of the product's risks and benefits. The document also notes that recent FDA positions suggest generics cannot utilize the CBE process and that federal law may preempt state-law failure-to-warn claims against generic manufacturers, as highlighted in the amicus briefs related to the Colacicco v. Apotex Corp. case.
Hatch-Waxman Act and FDA regulations preempt state failure-to-warn claims against both listed and generic drug manufacturers, with the FDA asserting that generic manufacturers cannot use the Changes Being Effected (CBE) process. The Third Circuit upheld the preemption of these claims. Following the Supreme Court's decision in Wyeth v. Levine, the Court vacated the Third Circuit's judgment in Colacicco and remanded for reconsideration. Subsequently, the United States withdrew its amicus status in Colacicco, stating it had not assessed preemption issues related to Levine. The FDA’s previous position, which suggested that generics could not utilize the CBE process, has been diminished, as the relevant footnote was omitted from the final rule regarding CBE regulations. This rule emphasizes that CBE supplements apply only to newly acquired information about name-brand drugs and does not address generics comprehensively. Actavis argues that this omission implies that the CBE process does not apply to generics, though the FDA's earlier commentary and the withdrawal of its amicus brief indicate a potential reconsideration of its stance on generics in the context of the CBE process. The 2008 final rule makes only a single mention of generics, referencing their obligations to change drug labeling, but lacks clarity on their application to the CBE process.
The excerpt outlines regulatory guidance regarding labeling changes for generic drug manufacturers under the CBE (Changes Being Effected) and prior approval processes as stipulated in 21 C.F.R. 314.70 and related documents. It clarifies that all labeling modifications for ANDA (Abbreviated New Drug Application) products must comply with 21 U.S.C. 355(j), yet there is no explicit prohibition against generic manufacturers utilizing the CBE process. The FDA's previous positions, lacking current agency endorsement, are not entitled to deference.
Additionally, the excerpt emphasizes that the FDCA (Federal Food, Drug, and Cosmetic Act) and the Hatch-Waxman Amendments do not prevent generic manufacturers from proposing any labeling changes through the prior approval process. The authoritative guidance allows for a wide array of labeling changes, suggesting that regulatory language does not impose restrictions on the types of changes that can be proposed.
Furthermore, it discusses the potential for manufacturers to fulfill their duty to warn through “Dear Doctor” letters directed at healthcare providers. Although these communications require FDA approval, the FDA has indicated that manufacturers can request the agency to send such letters if necessary for risk evaluation. Louisiana law supports that a drug manufacturer can satisfy its warning obligations through communication with prescribing physicians.
The text underscores the manufacturer's responsibility to ensure that labeling remains consistent with safe and effective use, requiring them to inform the FDA and provide scientific evidence for any necessary changes. Ultimately, the FDA evaluates whether the proposed labeling changes are scientifically justified, maintaining oversight in the process.
Demahy's use of metoclopramide occurred prior to the relevant FDA process, but the FDA's subsequent endorsement supports Actavis's argument that Congress did not intend for generic manufacturers to independently issue “Dear Doctor” letters. While drug manufacturers may communicate important drug information to healthcare professionals, FDA guidelines primarily target pioneer drug companies. The FDA retains ultimate authority over labeling changes, while manufacturers are responsible for their label content. The federal goal is to ensure consistent and safe labeling across brand and generic drugs. Actavis's interpretation of the CBE (Changes Being Effected) process is insufficient to establish a clear congressional intent for preemption. Even if the CBE regulation does not allow an ANDA (Abbreviated New Drug Application) holder to amend labels without FDA approval, generic manufacturers can still comply with federal and state law through prior approval processes and direct communications with healthcare providers. Most courts have focused on the CBE process, but it is not the sole basis for rejecting preemption claims as illustrated in Levine, which emphasized that manufacturers, not the FDA, hold primary responsibility for labeling. Actavis's assertion that Congress intended to preempt state law due to a lack of federal obligations on generic manufacturers does not address whether state law duties conflict with federal requirements. The uncertainty surrounding the FDA’s potential responses reinforces the notion that federal preemption is less likely.
Clear evidence is lacking to conclude that the FDA would have rejected a proposed label change for the drug in question, which suggests that the manufacturer could comply with both federal and state requirements. The record does not provide any indication that the FDA would have denied a labeling proposal from Actavis. Notably, the FDA recently mandated that metoclopramide manufacturers update their labels to include additional risks of tardive dyskinesia from long-term use. Actavis’s reliance on Justice Breyer’s concurrence in the Levine case is ineffective, as there is no regulation with preemptive effect currently applicable. The FDA's recent shift regarding preemption and the Changes Being Effected (CBE) provision further undermines Actavis's position.
Even if compliance with both state and federal laws is feasible, state law can still be preempted if it obstructs congressional objectives outlined in the Hatch-Waxman Amendments and the FDCA. If preemption is established, it leads to two conclusions: first, Congress intended for brand-name manufacturers to bear the responsibility for managing risks, even after ceasing production; second, Congress either intended for brand-name manufacturers to be liable for all failure-to-warn claims, including those involving generics, or for injured plaintiffs to have no remedy. These implications regarding congressional intent must be considered when evaluating the case. The court emphasizes that it does not universally preempt failure to warn claims but rules that allowing the plaintiffs' claim would contradict the FDA's explicit disallowance of such a warning, given the agency's consistent stance against linking the drug to suicide.
Actavis argues that Louisiana’s failure-to-warn law imposes excessive burdens on generic manufacturers by requiring them to conduct duplicative studies and trials before they can initiate label changes. This could lead to increased development costs and higher prices for generic drugs, countering the goal of the Hatch-Waxman Act to provide more affordable generics. However, the argument overlooks that Louisiana law does not mandate that manufacturers conduct their own clinical trials for labeling changes. While the FDA requires scientific evidence for label changes, it does not specify that this evidence must come from the manufacturers' own studies. Instead, the FDA allows labeling updates based on "reasonable evidence" of a hazard, which can include data from existing studies or reports of adverse events. The FDA has demonstrated this by enhancing warnings for metoclopramide without conducting new studies. Furthermore, generic manufacturers are already obligated to report serious adverse drug experiences promptly and to maintain surveillance procedures for postmarketing data. This regulatory framework suggests that while evidence is necessary for label changes, extensive new trials are not a prerequisite.
The Supreme Court's decision in Levine establishes that multiple reports of adverse drug effects can substantiate a request for stronger warnings regarding drug risks. In the specific case of metoclopramide, medical literature from the 1980s and 1990s noted the potential for increased risks associated with long-term use. Although state law may require Actavis to inform the FDA of such information, Actavis has not demonstrated that compiling and analyzing existing data would incur significant costs. The duty to warn typically relies on the manufacturer's superior knowledge, which is more pronounced for pioneering drug manufacturers who conduct extensive research. In contrast, generic manufacturers, under the Hatch-Waxman Act, conduct limited research and can gain approval for drugs by demonstrating they are equivalent to branded versions. This regulatory framework aims to reduce redundancy and ensure that both generic and branded drugs are perceived as safe and effective. However, there exists a tension between the objectives of the Hatch-Waxman amendments, which facilitate quicker market entry for generics, and state tort laws that provide remedies for consumers harmed by inadequate labeling of these drugs. The Hatch-Waxman amendments are not standalone; they are part of a broader regulatory environment that mandates all drugs, regardless of cost, to maintain safety and efficacy. The FDCA imposes primary responsibility for drug labeling on manufacturers, as the FDA has limited capacity to oversee all marketed drugs and relies on manufacturers to report new risks as they arise. Congress recognized that state law remedies are crucial for consumer protection by incentivizing manufacturers to uphold safety standards.
Adequate warnings are essential, and the Hatch-Waxman Amendments to the FDCA do not negate state failure-to-warn claims. The inquiry does not evaluate the propriety of such claims but acknowledges their existence. Louisiana asserts that patients should have state-law claims against drug manufacturers for inadequate warnings. Despite Congress's apparent belief that such claims should not exist, the preemption analysis suggests that if Congress intended to eliminate this form of compensation, it would have done so explicitly. The court finds it illogical that Congress would implicitly deny remedies to patients prescribed generic drugs while allowing claims for name brand drugs. The statutes and regulations reviewed do not provide clear evidence of Congress's intent to preempt state law, which reflects a judicial reluctance to allow federal law to override state law without explicit direction. The preservation of federalism requires more decisive action from Congress or the FDA than has been demonstrated in this case. Since imposing state duties to warn on generic drug manufacturers does not conflict with federal regulations or obstruct their objectives, the district court's ruling that Demahy's state-law failure-to-warn claims are not preempted is affirmed.
