by Brian Wolfman
Indiana University medical school professor Jon Duke and two co-authors have published this study entitled "Consistency in the safety labeling of bioequivalent drugs." The study could have been entitled "Inconsistency in the safety labeling of bioequivalent drugs" because it finds that the warnings on generic drug labels often deviate from the brand-name labels on which they are supposed to be based — sometimes quite significantly. The study maintains that, overall, "68% of multi-manufacturer drugs [studied] had discrepancies in ADR [adverse drug reaction] labeling."
The problems identified by Duke raise concerns for patients and their prescribing doctors who, when labels are inaccurate, may be in the dark about a generic drug's adverse effects, contraindications, and other hazards. The study concludes that doctors prescribing generic drugs should review the branded label as well as the generic label. In a press statement, Duke also said that the best solution
may be a centralized listing of drug side-effects, maintained
independently of individual manufacturer labels. Drug labels would
simply reference this common repository rather than attempting to
maintain all the information within a single document. Clinicians could
refer to this resource for the most up-to-date safety information
regardless of generic manufacturer.
Duke's study also raises legal concerns. Generic drugs are supposed to be bioequivalent to the brand-name drug on which they are based, and the FDA's marketing approval for a generic drug is premised largely on the FDA's finding of bioequivalence. When the FDA approves a generic drug, it requires the generic's label to ape the label on the equivalent branded drug. Although lawyers, drug companies, and advocacy groups have disagreed over the years about whether a generic manufacturer may make safety-related label changes without FDA pre-approval — as the generic manufacturer learns over time about the drug's hazards — the FDA takes the position that a generic manufacturer may not alter the label on its own. (In this regard, note that Public Citizen has filed a petition with the FDA asking that generic manufacturers be authorized to warn of drug hazards that come to their attention without prior FDA approval on the same or similar terms currently available to brand-name manufacturers.)
Last year, in PLIVA v. Mensing, the Supreme Court held 5-4 that state-law damages claims premised on generic drug manufacturers' failures to warn of a generic drug's hazards were preempted by federal law because federal law prohibited the generic manufacturers from changing their labels to meet the dictates of state law, but rather required that the labels stay the same as the branded labels. The Court explained that if the defendant generic drug manufacturers had
independently changed their labels to satisfy their state-law duty, they would have violated federal law. Taking [the plaintiffs'] allegations as true, state law imposed on the [generic] Manufacturers a duty to attach a safer label to their generic metoclopramide. Federal law, however, demanded that generic drug labels be the same at all times as the corresponding brand-name drug labels. See, e.g., 21 CFR §314.150(b)(10). Thus, it was impossible for the [generic] Manufacturers to comply with both their state-law duty to change the label and their federal law duty to keep the label the same.
PLIVA had an immediate impact, making it nearly impossible for a plaintiff to maintain a state-law damages claim based on a generic drug manufacturer's failure to warn. For more detail on PLIVA's reasoning and future implications, see this article I wrote with Dena Feldman.
Duke's study challenges the existence, in fact, of the "sameness" that formed the legal premise for the Court's decision in PLIVA. It also suggests that implementation of PLIVA is no easy task for the courts. If actual sameness is lacking between the generic label and the branded label with respect to an allegedly inadequate warning that a plaintiff says caused her generic-drug-based injury, what is the basis for preemption under PLIVA? [Note: The Supreme Court recently granted review in Mutual Pharmaceutical Co. v. Bartlett,
which presents the question whether FDA approval of a generic drug preempts a state-law damages claim premised on the
drug's design defect. I wonder whether Duke's study will play a role in the briefing in Bartlett. For more on Bartlett, go here.]
Here are the Duke study's "Key Points":
• FDA mandates identical labeling between bioequivalent brand and generic medications, but
this consistency has never been validated
• Analyzing structured product labels, we found the majority of bioequivalent drugs show differences in safety warnings between manufacturers
• Reasons for these differences included missing tables, outdated post-marketing reports, and
• New strategies should be considered for harmonizing bioequivalent labels
Here is the study's conclusion:
Despite existing mandate, bioequivalent medications from different manufacturers often differ in their safety labeling. This variation stands in contrast to the expectations of providers, the FDA, and, more recently, the United States Supreme Court. While the clinical significance of such labeling discrepancies remains unclear, we suggest for now that physicians review branded drug labeling even when a patient is taking a generic version of a medication. Further research will be necessary to determine the clinical importance of these labeling discrepancies as well as to identify optimal solutions for ensuring ongoing harmonization of safety data across bioequivalent drugs.
The study's abstract is reproduced after the jump. You may also want to look at Indiana University's press release.
Purpose Bioequivalent medications are required by the Food and Drug Administration to have identical warnings on their labels. This requirement has both clinical and legal importance, yet has never been validated. We sought to determine the real-world consistency of electronic labeling for bioequivalent drugs from different manufacturers.
Methods Using natural language processing, we indexed the adverse drug reactions (ADRs) found in the Adverse Reactions and Post-Marketing sections of 9105 structured product labels. We calculated the standard deviation in ADR labeling for each bioequivalent drug and the percent deviation of each generic label from its corresponding brand. We also analyzed the performance of individual generic manufacturers. For the 25 drugs with the greatest discrepancy in labeled ADRs, we performed manual review to identify causes of inconsistency.
Results 68% of multi-manufacturer drugs had discrepancies in ADR labeling. For a given drug, the mean deviation in number of labeled ADRs was 4.4, and the median was 0.8 (IQR 0 to 3.2). The mean range in number of labeled ADRs was 12 +/! 0.9, and the median was 2 (IQR 0 to 9). Overall, 77.9% of generic manufacturers produced labels differing from brand. Causes of inconsistency included missing tables, outdated post-marketing reports, and formatting issues.
Conclusions Despite FDA mandate, bioequivalent drugs often differ in their safety labeling. Physicians should be aware of such differences and regulators should consider new strategies for harmonizing bioequivalent labels.