Examination of the Relationship Between Oncology Drug Labeling Revision Frequency and FDA Product Categorization

The primary mission of the US Food and Drug Administration (FDA) is to ensure the safety and efficacy of drugs, medical devices, and biological products.1 The FDA's Center for Drug Evaluation and Research (CDER) is responsible for the safety and efficacy of drugs, including certain therapeutic biological drugs.2 Although CDER must exercise stringent control to ensure drugs' efficacy and safety, it must also ensure that vitally needed products receive timely approval. Four major legislative and regulatory tools aid in that process: accelerated approvals, priority reviews, orphan drug designations, and fast-track designations. Accelerated approval, which was established through a notice in the Federal Register on December 11, 1992,3 is the process by which certain products that treat serious unmet clinical needs are approved before final safety and efficacy data have been gathered. These approvals are based on an FDA finding that a surrogate marker of efficacy (or surrogate endpoint) has been satisfied.4 For example, the FDA usually wants to know if a new chemotherapeutic agent increases patient survival time compared with the current standard of care or placebo. Because gathering such data can take many years, a delay in time to recurrence might be used as a surrogate endpoint instead of survival time. Generally, the FDA requires that surrogate endpoint evidence be compelling. In addition, such approvals are often made with the promise that the manufacturer seeking approval will conduct subsequent studies to ensure that the surrogate endpoint findings truly reflect the product's safety and efficacy.4 Priority review, which was established as a result of the Prescription Drug User Fee Act of 1992,5 is the process by which products submitted to the FDA receive faster review. This designation is typically given to products that, if approved, will represent a substantial improvement over current treatment options.6 The targeted review time for these products is 6 months rather than the standard 12 months.7 The Orphan Drug Act of 19838 established the orphan drug designation, which is given to products that treat rare conditions or diseases.9 The orphan drug system is administered through interactions between the Office of Orphan Product Development and the relevant FDA center, usually CDER. Orphan drug designations can be made at or prior to FDA approval. Orphan products receive benefits such as a waiver of user fees10 and extended patent exclusivity.11 Fast-track designation, which was added to the FDA's regulatory arsenal in 1997 under the Food and Drug Administration Modernization Act of 1997,12 is a supplementary process to such existing programs as accelerated approval and priority review. Using the fast-track process, manufacturers seeking approval for drugs that treat serious or life-threatening conditions and show the potential to address currently unmet medical needs receive additional regulatory assistance. For example, the manufacturer seeking approval may have more frequent interactions with the FDA to discuss product issues or regulatory concerns. The FDA undoubtedly strives to accurately categorize the products it examines and to use consistent procedures for reviewing products. However, current review processes are not necessarily ideal. One way to measure the program's success would be to observe what happens once these products enter the market. A recent US Government Accountability Office report on the FDA's postmarket surveillance provides insight into the efficacy of the FDA's postmarket regulation.13 I focused on labeling changes to examine how FDA decisions made during the approval process related to product development postapproval. A product's label describes the risks and benefits associated with its use.14 Under a variety of circumstances, a manufacturer either must revise or chooses to revise its product's label. Changes in a label may reflect new information—negative or positive—about the product. For example, discoveries about inefficacy or unknown toxicities may require that a drug be relabeled. However, even positive new findings provide reason for concern, because this means a product is reaching the public without the FDA and the medical community fully understanding its potential therapeutic uses. To explore the relationship of product categorization to labeling changes, I examined how often labels are revised for different product categories. These revision rates may provide some insight into the adequacy of the FDA's review processes. For this review I focused on the effect of regulatory categorization on oncology drugs because they are numerous enough for statistically robust analysis, but not so numerous as to be unmanageable. In addition, because oncology products are often designated as priority review, accelerated approval, or orphan drugs, they provide a diverse data set. (I did not examine fast-track designation, because it is solely a supplementary process and designations are often not publicly disclosed.) Finally, given the high prevalence of cancers and substantial associated mortality, oncology products are vitally needed. The relationship of product development and labeling is too complex to expect that a single factor, regulatory categorization, could by itself predict how often labels would be revised. However, if the frequency with which labels are revised does in fact correlate with regulatory categorizations, we would expect to observe certain relations. For example, because orphan drugs target a smaller and highly specific patient population, one would expect fewer labeling revisions than would be observed for nonorphan drugs. Limited product usage for orphan drugs, both in terms of diversity of conditions and number of patients, provides less opportunity to learn about product issues in the clinical context. By contrast, one would expect accelerated approval to be associated with an increased frequency of revision. Accelerated approvals are made based on surrogate endpoints. The endpoint data will then be supplemented by subsequent clinical experience and postmarket research, and the manufacturer will alter its product's label to reflect additional data. Accelerated approval products should therefore receive more revisions over the product's lifetime compared with products that undergo regular approval. Finally, products designated for priority review and those not so designated should show little difference in the frequency with which their labels are revised. Although priority review products are targeted to an unmet clinical need and are being reviewed over a compressed period of time, under the FDA regulations they face a review process as stringent as that for other products.