Oncology drug labels, especially those that have been on the market for more than 15 years, may not always be up-to-date. Critical data about safety, efficacy, or prescribing information may be missing. Modernizing the labeling process can correct inaccurate information, add data for indications beyond initial approval, remove impediments to reimbursement where labeling is used to guide payment decisions, and establish greater clarity regarding real-world evidence. These issues were among those discussed by a panel at the 2017 Friends of Cancer Research Annual Meeting held in Washington, DC.
Janet Woodcock, MD, Director, U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research, said: “Reimbursement is often tied to labeling data. We would like to see payment policies change to encourage reimbursement for more new indications.
The Way Things Stand Now
Drug labels are written by drug manufacturers but must be approved by the FDA. The 1984 Hatch-Waxman Amendments to the Food, Drug, and Cosmetic Act require that a generic drug label be the same as that of the brand name—as the generic drug is the same as the original. In fact, the FDA cannot approve a generic if the label differs from the original. Generic drugs cannot be changed in any way after the original drug is off the market; thus, the label is “frozen,” said Dr. Woodcock.
If the label is kept up-to-date, it represents the most complete information available to prescribers. The label can fall out of date when new information becomes available after the drug has been in use for a while, making the label less valuable than it should be.
Brand and generic manufacturers have a duty to report new safety data to the FDA, which in turn has the authority to mandate labeling changes as a result. But manufacturers that will soon lose their patents or have already lost market exclusivity—even some that intend to stick with a drug—have little incentive to devote to the effort of rewriting labels.
Prescribers routinely use other sources of information when making decisions about drugs: clinical practice guidelines and compendia, peer-reviewed journal articles, and real-world evidence.
The public health effect of outdated labels can be serious. First, important information does not reach prescribers. Second, incorrect information is disseminated. Third, as labeling falls out of date, its credibility as a useful resource may decline. Fourth, many older drugs are repurposed as part of new combinations, but if labeling misinformation is included on the label of a newer combination, confusion may ensue. Fifth, the number of drugs with outdated labels will increase in the coming years, particularly for generics, creating more confusion.
Solving Some of the Problems
The panel discussed ways that practitioners should use older drugs. Two major problems exist: First, although the new drug application is still active, the label may be missing critical information or contain incorrect prescribing instructions. Second, the new drug application may have been withdrawn or discontinued for reasons other than safety or efficacy.
Given the speed with which new information arises, it is difficult for an older drug label to be completely up-to-date and accurate for a number of reasons, some of which are listed here:
- Many labeling changes (except safety updates mandated by the FDA) are made only at the sponsor’s discretion.
- A supplemental new drug application, for example as a result of postmarket information, also is made at the sponsor’s discretion, and there is much subjectivity about what is considered important enough to change the label.
- A manufacturer may withdraw a drug from the market and is therefore no longer responsible for the contents of the label. Generic manufacturers may not write their own labels, so if the original no longer exists, outdated data remain extant.
- Many entities rely on compendia and sources other than the label to make reimbursement decisions.
However, regulatory pathways exist for manufacturers to update a label. A sponsor can submit a supplemental new drug -application, and there is the 505(b)(2) pathway, permitted by the Hatch-Waxman Amendments, a type of new drug application where at least some of the information required for approval comes from studies not conducted by or for the applicant (sponsor). Despite these opportunities, drug sponsors do not always keep their labels up-to-date.
Proposal to Update Labeling
The panel discussed a way to update labels by lowering these barriers. The proposal provides manufacturers with ways to submit supplemental applications in a less burdensome way. It also allows generic manufacturers to update labels when the brand name (reference) drug has been withdrawn from the market.
Step 1: The FDA identifies drugs that have outdated labels.
Step 2: The FDA notifies the sponsor.
Step 3: The FDA works with various stakeholders to review postmarket evidence about safety, efficacy, and dosing.
Step 4: The FDA determines whether the evidence found above meets existing standards.
Step 5: The update process begins via a notice in the Federal Register. The FDA publishes a summary of the appropriate findings, states the label modifications that should be made, and describes the process for approving them.
Step 6: The sponsor submits a supplemental new drug application that, if approved, would modify the label.
Questions and unresolved issues remain:
- If the FDA facilitates updates for older drugs, will it lower the incentive for manufacturers of newer drugs to submit labeling updates via a supplemental new drug application?
- To what extent would the sponsors of drugs nearing the end of their patent life be willing to update labels?
- How can the unintended consequence of motivating payers to end compendia-based reimbursement be avoided?
- How will the FDA ensure that all versions of a generic drug and its label remain the same at all times?