Discovering and communicating new risks associated with approved drugs is a core part of CDER’s work. When a new drug is first approved, we know about many of the risks associated with its use from the clinical trials that we evaluated to support the drug’s approval. But once that newly approved drug goes on the market and is used by a far greater number of people than were involved in clinical trials, new safety issues—or signals—can emerge. One way we learn about many of them is by analyzing adverse event reports throughout a drug’s lifecycle (e.g., development, approval and post-approval stages).

Gerald Dal Pan, M.D., M.H.S., who is the director of CDER’s Office of Surveillance and Epidemiology (OSE), describes how the agency tracks, analyzes and acts on the adverse event data collected over time.

How do we primarily collect data on a drug’s adverse effects after it has hit the market?

We receive reports from patients, health care professionals and manufacturers about adverse events associated with FDA-approved drugs in several ways. One of our most robust tools is the FDA Adverse Event Reporting System (FAERS). In 2018, FAERS received more than two million reports—a record number of reports. The increase in reports does not suggest that FDA-approved drugs suddenly have become riskier. Rather, the increase reflects the fact that more drugs are on the market. It also suggests that stakeholders have become more aware of the value of reporting adverse events to help us enhance drug safety.

Some of the reports describe adverse events previously known and already on the drug’s label, some are about a drug that had only a minor adverse effect on the patient, and some reports turn out to be unrelated to the drug. But others provide important clues about a serious safety issue, indicating a potential new risk associated with a drug. It’s our job to monitor the FAERS database to identify these safety signals and validate them by analyzing and interpreting the data, and then combining it with other scientific information to generate meaningful data that we use to help make decisions on safety issues. We can also require the manufacturer, under certain circumstances, to conduct studies that address a potential new risk.

What actions do we take after we have confirmed a new safety issue with an approved drug?

After we confirm a new risk associated with a drug, we generally require that the risk be added to the product’s label. The label of each FDA-approved prescription drug describes all of the drug’s known risks and approved indications, as well as all other essential scientific information that health care professionals need in order to safely and appropriately prescribe the drug. If a drug has the potential for serious adverse effects, we may require that the manufacturer establish a Risk Evaluation Mitigation Strategy (REMS) to ensure that the benefits of the drug outweigh the risks. Rarely, we may remove the drug from the market.

What are the different ways that we can present newly identified risk information on the drug’s label?

Risk information is included in multiple sections of the label, depending on the nature and severity of the particular risk. The sections of the label that describe important risk information include:

• Boxed Warnings, which are the most prominent type of warning;
• Warning and Precautions;
• Contraindications, which describe the circumstances under which the drug should not be used;
• Adverse Reactions, also called side effects;
• Drug Interactions.

Recently, researchers in OSE conducted a study to determine the extent to which new risk information is added to drug labels over time. Can you tell us what you found?

In 2017, OSE studied the number of new risks added to a drug’s label after approval and where in the label the risk information was placed. From 2002 through 2014, CDER approved 278 new molecular entities (NMEs). NMEs are drugs never previously FDA-approved or marketed. We then measured the number of safety labeling changes added to each of these drugs over time. The results showed that, in general, as long as these 278 drugs remained on the market, new safety issues were discovered and added to their labels. It also shows that over time, relatively few drugs stayed on the market without having new safety information added to their labels. [See Figure 1].

Timing of Safety-related Changes, as of December 31, 2015

Figure 1: The x-axis shows the year of approval of each drug. The y-axis shows the number of years after the drug has been approved. The red line shows the number of years each drug has been approved. The various symbols represent the different safety warnings added to the drugs’ labels. The circles directly above the x-axis indicate drugs for which no labeling changes were added. Source: Pinnow et al. Clin Pharmacol Ther. 2017 Dec 20 doc:10.1002/cpt.994 [epub ahead of print]

For this group of 278 drugs, we recorded 703 label updates. Each update can add more than one risk to a label. These updates addressed 2505 individual new risks. Because a new risk is sometimes placed in multiple sections of a label, adding these individual risks together results in a number larger than the total number of updates. For instance, if we required a Boxed Warning for a risk, we typically also put more detailed information in the Warnings and Precautions section. [See Figure 2.]

Our findings illustrate how important it is for the safety of every drug to be monitored across its entire lifecycle—from development, to approval and through its entire time on the market—no matter how long that may be.

Label Updates and Safety Issues

Figure 2: For the 278 drugs examined, we recorded 703 label updates, reflecting 2505 safety issues altogether. The figure illustrates where the safety information was placed on the drug’s label.

What are the implications of these findings for patient safety?

Given that new risks are added to a label after a drug is approved, physicians and other health care professionals who prescribe medications should read the drug label updates issued by the agency, to ensure they are up-to-date on the latest risk information. We can identify newly discovered safety issues many years after approval, even for drugs that have been on the market for a while and have a strong track record for safety.

The continued success of our adverse event reporting program relies on the input from our drug safety stakeholders. Industry is regularly required to report adverse events, but information from patients and health care professionals is also vital. The reports are critical to CDER’s efforts to effectively uncover new safety issues and help protect the American public. Reports can be submitted via our MedWatch website.