Postmarket Drug Safety: The View From the FDA

Two recent studies have raised questions about postmarketing safety issues with newly approved drugs, particularly those granted approval on the basis of limited data. The first study, conducted by Alison M. Pease, a medical student at State University of New York Downstate College of Medicine in Brooklyn, and published in the BMJ, used the Drugs@FDA Database to identify all novel drugs that were approved by the US Food and Drug Administration (FDA) between 2005 and 2012 on the basis of either a single pivotal trial or pivotal trials focused on surrogate markers of disease. During this period, more than a third of new approvals were awarded on the basis of a single pivotal trial; just under half (44%) were approved on the basis of studies that used surrogate disease markers rather than clinical outcomes. The researchers then conducted a systematic review of prospective controlled clinical studies published after approval. For 35.0% of these newly approved indications, the researchers were unable to identify any postmarket clinical trials. A median of one to three postapproval studies was identified for agents or indications approved on the basis of a single pivotal trial, and the aggregate number of patients enrolled in these postapproval studies was 90.

The second study, conducted by Nicholas S. Downing, MD, from the Department of Medicine at Brigham and Women's Hospital in Boston, Massachusetts, and colleagues, and published in JAMA in May 2017, also used data from the Drugs@FDA database to identify postmarket safety events reported for 222 novel therapeutics approved by the FDA between 2001 and 2010. Over a median follow-up period of 11.7 years, postmarket safety events were reported for 32% of these agents. These safety issues led to three drug withdrawals.

To discuss the issue of postapproval monitoring of newly approved agents, Medscape spoke with Gerald Dal Pan, MD, MHS, director of the Office of Surveillance and Epidemiology at the FDA's Center for Drug Evaluation and Research, about the postmarket approval process and its implications for clinicians prescribing newly approved agents.

Evaluating Safety Through the Lifecycle

Medscape: Can you describe the lifecycle evaluation process and the role of postapproval study in this process? What kinds of postapproval clinical information are mandated as part of the FDA approval of a new agent?

Gerald Dal Pan, MD, MHS

Dr Dal Pan: We do take a lifecycle approach to a drug product—from the first human exposure all the way through its continued marketing life—and we monitor the safety throughout. We have a particularly active postmarket program and obtain that postmarket safety data in a few different ways. The backbone of our system for over 40 years is adverse event reporting. These are reports describing an adverse event that took place while using a medicine which people at the point of care send either to the drug's manufacturer or to the FDA using our MedWatch system. These reports, importantly, include untoward occurrences that may or may not be later determined to be related to the drug.

Manufacturers are under a regulatory obligation to send certain reports to the FDA. We receive about 1.7 million reports a year and now have over 14 million reports in our database. About 95% of our reports come from industry and only about 5% come directly from the public—patients, their families, physicians, pharmacists, nurses, anyone. None of those people at the point of care are required to send the report either to the FDA or to the manufacturer. But to clarify: All reports, whether they come to us from industry or come directly to us, are from the point of care.

We use data mining and other computer-based techniques to sift through these reports to identify a signal that suggests that there might be a new problem with the medicine that we want to evaluate. We begin by actually reading the reports to see if there is sufficient information to determine whether a causal relationship exists between the medicine and the adverse event. Often there is not enough information because people who take medicines are experiencing a lot of health problems before they take the medicine. That's why they take the medicine. It's hard to separate the effects of the underlying illness and the medicine, so further analysis is necessary.

We can further explore this potential association between the medicine and the adverse event in a few ways. First, we can examine existing observational studies or conduct our own observational study to see what happens in the course of normal clinical care, and then try to make an inference about a causal, or potentially causal, relationship between a drug and an adverse event. We can also ask the drug manufacturer to do a study or a clinical trial to try to address this issue. Another method is to work closely with our clinical pharmacologists here at the FDA to analyze the pharmacology of the medicine and see if there's a biologic or pharmacologic basis for the drug causing the adverse event. We have a lot of tools in our toolbox.

When certain regulatory requirements are met, the FDA has the authority to require companies to perform a postmarket study or clinical trial. Before we can invoke that authority, however, the law requires us to demonstrate that our active risk identification and analysis system isn't sufficient to answer the particular safety question. That system was mandated by the Food and Drug Administration Amendments Act (FDAAA) of 2007, and it required FDA to amass data on at least 100 million lives (generally, electronic healthcare data) to be able to answer these questions.

Medscape: So, the FDA can mandate postmarket research to be carried out by the manufacturer after demonstrating that analysis of information from the adverse events reporting system is not sufficient to answer any outstanding clinical questions. This is distinct from postmarket research, via either a randomized clinical trial or an observational trial, which can be mandated at the time of approval. Is that correct?

Dr Dal Pan: Correct. The FDA has several different authorities through which it can mandate postmarketing studies or trials when a concern arises about safety issues. We may identify a safety issue during development and, at the time of approval, require a postmarketing study or clinical trial to clarify further that issue. Alternatively, we can invoke that authority after approval if we obtain new safety information that requires more evaluation.

The general framework for the conditions under which we can require this is either when there is a known safety issue and we need some more information to understand it better, or when a signal of a potential safety issue is identified that we want to understand better. A postmarket study can also be mandated when there is a broader potential for a problem even though we've not had any clinical data that might warrant study. An example of the third category would be in the situation where there is a concern that a drug may pose a teratogenic risk and a pregnancy registry is mandated.

There are separate authorities under the accelerated approval regulations, the Pediatric Research Equity Act, and the animal rule, through which the FDA can require a postmarket study. These are generally different from the postmarket safety studies described above and often deal with questions of efficacy.

Medscape: Does the FDA determine the design of studies that will be conducted to generate postapproval evidence?

Dr Dal Pan: We are required to justify what we mandate, be it before approval or after approval. And that is true whether the postmarket research will be conducted via an observational study or a clinical trial. The details of these trials, such as the specifics of the protocol, might not be known at the time of approval. But in either case, whether the study is mandated before approval or after approval, we do work with the pharmaceutical company on the design of the study or trial.