Researchers at Stanford and the University of Minnesota have found that pharmaceutical manufacturers often wait for months, and sometimes more than a year, before telling federal drug regulators about patients who became sick after taking a medication.
In particular, the researchers conclude, drug companies are at their slowest in telling regulators about adverse events that end in a patient’s death.
The new analysis, published July 27 in JAMA Internal Medicine, is based on analysis of more than 1.6 million adverse-event reports that drug companies sent to the Food and Drug Administration (FDA) over the past 10 years.
The longer a report was overdue, they found, the more often it involved a patient’s death. The findings suggest that at least some drug companies are increasing the risk for patients by dragging their feet on disclosing data about potentially unrecognized side effects.
“That is exactly the opposite of what firms should be doing,” says Iván Marinovic, assistant professor at Stanford Graduate School of Business and a co-author of the new analysis. “The FDA requires pharmaceutical manufacturers to inform the FDA within 15 days of when they get reports of a serious adverse event. You would hope that companies would be especially prompt about passing along reports of deaths. Instead, those are the reports that are most likely to be delayed for months or longer.”
The issue has life-and-death significance. The FDA relies heavily on adverse-event reports to identify potentially dangerous side effects of medications that are often used by millions of people. The reports are routinely a starting point for regulators in deciding whether to require new warnings for a drug, to restrict its use, or to ban it altogether.
For example, in 2010, the FDA heavily restricted the use of Avandia, a top-selling drug by Glaxo Smith Klein to treat diabetes, after a study linked it to 47,000 cases of heart attack, stroke, and heart failure. The FDA removed the special restrictions in 2013, concluding that the drug did not actually impose higher cardiac risks. But Glaxo paid $3 billion to the federal government to settle a raft of charges related to several drugs, including charges that it had withheld safety data about Avandia.
Last year, the New York Times highlighted disturbing adverse-event data about Acthar, a costly drug to treat a rare syndrome in children, called infantile spasm. The manufacturer, Questor, had forwarded reports to the FDA that showed 5% of the children who received Acthar in 2013 developed new problems and 20 had died. Yet Questor held back on mentioning those results as a risk factor in its financial reports to the Securities and Exchange Commission.
Under federal law, anyone who has information about a potential bad reaction to a drug can file an adverse-event report directly to the FDA or to the pharmaceutical manufacturer. About 85% of those reports go to drug companies, but the companies are required to forward any report of a “serious” and “unexpected” event to the FDA within 15 days.
An adverse event does not in itself mean that the drug at issue was responsible for a bad side effect. It only means that someone — a patient, a doctor, or someone else — has reported an unexpectedly bad outcome after a patient took the medication.
Why Speed Matters
Much like National Highway Traffic Safety Administration’s method for collecting reports about safety problems in cars, the FDA’s Federal Adverse Event Report System amounts to an early-warning system.
But prompt reporting is crucial to an early-warning system, so Marinovic teamed up with Paul Ma and Pinar Karaca-Mandic at the University of Minnesota to find out how quickly drug manufacturers were complying with their obligations.
The good news was that pharmaceutical companies appear to have been on time with 90% of their adverse-event reports from 2004 to 2014. But the remaining 10%, a non-trivial 160,000 reports, dribbled in over many months. More than 75,000 reports took between three and six months to get from the drug manufacturer to the FDA. Almost 40,000 took longer than six months.
More disturbing, the researchers found that pharmaceutical companies were more sluggish about forwarding reports that involved patient deaths. The companies forwarded 5.2% of reports that did not involve death, but 6.4% of reports that involved death between 16 and 90 days. Drug companies waited more than 90 days or more in forwarding 4% of reports that didn’t involve a death, but almost 6% of reports that did.
The bottom line: The odds of delayed reporting were significantly higher when the incident involved a death, compared with the odds of delayed reporting when it involved non-fatal illnesses.
“What we find is that firms are systematically violating the regulations and there are two possible reasons: Either the regulations are not reasonable or the FDA’s enforcement is weak,” says Marinovic.
The researchers say they see no plausible practical reason for delays that stretch out months. The FDA does not ask pharmaceutical companies to make a judgment about causal relationships or even about the accuracy of the reports they receive from doctors and patients. The FDA simply wants companies to promptly forward the raw information.
The researchers note that their results may well understate the amount of strategic foot-dragging. Their analysis is based on self-reporting by pharmaceutical companies, but in practice companies can escape the 15-day deadline by downgrading a report to less than “serious” or by fudging the date when they first receive a report. The FDA has sent pharmaceutical companies enforcement letters, complaining of both practices.
“FDA warning letters suggest there is scope for manufacturers to manipulate the timing or even withhold a report altogether,” Marinovic says. “This is why we believe our findings underestimate the degree of selective compliance.”
Marinovic and Ma — who earned his doctorate at Stanford — both specialize in how companies handle strategic communications with the public. Much of their research focuses on communication about financial performance and other information aimed primarily at shareholders.
But the two are increasingly exploring strategic communication about data with broader social implications, such as product safety information on cars, medical devices, and pharmaceuticals.
The researchers argue that the FDA has at least two good options to improve the timeliness of adverse-event reporting. The simplest strategy is to encourage patients and doctors to report their experiences directly to the government, rather than through the drug manufacturers. A second is to get tougher about enforcement, upping the penalties for companies that lag behind.
"It turns out that only a tiny fraction of these adverse-event reports go directly to the FDA — roughly 30,000 out of 640,000 in 2013,” said Ma. “If the FDA really promoted the idea of submitting those reports directly, we might meaningfully improve the timeliness of relevant safety information.”