As Emily Walden watched her son struggling with addiction to the opioid Opana, one place she turned to for help was the company that made it: Endo Pharmaceuticals.
She wrote to Endo in 2011. She heard back a year later. The corporate email arrived “one month after I buried my son,” Walden said. His name was TJ, he’d served in the Kentucky National Guard, and he was first prescribed painkillers at age 11, after a surgery. He became addicted at 17.
Endo, which now has U.S. headquarters in Malvern, thanked Walden for contacting the company the previous year to “discuss or report an adverse event(s)” from taking Opana. Endo wanted more details on what she’d observed, so it could report the information to the Food and Drug Administration.
Five years later — and engulfed in nationwide lawsuits and investigations about the marketing of opioids — Endo suddenly began to tell the FDA about a tidal wave of fatalities associated with Opana, and painkillers made by other companies. From November 2017 through August 2018, Endo reported 20,115 deaths to the FDA, a review of the agency’s public database of adverse events shows.
Before 2017, the company reported approximately 250 deaths, over a 10-year stretch, in which Opana was a suspect drug.
The thousands of deaths span roughly two decades, and entries for individual fatalities, in some cases, list more than a dozen different opioids. Endo began submitting the reports two months after it voluntarily pulled Opana ER, a top-selling painkiller, from the market — following a 2017 request by the FDA to do so, because of abuse. Together, Opana and Opana ER, first launched in 2006, generated more than $2 billion in sales.
The batches of reports represent some of the information being pried loose amid roughly 2,000 lawsuits against opioid makers and distributors. Counties in Pennsylvania and across the U.S. — along with Native American tribes, labor unions, individuals, and state attorneys general — have all filed suit. Both Endo and the FDA acknowledged the increase in reports, and attributed the spike to the litigation.
Reports don’t necessarily mean there’s a causal link between the product and the outcome. Endo said it submitted the reports out of “an abundance of caution,” even though in most events reported, it wasn’t clear whether its own products allegedly caused harm, the company said.
The influx of reports also highlights shortcomings of how the U.S. tracks safety risks and outcomes for FDA-approved drugs. The FDA itself cautions that the database, known as FAERS, can reflect underreporting and overreporting of events, as well as duplicates, and incomplete information about what happened. In 2017, the agency put an interactive version of the data online, in hopes of attracting more detailed reports from consumers and doctors.
Drug manufacturers have to tell the FDA about adverse events — if they learn of those outcomes. But they don’t have to actively look for them, said Thomas Moore, a senior scientist at the Institute for Safe Medication Practices (ISMP) in Horsham. When it comes to therapeutic drugs, including opioids, “we do an abysmal job of monitoring deaths related to drugs in the country,” Moore said.
As municipalities have filed lawsuits, some have included allegations about the number of people who died in connection with opioids. Endo said more suits started coming in 2017, and the company reviewed them for potential adverse-event reporting to the FDA.
“For a period of time, in an abundance of caution, Endo’s pharmacovigilance department reported each complaint to the FDA, even though most of the complaints did not identify or distinguish between harm allegedly caused by Endo products and harm allegedly caused by other manufacturers’ products," company spokesperson Heather Zoumas Lubeski said in an emailed statement. "It is this practice which accounts for the observed spike in adverse event reporting.”
The company, Zoumas Lubeski added, “is vigorously defending these lawsuits, denies that it has any liability to the plaintiffs, and continues to work with the FDA to submit appropriate reports.”
Walden’s correspondence from the company in 2012 is referenced in a Kentucky attorney general suit against Endo. “What bothered me so much about this email is … why weren’t they reporting these issues to the FDA?” she said. “It shouldn’t take over a year for that to happen.” The company declined to comment on the litigation.
Endo — which also makes the opioid Percocet — has publicized other changes in light of the opioid crisis: It got rid of its U.S. sales force for pain products, and says on its website that it “discontinued the research and development of new opioid products.”
The opioid litigation is but one of the challenges Endo is facing, amid what CEO Paul Campanelli has deemed a “multiyear turnaround plan.” Its annual revenue fell 15 percent last year, to just under $3 billion, and the company has forecast that 2019 revenue will stay about the same.
A Morningstar analyst note last month said the combination of the company’s high debt, settlement payments for the mesh cases, and potential liability from opioid suits made bankruptcy “a plausible scenario.”
The FDA said drug companies are required to report adverse events for their products if they become aware of them through lawsuits, and if the reports meet the bar for a minimum amount of data.
“The majority of the recent reports submitted by Endo Pharmaceuticals with a fatal outcome are from lawsuits, including multiple class action lawsuits from across the U.S.,” said FDA spokesperson Amanda Turney. The reports, she said, describe the deaths as a result of both prescribed and “nonmedical” opioid use.
Asked if the volume of reports raised any concerns at the agency, Turney said: “FDA does not solely focus on the volume of adverse event reports received for a particular drug as a measure of risk; we also rely on the quality of information.”
The reports contain few details, observed Moore, whose group analyzes adverse-event data submitted to the FDA. Using ISMP’s own database, he looked at a collection of 15,475 reports for oxymorphone, the opioid in Opana ER, for the 12 months ended in the third quarter of 2018.
“Ninety-one percent of them are vague, meaning it lacks age or gender,” Moore said. Such reports wouldn’t meet ISMP’s quality standards for a “minimally complete” report.
“It’s indicative of poor-quality industry reporting, of which there are many examples," he said.
ISMP has previously raised concerns to the FDA about how deaths are reported, and, in a 2015 analysis, critiqued FAERS for suffering “from a flood of low quality reports from drug manufacturers."
Companies might also be afraid of getting caught in a regulatory violation if they don’t report. “The way regulations work now, we’re getting the worst of both possible worlds: A burden on manufacturers to report patient deaths where the drug may not have contributed, and on the other hand, a lack of adequate information on deaths we should really be concerned about," Moore said.
Opioids are their own special case. “With opioids," he said, “we pretty much know from all our other sources that this is a very serious problem, but sometimes we don’t.” The Centers for Disease Control and Prevention estimates that, between 1999 and 2017, nearly 218,000 overdose deaths were related to prescription opioids.
Drugmakers do have to create written procedures for monitoring adverse experiences, the FDA said. But the agency also said that it’s revising post-marketing safety reporting requirements, for drugs in general, and that it is “very interested in improving the quality of information reported to FAERS.”
In 2014, the City of Chicago became one of the first local governments to sue opioid makers. The suit accused Endo and others of downplaying the risk of addiction, even as they had access to data — including adverse-event reports — that “demonstrated the widening epidemic of opioid abuse and addiction.”
The Chicago suit has since been consolidated with about 1,600 opioid cases in federal court in Cleveland, where the first trial is scheduled to start in October.
Endo allegedly gave millions of dollars in grants, and used speaker programs and front groups to spread the message that Opana had a low risk of addiction.
In 2016, the company reached a $200,000 settlement with the New York Attorney General’s Office, which found that Endo trained its sales reps to “distinguish addiction from ‘pseudoaddiction’” — a concept that “has never been empirically validated.”
Endo’s history with oxymorphone dates back to 1959, when it launched the painkiller as Numorphan. Problems with abuse surfaced the following decade. The company stopped marketing a tablet version in 1971, and officially withdrew it from the market in 1982, citing “commercial reasons,” according to the FDA. “Of note, there were anecdotal reports of abuse by injection of Numorphan tablets in the 1960s and early ’70s,” an FDA official testified at a March 2017 advisory committee meeting, where members were weighing the abuse risk of Opana.
By that time, intravenous abuse of Opana ER had been linked to cases of a blood disorder, and to what another FDA official described as an “unprecedented” HIV outbreak in rural Indiana. The committee voted that the benefits of the drug no longer outweighed the risks, and the FDA later requested its removal from the market.
Walden provided testimony at the 2017 advisory meeting as well, and she asked Kentucky’s now-attorney general — while he was running for the office — to investigate the company. She’s on a mission, she said.