1998–2010
Durham, North Carolina
For three decades, Joe and Terry Graedon had been on the side of patients. The husband-and-wife duo, a pharmacologist and a medical anthropologist, respectively, wrote a syndicated newspaper column and hosted a National Public Radio program, The People’s Pharmacy. Over the years, as they worked to empower and educate patients in their search for cures, the Graedons held a bedrock assumption: the FDA was a competent regulator whose claims could be believed.
Even during the dark days of the generic drug scandal in the late 1980s, the Graedons expressed confidence that the FDA’s “exhaustive analyses” had found no problems that would endanger consumers; they remained staunch advocates for generic drugs. “We were steadfast in maintaining they were identical and you would have to be a total idiot to pay for a brand-name drug when a generic was available,” Graedon recalled.
A chance encounter at their attorney’s office a decade later sparked the Graedons’ first real doubts about just how exhaustive the FDA’s analyses were. There, an employee whose young son had attention deficit disorder told them, “When he goes off to school on Ritalin, he does very well.” But when he was on the generic, the teachers complained about his ability to function for the same length of time. In the late 1990s, the Graedons started to receive letters from readers and radio listeners recounting bad experiences with a range of generic drugs. One patient had suffered anxiety and insomnia after switching to generic Synthroid: “I was sweating more than usual and my heart felt as though it would pound out of my chest.” Another patient had become manic after taking generic Fioricet for a migraine: “I was stimulated beyond belief—typing letters and sending faxes at 3:00 a.m.”
The Graedons published these cases in a 1998 newspaper column, raising the question of “how well the FDA monitors generics after they have been approved.” By 2002, Joe Graedon had contacted the FDA and connected with the director of the Office of Generic Drugs, Gary Buehler. It was the start of a fraught communication that spanned years.
Before long, the People’s Pharmacy website became a clearinghouse for patients wrestling with terrible symptoms after a switch to generic drugs. Patients wrote in, desperate for answers. Graedon forwarded the complaints to Buehler at the FDA. Between 2007 and 2009, he relayed complaints about at least twenty different drugs, believing that highly placed officials would want to know what patients were experiencing.
In a January 2008 email to Robert Temple, deputy director for clinical science at the FDA’s Center for Drug Evaluation and Research, Graedon forwarded a complaint about generic Dilantin, an epilepsy drug: “After being on 300 mg. of dilantin for more than 20 years, I tried the cost cutting measure of replacing it with the generic. Numerous times I had seizures.” Graedon wrote to Buehler about the complaint, “This is most worrisome. We trust you are taking this as seriously as we are.”
As Graedon scrutinized the FDA’s standards for bioequivalence and the data that companies had to submit, he found that generics were much less equivalent than commonly assumed. The FDA’s statistical formula that defined bioequivalence as a range—a generic drug’s concentration in the blood could not fall below 80 percent or rise above 125 percent of the brand name’s concentration, using a 90 percent confidence interval—still allowed for a potential outside range of 45 percent among generics labeled as being the same. Patients getting switched from one generic to another might be on the low end one day, the high end the next. The FDA allowed drug companies to use different additional ingredients, known as excipients, that could be of lower quality. Those differences could affect a drug’s bioavailability, the amount of drug potentially absorbed into the bloodstream.
But there was another problem that really drew Graedon’s attention. Generic drug companies submitted the results of patients’ blood tests in the form of bioequivalence curves. The graphs consisted of a vertical axis called Cmax, which mapped the maximum concentration of drug in the blood, and a horizontal axis called Tmax, the time to maximum concentration. The resulting curve looked like an upside-down U. The FDA was using the highest point on that curve, peak drug concentration, to assess the rate of absorption into the blood. But peak drug concentration, the point at which the blood had absorbed the largest amount of drug, was a single number at one point in time. The FDA was using that point as a stand-in for “rate of absorption.” So long as the generic hit a similar peak of drug concentration in the blood as the brand name, it could be deemed bioequivalent, even if the two curves reflecting the time to that peak looked totally different.
Two different curves indicated two entirely different experiences in the body, Graedon realized. The measurement of time to maximum concentration, the horizontal axis, was crucial for time-release drugs, which had not been widely available when the FDA first created its bioequivalence standard in 1992. That standard had not been meaningfully updated since then. “The time to Tmax can vary all over the place and they don’t give a damn,” Graedon emailed a reporter. That “seems pretty bizarre to us.” Though the FDA asserted that it wouldn’t approve generics with “clinically significant” differences in release rates, the agency didn’t disclose data filed by the companies, so it was impossible to know how dramatic the differences were.
As more patients wrote in to the People’s Pharmacy website about their struggles with generics, the Graedons found that time-release drugs received more complaints than others. One was generic Toprol XL, the drug that had so troubled Harry Lever’s patients. Almost as soon as the generic became available, patients taking it began writing in to the Graedons, reporting dramatic increases in blood pressure and heart rate. They were nauseous and dizzy, they had hives and headaches, their hair fell out, and they had trouble sleeping and suffered vivid nightmares. Graedon forwarded some of the accounts to Buehler at the FDA. “What are you doing about this?” he asked. “If there are deaths it could turn into a big scandal.” As the Graedons later wrote of the response in one of their columns, “We were told, in essence, ‘We’ll get back to you.’ We heard nothing more.”
But it was another drug entirely on which Graedon planted his flag. Wellbutrin XL was a popular antidepressant sold by GlaxoSmithKline. As an “extended-release” formula, the drug dispensed its medicine into the bloodstream over hours, unlike older forms of the drug, which had to be taken several times a day. When the patent on Wellbutrin XL expired in December 2006, the Israeli manufacturer Teva began marketing the first generic version of the pill and contracted with Impax Laboratories to manufacture it. Teva sold the generic under the trade name Budeprion XL. The active ingredient was bupropion. Almost immediately, the People’s Pharmacy was flooded with troubling emails from patients complaining of headaches, nausea, dizziness, irritability, sleep problems, and anxiety attacks. Some people said that their generic pills smelled bad. Many cried easily. Some became suicidal. Others reported having tremors and even seizures. “I shake so badly sometimes I have trouble drinking water from a glass or I can’t hit my mouth with a forkful of food!” one patient wrote. Nearly all the patients reported that their depression had returned.
The similarity of the reports astounded Graedon. One patient wrote, “I have no history of suicidality, but a day after switching to the generic, I went into a week of steadily rising panic. . . . I was psychotic, self-loathing way WAY beyond anything I have ever experienced. I made it through the worst of it, called a suicide hotline, took two Ativan and didn’t take any more of the Budeprion. The next day I felt much better, and today I’m back to my normal self.” Another patient reported that after two weeks on generic Wellbutrin, “I ended up getting highly aggressive. I spent all the money in my checking account. I cut off cars in the highway and ran a red stop light. I could have been killed or killed someone else.”
One patient suffered a “full-blown panic attack with dizziness at 65 mph. . . . Then I began to cry . . . thinking, what’s wrong with me? AM I going crazy? Not getting any relief, I got out of my car and sat on the side of the turnpike as the giant trucks and cars went flying by. I was forced to lie down in a drainage ditch along the road and covered my ears to calm myself down because I had uncontrollable thoughts of running into traffic.”
Graedon reported the deluge of messages to Robert Temple at the FDA, who didn’t respond. But the FDA had also been amassing patient complaints. Between January and June 2007, more than eighty-five reports of adverse reactions to Budeprion XL rolled into the agency, where officials were largely dismissive, suggesting that the patient reactions could be psychosomatic and might be caused by changes in the tablet’s shape and color.
By April 2007, however, the Graedons announced good news to their readers that seemed to herald cooperation from the FDA: “We have arranged with the FDA to analyze any generic pills that readers of The People’s Pharmacy suspect are not equivalent to their branded counterparts,” they wrote. “Please describe your experience and send your generic pills with as much information as possible.” Medicine from across the country filled the Graedons’ mailbox, including “hundreds and hundreds” of Teva’s Budeprion XL tablets. Right away, Graedon could tell something was wrong: “They smelled to high heaven.” He sent them to the FDA.
At a fund-raiser, Graedon happened to run into a chemist at Burroughs Wellcome, the company that had developed the chemistry behind Wellbutrin. “What’s going on with this funny smell?” Graedon asked.
“That’s a no-brainer,” the man said, explaining that it was a sign that the pills were deteriorating. “It’s a problem with the manufacturing process.”
As he waited for results from the FDA’s tests, Graedon continued to forward complaints about Teva’s Budeprion XL to the agency. “What alarms us most,” he wrote to Temple on June 21, 2007, “is that many of these people have described suicidal thoughts as a result of this switch.”
Graedon was sick of waiting for the FDA’s test results. He spoke with experts about what could produce the symptoms that patients were reporting. He even reached out for help to independent laboratories. Tod Cooperman, the president of ConsumerLab in White Plains, New York, was quick to join his cause. ConsumerLab tested the 300-milligram dose of Teva’s Budeprion XL against that of GSK’s Wellbutrin XL. The results revealed the likely source of patient distress: the generic dumped four times as much active ingredient during the first two hours as the brand name did. Graedon compared the effect to guzzling alcohol. “If you sip a glass of wine over the course of two or three hours, you’re not going to feel drunk,” he explained. “But if you drink the whole thing in fifteen minutes, you’re getting too much too fast.”
The Graedons believed that this “dose dumping” explained why many patients were experiencing signs of overdose, such as headaches and anxiety, followed by symptoms of withdrawal, including renewed depression and suicidal thoughts. Teva flatly rejected the ConsumerLab report and claimed that the independent laboratory’s testing method was “inappropriate.” The FDA was silent.
In December 2007, Graedon and Temple of the FDA were both asked to be guest speakers on a Los Angeles radio show to discuss the FDA’s requirements for generic drug approvals. During the show, the host asked Temple about the differences between generic and brand-name Wellbutrin uncovered by ConsumerLab. For the first time, Temple admitted that the generic and brand-name drugs released their active ingredient at different rates. “The main point here is that yes, the generic releases a little sooner,” Temple said. “That could be described as an advantage.” He added that the early release was “unlikely” to make any real difference in treating patients’ depression. Graedon was astonished to hear Temple describe the early release as an advantage, as he wrote to Tod Cooperman after the show. “One wonders what Alice-in-Wonderland world the FDA is living in where up is down and a rapid release of 300 mg. bupropion is desirable.”
Temple later told a journalist, “Most of the excitement from people who worry about this come from isolated reports. Then you look at the results of bioequivalence studies, and there is nothing to worry about.”
Graedon wanted to speak to Temple personally. But in January, after getting no reply from him, he tried reaching Buehler: “We are at our wits end about how to proceed with this Budeprion XL situation. . . . You cannot seriously believe that the hundreds of similar reports are all coincidence,” he wrote. He continued to pepper the FDA with messages, sometimes on a daily basis. As he wrote to a colleague, “We have been nagging, cajoling, badgering, whining, complaining and otherwise making asses of ourselves with regard to the FDA.”
By March 2008, Graedon was furious. It had now been almost a year since the FDA’s promise to investigate Teva’s drug. But seemingly nothing had happened. The issue was devouring his time, and he’d have preferred to drop it. But complaints from patients continued to stream in: they were hospitalized, underwent invasive workups, lost jobs and homes to depression. As one patient wrote, “I have a long road ahead of me—just to get back to where I was—but then I’ll never get back. Because my experience with the generic destroyed everything in my life that was important to me.”
On March 17, 2008, unable to restrain himself any longer, Graedon wrote Buehler about the messages, “They JUST KEEP COMING! . . . These people are YOUR boss! They pay your salary. You are accountable to them. They are not nutcases, crackpots or idiots. They are real people with real problems and you must be responsible.” The next day, Buehler sent a curt reply to say that the agency was still working on the report. Graedon wasn’t pacified. The next month he followed up again: “I keep saying this . . . lives are at stake here. We must have your report sooner rather than later.”
On April 16, 2008, more than a year after Graedon first alerted the agency to patients’ troubles with the drug, the FDA released its report and assured consumers that it had been right to approve the 300-milligram dose of Budeprion XL. Despite “small differences” in how it dissolved, the FDA said that Teva’s drug met the agency’s standards and therefore was “therapeutically equivalent” to Wellbutrin XL. It concluded that the “recurrent nature” of depression—not drug failure—was the likely cause of patients’ problems.
As Graedon read through the report, he was appalled. Rather than test samples in a laboratory, which Graedon had been promised in 2007, the FDA simply reviewed the bioequivalence data that had been submitted by Teva with the drug’s application in 2003. Even worse, the data that the FDA had reviewed was from the 150-milligram dose, not the 300-milligram dose. Typically, generic manufacturers test only the highest dose, known as the “reference listed drug.” The FDA assumes that the lesser doses are proportional and will behave similarly in the body. But in the case of Budeprion XL, the higher 300-milligram dose was never tested “because of the potential risk of seizures” in volunteers, the FDA explained. Graedon was astonished. How could the FDA know the 300-milligram dose was bioequivalent without any data? Yet the agency had approved it for millions of people to take, based on test data from a lower dose.
What really floored Graedon were the test results for the generic and brand versions of the 150-milligram dose, which the FDA had included in its report. These were reflected in two curves that mapped the subjects’ blood test results. The curves were completely different. With one glance, Graedon knew that they couldn’t possibly have the same effect on a patient. The brand had a gradual slope leading to a high peak at around five and a half hours. The generic had a sharp rise that peaked at around two hours. The difference was “so incredibly obvious,” he said, that “any school kid” could have figured it out.
If that was what the FDA was relying on to call the same—a drug the agency had no data on, which they didn’t even test for their report, which was presumed the same based on results for a lower dose, and which were obviously different to the naked eye—things were even worse than the Graedons had suspected. “We were like, ‘Holy cow, we’ve got something big here,’” Graedon recalled. “This is the card that brings down the house of cards. In some respects, it changed everything. I just never imagined the approval process was so screwed up.”
The Graedons wrote to Temple and Buehler: “After reviewing the report posted today, we believe you have misled the American public.” Graedon had hoped that the FDA would come to the rescue of patients, but the agency seemed to be operating instead to their detriment, and from behind a closed door. Except for those two curves, the agency did not publicly release any bioequivalence data submitted by the companies. Temple later told a journalist that while the FDA study was “not misleading, it may have been inadequate. . . .” Uncertain what else to do, Graedon cast a wide net throughout the scientific community. He saw the issue as a public health emergency, but he felt stumped. Should he go to Congress? To medical lobbyists? To journalists? What was the magic pressure point to make the agency act?
By now, Graedon had become email companions and confidants with Harry Lever at Cleveland Clinic, both men swimming against the tide of accepted medical and political wisdom. Both were asking similar questions. In a sympathetic email to Graedon, Dr. Steven Nissen, chairman of Cleveland Clinic’s Cardiovascular Medicine Department, who had initially put the two men in touch, called the agency’s stonewalling “appalling.” As a high-profile patient advocate, Nissen was familiar with FDA inaction. He’d led numerous inquiries into drug safety that raised questions about the agency’s review process. He wrote to Graedon, “Don’t expect any action from the FDA. In these cases, they invariably operate in denial mode because, to acknowledge the problem, it makes it look like they screwed up.”
Graedon started hearing from a former high-ranking FDA official, who had offered Graedon guidance and information on the condition of anonymity. Graedon referred to his source as Deep Throat. “He basically reinforced our position that there is a problem and that we are on the right track and that we should not give up or give in,” Graedon wrote to Cooperman. In July 2008, Graedon met with FDA officials. They agreed to collaborate with him on a study evaluating the bioequivalence of Budeprion XL in patients who had problems with the generic. He figured the agency had agreed to the study to “shut us up once and for all,” Graedon told a reporter. Yet six months later, in January 2009, the FDA had yet to make any headway. As Graedon wrote to an FDA official, “It frequently feels as if we are dropping pebbles down a very deep, dark well. We never hear a splash.”
He continued to send complaints, including one in which a man wrote that the Teva version of Wellbutrin XL “almost caused my wife to commit suicide.” Graedon forwarded the report to Buehler and Temple on a Friday evening in February 2009. “Guys, this has to affect you, right?” he wrote. “I mean seriously, after all this time you are not going to tell us that this is psychosomatic. . . . When are we going to do something about this?”
In December 2009, the Wall Street Journal reported that Teva and Impax planned to conduct a bioequivalence study of the 300-milligram dose of Budeprion XL under the agency’s guidance. After a year, that study faltered, and the FDA decided to undertake its own.
Finally, in October 2012, the agency issued a press release about its findings, which confirmed what the Graedons had known all along: the 300-milligram Budeprion XL dose was not therapeutically equivalent to Wellbutrin XL, as the drug did not deliver enough active ingredient. The generic “is not absorbed into the bloodstream at the same rate and to the same extent” as the original drug, the FDA reported. Tod Cooperman of ConsumerLab was pleased but unimpressed. “We’re proud we were able to help uncover this problem, but it’s unfortunate that it’s taken the FDA five years to get the product removed,” he told the Associated Press. By then, the FDA had asked the other four manufacturers of generic Wellbutrin XL to conduct bioequivalence studies of their own 300-milligram pills. Of the four generic brands, one made by Watson Laboratories also failed, and the company withdrew its product.
Graedon wanted to contact Gary Buehler, director of the FDA’s Office of Generic Drugs, and ask: Why did it take the agency five years after he’d first reported patient problems with it to test Teva’s drug? Why had the drug been approved without specific bioequivalence data? But he couldn’t, because in October 2010, about eighteen months after plaintiff lawyers geared up to sue Teva on behalf of patients, Buehler had left the FDA. He’d taken a job as vice president of global regulatory intelligence and policy—at Teva.
Had the FDA wanted to tackle the problem of bioequivalence head-on, it needed to look no further than its own adverse event database, which collected reports from the public. It was also chock-full of complaints about generic drugs: patients had found their medicine covered in mold or smelling intensely of “rotten fish” or “cat urine”; some reported no therapeutic effect from their drugs, “as if the drug was not working at all,” as one patient wrote in; others had been directed by the FDA to contact the drug makers directly, only to hear nothing in return when they sent in their drugs for testing; and there were reports of foreign objects in pills, from eyelashes to insects.
While the FDA viewed these complaints as “an important source of information about potential safety concerns,” an agency spokesperson later explained that they required “careful review and interpretation.” The number of complaints could be affected by anything from legal proceedings to press coverage.
In Mount Laurel, New Jersey, in January 2016, Carla Stouffer, a seventy-one-year-old retiree, would have simply swallowed her daily capsule for high blood pressure, amlodipine/benazepril, were it not for a flash of movement. On closer inspection, she noticed a small, centipede-like bug stuck halfway inside the capsule, alive and wiggling. Horrified, she watched as the bug tried to free itself from the pill casing. She’d never thought before about who made her medicine. But she learned that the maintenance drug, which she’d gotten in a three-month supply from the prescription benefit manager Express Scripts, was made by the Indian company Dr. Reddy’s Laboratories. Her complaint became one of over a million related to pharmaceuticals filed with the FDA that year.
Much like the doubtful patients, Graedon had lost his trust in the FDA. “I had always believed the FDA had its stuff together, and just accepted that the approval process was perfect, because that’s what everybody believed,” said Graedon. But the more he learned, the less confident in the FDA he felt. One night at a party, he spoke with a GlaxoSmithKline executive who’d had too much wine. The man shared with him that many companies were moving their manufacturing operations to China in order to reduce operating costs—a new problem for Graedon to consider. He suspected that while the FDA was busy with its decades-old regulations, the companies making America’s medicine were playing hide-and-seek with the agency all over the world.
This flipped Graedon’s thinking on its head. He had assumed all along that the drugs the FDA approved met the agency’s standards, but the standards, he realized, were flawed. What if the drugs plaguing America’s patients were so bad that they did not meet even the FDA’s flawed standards and were being wrongly approved? That would mean that both the FDA’s standards and its approval process were broken. Even if the FDA fixed both, however, that would do nothing to solve the larger manufacturing problem: America no longer made its own drugs.