I’m kneeling on my driveway, watching blood pour from my nose and stream toward the street. It’s my fourth big nosebleed in four days, and as my husband bundles me into the car, I’m thinking the worst.
After a gauntlet of tests, all of which are negative, my doctor says she thinks the nosebleeds were triggered by my antidepressant—specifically by my switching from a generic version to the brand-name. A few months earlier, when the generic hadn’t diminished my panic attacks, she had suggested trying the brand-name, and I’d started it a few days earlier. “You’re suddenly getting a lot more of the active ingredient,” she explains now. “Which you were supposed to get before, on the generic, but clearly weren’t. That’s why you’re having nosebleeds. They’ll stop in a few days.”
Most people think generic medications are identical to brand-name drugs; I certainly did. After all, that’s what pharmacists, insurance companies, and doctors tell us. But it’s not exactly true. For one thing, most generics are manufactured abroad, where lax standards, lack of regulation, and outright fraud compromise their quality. Those issues have gotten some well-deserved attention in recent years. For another, while generics are considered “bio-equivalent” to brand-name drugs—meaning they behave the same way in the body—they are not required by the Food and Drug Administration (FDA) to contain exactly the same amount of active ingredient or to deliver it at the same rate or in the same way. In fact, they can’t deliver it the same way, since patents on brand-name medications often include the delivery system.
Most people think generic medications are identical to brand-name drugs; I certainly did. After all, that’s what pharmacists, insurance companies, and doctors tell us. But it’s not exactly true.
While many people tolerate the differences between generic and brand-name formulations, some of us—as I learned the day I found myself bleeding in the driveway—do not. When I went looking into those differences, I found significant evidence to support this conclusion. Yet for the most part, western medicine insists it cannot be true.
Ever since the 1984 Hatch-Waxman Act cleared the way for the wide-scale marketing of generic drugs in the U.S., the FDA has required that generic drugs have the same active ingredient, strength, and dosage form as brand names. “The generic manufacturer must prove its drug is the same (bioequivalent) as the brand-name drug,” said Sandy Walsh, an FDA press officer, in an email. Given that generics make up close to 90% of the U.S. drug supply, and that Americans spend around $300 billion a year on prescriptions, a lot is riding on this system working—about $117 billion a year.
So it helps to understand the ways in which brand names and generics hit the market. Pharmaceutical companies that are developing a new (brand name) medication file a New Drug Application (NDA) with the FDA, showing that the drug is both safe and effective for humans. This is done by submitting meticulous documentation of animal and human studies, detailed records of the manufacturing process, analysis of dosage and inactive ingredients, and other evidence that the benefits of the new drug outweigh any risks. Putting together an NDA takes years and costs millions of dollars, much of it spent on research.
The road to generic approval is a lot shorter. When the patent on a brand-name drug is about to run out, companies typically file an Abbreviated New Drug Application (ANDA), signaling their intent to produce a generic version of the drug. An ANDA requires no animal trials and very limited human trials. While a generic is supposed to be chemically similar to its brand-name counterpart, with the same active ingredient in roughly the same amount, it is allowed to vary in quantity by about 10% in either direction. Manufacturers need only test their generic against the brand name in a tiny group of healthy volunteers to show it is bioequivalent. They don’t have to show therapeutic equivalency—that is, they don’t have to prove that patients respond to the generic in the same way they respond to the brand name. It is instead assumed that the generic will produce the same effect because the active ingredient is supposed to be the same. Many ANDAs are aspirational, first filed before a manufacturer has figured out how exactly to produce a generic version of a brand-name drug. And since FDA approval can take as little as six months, an ANDA might be approved before a manufacturer has finalized a generic formulation.
Many medical professionals believe this approval process is enough to protect patients and ensure consistency. Experts like Michel Berg, a neurologist who directs the University of Rochester’s Epilepsy Center, say that when people complain about generics not working the way brand names do, it’s usually because they didn’t take the medication correctly: They skipped or added a dose, took it at the wrong time of day, swallowed it with or without food, or in some other way violated what Berg calls good “medication hygiene.”
The road to generic approval is a lot shorter.
Richard Hansen, dean of Auburn University’s Harrison School of Pharmacy, points to another contributing factor: the nocebo effect. People expect generics to cause more side effects and be less effective, so that’s what they experience. Hansen calls this the public perception bias. “There’s actual clinical studies that show if you give 100 people the exact same thing but tell half of them that they received a generic, the half you told are going to have more adverse events and lower efficacy,” he said. His solution: education. Teach people that generics are just as good as brand-name drugs and their attitudes will change.
But human error and the power of suggestion can’t possibly be the whole story. What about experiences like mine, in which switching to a brand-name drug from the generic caused the problem? Clearly that wasn’t the nocebo effect. And while I’m as fallible as anyone else, I’m certain that in this case I was taking the medication correctly.
Many of the experts I talked to for this story dismissed or downplayed questions about generics. One researcher who didn’t is Jacinthe Leclerc, an assistant professor of nursing at the University of Québec at Trois-Rivieres. Leclerc and her colleagues noticed an interesting pattern when they studied cardiac drugs: When a new generic became available and patients switched, they saw many more adverse effects. “For example, switching from a brand name anti-hypertensive drug to a generic one, the patients got more swollen,” she explained. Leclerc and her team analyzed data for a number of widely prescribed cardiac medications and found that when new generics were introduced, and people switched to them, hospitalizations and emergency room visits went up. Leclerc says the nocebo effect can’t possibly explain this finding.
In fact, there’s a counterargument to the nocebo premise, one Hansen and others don’t take into account: Most people want generics to work because that’s the only way they can afford their medication. (When asked if his team had considered this, Hansen said, “That’s not something we’ve looked at in particular.”) Erica Smith, a 50-year-old software designer in Oakland, California, found herself in this situation after her pharmacy switched her to a generic antidepressant made in India. Smith began having symptoms like brain “zaps” and extreme irritability, signs that she wasn’t getting as much of the active ingredient as she had before. She looked into getting the brand-name, which cost $400 for a month’s supply. “Insurance of course did not cover that, so of course I didn’t get it,” she recalled.
Charlynn Schmiedt, a 36-year-old entrepreneur in San Dimas, California, was one of hundreds of patients who reported massive side effects and symptoms after switching from the brand-name Wellbutrin, a popular antidepressant, to Teva Pharmaceuticals’s generic extended-release, version, bupropion XL. Schmiedt’s doctor had given her a few weeks’ worth of brand-name samples, and as she took them her depression and anxiety began to subside. When the samples ran out, she filled a prescription and got the Teva generic. “It was a massive 180-degree shift,” she remembered. “It was horrible. I got really angry, I got agitated, I would cry at the drop of a hat. I was a wreck.”
Schmiedt lasted three weeks on the generic before she quit. Like many patients, she couldn’t afford the brand-name, so she went through months of trial and error before finding another medication that helped her symptoms. In 2012, after years of complaints from patients like Schmiedt, the FDA more or less acknowledged that Teva’s generic was problematic by pulling it from sale, a step the agency almost never takes.
Journalist Katherine Eban, author of the book Bottle of Lies: The Inside Story of the Generic Drug Boom, was surprised by the FDA’s reversal but not by Teva’s problems. The vast majority of generics—no one seems to know exactly what percentage—used in the U.S. are sourced or manufactured in India, China, and other countries. Eban spent 10 years investigating overseas manufacturers and found a jaw-dropping range of problems, including poor-quality ingredients, contamination, dangerous plant conditions, and outright fraud and deception. Pharmaceutical companies like Ranbaxy, a former Indian manufacturer, deliberately falsified data to fool regulators, lying to regulators about safety tests and results and then covering up those lies with more falsehoods.
The reality is that the FDA simply doesn’t have the resources to monitor overseas drug makers the way they do U.S. manufacturers. The result, according to Eban, is that many of the medications we take today are ineffective or worse. “We need systematic surveillance testing of our drugs, which is not happening,” she told me. And that doesn’t apply just to medicine made overseas. No matter where they’re made, generics are subject to far less testing than original brand-name drugs. As the FDA’s Walsh explained, “Generic drug applications are termed ‘abbreviated’ because they are not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product performs in the same manner as the innovator drug.”
Pharmaceutical companies like Ranbaxy, a former Indian manufacturer, deliberately falsified data to fool regulators, lying to regulators about safety tests and results and then covering up those lies with more falsehoods.
“We’ve got a lot of companies that lie, that manipulate data,” said Joe Graedon, a pharmacologist and co-founder of the pharmaceutical watchdog site People’s Pharmacy. “There’s examples of fraud left and right. Quality control has been clearly a huge problem both in China and India but many other countries as well, and the FDA is probably not monitoring many of these countries as well as it should.”
Douglas Kamerow, a family doctor and medical researcher in Washington, D.C., put it this way in an article in The BMJ: “Full clinical trials are not required to approve generics—that’s why they are so inexpensive, after all—so true clinical equivalence is never tested.”
But what about the Wellbutrin example? Presumably that wasn’t the result of fraud or low standards. How could something like this happen if, as the FDA insists, generics makers are required to prove that their products are bioequivalent? The problem in this case turned out to be the rate at which the extended-release generic was absorbed into the body. “[Levels of] the brand name peaked somewhere around five or six hours. The generic peaked around one or two hours,” said Graedon. So people who took the generic got a big dump of the active ingredient too quickly, and then it left their systems too soon. “That was what, in my estimation, led to all the complications people experienced,” he added. “They had a lot of side effects from the generic and they didn’t get the clinical benefit of this antidepressant.” (Teva did not respond to multiple requests for comment.)
To visualize the process, Graedon asked me to imagine a spreadsheet tracking a city’s water usage over a 24-hour period, showing peaks and valleys depending on the time of day. For instance, a lot more water would be used at 7 a.m., when people are showering and cooking, than at 2 a.m., when most people are asleep. That, he says, is the kind of detailed data needed to follow exactly how a generic is absorbed. “You want to know how much was absorbed at half an hour, an hour, two hours, all the way through,” he said. The bupropion XL problems would have been obvious with this kind of tracking over time. According to Graedon, the FDA asks for this information from drug companies but doesn’t incorporate it in decisions about which generics are approved.
Another reason generics sometimes don’t behave the way brand drugs do involves what’s known as inter-subject variability. William Ravis, a retired professor of drug discovery and development at Auburn University, spent four decades studying pharmacokinetics, or how drugs move through the body. He pointed out that certain drugs have a lot of variability in terms of how they metabolize and behave. “The majority of patients might not show a difference in exchanging one product for another,” he explained. “But if you handle the drug too much differently from somebody else or you’re taking other medications than somebody else, that may put you right on the edge where it’s toxic or you lose the therapeutic effects.”
For example, Ravis said, it’s been well documented that switching from one thyroid medication to another, even if they’ve been shown to be bioequivalent, can cause problems. “There are things going on there in absorption, or body sensitivity to T4 or T3 products, or thyroid hormones, that is different in different patients,” he said. “Drugs produce their effects on receptors in the body and those all don’t respond the same way in every patient.” In fact, one member of his own family pays out of pocket for a brand-name thyroid drug that’s not covered by their insurance, because the generics don’t work for them.
Neurologist Gregory Krauss of Johns Hopkins University actually filed Freedom of Information Act requests to get bioequivalence data from the FDA on five generic versions of the epilepsy drug carbamazepine, and learned that maximal concentrations—the peak amount of active ingredient—differed by as much as 40 percent. While many people tolerate those kinds of discrepancies, many don’t. And they might never realize that the problem is the generic version they’re taking rather than the medication itself.
Finally, there’s the issue of what experts call the therapeutic index, meaning the margin between an effective dose and a toxic one. If that margin is large, manufacturing discrepancies don’t matter as much; a little more or less of the active ingredient will go unnoticed by most patients. But the smaller the margin—the narrower the therapeutic index—the more likely patients are to experience side effects and failures.
While many people tolerate those kinds of discrepancies, many don’t. And they might never realize that the problem is the generic version they’re taking rather than the medication itself.
Many psychiatric drugs fall into this category, which might explain why they’re among the most problematic. Studies of antidepressants like Effexor and Celexa, along with anti-psychotics like Risperdal, Clozaril, and Dogmatil, all highlight the fact that some patients do worse on the generic versions than on the brand-name medications. Research on other drugs with narrow therapeutic indexes, or NTIs, like cardiac drugs, immunosuppressants for transplant patients, and epilepsy drugs suggest similar discrepancies, though other studies on seizure medications showed no significant differences between brands and generics. “The narrow therapeutic index drug class, those are tricky,” agrees Jingjing Qian, an associate professor in health outcomes and research at Auburn University. “But in order to verify if that difference is perception or real difference—that needs more research. And there’s no incentive for industry to study generic drugs.”
Which is unfortunate for those of us who take those drugs. One of my daughters had a terrifying experience after a change in her insurance forced her to switch from a brand-name antidepressant to a generic one. When her depression roared back following the switch, the psychiatrist upped her dose. A month later, the pharmacy switched her prescription from the Indian generic she had been taking to what’s called an authorized generic, meaning it’s the same exact drug made by the same company that produces the brand-name, but it’s marketed as a generic. And now something was clearly, scarily wrong. Even from a thousand miles away I could tell she was not in good shape. She was speaking so fast I could barely follow; what I did understand was that her anxiety was off the charts, her muscles were twitching and spasming, she hadn’t slept properly in days, and she was talking about suicide.
Because I’ve had my own history with generics, I wondered about the medication change. Her symptoms were consistent with serotonin syndrome, a potentially fatal condition caused by a sudden overload of serotonin. Maybe her depression symptoms came back on the generic because it didn’t contain enough active ingredients; then, when the pharmacy switched her to the authorized generic, maybe she was suddenly getting way too much of the active ingredient. She cut back the dose, and thankfully her symptoms subsided. I now pay out of pocket for her to take the brand-name version. She’s had no further problems.
Raising these kinds of questions about generics is deeply unpopular. And it’s understandable, in a way, because our healthcare system relies so heavily on generics. Michel Berg, who directs the University of Rochester’s Epilepsy Center, represents the views of many medical professionals when he says, “There’s no perfect here. I think mostly [generics are] pretty good. The cost savings of generics is just so great. I think the advantage of the generics by far in that sense outweighs what problems that might exist that I think are fairly infrequent.”
Whether Berg is right or not, without generics, we’d be seeing much higher drug prices and even more drug shortages. Atorvastatin, a generic cholesterol medication, costs about $15 a month, while its brand-name equivalent, Lipitor, goes for between $450 and $500 a month. Abilify, an antipsychotic and antidepressant made by Bristol-Myers Squibb, costs between $700 and $900 a month; the generic version, aripiprazole, goes for around $8. And these aren’t even extreme examples. Cuprimine, a brand-name drug made by Bausch Health to treat rheumatoid arthritis, retails for $26,000 a month; the generic version, penicillamine, costs $7,000.
Raising these kinds of questions about generics is deeply unpopular. And it’s understandable, in a way, because our healthcare system relies so heavily on generics.
Last September, the Trump administration approved a plan to let states import cheaper medications from Canada and elsewhere, though it is still unclear how exactly this will affect consumers. Several years ago AARP, whose more than 38 million members take an average of 4.5 medications apiece, announced an initiative called Stop Rx Greed, inviting people to “tell Congress to stop Rx greed and cut drug prices now!” Media coverage about profit-hungry pharmaceutical companies like Mylan, the makers of EpiPen that infamously jacked up its price 400 percent, make it politically untenable to do anything that makes the situation worse for consumers.
“There’s no plan B for our drug supply,” Eban told me. “We’re facing critical drug shortages, we are reliant on these medications, and there is no meaningful price regulation for brand-name drugs. There is a tremendous amount of political pressure for these low-cost generics.” In a recent story about Eban’s book, published in a trade magazine for biopharma executives, a reviewer commented, “The entire U.S. pharma industry is under attack for its pricing policies, so who wants to question the quality of generics . . . that keep drug costs down?” Who indeed. We’d much rather believe that patients who report issues with generics are biased or victims of misperception because if they’re not, if they’re right about these problems, the whole system is screwed.
So where does that leave people like Erica Smith, Charlynn Schmiedt, and the rest of us who have struggled with generics? Awareness is key, starting with awareness of our own perceptions and behaviors. While reporting this story I bought a pill dispenser so I could, as Michel Berg suggested, practice better medication hygiene. But we also need to be aware that there are major manufacturing and safety concerns with some generics. If you think something’s wrong with any medication, generic or not, report it on the FDA’s MedWatch site so the agency can track complaints about it and, ideally, investigate.
There is clear scientific evidence that some drugs do affect some people differently, no matter what doctors and pharmacists and insurance companies say. LeClerc of the University of Quebec thinks people need to learn to advocate for themselves when things don’t feel right, and medical professionals need to listen. “When we listen carefully to patients, they say there is something wrong once they switch [from a brand to a generic],” she said. “It cannot only be in their heads.”