Just as good?
In the contentious debate over insuring Americans’ health, the value of generic prescription drugs is a rare point of consensus. Patients, physicians, employers, politicians -- all hail generics as powerful treatment for a swelling healthcare tab. On average, these copycat medicines cost less than a third of the brand-name drugs they mimic. In turn, the competition they provide drives down the cost of those first-to-market drugs.
Officials of the Food and Drug Administration insist this feat of economics comes without any compromise to a medicine’s effectiveness. To be marketed in the United States, these low-cost medicines must be approved by the FDA, which ensures they are “bioequivalent” to their brand-name counterparts -- the same dose of the same active ingredient, delivered in the same way, and manufactured according to the same standards of quality.
The Generic Pharmaceutical Assn. touts them with a slightly catchier slogan: “Same Medicine. Same Results.” But sometimes, patients and their doctors beg to differ.
A switch from a long-used brand-name drug to its generic equivalent can, on occasion, bring a shifting profile of side effects. In a number of cases documented in medical journals and recounted in interviews with physicians, a generic version of what is often called a “pioneer” drug simply doesn’t appear to work as well for many patients.
“Everybody thinks generics are swell: To suggest otherwise is like saying you don’t love your mother,” said Dr. Peter R. Kowey, chief of cardiovascular diseases at the Philadelphia area’s Main Line Health System, who reviewed the issue of generic substitution of certain heart drugs for the American Heart Assn. But between some pioneer drugs and their generic imitators, Kowey said, “we are concerned that the margin of difference is large enough” to risk patients’ health.
Last December, the American Epilepsy Society called on the FDA to approve a large clinical trial to determine “once and for all” whether the substitution of brand-name drugs with generics increases the risk of “breakthrough” seizures or toxicity among patients with epilepsy. This type of research would probably take years. But until such a study is completed, the society declared, it would oppose measures by state, federal or private insurance programs that would limit physicians’ choices in prescribing anti-seizure medicines.
Last fall, an independent laboratory, prompted by a flurry of consumer complaints, presented evidence that a generic version of the once-a-day antidepressant Wellbutrin XL may be less effective than the original at reducing some patients’ depressive symptoms. An agency spokeswoman said the FDA is investigating the matter and will make its findings public when the inquiry is complete.
In a report released today, the New York-based ConsumerLab.com, which conducted the Wellbutrin XL analysis, also urges the FDA to review the performance of a new generic for Toprol XL, a once-a-day version of a high blood pressure drug that is the fifth most-prescribed medicine in the United States. That challenge comes after dozens of patients complained to the People’s Pharmacy -- a multimedia source of information about drugs and supplements -- of erratic spikes in blood pressure and side effects after they had switched from Toprol XL to a new generic version of the drug.
Cardiologists, meanwhile, have been growing more vocal in their concern about “generic substitution” for newer, brand-name drugs. They have had long-standing worries about the effect of switching patients whose blood has been thinned with Coumadin to generic versions of the anticoagulant, including warfarin. Many have warned that patients with heart arrhythmias should be switched to generic drugs only when necessary. And many cardiologists view the swelling field of generic blood-pressure and cholesterol drugs with some distrust.
The American Assn. of Clinical Endocrinologists, the Endocrine Society and the American Thyroid Assn. joined voices in 2004 to warn that patients with hypothyroidism could be harmed by switching among the many generics used to treat the condition. And physicians who care for organ transplant recipients have opposed generic substitution of immunosupressant drugs for their patients without a transplant specialist’s prior approval. Societies that represent these doctors have been active in seeking state laws that would limit such switches.
Kathleen Jaeger, president and chief executive of the Generic Pharmaceutical Assn., dismisses all of these debates as “misinformation campaigns” masterminded by brand-name pharmaceutical companies. As these companies’ most profitable medicines face competition from generic upstarts, Jaeger said, they seek to “extend their monopoly” by sowing doubt in the minds of physicians, pharmacists and patients about the quality of the cheaper substitutes.
Those who would question generic drugs’ equivalence to the brand-name drugs they mimic are calling into question a stringent FDA review process, said Jaeger. “They do a disservice to our healthcare system,” she added. “Consumers deserve better.”
But many physicians and pharmacologists interviewed said that with some drugs, the FDA -- an agency that has come in for harsh criticism on matters of drug safety in recent years -- may be overlooking differences that could be important to patients’ health.
FDA officials “have adopted a position that is in some respects quite brave,” said Peter Meredith, a University of Glasgow pharmacologist who has written extensively about generic drugs and their regulation. “The FDA quite rigidly states that when they say a drug is substitutable, they mean that with no caveats, no qualifications. My concern would be that if you don’t look for one, you don’t see it.”
With about 9,000 generic drugs on the U.S. market, concerns raised about a handful do not suggest a broad failure in the nation’s formulary of low-cost medications. But many physicians and pharmacologists caution that with new generics entering the market at a rate of almost 500 per year, and millions of consumers switching to them, their safety and effectiveness will be increasingly critical.
“The reasonable people I know aren’t pounding their fists saying all generics are bad,” Kowey said. “They’re saying to the FDA, ‘C’mon guys, there may be some situations in which [these differences] may turn out to be important.’ ”
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Doctors, users speak out
Dr. Gerald Naccarelli, chief of the Pennsylvania State medical center’s division of cardiology, believes a switch to a generic drug to control heart arrhythmia contributed to the death of one patient in Houston early in his career. Recently, he said, another of his patients suffered a life-threatening ventricular arrhythmia after the man was switched from a long-standing regimen of a brand-name medication to a new generic. The patient was hospitalized but lived. When the FDA approved a generic version of an anti-arrhythmia drug that Naccarelli did not believe had been studied properly at higher doses, he wrote a letter to the FDA.
“I’m confused why there’s one set of standards for patented trade-name drugs for FDA approval and a separate standard for generic substitutions,” he said. “Some generic drugs . . . should be held to higher standards than the FDA now enforces.”
Jillian Bealer of Buffalo, N.Y., is a fan of generics and the savings they bring. But she says her faith in their equivalence to brand-name drugs was shaken by a nasty recurrence of depression she suffered recently when she switched to a new generic for Wellbutrin XL.
For three years, Bealer, who has been diagnosed with attention deficit disorder and an anxiety disorder, took 300 milligrams of the antidepressant Wellbutrin XL to stabilize her mood and maintain her focus and attention. It helped her feel like herself, she said, “very outgoing and very upbeat.”
But in early November, a new pharmacy refilled her prescription with a large yellow caplet -- a newly approved generic version of Wellbutrin XL identified by its chemical name, Bupropion Hydrochloride XL, and marketed by the generic manufacturing giant Teva under the commercial name Budeprion. The new generic had a smaller co-pay than the branded product under Bealer’s employer-provided insurance policy, and the pharmacist assured her that the new pill would work just as well.
Bealer began taking the pill. But as the holiday season approached, she found that her favorite time of year was feeling like “just a burden.” For weeks, she didn’t answer the phone, didn’t go to parties and used up vacation days because she didn’t want to get out of bed. She had headaches that made holiday shopping miserable and in spite of a flagging appetite, felt she was gaining weight.
Bealer suspected that the new generic version of Wellbutrin XL wasn’t working the way the original had. On a sleepless night in early January, she started combing the Internet to see if other patients might have detected a difference. Bealer discovered she had lots of company -- and some lab evidence to suggest her suspicions were on-base.
“I was just so angry,” the 30-year-old pharmaceutical saleswoman said. “I was so miserable . . . I am not the only one who’s had these side effects. Something needs to be done, because someone could get really hurt or kill themselves.”
Denise Bradley, a spokeswoman for Teva Pharmaceutical Industries, said Teva’s 300-milligram extended release antidepressant has met the FDA’s specifications and performed well in its first year on the U.S. market. As of mid-October, 4.5 million prescriptions had been filled last year, and Teva had received 101 consumer complaints. That rate of concerns expressed, 0.002%, is “consistent with the rate of such reports for all prescription pharmaceuticals,” said Bradley.
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Expanding market
Currently, 64% of all prescriptions filled in the United States are for generics. That percentage is expected to rise steeply over the next few years.
In 2007, the FDA approved manufacturers’ plans to market 682 new generics in the United States. The agency still is working its way through a backlog of about 1,300 more applications from generic pharmaceutical manufacturers -- a tally that grows weekly. Among the widely prescribed medications expected to appear in generic form in the next few years: the migraine drug Imitrex; the cholesterol drug Lipitor; the blood pressure drug Norvasc; the gastrointestinal reflux drug Prevacid; and the psychiatric medications Risperdal, Effexor and Zyprexa.
At the same time, consumers are finding themselves constrained by their health plans, or lack of one.
In 2000, 22% of American workers with employer-sponsored health insurance had plans that made no distinctions in their coverage of medications: A patient’s co-payment was the same whether she chose the expensive brand-name or the generic formulation of a drug.
Today, only 6% of workers have prescription plans with such free choice, reports the Kaiser Family Foundation, which conducts an annual survey of employer health benefits. Kaiser’s survey shows that more insurers are making more distinctions among medicines for which they will help pay and, in most cases, asking workers to shoulder a higher proportion of costs for drugs that cost more.
Most patients welcome generics enthusiastically. Retail giants such as Wal-Mart and Target have begun filling most generic prescriptions for prices as low as $4 apiece. Generic drugs cost between 30% and 80% of the brand names they mimic, and price tags on those pioneer medicines are headed upward. Wholesale prices for the top-selling 50 brand-name medications rose by about 8% in 2007, according to a report by Delta Marketing Dynamics, which tracks drug trends. That’s after hikes of about 7% in 2006 and about 6% in 2005.
At the same time, Medicare, Medicaid, private insurance companies and hospital pharmacies are trying to hold down rising costs by aggressively encouraging patients to use generics. Increasingly, many are going further: They are asking patients to switch to a different class of drugs to treat a condition -- say, from an ACE inhibitor to a beta blocker to control high blood pressure -- because more generics may be available in one drug class than another. Such “formulary switches” can be more problematic than a brand-to-generic switch, because the old and new drugs work differently.
As generics move into Americans’ medicine chests in growing numbers, two things are likely, say experts: There will be copycat medications that work differently -- and sometimes less effectively -- than originals; and there will be patients who do not respond as well to them. Patients and doctors should be alert to variations in a new prescription’s effectiveness, they advise, and report their concerns to the FDA’s adverse-events monitoring system, called MedWatch ( www.fda.gov/medwatch).
“The generics industry is highly successful, and it wouldn’t be if it was always failing patients,” said R. William Soller, a professor of pharmacology at UC San Francisco. But, he added, “it’s pretty hard to think you have an absolutely perfect system.”
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‘Pandora’s box’
In recent years, the system by which generic prescription drugs are approved as “bioequivalent” to their brand-name counterparts has come in for criticism from many quarters. FDA’s regulation of generics is most vulnerable to criticism in cases where a medicine must be administered in very precise doses and on a precise schedule to be safe and effective. These drugs have what pharmacologists call a “narrow therapeutic index”: There’s a fine line between a dose that’s ineffective and one that could be dangerous.
Typically, a patient’s response to such medicine must be carefully monitored, and the consequences of failure could be dire: a seizure, dangerously erratic heartbeat, soaring blood pressure, blood clots or uncontrolled bleeding.
But FDA regulators have been “very categorical” in their insistence that no differences exist between generics and the pioneer drugs they follow, said Kowey. As a result, the agency has resisted studies that might call that into question with any single class of drugs, fearing that consumers will come to question the equal effectiveness of all generics. “They don’t want to open the Pandora’s box,” said Kowey.
Dr. Gary Buehler, director of the FDA’s office of generic drugs, declined an interview request. But FDA spokeswoman Sandy Walsh told The Times the “FDA cannot offer any examples where generics have been shown to not perform as expected.”
The “FDA has many years of experience in the review of generic drugs and has great confidence in the quality and equivalence of generic drug products,” added Walsh.
By the time Jillian Bealer turned to the Internet for information early this year, she found a chorus of complaints from Wellbutrin XL users who had switched to a new generic made by Teva. Their disappointment in the generic’s performance began showing up on drug- and depression-related Internet chat sites in March 2007, about two months after Teva’s generic hit the market.
More than 300 of those patients had sent anguished letters and e-mails to Joe and Teresa Graedon, the founders of a respected multimedia clearinghouse that dispenses independent advice on drugs and dietary supplements. (The Graedons’ syndicated column, People’s Pharmacy, runs in this and other newspapers.)
These consumers reported increased anxiety and irritability, headaches, nausea and insomnia since switching to the generic. Many reported a return of their previously controlled depressive symptoms.
By summer 2007, the Graedons had collected enough letters from readers to alert the FDA and to ask an independent testing and certification lab, ConsumerLab.com, to compare the new Wellbutrin generics against their original counterparts and assess claims of equal performance.
The results, confirmed by a second test lab and released last fall by ConsumerLab.com, raised questions about at least one version of the generic copies -- a 300-milligram dose of bupropion marketed by Teva -- as well as the FDA process by which a proposed generic’s equivalence to a pioneer drug is established.
“We were shocked when we got the results” comparing the 300-milligram tablet of Wellbutrin XL -- the most frequently prescribed dose of the product -- and Teva’s generic, said Tod Cooperman, president of ConsumerLab.com. The rate at which the two pills dissolved when in a medium mimicking the human digestive system “was very different,” he said.
Both products released the same amount of bupropion hydrochloride into the solution over 16 hours, but the generic pumped out its active ingredient much faster than did the branded product: In the first two hours, the generic released a third of its active ingredient -- four times as much as its brand counterpart. At four hours, the generic had released almost half of its medicine, the brand-name about a quarter.
The difference might well explain why consumers accustomed to taking Wellbutrin XL would feel different when taking Teva’s generic, marketed as Budeprion XL, said Cooperman. With a more rapid release rate, the concentration of generic bupropion in the blood will rise quickly, but may also fall lower late in the 24-hour cycle than would be the case with the branded Wellbutrin XL.
With a greater-than-accustomed dose of medicine in her system soon after taking her pill, a patient like Jillian Bealer might experience more of bupropion’s recognized side effects, including irritability, headaches and insomnia. In the second half of her 24-hour pill cycle, she may feel the effects of a lower-than-accustomed dose, including depressed mood.
Cooperman adds that the different dissolution rates of the two products could have safety implications, since patients who take too high a dose of bupropion are at increased risk of having a seizure.
In December, Dr. Robert Temple of the FDA’s Center for Drug Evaluation and Research confirmed that in the lab and in volunteers, the two products differed significantly in their dissolution rate. But that difference was within allowable limits set by regulators. By the time both pills had dissolved, he said, they had released equal levels of Wellbutrin’s active ingredient into the bloodstreams of subjects.
The agency thought the allowed variations in the rate at which the medicine was absorbed by patients “wouldn’t make any difference,” Temple told Southern California public radio station KPCC-FM (89.3).
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Back to brand names
Jillian Bealer thinks it made the difference between functioning effectively and dragging herself through a holiday season she usually loves. When she shelled out $150 to refill her prescription with Wellbutrin XL, Bealer said, she regained her good humor within a week and a half. She now pays a $45 co-payment instead of $15 for a generic refill. But she said she’ll never go back.
The FDA, she said, will probably dismiss stories like hers as flukes. With so much company, Bealer thinks that would be a mistake. “This many people,” she said, “could not be wrong.”
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