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Image by AntonioGuillem

Recalls, research for generic drug safety

Probable carcinogens have been found in angiotensin-receptor blockers, but experts say generic drugs remain safe overall.


Recent drug recalls have intensified concerns over the safety and effectiveness of generic versus brand-name medications, but generic drugs remain safe overall, experts say.

In July 2018, three angiotensin-receptor blockers (ARBs)—valsartan, losartan, and irbesartan—were recalled by manufacturers after investigators found traces of nitrosamine compounds, which are probable carcinogens. In the following months, major pharmacies pulled the popular generic heartburn drug ranitidine after the FDA found low levels of some of the same impurities.

Drug recalls are not particularly unusual, but the ARB recall is notable for its scope—potentially impacting millions of patients—and the fact that the problems stem from flawed manufacturing processes affecting active ingredients, as opposed to more innocuous issues with size or color variations.

Concerns over potential contamination have been increasing over the past decade, along with an industry-wide shift toward making drugs and drug ingredients overseas, said Randall C. Starling, MD, MPH, a cardiologist at the Cleveland Clinic's main campus in Cleveland and immediate past president of the Heart Failure Society of America. An FDA investigation revealed that the lots affected by the recent ARB recall originated at plants in India and China, where manufacturing standards may differ from those in the U.S.

Cleveland Clinic has taken proactive steps to avoid prescribing drugs from the plants in question, said Dr. Starling. All generic drugs are now carefully vetted by pharmacy experts before being added to the clinic's formulary or sold in its pharmacies.

In addition to the recalls, recent research raised questions about the clinical efficacy of generic ARBs compared with branded drugs. A 2017 study published in Circulation: Cardiovascular Quality and Outcomes showed an increase in hospitalizations after three generic ARBs—valsartan, losartan, and candesartan—went on the market in Quebec, Canada. Investigators tracked 136,777 patients in the 24 months before and 12 months after commercialization and found that the generics were associated with higher rates of adverse events, ranging from 7.5% to 17.1%, compared with their brand-name equivalents.

While the results are potentially alarming on the surface, it's important to note the study's limitations, said the author of an accompanying editorial, David Alter, MD, PhD, associate professor of medicine at the University of Toronto and senior scientist at the University Health Network-Toronto Rehabilitation Institute.

“This study adds to the conversation about generics and helps us look at data differently, but it's important to remember that it is observational in design and does not adjust for individual patient risks,” he said. “There are many reasons that could potentially account for the hospitalizations beyond the drugs themselves.”

Getting a handle on risks

In announcing the ARB recall, the FDA included the following theoretical estimate of risk based on the literature: If 8,000 people took the highest valsartan dose (320 mg) containing N-nitrosodimethylamine (NDMA) for four years, there may be one additional case of cancer over the lifetimes of those patients. The actual risk is much lower, the agency noted, as the vast majority of patients received much smaller amounts of NDMA for shorter periods of time.

“Even if a patient was taking an ARB from one of the affected lots, their individual risk of cancer is very small,” said ACP Member Andrew M. Davis, MD, MPH, an internist and professor of medicine at the University of Chicago. “And over time that risk is likely outweighed by the risk of heart failure or stroke if they stop taking the medication.”

Still, the ARB recalls triggered an influx of questions from patients and physicians, noted Zachary A. Pape, PharmD, assistant professor in the department of clinical sciences at the Medical College of Wisconsin, in Milwaukee, who practices at an affiliated outpatient cardiac clinic. In addition to asking about the recall process, many wondered how concerned they should be about taking or prescribing ARBs in general.

“We emphasize that the recalls concern specific manufacturers and lot numbers, and patients should check with their pharmacy to see if they are affected,” he said. “We don't question the value of the drug itself. These drugs have been recommended and successfully used for years.”

The Circulation: Cardiovascular Quality and Outcomes study brought up potentially more serious issues surrounding ARBs, connecting the commercialization of generics with a rise in hospitalizations for adverse events. As the authors pointed out, previous studies have raised doubts about the clinical effectiveness of several classes of generic versus branded drugs, and there remains uncertainty about whether the methods used to determine bioequivalence translate into clinical equivalence at the population level.

To be approved by regulators, generics must show bioequivalence with the branded versions within a 90% confidence interval, meaning they are absorbed into the blood at the same rate and concentration. In the Circulation: Cardiovascular Quality and Outcomes study, investigators inferred that where a generic drug falls in that range of acceptability may impact clinical outcomes, as the generic ARB with the largest difference in bioavailability—candesartan—also was associated with the highest rate of adverse events.

“Regulators say that it should not be a big problem clinically to have a small difference in bioavailability when patients make the switch to generic,” said lead investigator Jacinthe Leclerc, RN, PhD, professor of nursing at the University of Quebec at Trois-Rivières. “One message from our study is to trust the patient if they feel a difference after switching, as it's possible that there is an actual difference in outcomes.”

The findings are worth taking into consideration as one factor when patients switch from a branded to a generic ARB, or from one generic to another, said Niteesh Choudhry, MD, PhD, professor of medicine at Harvard Medical School in Boston and lead author of ACP's 2016 Best Practice Advice paper, “Improving Adherence to Therapy and Clinical Outcomes While Containing Costs: Opportunities From the Greater Use of Generic Medications.” However, like Dr. Alter, he noted that the study has significant limitations.

For example, the observational, population-level study was not designed to track individual patients over time or account for risk factors that might affect outcomes, he said. As the investigators acknowledged, their findings are based on administrative data, not clinical charts, and there is no basis for linking the increases in hospitalizations and ED admissions with taking generic drugs.

“The people who were taking generics after their introduction may have been different than those taking them before the generics were introduced. They might have been sicker and/or more likely to experience side effects in the first place,” said Dr. Choudhry. “It's difficult to draw the conclusion that the introduction of these generic ARBs as opposed to the broader use of ARBs in general were responsible for the trends observed.”

There are many other potential reasons that could account for the rise in adverse events beyond the drugs themselves, agreed Dr. Alter.

“There is no reason to assume that switching to a generic drug caused a patient to be hospitalized for heart failure or heart disease,” he said. “We can't be certain that the drug wasn't providing benefit and that something else caused the patient to land in the hospital, or even that someone might have been hospitalized earlier if they weren't taking the drug.”

Although such studies do not offer enough evidence to support changing prescribing practices for ARBs, they should be kept in mind when problems arise, said Dr. Starling.

For example, a recent switch from a brand-name to generic drug might be one factor to consider if a patient's blood pressure suddenly goes out of control, he said. Besides checking on whether their prescription is involved in the recall, physicians might try another generic ARB.

“As a nurse, I've observed problems at the time a patient switched from brand-name to generic,” said Dr. Leclerc. “Switching from one generic to another can also lead to different outcomes as the range of differences between generics in the same class are often greater than between a specific generic and the brand-name drug.” She noted that she and her coauthors confirmed the results of the 2017 study in follow-up studies published by the American Journal of Cardiovascular Drugs in 2018 and by Drugs and Aging in 2019.

Generics' image problem

The recent recalls feed into a common perception that generics are somehow inferior knockoffs of “real” drugs, noted Dr. Choudhry. However, it's important to remember that contamination or poor manufacturing practices can also affect branded drugs.

In ACP's paper, Dr. Choudhry and colleagues acknowledged that there have been sporadic case reports of generics not working as well as branded counterparts. For example, the FDA received reports about loss of antidepressant effect following the introduction of generic bupropion. However, those reports stand in contrast to most peer-reviewed evidence.

For example, a meta-analysis of 47 studies comparing generic and brand-name drugs in nine classes of cardiovascular medications found no evidence that branded drugs were clinically superior, according to the ACP paper. Similarly, studies comparing various proton-pump inhibitors have found no meaningful differences in clinical effectiveness.

Nonetheless, patient and physician perceptions remain a major barrier to increasing the use of generic drugs, the ACP authors stated. About 25% of physicians express concerns about the safety and efficacy of generics and prefer not to use them for their own families, the paper noted. In addition, physicians sometimes prescribe brand-name drugs in response to patient requests.

While such concerns have existed for decades, they may be intensifying recently due to rising costs of generics, Dr. Choudhry noted.

“The other dimension here is affordability,” he said. “The case for generics used to be that they were much cheaper while being equally safe and likely just as or slightly less effective. If the cost of generics is comparable with brand-name drugs, the tradeoffs become harder to defend—especially with the advent of consumer-directed, high-deductible health plans where patients are paying out of pocket.”

Need for postmarket surveillance

Single studies and case reports shouldn't change practice, but they can sometimes be early indicators of serious problems, said Dr. Alter. For example, the first study to raise concerns about heart attacks and strokes in patients taking the cyclooxygenase-2 inhibitor rofecoxib, which was approved in 1999, did not change policy. However, the findings spurred further investigations, which eventually confirmed suspicions and led to the drug being pulled from the market in 2004.

“If drugs are actually harmful, results should be reproducible in many studies, populations, and databases over time,” said Dr. Alter. “The recent recall of multiple ARBs should prompt follow-up and questions about why this is happening now, and whether there is something about the manufacturing of these compounds that's problematic.”

While randomized trials are the gold standard for demonstrating clinical efficacy prior to approval of new drugs, they are not practical for generic drugs, he noted. Requiring drugmakers to invest in large trials in order to prove therapeutic equivalence would effectively shut down production by removing the profit incentive to make generics.

Instead, ramping up postmarket surveillance makes sense on a system level, said Dr. Davis.

“If we are increasingly importing drugs from around the world, our ability to regulate them gets trickier,” he said. “We need better data systems for tracking the source of drugs when problems arise, from sourcing of raw ingredients to manufacturing the finished drugs.”

Key to better surveillance is leveraging the power of existing electronic health record (EHR) systems, he added. EHRs can provide extensive, long-term data on real-world clinical outcomes for patients taking generics versus branded drugs.

For now, however, evidence from large studies suggests that generics are as effective as their branded counterparts while being less costly for patients and the health care system as a whole. According to the ACP paper, prescriptions for brand-name drugs are almost twice as likely to be abandoned as those for generics. In addition, most studies associate generics with better long-term adherence to treatment, which potentially leads to better outcomes and reduces overall health care costs, the paper said.

“There may be individual cases where genetic or physiologic differences between patients might affect outcomes with generics, but we are in the very beginning stages of understanding that,” said Dr. Choudhry. “Recent events bring up legitimate safety concerns that we need to monitor ongoing, but there is no large-scale epidemic of generic drug safety.”