Neurologists worldwide have concerns about the use of generic anti-seizure medications, including poor or inconsistent quality, limited access, cost, and lack of regulatory control, according to a global survey of health care professionals conducted by the ILAE Generic Substitution Task Force.
The survey collected 800 responses; 84% were from neurologists or epileptologists. About 31% of responders practiced in a university hospital, 22% in a government-run hospital, 12% in a community private hospital, and 11% in an epilepsy clinic.
Safety and effectiveness of generics
Overall, less than half of respondents (40.3%) agreed that generic anti-seizure medications (ASMs) are as safe and effective as brand-name products. Of the remaining responders, 22.6% said that generic ASMs were not comparable to brand-name products, and 37.1% were undecided.
Respondents from high-income countries were more likely to endorse the safety and effectiveness of generic ASMs (46.5%), compared with respondents in middle-income (26.7%) and low-income (35.9%) countries.
These differences may reflect variable regulatory environments, said Timothy Welty (USA), who chaired the task force. Physicians in countries with more rigorous standards for approval and manufacturing—which tend to be higher-income countries—may have more confidence in generic medications.
Most research on generic medications also comes from countries with high levels of regulatory control, he said.
“We don’t have a lot of good data from countries without strong regulatory control,” said Welty. “[The task force found] one older study from Thailand, a smaller study, which didn’t show a difference between generic and brand, but that’s the only one.”
While physicians in lower-income countries must seriously consider the regulatory environment when evaluating the use of generic ASMs, other factors also affect the use of generics, said task force member and senior author Hazel Paragua-Zuellig (Philippines/France).
“In France, generic medications are very commonly used because that’s what the government will cover,” she said. “The patient hardly ever has a say in whether they get a generic or a brand version. In lower-income countries, like in the Philippines, most medications are an out-of-pocket expense. Insurance there will cover inpatient medications, but epilepsy medications are outpatient expenses, so it’s up to the patient to pay for them.”
Training on generic ASMs
About one-quarter of survey respondents said they had no training or education about generic medications. Respondents from lower-income countries were more likely to have had training.
“Doctors who work in low-income countries have received more information about generic medication, but they have more concerns about its use,” said task force member Damian Consalvo (Argentina). “If you don’t trust the regulatory control in your country, then maybe you would have concerns, but I don’t know if that explains everything. Maybe some of the education about generic medications is coming from the pharmaceutical industry, which could be biased against generics. So we need more, unbiased education.”
Standards and bioequivalence
For a generic medication to be considered bioequivalent to the brand product, the US Food and Drug Administration (FDA) states that the 90% confidence interval in analysis of variance of log-transformed ratios of the generic drug to the brand-name drug for both the maximum drug concentration (Cmax) and overall drug exposure (area under the curve, or AUC) must lie between 80% and 125%.
This does not mean that the actual, observed Cmax and AUC ratios or plasma concentrations can vary by -20% to +25%, noted Welty. Practically speaking, he said, the differences in the pharmacokinetic variables of the two products—generic and brand—would have to be less than 10% to satisfy the bioequivalence requirement. However, differences among generics could be wider; if a person is switched from a generic at the high end to one at the low end, for example, the pharmacokinetic shift could be clinically meaningful.
The European Medicines Agency (EMA) has slightly different guidelines than the FDA, and while most countries use either FDA or EMA guidelines for bioequivalence, some may use others. In the task force survey, 47% of respondents said their country used its own national or federal bioequivalence standards; 13% said standards were adopted from another country; 12% said they were set by pharmaceutical companies, and 24% said they did not know how their country’s bioequivalence standards were set.
Some countries do not require any demonstration of bioequivalence prior to the marketing of a drug, Welty said. “For example, in Argentina, a generic product can be put on the market without showing bioequivalence; the company has six months to show bioequivalence in order for the product to remain on the market.”
As a result, he said, companies put a drug on the market for six months and then withdraw it. “There’s a constant churning of products,” Welty said, “and most have not been reliably shown to be bioequivalent.”
A similar environment exists in the Philippines, said Paragua-Zuellig, where generic medications are not tested for bioequivalence. “It’s up to the pharmaceutical company to volunteer the data to show bioequivalence, and it’s a very expensive test,” she said. “They may not do it; they just register the product. So in the end it’s up to the physician – you are the last frontier, protecting your patient against fake medications.”
Did my patient receive what I prescribed?
About 20% of those surveyed said their patients either almost never received the ASM specified on the prescription, or they didn’t know whether patients ever received what was prescribed.
“If you’re in a country that allows [brand-to-generic] switching, then the pharmacy will decide what the person receives,” said Paragua-Zuellig. “So you may not know, as the prescriber, if your patient is taking the brand or the generic, or which generic they are taking.”
The Philippines has a generic law that requires the prescriber to use generic terminology, said Paragua-Zuellig. If the prescriber does not specify the brand formulation, the decision rests with the pharmacist and the patient. “If you do not prescribe the brand, you are sort of giving permission to the pharmacist to give whatever is available,” she said. “Or the patient can ask the pharmacist for the least expensive option, or the pill that’s easiest to swallow, or the like.”
At least in the United States, studies have shown that at least half of the time, physicians are unaware of whether their patients are taking brand or generic formulations, said Welty. “If I’m a prescribing physician, I submit the prescription electronically, the patient picks it up or I assume they pick it up, and I usually don’t ask what they received, unless the patient volunteers that information or has a complaint,” he said.
Generic switching: Concerns
Poor or inconsistent quality of generic drugs was the most common concern of survey respondents, cited by 36.4%. Lack of regulatory control and limited access also were concerns. And 6.8% said their main concern regarding generics was the expense.
Of the medications on the World Health Organization essential medications list, problems with generic versions were most frequent for carbamazepine, lamotrigine, and valproic acid.
Besides initial prescribing of a generic, switching from brand to generic, or from one generic to another, also is a general concern among providers treating people with epilepsy. About 40% of respondents said they had observed increased seizure frequency in patients after switching to a generic formulation. Another 17% saw dose- or concentration-related toxicity, and 7% said they observed changes in seizure semiology or characteristics.
There are several hypotheses about why generic switching can be associated with increased seizures and adverse side effects. One is that a change in medication shape, size or color may affect adherence. Another is that patient perception of treatment value – that is, that a more expensive ASM is more effective – could play a role, as studies have shown for Alzheimer’s disease and pain relief.
A 2011 study noted that “switches between generic AED products may cause greater changes in plasma drug concentrations than generic substitutions of reference products.” Other studies have shown that switching drug manufacturers has been associated with increased risk for seizures and side effects, though published studies are few and at least one publication has found no increased risk. Most articles also focus on high-resources areas, such as Europe and North America, where regulatory control is more rigorous.
Welty said the task force had considered developing a policy statement regarding the use of generic ASMs, but the variable regulatory environments make a uniform statement unrealistic.
Compromises in lower-resource regions
Neurologists in lower-resource countries may need to seek out more education about generic medications out of necessity, said Paragua-Zuellig. They also may have fewer medication choices and more pressing quality concerns.
“You might want to prescribe a [brand-name ASM] but the patient cannot afford it, so they won’t take it,” she said. “So you prescribe the generic, which may not be bioequivalent, but at least they take something twice a day,” she said. “You really have to consider these things and discuss them with your patients, and you wish you were in a country where it was all reimbursed so you can choose the best option for your patients without having to worry about quality or cost.”
Neurologists become familiar with generic brands and learn to trust some over others, she said. “Over time, you may see that some patients are doing well on a particular generic, so you just stay with that particular generic. We probably have one or two generic sources that we trust for every medication, but it’s essentially self-regulation.”
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