These studies — which, unlike those required from generic manufacturers under current FDA regulations, examine drug pharmacokinetics in epilepsy patients and under chronic dosing — could show that some current generic AEDs vary enough to put patients at risk.
The FDA has shown a willingness to modify its rules if, indeed, the evidence is there, said Barry Gidal, PharmD, of the University of Wisconsin, at a press briefing held at the American Epilepsy Society (AES) annual meeting. “We’re bringing the evidence.”
Michael Privitera, MD, of the University of Cincinnati and the AES’s vice president, who is leading some of the new studies, said that, when the organization and others first suggested to the FDA that modifications for AEDs and other narrow-index drugs were needed, the agency resisted.
But after seeing preliminary evidence from open-label studies and analyses of generic manufacturers’ bioequivalence data, FDA officials have now “agreed that perhaps there should be some studies.”
And, in fact, it has provided funding to conduct them. Privitera said that results should be forthcoming next year, although he cautioned that the FDA tends to move slowly.
Current bioequivelance regulations allow some variation in generic drug pharmacokinetics relative to the original branded drug. In particular, the lower boundary for 90% confidence intervals in measures of bioavailability can be as low as 80% of the mean for the branded drug, and the upper boundary can be as high as 125% of the branded drug mean.
Small studies have found that, when generic versions of the same drug but from different manufacturers are compared with each other, they can vary more than when compared with the branded drug. Therefore, when a pharmacy changes suppliers, the variations can put patients at risk either for breakthrough seizures because of inadequate blood levels, or toxic effects from excessive drug exposure.
Privitera pointed out that, under current FDA rules, single-dose studies in healthy volunteers are adequate to show bioequivalence. He said that this poses two problems: drug availability and metabolism may be different in patients than in healthy people, and it may also be different with chronic dosing.
Consequently, the FDA is funding two studies addressing those problems, Privitera said. Both involve lamotrigine (Lamictal): one will examine single-dose pharmacokinetics of two different generic versions in 54 patients with epilepsy, and the other will test two generic versions in 36 patients when dosed daily for approximately 2 weeks.
Lamotrigine was a reasonable choice, Gregory Krauss, MD, of Johns Hopkins University in Baltimore, told MedPage Today, because it has been the source of many physician and patient complaints about generic equivalence.
But Krauss said he didn’t expect the studies to find a great deal of variation. Other drugs such as oxcarbazepine (Trileptal) have shown more variability in maximal concentrations and total exposure in earlier studies, he said.
On the other hand, a benchtop study of lamotrigine dissolution presented at the AES meeting Monday indicated a reason for concern. Conducted by a team that included Gidal and Privitera, it found that the amounts of dissolution after 15 and 30 minutes of generic tablets made by six different companies varied from each other substantially, and also among different dosage strengths (25 versus 100 mg).
There was considerable variability even among different lots from the same manufacturer, the study found, and the results did not always match those submitted by the manufacturers to the FDA in their marketing applications.
The issue of real-world generic equivalence is not confined to AEDs, Privitera said. Immunosuppressants are another drug class with narrow therapeutic indices, and an FDA-funded study of tacrolimus bioequivalence is also underway.
Another view of the bioequivalence issue was provided by another University of Cincinnati study led by Lisa Garrity, PharmD — a survey of Cincinnati-area pharmacists about their knowledge and experience with generic AEDs.
Garrity and colleagues obtained responses to a one-page questionnaire from 30 retail pharmacists who had a mean of 15.6 years in practice (SD 8.8). Of these, 20 reported having no specific education about possible issues with generic AEDs when switching from one manufacturer to another.
Responses indicated that 22 believed that switching from a branded version to a generic could cause problems, but only 18 said that issues could arise when switching between generic versions of the same drug. “I think these [types of switches] should be equally concerning,” Garrity said.
Most of the respondents (26) said they verbally inform patients when a drug supplier is changed, but the same number said they did not inform the patients’ physicians. Nearly as many, 24, said they made efforts not to change AED manufacturers.
But, when asked about the FDA’s current bioequivalence standard, most of the pharmacists got it wrong. Three said the generic versions had to exactly match the branded drug’s pharmacokinetics, and 16 put the acceptable variability at 90%-111%. Only 11 correctly indicated the actual standard of 80%-125%.
Privitera said that the FDA has said it would consider a new standard of 90%-111% for certain narrow-index drugs if new studies support it.
Gidal said another problem with the current system is the lack of transparency regarding generic drugs’ pharmacokinetics. Data from manufacturers’ FDA submissions “are not readily available,” he said. “It should be available on a web site.”
But he also cautioned against fomenting worry about generic drugs, which he and Privitera agreed are good for most patients and a necessary component of cost-effective care.
It’s important to raise questions and urge the FDA toward improved standards to protect patients, but “we need not make patients fearful,” Gidal said.
The bioequivalence studies are funded by the FDA. The pharmacist survey had no external funding.
Presenters had no financial disclosures.