Dr. Ting: I'm speaking for the first study that was completed in this endeavor, which was the Bioequivalence in Epilepsy Patients (BEEP) study. As you know, many people are familiar with generic substitutions for their prescription medicines. Many people do very well with them and they appreciate the cost savings. Yet, some patients and doctors, especially in the field of epilepsy, are concerned that their generic substitutions are not quite the same as the brand, that a failure for them might mean a breakthrough seizure, which is very great concern. For this reason, we embarked with the US Food and Drug Administration (FDA) to test the current standards that allow generic drugs to be approved in the United States. These standards rely heavily on what we call bioequivalence testing, which means that healthy volunteers will take a dose of a medication and have levels drawn, including the rate and extent of absorption of these medicines. They have to be the same. They have to match when these healthy volunteers take the brand name.
Patients and doctors are concerned that, for patients with epilepsy, they are not like healthy volunteers. They may be more at risk from minor differences that are allowed by current standards. This is why, at our center at the University of Maryland, we conducted the study on patients who had epilepsy and were considered "generic-brittle"—folks who might have more problems or reported problems with generic substitution of their brand-name seizure medications. These folks took their medicine for 2 weeks, after which we would switch them either from brand to generic or generic to brand and see how they did. What was the bioequivalence? How were their levels, the rate, and extent of absorption compared with when they were on the other medicine? And did they have any problems with it? Did they have more seizures when they switched between the two?
It was very interesting. We did complete the trial. It was very feasible and the patients did quite well. We found that, on average, whether they were on the brand or generic, the medication levels were almost identical, and these are patients who had other medical conditions. They were on other medicines, which is very different from the healthy volunteers that the FDA typically requires for bioequivalence testing. We really pushed the limits of the standards that the FDA holds for generic medication approval and showed that they are relevant even for patients with epilepsy and patients with other medical conditions...
We were concerned that these patients, having possibly had a history of problems with generic substitutions, would have too much of what we call a nocebo effect or expectations that would affect how they did in the trial or whether they would be adherent to the medications. So, we did blind them. We overencapsulated both the generic and the brand—we picked lamotrigine as the test case—so they wouldn't know whether they were being switched from one to the other. That really holds up the science behind this prospective study.
Dr Wilner: So the bottom line is that, at least for generic lamotrigine, the patients couldn't tell the difference, the lab tests had no difference, and there was no apparent difference in seizure frequency. Is that right?
Dr Ting: That is true for the vast majority of our patients, which was about 35 patients. All of them tolerated it very well and the levels were exactly the same between the generic and the brand, except for a few patients. Very interestingly, we had one man who seemed to have a lot more seizures whenever he was on the generic product. They were focal and brief and didn't endanger him, but it made us wonder whether there is a population of people out there who may be more at risk than the general vast majority of patients. That is something that we'd like to study further.
If nothing else, this study gives everyone reassurance that the standards that the FDA sets for generic approvals are sound, they're good, and they apply to most patients. You can really rely on the medicines. But what we want to know is whether there's a small population that may be more at risk, so we are going ahead with the next study. We call it the BEEP2 study, and we're trying to identify whether there is a medical condition that might give certain epilepsy patients a slight predisposition to have trouble with very small differences between medications that might be allowed with the current approval standards. Is there a genetic inclination for how some patients handle and process medicines? Maybe they metabolize them more quickly and that brings out minor differences between products. We are also interested in whether it is their state of mind. It's patient expectation. This negative placebo effect, which we call the nocebo effect, is having a hearty effect on patients when they know that they're getting a generic substitution of what they're used to. Maybe that gives them a predisposition or inclination to not do as well or have a harder outcome than if they believed that they were on the brand-name drug.
Ting TY, Jiang W, Lionberger R, Wong J, Jones JW, Kane MA, Krumholz A, Temple
R, Polli JE. Generic lamotrigine versus brand-name Lamictal bioequivalence in
patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia. 2015 Sep;56(9):1415-24.
To test the current U.S. Food and Drug Administration (FDA)
bioequivalence standard in a comparison of generic and brand-name drug
pharmacokinetic (PK) performance in "generic-brittle" patients with
epilepsy under clinical use conditions.
This randomized, double-blind, multiple-dose, steady-state,
fully replicated bioequivalence study compared generic lamotrigine to
brand-name Lamictal in "generic-brittle" patients with epilepsy (n =
34) who were already taking lamotrigine. Patients were repeatedly switched
between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at
the end of each 2-week treatment period yielded two 12-h PK profiles for
brand-name and generic forms for each patient. Steady-state area under the
curve (AUC), peak plasma concentration (Cmax ), and minimum plasma
concentration (Cmin ) data were subjected to conventional average
bioequivalence (ABE) analysis, reference-scaled ABE analysis, and
within-subject variability (WSV) comparisons. In addition, generic-versus-brand
comparisons in individual patients were performed. Secondary clinical outcomes
included seizure frequency and adverse events.
Generic demonstrated bioequivalence to brand. The 90%
confidence intervals of the mean for steady-state AUC, Cmax , and Cmin for
generic-versus-brand were 97.2-101.6%, 98.8-104.5%, and 93.4-101.0%,
respectively. The WSV of generic and brand were also similar. Individual
patient PK ratios for generic-versus-brand were similar but not identical, in
part because brand-versus-brand profiles were not identical, even though
subjects were rechallenged with the same product. Few subjects had seizure
exacerbations or tolerability issues with product switching. One subject,
however, reported 267 focal motor seizures, primarily on generic, although his
brand and generic PK profiles were practically identical.
Some neurologists question whether bioequivalence in healthy
volunteers ensures therapeutic equivalence of brand and generic antiepileptic
drugs in patients with epilepsy, who may be at increased risk for problems with
brand-to-generic switching. Bioequivalence results in
"generic-brittle" patients with epilepsy under clinical conditions
support the soundness of the FDA bioequivalence standards. Adverse events on generic
were not related to the small, allowable PK differences between generic and