Sunday, April 24, 2016

Generic vs brand-name epilepsy drugs

Dr. Ting:  I'm speaking for the first study that was completed in this endeavor, which was the Bioequivalence in Epilepsy Patients (BEEP) study.[1] 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


  1. When the price of eggs rose to unprecedented levels in 1966, President Lyndon B. Johnson ordered his surgeon general to decrease demand by warning his fellow Americans of the health hazards of egg consumption. The evidence against the lowly egg was at best shaky, and recent studies suggest that the health risks from eggs, if any, were greatly exaggerated. Nevertheless, millions of health-conscious Americans dutifully altered their diets, secure in their belief that eggs must be bad for one's health. Are we physicians so gullible and easily manipulated that we could possibly fall for such an arrogant ploy? Evidently, because most physicians of the day accepted the marginal idea that eggs are worse than other foods with the same lack of skepticism that many neurologists today display toward the notion that generic antiepileptic drugs (AEDs) pose a frequent patient risk...

    Is there convincing evidence that generic drugs are risky or is this debate just a clever smoke screen designed by those with much to gain in promoting the continued use of more expensive drugs? There are really 2 separate, though often confused, issues in this discussion. One is whether physicians should try to prevent the use of generic AEDs based on persuasive evidence that these drugs are less effective than their brand-name counterparts. An entirely different issue is whether pharmacists or payers should be able to substitute a cheaper generic drug without the authorization of the patient's physician...

    A few individuals with epilepsy apparently do not tolerate even minor differences in antiepileptic bioavailability without developing either seizures or adverse effects.3- 6The existence of such case reports is perhaps reason enough to require physician approval prior to substituting a generic AED, because even a physician who generally favors the use of generic drugs might have a very good reason to insist on a specific AED brand in select individuals. But concern about unauthorized substitution is not the same thing as opposing the use of generic medication for all individuals...

    The data supporting an increased seizure risk after conversion to generic AEDs are weak. Carefully designed comparison studies of the caliber required by the FDA to initially establish a drug's safety and efficacy do not exist. Berg and colleagues11described a physician survey that was bolstered by the submission of case descriptions of individuals who had seizures after switching to a generic AED. Another report retrospectively analyzed demographic data to suggest that generic AEDs increase the need for emergency care for seizures, though the inclusion of individuals with recent dosing-schedule changes and those taking various AEDs make this study more difficult to interpret. Another study used a physician survey to support a conclusion that generic AEDs are not equivalent, emphasizing the fact that more than two-thirds of the responding physicians believed that they had encountered a patient with epilepsy whose seizures were not as well controlled while taking a generic AED. A questionnaire survey seeking anecdotal and retrospective data in which only 4.7% of 6420 surveyed neurologists even bothered to respond is hardly the foundation of a successful FDA new drug application, yet many of us use this flimsy evidence to reject generic AEDs. (continued)

  2. (continued)It is important to recognize potential sources of bias and conflict of interest when analyzing the suitability of generic drugs. The cost of developing and marketing a new drug is huge, so it is easy to understand the desire to continue selling an expensive brand-name drug after its patent has expired. The fact that many of the articles promoting brand-name AEDs over generic drugs have been written by individuals who are employed by AED manufacturers or those receiving personal financial and research support from these companies does little to promote confidence. What is difficult to explain, however, is how usually questioning physicians could accept such weak arguments without even a trace of skepticism or a demand for more evidence. We argue every minor point about the optimal treatment for stroke, Parkinson disease, or multiple sclerosis, but when it comes to the use of generic drugs, many of us seem to accept without a whimper of protest that a brand-name AED is somehow superior.

    To prospectively compare the frequency and severity of seizures when converting to generic medication seems to be a relatively straight-forward study, and from there one might be able to develop ways to identify any individuals with a narrow therapeutic window. With so many patients affected and so much money at stake, why has this debate about the use of generic AEDs simmered for a quarter of a century? A well-designed prospective study would likely show parity of generic and brand-name AEDs in all but a few patients. The results of such a study might be inconvenient to those better served by smoke screens, but we should demand no less.

    Roach ES. The cost of gullibility. Arch Neurol. 2009 Nov;66(11):1418-20.

  3. Johnson EL, Chang YT, Davit B, Gidal BE, Krauss GL. Assessing bioequivalence of generic modified-release antiepileptic drugs. Neurology. 2016 Mar 25. pii:10.1212/WNL.0000000000002607. [Epub ahead of print]

    The purpose of this study was to determine how closely generic modified-release antiepileptic drugs (MR-AEDs) resemble reference (brand) formulations by comparing peak concentrations (Cmax), total absorption (area under the curve [AUC]), time to Cmax (Tmax), intersubject variability, and food effects between generic and reference products.
    We tabulated Cmax and AUC data from the bioequivalence (BE) studies used to support the approvals of generic Food and Drug Administration-approved MR-AEDs. We compared differences in 90% confidence intervals of the generic/reference AUC and Cmax geometric mean ratios, and intersubject variability, Tmax and delivery profiles and food effects.
    Forty-two MR-AED formulations were studied in 3,175 healthy participants without epilepsy in 97 BE studies. BE ratios for AUC and Cmax were similar between most generic and reference products: AUC ratios varied by >15% in 11.4% of BE studies; Cmax varied by >15% in 25.8% of studies. Tmax was more variable, with >30% difference in 13 studies (usually delayed in the fed compared to fasting BE studies). Generic and reference MR products had similar intersubject variability. Immediate-release AEDs showed less intersubject variability in AUC than did MR-AEDs.
    Most generic and reference MR-AEDs have similar AUC and Cmax values. Ratios for some products, however, are near acceptance limits and Tmax values may vary. Food effects are common with MR-AED products. High variability in pharmacokinetic values for once-a-day MR-AEDs suggests their major advantage compared to immediate-release AED formulations may be the convenience of less frequent dosing to improve adherence.