Abstract
Generic Lamotrigine versus Brand-Name Lamictal Bioequivalence in Patients with Epilepsy: A Field Test of the FDA Bioequivalence Standard
Ting TY, Jiang W, Lionberger R, Wong J, Jones JW, Kane MA, Krumholz A, Temple R, Polli JE. Epilepsia 2015;56(9):1415–1424. doi:10.1111/epi.13095.
OBJECTIVE: 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. METHODS: This randomized, double-blind, multiple-dose, steady-state, fully replicated bio-equivalence 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. RESULTS: 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. SIGNIFICANCE: 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 brand.
Commentary
Few issues in the clinical management of epilepsy have resulted in as much controversy, confusion, and angst as the issue of generic substitution of antiepileptic drugs (AEDs) (1, 2). Surveys of both clinicians and patients have suggested an increasing level of concern over the introduction of multiple generic formulations of virtually all of our commonly used medications (3). Fueling these concerns are reports, including anecdotal reports, and retrospective database analyses that suggest both worsening of seizure control and increased healthcare costs, coincident with the generic substitution of AEDs (4–6). Data analyses by Krauss et al. further raise the questions regarding generic-to-generic substitution of approved AEDs (7).
These concerns have prompted several professional societies, including the American Epilepsy Society and the American Academy of Neurology, to oppose generic substitution in patients with epilepsy without prior authorization by both physician and patient. These concerns are well placed given that many of our patients are “brittle,” meaning that minor variations in AED plasma concentrations appear to be associated with either breakthrough seizures or adverse effects.
Despite these concerns, generic substitution in all areas of medicine is here to stay. Between 2003 and 2012, use of generics resulted in over $1.2 trillion in savings to the U.S. health-care system. (8). The dilemma becomes how to reconcile the obvious economic benefits of generic drugs with the clinical perceptions of risk in our patients with epilepsy? The keyword here is perceptions. Until recently, much of our evidence was comprised of either personal experience, or retrospective pharmacy claims analyses utilizing surrogate indicators. There was a paucity of prospective, controlled pharmacokinetic (PK) data verifying the appropriateness of FDA testing guidelines, specifically in patients with epilepsy. Despite FDA assurances of product similarity, the epilepsy community called for evidence.
Ting and colleagues have now published the first such evidence. These investigators sought to address several important concerns regarding the FDA's methodology (9) such as testing being done only in healthy subjects following a single dose versus chronic dosing in patients. Importantly, typical average bioequivalence (ABE) studies are focused on groups; clinicians are very concerned about individuals as well. Standard regulatory testing designs may fail to detect small changes in absorption profile that might have great implications in actual patients who may have very narrow individual therapeutic ranges. These investigators sought to also address another very important and pragmatic issue. To date, most of the attention has been directed toward the question of variability when switching from a branded product to a generic formulation. It's plausible that even if the generic formulation fell within FDA bioequivalence boundaries, that the increased variability resulting from product switching might jeopardize seizure control in the brittle patient. Implicit in this belief, however, is the assumption that minimal, if any, variability is present following repeated administration of the same branded drug product. In other words, before we can properly address the issue of variability associated with drug substitution, we really should have an understanding of the likely within patient variability of repeated dosing of branded product. This type of data is not always easy to come by.
Using an enriched population of patients (defined as those patients who by history demonstrated problems with generic switching or had refractory seizures), Ting et al. conducted a four-period crossover PK study in 34 “generic-brittle” patients currently receiving Lamictal (lamotrigine) as part of their AED regimen. Detailed PK analysis was performed allowing comparison not only between brand-to-generic switching, but also brand-to-brand and generic-to-generic replicate administration. In addition to conventional ABE analysis favored by regulators, these investigators also conducted a reference-scaled ABE analysis (10). The value of this approach is that now we can not only assess whether a generic formulation is bioequivalent to its branded counterpart but also evaluate the more interesting question of magnitude of PK variability associated with repeat administration of either formulation.
As for the first question, these authors found that indeed, even in an enriched, potentially vulnerable population, the generic product was bioequivalent to the brand formulation, with the 90% confidence intervals of the steady-state ratios of area under the curve (AUC), peak, and trough (Cmax and Cmin, respectively) plasma concentrations falling well within the conventional 80 to 125 percent limits. The ratios of generic-to-brand PK parameters also fell within the much narrower reference-scaled goalposts (93.65–106.78% [AUC], 91.85–108.88% [Cmax], and 90.8–110.14% [Cmin]).
First and foremost, these observations should reassure clinicians that FDA-approved generic formulations can be expected to perform similarly to their branded counterparts. But this is not all that the data from this study tells us. Given the potential clinical consequences resulting from individual variability, average performance does not always seem sufficient. Clinicians are always concerned about outliers. As part of this analysis, variability comparisons of the PK profiles for both branded and generic products were also made. As might have been anticipated, there was indeed within-subject variability (WSV) observed for the generic product for each of the PK parameters (8.26–13.55%). What might have not been expected was that the WSV for the branded product was not much different (6.38–9.39%). On an individual basis, neither brand nor generic ever produced an identical PK profile following repeat administration. In some cases, the PK profiles did differ in individual patients when switched between brand and generic. Unfortunately, detailed analysis of patient-specific characteristics was unable to uncover potential mechanisms or identify obvious subpopulations of patients.
What then should we take away from this study? First, even in a potentially vulnerable patient population, brand- and FDA-approved generic product performance (at least from a PK perspective) are essentially the same. Given the rather stringent requirements required for bioequivalence by FDA, this is not surprising. Second, is the observation that individual biological variability is a therapeutic fact of life. Even in the most rigorous and controlled of experimental settings, lamotrigine systemic exposure displayed individual variability of about 10%, regardless of product formulation. This is an important observation. Much of the anecdotal reports regarding “switchability” issues with generic AEDs have based their conclusions regarding generic product performance on plasma drug concentrations derived from routine clinical practice. Without detailed knowledge of medication adherence, and timing of both drug ingestion and sample acquisition, it is quite likely that WSV would be much greater than in the present study. In other words, blood levels, even in patients taking a trusted brand product, are likely to vary.
If we accept the findings of pharmacokinetic similarity, does this study also allow us to accept the therapeutic equivalence of AED switching? While this was clearly not an efficacy trial, both seizure exacerbation and tolerability were secondary outcome measures. The fact that no obvious relationship between PK variability and either efficacy or toxicity was observed in this study population is comforting.
We still have the earlier retrospective data to reconcile that have suggested increased switchback rates (lamotrigine in particular) (11), as well as apparent therapeutic failures resulting from generic AED substitution (12). The question, therefore, of true therapeutic equivalence remains unanswered. It is possible to speculate however.
In response to the perceptions of problems associated with generic substitution, many patients have been cautioned to question whether they are receiving, or even should receive, a generic product. No doubt, this leaves many with the idea that cheaper generic products are inferior to their branded counterparts. Is it possible that this perception might predispose a patient to a poorer clinical response? Possibly.
A recent study in Parkinson's patients demonstrated the influence of stated medication cost on the efficacy of a dopamine agonist that was, in fact, a placebo. Patients were told that while both formulations were considered to be efficacious, one was substantially less expensive. Of interest, while both placebo treatments improved treatment outcome, the “more-expensive” treatment was associated with superior response (13). Similar “cost-benefit” was seen in a placebo study evaluating analgesia in normal volunteers (14). While no doubt there are many factors that influence patient response to AED treatment, patient perception of value for any given treatment matters. Likewise, provider perception of value might also play a role. Clinicians and pharmacists should reassure patients that less-expensive drugs are not lower potency, or suboptimal, alternatives.
So, do these data finally settle the issue of generic substitution in patients with epilepsy? Probably not. Clearly, this well-designed study represents a major step forward in addressing the epilepsy community's concerns and provides valuable insight regarding AED PK variability. While encouraging, these observations do require confirmation in other patient populations. This issue of individual outliers certainly merits further study. Final data analysis from the EQUIGEN study group (EQUIvalence among GENeric AEDs) is near completion and should help further clarify this issue.