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CONTEMPORARY ISSUES IN NEUROLOGIC PRACTICE: J. LeLorier, M. S. Duh, P. E. Paradis, P. Lefebvre, J. Weiner, R. Manjunath, and O. Sheehy Clinical consequences of generic substitution of lamotrigine for patients with epilepsy Neurology 2008; 70: 2179-2186 [Abstract] [Full text] [PDF]

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Clinical consequences of generic substitution of lamotrigine for patients with epilepsy

Laura S. Boylan   (2 October 2008)

Reply from the authors

J. LeLorier, MD, PhD, M. S. Duh, MPH, ScD, P. E. Paradis, MA, DESS, P. Lefebvre, MA, . Weiner, MPA, R. Manjunath, MSPH and O. Sheehy, MSc   (2 October 2008)

Clinical consequences of generic substitution of lamotrigine for patients with epilepsy 2 October 2008
Laura S. Boylan, New York University School of Medicine 462 First Ave H7W11, New York, NY 10016 Send Correspondence to journal: Re: Clinical consequences of generic substitution of lamotrigine for patients with epilepsy laura.boylan{at}nyumc.org Laura S. Boylan	LeLorier et al. studied the risks associated with patients switching to and from generic AEDs in Quebec. The authors did not consider that such changes could be attributed to promotionally-driven doctor and patient preferences. [1] Industry representatives vigorously promote the idea that generics are less potent ("up to 20% less effective") than their brand name equivalents despite FDA assertions to the contrary. [2] Study patients on generics underwent dose escalations. The authors suggest that dose escalations were in response to increased side effects, but this is counter-intuitive. More plausibly, anxiety-induced dose escalations contributed to side effects and, in turn, switchbacks. The unspoken hypothesis that switches to generic led to more seizures is unaddressed by the presented data, which blur psychiatric and neurologic indications for lamotrigine (LTG). LTG is used heavily in psychiatry and most recent growth in sales is driven by the psychiatric market. [3] A single claim submitted with a code for epilepsy is considered sufficient evidence that LTG is being prescribed as an anti-epileptic, but this is unlikely. The leading outpatient diagnostic code as well as 4/5 diagnostic codes for outpatient visits and 2/3 diagnostic codes for inpatient hospitalizations were not for epilepsy. By contrast, all comparator non-AED drugs in this study lent themselves to readily available objective efficacy assessment (blood pressure and lipid levels). There is no such equivalent for any LTG indication. FDA standards for generic bioequivalence are the same standards applied to branded medication for between batch variability. [2] Bioequivalence is complex. [4] For example, the area under the curve and maximum concentration but not time to maximum (tmax) concentration are used by the FDA in determining bioequivalence. Manufacturer disclosures of bioequivalence data indicate that branded LTG tmax varies from half an hour to six hours for various formulations of the 100 mg tablets. [5] Clinical relevance of FDA permitted variance within a brand or between brand and generic medication is unclear. Millions of doses of generic medications have been dispensed with no well-documented instances of therapeutic failures for medications produced in accordance with existing FDA standards. [4] It is clear that promotional activity influences prescribing behavior. Furthermore, under experimental conditions, expensive placebos are more effective. [6] Not only patients but neurologists are anxious about generic medications encouraged in this regard by controversial AAN policies on generic substitution of AEDs.[7] The authors should compare switches to and from generics by specialty of the prescriber (neurologist, psychiatrist, primary care) and by first indication for which the medication was prescribed, stratifying by promotional dollars spent per indication and specialty. References 1. LeLorier J, Duh MS, Paradis PE, et al. Clinical consequences of generic substitution of lamotrigine for patients with epilepsy. Neurology 2008;70(22 Pt 2):2179-2186. 2. FDA. http://www.fda.gov/cder/index.html Accessed 6/15/2008. 3. GlaxoSmithKline. http://www.gsk.com/investors/presentations/q32004/q32004.pdf. Accessed 8/08/2008. 4. Meyer MC. United States Food and Drug Administration requirements for approval of generic drug products. J Clin Psychiatry 2001;62 Suppl 5:4-9. 5. GlaxoSmithKline. http://ctr.gsk.co.uk/Summary/lamotrigine/I_US51.pdf Accessed 8/08/2008. 6. Waber RL, Shiv B, Carmon Z, Ariely D. Commercial features of placebo and therapeutic efficacy. JAMA 2008;299:1016-1017. 7. Miller JW, Anderson GD, Doherty MJ, Poolos NP. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy: what's the problem with generic antiepileptic drugs? A call to action. Neurology. 2007;69:1806-1808. Letter. Disclosure: The author reports no disclosures.
Reply from the authors 2 October 2008
J. LeLorier, MD, PhD, Centre de Recherche Montréal, Québec, Canada, M. S. Duh, MPH, ScD, P. E. Paradis, MA, DESS, P. Lefebvre, MA, . Weiner, MPA, R. Manjunath, MSPH and O. Sheehy, MSc Send Correspondence to journal: Re: Reply from the authors jacques.le.lorier{at}umontreal.ca J. LeLorier, MD, PhD, et al.	We appreciate Dr. Boylan’s interest in our research and would like to respond to several points raised in her correspondence. [1] We find Dr. Boylan’s statements about the “controversial” nature of AAN policies, as well as “promotionally driven doctors and patient preferences” speculative. Our research was an observational study that examined the real-world prescribing patterns and measured medical resource utilization in patients with epilepsy treated with AEDs. It would be beyond the scope of our study to investigate the impact of promotional activities on physicians’ prescribing behaviors. Also, we do not believe that industry promotional activities would be systematically less vigorous or influential in any of the drugs in the three control groups reported in our research relative to anti-epileptics. Our inclusion criterion was at least one claim for epilepsy, and not “a single claim” as described by Dr. Boylan. Ninety-one percent of our study population had at least two claims for epilepsy, and more than half of the patients received a diagnosis for epilepsy at least 10 times during the observation period. We think this demonstrates that for these subjects, lamotrigine was likely prescribed as an anti-epileptic agent and was not used as a psychiatric treatment. Two main findings emerged from our study. First, AED users exhibited a higher propensity of switchback to branded drugs compared to patients treated with other chronic-disease drugs. Secondly, the use of generic lamotrigine was associated with increased physician visits and hospitalizations compared to brand use. We do not attribute these results strictly to seizure activity. As we stated, while these findings may signal reduced clinical effectiveness or increased side effects associated with generic lamotrigine use, this study lacked access to data on whether drugs dispensed were actually taken according to prescribed instructions, or on disease severity. Dr. Boylan’s statement that “anxiety-induced dose escalations contributed to side effects and, in turn, switchbacks” in patients treated with generic lamotrigine could be one of the plausible explanations for the findings. Disclosure: This study was sponsored by GlaxoSmithKline (GSK), Research Triangle Park, NC. GSK participated in the design, review, and approval of the manuscript. J. LeLorier has a consulting agreement with Analysis Group, Inc. and has received grants from GSK for other research projects in excess of $10,000. M.S. Duh, P.E. Paradis, P. Lefebvre, and J. Weiner are employees of Analysis Group, Inc., which has received research grants from GSK. R. Manjunath is an employee of GSK. O. Sheehy reports no conflict of interest.