Comment
The safety of generic substitution in epilepsy Generic drugs bring substantial economic benefits to consumers and to society. According to a report from the US Food and Drug Administration (FDA), the use of generics in the USA (where eight out of ten prescriptions are for generic drugs) saved consumers as much as US$158 billion in 2010 alone.1 In China, switching only four medicines from branded drugs to generics in public hospitals could save US$370 million per year, or an average of 65% in costs.2 In low-income and middle-income countries, 9–89% of expenditure for medications could be saved by switching private sector purchases from originator brands to the lowest-priced generics—a crucial consideration for settings where the price of medicines hampers access to effective health care.2 From a broader perspective, the availability of generics also benefits society by promoting therapeutic innovation because loss of marketing exclusivity stimulates investment into the discovery of new medicines. However, these benefits do not come without concerns. For a long time, patients and prescribers have worried that generic drugs might not be therapeutically equivalent to the branded versions. Frequently voiced concerns are that bioequivalence criteria for the approval of generics are too lax, and that studies to demonstrate bioequivalence (typically single-dose studies in healthy volunteers) are not representative of the real-life setting in which a medication is used. In fact, some of these concerns are indicative of poor understanding of regulatory processes and related data. For example, contrary to a commonly voiced statement that regulators allow a 45% difference in effectiveness (based on current bioequivalence standards) between a generic drug and the brand,1 in a FDA survey of 2070 bioequivalence studies done between 1996 and 2007, the average difference in bioavailability between generics and brands was just 3·5%.3 Another concern relates to the fact that existing regulations require a generic to be bioequivalent to the brand, but not necessarily to other generics of the same drug. 4 Specifically, a generic yielding slightly lower plasma drug concentrations than the brand (within acceptability limits) might not be bioequivalent to another generic that has slightly higher bioavailability than the brand. Theoretically, this
situation could lead to clinically significant differences in plasma drug concentration and clinical response when switching between generics; this is especially of concern with narrow therapeutic index medicines such as antiepileptic drugs.4 These concerns have been reinforced by reports of seizure exacerbations or adverse effects after generic substitution in epilepsy, although most studies in this topic were subject to bias and overall evidence of health risks is inconclusive.5 Even regulatory authorities have conflicting positions on this issue: for example, the FDA supports the use of generics and makes no special provisions for the use of generics of antiepileptic drugs,1 whereas the UK Medicines and Healthcare products Regulatory Agency (MHRA) classifies antiepileptic drugs into three categories based on putative risks with generic substitution, and advises against switching products for category 1 drugs (phenytoin, carbamazepine, phenobarbital, and primidone).6 Not surprisingly, recommendations from scientific organisations also differ, even within the same country: in the UK, the Scottish Intercollegiate Guidelines Network (SIGN) guidelines state that “routine switching between different manufacturers of antiepileptic drugs should be avoided”,7 whereas the National Institute for Health and Care Excellence (NICE) does not advise against switching and merely cites the MHRA’s advice as a footnote.8 The EQUIGEN trial by Michael Privitera and colleagues published in The Lancet Neurology9 provides strong evidence that, at least for lamotrigine, concerns about generic substitution are largely misplaced. The study compared steady-state lamotrigine plasma concentrations in 33 patients with epilepsy who underwent repeated switching between the two generic products identified as having the highest and the lowest bioavailability among immediate-release lamotrigine generics available in the USA. Lamotrigine plasma concentrations and within-patient variability in exposure were equivalent between the two products. The 90% CIs of the ratios of both Cmax and AUC were within 80–125% equivalence limits (Cmax 90% CI 98–103, AUC 90% CI 99–105), indicating bioequivalence, and there were no significant changes in seizure control or adverse effects. Correctly, the authors ascribe previous reports of adverse outcomes from generic substitution
www.thelancet.com/neurology Published online February 11, 2016 http://dx.doi.org/10.1016/S1474-4422(16)00042-9
Lancet Neurol 2016 Published Online February 11, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)00042-9 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(16)00014-4
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Comment
to reporting bias, nocebo effects, and possibly reduced compliance when patients switch to products that they believe to be of lower quality than the brand. The main strengths of the EQUIGEN study are the robust design, the inclusion of chronically treated patients rather than healthy volunteers, and careful monitoring of compliance. Relative weaknesses of the trial include a low power for seizure outcomes and the fact that few study participants were generic-brittle patients (patients with a history of adverse outcomes after generic switching), who might be more susceptible to reporting adverse consequences from formulation changes than patients without this history. Overall, Privitera and colleagues’ findings are quite reassuring, and organisations with a negative attitude to generic antiepileptic drug substitution should consider reviewing their position. The question also arises as to whether or not these results can be extrapolated to other antiepileptic drugs or to other settings. Bioequivalence data for lamotrigine might not necessarily be representative of drugs or formulations known to be more susceptible to bioavailability problems, such as antiepileptic drugs with lower solubility, lower gastrointestinal permeability (eg, gabapentin), and modified-release formulations. In the MHRA classification (which is based on therapeutic index, solubility, and permeability), lamotrigine is categorised among antiepileptic drugs for which “the need for continued supply of a particular manufacturer’s product should be based on clinical judgment and consultation with patient”, rather than among those for which switching between products is generally discouraged.6 With respect to geographical setting, US data are probably applicable to regions such as the European Union, which apply equally strict regulatory criteria and control. However, in some regions of the world, especially low-income countries, control over quality of pharmaceuticals is less stringent,
2
and inadequate products might reach the market.10 In those settings, it is probably wise to favour formulations produced by established manufacturers adhering to international standards, and to avoid switching antiepileptic drug formulations whenever feasible. Emilio Perucca Department of Internal Medicine and Therapeutics, University of Pavia and C. Mondino National Neurological Institute, Via Ferrata 9, 27100 Pavia, Italy [email protected] I have received research funds from the European Union, the Italian Medicines Agency, the Italian Ministry of Health and the Italian Ministry for Education, University and Research, and speaker’s or consultancy fees from Biopharm Solutions, Eisai, GW Pharma, Sanofi, Sun Pharma, Takeda, UCB Pharma, and Viropharma. 1
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US FDA. Understanding generic drugs. http://www.fda.gov/drugs/ resourcesforyou/consumers/buyingusingmedicinesafely/ understandinggenericdrugs/ucm167991.htm (accessed Jan 18, 2016). Cameron A, Mantel-Teeuwisse AK, Leufkens HG, Laing RO. Switching from originator brand medicines to generic equivalents in selected developing countries: how much could be saved? Value Health 2012; 15: 664–73. Davit BM, Nwakama PE, Buehler GJ, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother 2009; 43: 1583–97. Karalis V, Macheras P, Bialer M. Generic products of antiepileptic drugs: a perspective on bioequivalence, bioavailability, and formulation switches using Monte Carlo simulations. CNS Drugs 2014; 28: 69–77. Kesselheim AS, Stedman MR, Bubrick EJ, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs 2010; 70: 605–21. MHRA. Antiepileptics: changing products (last modified Nov 25, 2013). http://webarchive.nationalarchives.gov.uk/20141205150130/http://www. mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/ Product-specificinformationandadvice/Productspecificinformationandadvice-A-F/Antiepilepticschangingproducts/index. htm (accessed Jan 18, 2016). Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of epilepsy in adults. Edinburgh: SIGN, 2015. http://www.sign.ac.uk/pdf/SIGN143.pdf (accessed Jan 17, 2016). National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and treatment. Clinical guideline 137, London 2012 (last modified January, 2015). http://www.nice.org.uk/guidance/cg137 (accessed Jan 17, 2016). Privitera M, Welty TE, Gidal BE, et al. Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial. Lancet Neurol 2016; published online Feb 11. http://dx.doi.org/10.1016/ S1474-4422(16)00014-4. Laroche ML, Traore H, Merle L, Gaulier JM, Viana M, Preux PM. Quality of phenobarbital solid-dosage forms in the urban community of Nouakchott (Mauritania). Epilepsia 2005; 46: 1293–96.
www.thelancet.com/neurology Published online February 11, 2016 http://dx.doi.org/10.1016/S1474-4422(16)00042-9
The safety of generic substitution in epilepsy Generic drugs bring substantial economic benefits to consumers and to society. According to a report from the US Food and Drug Administration (FDA), the use of generics in the USA (where eight out of ten prescriptions are for generic drugs) saved consumers as much as US$158 billion in 2010 alone.1 In China, switching only four medicines from branded drugs to generics in public hospitals could save US$370 million per year, or an average of 65% in costs.2 In low-income and middle-income countries, 9–89% of expenditure for medications could be saved by switching private sector purchases from originator brands to the lowest-priced generics—a crucial consideration for settings where the price of medicines hampers access to effective health care.2 From a broader perspective, the availability of generics also benefits society by promoting therapeutic innovation because loss of marketing exclusivity stimulates investment into the discovery of new medicines. However, these benefits do not come without concerns. For a long time, patients and prescribers have worried that generic drugs might not be therapeutically equivalent to the branded versions. Frequently voiced concerns are that bioequivalence criteria for the approval of generics are too lax, and that studies to demonstrate bioequivalence (typically single-dose studies in healthy volunteers) are not representative of the real-life setting in which a medication is used. In fact, some of these concerns are indicative of poor understanding of regulatory processes and related data. For example, contrary to a commonly voiced statement that regulators allow a 45% difference in effectiveness (based on current bioequivalence standards) between a generic drug and the brand,1 in a FDA survey of 2070 bioequivalence studies done between 1996 and 2007, the average difference in bioavailability between generics and brands was just 3·5%.3 Another concern relates to the fact that existing regulations require a generic to be bioequivalent to the brand, but not necessarily to other generics of the same drug. 4 Specifically, a generic yielding slightly lower plasma drug concentrations than the brand (within acceptability limits) might not be bioequivalent to another generic that has slightly higher bioavailability than the brand. Theoretically, this
situation could lead to clinically significant differences in plasma drug concentration and clinical response when switching between generics; this is especially of concern with narrow therapeutic index medicines such as antiepileptic drugs.4 These concerns have been reinforced by reports of seizure exacerbations or adverse effects after generic substitution in epilepsy, although most studies in this topic were subject to bias and overall evidence of health risks is inconclusive.5 Even regulatory authorities have conflicting positions on this issue: for example, the FDA supports the use of generics and makes no special provisions for the use of generics of antiepileptic drugs,1 whereas the UK Medicines and Healthcare products Regulatory Agency (MHRA) classifies antiepileptic drugs into three categories based on putative risks with generic substitution, and advises against switching products for category 1 drugs (phenytoin, carbamazepine, phenobarbital, and primidone).6 Not surprisingly, recommendations from scientific organisations also differ, even within the same country: in the UK, the Scottish Intercollegiate Guidelines Network (SIGN) guidelines state that “routine switching between different manufacturers of antiepileptic drugs should be avoided”,7 whereas the National Institute for Health and Care Excellence (NICE) does not advise against switching and merely cites the MHRA’s advice as a footnote.8 The EQUIGEN trial by Michael Privitera and colleagues published in The Lancet Neurology9 provides strong evidence that, at least for lamotrigine, concerns about generic substitution are largely misplaced. The study compared steady-state lamotrigine plasma concentrations in 33 patients with epilepsy who underwent repeated switching between the two generic products identified as having the highest and the lowest bioavailability among immediate-release lamotrigine generics available in the USA. Lamotrigine plasma concentrations and within-patient variability in exposure were equivalent between the two products. The 90% CIs of the ratios of both Cmax and AUC were within 80–125% equivalence limits (Cmax 90% CI 98–103, AUC 90% CI 99–105), indicating bioequivalence, and there were no significant changes in seizure control or adverse effects. Correctly, the authors ascribe previous reports of adverse outcomes from generic substitution
www.thelancet.com/neurology Published online February 11, 2016 http://dx.doi.org/10.1016/S1474-4422(16)00042-9
Lancet Neurol 2016 Published Online February 11, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)00042-9 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(16)00014-4
1
Comment
to reporting bias, nocebo effects, and possibly reduced compliance when patients switch to products that they believe to be of lower quality than the brand. The main strengths of the EQUIGEN study are the robust design, the inclusion of chronically treated patients rather than healthy volunteers, and careful monitoring of compliance. Relative weaknesses of the trial include a low power for seizure outcomes and the fact that few study participants were generic-brittle patients (patients with a history of adverse outcomes after generic switching), who might be more susceptible to reporting adverse consequences from formulation changes than patients without this history. Overall, Privitera and colleagues’ findings are quite reassuring, and organisations with a negative attitude to generic antiepileptic drug substitution should consider reviewing their position. The question also arises as to whether or not these results can be extrapolated to other antiepileptic drugs or to other settings. Bioequivalence data for lamotrigine might not necessarily be representative of drugs or formulations known to be more susceptible to bioavailability problems, such as antiepileptic drugs with lower solubility, lower gastrointestinal permeability (eg, gabapentin), and modified-release formulations. In the MHRA classification (which is based on therapeutic index, solubility, and permeability), lamotrigine is categorised among antiepileptic drugs for which “the need for continued supply of a particular manufacturer’s product should be based on clinical judgment and consultation with patient”, rather than among those for which switching between products is generally discouraged.6 With respect to geographical setting, US data are probably applicable to regions such as the European Union, which apply equally strict regulatory criteria and control. However, in some regions of the world, especially low-income countries, control over quality of pharmaceuticals is less stringent,
2
and inadequate products might reach the market.10 In those settings, it is probably wise to favour formulations produced by established manufacturers adhering to international standards, and to avoid switching antiepileptic drug formulations whenever feasible. Emilio Perucca Department of Internal Medicine and Therapeutics, University of Pavia and C. Mondino National Neurological Institute, Via Ferrata 9, 27100 Pavia, Italy [email protected] I have received research funds from the European Union, the Italian Medicines Agency, the Italian Ministry of Health and the Italian Ministry for Education, University and Research, and speaker’s or consultancy fees from Biopharm Solutions, Eisai, GW Pharma, Sanofi, Sun Pharma, Takeda, UCB Pharma, and Viropharma. 1
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US FDA. Understanding generic drugs. http://www.fda.gov/drugs/ resourcesforyou/consumers/buyingusingmedicinesafely/ understandinggenericdrugs/ucm167991.htm (accessed Jan 18, 2016). Cameron A, Mantel-Teeuwisse AK, Leufkens HG, Laing RO. Switching from originator brand medicines to generic equivalents in selected developing countries: how much could be saved? Value Health 2012; 15: 664–73. Davit BM, Nwakama PE, Buehler GJ, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother 2009; 43: 1583–97. Karalis V, Macheras P, Bialer M. Generic products of antiepileptic drugs: a perspective on bioequivalence, bioavailability, and formulation switches using Monte Carlo simulations. CNS Drugs 2014; 28: 69–77. Kesselheim AS, Stedman MR, Bubrick EJ, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs 2010; 70: 605–21. MHRA. Antiepileptics: changing products (last modified Nov 25, 2013). http://webarchive.nationalarchives.gov.uk/20141205150130/http://www. mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/ Product-specificinformationandadvice/Productspecificinformationandadvice-A-F/Antiepilepticschangingproducts/index. htm (accessed Jan 18, 2016). Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of epilepsy in adults. Edinburgh: SIGN, 2015. http://www.sign.ac.uk/pdf/SIGN143.pdf (accessed Jan 17, 2016). National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and treatment. Clinical guideline 137, London 2012 (last modified January, 2015). http://www.nice.org.uk/guidance/cg137 (accessed Jan 17, 2016). Privitera M, Welty TE, Gidal BE, et al. Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial. Lancet Neurol 2016; published online Feb 11. http://dx.doi.org/10.1016/ S1474-4422(16)00014-4. Laroche ML, Traore H, Merle L, Gaulier JM, Viana M, Preux PM. Quality of phenobarbital solid-dosage forms in the urban community of Nouakchott (Mauritania). Epilepsia 2005; 46: 1293–96.
www.thelancet.com/neurology Published online February 11, 2016 http://dx.doi.org/10.1016/S1474-4422(16)00042-9
