J Neurol DOI 10.1007/s00415-011-6126-6
REVIEW
Requirements for generic antiepileptic medicines: a clinical perspective Eugen Trinka • Gu¨nter Kra¨mer • Martin Graf
Received: 7 January 2011 / Revised: 25 May 2011 / Accepted: 26 May 2011 Ó Springer-Verlag 2011
Abstract Many antiepileptic drugs (AEDs) are now available as a generic product. This can potentially save the healthcare providers massive costs. Hence, governmental authorities have introduced rules and incentives for clinicians to switch from the original branded AED to a generic product. Clinicians and patients with epilepsy are reluctant to switch. The licensing of generic AEDs is based on the equation that bioavailability means therapeutic equivalence. However, from a clinical standpoint one has to consider several other relevant issues: (1) Do generic AEDs have the same efficacy, safety and quality? (2) Can generic AEDs be used as substitutions for brand AEDs? (3) Can generic products of AEDs be used interchangeably? (4) Does the generic AED manufacturer guarantee the longterm consistency of availability on the market? (4) Do generic AEDs reduce the costs, and—if so—are these costs worth any additional risk to patient’s safety? This article reviews the clinical issues related to current bioequivalence, prescribability, and switchability of AEDs. Keywords Antiepileptic drugs Generics Epilepsy Health economy Bioequivalence
E. Trinka (&) Department of Neurology at the Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Ignaz Harrerstrasse 79, 5020 Salzburg, Austria e-mail:
[email protected] G. Kra¨mer Swiss Epiklinik, Zurich, Switzerland M. Graf Department of Neurology, Donauspital, Wien, Austria
Introduction Epilepsies are one of the most common chronic neurological disorders with a prevalence between 0.5 and 1% in most countries [37]. Though antiepileptic drugs (AEDs) are not considered as very expensive compared to other medication, the high prevalence and the long treatment duration makes the overall expenditure on these drugs high [3, 36]. In recent years the escalating costs for the healthcare, driven by the increase in the elderly population, together with the introduction of new and expensive treatment urges the health care providers to introduce measures to maintain costs. The most common example to reduce direct costs has been the encouragement or the mandatory requirement for the use of cheaper generic drugs instead of their branded products. Prescription of generic AEDs may lead to substantial savings in the healthcare system. In Italy savings of at least €25 million were made in 2002 as a result of the introduction of generic drugs. [8]. In the UK generic drugs accounted for 53% of all prescriptions dispensed, but only 20% of the total drug cost [26]. Potential savings associated with a broad generic substitution could result in annual savings of 11% of drug expenditures in the US market [18]. Therefore, many governmental bodies across Europe and North America set firm guidelines to encourage the use of generic AEDs, to ensure, that the cheapest possible generic form is considered at every stage of the care cycle. On the basis of WHO recommendations, manufactures have a legal requirement to demonstrate bioequivalence between the generic and the branded (or innovative) drug. The current concept is that bioequivalence is used as a surrogate measure for therapeutic effect. Based on the assumption, that bioequivalence equals therapeutic equivalence, generic and branded AEDs can be used interchangeably.
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For decades the establishment of bioequivalence has generally relied on the comparison of population averages between the test and the reference formulations. Many authors and health care providers consider products which are bioequivalent as also therapeutically equivalent. However, from a clinical standpoint, we have to raise several questions [5]: 1. 2. 3. 4. 5.
Do generic AEDs have the same efficacy, safety and quality? Can generic AEDs be used as substitutions for brand AEDs? Can generic products of AEDs be used interchangeably? Does the generic AED manufacturer guarantee the long-term consistency of availability on the market? Do generic AEDs reduce the costs, and—if so—are these costs worth any additional risk to patient’s safety?
Bioequivalence of generic AEDs Over the years, concerns have been raised regarding the appropriateness of using the average bioequivalence approach for evaluation of comparability between formulations [2, 5, 6, 9–12, 14, 15, 19–23, 31–33, 38, 39]. Traditionally, the average bioequivalence is based on the ratio of geometric mean bioavailability measure (AUC, Cmax) of the brand and generic formulation over all individuals in the study population [7, 25]. The two measures are tested typically in 24–36 healthy adults [4, 5]. The European Agency for the Evaluation of Medicinal Products (EMEA) and the Food and Drug Administration (FDA) recommends that bioequivalence between generic treatment and innovator brands is achieved when the 90% confidence intervals for the mean of the ratios (AUCgeneric/AUCbrand) fall within the acceptable boundaries of 80–125%. This rule implies that the difference could be as much as a 56% increase or 36% decrease in bioavailability when switching a patient from one generic to another generic formulation. Perucca et al. [35] pointed out that even with this definition of bioequivalence the AED plasma level can change as much as 45% compared to a branded product, although this may not be the case in most instances. However, two reviews conducted by the FDA showed, that the average difference between mean AUC and Cmax of the reference and generic compound is between 3 and 4% [27, 34]. Notably, a greater than 10% difference in mean AUC was found in 13 of 224 (5.8%) of bioequivalence studies [34]. Nevertheless, the FDA states that ‘‘a generic drug is identical or bioequivalent to a brand name drug in dosage
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form, safety strengths and rout of administration quality, performance characteristics and intended use’’. Therefore, the FDA’s position is clear that there is no evidence that a bioequivalent generic product could not be used interchangeably with a corresponding brand name drug. The position of the EMEA is similar. This is in striking contrast to the perception and experience of the neurological community where the majority of doctors have concerns that average bioequivalence indicates also therapeutic equivalence and, therefore, also exchangeability. In a recent survey, 81.6% of 6,420 neurologists in the US regarded the FDA standards for AED bioavailability as not sufficient [40]. These concerns come from anecdotal evidence. In the same survey, which provided an overall response rate of 4.7, 67.8% of neurologists reported breakthrough seizures after a switch from a brand name to generic, while 32.2% did not. In the survey, 56% reported increased side effects in their patients after a switch which is consistent with similar surveys performed in different countries (reviewed in [13]). The pharmacoeconomic driving force to reduce healthcare costs has sparked recent debates on the cost benefit ratio of switching antiepileptic patients from brand AEDs to the cheaper generic AEDs. In many countries, a mandatory switching from brand to generic has been introduced or at least there is a strong encouragement for automatic substitution of brand product with cheaper generic product. In numerous countries, if patients insist on receiving the brand product, they have to pay the difference in costs over the lowest price generic product. And some US states mandate the pharmacists to substitute a generic version of the prescribed drug if all prescription requirements are met. Consequently, guidelines by professional bodies in several countries were established to provide a safe and satisfactory framework for generic substitution of AEDs (reviewed in [28]). For example, the guidelines developed by the German Chapter of the International Liga against Epilepsy recommend to consider a low cost generic brand when first initiating treatment but a switch from a brand to generic drug in a well-controlled patient is not recommended [29]. In concordance with this are the Italian guidelines which state that in patients who achieved complete seizures remissions, switching is not recommended [35]. Similarly, the Swedish Medicinal Product Agency states that a switch between formulations is considered to carry a risk of unstable seizures control. The Scottish Intercollegiate Guidelines Network even regard formulations of antiepileptic drugs as not interchangeable and state that generic substitution should not be employed. The American Academy of Neurology (2006) opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without attending physicians’ approval.
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Does bioequivalence indicate therapeutic equivalence and switchability? Given the fact that many, particularly some of the classic AEDs, have complicated pharmacokinetics, like phenytoin, and important dose-related side effects resulting in narrow therapeutic window and the need for careful dose titration in individual patients. One has to look closer to the equation bioequivalence, equals therapeutic equivalence [5]. Hauck and Andersen [22, 23] introduced two concepts of bioequivalence: prescribability and switchability. While current bioequivalence testing was regarded as sufficient for marketing approval, Hauck and Andersen suggested using individual bioequivalence for the assessment of switchability. In clinical practice, switchability is of great relevance for several reasons. (1) Since it is most likely that the bioequivalence of the generic product was documented utilising the brand antiepileptic drug as a reference, the switch from one generic product to another carries even a higher risk because the difference between the two generic products may well be outside the accepted population bioequivalent studies. (2) In addition, once a patient is put on a generic drug, it is likely that repeated substitution over time occur due to lowest costs alternative policy [17]. (3) Furthermore, when companies withdraw from the market, overall supply of the generic drug is not guaranteed. Therefore, these patients may face several switches between different generics and branded drugs. The average bioequivalence approach does not address that the individual mean ratios of AUC and Cmax differ from individual to individual. If individuals vary in their ratios of average responses of two formulations, a subject by formulation interaction is present [25]. In a common two way crossover bioequivalence study within subject variability or intrasubject variance and the subject by formulation indirection of the formulations are not taken into account [22]. Thus, ordinary bioequivalence addresses the question of prescribability but does not ensure the switchability between prescribable formulations. Switchability between two formulations can only be addressed by individual bioequivalence studies. The criteria for individual bioequivalence are derived from the concept that each patient has an individual therapeutic window of a drug as well as an individual therapeutic variability. When a generic product is approved that it is interchangeable with a brand drug, it is assumed that a distribution of an individual patient’s responses to the generic product must fall within the brand drug’s therapeutic window. to assess the intrasubject variability, both the brand and the generic products need to be given in replicate design studies where both the reference and the test product are given twice to the same subject. Instead of the traditional two way crossover bioequivalence study, the replicate design is a four way
crossover study which poses additional burden on generic product manufacturers and may complicate the statistical method. However, individual bioequivalence studies can handle highly variable drug products by scaling criteria to the variability of the reference (brand formulation) [24].
What is the clinical experience with generic substitution in the treatment of epilepsy? Many case reports of individuals experiencing adverse events (breakthrough seizures or toxicity) after switching from branded AED to generics are available (reviewed in Crawford et al. [13]). Clearly these reports are heavily biased of cases that experience adverse events after switching and the majority of patients may have been switched without any problems. In several surveys of patients and physicians perceptions the majority of neurologists experienced problem with generic substitution of AEDs [4, 13]. However, recent well-designed prospective studies support the view that compulsory generic switching is not without problem. Andermann et al. [1] analysed a public payer pharmacy claims database in Ontario, Canada to analyse the switch-back rates from generic to branded AEDs. They found that 12.9% of the 1,354 patients who received generic lamotrigine were switched back to branded lamotrigine (LamictalÒ). The switch-back rates for clobazam and valproic acid from generic to branded drugs were around 20%. These rates were substantially higher than for non-AEDs which were switched back in only 1.5–2.9%. In addition, significant increases in lamotrigine doses were observed after generic substitution for those who did not switch back. There was also a significant increase in the average number of co-dispensed AEDs and non-AEDs after generic lamotrigine entry. The authors concluded that this reflects full acceptance of switching AEDs to generic compound or may also indicate increased toxicity and loss of seizure control associated with the generic use. Le Lorier and co-workers assessed the clinical consequences of generic substitution of lamotrigine in Quebec, Canada [30]. Out of the 671 patients treated with branded lamotrigine, 27.9% switched to a generic and 27.5% of these patients switched back to the branded medication. The switch-back rates varied from 20.8 to 44.1% for various AEDs which was substantially higher than the 7.7 to 9.1% switch-back rate for non-AEDs. Relative to the branded lamotrigine use, generic lamotrigine use was associated with a 5.1% increase in mean daily dose of lamotrigine and a higher number of dispensations of other AEDs as well as non-antiepileptic drugs. Moreover, there was also a higher utilisation rate of medical services after generic substitution of lamotrigine (8.7 vs. 9.8 visits per person/year) and a longer hospital length of stay
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(3.29 days vs. 4.86 days per person/year). This study confirmed the findings of Andermann et al. [1] and, likewise, challenges the cost effectiveness of generic switching. In a later study the same group analysed the economic consequences and the risk of multiple generic substitutions of topiramate in Quebec, Canada [16]. Within 1 year a total of 23 out of 948 patients received at least two generic versions of topiramate. Compared to brand use, multiple generic uses was associated with a higher utilisation of other prescribed drugs, a higher hospitalisation rate and longer hospital stays. The effect was less pronounced in single generic use. In this study, the risk of head injury or fracture was nearly three times higher (hazard ratio 2.84, 95% confidence interval, 1.24–6.48) following generic to generic topiramate switch compared to brad use. The health costs per patients were significantly higher in the multiple generic groups than in the brand period. The authors concluded that due to the negative outcome with increased hospitalisation and injury, the increased healthcare costs outweigh the benefit from reduced price of generic topiramate. Another case control study from the US found a clear association between patients receiving epilepsy care in an emergency and in-patient setting and the recent occurrence of antiepileptic drug formulations switching [41]. These studies are strong indicators that the current bioequivalence testing does not adequately address switchability of AEDs. Seizure control should not be sacrificed on the basis of cost alone. The main goal in treating epilepsy patients is full seizure control without side effects. This outcome guarantees participation in normal life without restrictions. A single breakthrough seizure may have catastrophic consequences for the individual patient (e.g. driving licence, employment, etc.), in addition to the physical risks (injuries, head traumas). Until we have individual bioequivalence data on generic AEDs a switch from brand to generic antiepileptic drug or between generic AEDs in seizure-free patients is not recommended. Current bioequivalence testing is based on traditional average bioequivalence analyses though the test criteria are sufficient to guarantee prescribability. Switchability between two prescribable drugs is a different issue which cannot be addressed adequately by average bioequivalence testing. In case of AEDs where individual bioavailability may vary considerably compulsory switching from brand to generic AED or between generic AEDs poses the patient at an undue risk for a breakthrough seizure that could lead to injury, driving restriction and disability. Until individual bioequivalence data on generic AEDs are available, a switch of AED products in seizure-free patients is not generally recommended. Conflict of interest Eugen Trinka has acted as a paid consultant to Eisai, Medtronics, Bial, and UCB. He has received research funding
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from UCB, biogen-idec, sanofi-aventis, and speakers’ honoraria from Bial, Cyberonics, Desitin Pharma, Eisai, Gerot, Bo¨hringer, Sanofi, Medis, and UCB.
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