藥學雜誌電子報99期
104
Vol. 26 No. 3
Sep. 30 2010
中華民國九十九年九月三十日出版

Controversies in Generic Substitution in the Real World


Chien-Ning Hsu
Department of Pharmacy, Chang Gung Memorial Hospital at Kaohsiung

Abstract

Growing healthcare cost and the rise in pharmaceutical expenditure component prompt many cost-containment initiatives by policy makers and health providers worldwide. Most countries have been gradually adopted generic substitution strategy to get promises for cost containment, while there has been disappointment in drug safety and effectiveness. To address the issues of concern, the use of generic antiepileptic drugs (AEDs) will be the example in this paper around the approval process for the generic drugs, characteristics of AEDs, bioequivalence versus therapeutic equivalence, and evidence from clinical practice.

Key Words: Cost-containment strategy, pharmaceutical expenditure, generic substitution, BA/BE (bioavailability/bioequivalence), anti-epileptic drug (AED)

Regulatory Approval Process for Generic Drugs

In many countries, the regulatory agency requires that a generic drug compared with the corresponding brand-name drugs is bioequivalent or biosimilar. In Taiwan, the U.S., and other developed countries this notion of essential similarity is comprised of three fundamental aspects: compared with the brand-name drug, the generic drug must have (1) the same quantity and type of active ingredient, (2) the same route of administration, and (3) the same therapeutic effectiveness, as demonstrated by a bioequivalence study. A bioequivalent (BE) study is conducted in small crossover trials involving 24 to 36 healthy volunteers (most of them are young male subjects).1

The U.S. Food and Drug Administration (FDA) concludes that a generic drug and its corresponding reference listed drug are bioequivalent in the rate and extent of absorption (i.e., bioavailability) if the 90% confidence intervals of the geometric mean test/reference ratios for both peak drug concentrations (Cmax) in plasma and the area under the drug plasma concentration versus time curve (AUC) falls within the bioequivalence limits of 80-125%.2 The generic manufacturers do not have to prove therapeutic equivalence, which would require further efficacy and safety studies; the drug simply passes with the surrogate indicator for therapeutic equivalences and a comparator of pharmaceutical quality of the generic and brand drugs.

Bioequivalence versus Therapeutic Equivalence

By definition, bioequivalence implies the reference and generic drug reach the blood at comparable concentrations over time and depends on the equivalence of selected pharmacokinetic parameters. However, therapeutic equivalence implies that the reference and generic drugs will provide equal therapeutic effect and depends on the equivalence of selected clinical parameters (e.g., efficacy or tolerability). The therapeutic interchangeability of generic drugs is the major disadvantage of the current regulatory criteria for generic drugs, particularly in view of the fact that use of these generic formulations is widespread. Numerous factors can contribute to the variability of bioequivalent parameters (Cmax and AUC, the indicator for absorption): (1) substance characteristics, (2) the product's formulation, and (3) individual variations.2 Bioavailability becomes crucially important in the evaluation of bioequivalence if the substance characteristics are related with poor aqueous solubility, a narrow therapeutic index, or non-linear kinetics.

Figure 1 depicts the variability of bioavailability in the bioequivalence studies reviewed by the U.S. FDA. For highly variable drugs, the 90% confidence interval will be narrower and pass the FDA regulatory criterion when using more study subjects. It is noteworthy to mention that the permitted difference in statistical evidence of bioequivalence for generic drugs does not guarantee the therapeutic equivalence and safety profile comparing to the corresponding branded drug. More importantly, it implies potential discrepancies among individual patients in practice when switching from a brand-name drug to a generic drug, or even a generic drug to another generic drug. The consequences can be particularly serious and difficult to rectify in conditions of complexity of disease management such as epilepsy.

 

09-1.tif

Figure 1. A visual representation of some possible results of the statistical analyses of bioequivalence studies (with permission from The AAPS Journal)

T denotes the test drug (generic drug), and R denotes (corresponding reference listed drug)

The three bars represent the widths of hypothetical 90% confidence intervals from bioequivalence studies of drugs with normal variability (green bar), low variability (blue bar), and high variability (red bar). A bell-shaped curve is superimposed over green bar, representing the 90% confidence interval, distributed around the geometric mean test/reference ratio (“point estimate”), for the normal variability drug.

 

Generic Substitution for Antiepileptic Agents (AEDs)

Four major brand-name AEDs are expected to lose patent protection and face generic competition in 2009 and 2010. Those four drugs (topiramate, lamotrigine, levetiracetam, and valproate semisodium) generated more than $5 billion in U.S. sales in 2006. Some AEDs have been known for their high variability in pharmacokinetic characteristics, such as phenytoin, carbamazepine and valproic acid. There have been concerns raised about anecdotal reports that some patients experienced seizures and side effects after switching epilepsy drugs. To date, there are no published randomized controlled trials that has demonstrated generic AEDs are not therapeutic equivalence to branded AEDs, but some studies are limited with control group; however, a series of case reports, physician surveys, and“switchback”rates from large-scale generic conversions imply that all generic formulations may not be equal to the brand drug for all patient groups.3-5

Phenytoin has poor solubility in water, a narrow therapeutic index, and nonlinear kinetics (or capacity-limit metabolism). The clinical consequences of these pharmacologic characteristics have been studied since the 1960s. Despite the fact that the generic formulation of phenytoin satisfied FDA standards for bioequivalence, differences in its absorption profile between manufacture and clinical use have been reported.6

This nonlinear pharmacokinetic property coupled with phenytoin's narrow therapeutic concentration range is complicated, and similar considerations apply to generic products of carbamazepine and valproic acid, but not other newer AEDs such as lamotrigine, gabapentin, and topiramate. A narrow therapeutic index (NTI) of a drug implies that slight variations in drug absorption could result in significant negative health outcomes. The controlled studies also found differences in BE between the generic and brand-name drugs, but they reported no clinically significant differences.7 However, when a narrow margin for dosage is coupled with the rather limited conditions in which the FDA formally tests drugs for bioequivalence and concerns in patient compliance, the risk for unwanted treatment effect increases.

Epilepsy is a chronic disorder that often requires lifelong treatment. Avoidance of seizures is the primary goal, while keeping adverse effects to a minimum. When long-term remission has been achieved, it becomes important to avoid even a single breakthrough seizure. A breakthrough seizure after a long remission can have significant psychosocial and physical consequences for patients in areas of life such as employment and driving, and could lead to injury.8 Establishing seizure control can be difficult and many AEDs have to be tried and titrated at various doses to achieve the treatment appropriateness. Drug interactions between AEDs (a inducer or inhibitor of CYP P450) and concomitant medications could add additional concerns about the potential unwanted consequences if the seizure treatment is inadvertently disturbed.

Much discussion in recent literature express wide-spread uncertainty regarding generic inequivalence for patients switching from branded to generic AEDs.3,5,9 Andermann et al. reported a switchback rate of approximately 20% for carbamazepine and valproic acid, and 12.9% for lamotrigine.3 Similarly, the switching back to the branded AEDs or increasing dosage for non-switchback patients were seen in the Le Lorier et al. study.5 The evidence of inequivalence in lamotrigine is also confirmed by the direct comparison drug concentration levels before and after a switch, showing that the blood level of the drug was lower with the generic formulation.4

Further substantial concerns arise about multiple drug suppliers of the product and uncertain consequences of switching from one generic to another generic drug. Although newer AEDs, such as lamotrigine, gabapentin, and topiramate, may appear to have a wider therapeutic index, variations in blood level of the drugs between a generic and the branded drug or between generics from different manufacturers may produce different effectiveness in seizure control. With these concerns, clinical experts and regulatory agencies express concerns over generic substitution in epilepsy to all AEDs and recommend generic substitution is not allowed for patients with special factors that could result in therapeutic differences.8, 10

Generic substitutions might provide great incentives for reducing AEDs expenditures. The true cost of generic substitutions should include the cost of additional visits to a physician or the hospital if the substitution causes problems, and the cost of treatment failure, if a seizure occurs. Current literature suggests that brand-to-generic substitutions of AEDs do not necessarily reduce overall healthcare costs and may even increase them due to the greater use of primary care services.11

Lessons to Learn from Generic Substitution for AEDs

The top priority of implementing cost containment strategies is not compromising the benefits to patients, in terms of effectiveness and safety. Mounting evidence shows that generic substitutions without adequate information and close supervision during the therapy can result in clinical inequivalence and subsequent greater healthcare costs. Issues of concern about AEDs generic substitution are not just a matter of cost control on pharmaceutical expenditure. Much of current debates focus on implications of BE study and a number of critical issues have been identified.

First, the BE standards are designed to allow for generic interchange with the same consistency of the brand-name drug. The assumption that BE in a small set of normal and healthy volunteers equates to both bioequivalence and comparable efficacy and tolerability in the patient population is questionable. This issue is particularly relevant to (1) special patient populations (e.g., elderly, children patients), (2) serious consequences of having over-dosing or under-dosing (e.g., breakthrough seizure), (3) drugs with NTI (e.g., phenytoin, warfarin), and (4) drugs with high variability in their pharmacokinetics (e.g., proton pump inhibitors). In the majority of therapeutic categories, these disadvantages may not be relevant in comparison to the economic benefits. However, health professionals and policy makers should recognize the differences in the ways they affect patients, and be aware that changing the supplier of medicines might compromise care of patients with certain conditions.

Second, potential problematic issues related with generic substitutions are patients' perception of risk, awareness of differences in product, and packaging appearance. All of these issues are of particular importance to special populations (with consequent alterations in pharmacokinetics); disease populations require continued caution on dose responses (such as patients with epilepsy) and therapeutic class of drugs.12,13 The questions of legal responsibility also arise if adverse consequences came from generic substitutions.8

It is often difficult to prove the adverse consequence or inconsistency definitely associated with the generic substitution. Efforts to offer adequate information about generic drugs may assist patients in making informed decisions and may influence their personal preferences for generics use, which could be helpful on adherence to essential medicine.12 Furthermore, an effective pharmacovigilance network would perform periodic surveys of health professionals to elicit any observed differences in generic substitutions. Health professionals (in particular, pharmacists) should have an obligation to inform those caregivers of any switching from a brand-name drug to a generic drug or the switching between generic drugs.

Third, although the use of generic products may produce considerable savings, these savings should not be offset by increased additional healthcare services and should not compromise patient's disease stability. In Taiwan, the Bureau of Pharmaceutical Affairs (BPA) in Department of Health (DoH) exercises as a“gate-keeper”to the quality of generic drugs, whiles the Bureau of National Health Insurance (BNHI) is the final“decision-maker”to the formulary. The BNHI should bear chief responsibility for monitoring relationships between generic price policy and use of generic substitutes, and their impacts on cost saving. It is imperative to notice that the economic evaluation for healthcare system saving cannot be the only criterion for the entry of a drug into the market, particularly in the absence of procedures designed to protect patients' health and safety.

Last but not the least, pharmacists have a unique role in the interdisciplinary efforts to support an efficient cost containment strategy for affordable pharmaceutical cares. Pharmacists may face challenges when determining whether substitution is appropriate in a given situation, a decision that needs to be grounded in research, clinical information, financial factors, quality of pharmaceuticals, and consideration of how the substitution would impact the patient in a timely manner. Pharmacists must be prepared to identify situations where the process should be paused because further research is indicated. In response to these challenges, a decision support tool has been suggested to guide the American pharmacists through a series of considerations and questions that should be addressed to determine when substitution is appropriate and safe to support the recommendation for substitution.14

Pharmacists are also encouraged to (1) support proposals to the DoH in Taiwan to altering the approval process for generic drugs to assure a greater sense of clinical security; (2) suggest to the DoH and generic manufacturers that a post-marketing surveillance system be applied for both branded and generic drugs so that any changes occurring in the product due to alternations in the manufacturing process (such as bulk material supplies) would be detected; (3) suggest to the DoH to establish an authorized source of therapeutic equivalence information among branded and generic products and products with the same active ingredients produced by different companies approved in Taiwan, so that health professionals can determine when substitution is appropriate and safe (such as the“Orange Book,”formally titled Approved Drug Products With Therapeutic Equivalence Evaluation, published by the U.S. FDA).15

This article was not written with support from or discussion with any pharmaceutical manufacturer.

Reference:

1. U.S. Dept. of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations. March 2003, BP. Revision 1. (Accessed Oct. 2009, at http://www.fda.gov/cder/guidance/5356fnl.pdf )

2. Davit B, Conner D, Fabian-Fritsch B, et al: Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications The AAPS Journal 2008;10(1):48-156.

3. Andermann F, Duh M, Gosselin A, et al: Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia 2007;48:464-9.

4. Berg M, Gross R, Tomaszewski K, et al: Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology 2008;71(7):525-30.

5. LeLorier J, Duh M, Paradis P, et al: Clinical consequences of generic substitution of lamotrigine for patients with epilepsy Neurology 2008;70((22 Pt 2)):2179-86.

6. Burkhardt R, Leppik I, Blesi K, et al: Lower phenytoin serum levels in persons switched from brand to generic phenytoin. Neurology 2004;63:494-1496.

7. Mikati M, Bassett N, Schachter S. Double-blind randomized study comparing brandname and generic phenytoin monotherapy. Epilepsia 1992;33:359-65.

8. American Academy of Neurology. Assessment generic substitution for antiepileptic medication. . Neurology 40:1641-3.

9. Crawford P, Feely M, Guberman A, et al: Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006;15:165-76.

10. National Institute for Clinical Excellence.The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. CG20. NICE, October 2004. Section 4.8.8. (Accessed Oct. 2009, at http://www.nice.org.uk/pdf/CG020fullguideline.pdf.)

11. Duh M, Cahill K, Paradis P, et al: The economic implications of generic substitution of antiepileptic drugs: a review of recent evidence. Expert Opin Pharmacother 2009;10(14):2317-28.

12. William H, Shrank E, Cox R, et al: Patients' Perceptions Of Generic Medications. Health Affairs 2009;28(2):546-56.

13. Van Wijk B, Klungel O, Heerdink E, et al: Generic substitution of antihypertensive drugs: does it affect adherence? Ann Pharmacother 2006;40:15-20.

14. Manolakis P. Prescription Drug Product Substitution Decision Support. J Am Pharm Assoc 2007;47:328-47.

15. U.S. Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. (Accessed Dec. 2009, at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.)

摘要

醫療支出的成長及藥物費用的提升促使世界各國的醫療政策決定者必須進行成本控制的策略。許多國家採用學名藥替代同成分的原廠藥方式以控制藥費支出;然而,學名藥因為其療效不如同成分的原廠藥及病患使用學名藥的安全性有爭議,導致全面執行學名藥替換作法是否有助藥費控制的成效備受疑慮。

為逐一闡述上述疑慮,本文將討論學名藥核准的法規科學依據(生體可用率及生物相等性)、生物相等性是否等同治療相等、並以抗癲癇藥物學名藥替換為例,討論現有的臨床證據,最後針對藥師將來可能面對大量學名藥替換提出應有的準備以供作參考。

作者

高雄長庚紀念醫院藥劑科藥師 許茜甯