1. Generic Substitution of AEDs: Is There Cause for Concern? Barry E. Gidal, PharmD Professor of Pharmacy and Neurology University of Wisconsin School of Pharmacy & Dept. of Neurology Madison, WI

2. Definitions Generic drug: identical, or bioequivalent to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. Bioequivalence: demonstration that both the rate and extent of absorption of the active ingredient of the generic drug fall within established parameters when compared to that of the reference listed drug. Office of Generic Drugs, http://www.fda.gov/cder/ogd/

3. Hatch-Waxman Amendments to FFD&C Act - 1984 Considered one of the most successful pieces of legislation ever passed Created the generic drug industry Increased availability of generics 1984 12% prescriptions were generic 2000 44% prescriptions were generic - yet only 8% of revenue for prescription drugs Compromise legislation to benefit both brand and generic firms

4. Hatch-Waxman Amendments to FFD&C Act - 1984 Allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities (do not have to repeat expensive clinical and pre-clinical trials) Allowed patent extensions and exclusivities to innovator firms

5. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH OFFICE OF GENERIC DRUGS APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE EVALUATIONS 23 rd EDITION THE PRODUCTS IN THIS LIST HAVE BEEN APPROVED UNDER SECTION 505 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT. 2003 Electronic Orange Book - http://www.fda.gov/cder/ob/

6. All FDA approved drug products listed (NDA’s, OTC’s & ANDA’s) –Therapeutic equivalence codes  “A” = Substitutable  “B” = Inequivalent, NOT Substitutable –Expiration dates: patent and exclusivity –Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products Orange Book “ Orange Book ”

7. Reasons Underlying Use of Generic Medicines Need by payers, including government, and formularies to reduce healthcare costs –Congressional Budget Office estimates generics save consumers $8 to $10 billion a year at retail pharmacies (http://www.fda.gov/cder/ogd/) Expense of brand name drugs for patients, such as seniors on fixed income, can be substantial

8. Reasons Underlying Use of Generic Medicines FDA’s commitment to generic medicines –“FDA will continue to make the generic drug approval process more efficient with the goal of lowering national health care costs by reducing the cost of bringing safe and effective generic drugs to market.” FDA press release August 8, 2003 Belief by payers, some physicians and some patients that brand products and generic versions are entirely equivalent and interchangeable

9. Potential Disadvantages of Generic Medicines Rate and extent of absorption (bioavailability) differs between different generic versions of branded products Generic names are not as easy to remember, spell or pronounce as branded names Generic products usually differ in appearance from the brand and from other generic versions of the same product, leading to patient confusion and anxiety Excipients and colorants used in generic products may differ from the brand, potentially causing problems Crawford et al. Seizure 2006;15:168-176

10. Substitution of Generic AEDs: Perceptions Wilner (Epilepsy Behav. 2004;5:995-998) –6420 neurologists surveyed, 301 responded 67% reported breakthrough seizures 56% reported increased adverse effects Guberman & Corman (Can J Neurol Sci. 2000;27:37-43) –83 patients/46 neurologists surveyed Patients generally viewed generics as safe 22% unsure if they were receiving a generic product 86% patients receiving generic reported no problems after switch Clinicians tended to overestimate patient concerns over switching Crawford et al (Seizure. 1996;5:1-5) –2285 patients surveyed, 1330 responded –70% reported no problems –11% reported either increased seizure or adverse effects

11. AAN Position Statement on AED Generics: April 2007 The AAN –Opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician’s approval The FDA –Has allowed for significant differences between name-brand and generic drugs Anticonvulsant drugs for the treatment of epilepsy differ from other classes of drugs in several ways that make generic substitution problematic –Small variations in concentrations between name-brand drugs and their generic equivalents can cause toxic effects and/or seizures when taken by patents with epilepsy –Unlike other diseases, a single breakthrough seizure due to change in delivered medication dose can have devastating consequences, including loss of driver's license, injury, and even death Liow K, et al. Neurology. 2007;68:1249-1250.

12. AAN Position Statement on AED Generics: April 2007 The AAN opposes –All state/federal legislation that would impede the ability of physicians to determine which anticonvulsant drugs to prescribe for epilepsy –Policies that would result in arbitrary switching among anticonvulsants, including generic substitution of anticonvulsants for epilepsy at the point of sale, without prior consent of the physician and the patient The AAN believes –Formulary policies should recognize and should support complete physician autonomy in prescribing, and patients in accessing, the full range of anticonvulsants for epilepsy –The use of anticonvulsant drugs in the treatment of epilepsy should be distinguished from the use of anticonvulsant drugs in treating other disorders The AAN supports –Legislation that would require informed consent of physicians and patients before generic substitutions of anticonvulsants are made at the point of sale Liow K, et al. Neurology. 2007;68:1249-1250.

13. Epilepsy Foundation Policy on Generic AEDs The Epilepsy Foundation is seriously concerned about mandatory substitution of generic antiepileptic drugs without prior approval of the patient and treating physician. Because changing from one formulation of an AED to another can usually be accomplished, and risks minimized, if physicians and patients monitor blood levels, seizures and toxicity, the Foundation maintains that the individual and physician should be notified and give their consent before a switch in medications is made, whether it involves generic substitution for brand name products, or generic to generic substitutions. http://www.epilepsyfoundation.org/advocacy/care/genedrev.cf m

14. AMA: Policy on Generic Drugs (June 2002) For the most part, controlled studies based on average bioequivalence measures, as well as therapeutic measures, support the contention that “A”-rated generics for carbamazepine, phenytoin, and valproate are equivalent to their brand-name counterparts –However, many neurologists remain unconvinced by average bioequivalence studies and hold the view that interchangeability of products in previously stabilized individual patients can be problematic Available at: http://www.ama-assn.org/pub/category/15279.html.

15. AMA: Policy on Generic Drugs (June 2002) The AMA believes –Substitution with FDA “B”-rated generic drug products (ie, products with potential or known bioequivalence problems) should be prohibited by law, except when there is prior authorization from the prescribing physician (Policy) –AMA Policy H-115.974 be reaffirmed This policy states, in part, that when a physician desires to prescribe a brand name drug, he or she do so by designating the brand name drug product and the phrase "Do Not Substitute" (or comparable phrase or designation, as required by state law or regulation) on the prescription –Physicians should report serious adverse events that may be related to generic substitution, including the name, dosage form, and the manufacturer, to the FDA’s MedWatch program (Policy) Available at: http://www.ama-assn.org/pub/category/15279.html.

16. Brand Name DrugGeneric Drug Requirements 1. Chemistry2. Manufacturing3. Controls4. Labeling5. Testing 6. Animal Studies 7. Clinical Studies6. Bioequivalence 8. Bioavailability Generic Drugs: The Review Process

17. Therapeutic Equivalence and Bioequivalence FDA criteria –Rate and extent of absorption of the active ingredient(s) fall within established parameters –Bioequivalence accepted when the 90% confidence interval of the ratios of AUC, C max, and T max fall between 0.8 and 1.25 of the branded drug FDA requirement for testing –Single dose of reference drug and test drug given to healthy adults in a crossover design FDA criteria –Contains same active ingredients –Identical in strength, dosage form, and route of administration –Bioequivalent –Adequate labeling –Manufactured in compliance with GMP FDA ratings –Category A: equivalent –Category B: not equivalent Bioequivalence Therapeutic Equivalence U.S. Food and Drug Administration. Office of Generic Drugs. http://www.fda.gov/cder/ogd. Meyer MC. J Clin Psychiatry. 2001;62(suppl 5):4-9.

18. Therapeutic Equivalence and Bioequivalence FDA criteria –Rate and extent of absorption of the active ingredient(s) fall within established parameters –Bioequivalence accepted when the 90% confidence interval of the ratios of AUC, C max, and T max fall between 0.8 and 1.25 (log- transformed data) of the branded drug FDA requirement for testing –Single dose of reference drug and test drug given to healthy adults in a crossover design FDA criteria –Contains same active ingredients –Identical in strength, dosage form, and route of administration –Bioequivalent –Adequate labeling –Manufactured in compliance with GMP FDA ratings –Category A: equivalent –Category B: not equivalent Bioequivalence Therapeutic Equivalence U.S. Food and Drug Administration. Office of Generic Drugs. http://www.fda.gov/cder/ogd. Meyer MC. J Clin Psychiatry. 2001;62(suppl 5):4-9.

20. Testing for Bioequivalence 0.8 1.25 1.0 Test Product High Nonequivalent Test Product Bioequivalent Bioequivalent 0.8 1.25 1.0 0.8 1.25 1.0 Test Product Low Nonequivalent

21. Bioequivalence: Assumption: Generic = Brand 0.8 1.25 1.0 Generic #1 Generic #2 0.8 1.25 1.0 0.8 1.25 1.0 BrandProduct What About Generic = Generic?

22. Generic Substitution of AEDs: Issues Regulations Don’t Address Frequent product switching at large chain pharmacies due to contract, supply issues Patients moving to different pharmacies due to logistics (driving), or because of price shopping $$.....barriers due to 3 rd party/formulary mandated co-pays Multiple stakeholders, much confusion, little communication

23. Conclusions Substitution of generic AEDs is controversial! Given the potential consequences, increased vigilance (eg, serum drug monitoring would seem prudent when switching between formulations Patients and pharmacies should be discouraged from frequent generic switching Quality control of generic products is essential, both in manufacture and storage Good communication between physician/pharmacist/patient is essential