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Generic Drugs: What does equal really mean? Dr. Peter J. Lin Director Primary Care Initiatives Canadian Heart Research Centre Conflict Disclosure Information Speaker: Dr. Peter Lin Title of Talk: Alzheimer’s Update FINANCIAL DISCLOSURE Grants/Research Support: None Speakers Bureau/Honoraria: Astrazeneca, Takeda, Boeringher Ingelheim, Eli Lilly, Sanofi, Jansen Merck, Pfizer, Servier , Abbott, Forest Laboratories, Novartis, Purdue Consulting Fees: None Research Funding: None Other: None BRAND Name Generic? Blue Cross Blue Shield of Michigan Billboards $20 million to test quality of Generics Antihypertensive Agents Currently Available in Canada ACE-Is Benazepril Captopril Cilazapril Enalapril Fosinopril Lisinopril Perindopril Quinapril Ramipril Trandolapril ARBs Candesartan Irbesartan Losartan, Olmesartan Telmisartan Valsartan Beta-blockers Acebutolol Atenolol Bisoprolol Labetolol Metoprolol Nadolol Pindolol Propanolol Timolol CCBs Amlodipine Diltiazem Felodipine Nifedipine Verapamil Renin Diuretics inhibitors Acetazolamide Aliskiren Furosemide Hydrochlorothiazide Indapamide Metolazone Spironolactone Triamterene ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker Snake-oil Salesman •How to calm kids down. Infants Relief Cannabis Chloroform FDA – Companies had to prove that a drug was both safe and effective before it reached the market place. All new drugs had to go through a lengthy and expensive process that included large-scale human trials. 1962 Impala REVIEWERS Scientific Investigations Preclinical Phase 1 Phase 2 Phase 3 Phase 4 Compliance (CMC) Chemist Microbiologist Pharmacologist Biopharmaceutist Clinician Statistician NDA Drug Advertising Advisory Committee Office Drug Safety 12 Searching for Molecules Drug Development Timeline Graph Source: www.PhRMA.com 15 Production Sameness Discovery Safety Efficacy 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) Center for Drug Evaluation & Research U.S. Food & Drug Administration 17 Human bioequivalence studies have been required for generic drugs since 1984 “Bioequivalence refers to the absence of a significant difference in the rate at which or the extent to which the active ingredient in pharmaceutical equivalents becomes available at the site of drug action when two drug products are administered under similar experimental conditions in an appropriately designed study.” Welage LS et al. J Am Pharm Assn 2001;41(6):856-857 Abstract Human bioequivalence studies have been required for generic drugs since 1984 “Bioequivalence refers to the absence of a significant difference in the rate at which or the extent to which the active ingredient in pharmaceutical equivalents becomes available at the site of drug action when two drug products are administered under similar experimental conditions in an appropriately designed study.” Non-Inferiority Study Welage LS et al. J Am Pharm Assn 2001;41(6):856-857 Abstract What are the requirements for a generic drug? • Same active ingredient(s) • Same route of administration • Same dosage form • Same strength • Same conditions of use Compared to reference listed drug (RLD) - (brand name product) Center for Drug Evaluation & Research U.S. Food & Drug Administration 20 Same ?? Bioequivalence Example 8 Test/Generic 7 Reference/Brand 6 5 4 3 2 1 0 6 12 18 24 30 36 42 48 24 Bioequivalence Example 8 Test/Generic 7 Reference/Brand 6 5 4 3 AUC 2 1 0 6 12 18 24 30 36 42 48 25 Bioequivalence FDA “The relative mean measured AUC of the modified-release formulation to the conventional formulation should be between 80% and 125% in the fasting state.” Source: Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part B: Oral Modified Release Formulations. What does Equal Mean? -20% 80% +25% 45% Window 125% What does Equal Mean? -20% 80% +25% 45% Window 125% How many people do you need to test? 12 FACT: Research shows that generics work just as well as brand name drugs. A recent study evaluated the results of 38 published clinical trials that compared cardiovascular generic drugs to their brand-name counterparts. There was no evidence that brand-name heart drugs worked any better than generic heart drugs. [Kesselheim et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. 2008;300(21)2514-2526]. Generic only 3% off Looked at 8556 studies – only 47 matched criteria Generic and Brand-Name Drugs Used in Cardiovascular Disease - 0.03 30 Studies 28 per study 837 Patients Fillers ??? Inactive Ingredients Prinivil (Lisinopril) Merck & Co Inactive Ingredients in 20mg dose 1.Calcium Phosphate 4. Starch 2.Mannitol 5. Iron Oxide 3.Magnesium Sterate Lisinoril by Mylan Inc. Generic Inactive ingredients in 20 mg dose 1.Collidal Sillicon Oxide 5. Providone 2.Croscarmellose sodium 6. pregelatinized starch 3.Diabasic calcium phosphate 7.Sodium lauryl sulfate 4.Mannitol 8.D&C Yellow #10 Aluminum lake HT Generic version almost doubles the inactive ingredients Additional ingredients may increase the risk for allergic response and pharmacists rarely caution patients against potential adversities and no labeling is required. It is unclear how these ingredients will effect the outcomes of the drug. Ex. sodium lauryl sulfate is (surfactant soap) that can be used in a degreaser Inactive Ingredients Prinivil (Lisinopril) Merck & Co Inactive Ingredients in 20mg dose 1.Calcium Phosphate 4. Starch 2.Mannitol 5. Iron Oxide 3.Magnesium Sterate Lisinoril by Mylan Inc. Generic Inactive ingredients in 20 mg dose 1.Collidal Sillicon Oxide 5. Providone 2.Croscarmellose sodium 6. pregelatinized starch 3.Diabasic calcium phosphate 7.Sodium lauryl sulfate 4.Mannitol 8.D&C Yellow #10 Aluminum lake HT Generic version almost doubles the inactive ingredients Additional ingredients may increase the risk for allergic response and pharmacists rarely caution patients against potential adversities and no labeling is required. It is unclear how these ingredients will effect the outcomes of the drug. Ex. sodium lauryl sulfate is (surfactant soap) that can be used in a degreaser Shelf Life Ramipril vs 22 Generics Ramipril vs 22 Generics STABILITY: Metabolite Ramipril-diketopiperazine (DKP) Clopidogrel 75mg Clopidogrel 60mg good enough? What about eye drops? ADD Methylphenidate (ng/mL) Pharmacokinetic Profiles for MOH and OROS MPH Time (h) 1OROS MPH (methylphenidate HCI) ER Tablets Citizen Petition. McNeil Consumer & Specialty Pharmaceuticals. 2004 UK Switch to Simvastatin Phillips, Br J Cardiol 2007;14:280-5 Osteoporos Int (2012) 23:213–221 Still on Therpary Osteoporos Int (2012) 23:213–221 Epilepsy – switch to Levetiracetam November 1, 2008 all patients switched to generic Retrospective Chart review 260 patients 105 patients Switched back (42.9%) % Patients with Increased in seizure frequency: 19.6% vs 1.6% p<0.0001 Polytherapy: 3.225 (1.512-6.880) p<0.05 Epilepsia. 2011 Apr;52(4):810-5. doi: 10.1111/j.1528-1167.2011.03025.x. Epub 2011 Mar 22. N=37,756 Brand only = 4468 1 Generic=20, 292 Switchers = 12,996 Hemorrhagic Events 0 1 2 Ann Pharmacother 2011;45:701-12 N=37,756 Brand only = 4468 1 Generic=20, 292 Switchers = 12,996 Thrombotic Events Ann Pharmacother 2011;45:701-12 Clinical/PD Response Clinical/PD Dose-Response Log Dose Center for Drug Evaluation & Research U.S. Food & Drug Administration 57 Government Ranbaxy “Because this company continued to violate current good manufacturing practice regulations and falsify information on drug applications, the FDA took these actions in an effort to protect consumers,” said Dara Corrigan, FDA associate commissioner for regulatory affairs. May 15, 2013 1. Substitute Cheaper, Lower Quality 2. Substitute brand name drugs in lieu of their own generics in bioequivalance tests to produce better results http://features.blogs.fortune.cnn.com/2013/05/15/ranbaxy-fraud-lipitor/ Patent Challenge 180 days exclusivity (USA) The lots of atorvastatin, packaged in bottles of 90 and 500 tablets, are being recalled due to possible contamination with very small glass particles similar to the size of a grain of sand (less than 1 mm in size). Alysena is produced in Spain by Laboratorios Leon Farma and distributed in Canada by Apotex. There have been growing concerns over the quality and safety of drugs produced overseas and many health advocates question whether Health Canada is doing enough to ensure overseas plants are following good manufacturing practices. Background An inspection of a Pharmaceutical Factory in China was conducted by the European Directorate for the Quality of Medicines and Healthcare (EDQM) recently. During this inspection, a concern was identified about possible contamination of clindamycin with quetiapine. This contamination may have resulted from trace amounts of quetiapine on common equipment. Think: • Adherence? • Drug working? • Disease getting worse? THE CANADIAN SIDE Thanks for Staying Awake