Generic Drugs: What does equal really mean? Dr. Peter J. Lin Director Primary Care Initiatives Canadian Heart Research Centre

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$20 million to test quality of Generics

Antihypertensive Agents Currently Available in Canada ACE-Is Benazepril Captopril ARBs Candesartan Irbesartan Beta-blockers Acebutolol Atenolol CCBs Amlodipine Diltiazem Diuretics Acetazolamide Furosemide Renin inhibitors Aliskiren Cilazapril Losartan, Bisoprolol Felodipine Hydrochlorothiazide Enalapril Olmesartan Labetolol Nifedipine Indapamide Fosinopril Telmisartan Metoprolol Verapamil Metolazone Lisinopril Valsartan Nadolol Spironolactone Perindopril Pindolol Triamterene Quinapril Propanolol Ramipril Timolol Trandolapril ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker

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

Scientific Investigations Preclinical Phase 1 Phase 2 Phase 3 Phase 4 REVIEWERS NDA Chemist Microbiologist Pharmacologist Biopharmaceutist Clinician Statistician Advisory Committee Compliance (CMC) Drug Advertising Office Drug Safety 7

Production Sameness Discovery Safety Efficacy

The FDA Process for Approving Generic Drugs Gary J. Buehler, R.Ph. Dale Conner, Pharm. D. Director Director, Division of Bioequivalence Office of Generic Drugs

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 11

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 14

In proving that their products are safe and effective, generic drug manufacturers have two options. 1. One is to repeat most of the chemistry, animal and human studies done by the manufacturer of the original brand name drug. 2. The other is to show how the generic drug performs compared with the original brand name drug. In comparative bioavailability studies, the level of a medicinal ingredient in the blood of healthy human volunteers is measured. During the studies each volunteer receives the original brand name drug and the new generic drug on two separate occasions. The generic drug must show that it can deliver the same amount of medicinal ingredient at the same rate as the original brand name drug. 15

Bioequivalence Example 8 7 6 Test/Generic Reference/Brand 5 4 3 2 1 0 6 12 18 24 30 36 42 48 16

Bioequivalence Example 8 7 6 Test/Generic Reference/Brand 5 4 3 AUC 2 1 0 6 12 18 24 30 36 42 48 17

Bioequivalence Health Canada 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% +25% 80% 125% 45% Window

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 30 Studies 837 Patients 28 per study - 0.03

Labeling Same as brand name labeling May delete portions of labeling protected by patent or exclusivity May differ in excipients, PK data and how supplied Center for Drug Evaluation & Research U.S. Food & Drug Administration 27

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

Heat Humidity

Ramipril vs 22 Generics

STABILITY: Metabolite Ramipril-diketopiperazine (DKP)

UK Switch to Simvastatin Phillips, Br J Cardiol 2007;14:280-5

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 41

FDA has approved five generic versions of Wellbutrin XL 300 mg. Each of these generics was approved based on bioequivalence studies comparing the 150 mg strength of the products to Wellbutrin XL 150 mg. Studies were not performed directly on the 300 mg strength of the products. Rather, the bioequivalence studies were performed using the 150 mg strength, and the results were extrapolated to establish bioequivalence of the 300 mg product. This methodology was based on FDA s guidance at the time the products were approved. FDA has determined that this approach is no longer appropriate to establish bioequivalence of 300 mg bupropion hydrochloride extended-release tablets to Wellbutrin XL 300 mg, and the Agency is revising its guidance to industry for how to conduct premarket bioequivalence studies in generic bupropion products.

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/

$20 million to test quality of Generics

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