Generics and Manufacturing: What Prescribers Need to Know

Transcription

1 Generics and Manufacturing: What Prescribers Need to Know Michael B. Bottorff, Pharm.D., FCCP,FNLA,CLS Professor and Chair Department of Pharmacy Practice South College School of Pharmacy

2 Disclosures Speaker bureaus for Sanofi-Aventis, Boehringer-Ingelheim, Bristol- Myers Squibb, Pfizer, Amarin Consultant Abbott Labs I still write with pens having drug company names

3 Outline Define a generic drug Explore the US landscape of generic drug use Review the criteria for FDA approval of a generic drug Describe the FDA Orange Book and its AB designation for generic substitution Explore the complexities of the 1984 Hatch-Waxman Act and its impact on generic drug approvals

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5 US Top 200 Drugs of Interest Simvastatin (5) Metformin (6) Atorvastatin (13) Warfarin (23) Clopidogrel (25) Lovastatin (37) Pravastatin (40) Rosuvastatin (46) Fenofibrate (63) Niacin (ER) (134) Gemfibrozil (141) Lisinopril (1) Levothyroxine (2) Hydrocodone (3) Omeprazole (4) Sigler drug cards 29 th edition

6 What is a Generic Drug? Per the FDA, generic drugs are: copies of brand-name drugs and are the same in terms of Dosage form Strength Route of administration Safety Quality Performance characteristics Intended use Furthermore, generic manufacturing, packaging and testing sites must pass the same standards as the originator drug Ranbaxy USA, a subsidiary of an Indian generic manufacturer was fined $500 million due to the distribution of adulterated cipro and gabapentin (Dept of Justice May 13, 2013) accessed 7/23/2013

7 Generic Drugs in the U.S. Nearly 8 in ten prescriptions are for generic drugs Generic drugs must be proven to be bioequivalent to brand name counterparts Average cost of a generic is 80-85% below the branded counterpart Approximately $5 billion saved each week due to generic drug use 57% of which are CNS and cardiovascular drugs Generic Drug Usage in the U.S., GPhA, September 2011, page 1

8 Origin of Generic Drugs 1984 Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman) Incentivizing the development of new drugs Adding up to five years of patent protection for branded drugs due to the delay in FDA approval Facilitating the availability of less expensive drugs for the consumer Prohibits the FDA from requiring more than bioavailability studies for generic drug ANDAs Paragraph IV sets 180 day exclusivity to companies first-to-file a generic ANDA accessed 8/12/13

9 What is an ANDA Abbreviated New Drug Application (ANDA) Generic drug data submitted to the FDAs Center for Drug Evaluation and Research (CDER), Office of Generic Drugs Abbreviated since they do not contain pre-clinical and clinical data to establish safety and efficacy Must scientifically demonstrate bioequivalence Same rate and extent of absorption, therefore delivering the same amount of active ingredient over the same amount of time Guidance Documents for ANDAs Bioequivalence testing, statistical approaches, food-effect testing, etc. accessed 7/23/2013

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11 NDA vs ANDA Reviews Original Drug NDA Chemistry Manufacturing Controls Labeling Testing Animal Studies Clinical Studies (including bioavailability) Generic Drug ANDA Chemistry Manufacturing Controls Labeling Testing Bioequivalence Studies (in vivo and possibly *in vitro) *Comparative dissolution testing may be allowed when there is an established in vitro/in vivo correlation per CDER handbook 2003

12 Pharmacokinetic / Pharmacodynamic Relationships MEC Drug Toxicity Drug Effect (Cp) Peak Effet (Cmax) Systemic Exposure (Area Under The Curve, AUC) Therapeutic Window MEC Drug Effect Onset of effect Time

13 2 x 2 CROSS-OVER DESIGN subjects R A N D O M I Z A T I O N sequence 1 sequence 2 period 1 period 2 R T W A S H O U T T R

14 FDA Standardized High-Fat Test Meal Two eggs fried in butter Two strips of bacon Two slices of toast with butter Four ounces of hash brown potatoes Eight ounces of whole milk Protein Carbohydrate 150 kcal 250 kcal Fat kcal

15 Calculating Area Under the Curve (AUC) Malinowski and Johnson, in Remingtons 2006

16 Bioavailability Parameters and BE Tmax Plasma Concentration Plasma Concentration Cmax Time (hr) Time (hr) Two products can have same Tmax or Cmax and not be bioequivalent

17 Bioequivalence Examples Malinowski and Johnson, in Remingtons 2006

18 Definitions Definitions in terms of the ratio of the two geometric means µ T /µ R, where µ T and µ R are the geometric means of the test and reference products, respectively Bioequivalence interval [80%, 125%] Bio-inequivalence regions (0, 80%) or (125%, ) µ T /µ R 0 Bio-inequivalence Region 80% 125% Bioequivalence Interval Bio-inequivalence Region Li et al, CDER

19 Evaluating Three PK Endpoints Three PK parameters (AUC t, AUC, C max ) used to assess bioequivalence. Bioequivalence of two drugs requires that all the three PK parameters should be equivalent in terms of the bioequivalence interval using ratios µ T /µ R. There are FDA guidelines for Log transformation of pharmacokinetic data Methods to evaluate sequence effects Methods to evaluate outlier data

20 Three PK Endpoints for Bioequivalence The statistical criteria used to demonstrate bioequivalence for the three PK parameters are to have all the 2-sided 90% CIs for the ratios to be within [80%, 125%]. D.J. Schuirmann: A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokinet. Biopharm. 15: , 1987.

21 90% CONFIDENCE INTERVAL 90% CI 1.04 ( ) point estimate Based on the statistical power to detect a 20% difference in the ratio of geometric means and SE for BE parameters, it is difficult for a drug whose actual arithmetic mean differs by more than 10% to meet the requirements for approval (Henderson et al, S Med Journal 2001)

22 Statistical analysis BE criteria -Two one-sided tests procedure Test (T) is not significantly less than reference Reference (R) is not significantly less than test Significant difference is 20% (α = 0.05 significance level) T/R = 80/100 = 80%, or 100/80 =125%

23 Assessment of BE Based on Point Estimate and 90% CI Demonstrates BE Fails to demonstrate BE Fails to demonstrate BE Demonstrates BIE Demonstrates BIE 80% 125% T/R (%)

24 Example: Generic Drug X Parameter Test A Reference B Ratio 90% CI AUC 0-t (ng*hr/ml) AUC 0- (ng*hr/ml) Cmax (ng/ml) Log transformed data with serum nicotinuric acid, N=45

25 Position of FDA on Narrow Therapeutic Index Drugs (NTI) To date, there are no documented examples of failure of a generic drug due to a bioequivalence issue (warfarin, digoxin) Products determined bioequivalent should not require any additional clinical testing or monitoring Am J Health Syst Pharm 1997

26 Approved Drug Products with Therapeutic Equivalent Evaluations The Orange Book Due to numerous states requesting the FDA for a list of equivalent drug products, the FDA announced in 1978 the creation of the Orange Book The Orange Book is so named since it was finished in October 1980 Orange book is available at the FDA website and updated every few weeks Lists all approved drug products with their therapeutic equivalent codes and relevant patents accessed 7/23/2013

27 Therapeutic Equivalence Evaluation Codes A Codes drug products deemed therapeutically equivalent to other products AA products in conventional dosage forms not considered bioequivalence problems (eg., ophthalmic solutions) ABproducts meeting bioequivalence requirements There are other codes for aerosolization, injectable oil/aqueous solutions, topical products B Codes drug products that the FDA does not consider to be therapeutically equivalent to other pharmaceutically equivalent products BC extended release capsules, tablets, injectables BN products in nebulizer drug delivery systems Accessed August 12, 2013

28 AB Rated Generic Drugs for Dyslipidemia on the US Market Lovastatin (Mevacor) Actavis, Apotex, Carlsbad, Lupin, Mutual, Mylan, Sandoz, Teva Pravastatin (Pravachol) Apotex, Glenmark, Lupin, Mylan, Teva, Watson, Zydus and Dr. Reddys Labs Simvastatin (Zocor) Accord, Aurobindo, Blue Caribe, Dr. Reddys Labs, Ivax, Lupin, Micro, Mylan, Prosan, Ranbaxy, Watson, Zydus Atorvastatin (Lipitor) Apotex, Dr. Reddys Labs, KudCo, Mylan, Ranbaxy, Sandoz Fluvastatin (Lescol) Mylan, Teva Fenofibrate and fenofibric acid (Tricor, Trilipix) Anchen (FA July 18, 2013), Mylan, Apotex, Dr. Reddy, Cypher, Impax, Lupin, Teva, Ranbaxy, etc.

29 Patent Issues If an ANDA is filed for a generic drug prior to the end of the patent life, the sponsor of the ANDA must prove that the patents at issue are either Invalid Not infringed upon Once the ANDA is filed, the innovator company has 45 days to file suit and the ANDA approval is on hold for 30 months Issues: NDA patent holders file with the FDA but the FDA does not review patents, only lists them Numerous lawsuits result from the separation of the patent approval process and the drug approval process Borecki CASRIP 2001

30 Patents, Challenges, Antitrust Issues Patents on NDA approved drugs are awarded for a period of 20 years Prospective generic companies have submitted ANDAs prior to this period in hopes of challenging the validity of innovator drug patents Many of these patent challenges are settled out of court and raise antitrust issues Apotex introduced a generic clopidogrel ($3.2 billion 2005) distributed in the US for three weeks in 2006 before a district judge halted further sales Several settlement attempts were rejected and the Department of Justice opened an investigation BMS plead guilty and fined $1 million for misrepresenting the terms of the settlement to the Antitrust Division of the Justice Department Apotex pays $442 million in damages to BMS/Sanofi when patent is upheld Wall Street Journal Feb 8, 2012

31 Proposed Pathways of Niacin Metabolism Biomed Chromatog 2011; 25: Niaspan Patents Safety of once a day administration of an extended release form Pharmacokinetic parameters such as Cmax and AUC Urinary recovery of Pathway I and II metabolites Co-aministration with a statin, ASA

32 Case History: Niacin (Niaspan) Niaspan approved by the FDA in 1997 Two patents expire in 2013 and 2017 US patent number 6,080,428 and 6,129,930 Barr (now Teva) filed an ANDA in 2001 and Kos (now Abbott) sued, reaching an agreement in 2005 Barr received $5 million payment plus a quarterly amount and retained the 180 day exclusivity period Barr scheduled to launch generic versions of Niaspan and Advicor in Sept, 2013, 3 months before the first patent expiration date and 4 years before the expiration of the 2017 patent A New York hotel workers union filed an antitrust class action suit in May 2013 for so called reverse payments Other Niaspan settlements include Lupin, Sun, Watson, Mylan and Sandoz Hemphill, Sierra May 20,

33 Recent Rulings of Interest Supreme Court Ruling in FTC vs Actavis Ruling on reverse payment agreements (pay for delay) Orders district court to evaluate each case on the rule of reason, a standard for determing violations of antitrust law Reverse payment agreements therefore are not immune from antitrust litigation per se and must be evaluated case-by-case NEJM August 2013

34 Prescription Omega-3 Fish Oil (lovaza) In April 2009, Pronova (manufacturer, GlaxoSmithKline marketer) filed patent infringement suits against Par and Teva for generic versions of Lovaza September 12, 2013 a US appeals court ruled the patents in question invalid, reversing a lower court decision upholding the patents May open the door for early entry of lovaza generics unless appealed to US Supreme Court Reuters September 12, 2013

35 Summary and Conclusions Generic drugs are an important part of prescribing in the US and leads to more affordable medications The bioequivalence and statistical criteria to approve most generic drugs assures minimal difference from the original branded drug Attempts to delay the early introduction of generics puts major pharmaceutical companies at risk of violating antitrust laws