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pharma regulatory a Presentation Transcript

  • 1. 1
  • 2. Date:-12-11-2013 Presented by: Swapnil N. Dharmshale M.Pharm-1st (Q.A). D.S.T.S Mandal’s College of Pharmacy, Solapur. 2
  • 3. Content Introduction New drug Overview of global Pharma. Industry Global generic market Indian relevance to global generic industry FDA requirements for generic drugs Hatch-Waxman Act Orange book USFDA approval process Conclusion 3
  • 4. Introduction New drug : Generic name /Brand name A generic drug is exactly the same molecule as branded drug. Generic drug cost effective Alternative to branded drug. Drug Approval: Investigational New Drug (IND) New Drug Application (NDA): New chemical entities Abbreviated New Drug Application (ANDA): Generic Drug 4
  • 5. Overview of the world Pharmaceutical Industry The data as per the year 2007 - the generic industry is growing at a rate faster than the overall pharmaceutical industry Reasons – Economic changes Changing consumer demands for low prices high quality drugs Changing societal values Significant health-care demands Changing composition of workforces The major contribution being the increase in competition amongst the generic and the brand name industry which has come due to the change in the USFDA approval process from a slow time consuming to a comparatively faster process 5
  • 6. GLOBAL GENERIC MARKETS The global pharmaceuticals industry generated total revenues of $615.1 billion in 2008. The global market for generic drugs was worth $84 billion in 2009. In 2014, the market is expected to amount to $129.3 billion, for a compound annual growth rate (CAGR) of 9% in the 5-year period. Sales of U.S. generic drugs currently dominate the market, at $34 billion in 2009 and projected to increase at a CAGR of 9.7% to $54 billion in 2014. Japan‟s generic drugs market is expected to have the highest rate of growth among major markets at 12.2%, increasing from $5.4 billion in 2009 to $9.6 billion in 2014. Major Pharma company share will decrease due number of patent expiries and intensifying competition from generics. 6
  • 7. GLOBAL GENERIC MARKETS Parameters Size ($bn) Global pharmaceutical Generic share industry 643 55 Growth rate 7% 11% Key players Expected growth US ($245 bn) Japan ($60 bn) Germany ($27 bn) France ($24 bn) UK ($15 bn) 5-7% US ($28 bn) Japan ($5 bn) Germany ($6 bn) UK ($3.4 bn) France ($2 bn) 13-15% Projected size (by 2010) $812 bn at 6% growth rate $93 bn at 14% growth rate 7
  • 8. WHY GENERICS: A $90B GLOBAL OPPORTUNITY Western Europe $17bn US, Canada: $50bn Eastern Europe & Russia: $10bn China: $3bn Japan: $4bn Rest of World: $4bn Latin America: $2bn Total World Pharmaceutical Sales: $600bn 8
  • 9. BRAND V/S GENERIC PRICES Drugs Brand Price $/30 Generic price $/30 Lisinopril (Zestril® ) 20 mg 46.69 20.69 Citalopram (Celexa® ) 20 mg 100.99 52.99 Ciprofloxacin (Cipro®) 500 mg 215.99 88.59 Merformin (Glucophage®) 1000mg 71.59 30.69 Fluconazloe (Diflucan®) 200mg 609.99 372.99 Fluoxetine(Prozac®) 20mg 139.99 32.29 9
  • 10. TOP 14 DRUG GOING OFF PATENT IN 4 YEARS Drug Therapeutic Area Company Expiry Year Global Sales (2008 billion $) Lipitor (Atrovastin Calcium) CVS Pfizer 2011 13.5 Plavix ( clopidogrel bisulfate) CVS Sanofi Aventis BMS 2011 9.4 Advair ( Fluticasone Propionate & Salmetraol) Respiratory GSK 2010 7.8 Diovan (Valsartan) CVS Novarties 2012 5.8 Zyprexa (Olanzapine) CNS Ell lily 2011 4.7 Singular (Montelukast) Respiratory Merck 2012 4.6 Seroquel(Quetiapine fumarate) CNS Astrazeneca 2011 4.6 Lovenox (Enoxaporin sodium) CVS Sanofi Aventis 2012 4.0 Actos (Pioglitazone) Antidiabetic Takeda 2011 3.9 Prevacid ( Lansoprazole) GIT Takeda 2010 3.7 Cozaar ( Losartan Potassium) CVS Merck 2010 3.6 Aricept (Donepezil) CNS Pfizer 2010 3.6 Lexapro (Escitalopram) CNS Forest Lab 2011 3.4 Eloxatin (Oxalipaltin) Oncology Sanofi Aventis 2013 3.0 10
  • 11. Indian Relevance to global generics industry Major Indian Players: Ranbaxy : Amongst Top 10 global players Dr Reddys Cipla Wochardt Sun Pharmaceuticals Glenmark Lupin Nicholas Piramal Torrent Matrix Laboratories 11
  • 12. INDIAN GENERICS APPROVED BY FDA 120 100 80 Tentative Final 60 40 20 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 12
  • 13. GENERIC DRUG Brand Name Drug - The brand name drug is the name under which a new innovator medication is developed and marketed. When a pharmaceutical company develops a new medication, they obtain patent for it. Generic Drug – Generic drugs are considered identical, or bioequivalent to the brand-name originals. They contain the same active substances and have the same quality, efficacy and safety. Definition: •GENERIC DRUG IS A PHARMACEUTICAL PREPARATION THAT IS ESSENTIALLY SIMILAR TO AN ORIGINAL PRODUCT, INVOLVING AN ACTIVE INGREDIENT THAT IS NO LONGER PROTECTED BY A PATENT* AND IS SOLD UNDER A COMMON NAME WITH LITTLE OR NO PROMOTION. * THOUGH THE FORMULATION MAY OR MAY NOT BE PATENTED 13
  • 14. FDA REQUIREMENTS FOR GENERIC DRUG Contain the same active ingredients (Pharmaceutical equivalent) Be identical in strength, dosage form, and route of administration Have the same indications Phases Of validation Meet the same batch requirements for identity, strength, purity, and quality Be bioequivalent Be manufactured under the same strict standards of FDA's good manufacturing practice regulations required for reference Listed drug (RLD)-brand name Product listed in “Orange book” ( 14
  • 15. DEFINITIONS Pharmaceutical Equivalence Same active drug ingredient ,same strength, same dosage form and route of administration, comparable labeling, meets compendial or applicable standard of strength. Bioavailability The rate and extent to which the active moiety is absorbed from a drug Product and become available at site of action. Bioequivalence Two pharmaceutical equivalent drug product are bioequivalent if after drug administration, the bioavailabilities (rate and extent of drug availability) provide similar effect with respect to efficacy and safety. Therapeutic Equivalence Therapeutic equivalence means that a chemical equivalent of a drug product (i.e., containing the same amount of the same drug in the same dosage form) when administered to the same individuals in the same dosage regimen will provide essentially the same efficacy and toxicity. 15
  • 16. ACT GOVERNING DRUG APPROVAL The act governing generic drug approval process of the USFDA “Hatch-Waxman Act of 1984” or “Drug Price Control and Patent Term Restoration Act of 1984”. 16
  • 17. Earlier Scenario (before “Hatch-Waxman Act of 1984” ) Market was ruled by brand name drug manufacturers – innovators Lack of competition Innovator enjoyed his elite monopoly period within which no other brand of the same drug can enter into the market Highest prices of the drugs To stop these practices and to make user friendly drug market, the US congress passed the Hatch Waxman Act in 1984 17
  • 18. Birth of Generics: The Hatch-Waxman Act The Drug Price Competition and Patent Term Restoration Act of 1984, signed into Law on September 24, 1984 Hatch-Waxman was designed to speed entry of generic drugs to compete with patented pharmaceuticals The results of the act seek to balance the interests of the branded manufacturers with those of generics 18
  • 19. Objectives of the act Offset the drug approval delay: Earlier innovators used to encounter delay in approval of their NDA which affected their brand entry in the market and hence financial loses!!!!! Types to Bring healthy competition andof avoid price rise: Process Earlier no scope for generics to enter the market until innovator patent validation term expired as no provisions to challenge the validity of innovator patent. This product monopoly kept competion away and drug prices high as per innovator will!!!!!! Make life easier for the generic: Generic manufacturers used to face a lot of difficulties in doing all the preclinical and clinical studies as done by brand manufacturer to get generic approved!!!!! 19
  • 20. Benefits received by the brand name manufacturers Regulatory delays in brand approval were deciphered The market exclusivity and the „effective patent life‟ was extended from 8.5years (1980) to 13 years (late 1980s) and now it‟s nearly 16-17years 20
  • 21. Benefits received by the generic manufacturers The generic could challenge the validity of the patent issued to the innovator The act provided with the stipulation to file an ANDA to leave out the expensive pre-clinical and clinical trials as done by the innovator Provided with the provision of relying on the safety and efficacy data of the innovator drug and to perform a much cheaper „bioequivalence‟ to establish equivalence with the innovator Once approved the generic gets an exclusivity period of six months to market the product along with the innovator during which no other generic can be given approval 21
  • 22. The Orange Book The FDA publishes a list of all drugs approved for marketing in the US under the title “Approved Drug Products with Therapeutic Equivalence Evaluations” - “Orange Book” Lists the NDA‟s and ANDA‟s along with the expiry dates of patents and generic exclusivities Ready reference of brand drug products for the generic companies who usually use this information to identify the reference for developing their generic version Also contains therapeutic equivalence codes (two letter coding system e.g. AB) A- prefixing product is considered to be substitutable B- prefixing is a safe and effective product for use but is regarded in22 equivalent and non-substitutable with the brand name drug product
  • 23. ANDA certifications Para I – there is no patent for the drug listed in the Orange Book Para II – patent is listed but has expired Para III – patent is listed, is valid but the generic wants approval to market the drug once the pertinent patent expires Para IV – the generic manufacturer either challenges the validity of the patent asserting it to be invalid or fake, or it affirms the non-infringement of the brand name patent claims. Most critical and gives rise to anti- competitive practices 23
  • 24. USFDA approval requirements: Brand name (NDA) vs Generic (ANDA) The generic must have – Same active ingredient, Same route of administration, Same dosage form, Same strength, Same condition of use 24
  • 25. NDA vs ANDA Review Process 25
  • 26. USFDA Approval Process (Para IV certification) The ANDA applicant must provide appropriate notice of a paragraph IV certification to each owner of the patent that is the subject of the certification and to the holder of the approved NDA to which the ANDA refers The ANDA applicant may certify with a legal ground that a listed patent is invalid or will not be infringed by the manufacture, use, or sale of the generic product. This gives an immediate right to innovator to file a patent infringement lawsuit against the generic manufacturer The innovator can file this lawsuit within 45 days of the ANDA filing notice from the generic This sets in a process which detains the FDA from giving approval to the generic for a period of 30 months FDA is free to grant approval after 30 months which depends upon the result of the pending litigation 26
  • 27. The six month generic exclusivity An incentive to the „first approved generic‟ after filing a Para IV certification This incentive gives the first generic an exclusivity period of 180 days to market and earn profits During this period, the brand name drug is the only competition and FDA can not approve any other generic until this exclusivity period perishes The 180 day cycle begins on the day the generic comes into the market for the first time or the day of courts decision in favor of the generic 27
  • 28. Loopholes in Hatch-Waxman Act  Warehousing patents and frivolous lawsuits Also referred to as “Evergreening” of patents Innovator may patent multiple attributes of a product like manufacturing process or metabolite and keeps on adding patents in the Orange Book, forcing the generic to wait for the patent to expire or file para IV which brings along risk of litigation and associated cost and delays!!! 28
  • 29. CASE STUDY Case Study – Buspar Case : BMS v Mylan Pharmaceuticals BMS had US Patent 4,182,763 (Expiry – July 21, 2000) Claims cover buspirone as an anxiolytic agent Mylan filed para III against this patent and obtained tentative approval to market the drug not before July 22, 2000 BMS obtained another patent just 12 hours before the expiry of first patent covering the active metabolite of the buspirone having anxiolytic activity and listed it in the OB Mylan filed para IV against this newly listed patent BMS responded by filing infringement lawsuit immediately halting the final market approval This gives the brand name manufacturer at least an additional two and a half years of product monopoly 29
  • 30. Maneuvering the six month Generic Exclusivity Commonly referred to as “Sweetheart deals” Allows the first generic manufacturer and the innovator to enter into an agreement and to have control when to introduce the generic This would not trigger the 180days generic exclusivity period offered to the first generic The FDA is bound not to approve another generic until the 180 day generic exclusivity period perishes This allows the innovator and first generic to share financial awards keeping other generic competitors in an indeterminate state 30
  • 31. CASE STUDY 1) Diltiazem hydrochloride (Cardizem CD by Hoechst-Marion Roussel, Inc. (“HMRI”)) Used to treat angina and hypertension Andrx Pharmaceuticals Inc. was first ANDA filer with para IV for Cardizem CD; HMRI filed suit against Andrx In September 1997, FDA tentatively approved Andrx‟s generic product Andrx would have been expected to be able to enter the market upon the expiration of 30 month stay in July 1998 However, Andrx and HMRI settled the litigation In settling the litigation, both the parties agreed that, beginning upon the final FDA approval of Andrx‟s generic product, HMRI would pay Andrx $10 million per quarter not to enter the market with its generic product until the conclusion of the 31 patent litigation
  • 32. CASE STUDY 2) Terazosin hydrochloride (Hytrin by Abbott) Used for the treatment of high blood pressure and enlarged prostate Litigation involves agreement between Abbott and Geneva Pharmaceuticals Inc. and also between Abbott and Zenith Goldline Pharmaceuticals Inc. Agreement between Abbott and Geneva was an “interim” settlement that did not finally resolve the patent issues Geneva agreed to accept $4.5 million per month from Abbott to refrain from marketing generic product of Hytrin until another generic maker sold a generic version in the USA or Geneva received a final, unappealable judgement that its proposed generic tablet did not infringe Abbott‟s patents Also, as part of the agreement, Geneva and Abbott allegedly agreed to 32 continue the patent infringement litigation on Geneva‟s generic tablet
  • 33. FDA Generic Approval Criteria: Establishing In Vitro Equivalence and Bioequivalence with the Reference Listed Product (RLP)  Generic manufacturer must establish equivalence with the RLP developed by the innovator  FDA has established two basic criteria for the generic to be equivalent with the innovator – • In vitro equivalence criteria • In vivo bioequivalence 33
  • 34. In vitro equivalence criteria   Comparison of the dissolution profile of generic drug and brand name drug by similarity factor of f2 f2 = 50 * log ( 1 + (1/n) summation (Rt –Tt) 2 ) 0.5 * 100 Comparison is done especially to assure similarity in product performance  Regulatory interest is knowing how similar the two curves are and to have a measure which is more sensitive to large differences at any particular time point  When the two profiles are identical, f2 = 100  FDA has set a public standard of f2 value between 50-100 to indicate similarity between dissolution profiles 34
  • 35.  Single dose; two-way crossover fasted or fed state studies - This means all the test subjects receive both the generic and the brand name product, done in a crossover manner and products are given once to each subject on different occasions and the pharmacokinetic data are compared between the two treatments between each subject  This study gives an idea of the inter-subject variability  Replicate design – This design gives the same product to each subject more than once.  The overall number of subjects is reduced but the number of times each subject has to come increases  Two most common parameters which are studied and compared are Cmax and the AUC related to rate and extent of drug absorption in the blood respectively  These parameters are accessed using the 90% confidence intervals that must fit between 80-125% 35
  • 36.  The dissolution measurements of the two products (test and reference) should be made under the same test conditions  Dissolution time points should be same for both the products  f2 value of 50 or greater (50-100) ensures sameness or equivalence of the two curves, and, thus, the performance of the two products  f2 value less than 50 does not necessarily mean lack of similarity 36
  • 37. In vivo equivalence  Generic manufacturer has to conduct bioequivalence study in place of preclinical and clinical studies to establish equality with the innovator  Purpose of bioequivalence is to have a generic drug product which is substitutable for a reference product „without any additional prescriber intervention‟  There should not be any change in the efficacy and no additional incidents of side effects  The usual study designs are single dose; two-way crossover fasted or fed state studies and replicate designs 37
  • 38. Biowaivers FDA allows the generic manufacturers to not have to study every single strength of a product and requires some in vitro tests for the same e.g. the testing on the low strength version of an already bioequivalence established product. As lower strengths are proportional to their matching higher strengths; FDA only requires some in vitro testing Other types of products which may be granted biowaiver include – Parenteral solutions Inhalational anaesthetics topical solution Oral solutions 38
  • 39. CONCLUSIONS US congress passed the Hatch Waxman Act in 1984 for the benefit of consumers in an attempt to stop dominance and monopoly of the innovator and to encourage the use of cheaper and equally effective GENERICS 39
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