Generics and public health

1. Generics and public health Andrew Creese - Valerio Reggi Department of Essential Drugs and Medicines Policy - EDM Health Technology and Pharmaceuticals Cluster World Health Organization May 2002

2. Definitions Generics are pharmaceutical products that contain well-established drugs. They are:-intended to be interchangeable with the original product, -usually manufactured without a licence from the original manufacturer,-marketed after the expiry of patent or other exclusivity rights,-marketed either under a non-proprietary name (INN or other approved name) or under brand names ("branded generics").

3. Public health need Nationalstrategies Socialresponsibility The worldwide role of generic pharmaceuticals

4. Public health need Social responsibility The worldwide role of generic pharmaceuticals National strategies

5. Public health need In poor countries drugs are largest household and second largest public expenditure for health Pharmaceutical spending, as % of total health spending Greece Germany Developed countries Italy (7 - 20%) France Spain Denmark UK United States Netherlands Norway Bulgaria Transitional countries Czech Rep. (15 - 30%) Hungary Croatia Poland Estonia Slovenia Lithuania Mali Egypt China Indonesia Thailand Developing countries Tunisia Jordan (24 - 66 %) Argentina South Africa 0 10 20 30 40 50 60 70

6. Public health need The cost of medicine is substantial - number of working hours to pay full treatment course And the burden falls heaviest on those least able to pay: • Developed countries: 50-90 % publicly funded • Developing countries: 50-90 % paid out-of-pocket Based on average worldwide price and national per capita income. Source: WHO/DAP

7. Public health need Despite the potential health impact and expenditure,too many people still lack access to essential drugs • >1/3 of world’s population lacks regular access • 320 million in Africa have <50% • Problem worsens with economic pressures Percentage of populations and number of countries with regular access to essential drugs: (43) 1 = <50% (64) 2 = 50-80% 3 = 80-95% (30) (41) 4 = >95% (1) 5 = No data available

8. Developing Country Deaths (millions) 1990 INFECTIOUS & PARASITIC DISEASES Respiratory infections Age 5 & over Under 5 Diarrhoeal disease Tuberculosis Measles Malaria Tetanus Pertussis HIV Meningitis NON-COMMUNICABLE DISEASES - A GROWING CHALLENGE Heart attacks, strokes Cancer 6 4 1 3 5 0 2 Public health need Millions of children and adults still die from diseases readily treated with generic essential drugs

9. National strategies Social responsibility The worldwide role of generic pharmaceuticals Public health need

10. National strategies As of the mid-1990’s, few countries had achieved large generic coverage Source: DAP Global comparative pharmaceutical expenditures and IGPA

11. National strategies Price differentials between generic and brand products vary greatly among countries Belgium Italy Spain Germany France Canada UK US 20% 20% + 25% 25% - 30% 25% - 35% 40% - 50% 80% + 50% - 90% Source: IMS, Pharma Strategy Group

12. National strategies Drug sales 1990 and 2000: originator and licensed products grew from 50% to 64% of world market value Source: IMS Health, customised study. Data from 52 countries/areas

13. National strategies Drug sales 1990 and 2000: market share of originator and licensed products in high, middle and low income country markets Source: IMS Health, customised study. Data from 52 countries/areas

14. National strategies Drug sales 1990 and 2000: originator and licensed products in high, middle and low income country markets Source: IMS Health, customised study. Data from 52 countries/areas

15. National strategies Rapidly changing drugs markets Czech Republic*, 1990 and 2000 *2000 Population: 10.3 million Source: IMS Health, customised study. Data from 52 countries/areas

16. What are the potential benefits of generics? Better access to needed medicines. Well chosen generics make government or household spend less without loss of quality or safety 1998 study by US Congressional Budget Office: average generic medicine prescription price was less than one third of average price of single-source innovator brand drug

17. What are the potential benefits of generics? Impact on the price of non-generics through competition: generics may be the only way to bring price competition to a market that is based on product differentiation, patent protection and heavy brand promotion to both prescribers and patientsaccess to needed medicines.

18. Why are generics less expensive? Not because they are inherently different in composition from patented drugs, but mainly because of the structure of the generics market: competitive, free from IPRs, often without the R&D and particularly the marketing cost that goes into branded proprietary drugs

19. National strategies Building a large generic market takes time- and requires a combination of strategies National strategies for generics: 1. Supportive legislation & regulation 2. Reliable quality assurance 3. Professional, public acceptance 4. Economic incentives Percent of new prescriptions, U.S.

20. National strategies 1. Supportive legislation and regulation • product development authorized during patent life • abbreviated marketing authorization • differential registration fees • generic labeling • generic prescribing and substitution

21. National strategies Product development during patent period varies among countries • Examples of “early workings” for generics • access to innovator product safety and efficacy data • production tests on a patent-protected product • laboratory tests for marketing approval – e.g. bioequivalence • production and stockpiling prior to patent expiry • Countries with some early workings provisions • Argentina  Hungary • Australia  Tunisia • Canada  USA

22. National strategies 2. Reliable quality • substitution / non-substitution lists • national regulatory capacity • enforcement of good manufacturing practices (GMP) • distribution system inspection and enforcement GMP

23. Drug registration Requirements for abridged marketing authorization application (i.e. without pre-clinical and clinical data) • product information previously approved, • active ingredient previously approved, • route of administration, strength and dosage form equal to those of previously approved product, • adequate information on analytical methods, manufacturing process, manufacturers of finished product and starting materials, • stability studies, • proof of therapeutic equivalence with previously approved product.

24. Drug registration Definitions (1) Pharmaceutical equivalents: Products that contain the same amount of the same active substance(s) in the same dosage form; meet the same or comparable standards; are intended to be administered by the same route. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence as differences in excipients and/or manufacturing process can lead to differences in product performance.

25. Drug registration Definitions (2) Generic (multi-source): • pharmaceutical equivalent of a non-patent-protected product (comparator product) whose safety and efficacy are well established; • can be marketed under its INN or a brand name; • may or may not be interchangeable with its comparator product.

26. Drug registration Definitions (3) Comparator product: • product with which a generic is expected to be interchangeable; • product whose safety and efficacy studies are well established and will be the basis for approval of all its pharmaceutical equivalents; • product that often has the largest market share.

27. Drug registration Definitions (4) Therapeutic equivalents: pharmaceutical equivalents whose bioavailability or dissolution profiles, after the same molar dosis, are similar to such an extent that their safety and efficacy can be assumed to be substantially equal. Therapeutic equivalents are interchangeable.

28. Drug registration Therapeutic equivalence Depending on active ingredient and formulation: • dissolution (in vitro) • bioequivalence studies (in vivo) • pharmacodynamic studies (in vivo) • clinical trials (in vivo)

29. Drug registration Active ingredient and formulation characteristics affecting dissolution/absorption Particle size: digoxine, griseofulvine, nitrofurantoin Crystal form (different forms with equal internal structure, different internal structures, solvates) : riboflavine, cimetidine, erithromycine, clortalidon, chloramfenicol, cefalexine Wettability: phenytoin Dependence on pH: aspirin, ketoconazol, sulfonamides Excipients: nystatin, sulfadimidine with PVP or gelatin, phenytoin  with con lactose

30. Drug registration Examples of drug with high first-pass metabolism • Alprenolol • Amitriptyline • Chlormethiazole • Desipramine • Dextropropoxyphene • Dihydroergotamine • Diltiazem • 5-Fluorouracil • Hydralazine • Isoproterenol • Labetolol • Testosterone • Lidocaine • Methylphenidate • Morphine • Neostigmine • Nifedipine • Nitroglycerin • Papaverine • Pentazocine • Phenacetin • Propranolol • Salicylamide • Verapamil FA= 0.5 or less. From: Pond, S.M. and Tozer, T.N. : First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinetics 1984; 9:1-25

31. Drug registration Examples of drugs with “possible” BA/BE problems (104 substances) Sources: too many to list

32. Drug registration ¿In vitro or in vivo? (1) Different criteria exist: US-FDA: WHO : Http://www.fda.gov MULTI-SOURCE PHARMACEUTICAL PRODUCTS, WHO GUIDELINE ON REGISTRATION REQUIREMENTS TO ESTABLISH INTERCHANGEABILITY, 1996 EU: Http://www.eudra.org

33. Drug registration ¿In vitro or in vivo? (2) US-FDA’s Biopharmaceutic Classification System In vivo BE waiver based on solubility and permeability Peff = Qin (Cin – Cout) / Cout * 2rl Unfortunately, permeability is not easy to measure and published data are scarce Waiver probably never used in practice

34. Drug registration Bioequivalence (1) Compare two formulations to determine whether they provide substantially the same amount of active substance at a comparable rate. It is applied for authorizing : - ‘scaling up’ - post-approval changes - generics Almost no product is marketed in the same formulation used in phase I, II, and III clinical trials.

35. Drug registration Bioequivalence (2) Design: • 12-36 healthy volunteers (males, age 18-36) • possible effects of disease/age/sex assumed identical for the 2 formulations • each volunteer receives at least one dose of each formulation after suitable washout period Specific designs (~100 FDA, USP)

36. Drug registration Bioequivalence (3) 3 bioavailability parameters (including active metabolites if applicable):

37. Drug registration Bioequivalence (4) Evaluation: • AUC: • 90% CI of ratio of average AUC of the 2 products (both directions), • 90% confidence interval should generally be within 80 to 125% (EEUU, UE, Canadá, Australia) • Cmax: wider acceptance criteria • Tmax: considered only when clinically relevant

38. Drug registration Bioequivalence (5) 1962: FDA establishes BE requirement, implementation ‘from now on’, AUC and Cmax of TD/RD must be between +/-20% in majority of subjects 1977: 75/75-125: 75% of subjects must fall within 75-125% 1979: First Orange Book 1991: 90%CI must fall within 0.80-1.25 1999: Biopharmaceutics Classification System - BE waiver in selected cases.

39. Drug registration Bioequivalence (6) Practical implementation of BE study requirement: • manufacturer selects one batch for BE study and study for submission, • after approval, only dissolution is used for following batch releases and lower limits are based on BE batch data (i.e. data of one single batch).

40. Drug registration Bioequivalence (7) Implementation seems good enough because: • reports of clinical failures due to BA/BE problems are anecdotal • US-FDA claims “there are no documented examples of generic products manufactured to meet approved specifications that could not be used interchangeably with the corresponding brand-name drug” http://www.fda.gov/cder/news/nightgenlett.htm • Innovative industry and patients’ associations in US claim that no documented cases of “patient-formulation” interaction exist FDA hearing 23 September 1999

41. Drug registration Bioequivalence (8) Other elements to consider: - apparently-identical drugs of the same brand but manufactured and marketed in different countries are not necessarily bioequivalent - transitive property of bioequivalence (different formulations of same product or different products) - change in labelling resulted in reports of 20% ‘therapeutic failures’ (Glaxo, 1990) - superbioavailability  reformulation (first always best?) - WHO guidelines on interchangeability and comparator product

42. Drug registration WHO Guidelines What are the practical implications of requiring new BE studies in each country even for drugs from reliable source meant for use in non-chronic courses? MULTI-SOURCE PHARMACEUTICAL PRODUCTS, WHO GUIDELINE ON REGISTRATION REQUIREMENTS TO ESTABLISH INTERCHANGEABILITY, 1996 Selection of Comparator Pharmaceutical Product for Equivalence Assessment of Interchangeable Multi-source (Generic) Products,WHO, 1999

43. How to Identify Comparator Pharmaceutical Product: Decision Tree Comparator Pharmaceutical Product (CPP) Quality/Safety/Efficacy known Innovator known Yes No Available on local market Present on List B Yes No Yes No Consider Innovator as CPP Consider obtaining Innovator: List A Follow compendial standards approach Consider Market Leader Innovator available Quality of Market Leader known and well-documented Yes Yes No No Consider Innovator as CPP Consider Market Leader as CPP Conduct comparative compendial tests between Multi-source and Market Leader Consider Market Leader Acceptable test results Yes No Consider Market Leader as CPP Consider 2nd Market Leader

44. Drug registration Some ‘free’ considerations on BE • BE is a scientifically sound concept that has been applied with varying criteria in different regulatory systems over the last 38 years • at the same time, industry has mainly used dissolution as an indicator of uniformity of biopharmaceutical characteristics of products at lot release • during all this time, reports of ‘therapeutic failures’ have been scarce • it is likely that implementation of strict BE requirements is not high priority for countries that do not fully assess the quality part of MA applications, have no full market control, cannot ensure GMP compliance, and cannot monitor raw materials

45. National strategies 3. Professional and public acceptance • involvement of professional groups • phased implementation • all training by generic name • use of generic names in clinical manuals • brand-generic / generic-brand indexes • public promotional information and activities

46. National strategies Stages in Generic Substitution - legislative support for generic substitution may evolve over time 1. No substitution 2. Substitution permitted • brand dispensing assumed • generic may be requested 3. Substitution encouraged • generic dispensing assumed • brand may be requested 4. Substitution required Increasing generic support

47. National strategies Generic substitution laws can give each party a voice • Regulatory authority • declare products as ‘substitutable’ or ‘non-substitutable’ • Prescriber • write ‘no substitution’ by hand on the prescription • Pharmacist - must substitute a generic unless: • prescriber or patient forbid substitution • retail price of generic is higher than the brand • product has been declared not substitutable • Patient • may forbid generic substitution

48. National strategies Pocket manuals put generic names and brand-generic lists at health professionals’ figure-tips  100+ countries have treatment guidelines, formularies

49. National strategies Public education campaigns help professional and public acceptance to reinforce each other • Posters and brochures • Radio and TV messages • Other media

50. National strategies 4. Economic incentives • price information for professionals and the public • retail margins favorable to generics • use of generics for insurers / reimbursement • development of generic industry