1. WHO Prequalification Programme June 2007 Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Hotel Bratislava 1 Malyshko Street Kyiv, Ukraine Date: 25 to 27 June 2007 Multisource (generic) products

2. WHO Prequalification Programme June 2007 Introduction to the course Presenter: Dr Lembit Rägo Director and Coordinator, Quality Assurance and Safety: Medicines QSM) Medicines Policy and Standards (PSM) World Health Organization Geneva, Switzerland E-mail: ragol@who.intragol@who.int

3. WHO Prequalification Programme June 2007 Topics covered I. Multisource (generic) medicines: WHO Global perspective II. Prequalification Programme and its links to WHO normative functions III. Overview of new WHO guidelines and recommendations regarding multisource (generic) products

4. WHO Prequalification Programme June 2007 I. Multisource (generic) medicines: WHO Global perspective Innovative and generic medicines Generic medicines and public health Regulatory requirements and structure of the dossier for generic medicines

5. WHO Prequalification Programme June 2007 Usual perceptions may not help to make judgments about medicines … … and even pharmacists and medical doctors may not be in capacity of taking decisions without specific training Smell Appearance Taste

6. WHO Prequalification Programme June 2007 Why medicines are special category of products? Consumers, patients and health care workers have limited capacity to judge there –SAFETY –QUALITY –EFFICACY

7. WHO Prequalification Programme June 2007 Are all medicines safe, effective and meet quality criteria? No, they are not, and no they do not Some are safe, but not effective or necessarily meet the quality criteria Some may be effective, meet quality criteria but are not safe Some meet quality criteria but are not necessarily safe or have any efficacy

8. WHO Prequalification Programme June 2007 Quality - Safety Some safety parameters are determined by quality Some safety parameters are determined by the intrinsic properties of active pharmaceutical ingredient –However, in fact QUALITY in general perception (and often in policy documents) is incorporating also expectations for efficacy and safety without necessarily saying so

9. WHO Prequalification Programme June 2007 What type of medicines we have? Originator products Multisource (generic) products –KEY – INTERCHANGEABILITY, more important THERAPEUTIC INTERCHANGEABILITY –ALL LITERATURE IS BASED ON ORGINATORS –No interchangeability – NEED FOR NEW SAFETY and EFFICACY DATA, NEW BOOKS HAVE TO BE WRITTEN

10. WHO Prequalification Programme June 2007 How regulatory approach differs for originators and generics? For innovator products proof of QUALITY, SAFETY and EFFICACY is needed For multisource products QUALITY, safety and efficacy data is referred to the originator data, providing only evidence about THERAPEUTIC NTERCHANGEABILITY THERAPEUTIC INTERCHANGEABILITY is judged based on bioequivalence (BE) studies, dissolution data as surrogate for BE, or in certain cases other means such as clinical testing is allowed

11. WHO Prequalification Programme June 2007 Generic drugs In case of SAFETY and EFFICACY the only way for a generic is to refer to originator product –Thus the efficacy (indications, dosing) and safety information (side effects, warnings etc.) can not be different

12. WHO Prequalification Programme June 2007 Generic medicines are pharmaceutical products that contain well-established "actives" 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").

13. WHO Prequalification Programme June 2007 Medicine = tablet + information Good quality drug information including PILs is a shared responsibility of industry and regulators Regulators with limited resources could do more for public health by trusting scientific assessments by well resourced DRAs and concentrating more on ensuring the accuracy of drug information in national settings Not only accuracy of information, but also its proper communication is important GOOD QUALITY INFORMATION is needed also for GENERIC MEDICINES

14. WHO Prequalification Programme June 2007 …and realities In many countries do not have enough resources to check information or approve SPCs and PIL In some countries prescription only medicines do not have PIL (OTC medicines have) …but can be obtained without any prescription Most of the World population has only one prescription for all medicines – banknote. Can this give them also the information they need and understand?

15. WHO Prequalification Programme June 2007 Realities…

16. WHO Prequalification Programme June 2007 Generics and public health In poor countries drugs are largest household and second largest public expenditure for health

17. WHO Prequalification Programme June 2007 010203040506070 South Africa Argentina Jordan Tunisia Thailand Indonesia China Egypt Mali Lithuania Slovenia Estonia Poland Croatia Hungary Czech Rep. Bulgaria Norway Netherlands United States UK Denmark Spain France Italy Germany Greece Developed countries (7 - 20%) Transitional countries (15 - 30%) Developing countries (24 - 66 %) Pharmaceutical spending, as % of total health spending

18. WHO Prequalification Programme June 2007 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

19. WHO Prequalification Programme June 2007 Generic Drugs Market Share in Dollars is Low and Declining

20. WHO Prequalification Programme June 2007 Average Price Per Prescription for Brand Name is Approximately Three Times Generic Drugs

21. WHO Prequalification Programme June 2007 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: –more competitive, –free from IPRs, –often with minimal R&D cost –and the substantive marketing cost that goes into new branded proprietary drugs

22. WHO Prequalification Programme June 2007 Generic medicines: public health value Essential medicines are those that satisfy the priority health care needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost- effectiveness. The WHO Model Essential Medicines List (EML) includes around 300 drugs that should provide safe and effective treatment for the majority of diseases. Model lists are informational and educational tools originally intended for developing countries, but an increasing number of developed countries also use the key components of the essential drugs concept WHO Essential Medicines List (EML) still contains mostly generic medicines

23. WHO Prequalification Programme June 2007 WHO Essential Medicines List - evidence and information for action WHO Model EM List Clinical Guidelines Evidence, Systematic Reviews Model Formulary Drug Quality Information Cost Information Monitoring safety & use

24. WHO Prequalification Programme June 2007 Rapidly changing drugs markets: Czech Republic*, 1990 and 2000 *2000 Population: 10.3 million Source: IMS Health, customised study. Data from 52 countries/areas

25. WHO Prequalification Programme June 2007 What is required for regulatory approval of generics? FDA requirements for generic drugs (www.fda.gov/cder/ogd):www.fda.gov/cder/ogd Generic drugs must: 1. contain the same active ingredients as the innovator drugs as the innovator drug 2. be identical in strength, dosage form, and route of administration 3. have the same use indications 4. meet the same batch requirements for identity, strength, purity and quality 5. be manufactured under the same strict standards of GMP required for innovator products. 6. be bio-equivalent

26. WHO Prequalification Programme June 2007 Global Generic Content Issues Stability Bioequivalence Study Requirements Comparator Product Impurity Specifications Batch Documentation Colorants Relative Lack of Harmonization for Pharmacopeial Methods

27. WHO Prequalification Programme June 2007 Regulations: Global/Regional vs National National regulations still differ a lot – especially for generics What is ICH and what it is not? Regional harmonization initiatives Do global norms exist for generics?

28. WHO Prequalification Programme June 2007 Structure of the dossier Would it be harmonised a lot of resources would be saved –Industries would have one dossier structure for different submissions –Regulators could communicate better

29. WHO Prequalification Programme June 2007

39. II. Prequalification Programme and its links to WHO normative functions What it is and what are its objectives? How it functions? What are the linked to prequalification activities? How it links to WHO normative activitis? Which standards it uses?

40. WHO Prequalification Programme June 2007 Quality related safety of medicines still an issue – DEG tragedy in Panama in 2006 The medical nightmare of Lucia Cruz, a 74- year-old grandmother, began in mid- September 2006 when she realized that she had not urinated in two days. She was hospitalized but eventually she died. By today death toll beyond 100 The death were likely caused by diethylene glycol (DEG) found in medicines. It is toxic to the kidneys and can cause deadly renal failure. –Pictures. 1. Waiting for answer. 2. A popular medicine in Panama that turned to be a killer. 3. Medicines traced down and removed from supply chain

41. WHO Prequalification Programme June 2007 What is WHO doing to help the countries? Normative functions Capacity building Prequalification –"Three in one" – more tuned to real public health problems, immediate feedback, better quality, higher efficiency

42. WHO Prequalification Programme June 2007

43. Prequalification of essential medicines  The UN prequalification program is an action plan for expanding access for patients with  HIV/AIDS  Tuberculosis  Malaria  Reproductive health  Avian flu medicines (oseltamivir) ?  by ensuring quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM, UNITAID)

44. WHO Prequalification Programme June 2007 How prequalification is organized? (I)  Role of WHO: Managing and organizing the project on behalf of the United Nations. provides technical and scientific support and guarantee that international norms and standards are applied all through the process including assessment, inspection (GMP, GCP, GLP) and quality control  Partners: UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World Bank (IPC group); WHO disease oriented programs

45. WHO Prequalification Programme June 2007 How prequalification is organized? (II)  Stakeholders: Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department; other disease oriented programs Interested Governments (donors and beneficiaries) Funding partners: Governments (Belgium, France, China etc.), Gates Foundation, UNITAID

46. WHO Prequalification Programme June 2007 How prequalification is organized? (III)  Beneficiaries: UN Procurement, Global Fund and UNITAID procurement, NGOs (e.g. MSF) National Regulatory Agencies Developing country industries  Actors: Qualified assessors and inspectors from National DRAs (also from National Quality Control Laboratories) of ICH and associated countries, and inspectorates belonging to PIC/S  Open also to developing country assessors and inspectors

47. WHO Prequalification Programme June 2007 Assessment procedure- Product dossiers (I)  Innovator products Abridged procedure if approved by stringent authorities like EMEA and US FDA Assessment reports from Drug Regulatory Authorities (DRSs), WHO Certificate of Pharmaceutical Product (CPP), batch certificate, update on changes Trusting scientific expertise of well-established DRAs What if not covered by these options?

48. WHO Prequalification Programme June 2007 Assessment procedure- Product dossiers (II)  Multisource (generic) products Full dossier with all data and information requested Quality : information on starting materials and finished product including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc Efficacy and safety: Bio-equivalence study or clinical study report US FDA tentative approvals for ARVs – recognition scientific assessment based on information exchange (Confidentiality agreement between US FDA and WHO); the same approach will soon apply for EU Art58 and Canadian JCPA procedure)  Commercial sample  Requested, but not always analyzed before prequalification.

49. WHO Prequalification Programme June 2007 Prequalification: the technical documents are WHO normative documents The Expert Committee documents pass wide international consultation and are finally adopted by the Committee composed of outstanding international technical experts New TRS No 943 with 41 st Report from 2007 –Updated PQ general procedure –PQ of QC labs procedure

50. WHO Prequalification Programme June 2007

54. Bookorders@who.int

55. WHO Prequalification Programme June 2007 Which medicines and why PQ Programme deals with? Application to include a product on Expression of Interest (EOI) Lists published comes from WHO disease oriented programs Products should be of high public health value Products must be in line with WHO treatment guidelines Products must be in line with Essential Medicines List Rare exceptions from these principles, if justified

56. WHO Prequalification Programme June 2007 New Product Group from 2006: Selected Reproductive Health Products

57. WHO Prequalification Programme June 2007 Current status  Started with HIV/AIDS products in 2001 – malaria and TB products joined later  Prequalified products (May 2007) "Active" dossiers in pipeline (2006) 159HIV related medicines 60+ 12 anti-tuberculosis medicines 25+ 5 anti-malarial medicines 30+ 176 115+

58. WHO Prequalification Programme June 2007 News example

59. WHO Prequalification Programme June 2007 Transparency: WHO Public Inspection Reports (WHOPIRs)

60. WHO Prequalification Programme June 2007

62. WHO Public Assessment Reports (WHOPARs)

63. WHO Prequalification Programme June 2007 Increased transparency about the "pipeline"

64. WHO Prequalification Programme June 2007 Regulatory Challenge: ANTIMALARIALS Antimalarials prequalified so far Artesunate 50mg Tablets Sanofi-Synthelabo Blister 25 blister of 12 Artemether/ 20mg Tablets Novartis Pharma Blister 30 blisters of 6, 12, 18 or 24 lumefantrine 120mg Artemotil 50mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml Artemotil 150mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml Artesunate 50mgTablets Guilin Pharmaceutical Co Ltd PVC/AI Blister 12 –Some other manufacturers may have also achieved GMP level but GMP alone is not enough for prequalification

65. WHO Prequalification Programme June 2007 Since 2005 annual reports; 2006 annual report on the web

66. WHO Prequalification Programme June 2007 Outcome of 2006 44 products listed (32 in 2005) - 38% more than in 2005 But … –No new antimalarials –No new TB drugs (but 4 new ones added in early 2007) –No new QC labs

67. WHO Prequalification Programme June 2007 Year 2006: statistics (1) INSPECTIONS A total of 49 (2005 – 52) inspections were carried out: –17 (20) inspections of the manufacturing sites of finished product manufacturers –10 (10) inspections of the manufacturing sites of active pharmaceutical ingredients (APIs) –15 (14) inspections of contract research organizations (CROs) –7 (8) inspections of national pharmaceutical quality control laboratories (NPQCLs) in Africa.

68. WHO Prequalification Programme June 2007 Inspections: where? India – 28 China – 6 Belgium - 1 Canada – 1 Malaysia - 1 France - 1 South Africa – 3 Switzerland - 1 United States – 1 Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda – all 1

69. WHO Prequalification Programme June 2007 Year 2006: statistics (2) Assessments A total 334 (222 – 2005) assessment reports linked to 334 HIV/AIDS-related products were written A total of 78 (52) assessment reports — linked to 70 (50) TB products were written A total of 29 (73) assessment reports were written, linked to than 31 (40) malaria products –All together 75% increase in the number of assessment reports! More facts will be soon in Annual Report 2006 on the web

70. WHO Prequalification Programme June 2007 Publications 2005/2006 New, more user friendly prequalification web site launched in November 2006, updated and improved also later: http://mednet3.who.int/prequal/ Articles: –Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHO’s Prequalification Programme. Journal of Generic Medicines, 2006, 3(2):96–105.

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72. Capacity building of National Regulatory Authorities and Manufacturers Both remain important components and need strengthening Both need improvement and new approaches NB! In 2006 programme started to deliver in addition to general training focused to selected manufacturers technical assistance

73. WHO Prequalification Programme June 2007

75. Training and related activities in 2007 In June 2007 two days workshop in cooperation with WHO/EMRO about prequalification in Cairo In June three days workshop on BE/BCS and dissolution testing (new course) in cooperation with EURO and FIP in Ukraine In November 2007 TBS on Medicines Quality and Prequalification In November 2007 upon request from Chinese Gov on week training in China Targeted more specific trainings (EURO, WPRO) Repeating Pharmaceutical Development course in EURO region in October, training of assessors in AFRO (planning stage) …

76. WHO Prequalification Programme June 2007 Prequalification of Quality Control Laboratories (1) So far only for AFRO region, potential expansion 3 QC Labs prequalified –South Africa, CENQAM - 6/2005 –South Africa, RIIP - 7/2005 –Algeria, LNCPP - 10/2005 3 QC Lab near to PQ?? –South Africa, Kenya, Tanzania 11 QC Labs audited, corrective measures proposed –Cameroon, Mali, Madagascar, Niger, Senegal –Ghana, Etiopia, Kenya NQCL, Kenya MEDS, Uganda, Tanzania 4 QC Labs expressed interest, but not send LIF yet –Benin, Burkina Faso, Cote d'Ivoire, Guinea

77. WHO Prequalification Programme June 2007 Prequalification of Quality Control Laboratories (2) Technical assistance –Experts provided to 2 QC Labs : Ethiopia and Tanzania –Several in AFRO have received free of charge International Pharmacopoeia and other docs, plus chemical reference substances for ARVs 10 of the QC Labs were involved in Proficiency testing (Phase 3, 07/2004 - 06/2006) –Algeria, South Africa CENQAM, South Africa RIIP –Mali, Niger, Senegal –Ghana, Kenya MEDS, Tanzania, Uganda 3 other African QC Labs took part in Proficiency testing (Phase 3, 07/2004 - 06/2006) –Morocco, Tunisia, Zimbabwe

78. WHO Prequalification Programme June 2007 Summary and conclusion Quality can not be assessed, tested or inspected on the product, BUT It has to be built into it! We have (manufacturers and regulators) the obligation to ensure it with all the means we have, in the best way we can.