Multisource (generic) products

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

2. 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.int

3. 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. 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. 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 Taste Appearance Smell

6. Why medicines are special category of products? • Consumers, patients and health care workers have limited capacity to judge there • SAFETY • QUALITY • EFFICACY

7. 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. 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. 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. 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 isjudged based on bioequivalence (BE) studies, dissolution data as surrogate for BE, or in certain cases other means such as clinical testing is allowed

11. 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. 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. 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. …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. Realities…

16. Generics and public health • In poor countries drugs are largest household and second largest public expenditure for health

17. 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

18. 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. Generic Drugs Market Share in Dollars is Low and Declining

20. Average Price Per Prescription for Brand Name is Approximately Three Times Generic Drugs

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

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

25. What is required for regulatory approval of generics? • FDA requirements for generic drugs (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. Global Generic Content Issues • Stability • Bioequivalence Study Requirements • Comparator Product • Impurity Specifications • Batch Documentation • Colorants • Relative Lack of Harmonization for Pharmacopeial Methods

27. 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. 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

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. 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. 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

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. 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. 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. 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. 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. 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. 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 41st Report from 2007 • Updated PQ general procedure • PQ of QC labs procedure