1 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification of Essential Medicines Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines (QSM) Medicines Policy and Standards (PSM) WHO Headquarters, Geneva, Switzerland WHO/UNICEF Technical Briefing Seminar on Essential Medicines Policies 8 – 12 October, Geneva 1

2 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals WHO Today n Hosts three prequalification programs ä 1. Prequalification of vaccines (QSS/IVB/FCH) ä 2. Prequalification of diagnostics (EHT/HTP) ä 3. Prequalification for priority essential medicines (QSM/PSM/HTP)

3 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals VACCINES 1

4 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals DIAGNOSTICS 2

5 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals MEDICINES 3

6 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification of essential medicines The UN prequalification program is an action plan for expanding access for patients with HIV/AIDS Tuberculosis Malaria Reproductive health by ensuring quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM, UNITAID)

7 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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

8 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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 Funding partners: Governments (Belgium, France, China etc.), Gates Foundation, UNITAID Beneficiaries: UN Procurement, Global Fund and UNITAID procurement, NGOs (e.g. MSF) National Regulatory Agencies Developing country industries Actors: Mainly qualified assessors and inspectors from National DRAs (also from National Quality Control Laboratories) of ICH and associated countries, and inspectorates belonging to PIC/S

9 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Assessment procedure- Product dossiers 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? Multisource 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 analysed before prequalification.

10 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification: generics and not generics n Prequalification requirements for generics – fully in line with major regulatory agencies. A multisource (generic) medicine must: 1. contain the same active ingredients as the innovator drug 2. be identical in strength, dosage form, and route of administration 3. have the same use indications 4. be bio-equivalent (as a marker for therapeutic interchangeability) 5. meet the same batch requirements for identity, strength, purity and quality 6. be manufactured under the same strict standards of GMP required for innovator products. n What if not generics – full data set to prove the safety (including preclinical toxicology) and efficacy has to be presented n Not all non-innovator products in prequalification pipeline can be defined as generics – no innovator may be available

11 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Guidance for applicants

12 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification: the technical documents are WHO normative documents. When these are "silent" other guidelines such as selected ICH guidelines may be used

13 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Which medicines and why PQ Programme deals with? n Application to include a product on Expression of Interest (EOI) Lists published comes from WHO disease oriented programs n Products should be of high public health value n Products must be in line with WHO treatment guidelines n Products must be in line with Essential Medicines List n Rare exceptions from these principles, if justified

14 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals New Product Group from 2006: Selected Reproductive Health Products

15 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Current status Started with HIV/AIDS products in 2001 – malaria and TB products joined later Prequalified products (May 2007) "Active" dossiers in pipeline (2006) 164HIV related medicines anti-tuberculosis medicines anti-malarial medicines Ongoing assessments and follow-up Products Manufacturing sites (both for APIs and finished dosage forms) CROs

16 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals News example

17 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Transparency: WHO Pubilc Inspection Reports

18 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

19 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

20 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

21 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Increased transparency about the "pipeline"

22 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Problems encountered with products containing artemisinin derivatives n General ä Very few innovator products ä Many not typical generics as well ä Very few antimalarials recommended by treatment guidelines approved in ICH and associated countries ä Limited DRAs and regulatory experts having experience with antimalarials ä Fixed dose combinations more complicated than single component products n Quality related issues ä Manufacturers do not comply with GMP (even if located in the EU or EFTA countries – products not registered and produced only for export) ä Many dossiers have outstanding deficiencies in proving the quality of the product – non-compliance with established specifications or poorly defined manufacturers specifications; stability data either missing or not meeting requirements; no method validation etc. l Mostly manufacturers can overcome these problems if motivated. However, it may take a lot of time

23 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Since 2005 annual reports; 2006 annual report on the web

24 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Outcome of 2006 n 44 products listed (32 in 2005) - 38% more than in 2005 n But … ä No new antimalarials ä No new TB drugs (but 4 new ones added in early 2007) ä No new QC labs

25 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Year 2006: statistics (1) INSPECTIONS n A total of 49 (2005 – 52) inspections were carried out: ä 17 (20) inspections of the manufacturing sites of finished product manufacturers ä 10 (10) inspections of the manufacturing sites of active pharmaceutical ingredients (APIs) ä 15 (14) inspections of contract research organizations (CROs) ä 7 (8) inspections of national pharmaceutical quality control laboratories (NPQCLs) in Africa.

26 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Inspections: where? n India – 28 n China – 6 n Belgium - 1 n Canada – 1 n Malaysia - 1 n France - 1 n South Africa – 3 n Switzerland - 1 n United States – 1 n Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda – all 1

27 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Year 2006: statistics (2) Assessments n During the 6 ( ) dossier assessment sessions, 334 (222 – 2005) assessment reports linked to 334 HIV/AIDS- related products were written. n A total of 78 (52) assessment reports linked to 70 (50) TB products were written n A total of 29 (73) assessment reports were written, linked to than 31 (40) malaria products ä All together 75% increase in the number of assessment reports! More facts will be soon in Annual Report 2006 on the web

28 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Publications 2005/2006 n New, more user friendly prequalification web site launched in November 2006, updated and improved also later: n Articles: ä 3. Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHOs Prequalification Programme. Journal of Generic Medicines, 2006, 3(2):96–105.

29 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Measures taken to get more products prequalified n General ä Formerly very limited resources vs huge obligations and scope ä PQ programme started with only ONE professional, by the end of 2007 it may have up to 15 (three will be secondments from Governments) ä Business plan and funding proposals created, funds received (Gates; UNITAID) n Specific ä Internal SOPs and work procedures to facilitate process created ä Specific for antimalarials "Note for Applicants" prepared ä New regulatory guidance documents created and started ä Specific guidance on comparator products ä More direct discussions with manufacturers started ä Regulatory advise on complicated cases ä Additional work that could help manufacturers under way

30 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Capacity building of NRAs and Manufacturers n Both remain important components and need strengthening n Both need improvement and new approaches ä From 2006 one rotational post in PQ program for developing country regulators ä From 2007 second will be opened n NB! In 2006 programme started to deliver in addition to general training focused to selected manufacturers technical assistance (beneficiaries in countries such as China, Ukraine, Zimbabwe …)

31 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

32 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

33 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Training and related activities in 2007 n In June two days workshop in cooperation with WHO EMRO about prequalification n In June three days workshop on BE/BCS and dissolution testing (new course) in cooperation with EURO and FIP in Ukraine n In October repetition of Cape Town course on paediatric medicines development in WHO EURO n In November TBS on Medicines Quality and Prequalification n In November upon request from Chinese Gov on week training in China n Training of assessors in AFRO (planning stage) … n Training for QC lab personnel – EDQM Septmeber in Vienna

34 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification of Quality Control Laboratories (1) n So far only for AFRO region, potential expansion n 3 QC Labs prequalified ä South Africa, CENQAM - 6/2005 ä South Africa, RIIP - 7/2005 ä Algeria, LNCPP - 10/2005 n 3 QC Lab near to PQ?? ä South Africa, Kenya, Tanzania n 11 QC Labs audited, corrective measures proposed ä Cameroon, Mali, Madagascar, Niger, Senegal ä Ghana, Etiopia, Kenya NQCL, Kenya MEDS, Uganda, Tanzania n 4 QC Labs expressed interest, but not send LIF yet ä Benin, Burkina Faso, Cote d'Ivoire, Guinea

35 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification of Quality Control Laboratories (2) n Technical assistance ä Experts provided to 2 QC Labs : Ethiopia and Tanzania ä Several in AFRO have received free of charge International Pharmacopoeia and other docs, pluss chemical reference substances for ARVs n 10 of the QC Labs were involved in Proficiency testing (Phase 3, 07/ /2006) ä Algeria, South Africa CENQAM, South Africa RIIP ä Mali, Niger, Senegal ä Ghana, Kenya MEDS, Tanzania, Uganda n 3 other African QC Labs took part in Proficiency testing (Phase 3, 07/ /2006) ä Morocco, Tunisia, Zimbabwe

36 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Are there alternative regulatory pathways for products of public health needs? n EU Article 58 n US FDA tentative approvals linked to PEPFAR n Canadian Access to medicines scheme ä WHO cooperation with the above mentioned ä Confidentiality agreement with US FDA in place and working; CA with Health Canada expected by March 2007 n How better use the synergies?

37 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Summary and conclusion Quality can not be assessed, tested or inspected on the product, BUT It has to be built into it! We have the obligation to ensure it with all the means we have in the best way we can.