Published on October 22, 2007
Slide1: Update and Future Directions for Prequalification Programme of Medicines: Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines (QSM) Medicines Policy and Standards (PSM) [email protected] WHO PREQUALIFICATION OF DIAGNOSTICS AND MEDICINES 2ND CONSULTATIVE STAKEHOLDER MEETING Thursday, 11 January 2007, Geneva 1 Quality of medicines remains a problem in many countries – tragedy in Panama in 2006: Quality of medicines remains a problem in many countries – 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 sent to the hospital but her condition went from bad to worse. Nausea and vomiting came first. Then she could not breathe. Her kidneys continued to fail, her arms and legs got swollen and eventually she died. When she died, her physician told the family to cremate the body in case she carried a mysterious disease that might spread. As it turned out the cause of death of more than 30 other persons was more simple. The cough syrup and potentially other medicines produced in the governmental pharmaceutical factory were contaminated. The death were likely caused by diethylene glycol (DEG) found in medicines. DEG is a chemical cousin of antifreeze and used widely by various industries. 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 What is WHO doing to help the countries? : 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 Prequalification of essential medicines: 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) How prequalification is organized?: How prequalification is organized? 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 Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department 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 Assessment procedure: Assessment procedure Assessment of products dossiers i.e. quality specifications, pharmaceutical development, bioequivalence etc. teams of professionals from national drug regulatory authorities (DRA): Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe ... Copenhagen assessment week 8 to 20 assessors together during one week at least every two months at UNICEF in Copenhagen Every dossier is assessed by at least two assessors. An assessment report is issued; signed by two assessors Letter summarizing the findings and asking for clarification and additional data if necessary; signed by two assessors Letter is sent first by e-mail to the applicant followed by surface mail Assessment procedure- Product dossiers: 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 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. Prequalification: generics and not generics : Prequalification: generics and not 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 Prequalification requirements for generics – fully line with major regulatory agencies What if not generics – full data set to prove the safety (including preclinical toxicology) and efficacy has to be presented Not all non-innovator products in prequalification pipeline can be defined as generics – no innovator may be available Slide11: Prequalification: where the technical documents come from? The Expert Committee documents pass wide international consultation and are finally adopted by the Committee composed of outstanding international technical experts All major technical issues have passed EC procedure and printed in respective TRS Slide15: Quality Assurance (QA) of WHO prequalification process PQ team has its own Quality Assurance system: Quality Assurance and Safety: Medicines (QSM) Standard Operating Procedures (SOPs) Manuals and guidelines General Procedure for Prequalification Norms and standards (product dossiers, manufacturers etc) Slide16: Current status Started with HIV/AIDS products in 2001 – malaria and TB products joined later Prequalified products (Dec 2006) "Active" dossiers in pipeline (2006) 154 HIV related medicines 73 8 anti-tuberculosis medicines 33 5 anti-malarial medicines 30 167 136 Ongoing assessments and follow-up Products Manufacturing sites (both for APIs and finished dosage forms) CROs Slide17: 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 50mg Tablets 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 Slide18: Problems encountered with products containing artemisinin derivatives General Very few innovator products Many not typical generics as well Very few antimalarials recommended by treatment guidelines approved in ICH and associated countries Limited DRAs and regulatory experts having experience with antimalarials Fixed dose combinations more complicated than single component products Quality related issues Manufacturers do not comply with GMP (even if located in the EU or EFTA countries – products not registered and produced only for export) 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. Mostly manufacturers can overcome these problems if motivated. However, it may take a lot of time Slide19: Problems encountered with products containing artemisinin derivatives (II) Lack of reference products for bioequivalence studies For generic drugs safety and efficacy is proved by bioequivalence studies assuming that the same blood concentrations of active ingredient give the same safety and efficacy profile Only exceptions are artesunate from Guilin Pharma and the Novartis FDC product (artemether+lumefantrine) Safety and efficacy related issues Insufficient reporting of the evidence about the clinical efficacy and safety..... No fully documented trial reports No full evaluation of published literature No characterisation of pharmacokinetic properties of the product: for innovators and generics as well unacceptable General statements: No interaction known -> clearly not true; No (or minimal) adverse events: information has to be provided through literature survey if no original data Too broad efficacy claims Galenical development history not provided -> Do results of earlier studies apply to current formulation? Many manufacturers involved have no experience in these areas Slide20: New Product Group from 2006: Selected Reproductive Health Products Since 2005 annual reports; draft 2006 ready: Since 2005 annual reports; draft 2006 ready Outcome of 2006: Outcome of 2006 44 products listed (32 in 2005) - 38% more than in 2005 But … No new antimalarials No new TB drugs No new QC labs Year 2006: statistics (1): 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. Inspections: where?: 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 Slide25: Year 2006: statistics (2) Assessments During the 6 (9 - 2005) dossier assessment sessions, 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 Publications 2005/2006: Publications 2005/2006 New, more user friendly prequalification web site launched in November 2006: http://mednet3.who.int/prequal/ Articles: 1. Prequalifi cation of medicines. WHO Drug Information, 2005, 19:1. 2. WHO and its Prequalification Programme: an Overview. WHO Pharmaceuticals Newsletter, 2005, No. 2. 3. 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 Prequalifi cation Programme. Journal of Generic Medicines, 2006, 3(2):96–105. Slide28: Measures taken to get more products prequalified General Formerly very limited resources vs huge obligations and scope PQ programme started with only ONE professional, today it is 4.75 and 2 seconded persons and by the end of 2007 it will have at least 15 (three will be secondments from Governments) Business plan and funding proposals created, funds received (Gates) and expected (UNITAID) Specific Internal SOPs and work procedures to facilitate process created Specific for antimalarials "Note for Applicants" prepared New regulatory guidance documents created and started Specific guidance on comparator products More direct discussions with manufacturers started Regulatory advise on complicated cases Additional work that could help manufacturers under way Slide29: Capacity building of NRAs 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 Strengthening the prequalification programme for medicines : Strengthening the prequalification programme for medicines Additional funding – Gates, UNITAID Internal capacity building – restructuring, new high quality technical staff to be recruited, processes to be reviewed and improved Communication to be improved Regulators Manufacturers Donors and partners More proactive approach towards potential suppliers – new elements Regulatory advise Technical assistance to promising manufacturers Strengthening links with WHO regions Taylor made approach to different regions Building capacity in ROs/countries Increasing efficiencies: Increasing efficiencies All planned core technical staff expected to be on board from February 2007 Retreat planned for mid February to review processes and find new ways of increasing efficiency "Project" approach to be discussed for technically complicated products with a project leader and capable technical expert team – same experts from the beginning till the end Task force approach – specific small groups of experts working with clearly defined objectives for additional guidance documents or problems Slide32: Are there alternative regulatory pathways for products of public health needs? EU legal basis - Article 58 Regulation (EC) 726/2004 For products exclusively to be used outside EU WHO as a "gate keeper" – public health need the key; and partner – can propose experts for the EMEA Committee for Human Medicinal Products (CHMP) – WHO can nominate observer Scientific opinion in cooperation with WHO Part of the EU response To the need to protect public health To give assistance to non-EU countries Rapid access to important medicines Slide33: Are there alternative regulatory pathways for products of public health needs (2)? US FDA tentative approvals linked to PEPFAR Canadian Access to medicines scheme WHO cooperation with the above mentioned Confidentiality agreement with US FDA in place and working; CA with Health Canada expected by March 2007 How better use the synergies? Slide34: 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.