WHO Prequalification of Medicines Programme

Transcription

1 WHO Prequalification of Medicines Programme General overview and update Milan Smid, M.D., Ph.D. Slides benefiting from presentations of WHO PQP colleagues and BioBridge Strategies WHO PQP tutorial, 27 th September, 2012, Mumbai

2 UN Prequalification Programme for Priority Essential Medicines Action plan of UN from 2001 for expanding access to selected priority medicines Objective: To ensure quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM, UNITAID) to serve patients in developing countries Components: Evaluation of Quality, Safety and Efficacy of prioritised Essential medicines (FPPs and APIs), inspections of manufacturers and monitoring of the products after their prequalification. Prequalification of quality control laboratories. Building capacity of regulators, manufacturers and quality control laboratories. 2 2

3 Categories of medicines invited Primary categories of medicines: HIV/AIDS Malaria Tuberculosis Later added: Reproductive health Influenza Acute diarrhoea Neglected tropical diseases Potentially other categories of products, if there is the need Prequalification also applicable for APIs! Published in invitations for Expression of Interest (EOI) on Prequalification website 3 3

4 5 th Invitation for EOI, May 2010 Reproductive health medicines (1) 4

5 3 rd Invitation for EOI Active Pharmaceutical Ingredients Therapeutic area HIV/AIDS Malaria Tuberculosis Invited Active Pharmaceutical Ingredients Abacavir, Atazanavir, Darunavir, Didanosine, Efavirenz, Emtricitabine, Etravirine, Lamivudine, Lopinavir, Nelfinavir, Nevirapine, Raltegravir, Ritonavir, Stavudine, Tenofovir, Zidovudine Amodiaquine, Artemether, Artesunate, Dihydroartemisinin, Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Pyronaridine, Sulfadoxine Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, Para- Aminosalicylic Acid (PAS), Prothionamide, Pyrazinamide, Rifampicin, Streptomycin, Terizidone Reproductive health Neglected tropical diseases Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel, Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone, Norgestrel, Oxytocin Diethylcarbamazine, Mebendazole 5

6 Two prequalification routes Invitation for expression of Interest Expression of Interest Medicine not assessed by SRA Medicine assessed by SRA Dossier and SMF submitted for assessment WHO assessment and inspections organized Valid for innovators and generics SRA registration (assessment and compliance check) Simplified review Compliance Prequalification Acceptance 6 6

7 Essential steps of PQ evaluation procedure Need is specified and agreed by WHO treatment programmes Invitation for Expression of Interest (EOI) is published Interested parties submit dossiers 'Expression of interest' Dossiers receive initial screening Full dossiers are assessed Inspections are conducted at manufacturing sites and at CROs Samples are tested, if needed If outcome is positive, pharmaceutical product is listed on the website, including product information (SPC, PIL), assessment report (WHOPAR) and inspection report (WHOPIR) 7 7

8 Steps in WHO prequalification I Expression of Interest Assessment Additional information and data Compliance Product dossier SMF Prequalification Inspections Corrective actions Compliance Maintenance and monitoring 8 8

9 Essential steps of monitoring of PQ product Variations to the dossier of prequalified product Sampling and Testing Re-inspections Requalification Management of complaints De-listing or suspension (if and when appropriate) 9 9

10 Principles Same principles apply as for national regulatory approvals by stringent authorities Data on quality (FPP, API) Data on efficacy and safety or interchangeability Compliance with GMP (FPP, API), GCP/GLP (bioequivalence studies) Benefits prevail risks 10

11 Assessment of product dossiers One week meeting at least every 2 months, team of professionals from NMRAs Botswana, Canada, China, Congo, Ethiopia, France, Georgia, Germany, Ghana, Israel, Italy, Kenya, Malaysia, Netherlands, New Zealand, Portugal, Singapore, Spain, South Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zambia, Zimbabwe... Combined with capacity building Quality assurance of outcomes 11

12 Inspections Team of inspectors for each inspection WHO PQ inspector plus PIC/S member country plus local country inspector (observer) Some cases capacity building (recipient country) Preparation includes SMF, product information, inspection reports, complaints etc Inspections are product oriented and include data verification APIs and Bioequivalence studies inspected based on risk assessment 1 12

13 Standards WHO standards as defined in WHO guidelines are applied in prequalification process If these not exist, ICH guidelines are applied In case of need, guidelines of stringent regulatory authorities involved in ICH process Pharmacopoeias (Ph.Int., USP, BP, Ph.Eur., JP) as minimum standard Depending on product, assessors may ask for additional tests or tightening limits WHO GMP guidelines (compatible with PIC/S; references to pharmacopoeias, e.g. harmonized monographs) WHO GCP guidelines + Additional guidance for organizations performing in vivo bioequivalence studies (compatible with ICH) 1 13

14 Adapting the CTD-NDS (new drug) to CTD-ANDS (generic) Regional Admin Information Module 1 Not Part of the CTD Module 2 Quality Overall Summary Nonclinical Overview Nonclinical Summary Clinical Overview Clinical Summary The CTD Quality Nonclinical Study Reports Clinical Study Reports Module 3 Module 4 Module 5 14

15 Demonstration of bioequivalence Bioequivalence study or PD studies Clinical studies ONLY EXCEPTIONAL! In vitro methods 15

16 WHO BCS-based biowaiver Active substances selected for biowaiving by WHO HIV/AIDS: Lamivudine (BCS 3) Stavudine (BCS 1) Zidovudine (BCS 1) Abacavir sulphate (BCS 3) Emtricitabine (BCS 1) TB: Levofloxacin (BCS 1) Ofloxacin (BCS 1) Ethambutol ((BCS 3) Isoniazid (BCS 3) Pyrazinamide (BCS 3) 16

17 Time to PQP Approval The time to PQP approval can vary significantly but is influenced principally by the quality of the application and company response time The mean time to approval in 2011 was 24 months 8.4 months PQP processing time (35%) 15.6 months manufacturer response time (65%) 17

18 Outcomes of PQ procedure Information in public domain: List of PQ medicinal products WHOPAR (SPC, PIL, labelling) WHOPIR (both FPP and API) Notices of Concern and Suspensions Information on progress of assessment procedure and inspections Supportive documents: WHO guidelines, description of PQ procedure, training materials 1 18

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20 Prequalified medicines 1 June listed based on the approval by US FDA = 16 (HIV only) tentative approval by US FDA = 73 (HIV only) approval within Canada's Access to Medicines Regime = 1 (HIV) approval by EMA according to Article 58 = 3 (2 HIV + 1 Malaria) 20

21 Prequalified medicines according to countries of manufacture (1 June 2012) 21

22 Capacity building - objectives Good quality submissions for PQ supported by compliance with "good practices" platform for improvement of drug development, manufacturing, documentation and quality control Fast regulatory approvals of PQ medicines in recipient countries technical education of regulators as a platform for strengthening expertise, regulatory efficiency and networking Reliable quality monitoring technical education of staff of QCLs to strengthen expertise, effectiveness of quality monitoring and networking PQP standards and PQP example support strengthening of regulatory systems and capacity of manufacturers in general 22

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24 TBS 2, 24

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26 Technical Assistance Provision of expert consultants to Manufacturers Quality control laboratories Regulators Assistance focuses on GMP, GCP or GLP compliance Dossier development Assistance is separated from the assessment / inspections and may be followed by specific trainings 2 26

27 Conditions for provision of technical Manufacturers: assistance Participation in the prequalification programme, Found to be capable and willing to improve Location in a developing country Products: Inclusion in the list of expression of interest High value for Public Health purpose Poor representation on the Prequalification list. 27

28 Technical assistances in countries 28

29 Frequent misunderstandings Manufacturers/manufacturing sites are prequalified PQP issues WHO GMP certificates PQP provides direct financial support Prequalification gives right to succeed in tenders PQ substitutes national authorization (registration) in recipient countries All medicines used in treatment of HIV/AIDS and tropical diseases are invited for PQ Prequalified medicines may bear WHO logo 29 29

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31 Principles of proposed process Availability of PQP assessment, inspection outcomes and advice to facilitate national regulatory decisions making (registrations, variations, withdrawals) No interference with national legislation, decision making process and regulatory fees Co-operation among product manufacturer (PQP holder), NMRA in interested country and PQP to overcome confidentiality issues and assure information flow Procedure applicable for individual products Procedure voluntary for manufacturers and NMRAs 31

32 Steps of the procedure: agreement Interested NMRAs agree to participate in the procedure PQP lists committed NMRAs on its website 32

33 Steps of the procedure: registration PQ product is submitted for national registration to NMRA participating in the procedure NMRA is informed about the interest to follow PQP Manufacturer informs PQP about national submission and gives consent with information sharing Participating NMRA confirms its interest to participate in procedure for specific product PQP shares with participating NMRA outcomes of assessment and inspections Participating NMRA reviews WHO PQP outcomes, decides within 90 days decides upon the national registration and informs PQP about its decision 33

34 Win-win outcomes for all stakeholders NMRAs Availability of WHO assessment and inspection outcomes to support national decisions Opportunity for learning from experienced assessors Saving internal capacities Demonstrating NMRA efficiency WHO Prequalified medicines are faster available to patients Procurers Faster start of procurement Manufacturers Harmonized data for PQ and national registration Facilitated interaction with NMRAs in assessment and inspections Accelerated registration 34

35 Expert Review Panel (ERP) A panel of experts hosted by WHO since 2009 Assesses the potential risks/benefits associated with the use of FPPs that are not yet WHO-prequalified or SRAauthorized Eligibility criteria for dossier submission: product manufactured in GMP compliant site and dossier submitted to and accepted for review by WHO PQP or a SRA Assesses abbreviated product dossiers submitted by manufacturers (questionnaire + annexes) Makes time limited recommendations: validity maximum 12 months-contracts can be signed any time up to one year ERP status does not replace WHO PQ/SRA approval but should be seen as a step towards WHO PQ/SRA approval 35

36 Products reviewed by the ERP since 2009 Data from Dec rounds completed 348 product dossiers were submitted and reviewed by ERP; 69 products were permitted for use for a one year period; during the ERP period validity: 30 products have been WHO prequalified 7 products have been authorized by an SRA 36

37 Reported Procurement information Over 1, 400 million* US$ of transactions reported in the PQR system Products/Manufacturers distribution ARV Branded: 34% Antimalarial Branded: 70% anti-tb Branded: 22% Generic: 66% Generic: 30% Generic:7 8% Sophie Logez, GFATM, March

38 COUNTRIES RECEIVING COMMODITIES US$1.1Billion UNITAID funds HIV / AIDS 51 recipient countries Malaria 29 recipient countries > US$600 mil > US$300 mil Tuberculosis 76 recipient countries > US$200 mil - Cross cutting programs: US$109 m for PQ of drugs & diagnostics and transversal programs Lorenzo Witherspoon, UNITAID, March

39 What kind of investments does a company have to make to in seeking prequalification of a product? Bioequivalence Formulation development Stability studies Dossier preparation Capital Clinical and analytical studies to validate the equivalence to the established comparator If a company does not have a product on the market, it has to develop the formulation as specified by the EOI. Stability studies have to be carried out on multiple batches of material for climatic zone IV PQP requires CTD format of dossier and few additional specific documents and has well-defined requirements. The preparation and support require investment of personnel. Money may be needed for investment in both R&D and manufacturing equipment as well as quality control systems. Capital is also needed for facilities upgrades and construction of new facilities. 39

40 Investments varies depending on the experience of a company Inexperienced Bioequivalence Dossier Preparation Capital High High High Local manufacturer Bioequivalence Dossier Preparation Capital Medium - High Medium Low - Medium Global company Bioequivalence Dossier Preparation Low Low Capital $ 0 40

41 Potential benefits for manufacturers Participation in tender procedures organized by national and international procurers and financial profit Recognition as being WHO listed company Demonstration of social responsibility Facilitated registration in some recipient countries Reduction of inspections from recipient countries Possibility to be assisted by expert consultants (GMP, dossier, BE) Learning process improving company's chance to succeed with submissions to SRAs Identified sources of quality assured APIs Potential additional incentives (pro-export and pricing policies) 4 41

42 Who should you contact at the WHO Prequalification of Medicines Programme General enquiries: Jacqueline Sawyer, Liaison Officer, Dossier submission and assessment: Dr Matthias Stahl, Head of Assessments, Prequalification of APIs: Dr Antony Fake, Inspections: Ian Thrussell, Head of Inspections, Training and technical assistance: Dr Milan Smid, Prequalification of medicines quality control laboratories: Dr Jitka Sabartova, 42

43 Thank you for the attention 4 43