WHO prequalification: update on prequalification of diagnostics and medicines

133 WHO Drug Information Vol. 29, No. 2, 2015 WHO prequalification Update on prequalification of diagnostics and medicines In addressing shortcomings in manufacture, regulation and supply that exist across multiple diseases and product types, WHO prequalification is probably the single, most effective source of hands-on regulatory capacity building. And by serving as a single entry point to donor funding for manufacturers who are willing to offer quality products, it greatly facilitates international procurement and distribution. In 2014, the prequalification programme both consolidated its processes for the different product categories and continued to broaden its achievements. This article provides an overview of those achievements. Norms and standards Established on the basis of the norms and standards adopted by the WHO Expert Committee for Specifications on Pharmaceutical Preparations, the Prequalification Team has become an important source of feedback to the standard-setting process for medicines. In 2014 it contributed to a wide range of pharmaceutical quality guidelines and proposed a concept paper for new guidance on good data management. The Prequalification Team also provided significant input into discussions to align international quality assurance requirements for diagnostic products based on stringent regulatory principles and emerging global consensus. It further issued draft guidance on post-market surveillance of in vitro diagnostics (IVDs) for comment (1). Integration of workstreams The year 2014 saw the merger of the independent prequalification streams for diagnostics, medical devices, medicines and vaccines and the creation of the Prequalification Team. This generated greater synergy, but also demanded considerable time and effort for reorganization and establishment of a quality management system. For diagnostics, significant resources were dedicated to streamlining processes, in particular to improve communication and enhance transparency. Funding In the absence of WHO budgetary allocations, prequalification is currently largely funded by just two donors: UNITAID and the Bill & Melinda Gates Foundation. User fees were introduced for prequalification of medicines in 2014, fees had already been introduced previously for diagnostics and vaccines. A review of 2014 applications showed that the number of submissions for medicines did not appear to have been affected negatively by the introduction of user fees. A financing model aimed at creating a sustainable source of funding was developed and made available for comment (see also page 164). Results An overview of 2014 results for diagnostics and medicines is presented on the next pages. WHO prequalification WHO Drug Information Vol. 29, No. 2, 2015 134 WHO prequalification in numbers: 2014 results for diagnostics and medicines A participatory approach Rotational posts: Future partners in Member States 3 Rotational assessors for medicines completed a 3-month fellowship (2) From: Botswana, D.R. Congo, Uganda 2 Rotational inspectors completed a 4-month fellowship in the Prequalification Team – a “first” From: China, Uganda 12 Former rotational staff from eight countries were involved in collaborative registration (→page 136) Eligible products Invitations for Expression of Interest (EoI) for prequalification of medicines: Adapting to changing needs 6 Updated EoIs issued in 2014 (3) i.e. for: HIV-related products 2 Antimalarials 1 Reproductive health products 1 Active pharmaceutical ingredients (APIs) 2 32 HIV-related formulations added including 12 medicines to treat hepatitis B and C 7 Antimalarials for children re-specified according to input from the WHO malaria programme 3 Reproductive health products added: • Levonorgestrel intrauterine system for five years continuous use • Misoprostol 25 mcg tablet • Magnesium sulfate injection 8 APIs added: dolutegravir, clofazimine, linezolid, ribavirin, rifabutin, simeprevir, sofosbuvir, valgancyclovir Two APIs removed: didanosine, ofloxacin Assessment Diagnostics: Building streamlined procedures 54 Technologies under assessment as at December 2014 (38 through the full procedure, 16 through the abbreviated procedure): HIV-related: 31 Hepatitis C-related: 11 Hepatitis B-related: 5 Malaria-related: 7 24 Inspections performed in 2014 with regulatory staff participation 20 Submissions under screening (as at December 2014) Medicines: A tried and tested approach 81 Dossiers for finished products under assessment (as at December 2014) 6 Joint assessment sessions (“Copenhagen sessions”) held in 2014 Participation from regulatory authorities, including staff involved in collaborative registration 94 Inspections conducted in 2014 with participation of regulatory staff: Of finished product sites: 39 Of API sites: 32 Of contract research organizations: 11 Of quality control (QC) laboratories: 12 105 Invitations to submit an application for requalification sent to manufacturers, leading to: 73 submissions being assessed 29 products withdrawn by manufacturers 1 product cancelled by WHO. (2 invitations were awaiting a response.) 135 WHO Drug Information Vol. 29, No. 2, 2015 WHO prequalification WHO prequalification in numbers: 2014 results for diagnostics and medicines (continued) Lists of products and services Prequalified medicines: More choices for procurement 416 Medicines listed on WHO website (4) (as at 31 March 2015) 53 Medicines prequalified in 2014 “Firsts:” • Dexamethasone injection • Generic capreomycin injection • Azithromycin 250 mg tablets, • Dolutegravir tablets • Mifepristone tablets • Sulfadoxine/pyrimethamine + amodiaquine • Generic morphine tablets • First products manufactured in Egypt • First four Nigerian manufacturers comply with WHO-GMP “Firsts”, 2015: Buprenorphine, oxytocine Prequalified APIs: More choices for manufacturers 78 APIs listed on WHO website (5) (as at 12 March 2015) 22 APIs prequalified in 2014 “Firsts”: • Efavirenz • Levofloxacin • Pyronaridine • Zinc Prequalified quality control laboratories: Trusted partners in QC testing 38 Laboratories listed on WHO website (6) (as at 22 January 2015) WHO African Region: 8 WHO Region of the Americas: 7 WHO South-East Asia Region: 4 WHO European Region: 13 WHO Eastern Mediterranean Region: 2 WHO Western Pacific Region: 4 7 Laboratories prequalified in 2014 Prequalified IVDs: Safe, well-performing diagnostics to guide prevention and treatment decisions 38 IVDs listed on WHO website (7) (as at 31 March 2015) 9 IVDs prequalified in 2014 HIV assays 6 Malaria rapid diagnostic tests 2 Hepatitis B (HbsAg) assay 1 3 “Firsts”: • An IVD manufactured in India • An IVD manufactured in China • First product prequalified under the new streamlined process (a CD4 technology; assessment time: 81 days) 51 Clearing the backlog: Non-progressing applications closed or withdrawn in 2014 Bridging the gaps Expert Review Panel (ERP): Risk assessment for needed products that are not yet available as stringently assessed versions Diagnostics: Pilot and Round 1 (8) 0 Technologies found acceptable in pilot (of 2 point-of-care HIV early infant diagnosis technologies assessed) 5 Technologies found acceptable for time-limited procurement in Round 1 (of 12 accepted for review) For any international procurement: 2 On a case-by-case basis: 3 Medicines (9): Rounds 11 and 12 12 Products found acceptable for time- limited procurement including newer ARVs, paediatric anti- malarials, 2nd line tuberculosis products (of 64 products accepted for review) WHO prequalification WHO Drug Information Vol. 29, No. 2, 2015 136 Training and advocacy Events for manufacturers and regulators: Building capacity and awareness >350 Participants attended the joint UNICEF/UNFPA/WHO meeting for manufacturers and suppliers (10) – record participation Diagnostics, 2014: 19 IVD manufacturers incentivized to submit applications 6 IVD manufacturers reached in one- on-one meetings on their research and development activities 1 Training session held on diagnostics dossier screening and assessment Medicines, 2014: 33 Events organized or co-organized 27 Technical assistance missions Manufacturers supported: 20 Countries of manufacture: 5 (China, India, Kenya, Nigeria, Pakistan) 1 Technical assistance project for Nigerian manufacturers (11) 6 National QC laboratories supported with technical assistance Use of prequalified products in WHO Member States Pharmaco vigilance: Monitoring medicines safety 10 Countries participated in inter-regional active surveillance training workshop 3 Gap assessments for tubercu losis- related products completed (D R Congo, Swaziland, Zanzibar) 5 National cohort event monitoring (CEM) databases set up Use of prequalified products in WHO Member States (continued) Collaborative registration of medicines: Putting countries in the driving seat 23 Participating countries 19 African, 4 Eastern European 62 Marketing authorizations approved, listed on WHO website (12) + 55 submissions under review (as at 6 May 2015) 36 Marketing authorizations approved in 2014 93 days Median time from information- sharing to registration (2014) International procurement: Rewarding investments in quality US$ 399 million Global Fund-financed prequalified medicines delivered in 2014 By category, million US$ (PQ only*) Antiretrovirals: 301 (43%) Antimalarials: 67 (100%) Anti-tuberculosis products 1st line: 11 (100%) 2nd line: 19 (82%) *PQ-only = not approved by a stringent regulatory authority US$ 55.6 million Global Fund-financed prequalified IVDs delivered in 2014 By category million US$: HIV RDT& EIA: 30.5 Malaria RDT: 12.5 HIV CD4 technologies: 7.1 HIV virological technologies: 5.6 Source: Global Fund Price and Quality Reporting (PQR) database. Global Fund-financed procurement represents a significant portion of internationally-funded procurement. WHO prequalification in numbers: 2014 results for medicines and diagnostics (continued) 137 WHO Drug Information Vol. 29, No. 2, 2015 WHO prequalification Conclusions Driven by the stringent quality requirements of donors, WHO prequalification offers manufacturers a means of accessing markets for products that meet international quality norms and standards. In 2014, prequalification of medicines succeeded in making efficient use of its tried and tested “generic” approach to assess the quality of a wide range of chemical medicines, building on the safety and efficacy assessment of innovator products carried out by stringent regulatory authorities. Through its highly participatory and collaborative activities WHO leveraged these well-established processes to increase the capacity of manufacturers and regulators to implement stringent quality standards for pharmaceutical products. Quality assurance of diagnostic technologies presents more complex challenges. This product category is diverse and rapidly evolving, yet in many parts of the world, regulatory mechanisms for assessing diagnostics are very limited. WHO prequalification is playing a key role in international efforts to understand the markets and regulatory landscapes of needed diagnostic technologies for priority diseases, and to define stringent standards for their assessment and post- market surveillance in those countries where they are needed most. æ References 1 WHO. Guidance for post-market surveillance of in vitro diagnostics. Draft. Version 5, 19 January 2015. Posted at: http://www.who.int/diagnostics_laboratory/ postmarket/en/ 2 WHO Prequalification of Medicines Programme rotational fellowships. WHO Drug Information 2012; 26(3): 248-54. 3 WHO Prequalification. Invitations for Expressions of Interest (EOIs) [webpage]. 4 WHO List of prequalified medicinal products [webpage]. 5 Prequalification of Active Pharmaceutical Ingredients - List of Prequalified APIs [webpage]. 6 WHO List of Prequalified Quality Control Laboratories. 7 WHO list of prequalified in vitro diagnostic products. 8 The Global Fund to Fight AIDS, Tuberculosis and Malaria. Procurement and Supply Management. Information for Suppliers [webpage]. 9 WHO Prequalification of medicines programme. Expert Review Panel. Briefing paper, 27 April 2012. 10 Prequalification: Meetings. Joint WHO-UNICEF-UNFPA Meeting with Manufacturers and Suppliers of Diagnostic Products, Finished Pharmaceutical Products, Active Pharmaceutical Ingredients and Vaccines. 11 Building quality-assured manufacturing capacity in Nigeria. WHO Drug Information; 2014; 28(4): 425-30. 12 WHO Prequalification: Collaborative registration [webpage].