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New drugs uptake in WHO EURO Dr Ogtay Gozalov, Medical officer, WHO EURO [email protected] Dr Maya Kavtaradze, Regional Technical Adviser, Stop TB Partnership's GDF [email protected] Dr Elmira Gurbanova, rGLC/Europe consultant, [email protected] Dr Gunta Dravniece, Senior TB Adviser, KNCV [email protected] 18th Wolfheze Workshops and 15th WHO National TB Programme Managers’ Meeting The Hague, Netherlands June 2017 Analysis of rGLC/Europe reports on new drugs / new treatment regimens Methodology 2016 2017 Uzbekistan Ukraine Turkmenistan Tajikistan Republic of Moldova (Transtristria) Romania Moldova FYR Macedonia Kyrgyzstan Serbia (UN AT Kosovo) Kazakhstan Georgia Belarus Azerbaijan Armenia Year of the assessment 18 regional GLC mission reports from 15 sites were analyzed against elements needed to be addressed for introduction of new TB drugs (Bdq and Dlm), as per the Policy Implementation Package Availability of Bdq and/or Dlm in the country Available in Armenia, Belarus, Georgia, Kazakhstan, Serbia (UN AT Kosovo), Moldova, Romania, Moldova (Transnistria), Ukraine, Uzbekistan 4 No information on Tajikistan 1 10 Not available in Azerbaijan, FYR Macedonia, Kyrgyzstan, Turkmenistan Out of 15 countries assessed, 10 introduced Bdq and/or Dlm Number of countries that introduced new TB drugs Cumulative number of patients receiving new TB drugs Bdq-based treatment 33 8 2 2013 10 137 Dlm-based treatment 2 2014 2015 845 2016 Bdq+Dlmbased treatment National implementation plan for introduction of new TB drugs Availability of the National Implementation Plan 5 7 3 Available in Armenia, Belarus, Georgia, Kyrgyzstan, Moldova, Tajikistan, Uzbekistan No information on Kazakhstan, Turkmenistan, Ukraine Not available in Azerbaijan, Serbia (UN AT Kosovo), FYR Macedonia, Romania, Moldova (Transnistria) Minimum requirements for country preparedness and planning: National health context Availability of the National Strategy to fight TB up to 2020 Available in Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, Serbia (UN AT Kosovo), Kyrgyzstan, FYR Macedonia, Moldova, Romania, Tajikistan, Turkmenistan, Ukraine, Uzbekistan 1 No information on Moldova (Transnistria) 14 Minimum requirements for country preparedness and planning: Laboratory Drug susceptibility testing (DST) to first-line drugs (FLD) Quality assurance for DST to FLD 1 1 5 9 14 Available in Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, Serbia (UN AT Kosovo), FYR Macedonia, Moldova, Romania, Moldova (Transnistria), Tajikistan, Turkmenistan, Ukraine, Uzbekistan No information on Kyrgyzstan Passed in Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, FYR Macedonia,Tajikistan, Ukraine, Uzbekistan No information on Kyrgyzstan, Moldova, Romania, Moldova (Transnistria), Turkmenistan Not passed in Serbia (UN AT Kosovo) Minimum requirements for country preparedness and planning: Laboratory Drug susceptibility testing (DST) to secondline drugs (SLD) 2 Quality assurance for DST to SLD 1 2 1 12 12 Available in Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, Moldova, Romania, Moldova (Transnistria), Tajikistan, Turkmenistan, Ukraine, Uzbekistan No information on Kyrgyzstan Not available in Serbia (UN AT Kosovo), FYR Macedonia Passed in Azerbaijan, Armenia, Belarus, Georgia, Moldova, Kazakhstan, Romania, Tajikistan, Moldova (Transnistria), Turkmenistan, Uzbekistan, Ukraine Not passed in Serbia (UN AT Kosovo), FYR Macedonia No information on Kyrgyzstan Minimum requirements for country preparedness and planning: Drug supply and management • Registration of Clofazimin (Cfz) is problematic at all countries. • Bdq and Dlm are imported based on one-time license, mainly because these drugs are still on a clinical trial • TB drugs procured with the support from the Global Fund are quality assured. • However, drugs procured through local budget, mainly do not hold GMP or WHO-prequalification Minimum requirements for country preparedness and planning: Drug supply and management Shortage of TB drugs reported during the last 2 years No shortage reported in Armenia, Georgia, Kazakhstan, Serbia (UN AT Kosovo), FYR Macedonia, Moldova, Tajikistan, Turkmenistan, Uzbekistan 5 No information on Kyrgyzstan 9 1 Shortage reported by Azerbaijan, Belarus, Romania, Moldova (Transnistria), Ukraine Minimum requirements for country preparedness and planning: Case management National guidelines for the programmatic management of drug-resistant TB is updated as per the latest WHO recommendations Updated in Belarus, Kazakhstan, Ukraine 3 No information on Kyrgyzstan 1 11 Not updated in Azerbaijan, Armenia, Georgia, Serbia (UN AT Kosovo), FYR Macedonia, Moldova, Romania, Moldova (Transnistria), Tajikistan, Turkmenistan, Uzbekistan Minimum requirements for country preparedness and planning: Monitoring and evaluation • All countries use updated WHO definitions for TB (2013 update) • Some countries still do not have functional electronic TB database and execute paper-based reporting (Azerbaijan, Tajikistan, Turkmenistan, Uzbekistan, Kyrgyzstan) • Supportive supervisions in majority countries are performed by the National TB Programs, but are heavily relying on the Global Fund support Minimum requirements for country preparedness and planning: Pharmacovigilance • Armenia, Belarus and Georgia established: – Active pharmacovigilance (PV) – Centralized PV data collection – Cohort-event monitoring used as PV method • In remaining 12 countries the PV is not duly implemented New and companion drugs via GDF Access to New TB tools via Global Drug Facility and reporting requirements Global Drug Facility (GDF) An enterprise of the Stop TB Partnership, mainly funded by USAID, hosted in UNOPS and managed by the Partnership secretariat GDF Goal: Facilitate equitable and timely access to affordable, quality-assured, medicines and diagnostics, including new tools. GDF began supplying FLDs in 2001, and in 2007 added the supply of SLDs, pediatric TB medicines and diagnostics and is a major source for GeneXpert™ GDF order placed by Product Line 137 countries benefited from GDF procurement / bundled mechanism > 27 M Adult FLDs treatments > 1,59 M pediatric treatments > 239,321 SLDs patient treatments US$ 1.63 billion of TB commodities procured since GDF inception in 2001 (as of December 2016) www.stoptb.org The Product List and Catalogue http://www.stoptb.org/gdf/drugsupply/drugs_available.asp New Diagnostics www.stoptb.org www.stoptb.org Access to Laboratory and Diagnostic Products All products for WHO’s recommended techniques including New rapid diagnostic and DST tests! Equipment and accessories, diagnostics and consumables, microbiological tests and test systems for: GDF diagnostics catalogue • Equipment Kit for Microscopy laboratory Diagnostics and consumables kits for ZN or Auramine staining techniques • Liquid Culture and DSTs Becton Dickinson BACTEC MGIT 960 system MGIT Tubes, OADC Supplement, SIRE Kits and Rapid Diagnostic Test SD BIOLINE TB Ag MPT64 • Lyophilized drug for laboratory use (Amikacin, Capreomycin, Kanamycin, Moxifloxacin, Ofloxacin) • Solid culture and DST Loewenstein-Jensen-Medium • • Lifescience TB LAMP (Loopamp technology) Molecular line probe assays for 1st-line anti-TB drugs HAIN • Digital X-Ray GT-Blot 48, Twincubator, GenoType MTBDRplus and services • DNA Genotek - OMNIgene•SPUTUM (OM-SPD) Automated real-time nucleic acid amplification - Xpert MTB/RIF system • Quiagen - QuantiFERON-TB Gold Plus (QFT®-Plus) Laboratory instruments, consumables, chemicals and personal protective equipment • • Product coming to GDF portfolio in 2017 TM www.stoptb.org www.stoptb.org Access to WHO-recommended medicines Full range of medicines for any type of TB treatment regimens available from the GDF! Repurposed medicines with increasing demand: Clofazimine, linezolid, amoxicillin clavulanate, imipenem/cilastatin Products price list online Substantial price decrease for: Linezolid Price decrease for: Amoxicillin Clavulanate, Capreomycin, Imipenem/Cilastatin, Levofloxacin, Moxifloxacin and PAS Sodium Salt Clofazimine 100mg from Novartis Off label use in TB - disclaimer and quarterly A second manufacturer is expected in 2017 Application for inclusion in the WHO EML -March 2017 New dispersible pediatric formulations 2-FDC/RH-75/50; 3-FDC/RHZTreatment of Latent Tuberculosis Infection 75/50/150 Priftin® (rifapentine 150 mg tablet) from Sanofi www.stoptb.org www.stoptb.org New GDF Strategic Rotating Stockpile (SRS): aimed Improve the service level to GDF clients: • • Decrease lead time between the countries’ orders and delivery by serving countries from available stock Ensure flexibility of supply in case of over stocking or stock-out situations in countries: Adapt client orders with consumption by pre or postponement of deliveries Improve the service level to GDF suppliers : • • • Improve the GDF order cycle by a better scheduling of orders to suppliers Adapt replenishment orders and production capacity to smooth peaks in the ordering pattern Provide to suppliers more reliable forecast and information on the market especially on policy changes to SRS Product Name Amikacin 500mg/2ml injectable Amoxicillin 500mg+Clavulanic acid 125mg Amoxicillin 875mg+Clavulanic acid 125mg Bedaquiline 100mg tablet Clofazimine 100mg capsule Capreomycin 1gram powder for injectable Cycloserine 250mg capsule Delamanid 50mg tablet Ethionamide 250mg tablet Kanamycin 1g injectable solution Levofloxacin 250mg tablet Levofloxacin 500mg tablet Linezolid 600mg tablet Moxifloxacin 400 mg tablet PAS sodium sachet Prothionamide 250 mg tablet Pyrazinamide 400 mg tablet Pyrazinamide 500 mg tablet Syringe & needle (auto-disabling) Water for injections Isoniazid 300mg tablet Ethambutol HCI 400 mg tablet www.stoptb.org GDF value-adding package of services Delivering-only does not work any more The Goal of the GDF Technical Assistance and Capacity Building Strategy is twofold • To strengthen priority countries capacity to ensure timely equitable access to the GDF-supplied quality-assured medicines and products, including new TB products • To provide country information and evidence on TB product demand and country TB control trends for the GDF strategic procurement planning and decision-making, and global forecasting exercises www.stoptb.org GDF TA and Capacity Strengthening GDF tier 1 countries with core USAID support Tier 2 countries with additional USAID support Full package TA for expedited uptake of new TB tools managed by Regional Technical Advisors Managed by GDF HQ and RTAs Implemented by pool of GDF-trained consultants • • • • • Development of Transition PSM plans Assistance with functional EWS for monitoring uptake Ongoing focused technical assistance and capacity building for PSM systems strengthening PSM tools implementation: QuanTB (quantification, planning, Early Warning), data collection tools GDF Regional Technical Advisers: Zaza Munez – SE Asia and W.Pacific [email protected] Salama Mwatawala – Africa [email protected] Maya Kavtaradze – Europe/CAR [email protected] Erulappa Thanaraj – India [email protected] Targeted TA for PSM plans of the Global Fund proposals • Development of Transition PSM plans for new TB tools • Regional capacity building for forecasting and quantification • Assistance with functional Early Warning System • Joint missions: rGLC, TGF, WHO, partners (e.g. KNCV, UNION, etc.) Two additional RTAs to be hired for • Best practices and knowledge sharing Africa (Anglophone/Francophone) SE Asia Pool of trained regional consultants www.stoptb.org www.stoptb.org New TB tools Shorter MDR-TB treatment regimen New Paediatric Formulations New and repurposed drugs New diagnostics www.stoptb.org Bedaquiline 100 mg tablest Sirturo by J&J, Kemwell Biopharma, USFDA/EMA Packing size: HDPE container(s) of 188 Shelf life: 36 months USAID Bedaquiline Donation Program: free-of-charge to eligible countries following WHO interim recommendations As of April 2017: 10 705 treatment courses globally including MSF projects (delivered, orders placed with suppliers or in process) Of which in Europe and CAR countries: 2 944 courses without MSF projects Country Countries can request Technical Assistance from USAID and GDF ([email protected] ; [email protected]; [email protected]) Adverse events reported directly to Janssen or via GDF: [email protected] Armenia Azerbaijan Belarus Georgia Kazakhstan Kosovo Kyrgyzstan Republic of Moldova Tajikistan Turkmenistan Ukraine Uzbekistan Grand Total BDQ Order placed with supplier BDQ Order Completed BDQ Total 69 386 341 390 25 89 50 90 1440 91 139 60 332 2 110 67 70 40 200 393 1504 69 91 525 401 722 2 135 156 120 40 200 483 2944 www.stoptb.org www.stoptb.org Delamanid 50mg tablets Deltyba by Otsuka, EMA/Japan Packing size: Box(s) of 672 Shelf life: 60 months Countries eligible for TB Financing by The Global Fund and following WHO interim recommendations can access Delamanid via the GDF Price USD 1,700 for a full treatment course (6 months) Adverse events reported to Otsuka via the GDF: [email protected] As of April 2017: 2 448 treatment courses globally including MSF projects (delivered, orders placed with suppliers or in process) Of which in Europe and CAR countries: 626 courses without MSF projects Country Armenia Azerbaijan Belarus Georgia Kazakhstan Kosovo Kyrgyzstan Republic of Moldova Tajikistan Turkmenistan Ukraine Uzbekistan Grand Total DLM Order Completed DLM Order placed with supplier DLM Total MSF 144 35 130 193 80 337 35 210 8 25 8 25 MSF 309 11 317 11 + MSF 626 www.stoptb.org www.stoptb.org How to Access Bedaquiline and Delamanid via GDF (1) A. Countries/programs should ensure they follow the five WHO recommendations for optimal introduction of BDQ and DLM: Effective treatment and monitoring Proper patient inclusion Informed consent Adherence to WHO recommendations Active pharmacovigilance and management of adverse events aDSM ─ Active and systematic clinical and laboratory assessment of patients on treatment with new anti-TB drugs, novel MDR-TB regimens or XDR-TB regimens to detect, manage and report suspected or confirmed drug toxicities and adverse events; ─ Systematic and standardized recording and reporting at least Serious Adverse Events (may also monitor other AEs that are of clinical significance or of special interest to the program and can be expanded to eventually cover TB patients on treatment with any second-line drugs) aDSM is intended ─ to be an integral component of the programmatic management of drug-resistant TB (PMDT) and ─ to complement current capacities of national pharmacovigilance. www.stoptb.org How to Access Bedaquiline and Delamanid via GDF (2) B. Review the background documentation on the program and the order form from the GDF (http://www.stoptb.org/gdf/drugsupply/procurement_forms.asp) System for systematic and standardized recording and reporting of AEs is required Annex: Adverse Drug Reaction / Serious adverse event forms • • BDQ Adverse events reported to Janssen via GDF: [email protected] DLM Adverse events reported to Otsuka via the GDF: [email protected] www.stoptb.org www.stoptb.org How to Access Bedaquiline and Delamanid via GDF (3) C. Estimate the number of patients who will benefit from the Out- and in-coming medicines medicines: Dlm Cs BdqEto Cm Pto ─ Planning and executing the supply for multiple concurrent new and Am Imp AmCl PAS Cfz Km Mfx Lnz old regimens of different duration and at various implementation Lfx Z start dates ─ Mixed supply medicines in countries graduating from the GF support: Forecasting and quantification for multiple regimens become too complex for the maintaining quality and access existing level of expertise Increased individualization and number of treatment regimens D. Review the need for other second-line drugs that are Lack of data-driven rational phase-in / phase-out transition planning with scenarios Standard M/XDR 20 month: needed toand treat patients who will be receiving BDQ or cost estimations 8Cm70%Km30%Lfx50% Mfx50% Pto90%Cs90% PAS60%Z100%/12Lfx50% DLM Mfx50% Pto90%Cs90% PAS60%Z100% Need for functional Early Warning System including patient data collection to With new and repurposed drugs 20 months: ─ data-driven need-based approach to forecasting / manage transition without treatment interruptions 6Bdq90%/6Dlm30%/8Cm65%Imp\Cls35%Amx\Clv35%Cfz90%Lnz90%Mfx50%L quantification for all medicines (not cohort-based) ─ Phase-in / phase-out planning: scenarios and estimation of volumes and values of obsolete medicines for withdrawal and destruction E. Review needs based on the above descriptions fx10% Pto30%Cs30%PAS4% Z50% /12Cfz90%Lnz90%Mfx50%Lfx10% Pto30%Cs30%PAS4% Z50% STR 9 - 12 months (composition and duration may vary): (4-6)Km10% Cm80% Am10%Mfx20% Pto100% Cfz100% Hh100% Z100% E100% /(5 -6) Mfx100% Pto100% Cfz100% Z100% E100% www.stoptb.org Quantification and Early Warning System Benefits from EWS (quarterly QuanTB reports): • Proactively monitor TB medicines supply and medicines orders: Early action to prevent stock-out/overstock • Streamline medicine orders: Firm order schedules, streamlined supply to countries • Ensure uninterrupted supply for smooth transition to new medicines and regimens • Play scenarios for rational introduction of new TB tools • Reduce wastage of medicine: in-country reallocation of medicines where possible and changing delivery schedule - GDF needs advance notification! • GDF will improve global and strategic procurement forecasting (Cheaper medicines for countries) • Reports will also serve as foundation for evidence-based technical assistance to countries for rapid and rational transition to new medicines and regimens www.stoptb.org www.stoptb.org How to Access Bedaquiline and Delamanid via GDF (4) F. Place order for new and other second-line drugs as the turn-around time is likely to be several months, and TA activities can be carried out while awaiting drug arrival: ─ Need to capacitate laboratories to conduct SL DST (LPA, automated, conventional) ─ Development, approval and introduction of new treatment guidelines and training of staff at all levels ─ Need for approved policy for expedited uptake of new medicines and regimens, including for withdrawal and destruction of obsolete sub-optimal medicines • • • • • Delays in initiating orders… Delays in approving quotes… Delays in country to grant dispatch authorization… Last minute changes in required shipping documents.... Delays in country to import through customs, stock and deliver… G. Explore options to import new medicines in the country if they are not registered yet: ─ Registration/waivers and importation approvals (Donor and Domestic funded) H. Review clinical cases and patient histories to see who would benefit from new medicines. www.stoptb.org www.stoptb.org Message from WHO and GDF to NTP’s: 1. 2. 3. 4. All Medicines and diagnostic tools recommended by WHO, including STR and new drugs are available in GDF Technical assistance and capacity strengthening for the introduction of new TB tools are available through the GDF and USAID-funded projects NTPs should use current opportunities and should not delay the transition of use of new TB drugs, STR and new pediatric formulations NTPs are requested to follow reporting requirements including ADRs and EWS reports www.stoptb.org Introduction of new drugs and shorter DR-TB treatment regimen KNCV’s approach Gunta Dravniece, Michael Kimerling KNCV Wolfheze conference, May 31-June 2 2017 KNCV supports programmatic introduction and evaluation of any innovation • Diagnostics • Regimen design • Monitoring of safety and efficacy Monitoring • Drug management • Patient support • Infection control • Recording & reporting • Digital health KNCV’s patient triage approach allows initiation of the most effective treatment regimen for any TB patient in <5 days Patient with presumptive TB Rapid molecular test (e.g. Xpert MTB/RIF) No TB Rif susceptible TB Rif resistant TB START TREATMENT AFTER EVALUATION OF ELIGIBILITY FOR SHORTER REGIMEN Appropriate referral/ treatment Standard TB treatment with First Line Drugs Eligible Shorter DR-TB treatment regimen Ineligible Individualized DRTB treatment regimen Patient Triage Approach Linking the Bdq donation program with introduction of the STR KNCV’s support in WHO Euro Through USAID Challenge TB project (CTB) Four countries in the region • Ukraine (PATH and KNCV) • Uzbekistan (WHO and KNCV) • Kyrgyz Republic (KNCV) • Tajikistan (KNCV) Generic documents developed and adapted for country needs 1. Implementation planning tool 2. Programmatic and clinical guide 3. Job aids (Use of Bdq; QTE) 4. Generic SOPs (under development) 5. Generic Training materials (under development) COUNTRY SUPPORT: EXAMPLE FROM KYRGYZ REPUBLIC Regulatory environment and policy I 1.Advocacy work resulted in support from MoH 2. Use of new drugs included in national guidelines 3. National plan for new drugs and regimens developed and endorsed by MoH Regulatory environment and policy II 4. Triage approach and implementation of proposed regimens supported by inter-/national partners 5. Adverse event monitoring within MDR-TB program was revised and linked with PV authority Site preparation I 1. One functional diagnostic algorithm designed and includes Xpert and HAIN SL tests 2. Specimen transportation, procurement of consumables supported by other partners considering KNCV approach 3. UNDP/GF supports triage approach – drugs shorter and individualized regimens procured for Site preparation II 1. Clinical guide and SOPs developed 2. Access to all necessary monitoring tests supported by UNDP/GF in coordination with KNCV 3. Electronic data base developed 4. Training for clinical and laboratory staff 5. Patients’ enrolment new drugs 6. Continuous provided for shorter regimen and regimen with started in January 2017 on job training and supervision provided 44 Introduction timelines in Kyrgyz Republic • • Adjustment of guidelines Design of diagnostic algorithm and treatment regimens Q3 2015 • • • Q4 2015 Site selection/assessment Development of National plan Estimation of drug needs • Developmen t of guide Q1 2016 • Development of SOPs Endorsement of National plan Q2 2016 Q3 2016 • • • • On job training Patient enrollment Q4 2016 Finalization of guide and SOPs Training of clinical and laboratory staff Enrollment started in January 2017 Short treatment regimen is introduced starting from two sites (Bishkek city, Chui oblast) • 58 patients enrolled, including 3 children and 7 adolescents Individualized regimen containing new and repurposed drugs is provided for patients from whole country. • 58 patients enrolled, majority from the waiting list, many of them in severe condition at the time of enrollment Progress in other countries Tajikistan • Enrollment started in December 2016 • By the end of April 2017 24 patients enrolled in shorter regimen and 24 in individualized regimen Ukraine • Bdq ordered for 200 patients • Enrollment will be started in June 2017 Uzbekistan • CTB project just started • Guidelines adjusted • National plan developed Lessons learned from CTB countries I 1. Treatment regimen is only one of components in patient management. TA should address the essential PMDT elements Diagnost ics 2. Many PMDT components were not ready in countries therefore preparationTreatme takes longer (around 12 months). nt monitori ng 3. TA on ND&R provides an opportunity to strengthen MDR program. 4. Political support is crucial Treatment regimen Lessons learned from CTB countries II 5. Preparing national plan helps to identify all components and dividing tasks among partners 6. Preparation of introduction sites should be simultaneous Diagnost with preparations at national level ics 7. Specific needs for children Treatme and adolescents with TB should be considered nt monitori ng Treatment 8. Coordination with partners is essential regimen • Common approach • Coordinated procurement • Complementary activities Acknowledgements KNCV • Susan van den Hof • Agnes Gebhard • Ieva Leimane • Nick Blok • Maria Idrissova • Bakyt Myrzaliev • Sandra Kik • Edine Tiemersma • Fraser Wares • Job van Rest • Hadi Qawasmeh • Marcela Tommasi • Michael Kimerling PATH • Katya Gamazina • Olga Pavlova • Nina Zherebko • Aleksey Bogdanov Acknowledgements • rGLC/Europe members and consultants • NTP’s of Member States • Stop TB partnership GDF • KNCV and Challenge TB Project • MSF