Challenges in Developing Age-appropriate Formulations for Neglected Tropical Diseases
Daniel Schaufelberger, PhD IQ Consortium, Pediatric Working Group Webinar Series 20 November 2019
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 1 Outline
- Neglected Tropical Diseases - Products, Manufacturing, Supply Chain - Regulatory Processes - Organizations - Examples - Soil Transmitted Helminth Infections - Schistosomiasis - Learning from others - Q&A
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 2 Neglected Tropical Disease (NTD)
Neglected tropical diseases (NTDs) – a diverse group of communicable diseases that prevail in tropical and subtropical conditions in 149 countries – affect more than one billion people and cost developing economies billions of dollars every year. Populations living in poverty, without adequate sanitation and in close contact with infectious vectors and domestic animals and livestock are those worst affected. www.who.int/neglected_diseases
Buruli ulcer Mycetoma, chromoblastomycosis and other deep mycoses Chagas disease Onchocerciasis (river blindness) Dengue and Chikungunya Rabies Dracunculiasis (guinea-worm disease) Scabies and other ectoparasites Echinococcosis Schistosomiasis Foodborne trematodiases Soil-transmitted helminthiases Human African trypanosomiasis (sleeping sickness) Snakebite envenoming Leishmaniasis Taeniasis/Cysticercosis Leprosy (Hansen's disease) Trachoma Lymphatic filariasis Yaws (Endemic treponematoses)
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 3 Neglected Tropical Disease (NTD)
Neglected tropical diseases are a diverse group of tropical infections which are common in low-income populations in developing regions of Africa, Asia, and the Americas. They are caused by a variety of pathogens such as viruses, bacteria, protozoa and helminths. These diseases are contrasted with the big three infectious diseases [malaria, HIV/AIDS, tuberculosis] which generally receive greater treatment and research funding. In sub- Saharan Africa, the effect of these diseases as a group is comparable to malaria and tuberculosis. NTD co-infection can also make HIV/AIDS and tuberculosis more deadly. Ref: Wikipedia www.cdc.gov/globalhealth/ntd NTD Factsheet Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 4 Type of Products
Patented Off-Patent
Small Molecules New Molecular Entities New Formulation
Worldwide Development Better, age-appropriate formulation 1) Adult -> Pediatrics Biologics/ 2) Pediatrics = primary indication Generic market (Rx or OTC) Biosimilars Included in development for US/EU markets Stringent Regulatory Authorities, WHO list of Essential Medicines Vaccines Regulated with PIPs, PSPs
Regional/local approach
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 5 General Requirements
The “usual challenges”: acceptability, palatability, excipients
Plus: - Stability (temperature & humidity); shelf life - Large patient populations -> huge volume forecasts - Suitable packaging for long, fragmented supply chain - Simple instructions for administration, dosing - Mindful of costs -> access Source: www.EuPFI.org - Environmental impact (high volumes) - Consider culture, health literacy, other initiatives e.g. education, sanitation “Guidelines for Medicine Donations” 2010 by WHO & 11 other organizations, Third edition 2011 (www.who.int)
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 6 Dosage Forms
- Trend towards ORAL SOLIDS - Dispersible oral dosage forms - Granules (Sprinkle) - Minitablets - Suppositories, e.g. artesunate 100 mg, WHO prequalified, malaria Dosing devices – color coding - Thin Films Weight bands –> color zones - Microneedles => Reduce dosing errors Epinephrine injection i.m. - Avoid dosing devices? WHO List Essential Medicines Gerrard et al. (2019) “Innovations in Pediatric Drug Formulations and Administration Technologies for Low www.certadose.com Resource Settings”
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 7 Trend in Dosage Forms: Minitablets
Minitablets Dispensers Minitablet (1-3 mm) Advantages: - coating (taste masking) - dispersible (-> NG tube) - dose flexibility www.Balda-medical.de www.phillipsmedisize.com Workshops 2019: - MCERSI/IQ Consortium, Baltimore MD - 11th Annual EuPFI Congress, Malmoe, Sweden Trend/Publications: - Suitable for younger age groups; neonates (?) - Klingmann et al. (Prof. J. Breitkreutz) - Strickley 2019 – review article oral solids
www.Novartis.com Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 8 Manufacturing
Development/Clinical Commercial/Donation Supplies Products • Large volumes • Liquids -> Solids • Scale-up, batch size • Excipients: generally • Reduce costs accepted and available • Local manufacturing? • Handling, administration: test concepts
Fluid bed powder granulator/coater ref: www.glatt.com
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 9 Protect Your Supply Chain!
10-30% of medicines sold in API developing countries are counterfeit Bulk Product Packaged Product 20-90% of antimalarial drugs failed quality testing (7 African countries) Serialization
www.Healthcareglobal.com (accessed Oct 30, 2019) Anticounterfeiting measures (over/covert)
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 10 Rapidly Changing Environment
Temie Giwa-Tubosun, CEO Lifebank Nigeria; WeRobotics: non-profit organization, local training through “flying labs“ Africa Netpreneur Prize 2019 (Jack Ma) “….inclusion of local experts who know how to apply these [drone] www.netpreneur.africa www.lifebank.ng technologies effectively and sustainably” www.werobotics.org LinkedIn, Twitter, CNN
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 11 Regulatory Processes
• EU/US HA submissions • Mandatory, incentives (“stick & carrot”) • Incentives for NTDs • National HA submissions • Regional Harmonization? • African regions • CARICOM (Caribbean) • SEARN (South-East Asia) • Other Processes: • WHO prequalification process • WHO collaborative (registration) procedure; sharing of assessment, inspection reports • Compendia, International Pharmacopoeia
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 12 WHO Prequalification Process (PQ)
WHO Prequalification aims to ensure that diagnostics, medicines, vaccines and immunization-related equipment and devices for high burden diseases meet global standards of quality, safety and efficacy, in order to optimize use of health resources and improve health outcomes.
www.who.int/topics/prequalification
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 13 WHO Prequalification (PQ)
- Scope: only for certain therapeutic areas, limited to WHO priority medicines; medicines Process: are already in WHO Model List Essential Medicines and/or WHO treatment guidelines; - Pathways: - Expression of Interest - Multisource generic products: full review of dossier and inspection of sites by WHO (EOI) List PQT - Pre-submission meeting - Innovator products and generics approved by stringent health authority (SRA) - Others, e.g. EMA Article 58 – “EU Medicines for All” – EC No 726/2004 - Dossier Review - Screening - Quality standards for products worldwide - Assessment - Supply chain and distribution in climatic zone IVb - GMP inspections - Stability testing - Qualification - API testing at DP manufacturing site - Post-qualification - Dossier follow CTD structure but PQ template for summary modules variations - Impact: procurement processes! - Training offered by WHO
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 14 Organizations
- UN: WHO (Better medicines for Children - Academia, Tropical Institutes resolutions 2007), UNICEF - (Global) Public Health organizations - National Health Authorities - Patient organizations - Philanthropic organizations, e.g. - Pharmaceutical Companies - Bill Gates Foundation/Research Inst. - Research based - Clinton Health Access Initiative - Generics - Wellcome Trust - Pediatric focused: - Public-Private Partnerships (PPPs), e.g. - IQ Consortium, Pediatric Working Group - Children Without Worms - European Paediatric Formulation Initiative (EuPFI) - Drugs for Neglected Disease initiative (DNDi) - Indian Paediatric Formulation Initiative - GHIT (Japan) - Schistosomiasis Alliance - Tuberculosis Alliance Multiple organizations for POLICY, FUNDING, DEVELOPING & MANUFACTURING, DISTRIBUTION/DONATION
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 15 Assessments/Rankings
Access to Medicine Foundation
Access to Medicine Index
www.Accesstomedi cinesfoundation.org
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 16 Soil Transmitted Helminth (STH) Infections
- Intestinal worms: hookworms, roundworms, whipworms - High disease burden: 1.5 to 2 billion people affected worldwide (850 million children) - Economic/epidemiologic studies (Michael Kremer, Harvard, Nobel Prize Economics 2019) - Preventive Chemotherapy (PC) or Mass Drug Administration (MDA); WHO recommends MDA if > 20% Ascaris (roundworm) local STH prevalence; Review by Majid et al (2019) - Donations: mostly albendazole and mebendazole; future need for NMEs
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 17 VERMOX® Chewable (mebendazole) 500 mg
- Extend age-range down to one year (London Declaration NTDs) - Administration - Chew or place on spoon/water -> rapidly disintegrating - Formulation: 500 mg active, sweetener (sucralose) and flavor (strawberry) - Clinical study (Silber et al. 2017) - Regulatory pathway: US FDA approval; WHO prequalification (2019) - API testing at FPP manufacturer; polymorph specs for FPP - Partnering: Shaanxi Hanjiang Pharmaceutical (API) and Recipharm (formerly Lusomedicamenta) for finished pharmaceutical product (FPP) - Donation program: replace tablet with chewable tablet; committed to 1 billion doses 2021-25 Janssen/J&J press release April 29, 2019
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 18 Schistosomiasis
Ref: www.si.edu
• Bilharzia • Blood flukes (trematode worms), Schistosoma species • Freshwater snail (host) • 78 countries (mainly in sub-Saharan Africa) • >220 million require treatment (WHO 2017) • Disease leading to chronic inflammation of the organs that can be fatal • Disease causing anemia, stunted growth and impaired learning ability with devastating consequences for the lives of the very young children • Mass Drug Administration (MDA) Ref: DPRC Hospital & Diagnostic Lab, Dhaka www.dprcbd.com • Clean water, sanitation and hygiene Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 19 Praziquantel Pediatric
Pediatric Praziquantel Consortium started pivotal Phase III study in Kenya
“The availability of a pediatric medication is essential to address the • Merck KGaA (Germany) medical need of infected preschool-age children. Our investment today • Astellas Pharma Inc. (Japan) will secure our future generation” • Swiss Tropical & Public Health Institute (Switzerland) Dr. Maurice Odiere, PI, Kenya Medical Research Institute (KEMRI) • Lygature (The Netherlands) • Farmanguinhos (Brazil) • Schistosomiasis Control Initiative (UK) "Limited access to medical services is a challenge for developing • Kenya Medical Research Institute (Kenya) countries facing poverty. We wish to address it together through this • new collaboration“ Université Félix Houphouët-Boigny (Cote D'Ivoire). Dr. Jutta Reinhard-Rupp, Head of the Global Health Institute, Merck www.pediatricpraziquantelconsortium.com
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 20 Praziquantel Pediatric
Current: 600 mg Tablet for school age children + older
New (TPP): • Small, orally dispersible tablet • Take with or without water • Acceptable taste • Stable under Zone IVb conditions • Suitable for 3 month to 6-year old children • Intended for individual case treatment and mass treatment campaigns
Development: • Racemic API -> L-PZQ only, lower dose, reduce bitter taste • D-PZQ = inactive, bitter taste • Clinical program Ph I-III • Product availability target 2022 Ref: www.pediatricpraziquantelconsortium.com Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 21 Global Schistosomiasis Alliance
Mission: Eliminating schistosomiasis as a public health problem in partnership
“Schistosomiasis has a hugely detrimental effect on a child’s mental and physical development. By treating children we are giving them the opportunity to reach their full potential and live healthier, happier lives” Ref: Global Schistosomiasis Alliance (GSA) - www.eliminateschisto.org Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 22 Learning from “The Big Three”
• “Big Three” = HIV/AIDS, Malaria, Tuberculosis • Worldwide focus; not restricted to Low- and Middle-Income Countries (LMIC) • Various funding models; public-private partnerships • Philanthropic organizations starting drug discovery & development • CMC: the same challenges -> Learnings
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 23 Learning from HIV/AIDS
Multiple Challenges Pediatric Dosage Forms - Tablet size (!); fixed-dose combinations 2-4 actives! “4-in-1” granules – photo by DNDi - Ratio of active ingredients may differ across age groups - “4-in-1”: abacavir/lamivudine/lopinavir/ritonavir, taste-masked granules, sprinkle capsule children < 3 years (DNDi, Cipla Ltd) https://www.dndi.org/2019/media-centre/news-views-stories/news/study-for-a-child-friendly-hiv-treatment- begins-in-uganda/ Toolkit for Research and Development of Paediatric Antiretroviral Drugs and Formulations WHO and UNITAID in collaboration with IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) network, PENTA (Paediatric European Network for Treatment of AIDS) foundation and experts from the Paediatric Antiretroviral Working Group – Module 5 on “Acceptability” - 2018 https://apps.who.int/iris/bitstream/handle/10665/273151/9789241514361-eng.pdf?ua=1
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 24 HIV – Switch Oral to LA Injectable
• Rilpivirine 300 mg/ml and Cabotegravir 200 mg/ml injectable • Rilpivirine = TMC278 = EDURANT® (NNRTI) - Tablets 25 mg once-a-day (Janssen) • Cabotegravir = new molecular entity = CABENUVA® (INI) (ViiV Health Care) • Long-acting injectable nanosuspension (rilpivirine) • Physical/pharmacological properties, Baert et al. 2009 • Stabilizing excipients, tolerability, Chamanza et al. 2017 • Once-a-month, i.m. injection • LA formulation potential to improve convenience • PIP EMA decision P/0312/2017; studies in 12-18 y; 2-12 y • NDA and MAA submitted 2019
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 25 Summary
Age-appropriate formulations NTDs: • Manage, reduce complexity • Supply chain; local manufacturing • Access/Costs • Solids • WHO prequalification • Partnerships
Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 26 Selected References
Baert L, van’t Klooster, G, Dries W, Francois M, Wouters F, Basstanie E, Iterbeke K, Stappers F, Stevens P, Schueller L, Van Remoortere P, Kraus G, Wigerinck P, Rosier J “ Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment, Eur J Pharm Biopharm, 72 502-508 2009)
Bourgeois FT & Kesselheim “Promoting Pediatric Drug Research and Labeling-Outcomes of Legislation”, NEJM, 381(9) 875-881 (2019)
Chamanza R, Darville, N, van Heerden M, and De Jonghe S, “Comparison of the Local Tolerability to 5 Long-acting Drug Nanosuspensions with Different Stabilizing Excipients, Following a Single Intramuscular Administration in the Rat” Toxicol Pathol 1-17 (2017)
Gerrard SE, Walsh J, Bowers N, Salunke S, and Hershenson S, “Innovations in Pediatric Drug Formulations and Administration Technologies for Low Resource Settings” Pharmaceutics, 11 518-529 (2019)
Klingmann V, “Acceptability of Mini-Tablets in Young Children: Results from Three Prospective Cross-over Studies” AAPS Pharm Sci Tech, 18 (2) 263-266 (2017)
Klingmann V, Linderskam H, Meissner T, Mayatepek E, Moeltner A, Breitkreutz J, Bosse HM, “Acceptability of Uncoated Minitablets in Infants and Toddlers: A Randomized Controlle Trial” J Pediatr 201 202-207 (2018)
Majid MF, Kang SJ, Hotez PJ, “Resolving "worm wars": An extended comparison review of findings from key economics and epidemiological studies” PLoS Negl Trop Dis 13(3) (2019): e0006940. https://doi.org/10.1371/journal.pntd.0006940
Schaufelberger D “Trends and Opportunities in Pediatric Drug Development”, BioPharm Asia, March-April, 38-41 (2015)
Silber SS et al. “Efficacy and Safety of a Single-Dose Mebendazole 500 mg Chewable, Rapidly-Disintegrating Tablet for Ascaris lumbricoides and Trichuris trichiura Infection Treatment in Pediatric Patients: A Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study” Am J Trop Med Hyg 97(6) 1851-1856 (2017)
Strickley RG “Pediatric Oral Formulations: An Updated Review of Commercially Available Pediatric Oral Formulations Since 2007”, J Pharm Sci 108 1335-1365 (2019)
Walsh J et al. “Patient acceptability, safety and access: A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations” Int J Pharm, 536(2) 547-562 (2018)
Zajicek A et al. “A Report from the Pediatric Formulation Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms” AAPS Journal, Vol. 15 (4) 1072- 1081 (2013) Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 27 THANK YOU!
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