challenges in developing age-appropriate formulations for ...€¦ · • stabilizing excipients,...

Challenges in Developing Age-appropriate Formulations for

Neglected Tropical Diseases

Daniel Schaufelberger, PhD

IQ Consortium, Pediatric Working Group Webinar Series

20 November 2019

IQ PWG Webinar 20 Nov 2019 Schaufelberger Consulting LLC 1

Outline

- Neglected Tropical Diseases

- Products, Manufacturing, Supply Chain

- Regulatory Processes

- Organizations

- Examples- Soil Transmitted Helminth Infections

- Schistosomiasis

- Learning from others

- Q&A


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

IQ PWG Webinar 20 Nov 2019

Mycetoma, chromoblastomycosis and other deep mycosesOnchocerciasis (river blindness)RabiesScabies and other ectoparasitesSchistosomiasisSoil-transmitted helminthiasesSnakebite envenomingTaeniasis/CysticercosisTrachomaYaws (Endemic treponematoses)

Buruli ulcerChagas diseaseDengue and ChikungunyaDracunculiasis (guinea-worm disease)EchinococcosisFoodborne trematodiasesHuman African trypanosomiasis (sleeping sickness)LeishmaniasisLeprosy (Hansen's disease)Lymphatic filariasis

Schaufelberger Consulting LLC 3

http://www.who.int/neglected_diseases

https://www.who.int/neglected_diseases/diseases/mycetoma-chromoblastomycosis-deep-mycoses/en/

https://www.who.int/onchocerciasis/en/

https://www.who.int/rabies/en/

https://www.who.int/neglected_diseases/diseases/scabies/en/

https://www.who.int/schistosomiasis/en/

https://www.who.int/intestinal_worms/en/

https://www.who.int/snakebites/en/

https://www.who.int/taeniasis/en/

https://www.who.int/trachoma/en/

https://www.who.int/yaws/en/

https://www.who.int/buruli/en/

https://www.who.int/chagas/en/

https://www.who.int/denguecontrol/en/

https://www.who.int/dracunculiasis/en/

https://www.who.int/echinococcosis/en/

https://www.who.int/foodborne_trematode_infections/en/

https://www.who.int/trypanosomiasis_african/en/

https://www.who.int/leishmaniasis/en/

https://www.who.int/lep/en/

https://www.who.int/lymphatic_filariasis/en/

Neglected Tropical Disease (NTD)


www.cdc.gov/globalhealth/ntdNTD Factsheet

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


http://www.cdc.gov/globalhealth/ntd

Type of Products


New Molecular Entities

Worldwide Development

1) Adult -> Pediatrics

2) Pediatrics = primary indication

Included in development for

US/EU markets

Stringent Regulatory Authorities,

Regulated with PIPs, PSPs

Regional/local approach

New Formulation

Better, age-appropriate formulation

Generic market (Rx or OTC)

WHO list of Essential Medicines

Patented Off-Patent

Small Molecules

Biologics/

Biosimilars

Vaccines


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

- 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)


Source: www.EuPFI.org

http://www.who.int/

http://www.eupfi.org/

Dosage Forms

- Trend towards ORAL SOLIDS

- Dispersible oral dosage forms

- Granules (Sprinkle)

- Minitablets

- Suppositories, e.g. artesunate 100 mg,

WHO prequalified, malaria

- Thin Films

- Microneedles

- Avoid dosing devices?

Gerrard et al. (2019) “Innovations in Pediatric Drug

Formulations and Administration Technologies for Low

Resource Settings”


Dosing devices – color coding

Weight bands –> color zones

=> Reduce dosing errors

Epinephrine injection i.m.

WHO List Essential Medicines

www.certadose.com

http://www.certadose.com/

Trend in Dosage Forms: Minitablets

Minitablet (1-3 mm)

Advantages:

- coating (taste masking)

- dispersible (-> NG tube)

- dose flexibility

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


Minitablets Dispensers

www.Balda-medical.de


www.phillipsmedisize.com

www.Novartis.com

http://www.balda-medical.de/

http://www.phillipsmedisize.com/

http://www.novartis.com/

Manufacturing

Development/Clinical

Supplies

• Liquids -> Solids

• Excipients: generally

accepted and available

• Handling, administration:

test concepts


Commercial/Donation

Products

• Large volumes

• Scale-up, batch size

• Reduce costs

• Local manufacturing?

Fluid bed powder granulator/coater ref: www.glatt.com


http://www.glatt.com/

Protect Your Supply Chain!

10-30% of medicines sold in

developing countries are counterfeit

20-90% of antimalarial drugs failed

quality testing (7 African countries)

www.Healthcareglobal.com (accessed Oct 30, 2019)


API

Bulk Product

Packaged Product

Serialization

Anticounterfeiting measures (over/covert)


http://www.healthcareglobal.com/

Rapidly Changing Environment


Temie Giwa-Tubosun, CEO Lifebank Nigeria; Africa Netpreneur Prize 2019 (Jack Ma)

www.netpreneur.africa www.lifebank.ngLinkedIn, Twitter, CNN

WeRobotics: non-profit organization, local training through “flying labs“ “….inclusion of local experts who know how to apply these [drone]

technologies effectively and sustainably” www.werobotics.org

http://www.netpreneur.africa/

http://www.lifebank.ng/

http://www.werobotics.org/

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


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


https://www.who.int/topics/prequalification

WHO Prequalification (PQ)

Process:

- Expression of Interest (EOI) List

- Pre-submission meeting

- Dossier Review

- Screening

- Assessment

- GMP inspections

- Qualification

- Post-qualification variations


- Scope: only for certain therapeutic areas, limited to WHO priority medicines; medicines

are already in WHO Model List Essential Medicines and/or WHO treatment guidelines;

- Pathways:

- Multisource generic products: full review of dossier and inspection of sites by WHO

PQT

- Innovator products and generics approved by stringent health authority (SRA)

- Others, e.g. EMA Article 58 – “EU Medicines for All” – EC No 726/2004

- Quality standards for products worldwide

- Supply chain and distribution in climatic zone IVb

- Stability testing

- API testing at DP manufacturing site

- Dossier follow CTD structure but PQ template for summary modules

- Impact: procurement processes!

- Training offered by WHO


Organizations

- UN: WHO (Better medicines for Children resolutions 2007), UNICEF

- National Health Authorities

- Philanthropic organizations, e.g.

- Bill Gates Foundation/Research Inst.

- Clinton Health Access Initiative

- Wellcome Trust

- Public-Private Partnerships (PPPs), e.g.

- Children Without Worms

- Drugs for Neglected Disease initiative (DNDi)

- GHIT (Japan)

- Schistosomiasis Alliance

- Tuberculosis Alliance


- Academia, Tropical Institutes

- (Global) Public Health organizations

- Patient organizations

- Pharmaceutical Companies- Research based

- Generics

- Pediatric focused:- IQ Consortium, Pediatric Working Group

- European Paediatric Formulation Initiative (EuPFI)

- Indian Paediatric Formulation Initiative

Multiple organizations for POLICY, FUNDING, DEVELOPING & MANUFACTURING, DISTRIBUTION/DONATION



Access to Medicine

Foundation

Access to Medicine Index

www.Accesstomedicinesfoundation.org

Assessments/Rankings

http://www.accesstomedicinesfoundation.org/

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%

local STH prevalence; Review by Majid et al (2019)

- Donations: mostly albendazole and mebendazole; future

need for NMEs

Ascaris (roundworm)


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


/wikipedia/commons/b/b3/Mebendazol.svg

Schistosomiasis

Ref: DPRC Hospital & Diagnostic Lab, Dhaka www.dprcbd.com

Ref: www.si.edu

Schaufelberger Consulting LLC IQ PWG Webinar 20 Nov 2019 19

• 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)

• Clean water, sanitation and hygiene

Praziquantel Pediatric


Pediatric Praziquantel Consortium started

pivotal Phase III study in Kenya

“The availability of a pediatric medication is essential to address the

medical need of infected preschool-age children. Our investment today

will secure our future generation”

Dr. Maurice Odiere, PI, Kenya Medical Research Institute (KEMRI)

"Limited access to medical services is a challenge for developing

countries facing poverty. We wish to address it together through this

new collaboration“

Dr. Jutta Reinhard-Rupp, Head of the Global Health Institute, Merck

• Merck KGaA (Germany)• Astellas Pharma Inc. (Japan)• Swiss Tropical & Public Health Institute

(Switzerland)• Lygature (The Netherlands)• Farmanguinhos (Brazil)• Schistosomiasis Control Initiative (UK)• Kenya Medical Research Institute (Kenya)• Université Félix Houphouët-Boigny (Cote

D'Ivoire).www.pediatricpraziquantelconsortium.com


http://www.pediatricpraziquantelconsortium.com/

Praziquantel Pediatric

Ref: www.pediatricpraziquantelconsortium.com


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

http://www.pediatricpraziquantelconsortium.com/

Global Schistosomiasis Alliance

“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

Mission: Eliminating schistosomiasis as a public health problem in partnership


http://www.eliminateschisto.org/

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


Learning from HIV/AIDS

Multiple Challenges Pediatric Dosage Forms

- Tablet size (!); fixed-dose combinations 2-4 actives!

- 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


“4-in-1” granules – photo by DNDi

https://www.dndi.org/2019/media-centre/news-views-stories/news/study-for-a-child-friendly-hiv-treatment-begins-in-uganda/

https://apps.who.int/iris/bitstream/handle/10665/273151/9789241514361-eng.pdf?ua=1

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


Summary

Age-appropriate formulations NTDs:

• Manage, reduce complexity

• Supply chain; local manufacturing

• Access/Costs

• Solids

• WHO prequalification

• Partnerships


Selected ReferencesBaert 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)


https://doi.org/10.1371/journal.pntd.0006940

THANK YOU!

QUESTIONS?

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