Priority essential medicines: identifying products. Dr Suzanne Hill September 2010

Transcription

1 Priority essential medicines: identifying products Dr Suzanne Hill September 2010

2 The problem looks like this

3 Robertson, Forte, Trapsida & Hill. Bull WHO 2009

4 Robertson, Forte, Trapsida & Hill. Bull WHO 2009

5 Or this

6 WHO-UNICEF Plan, 2006 Work on a global project to make paediatric medicines a priority: Add missing essential formulations to the Model list in 2007; advise on doses Develop EML for children (2007-8) Update treatment guidelines (2007-9) Develop paediatric prescribing information a formulary Develop effective methods for provision of information at the point of care Collaborate with regulatory authorities to encourage appropriate drug development and approval processes in all regulatory authorities Develop quality standards for paediatric medicines Advocate for the development of paediatric medicines by the industry Develop a system for enhancing safety monitoring of medicines in children Provide guidance on procurement and supply of paediatric medicines

7 Essential medicines for children World Health Assembly Resolution 'Make Medicines Child Size' Normative work, research needs Medicines for specific conditions Specifications for dosage forms Improving use of medicines in children National implementation

8 Preliminary consultation September 6-7 Participants from academia, procurement, donors, industry, other stakeholders Review of possible priority essential medicines for children Identify existing products that can be used Identify what is mssing Next steps

9 principles To treat: burden of disease, based on current treatment guidelines Clinical approach Weight based dosing for preference Consideration of different prescribers Strategies to enhance adherence Simplified dosing regimens Technology feasible Consideration of regulatory issues

10 Background Main burden of disease in children Neonatal infections Diarrhoea Pneumonia Malaria HIV TB

11 Global Causes of Child Deaths Black et al. Lancet, 2010 WHO. The World Health Statistics 2010 Black et al. Lancet, % of under five deaths are associated with undernutrition

12 Diarrhoea Medicine Form and strength Pack size Regimen ORS As specified (low osmolarity) 1 litre, 200 and 500 ml According to the dehydration status/guidelines Zinc Sulphate 10 or 20 mg FSOD 10 of either Once daily for 10 days NOTE : combination product would be appropriate

13 Pneumonia - Low HIV setting Category Medicine Form and strength Pack size Regimen Pneumonia (Fast breathing) Oral amoxicillin 250 or 500 mg FSOD 10 of either Twice daily, 5 days Severe pneumonia (Chest Indrawing) Oral amoxicillin 250 or 500 mg FSOD 10 of either Twice daily, 5 days Very severe pneumonia (danger signs) Oxygen, Ampicillin + gentamicin or ceftriaxone Cylinder/oxygen concentrators -500 mg or 1 G -20 mg or 40 mg/ml 500 mg or 1 G Variable Pack?? Single dose As needed Variable daily x 10 days mg/day 5 days NOTE: cotrimoxazole may be an alternative for pneumonia/fast breathing

14 Pneumonia: High HIV setting Category Medicine Form and strength Pack size Regimen Pneumonia (Fast breathing) Oral amoxicillin 250 or 500 mg FSOD 10 of either Twice daily, 5 days Severe pneumonia (Chest Indrawing) Ampicillin + gentamicin or ceftriaxone -500 mg or 1 G -20 mg or 40 mg/ml 500 mg or 1 G Pack?? Single dose Variable daily x 10 days mg/day 5 days Very severe pneumonia (danger signs) Oxygen, Ampicillin + gentamicin or ceftriaxone Cylinder/oxygen concentrators -500 mg or 1 G -20 mg or 40 mg/ml 500 mg or 1 G Variable Pack?? Single dose As needed Variable daily x 10 days mg/day 5 days

15 Malaria Category Medicine Form and strength Pack size Regimen Malaria (uncomplicated) Artemeter +Lumefantrine (FDC) Artesunate + amodiaquine (FDC) Variable FSOD see treatment guideline For 3 day treatment 6x1 & 6x2 (30 blisters per box) 3 (25 blisters per box) Daily or twice daily x 3 days Malaria (severe or pre-referral) Artesunate Quinine hydrochloride 60 mg Injection 152 mg/ml injection?50/pack 100 ampoules/pack 2.4 mg/kg iv, 3 doses, then daily; 20mg infusion then 10mg/kg 8 hrly Artesunate rectal 50, 100, 200 mg Suppositories 6 per pack 10 mg/kg dose

16 HIV Category Medicine Form and strength Pack size Regimen HIV treatment AZT+3TC+NVP (< 3 years) AZT+3TC+EFV (>3 years) mg+50 mg FDC tablet, scored the 2nd one not available 30 days Once or twice daily HIV - Prophylaxis Isoniazid Cotrimoxazole 100 mg TMP 80+SMX 400mg; TMP 20+SMX 100 mg 30 days 30 days 10 mg/kg mg TMP /day age related doses

17 HIV ARV Prophylaxis Category Medicine Form and strength Pack size Regimen Breastfeeding population NVP 15mg once daily (10mg for low birth weight) Strength?? Form?? 30 days Variable according to weight and age Daily from birth until one week after all exposure to breastmilk Non breastfeeding population AZT or NVP 15mg twice daily or 15 mg once daily Strength?? Form?? 15 days? 45 days Variable according to weight and age For 4-6 weeks All exposed infants AZT or NVP 15mg twice daily or 15 mg once daily Strength?? Form?? 15 days? 45 days Variable according to weight and age For 4-6 weeks

18 Neonates Category Medicine Form and strength Pack size Regimen Neonatal sepsis Ampicillin + gentamicin or ceftriaxone Procaine penicillin? -500 mg or 1 G - 20 mg /ml 500 mg or 1 G?? Single dose Single dose -50 mg/kg x2 doses for 1 week and x3 doses for 2-4 wk mg/kg/day in 0-6 days and mg/kg in 7-59 days x mg/kg /day -40,000-60,000 units/kg/day Neonatal care Chlorhexidine Vitamin K Caffeine citrate 4% solution 1 mg/1 ml, 10 mg/ml 20mg/ml injection or oral liquid?? 500 ml Variable Variable Topical application mg x 1 at birth; 5mg/kg/day

19 Miscellaneous Category Medicine Form and strength Pack size Regimen Child survival Vitamin A 100,000 units capsule variable 100,000 units every 6 months Pain Paracetamol Variable FSOD 5-10 days supply 15 mg/kg 4-6 hours Morphine 10 mg oral dosage form 5 days Variable every 6 hours 10m/ml injection

20 TB Category Medicine Form and strength Pack size Regimen Treatment intensive phase, 2 months Isoniazid Rifampicin Pyrazinamide ethambutol 4 component FDC, flexible oral solid dosage form containing days In this does, weight based dosing, once daily Or product with same ratio Treatment, continuation phase, 4 months Isoniazid Rifampicin Pyrazinamide 3 component FDC, flexible oral solid dosage form containing Or 2 component FDC, flexible oral solid dosage form

21 FULL ASSET PROFILE: Amoxicillin Attribute Worst case BASE CASE Best case Comment Summary Profile Description Objective / Rationale Develop a dispersible amoxicillin product for pediatric patients in the developing world target age range? Dosing Regimen Twice daily Weight based dosing: 2-4kg 0.5 x 250mg tablet bd 5-9kg 1 x 250mg tablet bd 10-20kg 1 x 500mg tablet bd 21-30kg 2 x 500mg tablet bd Presentation (form and pack size) sachet? Taste-masked, dispersible tablet. Pack size 10 meltaway formulation flavor preferences? Can it be given in breast milk? Strength 250mg or 500 mg Both in packs of 10 Duration of Therapy Quality Standard Scoring 5 days SRA approval - WHO PQ, US FDA, or equivalent yes Packaging Blister packs? Any labeling requirements? Stability/shelf life Estimate Year of Launch Selling Price XX XXX XX Royalties 2 years minimum, zone 4 stability, store at or below X C 3 or more years no cold chain requirements *Prices taken from WHO/UNICEF Sources and prices of selected medicines for children Median price (USD) per dose, unless otherwise stated. XXX Current amoxicillin price*: 250 mg dispersible 0,022; 500 mg capsule 0,032; 250 mg capsule 0,018 will developing company get to charge "reasonable" or get other market advantage?

22 Weight based dosing Examples Antiretrovirals First line treatments for TB Amoxicillin

23 Amoxicillin/ cotrimoxazole weight (kg) amoxicillin bd (at least 50mg per day) cotrimoxazole bd (TMP at least 8mg/day) 250 total mg/kg per day 500 total mg/kg per day (TMP) total mg/kg per day (TMP) total per day tabs per dose tabs per dose tabs per dose tabs per dose

24 Strategies to enhance adherence Packaging and labelling Artemether-lumefantrine What pack size for long term treatments? TB, HIV What approach will work for community based administration of antibiotics?

25 Technology/dosage form Oral versus not Stable, long shelf life Avoiding liquids Flexible oral solid dosage form Simplified dosing schedules, weight based dosing

26 Regulatory questions - product Does a change of doing regimen need a change of label? Amoxicillin? What about pack size? 10 versus 21? What about different FDCs without an innovator? HIV, TB?

27 'Sure' ORS But with a smaller sachet and flavour, pack of 10 Zinc 20mg scored dispersible- with ORS ACT(s) Dispersible / FOSD dose optimised see WHO guidelines Artesunate Rectal, and injection (but better) HIV FDC (s) - see WHO guidelines Nevirapine, zidovudine Amoxicillin dispersible, scored 250 and 500, pack of 10 Oxygen TB FDCs next slide Analgesics paracetamol ( dispersible), morphine Vitamin A 100,000 IU

28 Work needed TB FDC correct component strength** Artesunate - injection and rectal mg dose range (10mg/kg) Caffeine citrate standard product, market readiness - 20mg/ml, liquid and injection Chlorhexidine solution, 4% regulatory pathway and patient pack Isoniazid / cotrimoxazole product strength not yet known for prophylaxis (HIV co pack?)

29 Problems -TB rifampicin: 15 mg/kg/d (10 to 20 mg/kg/day) isoniazid: 10 mg/kg/d (10 to 15 mg/kg/day) pyrazinamide: 35 mg/kg/d (30 to 40 mg/kg/day) ethambutol: 20 mg/kg/d (15 mg to 25 mg/kg/d) WANTED - Fixed Dose Combination (FDC) containing rifampicin 250 mg, isoniazid 150 mg, pyrazinamide 400 mg, and ethambutol 250 mg Dose: 0.5 to 2.0 'tablets' per day, 5-30 kg

30 Problems - TB

31 Solutions needed

32 Clinical evidence needed Optimised dosing regimens for Vitamin K? Gentamicin Ampicillin Procaine penicillin Ceftriaxone

33 Priority essential medicines for children Priority Essential Necessary

34 Priority essential medicines for children Necessary Essential Priority

35 Where is my essential medicine?