Access to paediatric ARV formulations

“Limitations due to regulations”

Experience from the field

MSF

Limitations due to regulations

• Prequalification – disqualification • Registration – marketing• Patents• Local distributors• Price • Lack of FDC due to lack of information

(Pharmacokinetics, homogeneity – stability tests, bioequivalence,…) • Other: Stiff regulation, poor stock management,…

Factors affecting access to paediatric ARV formulations

Examples from the field

AZT: 100 mg caps, syrup

• Thailand– 100 mg caps and syrup registered, not patent protected and

generically produced (GPO Thailand)

– On the field 100 mg caps often lacking (poor stock management, stiff regulations)

• Malawi– 100 mg caps registered and patent protected

– no price reduction offered for this formulation by originator

3TC: tablet 150 mg, syrup• Thailand

– Syrup and tablet: registered, not patent protected and paediatric formulation (scored tablet, syrup) available generically.

– Only syrup provided within National ARV program but children prefer tablets!

• Malawi– 3TC 150 mg tablet Cipla (scored) temporarily dequalified, – no more scored formulation available (Ranbaxy and Glaxo

are not scored). – We could be obliged to use non-qualified drugs

d4T 15, 20 mg and syrup

• Thailand– Syrup and tablet: registered, not patent protected and

paediatric formulation available generically (Syrup, 15 and 20 mg caps)

• Malawi– 15 mg is not marketed nor registered by local

distributor– Storage syrup is problematic (no fridge, no electricity)– Opened capsules can only be stored for 1 day– Grandmothers?

ddI

• Thailand– Patent: Court case challenging breath of patent delaying

production of generic version– CL not applied (political pressure)– Patent was revoked (out court agreement)– ddI 25, 50, 100 and 200 mg sachets now available (but

SE, disclosure)– Scored tablets of 50, 125 and 200 mg produced soon– Enteric coated: originator applied for patent but not

issued (yet), objection from generic producer (pending)

ddI (2)

• Malawi– Only 100 mg (generic) registered – 25 and 50 mg not available– Generic 25, 50 and 100 mg are not WHO pre-

qualified

NVP: syrup, 200 mg tablet

• Thailand– Patent for syrup formulation under

investigation – Generic formulations = dry powder

• Malawi– Patent ?? (under study)– Generic syrup available in MSF setting (huge

quantity)– Only Ranbaxy scored

EFV: syrup, 50 mg caps

• Thailand– 50 mg was registered but not marketed (not

distributed by local supplier)– syrup is not available– 600 mg available, still poor availability of 50

mg caps., paediatricians are told to break 600 mg tabs.

EFV: syrup, 50 mg capsThailand

“EFV 50 mg is a luxurious thing. We only have that formulation briefly. The company allow you to change the 200 mg cap to 50 mg cap, but not by mg-per-mg. Meaning that one 200 mg cap, you only can get two to three 50 mg cap. Recently, the MOPH gave us 600 mg cap. Go back to divide the capsule by yourself! Sometimes, I really feel emotional with these drug companies business!”

Paediatric FDC (3TC/d4T/NVP)

• Thailand– is produced but not marketed yet (on the

shelves, stability tests)– GPO drugs are not WHO-prequalified

Paediatric FDCeg.“mini-vir” Thailand

Paediatric FDC (3TC/d4T/NVP)

• Malawi– Not available– Expecting Cipla formulation

Adult FDC (3TC/d4T/NVP)

• Thailand– Registered, produced and marketed (GPO-vir, scored tablets)– Children (> 4 kg) get proportions of tablet, divided in

quarters without NVP supplementation

• Malawi– Generic available but Ranbaxy's FDC temporarily

dequalified– We could be obliged to continue dequalified drugs– Cipla: not scored and not WHO-prequalified

Common sense (guidelines)AZT AZT 3TC 3TC d4T NVP GPO-vir

Dosage 100-120 100-120 4 mg/kg 4 mg/kg 1 mg/kg 120-200

mg/m2 mg/m2 mg/m2

Preparation 10 mg/ml 100 mg caps 10 mg/ml 150 mg tab 30 mg tab 10 mg/ml 30/150/200 mg tab

Dosing Q 12 Q 12 Q 12 Q 12 Q 12 Q 12 Q 12

3-4 kg 4 ml 1/2 1. 5 ml 1/10 tab 1/8 2.5 - 4 ml -

>4-5 kg 4.5 ml 1/2 2 ml 1/8 tab 1/8 3 - 5 ml 1/4

>5-6 kg 5 ml 1/2 2.5 ml 1/6 tab 1/4 3.5 - 6 ml 1/4

>6-7 kg 5 ml 1/2 2.5 ml 1/6 tab 1/4 4 - 6.5 ml 1/4

>7-8 kg 6 ml 3/4 3 ml 1/4 tab 1/4 4.5 - 7 ml 1/4

>8-9 7 ml 3/4 3.5 ml 1/4 tab 1/2 5 - 8ml 1/4

>9-10 8 ml 3/4 4 ml 1/4 tab 1/2 5.5 - 9ml 1/2

>10-12 9 ml 3/4 4.5 ml 1/3 tab 1/2 6 - 10 ml 1/2

>12-14 kg 9 ml 1 5 ml 1/3 tab 1/2 6.5 - 11 ml 1/2

>14-16 kg 10 ml 1 6 ml 1/2 tab 1/2 7 -12 ml 1/2

>16-18 kg 10 ml 1 7 ml 1/2 tab 1/2 8 -14 ml 1/2

>18-20 kg 12 ml 1 1/2 8 ml 1/2 tab 3/4 9 - 15 ml 3/4

>20-25 kg 14 ml 1 1/2 9 ml 3/4 tab 3/4 10 - 17ml 3/4

>25-30 kg 15 ml 1 1/2 10ml 3/4 tab 1 11 -18 ml 3/4

>30-35 kg - 2 - 1 1 12 - 20 ml 1

LPV/r

• Thailand– Patent protected, very expensive– Only available through clinical trials– Can Thailand apply for the offered price

reduction? – (cfr China: 8000USD versus 500)

Paediatric formulations are expensive

Evolution on price for pediatric treatment according to the weight

0200400600800

100012001400

7 kg 10 kg 14 kg 20 kg 25 kg 30 kg 60 kg

Weight (Kg)

US

$/ye

ar

best generic

originator

Paediatric formulations are expensive

Cost of children (20kg) treatment per year ($) using adult tablets or oral solutions:

Decreasing cost, increasing complexity?

224566

1'706

631

Using oral solutions. Using adult tablets orcapsules.

USD/y generic

USD/y originator offer

7.6 times

Conclusions

• Procurement and supply management at program level is very complicated

• Boost pre-qualification of paediatric formulations (matter of priorities)

• National authorities should fast-track registration– Context: lack of commercial interest

• Prices reductions should be offered in a systematic, simple way

• Countries should be encouraged to apply ”Doha”.• We need paediatric FDC urgently.

Conclusions

• We are asking manufacturers to develop appropriate formulations (chocolate) and to register and market them at cost or low price… and there is no market!!!

• We need also political commitment from UN (WHO, UNICEF), donors, national governments