What do we mean with ‘ there is no access to Paediatric ARV Formulations ’ ?

CURRENT STATUS Formulations exist, and situation has improved in 2005 WHO prequalification normalised, formulations back in list FDA approval for PEPFAR procurement –generic zdv, d4T, lamivudine, nevirapine liquids –cost of nevirapine regimen reduced ( ± 10 kg scenario ) ZDV REGIMEN COST per DAY($) d4T REGIMEN COST per DAY ($) BRANDGENERICBRANDGENERIC

If there is access to Paediatric ARV Formulations, what should we be saying about it ?

CURRENT STATUS Formulations exist, and situation has improved in 2005 Need for a ‘public health friendly’ formulations; twice a day dosing, ideally FDC Adapting adult formulations to be split ( GSK ) Paeds FDCs exist, but not yet commercially available – 3 – 4 dispersible stavudine formulations – pwd for suspension zdv / 3TC / nvp – granules in 5mg, 10mg etc d4T REGIMEN COST per MONTH ($) BRANDGENERIC FDC3 - 7 $

Why can we not immediately start the procurement of these products ?

Main complexities in procurement of ARVs lie in international / national law, registration, availability, secure supply chain systems and patient compliance Forecast Funding Patents & Registration Procurement / Distribution Systems Compliance Demand Availability ? ?

What is best ? Shall we go for existing adult formulations and promote scoring ?

THE GSK DILEMMA Re-introducing 3 adult formulations as split tablets … Commercially not viable to introduce scored formulations in ACCESS countries only; –has to file improved formulations in the US, EU Many developing world regulators require a CPP supplied by (a) developed world/source country or (b) other country that approved dossier Development of scored tablets –Combivir tablet: High priority –Epivir (3TC) 150mg tablet, Ziagen (ABC) 300mg tablet to follow based on experiences

THE GSK DILEMMA Regulatory requirements to introduce scored tablets … Challenges: –ZDV twice a day in children, compared to 3, 4 times a day –ZDV in mg/kg vs. mg/m² Regulatory approval is required for changes in the formulation and label –Addition of score line –Clinical support of dosing  Scored Combivir (requires agreement on twice daily dosing of zidovudine for pediatric patients)  Combivir, Epivir, Ziagen (requires agreement on body weight range for dosing with one- half of a tablet)

THE GSK DILEMMA (copied as fair use ) Regulatory requirements to introduce scored tablets … The proposed plan for development and registration of scored tablets of these antiretroviral products has to be scientifically reasonable and appropriate, and depends on: –The physical-chemical properties of the drugs –The drug loading per product –Qualitative similarities among each of these products –The pharmacokinetic properties of the drugs –The long-term stability of current products

THE GSK DILEMMA (copied as fair use ) Regulatory requirements to introduce scored tablets … No direct comparison of zidovudine twice daily to zidovudine three or four times a daily. –But, adult dosing of zidovudine BID has proven track record. Is conversion from mg/m 2 to mg/kg feasible ? –Arguments based on setting appropriate age breakpoints –Pharmacokinetic evidence allows extrapolation that zidovudine BID would show comparable efficacy to zidovudine TID at equivalent daily doses in pediatrics. Partial clinical confirmation exist –PK confirmatory trial to confirm appropriateness of mg/kg conversion and appropriate exposures for BID dosing ?

THE GSK DILEMMA (copied as fair use ) Manufacturing plan and timeline … Scale up batch+ 5 months GSK Regulatory submission prep + 1 month? Regulatory authorities approval+ unknown Validation + 5 months Artwork/Supply+ 4 months Total scale up to supply 15 months + approval time ( meeting with drug regulators took place in Sept 2005; sounds feasible )

What is best ? Shall we go for new FDCs and introduce a whole supply line for kids ?

Main complexities in procurement of ARVs lie in international / national law, registration, availability, secure supply chain systems and patient compliance Forecast Funding Patents & Registration Procurement / Distribution Systems Compliance Demand Availability Can paediatric FDC’s pass the hurdle ?

CAN PAEDIATRIC FDCs pass the hurdle …… Are the paediatric FDCs new products, or can they be regarded as generic copies of something ? Has adult FDCs passed the hurdle in the US or Europe ? –What is the status of adult FDCs under the PEPFAR initiative ? New productGeneric equivalent Efficacyprove equivalence Safetyprove equivalence Product qualityestablish Product stabilityestablish

d4T/3TC/NVP Weight Band dosing ( UNICEF/WHO November 2004 consultation) Weight band (kg)d4T3TCNVP mL BID2 mL BID4 mL BID mg cap BID3 mL BID6 mL BID mg cap BID4 mL BID½ NVP tab BID ½ 30 mg d4T/3TC/NVP tab BID OR ½ 30 mg d4T/3TC tab BID plus ½ NVP tab BID ½ 40 mg d4T/3TC/NVP BID plus ½ NVP tab QD OR ½ 40 mg d4T/3TC tab BID plus 1 NVP tab in AM and ½ NVP tab in PM mg d4T/3TC/NVP tab BID OR 1 30 mg d4T/3TC tab BID plus 1 NVP tab BID mg d4T/3TC/NVP tab BID plus OR 1 40 mg d4T/3TC tab BID plus 1 NVP tab BID

CAN PAEDIATRIC FDCs pass the hurdle …… Are the paediatric FDCs new products, or can they be regarded as generic copies of something ? –What data exist, and what data need to be generated to establish efficacy ? –What data exist, and what data need to be generated to establish safety ? Product quality and stability in adult formulations have passed the WHO prequalification Suppliers of paediatric FDCs have indicated that they have submitted to WHO prequalification ; timeline 2006