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

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

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

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

  2. 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

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

  4. CURRENT STATUSFormulations 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

  5. Why can we not immediatelystart the procurementof these products ?

  6. Main complexities in procurement of ARVs lie in international / national law, registration, availability, secure supply chain systems and patient compliance Demand Forecast Availability Patents & Registration Funding Procurement / Distribution Systems Compliance 1 2 3 4 5 ? ?

  7. What is best ?Shall we go for existing adult formulations and promotescoring ?

  8. THE GSK DILEMMARe-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

  9. THE GSK DILEMMARegulatory 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)

  10. 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

  11. 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/m2 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 ?

  12. 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 )

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

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

  15. 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 ?

  16. d4T/3TC/NVP Weight Band dosing(UNICEF/WHO November 2004 consultation)

  17. 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

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