Transcript d4T/3TC/NVP Weight Band dosing

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($)
d4T REGIMEN
COST per DAY ($)
BRAND GENERIC BRAND GENERIC
2005
2.00
1.50
1.40
1.30
2006
1.80
0.60
1.40
0.50
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 ($)
BRAND
GENERIC
2005
42.00
39.00
2006
42.00
15.00
FDC
3-7$
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
Demand
Forecast
Availability
Patents &
Registration
Funding
Procurement / Distribution
Systems
Compliance
1
2
3
4
5
?
?
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/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 ?
THE GSK DILEMMA (copied as fair use )
Manufacturing plan and timeline …
•
•
•
•
•
Scale up batch
GSK Regulatory submission prep
Regulatory authorities approval
Validation
Artwork/Supply
+ 5 months
+ 1 month?
+ unknown
+ 5 months
+ 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
Demand
Forecast
Availability
Patents &
Registration
Funding
Procurement / Distribution
Systems
Compliance
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 ?
New product
Generic equivalent
Efficacy
prove equivalence
Safety
prove equivalence
Product quality
establish
Product stability
establish
• Has adult FDCs passed the hurdle in the US or
Europe ?
– What is the status of adult FDCs under the PEPFAR initiative ?
d4T/3TC/NVP Weight Band dosing
(UNICEF/WHO November 2004 consultation)
Weight band (kg)
d4T
3TC
NVP
5-6.9
1 mL BID
2 mL BID
4 mL BID
7-9.9
15 mg cap BID
3 mL BID
6 mL BID
10-11.9
15 mg cap BID
4 mL BID
½ NVP tab BID
12-14.9
15-16.9
17-19.9
20-24.9
25-29.9
30-34.9
35-40
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
1 30 mg d4T/3TC/NVP tab BID OR
1 30 mg d4T/3TC tab BID plus 1 NVP tab BID
1 40 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