1. Elaine Abrams and Carlo Giaquinto
Acceleration part 1: Prioritization and clinical research of priority formulations
Elaine Abrams and Carlo Giaquinto

2. Disclosure Relations that could be relevant for the meeting
Company names
Sponsorship or refund funds
CG; ViiV healthcare, J&J, Gilead
Payment or other financial remuneration
CG: AB ViiV.
EA: Viiv, Merck
Shareholder rights
N/A
Other relations
Reference:

3. Prioritization and optimal research are the critical initial steps for acceleration

4. Developing ARVs for children requires addressing unavoidable complexities
HIV natural history is different
Higher mortality and VL in younger children
HIV affects neurodevelopment and growth
Growth and puberty: dosing the same drug in a changing body and a changing brain
Drug metabolism is different from adults and can heavily depend on genetic polymorphisms (i.e. EFV)
Selection of drug resistance as a result of PMTCT exposure
Key comorbidities that impact drug use, tolerability, and toxicity in SSA (TB, malaria, malnutrition, anemia, etc.)
Palatability and ease of administration are critical to support adherence

5. Access to paediatric drugs takes too long…
SRA approval
Adults
Children
DELAY
Tenofovir DF
2001
2010
9 years
Atazanavir
2003
2014
11 years
Darunavir
2006
2011
5 years
Raltegravir
2007
2013
6 years
Rilpivirine NA ?
Elvitegravir
2012
Dolutegravir
2017 (partial)
4 years
TAF (FDC)
2016
EACH DRUG IS REGISTRED FOR DIFFERENT AGE GROUPS Carlo I think you can say that when you talk about this
Burger and van Rossum. Adapted from Improved labelling of antiretrovirals for paediatric use. Lancet HIV. October 2016.
Time from first approval in adults to full approval in children takes on average 5-9 years
BUT we don’t want everything…only what has the highest potential for public health impact

6. Paediatric ARV Drug Optimization List
Here we can emphasize the consistensy of the messaging and how drugs have graduated from long term to medium term priorities

7. PADO3 Implementation considerations
DTG single: 10 mg scored dispersible tablets remain the priority meantime 50 mg scored tablet could accelerate generic availability to children >15 kg.
DRVr: 120/20 mg tablet remains a priority and incentives are being explored.
DTG/ABC/3TC: 5/60/30 mg most likely dosing to be validated by the end of the year once 1093 is completed .
F/TAF and DTG/XTC/TAF: urgent review of originator timelines, preliminary feasibility work ton the FDC to be undertaken.
RAL: 5 mg (instead of 50 mg) scored dispersible to better reflect its added value for neonates and infants.
AZT/NVP: still a priority, but probably less urgently needed than other products.
DTG/DRVr: Concerns on the size and feasibility of the FDC (confirmed by CADO3) de-prioritized until further clinical trials support the strategy.
PADO3 Implementation considerations
The reason for keeping this to say that we dont just come up with the list but also actively reviewed it as we have done last december to develop some implementation considerations and provide some level of internal prioritization within the list in a way that is consistent with the expected evolution of policies....transition to next slides

8. Enabling alignment with policy development
GDG
Develops evidence based recommendations accounting for product development
PADO
Prioritize based on existing WHO Guidelines but also provide a vision for policy change
Guidance on product development to Industry
Indeed PADO does enable effective alignment between formulation development and expected policy change. We do that by reviewing evidence and providing advice to the WHO GDG as happened this last Dec. Now that the recommendations were revised we will consider them for our new round of prioritization in Dec 2018
IMPLEMENTATION

9. PAWG enabling role PAWG enabling role
Once we are done with the PADO prioritization we hand over to PAWG which plays as a critical technical enabler across prioritization, clinical research, development and regulatory approval
Defines standards for research to enable accelerated paediatric ARVs development
Advise WHO on clinical and pharmacokinetic issues related to the use of ARVs in children
Offers scientific advice to stakeholders involved in the development of paediatric ARVs

10. Closing the loop on paediatric development plans
PAWG
Industry
SRAs
PAWG to provide technical opinion on PIP/PSPs to regulators and promote further focus and alignment between agencies
Industry to seek PAWG technical advice to inform submission and implementation of PIP/PSPs that address real need
Move up
Better paediatric development plans completed and approved more quickly

11. Optimizing trial design for faster paediatric development plans
Just point out the concept
Penazzato et al., CID, 2017

12. Key principles to accelerate research to inform development
Getting studies right from the very beginning
Enrolling more rapidly (in parallel, not sequentially) and based on weight
Include adolescents in adult registrational trials
Maximizing the use of PK/PD studies and PK modelling
Innovating trial design (ie adaptive designs)
Collaboration between networks and investigators
You may want to check from the paper if anything you would like to add
Penazzato et al., CID, 2017

13. From a sequential to a parallel approach
Registrational trial
Dosing
Safety
Strategic trial
Efficacy
Simplified dosing
TB cotreatment
Guidelines introduction
Age specific recommendations
WHO weight band dosing
From a sequential to a parallel approach
2011
Dolutegravir
2021
P1093
DTG dosing and safety
4 weeks to <18 months in 5 cohorts
Coated tablets, granules and 5mg dispersible tablets
ODYSSEY
Enrolment of subjects following first 1093 cohorts
PK sub-studies to inform dose simplification
TB PK to investigate DTG BD plus Rifampicin
Guidelines Update
Extrapolated efficacy from adults
Safety and PK based on P1093
Simplified dosing based on ODYSSEY
Overarching rolling recommendation
2018
This will allow use of DTG in children 3 years earlier with potentially more children with access to a more effective regimen
Cohort I: Adolescents ≥12 to <18 years of age (Tablet formulation)
Cohort IIA: Children ≥6 to <12 years of age (Tablet formulation)
Cohort IIB: Children ≥6 to <12 years of age (Granules)
Cohort III - DT: Children ≥2 to <6 years of age (Dispersible Tablet)
Cohort IV - DT: Children ≥6 months to <2 years (Dispersible Tablet)
Cohort V - DT: Infants ≥4 weeks to <6 months (Dispersible Tablet)

14. Looking forward
Prioritization and clinical research remain the first critical steps on making better drugs available for children
Solutions to focus and accelerate the research undertaken are being tested and appear promising
Open and transparent communication with industry and regulators is of critical importance
PADO3 prioritization prompted discussion on TB and Hep and PADO like approaches for Hep and TB are being planned
When moving beyond HIV, priorities will need to be identified in collaboration with other global initiatives (e.g. DNDi for AMR etc)
“GAP-f as a model for rapid drug development is other “orphan” areas including potentially also Non Communicable Diseases” I removed this point because in these presentation we need to focus on prioritization and research rather than GAPf in general