21. Using feedback from the Vatican platform to leverage best practices and make earlier changes to development plans.
22. Sharing clinical development and regulatory plans, as well as enabling generic formulations of a TAF containing pediatric fixed-dose combinations, with submission of a formulation for low-dose f/TAF with unboosted third agents for children over 2 years (14-25kg) by end 2020 and continuing to develop a formulation for 3-25kg older than 4 weeks children.
23. Fulfilling ongoing PSPs and PIPs for capsid inhibitors with collaboration and feedback from the GAP-f partners.
24. Advancing discussions with CHAI and Monell to identify a universal bitter blocker appropriate for pediatric formulations.
43. Through PENTA and IAS CIPHER, work together to develop an enhanced monitoring and safety data platform for new and existing paediatric ARV drugs.
44. Convene or participate in a series of virtual consultations of key stakeholders in 2020-2021 to develop a model and mobilize resources for the platform.
An NDA supplement for low dose F/TAF with unboosted 3rd agents in children ≥ 2 years of age and weighing 14 to <25 kg was submitted to the FDA in March 2021 based on safety and efficacy data from the Genvoya Study GS-US-292-0106; approval is expected by 4Q 2021. The submission was delayed from 4Q 2020 to 1Q 2021 so that full Week 48 data (in addition to Week 24) could be submitted to the agency. Submission to EMA is planned.
A new relative bioavailability study to evaluate an F/TAF dispersible tablet formulation for children aged ≥4 weeks weighing 3 to <25kg is planned to initiate in early 3Q 202.
Filed an application with FDA in March for a low dose tablet formulation of F/TAF and to extend treatment to children 2 years of age and older (14-25kg) and will file with EMA this quarter. Gilead has developed a dispersible tablet formulation of F/TAF and will assess its pharmacokinetics relative to the marketed tablet in a study in 3Q before evaluating it in children 4 weeks and older (3 to <25kg) living with HIV in a clinical study.
37. Prioritize development of low dose F/TAF dispersible tablet and complete investigation of low dose paediatric dose for 15-25kg by end of 2019.
38. Undertake a bioavailability study for dispersible tablets of F/TAF by mid-2019 and begin enrolment of children under 15kg by end 2019, using parallel enrolment of weight bands where feasible.
Safety and efficacy of film-coated low dose F/TAF tablets were studied as part of an unboosted regimen in children (Study GS-US-292-0106) weighing 14-<25 kg and ≥ 2 years of age which experienced some delay due to COVID-19. As per Action 18 above, an NDA supplement containing Wk 24 data will be submitted for approval by FDA in Q4 2020. The commitment was to complete the investigation of the low dose tablet by the end of 2019 – the timing is actually Q3 2020 that Gilead has completed the investigation. There were more screen failures and slower enrollment than anticipated plus the impact of COVID-19 slowed down timelines. Data to support F/TAF dispersible tablet in an unboosted regimen will come from evaluation of children 3kg to < 25 kg taking B/F/TAF in Study GS-US-380-1474 mentioned in Action 15 such that development of the dispersible tablet is prioritized even though there are delays to the formulation of F/TAF as a fixed-dose combination tablet with the need for the ongoing new relative bioavailability study in #38.
The timing of completion of the relative bioavailability study was completion in Aug of 2020. Due to COVID-19, the timing of this phase 1 study was delayed and is now underway. Dosing of children 3-<25 kg with the F/TAF dispersible tablet using boosted third agents (Study GS-US-216-0128) is delayed by a year (from summer 2020 to summer 2021).
Commitments 37 and 38:
Bioavailability study on dispersible tablet should provide data to start enrollment children between 3 and 25kg, which will be divided into 4 WHO weight bands; parallel enrolment of different age groups will begin in early 2020. For low-dose tablet of FTC/TAF, there are 3 separate studies with NRTI backbone; 120/50mg tablet given to children between 14-25kg (around 60 children; will complete enrollment by the end of 2019); Plan to compile acceptability and palatability data from children in the study, particularly on the dispersible tablet and will be able to share that.
Study to support FTC/TAF for 14-<25 kg children ≥ 2 y of age – completed screening for all subjects in this cohort week of Sept 23 2019 [Wk 24 as primary endpoint for regulatory submission in Q3 2020][unboosted indication]. Regulatory filing expected in Q3 2020.
Clinical study to support FTC/TAF dispersible tablet – amendment in progress to be completed in Q1 2020. Will be enrolling as early as June/July 2020 in US and end of 2020 for other countries (Uganda, Zimbabwe, South Africa, Thailand), though could go into 2021 depending on the timelines for country approvals
BA study for dispersible tablet of FTC/TAF for < 14 kg completed in October 2019. Results showed that TAF was too low in this formulation. A second rBA/BE study on dispersible tablets with a couple of different FTAF ratios (each with increased TAF from our previous formulation) will be done in Aug 2020. Children will be enrolled by the summer of 2020.
April 2020: Gilead still intends to file for low dose TAF in children 14-<25 kg in the second half of this year. A second rBA study for dispersible F/TAF is still planned to occur in the early summer if the situation permits. F/TAF dispersible tablet data is still planned to come from the dispersible tablet of B/F/TAF which is planned to start enrollment by the end of the year (delayed due to country lockdowns). Enrollment of children into a pediatric study of the long-acting capsid inhibitor is planned for next year.
Pharmaceutical companies, SRAs, WHO Prequalification Programme (PQ) and NRAs commit to:
1. Accelerate the national drug registration process to enable registration of any ARV listed by WHO EOI in around 40 participating countries within 1 year by ensuring that:
FOR PRODUCTS WITH PQ APPROVAL:
Company submits for registration in countries requesting use of the CRP (based on PQ approval) and process completed within around 4-5 months (country decisions within 3 months, plus submission processing time)
FOR PRODUCTS THAT HAVE NOT YET RECEIVED PQ APPROVAL:
Company submits with USFDA for full approval or tentative approval and process completed within 6 months;
USFDA approval or tentative approval review shared with WHO for Collaborative Registration
Procedure-lite (CRP-lite), a pilot program at first allowing FDA to share up to 5 minimally redacted reviews.
Company submits for registration in countries requesting use of the CRP (based on WHO PQ, FDA (CRP-lite) or other SRA review) and process completed in around 4-5 months (country decisions within 3 months, plus submission processing time)
13. Share their methodological approaches to acceptability studies (including palatability and ease of administration) and contribute to a repository held by GAP-f partners to guide future investigation of acceptability for paediatric products.
14. Consider the use of the CRP for national registration of pediatric ARV products on PADO, Optimal formulary and Limited use lists.
15. Ensure all drug registration dossiers meet minimum requirements at the time of filing and that responses to specific queries are complete and provided in a timely manner
20. Manufacture new PADO priority pediatric ARV products “at risk” such that the new product is available for supply at time of approval/tentative approval/prequalification, including validation of manufacturing process during regulatory review.
Action 6: Prioritize PADO products in research and development plans.
Action 13: In pre-clinical and clinical development, initiate paediatric formulation development as soon as a given drug shows potential public health impact in adults, soon after Phase II trials are completed.
Action 14: Include adolescents when conducting initial adult efficacy trials, where possible and practical, or conduct parallel trials with the goal of providing information to support licencing for adolescents at the same time as adults.
Action 15: In the design of paediatric PK and safety studies, use weight-based dosing and enroll all children above 4 weeks concurrently, unless a strong rationale exists for not doing so.
Action 16: Assess acceptability and palatability of formulations for low-resource settings at early stages of the formulations development.
Action 17: Engage in early and regular consultations with the PAWG on PIP/PSPs, as well as recommended dosing and ratios for FDC development.
Action 18: Take all possible measures to rapidly complete development of priority paediatric drugs and formulations in the pipeline, with the goal of providing the maximum number of new formulations by end of 2018, especially for infants and young children.
Action 30: Strengthen and expand collaboration to overcome intellectual property challenges and otherwise facilitate technology transfer and knowledge sharing that can promote faster paediatric formulation development, including on challenges like taste-masking.
4. (individual commitment) Gilead committed to having clinical data ready for a low-dose TAF based regimen for children 2-12 years by late 2018/early 2019.
Gilead has a dedicated pediatric HIV project team that reviews and formulates best strategies for pediatric development of PADO priority ARVs on a continual basis. Gilead continues to prioritize PADO products, as evidenced by details described in actions below.
Formulation development is underway during phase 2 adult development for lenacaprivir (LEN) (the first in class, long-acting capsid inhibitor) in virologically suppressed (VS) individuals at least 2y of age that will commence in 2021 in parallel with the adult phase 3 VS study as described in #14.
Adolescents have been included in the ongoing heavily treatment experienced phase 2 adult study of lenacapravir and virologically suppressed adolescents and children will be enrolled in parallel to the adult phase 3 study evaluating virologically suppressed adults living with HIV as described in #13.
All children and adolescents are planned to enroll in parallel weight bands in the lenacapravir pediatric study of VS individuals – this plan has been accepted by the FDA.
All children who are 4 weeks of age and 3 kg to < 25 kg of age will be enrolled in 4 weight bands in parallel to be administered a dispersible tablet of B/F/TAF to begin enrollment by the end of this year in the US and next year at sites in Uganda, South Africa and Thailand (and possibly others to be determined) and the protocol amendment has been reviewed by FDA and parallel approach approved.
Acceptability/palatability has been in children and adolescents weighing at least 25 kg on the adult strength tablet. Gilead now has palatability/acceptability questionnaire responses from children at least 3 years of age and weighing 14-<25 kg being administered the low dose tablet of E/C/F/TAF (Study GS-US-292-0106) or B/F/TAF (Study GS-US-380-1474) and has submitted these in abstract form to the Pediatric HIV Workshop to take place in Nov. A careful and deliberate process was put in place to create an appropriate acceptability/palatability questionnaire for infants and young children receiving the dispersible tablet of B/F/TAF which assesses both the reaction of the participant to the dispersed tablet and the experience of the caregiver in preparing and administering the product. This will be administered to children 1m and 3 kg to < 25 kg who will enroll as stated in Action 15.
Gilead met with PAWG on the LEN PIP design in 2019 and plans to review plans again in late 2020 or 2021 as more data is gathered from adults and adolescents in ongoing studies.
Gilead has met this Action and will submit a regulatory file to the FDA at the end of 2020 to support administering F/TAF low dose tablet (120/15 mg) with an unboosted third agent to children 14-<25 kg.
Gilead and CHAI have entered a collaboration to allow transfer of information and technology to facilitate development of generic F/TAF and F/TAF-containing single tablet regimens in an age-appropriate and taste-masked formulation.
4 (Individual Commitment):
Gilead has clinical data on a low-dose TAF based regimen to be used with unboosted third agents for children 2-12y that will be used for a sNDA at the end of 2020 and was presented at World AIDS 2020 by Dr. Natukunda of JCRC in Uganda. This study was delayed as described below in #37.
Gilead will continue to support F/TAF development in children weighing at least 14 kg and taking a boosted third agent through collaboration with CHAPAS-4 with potential regulatory use of this data in 2021