HIV TREATMENT
2020
Action 27. Mobilize their networks and work with communities to help build treatment literacy, generate demand, and expand access to ARVs among children.
Action 34. Increase efforts to share information on the roll-out of new paediatric formulations, including lessons learned.
Paediatric HIV & TB : Rome Action Plan
2020 TB TREATMENT
I. Focus on and accelerating research and development of priority TB drugs and formulations for children living with HIV
Stop TB Partnership’s Global Drug Facility (STBP/GDF) commits to:
1. Ensure priority formulations are appropriately communicated to suppliers, including in regular meetings with suppliers, GDF tenders, and at GDF’s supplier meetings.
2. Include priority formulations in the TB Medicines Dashboard.
3. Identify and implement mechanisms to derisk suppliers who invest in development of child-friendly formulations.
4. Continuously monitor and project demand for pediatric formulations to identify when the market would benefit from additional suppliers.
TB Procurement and Market Shaping Action Team (TPMAT) commits to:
5. Assess proposed formulations against the intended use(s), available research results, and the market to ensure the final formulation will fulfill as many intended uses as possible minimizing market and supply chain barriers to introduction and scale-up.
6. Review the TB Medicines Dashboard and facilitate coordination and alignment across all stakeholders contributing lists and guidance documents to the dashboard.
WHO commits to:
7. Convene technical discussions to provide advice to innovators prior to submission of PSPs/PIPs, communicate technical opinions to SRAs in a timely manner, and provide dosing and ratio recommendations to generics for development of new formulations.
8. Update treatment guidelines in a timely manner to ensure that more effective drugs are recommended for children as soon as pharmacokinetic (PK) and safety data is available.
9. In collaboration with Stop TB Partnership (STBP)/Global Drug Facility (GDF) and the TB Procurement and Market-Shaping Action Team (TPMAT), continue to revise the minimum set of pediatric formulations to guide national procurement and ensure their inclusion in Essential Medicine List for Children (EML-C).
10. As convener of the Paediatric Drug Optimization for TB (PADO TB) process, set the research agenda for product development, update the list of priority products as needed; communicate outcomes to industry and regulators in a timely manner; and ensure inclusion of PADO priority products in the WHO PQ Expression of Interest list as soon as dosing is identified.
IMPAACT and PENTA commit to:
11. Focus research efforts and rapidly disseminate research findings on optimal drugs and regimens as defined by the PADO TB priorities list.
12. Optimize clinical research in line with PADO priorities, including:
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Use state of the art population PK methods to design and analyze paediatric PK studies allowing for inclusion of clinically relevant factors such as age, weight, formulations, HIV, malnutrition, etc.
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Complete palatability and acceptability work on new formulations early on in the field, ideally in diverse populations.
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Ensure coinfected patients are included to explore drug-drug interactions.
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Rapid dissemination of findings with WHO and key stakeholders to inform policy, practice, and field guides.
13. Use the following best practices for the design and implementation of research studies:
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Initiate preparation for paediatric studies as soon as a given drug shows promising efficacy and safety in Phase IIa adult studies.
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Always include adolescents when conducting initial adult efficacy trials, or conduct parallel trials with the goal of providing information to support licensing for adolescents at the same time as adults.
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In the design of paediatric PK and safety studies, study weight-based dosing and enroll all children above 4 weeks of age concurrently (i.e no age de-escalation), unless a strong rationale exists for not doing so.
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Assess acceptability and palatability of formulations, including for use in low-resource settings, at early stages of the formulation’s development.
14. Develop drug susceptibility testing (DST) and methods in parallel to new molecule development and make pure drug substance available for DST at the same time as the introduction of a new molecule.
GAP-f partners commit to:
15. Provide a platform to coordinate and support work led by key TB stakeholders in order to accelerate investigation, development, introduction and roll out of paediatric TB priority formulations.
16. Promote donor coordination and collaboration to cover the full spectrum of activities required to ensure accelerated research, development, registration, commercialization, roll-out, sustainable access, and appropriate monitoring of paediatric TB priority formulations.
17. When needed, review effectiveness of, identify and facilitate the most suitable incentive for TB priority formulations to be rapidly developed.
GAP-f partners and other researchers commit to:
18. Seek and direct funding to support the additional clinical research required to inform development of priority products.
19. Expand clinical trials site capacity to accelerate enrolment in paediatric TB studies (especially for Drug-Resistant TB) and for operational research.
Generics [Lupin, Macleods, Micro Labs, Viatris] commit to:
20. Prioritize the development and commercialization of products on the Global Fund Expert Review Panel (ERP) Expression of Interest (EOI) and the WHO PQ EOI.
21. Develop paediatric formulations in line with the PADO TB, GF ERP EOI and the WHO PQ EOI lists, including:
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Rifapentine 150mg scored dispersible tablet by 2021
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Linezolid 150mg dispersible tablet by 2021
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A second supplier of rifampicin/isoniazid/pyrazinamide 75/50/150mg FDC dispersible tablet
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A second supplier of isoniazid 100mg dispersible tablet
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A second supplier of ethambutol 100mg dispersible tablet.
Sanofi commits to:
23. Continue to support research networks conducting studies to confirm rifapentine dosing in young children, including children living with HIV.
24. Prioritize the development, registration, and commercialization of priority TB products in research and development plans.
25. Engage in early and regular consultations with GAP-f and other WHO-convened expert groups on PIP/PSPs.
26. Engage with the Medicines Patent Pool to enter into open, voluntary licensing agreements in preference to exclusive licensing agreements.
27. Facilitate technology transfer and knowledge sharing that can promote faster paediatric formulation development by generic companies.
28. Make pediatric formulations and data available to research networks advancing pediatric PK and safety studies.
29. Rapidly submit data to regulatory authorities and the WHO to facilitate updating of labelling and recommendations.
30. Use the following best practices for the design and implementation of research studies:
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Initiate preparation for paediatric studies as soon as a given drug shows promising efficacy and safety in Phase IIa adult studies.
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Always include adolescents when conducting initial adult efficacy trials, or conduct parallel trials with the goal of providing information to support licensing for adolescents at the same time as adults.
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In the design of paediatric PK and safety studies, study weight-based dosing and enroll all children above 4 weeks of age concurrently (i.e no age de-escalation), unless a strong rationale exists for not doing so.
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Assess acceptability and palatability of formulations, including for use in low-resource settings, at early stages of the formulation’s development.
31. Develop drug susceptibility testing (DST) and methods in parallel to new molecule development and make pure drug substance available for DST at the same time as the introduction of a new molecule .
Johnson & Johnson commits to:
32. Ensuring ongoing access to the 20mg bedaquiline tablet, which Johnson & Johnson, in partnership with Stop TB Partnership's GDF Pediatric DR-TB Initiative, has already made available for over 130 countries, following US FDA approval in May 2020.
33. Continue efforts in exploring additional clinical trial sites to ensure timely completion of study investigating the use of bedaquiline in children below 5 years of age.
34. Engage early and regularly with GAP-f and other WHO-convened expert groups on pediatric indication development.
35. Engage with the Medicines Patent Pool and/or generic companies to evaluate licensing agreements for pediatric formulations, where appropriate.
36. Make pediatric formulations and data available to research networks advancing pediatric PK and safety studies, where appropriate under collaborative agreements. Rapidly submit data to regulatory authorities and the WHO to facilitate updating of labelling and recommendations.
37. Use the following best practices for the design and implementation of research studies:
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Engage with regulators to explore options for pediatric studies as soon as a given drug shows promising efficacy and safety in Phase IIa adult studies.
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Consider Including adolescents when conducting initial adult efficacy trials or conduct parallel trials with the goal of providing information to support licensing for adolescents at or near the same time as adults, when appropriate from a scientific and ethical perspective and allowed by regulations.
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In the design of paediatric PK and safety studies, when appropriate from a scientific and ethical perspective and allowed by regulations, consider studying weight-based dosing and enrolling all children above 4 weeks of age concurrently (i.e., no age de-escalation).
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Assess acceptability and palatability of formulations, including for use in low-resource settings, at the earliest appropriate stage of the formulation’s development.
38. Support the development of drug susceptibility testing (DST) and methods in parallel to new molecule development and make pure drug substance available for DST at the same time as the introduction of a new molecule.
Otsuka commits to:
39. Ensuring global access to its child-friendly delamanid formulation in collaboration with the Stop TB Partnership's GDF Pediatric DR-TB Initiative, national TB programmes, and other stakeholders.
40. Performing technology transfer for child-friendly delamanid formulations used to treat DR-TB, to be completed shortly after first stringent regulatory authority approval of the formulation.
41. Expedite development and regulatory submission of pediatric versions of new TB compounds already in the Otsuka R&D pipeline, with an aim to have pediatric versions available shortly after regulatory approval of the adult formulation.
42. Prioritize the development, registration, and commercialization of priority TB products in research and development plans.
43. Facilitate technology transfer and knowledge sharing that can promote faster paediatric formulation development by generic companies.
44. Make pediatric formulations and data available to research networks advancing pediatric PK and safety studies.
45. Rapidly submit data to regulatory authorities and the WHO to facilitate updating of labelling and recommendations.
46. Use the following best practices for the design and implementation of research studies:
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Initiate preparation for paediatric studies as soon as a given drug shows promising efficacy and safety in Phase IIa adult studies.
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Assess acceptability and palatability of formulations, including for use in low-resource settings, at early stages of the formulation’s development.
47. Develop drug susceptibility testing (DST) and methods in parallel to new molecule development and make pure drug substance available for DST at the same time as the introduction of a new molecule.
Micro Labs commits to:
48. Finalize the development of child-friendly linezolid for the treatment of drug-resistant TB, with an aim of submitting a dossier to WHO PQ and GF ERP by the 3rd quarter of 2021.
49. Finalize the development of child-friendly ethambutol 100mg for the treatment of drug-sensitive and drug-resistant TB, by finalizing any remaining items with GF ERP in Q1-2021.
Viatris commits to:
51. Develop child-friendly formulation(s) for novel MDR-TB medicines for which Viatris has the requisite license(s).
52. Provide regular updates on pediatric pretomanid development plans and timelines alongside the TB Alliance.
53. Evaluate pediatric TB formulations that are not being developed by other partners and are identified by WHO and others partners as priorities to determine if there are any which can be developed and supplied by Viatris.
II. Expedite regulatory review of priority TB drugs and formulations for children
WHO PQ and National Regulatory Authorities commit to:
54. Expand use of the Collaborative Registration Procedure based on PQ or SRA approval to expedite national review of paediatric TB drugs and formulations.
55. Use the Paediatric Regulatory Network for advocacy of use of the Collaborative Registration Procedure and to explore models of regulatory reliance to promote equitable access to paediatric TB formulations.
National Regulatory Authorities commit to:
56. Expedite and simplify the review of priority paediatric formulations including by:
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Making better use of sub-regional collaborative regulatory approval processes and the WHO Collaborative Registration Procedure for accelerated registration;
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Increasing reliance on evaluations and opinions of SRAs and the WHO PQ programme
57. End requirements for local clinical trials when sufficient PK and safety data exists, even when no equivalent innovator product exists.
58. Minimize/remove country-specific packaging and labelling requirements for paediatric formulations.
SAHPRA commits to:
60. Continue to apply priority review of all TB drugs in alignment with the national strategy.
61. Conduct priority review for priority TB paediatric medicines (as defined in the TB PADO List).
62. Use reliance approaches and collaborative regulatory review processes, including WHO Prequalification and “Zazibona,” a sub-regional collaborative platform that allows joint review to expedite the review of TB drugs.
The European Medicines Agency (EMA) agrees to:
63. Continue the review of Paediatric Investigation Plans (PIPs) specifically taking into account the following points, always bearing in mind that PIPs are evaluated on a scientific case-by-case basis:
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Paediatric formulation development must be considered in an integrated way right from the beginning of the planning process together with the whole paediatric drug development after completion of phase 1 studies in adults, taking into account dose finding and clinical studies.
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Adolescents should be included in adult trials or adolescent trials should be conducted in parallel with adults unless scientifically justified.
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Studies of medicines across the paediatric spectrum of ages/weights should be conducted in parallel rather than in serial age-staggered approach, taking into account for example the pharmacological characteristics of the particular medicinal product, e.g. specific safety or drug disposition factors which may warrant a different approach.
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PIPs for new TB medicines should consider including systematically children with HIV and other common co-infections found in children affected by TB, taking into account safety or drug-drug interaction issues.
64. Provide guidance about when clinical trials for efficacy have to be done in children and when extrapolation of efficacy based on PK is sufficient.
65. For planned regulatory submissions to provide guidance on pathways for paediatric drug development programmes without reference products and/or TB indication in adults.
66. Continue to work with other non-EU regulatory authorities and WHO to foster alignment on development programmes for TB in children.
67. Identify specific mechanisms as defined by the legal framework to facilitate access to WHO Prequalified paediatric TB formulations in their countries/regions through specific mechanisms as defined by the legal framework.
68. Continue to offer the opportunity to target countries to participate as observers in the EMA evaluation.
The US Food and Drug Administration (USFDA) commits to:
69. Observing the following principles in its regulatory review process:
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Extrapolating efficacy from adults to children is acceptable for most children with TB.Extrapolation of adult efficacy to paediatric populations for the treatment of pulmonary TB may be appropriate for most paediatric populations, other than the very young as they can have different clinical and pathophysiologic characteristics. Pharmacokinetic (PK) and safety information in paediatric patients will be needed to support the appropriate dose for treatment of children.
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Adolescents with pulmonary TB can be included in phase 3 clinical trials, if appropriate.
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Paediatric patients can be enrolled in trials if sufficient safety and antimycobacterial activity data in adults are available and appropriate dosing regimens have been characterized.
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Studies of drugs across the paediatric spectrum of ages/weights can be conducted in parallel rather than sequentially unless there is a specific safety or pharmacokinetic properties that warrants a different approach.
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Paediatric development plans for new TB medicines could include children living with HIV and other common co-infections provided there are no safety or drug-drug interaction issues.
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Cohorts for paediatric studies can be defined based on chronological age or weight-based criteria, particularly for oral drugs.
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Paediatric formulation development should begin soon after adult Phase 2-b trials and dose selection.
70. Continue to work with other regulatory authorities to seek alignment on development of products for TB in children.
71. Continuing engagement on development of products and age appropriate formulations for treatment of TB in children.
Stop TB/GDF commit to:
72. Lead the external review of the Global Fund’s Expert Review Panel Expression of Interest (GF ERP EOI) through TPMAT and suggest prioritization of formulations for expedited review.
73. Monitor the development pipeline and work with the Global Fund to expedite access to new formulations and medicines.
74. Develop a strategy/roadmap for countries on TB paediatric drug registration that is linked to procurements and procurement goals.
Sanofi commits to:
75. Explore regulatory options to allow access to TB paediatric formulations in other regions and countries currently without access (e.g. EU, US, Canada, Australia etc.).
76. Consider the use of the CRP for national registration of paediatric TB products.
77. Ensure all drug registration dossiers meet requirements at the time of filing and that responses to specific queries are complete and provided in a timely manner.
78. Consider facilitating existing joint assessment procedures by planning the submission in different countries/regions to allow for joint assessment in existing networks.
79. Provide multilingual Patient Information Leaflets or Instructions for Use to facilitate appropriate use by Healthcare workers and caregivers.
80. Register new TB paediatric products quickly in countries where registration is required and import waivers cannot be granted for procurement (regardless of source of funding)
Otsuka commits to:
81. Explore regulatory options to allow access to TB paediatric formulations in other regions and countries currently without access (e.g. EU, US, Canada, Australia etc.).
82. Consider the use of the CRP for national registration of paediatric TB products.
83. Ensure all drug registration dossiers meet requirements at the time of filing and that responses to specific queries are complete and provided in a timely manner.
84. Consider facilitating existing joint assessment procedures by planning the submission in different countries/regions to allow for joint assessment in existing networks.
85. Provide multilingual Patient Information Leaflets or Instructions for Use to facilitate appropriate use by Healthcare workers and caregivers.
86. Register new TB paediatric products quickly in countries where registration is required and import waivers cannot be granted for procurement (regardless of source of funding).
Johnson & Johnson commits to:
87. Consider the use of the CRP for national registration of paediatric TB products.
88. Ensure all drug registration dossiers meet requirements at the time of filing and that responses to specific queries are complete and provided in a timely manner.
89. Consider facilitating existing joint assessment procedures by planning the submission in different countries/regions to allow for joint assessment in existing networks.
90. Provide multilingual Patient Information Leaflets or Instructions for Use to facilitate appropriate use by Healthcare workers and caregivers.
91. Consider prioritizing registration submission of new TB pediatric products in high burden countries where import waivers cannot be granted.
III. Introduction, Uptake and Procurement
Ministries of Health commit to:
92. Accelerate transition to more optimal regimens and formulations as described in WHO Guidelines by:
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Adopting and implementing new WHO TB guidelines relevant for children within one year of their release
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Revising national procurement plans to align with WHO recommended regimens and the EML-C
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Scaling-up use of dispersible fixed-dose combinations and single drug formulations for drug-sensitive and drug-resistant TB (including rifampicin + isoniazid + pyrazinamide [RHZ] and rifampicin + isoniazid [RH], INH dispersible single, ethambutol dispersible single and child-friendly second-line formulations)
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Supporting the provision of shorter TB Prevention Treatment regimens for children when these regimens have appropriate data and are available in child-friendly formulations (i.e., 3RH, 3HP, 1 HP)
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Strengthening reporting and recording systems for TB infection, contact tracing and provision and completion of TPT for children
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Strengthening PSM systems for TPT medicines.
93. Prioritize funding for paediatric TB prevention, diagnosis (including DST), and treatment in national budgets and requests to donors, including to provide these services free of charge and to support improved models of care for children and for training of HCWs.
94. Create a plan of action to reduce stigma and discrimination in health care systems and communities and support civil society and community generated initiatives focused on pediatric TB.
95. Collect data on TB-HIV co-infection and TB treatment outcomes in children living with HIV.
Unitaid commits to:
98. Supporting the TB treatment agenda through our grants (TB Speed – Université de Bordeaux, Cap-TB – EGPAF, Benefit Kids – Stellenbosch University, IMPAACT4TB – Aurum Institute, and WHO).
99. Identify and establish effective collaboration and funding support to advance the application of new technologies for delivery of improved paediatric formulations for TB treatment for susceptible and resistant TB.
100. Promote integration of different services to increase detection and treatment of children with TB.
101. Continue to support, with WHO and partners, the introduction of optimal paediatric formulations for treatment, and also preventive treatment (3RH and 3HP).
Global Fund commits to:
102. When negotiating grants, encourage countries to address health product management and domestic procurement challenges that may negatively affect the procurement of quality, affordable health products, including the procurement of small volume or small market products, such as pediatric DS and DRTB drugs.
103. Continue to use a flexible approach in the implementation of the co-financing policy, particularly related to small volume, small market products that might be more challenging to procure effectively via domestic procurement.
104. With partners, support and encourage countries to adequately prepare to procure small volume, small market products as they increase their role in domestic procurement and encourage the use of international pooled procurement platforms. In alignment with recommendations from the United Nations High Level Meeting on Tuberculosis in 2018, encourage the use of STBP/GDF when countries are unable to efficiently procure such products directly from suppliers.
Stop TB Partnership (STBP)/Global Drug Facility (GDF) commits to:
105. Lead the TB Procurement and Market-Shaping Action Team (TPMAT) to coordinate global TB stakeholders and develop implementation roadmaps for new formulations.
106. Work to build, stabilize and maintain access to small-volume products including child-friendly formulations for drug-resistant TB.
107. Continue to use the Launchpad Approach to support the introduction and scale-up of paediatric formulations in programmes.
All GAP-f partners commit to:
108. Lead efforts to facilitate and strengthen collaboration among relevant stakeholders to ensure the most efficient development and uptake of optimal paediatric TB drug formulations and regimens, in close consultation with the community of people living with and at risk of TB.
KNCV commits to:
110. Work with country stakeholders to develop a platform and mechanism to ensure all commitments turn into action
111. Support countries to develop national strategic plans and Global Fund concept notes that are data driven and addressing the needs of children in the entire patient pathway.
112. Collaborate and coordinate with in-country professional and regulatory bodies to ensure countries are prepared for early uptake of new innovations/medicines and develop a plan for scale up.
113. Produce high quality documentation of our best practices and evidence to share at global platforms to guide global policies and guidelines.
114. Engage with civil society to create sense of urgency at country level to ensure all children needs related to TB/HIV are implemented.
115. Support countries in scaling up the stool test with GeneXpert for TB diagnosis in children including development of generic SOP’s and training materials.
The Union commits to:
116. Continue to support countries to prioritize the identification, diagnosis, and scale-up of TB preventive treatment, including children living with HIV, including via the Union Sub Saharan Africa Centre of Excellence for Child and Adolescent TB as well as in countries where we are working with National TB programmes.
117. Support the scale-up of access to priority formulations and diagnostics and to take steps to facilitate their wider roll-out including by performing operational research via The Union’s Centre of Operational research, and ensuring The Union’s existing paediatric publications and training tools are up to date and disseminated widely in a number of languages to promote the highest standard of care for all children with or at risk of TB.
118. Advocate for the rights of all children, including those living with HIV, to receive TB care and treatment and promote a human-rights based approach to TB; to urge governments to ensure that all children have access to the latest formulations and models of care for TB prevention and care; and to work together to reduce stigma and discrimination that stops children from accessing care that they need.
Implementing Partners and Faith-Based Organizations commit to:
119. Advocate for and support Ministries of Health to rapidly transition to optimal paediatric formulations as outlined by the latest WHO guidelines, provide coordinated support for the development and implementation of transition plans, inform clinicians and patients of the value of transitioning to new formulations, and ensure communication of reliable information on the availability of new formulations in-country.
120. Support the scale up of access to priority formulations and diagnostics and take steps to facilitate their wider roll-out, including by performing operational research, developing introductory guidance and education, materials, and other tools for health facilities and local community health structures.
121. Promote the revision of national procurement plans to align with WHO recommended regimens and the EML-C, and support the provision of reliable forecasts and the consolidation of orders.
Networks of persons living with or affected by TB, Implementing Partners, and Faith-Based Organizations commit to:
122. Mobilize their networks and work with communities to help build treatment literacy, generate demand, and expand access to TB diagnosis and treatment among children in close collaboration with other stakeholders.
123. Raise awareness in local, national, and global fora about the unmet diagnostic and treatment and prevention needs of children with or at risk for TB.
124. Foster and more actively participate in coordinated and collaborative advocacy to:
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Increase funding for TB research & development, introduction and scale-up of priority paediatric drugs and formulations;
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Accelerate regulatory processes for rapid adoption and uptake of optimal paediatric TB drugs and formulations; and
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Ensure sustainable access to optimal TB testing and treatment for infants and children.
125. Tackle the TB stigma and discrimination in communities, schools, and healthcare settings that prevent children and adolescents living with TB or at risk of TB from accessing testing and treatment, including promotion of awareness of the difference between infection and disease and include messages of hope regarding treatment of both HIV and TB.
126. Promote uptake by mobilizing their networks of hospitals and community structures to distribute paediatric medicines in hard to reach places and in situations of conflict and crisis.
Faith Based Organizations commit to:
127. Support and increase TB treatment initiation and retention for children, adolescents, and families by:
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Identifying all TB-exposed children and connecting them to treatment and preventive TB treatment through FBO clinics and within communities of faith;
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Reducing TB stigma and discrimination through mobilization and evidence-based education and training of faith leaders and faith communities
UNICEF commits to:
129. Advocate for increased pediatric TB case-finding and access to child-friendly treatment as a core member of the TB Child and Adolescent Working Group and the TB PADO.
130. Support national governments to optimize the integration of TB with child health, HIV, and nutrition services.