Paediatric drug optimization standard procedure

NOVEMBER 2021 PAediatric Drug Optimization standard procedure

PAediatric Drug Optimization standard procedure NOVEMBER 2021 Paediatric drug optimization standard procedure ISBN 978-92-4-003952-0 (electronic version) ISBN 978-92-4-003953-7 (print version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Design and layout by 400 communications. iii Abbreviations iv Introduction 1 Aim 4 Goals and outputs 5 What is the goal of a PADO process? 6 What are the final products of a PADO process? 6 PADO process 8 Stakeholders involved 10 Steps to undertake prioritization 10 Alternative options for adoption and adaptation 15 Dissemination 15 Acknowledgements 16 Resources 17 References 17 Contents iv PAediatric Drug Optimization standard procedure Abbreviations 3TC lamivudine ABC abacavir DTG dolutegravir GAP-f Global Accelerator for Paediatric Formulations HCV Hepatitis C Virus HIV Human Immunodeficiency Virus PADO PAediatric Drug Optimization PK pharmacokinetic PPC Preferred Product Characteristics R&D Research and Development TB tuberculosis TPP Target Product Profile WHO World Health Organization 1Introduction 2The development of medicines for children lags unacceptably behind that for adults by nearly a decade – because of several challenges. Infants and children are typically not included in clinical development programmes until Phase 3 studies involving adults have started. Drug doses need to be tailored to a child’s drug metabolism and weight, and drug approvals often do not acknowledge dosing approaches based on weight bands. Young children cannot swallow tablets or capsules and acceptable palatability is difficult to achieve, and products for children are therefore often complex and costly to develop and manufacture, with limited market incentives. The global call to leave no one behind enshrined in the Sustainable Development Goals puts the world’s most vulnerable and marginalized people – including children – at the top of the global health agenda. Although there were significant achievements in child health in 2020, 5.2 million children younger than five years died from preventable causes, and urgent action is needed to achieve the Sustainable Development Goals, especially Sustainable Development Goal 3 to ensure healthy lives and promote well- being for all at all ages and the related target to achieve universal health coverage by 2030. Following the resolution at the 69th World Prioritizing and Evaluating: Developing a prioritized drug portfolio of the most needed formulations and assisting in the design and implementation of efficient, and high-quality clinical trials. Developing: Establishing and maintaining relationships to launch effective products and supporting regulatory submission activities to facilitate paediatric medicine approvals. Delivering: Supporting efforts to introduce new, adapted formulations in an equitable, accelerated, safe and coordinated manner. Health Assembly (1) on promoting innovation and access to quality, safe, efficacious and affordable medicines for children, WHO and partners have increased their efforts to deliver on this global commitment and scaled up activities to ensure that age-appropriate formulations are available for children. Several initiatives have been ongoing in various disease areas (2–3), and global stakeholders have recently come together to enable a more focused and coordinated action across disease areas to make age-appropriate formulations more rapidly available to infants and children and are now collaborating via the Global Accelerator for Paediatric Formulations (GAP-f), a WHO-hosted network (4). GAP-f works across the life cycle of drug development to give priority to, evaluate, develop and deliver optimal formulations for children by developing a clear priority-set drug portfolio, ensuring that efficient and high- quality clinical trials are completed, accelerating product development in coordination with key stakeholders and ensuring that products are introduced in an accelerated and coordinated manner (Fig. 1). FIG.1. PRIORITIZATION: THE FIRST STEP OF THE GAP-F PRODUCT LIFE-CYCLE Accelerating priority paedeatric drug formulation development and uptake Prioritization Evaluation Product Development Regulatory Affairs Adoption Procurement Monitoring Rollout & Uptake PAediatric Drug Optimization standard procedure 3Introduction PRIORITIZATION IS A NECESSARY FIRST STEP TO ENABLE A TARGETED APPROACH TO RESEARCH AND DEVELOPMENT, WHICH NEEDS TO BE UNDERTAKEN IN CONJUNCTION WITH DEVELOPING AND UPDATING NORMATIVE GUIDANCE ON THE USE OF MEDICINE FOR TREATING AND PREVENTING COMMUNICABLE AND NONCOMMUNICABLE DISEASES. AS SUCH, WHO LEADS AND CONVENES THIS WORK AND DEVELOPS IT IN COLLABORATION WITH APPROPRIATE STAKEHOLDERS ACTIVE IN EACH DISEASE AREA. WHY DO WE NEED PAEDIATRIC DRUG OPTIMIZATION? The field of antiretroviral drugs provides a useful model to reduce market fragmentation and to focus research and development efforts around a limited set of priority formulations that are expected to maximize impact at the country level and ensure equitable access to novel products to improve clinical outcomes. Over the years, the WHO-led Paediatric Antiretroviral Drug Optimization group has established medium- and long-term priorities for drug development to accelerate access to optimal formulations in the context of fragmented markets for antiretroviral drugs for children. Since its first release in 2013, the PADO-HIV list has provided an evidence-informed priority list and a clear and consistent message to guide industry and interested stakeholders on the most needed antiretroviral drug formulations for children to be investigated and developed. This list has reduced the number of unnecessary formulations to almost zero, has streamlined suppliers’ efforts around specific dosage forms and formulations (such as the 10-mg scored dispersible dolutegravir (DTG) tablets or DTG/ ABC/3TC 5/60/30 mg tablets) and has become a critical tool to focus research and development efforts and resources. Research and development efforts urgently need to be streamlined and target the products that are most needed. Developing formulations for children may require technologies that can be expensive, and efforts should therefore target the highest impact. The market for medicines for children is often small and/or fragmented, resulting in limited volumes and may lead to market failures. Clinical research is lengthy and expensive, so efforts should target the compounds with the highest chances to address people’s needs. 4PAediatric Drug Optimization standard procedure The PAediatric Drug Optimization (PADO) approach has been adopted and adapted for hepatitis C virus (HCV) and tuberculosis (TB) medicines, and these exercises have brought to light the need to provide further guidance to support similar processes for optimizing drugs for children beyond HIV, HCV and TB as well as tools to enable standardization across diseases while retaining opportunities for adaptation as required by the different therapeutic areas, including communicable and noncommunicable diseases. A comprehensive review of all essential medicines for children is ongoing to identify gaps in formulations for children. Future PADO exercises will be critical to focus research and development efforts and rapidly fill the key gaps identified. This document was developed to complement existing WHO guidance on setting priorities for research (5) and development of target product profiles, preferred product characteristics and target regimen profiles (6) Aim The aim of this document is to provide guidance on how to undertake a paediatric drug optimization exercise and identify key priority products for research and development. This guidance is for all WHO technical units undertaking a paediatric drug optimization exercise, all stakeholders involved in PADO processes as well as interested organizations and experts involved in the research and development of therapeutics in the public and private sectors. 5Goals and outputs PAediatric Drug Optimization standard procedure WHAT ARE THE GOALS OF A PADO PROCESS? • Identify priority drugs and formulations to be investigated and developed to fully implement existing WHO guidelines. • Identify priority drugs and formulations to be investigated and developed to enable future revisions of WHO guidelines. • Identify promising candidates that may require accelerating investigation plans. • Provide guidance to research and development to ensure that the unique needs of children are considered and effectively addressed (weight band dosing and dosing for preterm babies). • Define a clear research agenda to support and enable future drug optimization for children. • Enable alignment between funders, procurers, market-coordination entities, researchers, innovators, generics, product development partnerships and regulators on priority products to be investigated and developed. WHAT ARE THE FINAL PRODUCTS OF A PADO PROCESS? 01 A PADO priority list contains priority formulations (including details of the dosage form and dose strength when that is known) to be investigated and developed (with a time horizon of 3–5 years). Formulations included in this list: – should respond to public health needs on missing formulations for children, including specific subgroups: for example, a formulation that is needed for dosing in specific weight bands; – should be fit for purpose across possible different indications based on the ongoing and planned research to ensure that the selected medicines are adequately used; – may be generic versions of an innovator product to secure access in low- and middle-income countries; and – should take into account the market size and structure in a manner that supports market efficiency. 02 A PADO watch list contains promising candidates for investigation and development for children (with a time horizon compared with the PADO priority list of 5–10 years). These may include: – drug candidates undergoing Phase 2a or Phase 2b clinical trials among adults that are expected to have good tolerability and toxicity profiles without any major preclinical concern for use among children based on preclinical data; – new fixed-dose combinations that are being investigated in adults and are expected to be highly effective and have good tolerability and toxicity profile without any major preclinical concern for use among children; – formulations of existing medicines that may require a new technology to deliver medicines to children that are being investigated and developed; – new combination regimens that were never tested in adults but signal potential benefits for children; – new chemical or biological entities for disease areas with a lack of preventive or therapeutic options for children (especially for conditions that specifically affect children); and – formulations of an existing drug that may be repurposed for a new indication. 6 7Goals and outputs 03 A research agenda, including key research gaps to address, will support the development and appropriate use of the products included in the PADO priority list. These may include but are not limited to: – pharmacokinetic (PK) and safety data to support regulatory approval for indications of new chemical entities for children; – pharmacokinetic modelling and simulations to inform simplified weight-band dosing or among specific subgroups (such as malnourished children or genetic polymorphisms); – pharmacokinetic data and modelling to inform the selection of compounds and development of formulations, including delivery systems; – efficacy data for preventive or therapeutic strategies of concern for children when extrapolating efficacy from adult data is not possible or not suitable; – dose-optimization studies and strategies to improve tolerability, minimize toxicity, reduce the cost of commodities and increase suitability for low- and middle- income countries; – pharmacokinetic and safety data to investigate drug–drug interactions; – feasibility, usability, acceptability and palatability of new formulations for specific chemical entities in various settings and groups of children (with a strategic approach to ensure the generalizability of findings); – long-term safety data (pharmacovigilance), especially for conditions or diseases that require long-term or lifelong treatment; and – selection of drug resistance and impact on efficacy and durability of a specific treatment regimen over time when extrapolating from adults is not possible. ANTICIPATED USE OF THE PADO PRIORITY AND WATCH LISTS Both lists are designed for a wide audience, including various stakeholders, but some practical considerations can be outlined. The priority list is typically used: • by WHO as the basis for revising the WHO Expression of Interest list directed at suppliers that may want to submit for prequalification; • by the Expert Review Panel of the Global Fund to Fight AIDS, Tuberculosis and Malaria as the basis for procurement: • by product development partnerships interested or already engaged with developing new formulations in given disease areas; and • by innovators to inform the selection of dosage forms and/or compounds to be accelerated in their clinical development plans by adjusting existing paediatric investigation plans and paediatric study plans. The watch list is typically used: • by innovators to inform the development and implementation of their paediatric investigation plans and paediatric study plans; • by research networks to better target their efforts; and • by regulators to inform their early conversation with innovators and potential decisions around waivers or deferrals for paediatric investigation of new entities. 8PADO process 9PADO process PADO FOUNDING MEETING A founding PADO meeting should be convened to comprehensively assess the needs and gaps to be addressed by the PADO exercise. Information on current clinical research and development, a review of the current landscape of innovator and generic formulations and any relevant summary on the introduction and roll-out of relevant formulations will inform the discussion. The primary goal will be to reach consensus on the first PADO priority and watch lists and the related research agenda. PADO REVIEW MEETING This meeting will be convened periodically (every 2–3 years or more often based on need) as an in-person meeting, if possible. This meeting will comprehensively review the latest clinical developments and any relevant updates on the introduction and roll-out of relevant formulations (including the outcomes of separate priority-setting processes for adult if available). The primary goal will be to reach consensus on updated PADO priority and watch lists and the related research agenda. PADO INTERIM REVIEW MEETING These interim reviews would be convened virtually as needed between PADO review meetings and would be intended to provide a high-level review of the latest clinical and product developments and any updates on the introduction and roll-out of formulations included in the PADO list. The primary goal will be to set priorities for any urgent action to investigate or develop drugs and formulations included in the PADO priority and watch lists. A secondary goal would be to anticipate any modification for consideration of subsequent PADO review meetings. For example, when a new chemical entity or regimen indicates safety and efficacy in adults, providing a green light for accelerated research and development or, in contrast, once a new chemical entity presents a safety signal that may prevent it from becoming of interest for future treatment and prevention guidelines. 10 PAediatric Drug Optimization standard procedure STAKEHOLDERS INVOLVED After potential conflicts of interest and the specific needs of the therapeutic area represented are reviewed, the following stakeholders should be involved: • academia and research networks; • disease programme implementers and technical partners; • procurement agencies; • market-coordination entities; • civil society, community representatives and patient advocates; • representatives of health ministries with appropriate disease programme managers; • relevant United Nations agencies; • any other relevant stakeholders involved in research and development (input from industry is gathered before the meeting); • not-for-profit product development partnerships (observers); • funders (observers); and • regulators (observers). Representatives of other WHO technical departments will be included as relevant to ensure appropriate alignment of separate PADO processes when discussing comorbidities. STEPS TO UNDERTAKE PRIORITIZATION PROCESS The prioritization process is typically informed by a full understanding of the burden of the disease, a review of the need for specific therapeutics as recommended by WHO guidelines (or alternative normative standards), a detailed overview of the drug landscape and pipeline as well as a thorough review of current market, procurement and implementation challenges. BURDEN OF DISEASE Understand the burden of the diseases to estimate the need and target R&D WHO GUIDELINES Examine current and anticipated policies alongside appropriateness of existing formulations PIPELINE ANALYSIS Scan the horizon for new candidates or technologies to be targeted for new product development IMPLEMENTATION AND MARKET Review programme scale up and implementation needs to better inform R&D FIG.2. CORE COMPONENTS OF A PAEDIATRIC DRUG OPTIMIZATION PROCESS 11 PADO process The process comprises: • background assessment, undertaken and updated in preparation for the PADO meetings; • review of gaps and opportunities; and • setting priorities for research and development, core part of the process to be undertaken during the PADO inception meeting and full review meetings. Steps 1–9 below should lead the convened group to agreement on a relatively short list of high-priority products and/or formulations needed to provide optimal care for children in low- and middle-income countries in the next 3–5 years and another shortlist of high-value products and technologies that show significant promise but are still being developed and still require substantial additional data before being considered for prioritization, i.e., the watch list (these are more likely to be needed in the next 5–10 years). BACKGROUND ASSESSMENT 01 What is the population to treat and its characteristics? This first step is designed to fully appreciate the size and the characteristics of the target population (from birth through adolescence). This will require reviewing the natural history of the disease and its global epidemiology (especially focusing on low- and middle-income countries), burden, distribution and outcomes after treatment among children. This step may build on pre-existing assessments of the burden of disease among children. 02 What preventive and treatment interventions do children need for this disease? This step is designed to assess the need for specific formulations based on current WHO recommendations, policy uptake and the age and weight distribution of the children who need the formulation. This step also allows anticipated changes in the need for a given formulation as a result of anticipated changes in programme uptake and roll-out over time. If WHO recommendations are not available for any given treatment, an appropriate alternative normative reference should be identified, reviewed and used. 12 PAediatric Drug Optimization standard procedure 1 Quality-assured formulations are defined as those approved by a Stringent Regulatory Authority (https://www.who.int/ initiatives/who-listed-authority-reg-authorities/SRAs) or Prequalified by WHO REVIEWING GAPS AND OPPORTUNITIES 03 Review all available quality-assured formulations1 to prevent and treat the disease in children and their appropriateness This step needs to be based on WHO treatment and prevention guidelines if available and includes examining the appropriateness of formulations currently available in the market and, in particular, reviewing the following features: • Dose and dose flexibility. Does the formulation enable correct and flexible dosing according to patient age and weight across all children or a targeted population or are multiple formulations required, including for preterm or low-birth-weight infants? • Patient and programme acceptability. Are the route of administration, the dosage form (size and volume), dose frequency and duration, palatability (for oral formulations) and the irritation or discomfort on administration (for topical and parental agents) acceptable for patients and caregivers? • Administration. Can the required doses be easily and accurately administered with minimal preparation? Does splitting (if relevant) deliver appropriate dosing (functional scoring present)? Are administration devices readily available (if required and appropriate for the intended use (able to measure and/or deliver the required doses accurately and easily)? Considerations should include the setting where the medicine will be administered (home versus health-care facility). • Special handling. Does the formulation require any special shipping, distribution or storage capacity requirements (freezing or refrigeration, either in a pharmacy or home setting)? • Cost. Although current cost should not be the deciding factor in selecting a drug, the comparative cost of similar drugs and drug formulations should be considered. 04 Review access to and market for existing formulations This step aims to inform the PADO group on activities already ongoing by appropriate procurement agencies (UNICEF, the Stop TB Partnership Global Drug Facility (GDF), Global Fund and Pan American Health Organization) and the Medicines Patent Pool and intends to leverage existing access and market-shaping initiatives by flagging global access issues and any persisting intellectual property barrier (7) and reviewing any procurement and supply constraints that may result from market fragmentation. This will include considering national registration processes (timelines and barriers) and anticipated changes resulting from phasing in and phasing out new products. Even though PADO participants will discuss in detail access- and registration-related issues, the group should be aware of any anticipated issues with specific formulations that may impact timelines. For example: The TB Procurement and Market-Shaping Action Team led by the Global Drug Facility and comprising numerous TB stakeholders (8) is charged with identifying and addressing market and other issues that delay or limit access to optimal TB regimens and products. 13 PADO process 2 https://www.treatmentactiongroup.org/resources/pipeline-report/2020-pipeline-report 05 Review the drug pipeline for the therapeutic area This step reviews the investigational drug pipeline for the therapeutic area to describe promising drug candidates for both adults and children and review timelines for investigation in various populations. This step may build on parallel processes undertaken in the general adult population such as conferences on antiretroviral drug optimization (9) and is informed by broad industry outreach to gather updates before the meeting. This step is designed to anticipate future policy change as a result of new preventive and therapeutic approaches suitable for low- and middle-income countries. An example is Treatment Action Group reports.2 06 Review the research landscape for using drugs for children This step includes mapping current evidence and ongoing research on using relevant therapeutics for infants and children with the goal of examining the research gaps being addressed by ongoing studies and better informing timelines for product development and how they might contribute to policy. This work typically includes systematic literature review, data-mining efforts, carefully consulting clinical trial registries, conference proceedings, ongoing toxicity surveillance efforts and broad proactive outreach to innovators, research networks, product development partnerships and other stakeholders active in the therapeutic area. For some therapeutic areas, this review might also require carefully considering ongoing research on adults, especially to anticipate policy changes and inform long-term priorities and the related research agenda. 07 Review the technology landscape for drug delivery for children This step intends to review existing and anticipated technologies to inform the preferred product characteristics for priority formulations for children that are to be investigated and developed. This is an essential step to ensure that innovative technologies are considered and applied to address the most pressing needs. This review would likely be an integrated effort across therapeutic areas and only tease out disease-specific considerations as appropriate. It requires examining the existing product landscape and proactive outreach to academia and innovators who may be undertaking early-stage research on some of the novel technologies being considered (10). Carefully considering cost and the implications for scale to low- and middle-income countries will be critically important. 14 PAediatric Drug Optimization standard procedure RESEARCH AND DEVELOPMENT PRIORITIZATION 08 Refine and apply product priority-setting tool This step allows for a structured discussion among the expert group and represent the critical part of the process to define the priority list and watch list. The tool could be designed as a Pugh Matrix (a criteria-based decision matrix) and contains a number of criteria that can be adapted to the therapeutic area and help to systematically consider topics such as: efficacy, safety, drug–drug interactions, frequency and ease of administration, palatability, dosage form, time to develop, existing gaps in critical information (clinical, development etc.) and dosage flexibility. A system for scoring the various criteria helps to organize discussions and identify the priorities. An example can be found here. Formulations should be removed from the PADO priority list when: • they have been developed by at least two suppliers who can guarantee access to low- and middle-income countries or the sole source can be considered reliable and sustainable (based on the input from market- shaping entities); • new evidence is available on the efficacy, safety, dosing or acceptability of these or other drugs that indicates that a product previously given priority is no longer the best choice for children (until new evidence is available, the formulation should be retained); and • new or anticipated policy or guidelines change. 09 Define the research agenda for drug optimization This step requires reviewing the key discussion points during the course of the meeting and identifying the key research gaps to be addressed so that the drug products and formulations on the PADO lists can be developed and used effectively. These gaps often primarily relate to the evidence needed to inform dosing, product development and approval but may include research to inform the optimal use of these formulations in specific settings or populations. Finally, the gaps to be considered may also include remaining research questions to enable optimization of use of existing formulations. 15 PADO process ALTERNATIVE OPTIONS FOR ADOPTION AND ADAPTATION In some situations, the PADO process might need to be integrated or coordinated with other ongoing work in the technical areas. For example, several departments routinely revise their research and development pipeline directly or in collaboration with other stakeholders (such as the antimicrobial resistance clinical pipeline) or develop target product profiles or preferred product characteristics for therapeutics. The PADO process can easily be linked and adapted to avoid duplication and enable seamless implementation. If the research and development pipeline is available or being reviewed The PADO process can offer an opportunity to explore the detailed needs and gaps for children. Once the pipeline analysis is completed (whether led by WHO or in collaboration with other stakeholders), a small group of experts and interested stakeholders can be convened to review the research and development pipeline work, identify appropriate nuances for children and include a list of priority formulations to be developed for children (PADO lists). The process would be the same as the PADO process but could be easier since it will build on the pipeline work already completed for the general population. If target product profiles and preferred product characteristics are available or are being developed The target product profile and preferred product characteristics processes are often designed to address the general population, so the PADO process can complement this effort by focusing on the specificities for children. The PADO process should ideally be undertaken at the end of the target product profile and preferred product characteristics process so that the outcome can fully inform the component for children. In some instances, the PADO process might be integrated into the development of the target product profile and preferred product characteristics as a specific chapter or session as long as the appropriate expertise and steps to discuss the priorities for children are undertaken. DISSEMINATION A meeting report – including a summary of the latest developments presented, the rationale for modifications agreed by the group and the updated PADO priority and watch lists with appropriate commentary and description – will be developed following PADO full review meetings. The report will be published on the WHO website and will be disseminated among participants and relevant stakeholders, including academic institutions, research networks, industry and product development partnerships and funders. Additional opportunities for disseminating PADO-related discussions and outcomes should be sought. These should include: • sharing posters or oral presentations at relevant international conferences and symposia; • publishing in peer-reviewed journals: • debriefing relevant technical working groups; • debriefing GAP-f network members; and • dedicated webinars to inform innovator and generic pharmaceutical companies. Following virtual interim reviews of the PADO priorities, a one- or two-page brief will be developed, highlighting the main discussion topics and outlining drugs and formulations in the PADO lists that might represent potential shifts in priorities for which a final decision will be taken in the upcoming PADO full-review meeting. The brief will be published on the WHO website to ensure wide access. 16 PAediatric Drug Optimization standard procedure ACKNOWLEDGEMENTS WHO gratefully acknowledges the contributions of many individuals to develop this guidance document. Martina Penazzato (Department of Research for Health) led the development of the document under the leadership of John Reeder (Director, Department of Research for Health) and with the contribution of Tiziana Masini (consultant, Global Tuberculosis Programme) and Asma Hafiz (Department of Research for Health). The following WHO staff provided technical input and review: Annemieke Brands, Sabine Verkuijl, Kerri Viney (Global Tuberculosis Programme), Marie Valentin (Department of Regulation and Prequalification), Roberta Oritz Sequeira (Department of Noncommunicable Diseases), Vaseeharan Sathiyamoorthy (Department of Research for Health) and Wilson Milton Were (Department of Maternal and Child Health). WHO thanks the following individuals from the GAP-f Network member organisations who provided peer review: Anthony Garcia-Prats (Stellenbosch University), Brenda Waning and Brian Kaiser (Stop TB Partnership Global Drug Facility), Courtney Jarrahian (PATH), Elaine Abrams (ICAP at Columbia University), Janice Lee (Drugs for Neglected Disease initiative), Linda Lewis, Melynda Watkins and Paul Domanico (Clinton Health Access Initiative), Lindsay McKenna (Treatment Action Group), Marc Lallemant (Penta Clinical Research), Mary Atieno Ojoo (Unicef), Sébastien Morin (Medicines Patent Pool), Tim Cressey (Programme for HIV Prevention and Treatment, Chiang Mai University). 17 RESOURCES Unitaid landscape on innovative delivery systems for paediatric medicines technology https://unitaid.org/assets/Innovative-delivery- systems-for-paediatric-medicines-technology- landscape.pdf LEAP landscape https://longactinghiv.org/topics PADO-HIV 1 https://www.who.int/hiv/pub/guidelines/ arv2013/arv2013supplement_to_chapter07. pdf?ua=1 PADO-HIV 2 https://www.who.int/hiv/pub/meetingreports/ paediatric-arv-optimization/en/ PADO-HIV 3 https://www.who.int/hiv/pub/meetingreports/ paediatric-arv-optimization-pado3/en/ PADO-HIV 4 https://www.who.int/hiv/pub/meetingreports/ paediatric-arv-optimization-pado4/en/ PADO-TB 1 http://stoptb.org/wg/dots_expansion/ childhoodtb/assets/documents/PADO-TB1_ Meeting_Report_FINAL_v8March2019.pdf PADO-TB 1 virtual review https://apps.who.int/iris/bitstream/hand le/10665/340316/9789240022157-eng.pdf PADO-Hep 1 http://gap-f.org/wp-content/uploads/2019/06/ GAP-f__Outcomes_of_PADO_HIV_and_ HCV__2018-12-19__Slide_set__3__HCV.pdf Prescribing medicines for children https://www.pharmpress.com/ product/9780857111357/prescribing-medicines- for-children REFERENCES 1. 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