TOOLKIT FOR RESEARCH AND DEVELOPMENT OF PAEDIATRIC ANTIRETROVIRAL DRUGS AND FORMULATIONS WHO and UNITAID in collaboration with IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) network, PENTA (Paediatric European Network for Treatment of AIDS) foundation and experts from the Paediatric Antiretroviral Working Group
CPAEDIATRIC PHER HIV MATTERS ©WHO/Anna Kari TOOLKIT FOR RESEARCH AND DEVELOPMENT OF PAEDIATRIC ANTIRETROVIRAL DRUGS AND FORMULATIONS WHO and UNITAID in collaboration with IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) network, PENTA (Paediatric European Network for Treatment of AIDS) foundation and experts from the Paediatric Antiretroviral Working Group
CPAEDIATRIC PHER HIV MATTERS Toolkit for research and development of paediatric antiretroviral drugs and formulations
ISBN 978-92-4-151436-1
© World Health Organization 2018 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. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Toolkit for research and development of paediatric antiretroviral drugs and formulations. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The photographs in this material are used for illustrative purposes only; they do not imply any particular health status, attitudes, behaviors, or actions on the part of any person who appears in the photographs. Photo credits: Front and back covers: 1, ©WHO/Stéphane Saporito; 2, ©WHO/Christopher Black; 3, ©DNDi/Scholars & Gentlemen; 4, courtesy of Photoshare; 5, ©WHO/TDR /Andy Craggs; Inside cover, ©WHO/Anna Kari. Page 5, ©WHO/Christopher Black; page 7, ©WHO/Christopher Black; page 12, ©WHO/Sergey Volkov; page 15, ©WHO/Christopher Black, page 32, ©WHO/Garry Smyth; page 38, Courtesy of Photoshare; page 51, ©ICAP/ Sven Torfinn; page 67, ©WHO/Eduardo Soteras Jalil; page 72, Courtesy of Photoshare; page 79, ©WHO/SEARO/ Gary Hampton; page 84, ©WHO/Sergey Volkov; page 110, Courtesy of Photoshare; page 114, ©WHO/Stéphane Saporito; page 126, ©DNDi/Scholars & Gentlemen; page 137, ©DNDi/Anita Khemka; page 144, ©WHO/Sergey Volkov; page 154 ©ICAP; page 164, ©Deidre Schoo; page 168, ©WHO/Petterik Wiggersn; page 177, Courtesy of Photoshare; page 184, ©WHO/Harry Anenden; page 191, ©WHO/TDR/Andy Craggs. Layout: 400.co.uk Printed in Switzerland CONTENTS
Abbreviations ...... iv
Acknowledgements ...... vi
Introduction ...... 1
Module 1: Trial design ...... 9
Module 2: Pharmacokinetic modelling ...... 32
Module 3: Pregnant and breastfeeding women ...... 45
Module 4: Coinfections ...... 61
Module 5: Acceptability ...... 78
Module 6: Community engagement ...... 104
Module 7: Target product profiles ...... 120
Module 8: Product commercialization ...... 138
Module 9: Regulatory filing...... 148
Module 10: Pharmacovigilance ...... 162
Conclusion ...... 185
iii ABBREVIATIONS
3TC lamivudine ABC abacavir ART antiretroviral therapy ARV antiretroviral AUC24 h 24-hour area under the concentration–time curve C24 h 24-hour plasma concentration CL clearance CYP cytochrome 450 DTG dolutegravir EFV efavirenz EMA European Medicines Agency EU European Union FDA United States Food and Drug Administration FTC emtricitabine HBV hepatitis B virus HCV hepatitis C virus IMPAACT International Maternal Pediatric Adolescent AIDS Clinical Trials LPV/r lopinavir/ritonavir NRTI nucleoside reverse-transcriptase inhibitor PANNA Pharmac okinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women PENPACT PENTA 9/PACTG 390 PENTA Paediatric European Network for Treatment of AIDS PEPFAR United States President’s Emergency Plan for AIDS Relief TAF tenofovir alafenamide TB tuberculosis TDF tenofovir disoproxil fumarate UGT uridine diphosphate-glucuronosyltransferase UNICEF United Nations Children’s Fund WT body weight
iv ©WHO/Christopher Black
v ACKNOWLEDGEMENTS
The toolkit for research and development of States Food and Drug Administration or the paediatric antiretroviral drugs and formulations European Medicines Agency, or members of was developed under the leadership of the the European Medicines Agency Paediatric Treatment and care team in the HIV Department, Committee, are their own and may not be WHO, and supported by the WHO Paediatric understood or quoted as being made on behalf Antiretroviral Working Group. The project was of or reflecting the position of the United led by Martina Penazzato (WHO Paediatric HIV States Food and Drug Administration or of Lead, Geneva, Switzerland) and coordinated by the European Medicines Agency or any of its Claire Townsend (WHO consultant, Geneva, committees or working parties. Switzerland). Each module was drafted by one or more co-authors (listed in each module), The contents of this document do not with input from other collaborators and the necessarily reflect the official views of the project team. Designated reviewers reviewed the United States Department of State. modules, including at least one member of the The toolkit was developed with the financial Paediatric Antiretroviral Working Group and one support of Unitaid, the International Maternal external reviewer. Input from representatives of Pediatric Adolescent AIDS Clinical Trials drug manufacturers and regulatory authorities (IMPAACT) Network and the PENTA Foundation. was sought at key stages. The work of the Clinton Health Access Initiative WHO and Unitaid thank everyone who on optimal antiretroviral drugs for children is made contributed to developing this toolkit, including possible through the generous support of Unitaid. individuals from the Clinton Health Access Initiative, Drugs for Neglected Diseases initiative, List of partner organizations Medicines Patent Pool, ICAP at Columbia
University, the European Paediatric Formulation ■■ International Maternal Pediatric Adolescent Initiative and the IQ Consortium Drug Product AIDS Clinical Trials (IMPAACT) Network Working Group. ■■ PENTA-ID Network
Specifically, we thank the following individuals ■■ Unitaid for their input: Elaine Abrams (ICAP at Columbia ■■ Drugs for Neglected Diseases initiative University, New York, NY, USA), Sharon Nachman (State University of New York at Stony Brook, ■■ Clinton Health Access Initiative USA), Polly Clayden (HIV i-base, London, United ■■ United Nations Children’s Fund Kingdom), Carlo Giaquinto (University of Padua, ■■ ICAP at Columbia University Italy), Marissa Vicari (International AIDS Society, Geneva, Switzerland) and Diana Gibb (University ■■ Elizabeth Glaser Pediatric AIDS Foundation College London, United Kingdom). ■■ Industry Liaison Forum Comments were also provided by the Division ■■ United States President’s Emergency Plan of Antiviral Products of the United States Food for AIDS Relief and Drug Administration and by representatives ■■ Collaborative Initiative for Paediatric HIV of the European Medicines Agency and Education and Research members of the European Medicines Agency ■■ Medicines Patent Pool Paediatric Committee. Any views expressed in this publication by employees of the United vi INTRODUCTION
©WHO/Christopher Black
1 1. BACKGROUND
In 2016, an estimated 2.1 million children younger 1.1 Challenges in developing ARV drugs than 15 years and 17.8 million women were living for children with HIV worldwide (1). Despite advances in antenatal HIV testing and prevention of mother- Research and development of formulations of to-child transmission, about 160 000 children ARV drugs for children has traditionally lagged were newly infected with HIV in 2016, mainly in behind those for adults, with delays of up to a low- and middle-income countries (1). decade (Fig. 1) (5). The development of drugs for WHO recommends that all children diagnosed children is often only considered once preclinical, with HIV start antiretroviral therapy (ART) Phase I and Phase II studies end, which can take regardless of symptoms or clinical stage (2). This many years. The development of fixed-dose drive toward universal ART coverage has meant a combinations for children, which combine two huge increase in the number of eligible children, or more drugs into a single dosage form such as but less than half of the children who are eligible a tablet, requires additional steps and results in start treatment (3). There are many reasons for further delays (Fig. 1). this, including barriers to access to health care and Although regulatory frameworks in both the specifically HIV services, delays in HIV diagnosis, United States and Europe have encouraged the complexity of ART regimens for children and and provided incentives to programmes for difficulties in administering treatment to them and developing drugs for children, the development lack of support for families affected by HIV. and approval of such formulations has remained Compounding these issues is the lack of safe, a lengthy process (5,6). Further, the shrinking effective and well tolerated drugs in formulations market for drugs for children in high-income adapted for children of different ages, which countries, where rates of vertical HIV transmission has remained a key barrier to implementing are now extremely low, has further reduced the WHO treatment guidelines in low- and middle- incentives manufacturers have to invest in this income countries (4). Only about one quarter area. Fragmentation of the market has also been of antiretroviral (ARV) drugs approved by the an issue, resulting from the need for weight- United States Food and Drug Administration appropriate doses and formulations (5). (FDA) or the European Medicines Agency (EMA) for adults are approved for children younger than two years (5). Expediting the availability of 1.2 Recent initiatives to accelerate the such formulations is essential to scaling up of development of ARV drugs for children HIV treatment for children, to ensure that global targets can be met and that children with HIV In response to the need for novel approaches worldwide receive the treatment they need (5). to accelerate and streamline the process of developing ARV drugs for children, several A general paucity of treatment options for initiatives have been launched in recent years. pregnant and breastfeeding women also persists The WHO-led Paediatric Antiretroviral Drug as a limiting factor in treating this population Optimization group has established a set of mid- and preventing vertical transmission. Efforts to and long-term priorities for drug development ensure pregnant women are included in studies to accelerate access to optimal formulations and to rapidly generate safety data for use of in the context of fragmented markets for ARV new compounds are urgently needed.
2 Figure 1. Stages in developing and introducing fixed-dose combinations of ARV drugs for children
Approval by a Clinical trials to New compound Approval by a New compound in stringent regulatory compare the new in Phase I and II stringent regulatory Phase I and II trials: authority: age-based compound with the trials: simultaneous authority: weight- age-staggered mg/kg dose standard of care enrolment based dosing
Pharmacokinetic Pharmacokinetic Introduction in Introduction in modelling to inform modelling to inform Validation of ARV guidelines clinical guidelines the development the development weight-band dosing with weight-based with weight-based of fixed-dose of fixed-dose dosing dosing combinations combinations
Formulation Approval by a Formulation Approval by a Clinical studies development: stringent regulatory development: stringent regulatory to validate biostability and authority and in- biostability and authority and in- formulation bioequivalence country registration bioequivalence country registration
5–9 years from the development 2–3 years from the development of formulations for adults of formulations for adults
Source: adapted from Penazzato et al. (5). drugs for children (6–8). In conjunction with this, The Paediatric Antiretroviral Working Group WHO treatment guidelines (2) now recommend provides technical guidance on weight-band a limited set of regimens for children and have dosing and pharmacokinetic and acceptability harmonized recommendations for adults and studies of ARV drugs for children (12). ARV drug adolescents. manufacturers are encouraged to engage with the Paediatric Antiretroviral Working Group WHO also recommends the use of weight from an early stage when developing dosing and bands and weight-based dosing in developing designing pharmacokinetic and safety studies. drugs (rather than age-based dosing) to simplify and facilitate the implementation Platforms have also been established to support of treatment guidelines. WHO weight-band different stages of drug development and dosing (9) is a simplified approach to guide introduction. The Paediatric HIV Treatment age-appropriate dosing through which drugs Initiative (11) was established to overcome have been successfully delivered. This approach intellectual property barriers that prevented was recently revised to incorporate allometric individual drugs manufactured by different scaling, a method that accounts for the non- companies from being combined into fixed-dose linear relationship between weight and drug combinations and to facilitate and partly support clearance. The paediatric ARV drug formulary the development of key priority products. (10), developed by several international partners, provides guidance to HIV treatment Although these various steps have been programmes on product selection to deliver hugely beneficial in facilitating the process of WHO-recommended regimens. developing HIV drugs for children and bridging structural barriers, the availability of formulations for children remains inadequate. It has been
3 recognized that, with the development of new research, development, regulatory filing and drugs and indeed new classes of ARV drugs, such introduction and uptake of key ARV drugs for as long-acting injectable drugs, researchers, drug children in age-appropriate formulations, with manufacturers and regulators need to engage a target year of 2020. This framework aims earlier in the process of developing drugs (4). to capitalize on existing efforts to maximize the coordination and alignment of the public In 2016, the concept of a Global Accelerator and private sectors, including policy-makers, for Paediatric Formulations (12) was developed research networks, regulatory agencies, to build on existing initiatives and accelerate funding organizations and manufacturers.
2. OVERVIEW OF THE TOOLKIT
This section outlines the rationale, aims, engaged in developing and approving drugs objectives and intended audience of the toolkit and formulations;
and provides an overview of the modules. ■■ to establish overall standards to accelerate ARV drug investigation and approval while 2.1 Rationale for this toolkit enabling more rapid development of formulations for children; and
The toolkit was developed under the umbrella ■■ to promote alignment and coordination of the Global Accelerator for Paediatric between key stakeholders involved in developing Formulations initiative to address some of and approving drugs and formulations. the remaining challenges in developing HIV drugs for children and to serve as a global 2.3 Toolkit audience standard for accelerating high-quality research and development in this field. It provides an This toolkit targets: opportunity to capitalize on best practices and to set standards that enable drugs and formulations ■■ innovator and generic drug manufacturers; to be developed and introduced more rapidly. ■■ researchers involved in research and development related to HIV drugs for children; and 2.2 Aims and objectives ■■ nongovernmental and other organizations with an interest in drug development. The aim of this toolkit is to facilitate faster, more efficient and focused development of new formulations for the effective treatment of 2.4 Overview of the modules infants, children and adolescents living with HIV by synthesizing key considerations for different The toolkit comprises 10 modules, each addressing stages of the drug development process. a key area in the research and development of HIV The specific objectives of the toolkit are: drugs for children (Fig. 2). ■■ to provide guidance to manufacturers The first two modules address the generation (generic and innovator) and to researchers of data to support regulatory approval of ARV
4 Figure 2. Outline of the modules included in this toolkit
Toolkit for research and development of paediatric antiretroviral drugs and formulations
Research and Specific Patient Getting to Monitoring development populations experience market
Module 1 Module 3 Module 5 Module 8 Module 10 Trial design Pregnant and Acceptability Product Pharmacovigilance breastfeeding commercialization Module 2 Module 6 women Pharmacokinetic Community Module 9 modelling Module 4 engagement Regulatory filing Coinfections Module 7 Target product profile
drugs for children, by carefully designing and Module 2 on pharmacokinetic modelling implementing clinical trials and pharmacokinetic addresses how to establish appropriate modelling studies. Traditionally, research studies pharmacokinetic targets and doses for neonates among children have been delayed until sufficient and other children and describes some of the adult data on pharmacokinetics, safety and innovative methods that have been developed to efficacy have been obtained. Studies to ascertain answer these questions. correct dosing are then carried out sequentially, starting with older age groups. Module 3 addresses issues relating to pregnant and breastfeeding women, another population Module 1 on trial design discusses the key barriers poorly represented in drug development studies. to including children and adolescents in clinical This module recognizes the close interaction trials. These include ethical concerns as well as between maternal and infant health and the issues relating to market fragmentation and the importance of expanding access to treatment reluctance of manufacturers to invest resources for pregnant and breastfeeding women for in clinical trials involving children. This module preventing vertical transmission and treating the discusses the various ways of obtaining safety and mother. Including pregnant women in clinical trials efficacy data, by maximizing the use of available and pharmacokinetic studies is encouraged. It is data, advance planning of studies involving children also recommended that protocols allow women and using innovative trial designs to generate becoming pregnant during a trial involving non- the required data quickly and efficiently without pregnant adults to stay on the investigational compromising patient safety. Recommendations drug (or, if they stop the investigational drug, to include enrolling adolescents in adult clinical trials remain in the study), with appropriate follow-up to and simultaneous enrolment across different monitor pregnancy and infant outcomes. A more weight bands for younger children. inclusive approach to involving pregnant women in
5 clinical trials will also enable and facilitate research formulations, which can affect adherence and in on pharmacokinetics among neonates. turn resistance, which can compromise efficacy. Current regulations require drug companies to Module 4 on coinfections discusses challenges consider the specific needs of children, including relating to treating people living with HIV who the appropriateness of a formulation. Studies of are coinfected with hepatitis B or C viruses acceptability should be carried out early enough or tuberculosis (TB), an issue of particular to enable a formulation to be modified if required. importance in low- and middle-income countries, This module emphasizes the need for standardized where most children living with HIV reside. protocols for evaluating all components of To accelerate access to appropriate drugs, acceptability in the target age groups and for adolescents coinfected with TB or hepatitis B using standardized metrics. It advocates for or C should also be eligible for enrolling in trials systematically including acceptability studies in all for adults, and consideration should be given to research protocols involving children and stringent including coinfected children in trials for children. reporting of study findings. Good communication The potential for drug–drug interactions should should be established across stakeholder groups, be considered early in ARV drug development, so including formulation scientists, clinicians, research that timely and effective solutions can be found. teams, social scientists and regulators, and children This process can be facilitated by more effective and their caregivers should be involved from an communication between clinicians, researchers early stage. and drug manufacturers. Module 6 on community engagement describes Module 5 on acceptability recognizes the need the importance of involving the paediatric for better understanding of how the acceptability community throughout the process of drug of formulations for children should be defined, development. The paediatric community involves assessed and reported. Treating children poses not only children and adolescents living with specific challenges around the acceptability of HIV but also their parents and caregivers.
©WHO/Sergey Volkov
6 Recommendations for facilitating community Module 10 on pharmacovigilance addresses engagement in HIV drug development include key issues around safety and post-marketing working with community advisory boards and surveillance and monitoring to better establishing community engagement plans, understand the risks and safety profile of ARV which describe strategies and mechanisms to drugs for children in low- and middle-income help researchers collaborate with the relevant countries. WHO recommends a combination community. Engaging community members early of standardized toxicity monitoring, integrated in the research process is also advocated for, as is within national health systems, and active using appropriate language in all communications. surveillance for adverse drug reactions. Better pharmacovigilance systems are needed in many Module 7 explains the role of target product low- and middle-income countries, including profiles in establishing the desired attributes improving data management systems to collate of products before they become available. The data from multiple sources, training health-care purpose of target product profiles is to guide workers and using existing data sets better. industry in developing products that meet the needs of the target users, by outlining the In summary, the need for early and continual critical attributes of a product needed to ensure collaboration between the paediatric research that it is fit for purpose. This module discusses community, innovator and generic pharmaceutical considerations for designing target product companies, regulatory authorities and policy- profiles that will facilitate the development of makers is a recurring theme throughout this optimal formulations. toolkit. Good communication and alignment of stakeholders throughout the process of drug Module 8 on product commercialization addresses development can ultimately ensure that the factors related to commercializing and launching development of optimized ARV formulations for a pharmaceutical product. Once a drug or children can be accelerated and that appropriate formulation becomes available, carefully planning treatment options are made available to children its introduction to the market is important, so living with HIV throughout the world. that production can match demand. This can be achieved by coordinating procurement and the strategic management of demand and is facilitated 2.5 Next steps by rationalizing paediatric formularies.
Module 9 on regulatory filing describes key This toolkit is intended as a resource for those regulatory considerations for expediting involved in developing HIV drugs for children. It submissions for regulatory approval for drugs for will be reviewed periodically and updated when children. Recommendations are made for simpler major revisions are required. paediatric study plans and paediatric investigation Although the focus of this toolkit is HIV among plans; simultaneous product development for children, many of the principles outlined here are adults and adolescents; and a concurrent rather relevant to other disease areas. The toolkit will than sequential approach to enrolling children therefore be disseminated beyond the HIV field in clinical trials across weight bands. Using with the goal of stimulating acceleration for optimal standardized weight bands for dosing in trials products for children in other disease areas. involving children is recommended to facilitate implementation once a drug has been approved.
7 3. REFERENCES
1. UNAIDS data 2017. Geneva: UNAIDS; 8. Penazzato M, Lee J, Capparelli E, Essajee S, 2017 (http://www.unaids.org/en/resources/ Ford N, Ojoo A et al. Optimizing drugs to documents/2017/2017_data_book, accessed reach treatment targets for children and 22 May 2018). adolescents living with HIV. J Int AIDS Soc. 2015;18(Suppl. 6):20270. 2. Consolidated guidelines on the use of antiretroviral drugs for treating and 9. WHO generic tool for assessing paediatric preventing HIV infection: recommendations ARV dosing. Geneva: World Health for a public health approach – second Organization; 2018 (http://www.who.int/hiv/ edition. Geneva: World Health Organization; paediatric/generictool/en, accessed 22 May 2016 (http://www.who.int/hiv/pub/arv/arv- 2018). 2016/en, accessed 22 May 2018). 10. Inter-Agency Task Team (IATT) for Prevention 3. Prevention gap report, July 2016. Geneva: and Treatment of HIV Infection in Pregnant UNAIDS, 2016 (http://www.unaids.org/en/ Women, Mother and Children. Policy brief: resources/documents/2016/prevention-gap, IATT paediatric ARV formulary and limited- accessed 22 May 2018). use list: 2016 update. New York: United Nations Children’s Fund and World Health 4. Penazzato M, Amzel A, Abrams EJ, Kiragu K, Organization; 2016 (http://www.who.int/hiv/ Essajee S, Mukui I et al. Pediatric treatment pub/paediatric/iatt-paediatric-hiv-2016/en, scale-up: the unfinished agenda of the accessed 22 May 2018). Global Plan. J Acquir Immune Defic Syndr. 2017;75(Suppl. 1):S59–65. 11. UNITAID, Drugs for Neglected Diseases initiative (DNDi) and Medicines Patent Pool 5. Penazzato M, Gnanashanmugam D, Rojo (MPP). Paediatric HIV Treatment Initiative P, Lallemant M, Lewis LL, Rocchi F et al. (PHTI): closing the treatment gap through Optimizing research to speed up availability of innovation. Geneva: Drugs for Neglected pediatric antiretroviral drugs and formulations. Diseases initiative; 2016 (https://www. Clin Infect Dis. 2017;64:1597–1603. dndi.org/wp-content/uploads/2014/03/ 6. Penazzato M, Palladino C, Sugandhi N, PaediatricHIVTreatmentInitiative.pdf, Paediatric ARV Drug Optimization 3 Meeting accessed 22 May 2018). participants. Prioritizing the most needed 12. Penazzato M, Lewis L, Watkins M, Prabhu formulations to accelerate paediatric V, Pascual F, Auton M et al. Shortening antiretroviral therapy scale-up. Curr Opin the decade-long gap between adult HIV AIDS. 2017;12:369–76. and paediatric drug formulations: a new 7. Paediatric Antiretroviral Drug Optimization framework based on the HIV experience in (PADO) meeting 3. Geneva: World Health low- and middle-income countries. J Int AIDS Organization; 2017 (http://www.who.int/ Soc. 2018;21(Suppl. 1) (http://www.ncbi.nlm. hiv/pub/meetingreports/paediatric-arv- nih.gov/m/pubmed/29485727, accessed optimization-pado3/en, accessed 22 May 22 May 2018). 2018).
8 MODULE 1: TRIAL DESIGN
©WHO/Christopher Black
9 1. INTRODUCTION
The overarching goal of this toolkit is to facilitate where most children with HIV live (1). To generate the treatment of children with HIV with the most the timely data about modern ARV drugs needed efficacious medications. The selection of the for children in the fast-changing landscape of right drugs and formulations given priority for the ARV drug pipeline and dynamic treatment development is based on target product profiles guidelines, clinical trials must be strategic, (see the module on target product profiles). forward-thinking and efficient in implementation. Nevertheless, before an agent can be approved for use by regulatory bodies or included in national and global guidelines, data about dosing, 1.1 General considerations for HIV drug safety and efficacy must be considered adequate trials involving children in the intended population of children. This module reviews issues in selecting a clinical trial Clinical trials for drug development are classically design to generate the necessary data about a divided into four phases: I to IV (Fig. 1.1). After candidate antiretroviral (ARV) drug for children preclinical study in the laboratory, a drug is as quickly and efficiently as possible. generally first tested in humans in Phase I trials that generate key safety and pharmacokinetic The development and evaluation of ARV drugs and pharmacodynamic data for small numbers for children has historically been slow, with some of participants. Phase I trials are generally dose- agents being approved for children as long as finding trials that might aim to establish the a decade after they were approved for adults maximally tolerated dose for adults or identify (1,2). The limited number of agents with age- the dosing for children that yields exposure appropriate ARV drug dosing and formulations for equivalent to that of adults. Phase II trials children has remained a key barrier to simplifying, confirm safety and explore efficacy to facilitate harmonizing and implementing WHO treatment decisions about further development. Phase III guidelines in low- and middle-income countries, trials are pivotal trials that confirm safety and
Figure 1.1. Phases of clinical trials
Preclinical Phase I Phase II Phase III Phase IV
Pharmacology Evaluate short- Confirm safety Establish efficacy Evaluate long- (pharmacokitetic term safety Explore efficacy versus standard term safety and and care effectiveness Generate Hundreds of pharmacodynamic) pharmacokinetic participants Confirm safety Diverse groups, data and including those Demonstrate the Acceptability Toxicity pharmacodynamic excluded from benefits of the Hundreds to data for humans early trials In vitro and in vivo new treatment thousands of studies in animal Tens of participants Support additional models participants indications Support licensing Identify the safe Identify optimal and change starting dose for dose for a larger practice trials in humans trial
10 establish efficacy among a larger number of submit plans to study the agent among children participants; Phase III data are generally required or request a waiver (3,4). The EMA calls a plan for for regulatory approval of a new drug for adults. study among children a paediatric investigation Phase IV trials generate data on long-term safety plan and the FDA calls it a paediatric study and/or efficacy for a new drug after it has been plan. Stringent regulatory authorities require licensed in real-world conditions across different a paediatric investigation plan or paediatric populations. Developing drugs for children and study plan for every new drug being developed treatment optimization trials often combine for adults that is considered to be relevant features of different phases, commonly blending for children. Paediatric investigation plans Phases I and II and Phases II and III. or paediatric study plans are required to be submitted early in drug development (3,4) Clinical drug trials can also be classified into two and must be established before filing for the broad categories: regulatory and strategy trials. marketing authorization (Fig. 1.2 and the module Regulatory trials are conducted for licensing on regulatory filing). Trials for developing and applications that seek approval by stringent evaluating drugs for children are usually started regulatory authorities and may include features once trials involving adults show substantial of Phase I–III trials (dose-finding, safety and evidence of the efficacy and safety of the drug efficacy), depending on the extent to which of interest. Waivers are difficult to obtain but can the relevant data from adult studies can be be granted if an agent is not thought to have a extrapolated (see below). These trials generally role in care for children and/or because it would focus on pharmacokinetics and safety and use be logistically impossible to study (such as finding age-appropriate drug formulations for children eligible child participants being too difficult). already tested in adults for bioequivalence with In determining which data are needed to support the adult formulations. regulatory approval of an agent for use among To secure approval for an agent for adults, children, it is critical to first ask what data can be stringent regulatory authorities such as the extrapolated from adult trials and what data must United States Food and Drug Administration be generated de novo in trials involving children. (FDA) or European Medicines Agency (EMA) Fig. 1.3 summarizes FDA guidance on this topic. require pharmaceutical companies to either Depending on evidence-based assumptions on
Fig. 1.2. Timing of the development pathway for HIV drugs for children
Adult drug development Marketing authorization for adults
Preclinical Phase 1 Phase 2 Phase 3 Phase 4
Submit paediatric investigation Yes Clinical trials among children Is the drug plan or paediatric Deferral if neededa relevant for HIV study plan among children? No Apply for waiver aAdditional efficacy and safety data for adults are needed before initiating studies among children. Source: reprinted from The Lancet Oncology, 14, Vassal G, Zwaan CM, Ashley D, Le Deley MC, Hargrave D, Blanc P et al., New drugs for children and adolescents with cancer: the need for novel development pathways, e117–24, Copyright (2013), with permission from Elsevier. (5)
11 the appropriateness of extrapolating efficacy from treatment and exposure–response relationships adult trials, the regulatory trials can differ in design, are similar for children and adults, and efficacy ranging from non-comparative studies evaluating evidence from adult Phase III trials can therefore pharmacokinetics and safety (extrapolation be extrapolated to children. In other words, Phase possible) to a randomized controlled trial, I/II pharmacokinetic and safety non-comparative evaluating pharmacokinetics, safety and efficacy trials are generally considered sufficient to support (no extrapolation possible). Some agents, such regulatory approval of ARV drugs for children if as immunomodulatory agents designed for cure the same exposure as for adults can be achieved. strategies, may rely on mechanisms that cannot be reasonably extrapolated to children; these agents In contrast to regulatory trials, strategy trials are require more study, probably including evidence of used to evaluate various treatment approaches, efficacy for children, to be approved. Nevertheless, such as the sequence of regimens for first-, for studies of most ARV drugs that target the second- and third-line therapy, treatment viral life cycle among children, it is generally simplification and use of more pragmatic dosing accepted that progression of HIV, response to compared with the standard of care and focus on
Fig. 1.3. Algorithm for planning and extrapolating studies for children
Do children have similar (1) disease progression and (2) response to treatment to adults?
No to either Yes to both
Do children have similar exposure response to adults?
No Yes
Is there pharmacodynamic measurement to predict efficacy in children?
No Yes
No extrapolation Partial extrapolation Full extrapolation
Conduct among Conduct among children: Conduct among children: children: 1. Pharmacokinetic and pharmacodynamic 1. Pharmacokinetic studies 1. Studies to studies to establish exposure response among aimed at achieving establish dosing children for pharmacodynamic measurement exposure similar to that for adults 2. Safety and efficacy 2. Pharmacokinetic studies to achieve target studies at the exposure based on exposure response 2. Safety studies among identified dose(s) children at the 3. Safety studies among children at the identified dose(s) identified dose(s)
Sources: adapted from General clinical pharmacology considerations for pediatric studies for drugs and biological products: guidance for industry 2014 (4) and Dunne et al. (6).
12 effectiveness (efficacy in the real world). Strategy possible. Strategy trials are usually Phases III–IV trials aim to optimize drug delivery and uptake, and use randomized controlled designs, although to improve safety, adherence, acceptability or single-arm designs can be also used when a quality of life and to explore potentially better randomized controlled trial is not feasible and the treatment options for children with coinfections. assumptions for thresholds for success or failure These trials can nest pharmacokinetic substudies can be prespecified (12). to evaluate dosing differing from the licensed The effectiveness of an agent or regimen in dosing, such as once-daily dosing (7–9) or more pragmatic dosing with a limited number of real-world use is generally studied using large formulations to simplify procurement, prescribing observational databases from clinical settings. and drug administration (10). Strategy trials are Such studies can only be carried out once an usually carried out after a stringent regulatory agent has been approved and distributed for use authority has already approved a drug, but the in routine clinical care. These types of studies regulatory and strategy trials may overlap (Fig. can be useful for modifying guidelines and 1.4) (10,11). Strategy trials often bridge a gap from informing new strategy trials (see the module on the data required for regulatory approval to the pharmacovigilance). data needed to inform clinical use and guideline development and address the existing knowledge 1.2 Approach to trial design gaps in pharmacokinetics and pharmacodynamics, pharmacogenomics and long-term age-specific The process of any trial design starts with toxicity. Given the cost and time to set them up, clarifying the key questions defining the main they must efficiently answer as many questions as
Fig. 1.4. Developing drugs and optimizing treatment for children living with HIV: from dose-finding to clinical practice
Adult data
Regulatory trials
Dose-finding study Strategy trials
Safety (± efficacy) at the identified dose Efficacy and effectiveness and longer-term safety ■■ Simplifying dosing ■■ Combination treatments ■■ Treatment reduction Drug label approval by ■■ Other treatment optimization strategies regulators
Expanded indication or new labelling for children
Guidelines and policies
Clinical practice
13 objectives. Primary outcomes answer the among people for whom surrogate endpoints most important questions and are measured could not be measured in time. Secondary by the primary endpoints. In trials evaluating endpoints measure other important outcomes for drugs, a primary endpoint can be targeted drug patients, clinicians and policy-makers, such as the exposure parameters, safety outcome (such as safety, tolerability, adherence, acceptability and the proportion or rate of clinical and laboratory cost–effectiveness of the intervention. adverse events) or efficacy outcome (such as survival or absence of progression in HIV disease). Box 1.1 and Fig. 1.5–1.8 briefly summarize the trial A good endpoint should be clinically relevant, designs, including advantages, limitations and (13) provide more details on well defined and objective. Validated surrogate examples. Ford et al. HIV strategy trials involving children. endpoints correlating with clinical outcomes are frequently used to speed up treatment evaluation Good design is one of the most important (such as HIV-1 viral load suppression at certain aspects of a clinical trial. Poor design could cause time points). Many contemporary trials set a resources to be wasted or a promising treatment composite primary endpoint that combines clinical to be wrongly abandoned, and this is arguably and surrogate endpoints. This enables the capture unethical for trial participants who need new of a clinically relevant endpoint (such as death) treatment options.
Box 1. Examples of clinical trial designs
Open-label single-arm trial
Single-arm trials are commonly used for initially assessing safety and efficacy of novel regimens (Phases I and II) before proceeding to evaluation in a randomized controlled trial. They are also used when randomized controlled trials are not feasible (such as evaluating treatment in a small population with specific characteristics). In these trials, pre-specified safety and efficacy thresholds based on previous trials are used for comparing with the experimental intervention (12). The advantages of the design are small size and often short trial duration, whereas disadvantages include limited generalizability and comparability with the results of previous trials, since the difference with the set threshold can result from other factors than the studied intervention (12).
The design is also commonly used for pharmacokinetic and safety evaluation of drugs for children when (1) disease progression, (2) response to treatment and (3) response to exposure are assumed to be similar among children and adults (6). The trials start with the initial estimated doses for each age- or weight-based cohort using modelling and simulation that target exposure similar to those for adults. The sample size for evaluation of drug exposure is determined by variability (standard deviation) of the pharmacokinetic parameter of interest. The estimates of variability can be obtained from different sources, including pharmacokinetic studies in adults, physiologically based pharmacokinetic models, previous pharmacokinetic studies involving children and pharmacokinetic studies of drugs with similar physiochemical and metabolic characteristics (14). One approach to estimate the sample size would be to target a 95% confidence interval within 60% and 140% of the geometric mean estimates of clearance and volume of distribution for each subgroup of children to achieve at least 80% power (15). Two approaches for data analysis can be used: a standard non-compartmental pharmacokinetic approach and a population pharmacokinetic approach. The FDA (4) has provided further guidelines on dose selection, sample size and data analysis for children.
14 Evaluating safety at the selected doses aims to assess any signals of toxicity identified in animal studies and trials involving adults. However, trials involving children are generally not required to be powered for assessing specific adverse reactions in a statistically rigorous way. The sample size is often determined by the size of the affected population; a sample size of 100 patients across a range of ages is commonly considered as a minimum requirement, since it provides some confidence that a specific adverse reaction is observed at least once in the trial if the true rate is at least 3% (16). The length of follow-up for chronic infections is usually 24–48 weeks. Longer-term safety monitoring may be warranted if there are growth and development concerns. The trials can also provide supportive (non-confirmatory) efficacy results that can be indirectly compared with the current standard of care based on previous trials. IMPAACT (International Maternal, Pediatric, Adolescent AIDS Clinical Trials) P1066 was a Phase I and II open-label multicentre trial evaluating the dosing and safety of multiple raltegravir formulations for children (17,18). The shortcomings of this approach become apparent if the initial studied dose does not reach the target, causing the trial to be extended. Parallel dose-ranging short pilot studies and adaptive designs can provide valuable solutions (see below).
Traditional randomized controlled trials
A randomized controlled trial is a gold standard for evaluating various treatments. In a traditional two-arm trial, participants are randomly allocated to one of the treatment arms: intervention or control. The control arm receives current standard of care, alternative treatment or, if appropriate, placebo. Although the parallel design enables rigorous comparison of two treatments, randomized controlled trials can be costly and laborious to perform and should therefore generally be reserved for questions that will clearly change management. The PROMOTE paediatric trial randomized children to non-nucleoside reverse-transcriptase inhibitors or lopinavir-based antiretroviral therapy (ART) (19).
Multi-arm trials (Fig. 1.5)
Participants are randomized to one of several interventions or control. The design is more efficient than a two-arm randomized controlled trial because the same control group can be compared with each of the interventions (multiple pairwise comparisons) and because testing multiple interventions increases the chance of a positive answer. Like randomczed controlled trials, multi- arm trials are large and costly to perform and should generally be reserved for evaluating several pressing questions or multiple agents. CHAPAS-3 was a three-arm trial comparing stavudine, zidovudine and abacavir as part of regimens based on non-nucleoside reverse-transcriptase inhibitors and powered for toxicity as primary outcome (20).
Fig. 1.5. Multi-arm trials and multi-arm multistage trials
A. Multi-arm trial B. Multi-arm multistage trial
Control Control
Regimen 1 Regimen 1
Regimen 2 Regimen 2
Regimen 3 Regimen 3
Intermediate analysis
15 Multi-arm multistage trials
Multi-arm multistage trials are adaptive trials with multiple arms and stages that include predefined lack-of-benefit analysis at the interim stages based on intermediate outcome (Fig. 1.5B). A multi- arm multistage trial can compare multiple treatments (or different doses) and drop less-effective arms at the interim stages. The design offers efficiency benefits and enables direct comparison between arms, reduces the total number of participants and duration of the trial and saves money by performing one trial instead of several. It can also accommodate seamless transition from Phase I to II or II to III and streamline experimental treatment evaluation. The design has a few practical difficulties, requiring that several experimental treatments be available at the same time and buy-in from pharmaceutical companies to compare their treatments. Multi-arm multistage trials may not be suited for all diseases, since a short-term intermediate outcome predicting treatment effect should exist that correlates with the final outcome. Funding applications and planning the trial implementation may be challenging because of the uncertainty of the final sample size and duration unless certain adjustments to the design are made (21). The TAILor trial is an ongoing multi-arm multistage trial evaluating different doses of telmisartan for reducing insulin resistance among adults living with HIV receiving ART (22).
Crossover trials (Fig. 1.6)
Each participant receives the intervention, and comparator, in series. The design increases the statistical power derived from a small number of participants, since there are no differences between participants that may influence the response to treatments. However, the design works poorly for agents with long washout periods or when long-term effects are of interest, and the design is biased towards including participants who tolerate the interventions. Crossover design can be used in pharmacokinetic studies when different drug formulations, different combinations or different doses are evaluated. One example is the ODYSSEY tuberculosis (TB) pharmacokinetic substudy that aims to compare exposure to a standard dolutegravir (DTG) dose to double-dose DTG co-administered with rifampicin (10).
Fig. 1.6. Crossover studies
A. Classical crossover study B. Crossover pharmacokinetic study Period 1 Period 2 Period 1 Period 2
Group 1 Drug A Drug A Group 1 Dose A
Group 2 Drug B Drug B Dose B Time Time
Factorial randomized controlled trials (Fig. 1.7)
Participants are randomized to two (or more) independent interventions. The interventions are then analysed separately and tested for interaction. Factorial designs are efficient in facilitating multiple comparisons but can be underpowered if interactions exist. ARROW is an example of a factorial trial that compared three ART regimens (first randomization) and two monitoring strategies (second randomization) (23).
16 Fig. 1.7. Factorial randomized controlled trial
First randomization
First intervention A+ A-
Second randomization Second randomization
Second intervention B+ B- B+ B-
A+ B+ A+ B- A- B+ A- B-
A, B: allocated interventions; +: randomized to receive intervention; –: randomized to receive standard of care.
Cluster randomized controlled trials (Fig. 1.8)
Groups of individuals, not individuals themselves, are randomized to intervention or control, but outcomes can still be measured at the individual level. The design is appropriate when an intervention cannot be feasibly given to some members of a group but not others without contamination. For example, several large trials examining the impact of universal ART have randomized by community- level clusters; it would not have been feasible for providers and patients to not be aware of, and influenced by, differential approaches to ART initiation within their communities(24) . The primary disadvantage of cluster randomized controlled trials is that they can become very large, since the power for comparison is driven by the number of clusters and not simply the number of participants.
Fig. 1.8. Cluster randomized controlled trial
A B B A Randomization of groups of individuals (households and communities) rather than individuals. A, B = allocated interventions
Source: adapted from a personal communication from Elizabeth Chappell, University College London, 2017.
Basket trials
Basket trials include separate but related trials into one operation. They may evaluate the same intervention in different patient groups. Basket trials can be efficient by utilizing one protocol and regulatory approval for all trials and increasing combined power across the trials, but they can be large and costly. IMPAACT P1060 is a paediatric HIV trial that used this approach; it included two randomized controlled trials comparing lopinavir- to nevirapine-based ART among infants with and without perinatal nevirapine exposure (25,26).
17 Box 1.2 Superiority, equivalence and non-inferiority
Comparative trials are designed to demonstrate superiority, equivalence or non-inferiority.
Superiority trials are designed and powered to demonstrate that one treatment is better than another, but proving superiority may be difficult if the primary outcome for the comparator is already very good. A failed superiority trial cannot be interpreted to mean equivalence or non-inferiority of the interventions.
Equivalence trials aim to show that treatments are neither better nor worse than another, with effects differing by no more than a pre-specified amount (margin). Equivalence trials can be used to confirm the bioequivalence of formulations (such as fixed-dose combinations and component drugs or dispersible and film-coated tablets). The acceptable margin is prespecified as the design phase. The stringent regulatory authorities may specify certain margins for the regulatory studies based on statistical and clinical reasoning of what represents a clinically significant difference between the formulations.
Non-inferiority trials aim to demonstrate that a treatment is no worse than (or at least as good as) an existing treatment and that the difference in favour of existing treatment does not exceed a pre- specified amount (margin). These types of trials are used if there are other assumed benefits over the comparator, such as fewer side-effects, easier administration and/or less expensive production. One advantage of non-inferiority trials is that an intervention may be shown to be not only non-inferior but also superior.
Fig. 1.9 shows the differences between superiority, equivalence and non-inferiority with examples of how to interpret the results.
Fig. 1.9. Superiority, equivalence and non-inferiority trials
Superiority trials Equivalence trials Non-inferiority trials
Superior Equivalent Non-inferior* Non-inferior
NOT NOT NOT superior equivalent* non-inferior**
NOT NOT NOT superior equivalent** non-inferior**
0 0 0 Control better Intervention better Control better Intervention better Control better Intervention better
= Confidence interval = Acceptable margin * intervention is better; ** intervention may be worse
Source: adapted from a personal communication from Elizabeth Chappell, University College London, 2017.
18 2. CHALLENGES
Many pressures and operational challenges 2.3 Challenges in enrolment make impede the implementation and completion of decisions about sample size difficult clinical trials of ARV drugs for children. A classical randomized controlled trial designed 2.1 Pharmaceutical companies have limited to show benefits in efficacy over standard care incentives to support trials among children requires a relatively large sample size and may result in a prolonged recruitment period and high costs, especially when involving multiple sites Pharmaceutical companies generally have across multiple countries. In contrast, trials with minimal financial incentives to fund trials of new small sample sizes risk being underpowered and agents for children given the limited market yielding inconclusive results, leading to a missed potential. The high costs of running the trials, opportunity for detecting clinically relevant higher risk of liability compared with adults and outcomes and a substantial waste of resources. more restrictive regulatory requirements, which can be inconsistent between major stringent regulatory authorities, further discourage the 2.4 Staggered approach for dose-finding companies from conducting trials of ARV drugs studies can slow down completion among children. Dose-finding trials that step down into younger 2.2 Difficult to recruit and enrol children age bands (12–18 years, 6–12 years, 2–6 years, 4 weeks to 2 years, birth to 4 weeks) were designed to avoid exposing young children to adverse Clinical trials of ARV drugs can be slow to recruit events from age-specific differences in drug children because fewer children than adults absorption and metabolism, but their staggered living with HIV are able to participate in studies. approach can greatly extend the study duration. Ethical concerns and attempts to protect children from the excessive risks of using a new agent frequently result in strict inclusion criteria. 2.5 Landscape of ARV drug options is Adults provide their own consent, accepting rapidly changing potential risks, whereas children rely on their parents or guardians and ethical review boards to represent their interests. Trials enrolling children Finally, the landscape of drug options is must ensure an acceptable risk–benefit ratio rapidly changing, and new agents and fixed- and ideally provide a real prospect of individual dose combinations requiring assessment of benefit. This can result in narrow inclusion drug-dose ratios separately for children are criteria for children (for example, treatment- constantly entering the market. This raises the experienced children with few other options) need for rapid study of new agents in children that restrict recruitment. Children living with but conversely means that trials (or agents) can HIV are often orphans living with non-parental become obsolete before they are completed. guardians, presenting a challenge to enrolment given regulations governing who can consent to children participating in research.
19 3. SOLUTIONS
Designing a study of a candidate drug for options for children living with HIV. It is useful to children living with HIV requires carefully start by evaluating the current clinical context, considering the main questions, objectives and the ages and settings for children and where data requirements for (1) regulatory approval current choices fall short (Box 1.3). purposes and/or (2) the place of the studied drug or regimen in the current or future treatment Ideally, trials evaluate the dosing scheme and options. formulations that will be most relevant for the intended population. Although individual mg- This in turn informs the choice of trial designs, per-kg dosing of liquids might yield the most and of the possible options, the most efficient precise pharmacokinetic exposures, trials should design that maximizes the generation of aim to use age-appropriate formulations and evidence should be selected. weight-band dosing that are more practical for implementation globally and endorsed by WHO Once the design has been decided, one must (2). Fixed-dose formulations should be ideally consider the suitable sites for recruitment and evaluated in the same study once weight-band operational logistics to conduct the trial. During dosing is confirmed. the process, potential funders, collaborators and regulators must be engaged. Carefully reviewing the safety data from studies among adults is also critical. Were there adverse Although these steps are presented serially events that might be particularly significant for here, they often occur simultaneously, since children and require additional tests or long-term each step depends on others. A key element to safety evaluation in the trial, such as for nervous efficiently designing and conducting clinical trials system and mental reactions and bone toxicity? is that all potential stakeholders are involved throughout the process of developing the study. Efficacy data can be extrapolated from Close collaboration will align the trial design as adult studies, since the EMA and FDA now closely as possible with the objectives of funders, recognize that, for HIV disease in particular, regulators and clinicians. Such collaboration pharmacokinetic data demonstrating similar drug requires extra effort to coordinate but increases exposure to those among adults can be used to the likelihood that a trial will be funded, perform generalize clinical efficacy to children(3,4) . A efficiently and generate the information needed. regulatory clinical trial evaluating the efficacy of Suggested approaches to expedite a trial of a a drug for children has the potential to delay the new drug or treatment regimen among children regulatory approval of the drug. An extrapolation living with HIV are highlighted below. algorithm suggested by the FDA (4) and later discussed by Dunne et al. (6) is a useful tool in making the decision about what type of trials are 3.1 Evaluate what data are required required among children for drug approval (Fig. 1.3). Once dosing has been established, additional It is important to be judicious and specific in strategy trials may also be needed among deciding exactly what data are needed to support children to evaluate pragmatic dosing and inform a candidate agent for inclusion in treatment the role of the drug in wide clinical settings.
20 availability among children may affect dose Box 1.3 Questions to consider when determination. Incorporating preclinical data planning a clinical trial about drug disposition (metabolism, volume of distribution and clearance) in physiologically ■■ For what ages and settings will this drug be most relevant? based pharmacokinetic modelling can increase the precision in dose selection and help with ■■ Are there specific reasons to be concerned weight-band dosing. Physiologically based that the efficacy of this drug for children pharmacokinetic modelling has been used differs from adults, or is relying on adult to study antiretroviral drugs (28) and holds efficacy data reasonable? particular appeal for determining the doses ■■ What outcomes or margin of improvement for children (29,30) and neonates (31) (see would result in this agent replacing current the module on pharmacokinetic modelling). options? ■■ Study multiple ages and weight bands ■■ What are the safety concerns about simultaneously. Unless there are specific this agent and how might they differ for physiological or safety reasons to be children versus adults? concerned about a drug for children, moving rapidly into studying children is reasonable. The dramatic changes in certain metabolic pathways in the first days and week of life 3.2 Start drug trials for children early necessitate careful and distinct approaches to determining the dose. Nevertheless, Research communities should advocate studying outside the neonatal period, agents with new agents among children as soon as reassuring good safety profiles and well characterized safety data are available from adult trials, metabolic pathways could be studied across mitigating possible risks from exposure to new wide age and weight ranges simultaneously. medicines with careful safety monitoring in the As described above, pharmacodynamic and context of a clinical trial. Whenever possible, pharmacokinetic modelling can increase the Phase II trials should begin among children safety and efficiency of identifying starting before Phase III trials among adults end (27). doses. Pilot pharmacokinetics among a few children per weight band could also aid pharmacokinetic modelling and allow a more 3.3 Use efficient trial designs and consider precise prediction of the dose for the study innovative options determining the dose (11). ■■ Study adolescents alongside adults or include Several design principles can expedite the them in late-phase adult trials. Adolescents performance of clinical trials of agents to treat have been successfully included in cancer children living with HIV. clinical trials with adults (32). Studying older ■■ Use physiologically based pharmacokinetic children in parallel with adult trials proved modelling to select the test dose. The doses to be possible in the DTG development tested in trials are often classically derived programme, which enabled for the first time by extrapolating from weight-based doses licensing of a new ARV drug for children in the adjacent age groups. Maturational weighing ≥30 kg at the same time as for changes in drug metabolism and non-linear adults. Ideally, the late-phase adult trials should relationships between weight and drug include adolescents older than 12 years, which could save substantial resources.
21 ■■ Take advantage of washout data to design ■■ Carefully choose the most appropriate design trials for neonates. With rapid changes in and consider innovative statistical methods metabolism and drug clearance, neonates are and trial designs to increase efficiency. Multi- especially challenging to dose correctly (see arm randomized controlled trials, crossover the module on pharmacokinetic modelling). trials and factorial and basket trials use The washout data generated from the study financial and patient resources more efficiently of drug levels among infants exposed to than traditional two-arm randomized agents transplacentally can provide insight controlled trials. Adaptive trial designs and into the clearance of new agents by neonates, innovative analysis offer additional efficiency informing the modelling for dosing neonates. gains (Box 1.4). For example, IMPAACT P1026s has used Many conventional trial designs are static and rely an opportunistic design to characterize the on pre-specified enrolment criteria, interventions washout of many ARV drugs among neonates, and comparisons. By contrast, adaptive designs adding new arms when new ARV drugs come enable changes in trial design based on interim into use for adults (33); data from the 1097 study were instrumental in establishing the data while preserving statistical integrity (35,36). pharmacokinetics and safety of raltegravir for The FDA has endorsed adaptive designs since (37) for use in developing and evaluating full-term neonates (34). 2006 drugs (38,39). They can potentially increase ■■ Assess acceptability and feasibility within efficiency by enabling power and sample sizes the initial dose-finding and safety studies. to be re-estimated and arms to be added and Acceptability and feasibility are important deleted and overall increasing the likelihood characteristics for implementing formulations that a study will achieve its aim (36). A multi-arm in diverse populations. It is important to multistage design has been successfully used in evaluate them at early stages of drug ongoing cancer and TB trials (40,41), and in the development for children (2) and ideally TAILor trial on reducing insulin resistance among incorporate them into clinical trials. See the adults living with HIV and receiving ART (26). module on acceptability for more details.
Box 1.4 Examples of adaptive designs and innovative statistical methods
■■ Multi-arm multistage designs. Multi-arm multistage designs use adaptive methods and enable multiple agents to be compared with a single control group (Fig. 1.4B). Planned interim analysis enables unpromising arms to be dropped and new arms to be added while preserving the integrity of the trial. Multi-arm multistage designs can thus shorten the development process without compromising safety and efficacy by increasing the power for identifying the best clinical benefit of the drug product under investigation. A multi-arm multistage design could serve as a master protocol to examine the efficacy of new ARV drugs among children. Multi-arm multistage designs allow elements of Phase II trials such as determining dose to be combined with Phase III trials examining efficacy.
■■ Bayesian methods. Evidence from previous studies, including adult studies, can be borrowed to inform predictions and reduce the sample size. Data gathered within the trial are also used to adjust the sample size and modify the trial’s design while the trial is being carried out. Bayesian methods have the potential to make the trial design more efficient by increasing power and precision and can help to accelerate the completion of trials.
22 Although several statistical, logistical and 3.5 Align trials among children and operational complexities make multi-arm harmonize the approval process multistage trials difficult to implement(42,43) , many HIV clinical trials among adults and When different groups are studying the same children have adaptively modified some aspects agent, the study designs should be aligned so of their design to respond to a changing context that the results can be easily compared and be or intermediate results received, including complementary to address various data gaps. expanding the inclusion criteria (10,11), modifying For regulatory trials, the companies may choose the dose (10,11) and adding randomization to work together early with clinical experts to (21,44). A recent single-arm PHPT-5 trial on optimize their design of paediatric investigation ARV drug regimen intensification for preventing plans and paediatric study plans to generate intrapartum mother-to-child transmission clinically relevant data that are feasible to of HIV among mothers presenting late in obtain and meet the regulatory requirements. pregnancy used a Bayesian approach (45). The The WHO-led Paediatric Antiretroviral Working trial evaluated the efficacy of adding single- Group and Paediatric ARV Drug Optimization dose nevirapine during labour to maternal groups have pharmacological, clinical trial and triple lopinavir/ritonavir–based ART and using regulatory expertise and offer scientific advice triple ART prevention for infants instead of on paediatric investigation plans and paediatric zidovudine prophylaxis. Historical data from study plans free of charge. Drug developers previous randomized controlled trials in the should also consult the FDA and EMA on their same setting were used to generate the prior trials among children (see the module on distributions of mother-to-child transmission regulatory filing). probabilities. Prospective data from the trial were used to estimate the posterior predictive Alignment of regulatory requirements and distribution, which confirmed the probability linkage between the main stringent regulatory of superiority of the intensified prevention of authorities in the process of reviewing submitted vertical transmission over the standard of care trial data for a specific drug may considerably (45). When large randomized controlled trials are accelerate drug development for children (see not feasible and the predictions can be borrowed the module on regulatory filing). from trials involving adults or previous ones involving children, a Bayesian approach should be Efficient collaboration and a harmonized considered to confirm the studied treatments. approach are needed between policy-makers, the paediatric HIV research community, the pharmaceutical industry and regulatory agencies 3.4 Pool research resources to streamline the process of developing ARV drugs for children. Pooling the data and resources within large research collaborations can mitigate the 3.6 Community engagement challenge of recruitment for trials among children. Multicentre networks have productively performed in trials on cancer (46), rheumatology The community, including study participants, (47) and HIV (48,49) among children. Two large their caregivers and their clinicians should be paediatric HIV networks (PENTA and IMPAACT) involved early in designing a trial and throughout have been successfully working together in operation. Their perspectives can yield critical conducting the PENPACT-1 (PENTA 9/PACTG insight into the incentives and barriers to 390) trial (50) and, more recently, in linking recruitment and participation in clinical trials Phases II and III trials to accelerate the evaluation among children (see the module on community of DTG treatment among children (10,11). engagement).
23 4. CASE STUDIES
The integrase inhibitor DTG is currently being younger children, simultaneous enrolment was assessed in two trials among children. IMPAACT later implemented in the younger age cohorts. P1093 is a single-arm trial evaluating DTG dosing and safety among children for licensing purposes ODYSSEY is a Phases II and III randomized (11). ODYSSEY is a strategy trial, studying the controlled trial evaluating the efficacy and safety efficacy and safety of DTG in first- and second-line of DTG-based ART for children in various settings. ART for children in various settings (10) (Table 1.1). It uses a basket design: ODYSSEY A recruits children starting first-line ART and ODYSSEY IMPAACT P1093 is a Phases I and II, multicentre, B children starting second-line ART. ODYSSEY open-label, non-comparative intensive has a few nested pharmacokinetic substudies, pharmacokinetic and safety trial of DTG among aiming to evaluate pragmatic dosing for children children. Full extrapolation of efficacy from using a minimal number of formulations across adult trials was considered appropriate. Data on the age range and using WHO weight-band bioequivalence for adults between formulations dosing. ODYSSEY is also assessing DTG dosing for were used to guide dosing, and physiologically children coinfected with TB. The trial is producing based pharmacokinetic modelling was used data complementary to that from P1093, aiming to estimate the doses required to reach the to inform policy-makers on pragmatic treatment effective exposure targets. The study team options and streamline access to DTG for children consulted the FDA on the design and exposure living in various settings. targets before the trial started and as the study progressed. Various age-appropriate Collaboration between IMPAACT P1093, formulations for children, including film-coated ODYSSEY and ViiV Healthcare included early tablets, granules and dispersible tablets, are sharing of information on dosing between being evaluated. The trial initially used staggered ongoing studies and paved the way to aligning age cohort enrolment, starting with adolescents the dosing for younger children in ODYSSEY 12–17 years old followed by children 6–11 years and to expanding the possibilities for studying old. To streamline the evaluation of DTG for practical treatment approaches.
Table 1.1. Summary of IMPAACT P1093 and ODYSSEY trial details
IMPAACT P1093 ODYSSEY Registration IND 110847 ISRCTN91737921 numbers DAIDS-ES 11773 EudraCT 2014-002632-14 EudraCT 2010-020988-20 NCT02259127 NCT01302847 Study design Phases I and II, multicentre, open-label An open-label, multicentre, randomized (1:1), pharmacokinetic, safety, tolerability and non-inferiority, Phases II and III, 96-week, two- antiviral activity of DTG in combination arm clinical trial to compare the efficacy and regimens among infants, children and toxicity of DTG plus two nucleoside reverse- adolescents living with HIV-1. Stage I evaluates transcriptase inhibitors versus the standard of the short-term tolerability and safety of DTG, care among children younger than 18 years allowing the selection of a dose in stage II. old living with HIV-1 who are starting first-line Stage II provides long-term safety, tolerability, ART (ODYSSEY A) or switching to second-line and supportive efficacy data for DTG ART (ODYSSEY B)
24 IMPAACT P1093 ODYSSEY Participants Children living with HIV 4 weeks to Children living with HIV 4 weeks to 18 years old 18 years old Number of About 160 700 participants Interventions All participants receive age-appropriate DTG DTG + two nucleoside reverse-transcriptase formulations as part of their combination inhibitors (DTG arm) versus standard of ART regimen care (standard of care arm) in first-line and Dosing is by age and WHO weight bands second-line ART regimens Dosing is by WHO weight bands Primary Dose for each DTG formulation that Treatment failure (clinical or viral) by 96 outcome(s) achieves similar exposure to the 50-mg weeks, estimated using time to the first once-daily adult dose of DTG occurrence of: Safety and tolerability of DTG at 24 and 48 ■■ Insufficient viral response, defined as weeks <1 log10 drop at 24 weeks Steady-state pharmacokinetics of DTG in ■■ HIV-1 RNA ≥400 copies/ml at or after 36 combination with optimized background weeks, confirmed by next visit therapy and DTG dose determination ■■ Death due to any cause achieving targeted 24-hour area under ■■ Any new or recurrent AIDS-defining the concentration–time curve (AUC24 h; event (WHO stage 4) or severe WHO primary pharmacokinetic endpoint) and stage 3 event 24-hour plasma concentration (C24 h; secondary pharmacokinetic endpoint) Main secondary Viral response at 24 and 48 weeks Efficacy outcomes outcomes Immune response by 24 and 48 weeks ■■ Treatment failure (clinical or viral) by Change in HIV-1 genotype and phenotype 48 weeks and other optimized background therapy ■■ New resistance mutations compounds in children experiencing viral ■■ Clinical events (new or recurrent severe failure WHO stage 3 or 4 events and death) DTG exposure, its variability and clinical ■■ Immune recovery (change in CD4 or covariates affecting DTG disposition using CD4:CD8 ratio) intensive and sparse sampling and population pharmacokinetic analysis Safety outcomes Extended long-term (≥48 week) safety and ■■ Severe adverse events, grade 3 or 4 tolerability clinical and laboratory events and events Relationship between DTG exposure and of any grade leading to ART modification antiviral activity Quality of life, adherence and acceptability Duration 48 weeks, followed by long-term All participants will be followed until safety follow-up that will last at least three the last recruited participant reaches years week 96 Sponsor United States National Institutes PENTA Foundation of Health Funder ViiV Healthcare and United States National ViiV Healthcare Institutes of Health
25 5. SUMMARY
Improving access to optimal ART for children Dose-finding trials that step down into younger will require strategic clinical trial programmes age or weight bands were designed to minimize that address drug development and ART the risk of adverse events from age-specific optimization priorities set by the collaborative differences in drug absorption and metabolism, global Paediatric ARV Drug Optimization but this staggered approach greatly extends the initiative (51). Many pressures and operational study duration. Finally, the landscape of drug challenges specifically impede the development options is rapidly changing; new agents and and completion of clinical trials to develop ARV fixed-dose combinations requiring assessment drugs for children. Pharmaceutical companies of drug-dose ratios separately for children are have minimal financial incentives to fund trials of constantly entering the market. This raises the new agents for children given the limited market need for rapid study of new agents for children, potential. Clinical trials are slower because fewer but conversely means that trials (or agents) can children are able to participate in studies than become obsolete before they are completed. adults. Classical approaches to dose-finding for children are slow. Attempts to minimize the risks of using a new agent for children can result in very narrow inclusion criteria.
©WHO/Garry Smyth
26 6. KEY CONSIDERATIONS
■■ Identify the key data needed to give children physiological or safety reasons to be access to a prospective ARV drug. concerned about a drug for children.
−− Identify the minimum data needed for −− Study adolescents alongside adults or regulatory approval, remembering that include them in late-phase trials for adults. Phase III efficacy trials are generally not −− Use washout data from neonates. required for ARV drugs that have been −− Include acceptability and feasibility study studied in adults. within the initial dose-finding and safety −− Work with clinicians, community members studies. and experts to identify the key efficacy or −− Carefully choose the most appropriate formulation data needed from strategy design and consider innovative statistical trials to inform clinical guidelines. methods and trial designs to increase ■■ Start ARV drug trials among children as soon efficiency. as possible while Phase III trials among adults ■■ Ensure early and ongoing collaboration are underway. between policy-makers, the pharmaceutical ■■ Use innovative trial designs and procedures for industry, regulatory agencies, community efficiently generating data. members and paediatric HIV researchers −− Apply physiologically based pharmacokinetic to streamline the selection and completion modelling to help in selecting the dose. of essential clinical trials and accelerate the development of ARV drugs and the −− Study multiple ages and weight bands simultaneously, unless there are specific optimization of treatment for children.
7. ACKNOWLEDGEMENTS
Authors: Anna Turkova1 and Theodore Ruel2
Reviewers: Deborah Ford1, Ellen Chadwick3, Diana Gibb1 and Elaine Abrams4
1 University College London, United Kingdom 2 University of California, San Francisco, USA 3 Northwestern University, Chicago, IL, USA 4 ICAP at Columbia University, New York, NY, USA
Comments were also provided by the Division of Antiviral Products of the United States Food and Drug Administration and by representatives of the European Medicines Agency and members of the European Medicines Agency Paediatric Committee. Any views expressed in this publication by employees of the United States Food and Drug Administration or the European Medicines Agency, or members of the European Medicines Agency Paediatric Committee, are their own and may not be understood or quoted as being made on behalf of or reflecting the position of the United States Food and Drug Administration or of the European Medicines Agency or any of its committees or working parties.
27 8. REFERENCES
1. Penazzato M, Lee J, Capparelli E, Essajee S, 8. Bastiaans DE, Forcat S, Lyall H, Cressey Ford N, Ojoo A et al. Optimizing drugs to TR, Hansudewechakul R, Kanjanavanit reach treatment targets for children and S et al. Pharmacokinetics of pediatric adolescents living with HIV. J Int AIDS Soc. lopinavir/ritonavir tablets in children when 2015;18:20270. administered twice daily according to FDA weight bands. Pediatr Infect Dis J. 2. Penazzato M, Gnanashanmugam M, Rojo 2014;33:301–5. P, Lallemant M, Lewis LL, Rocchi F et al. Optimizing research to speed up availability of 9. Paediatric European Network for Treatment pediatric antiretroviral drugs and formulations. of AIDS. Once vs. twice-daily lopinavir/ Clin Infect Dis. 2017;64:1597–1603. ritonavir in HIV-1-infected children. AIDS. 2015;29:2447–57. 3. Guideline on the clinical development of medicinal products for the treatment of 10. Persaud D, Palumbo P, Ziemniak C, Chen J, HIV infection. London: European Medicines Ray SC, Hughes M et al. Early archiving and Agency; 2016 (http://www.ema.europa.eu/ predominance of nonnucleoside reverse docs/en_GB/document_library/Scientific_ transcriptase inhibitor-resistant HIV-1 among guideline/2016/07/WC500209918.pdf, recently infected infants born in the United accessed 22 May 2018). States. J Infect Dis. 2007;195:1402–10.
4. General clinical pharmacology considerations 11. Taha TE, Kumwenda NI, Hoover DR, Biggar for pediatric studies for drugs and biological RJ, Broadhead RL, Cassol S et al. Association products: guidance for industry 2014. of HIV-1 load and CD4 lymphocyte count Washington (DC): United States Food with mortality among untreated African and Drug Administration; 2014 (https:// children over one year of age. AIDS. www.fda.gov/downloads/drugs/guidances/ 2000;14:453–9. ucm425885.pdf, accessed 22 May 2018). 12. Zheng L, Rosenkranz SL, Taiwo B, Para 5. Vassal G, Zwaan CM, Ashley D, Le Deley MF, Eron JJ Jr, Hughes MD. The design of MC, Hargrave D, Blanc P et al. New drugs single-arm clinical trials of combination for children and adolescents with cancer: antiretroviral regimens for treatment-naive the need for novel development pathways. HIV-infected patients. AIDS Res Hum Lancet Oncol. 2013;14:e117–24. Retroviruses. 2013;29:652–7.
6. Dunne J, Rodriguez WJ, Murphy MD, Beasley 13. Ford D, Turner R, Turkova A, et al. Optimizing BN, Burckart GJ, Filie JD et al. Extrapolation clinical trials design to maximise evidence of adult data and other data in pediatric generation in paediatric HIV. J Acquir drug-development programs. Pediatrics. Immune Defic Syndr. In press. 2011;128:e1242–9. 14. Salem F, Ogungbenro K, Vajjah P, Johnson 7. Musiime V, Kendall L, Bakeera-Kitaka S, TN, Aarons L, Rostami-Hodjegan A. Precision Snowden WB, Odongo F, Thomason M et al. criteria to derive sample size when designing Pharmacokinetics and acceptability of once- pediatric pharmacokinetic studies: which versus twice-daily lamivudine and abacavir in measure of variability should be used? J Clin HIV type-1-infected Ugandan children in the Pharmacol. 2014;54:311–7. ARROW Trial. Antivir Ther. 2010;15:1115–24.
28 15. Wang Y, Jadhav PR, Lala M, Gobburu JV. HIV (TAILoR): protocol for a dose-ranging Clarification on precision criteria to derive phase II randomised open-labelled trial of sample size when designing pediatric telmisartan as a strategy for the reduction of pharmacokinetic studies. J Clin Pharmacol. insulin resistance in HIV-positive individuals 2012;52:1601-6. on combination antiretroviral therapy. BMJ Open. 2015;5:e009566. 16. Lewis LL. Assessing pre-market safety in pediatric drug development: the division 23. Kekitiinwa A, Cook A, Nathoo K, Mugyenyi of anti-viral products (DAVP) perspective. P, Nahirya-Ntege P, Bakeera-Kitaka S et al. Washington (DC): United States Food and Routine versus clinically driven laboratory Drug Administration; 2014. monitoring and first-line antiretroviral therapy strategies in African children 17. Nachman S, Alvero C, Acosta EP, Teppler H, with HIV (ARROW): a 5-year open- Homony B, Graham B et al. Pharmacokinetics label randomised factorial trial. Lancet. and 48-week safety and efficacy of 2013;381:1391–403. raltegravir for oral suspension in human immunodeficiency virus type-1-infected 24. Perriat D, Balzer L, Hayes R, Lockman S, children 4 weeks to 2 years of age. J Pediatric Walsh F, Ayles H et al. Comparative Infect Dis Soc. 2015;4:e76–83. assessment of five trials of universal HIV testing and treatment in sub-Saharan Africa. 18. Nachman S, Zheng N, Acosta EP, Teppler H, J Int AIDS Soc. 2018;21. Homony B, Graham B et al. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir 25. Palumbo P, Lindsey JC, Hughes MD, Cotton in HIV-1-infected children aged 2 through 18 MF, Bobat R, Meyers T et al. Antiretroviral years. Clin Infect Dis. 2014;58:413–22. treatment for children with peripartum nevirapine exposure. N Engl J Med. 19. Ruel TD, Kakuru A, Ikilezi G, Mwangwa 2010;363:1510–20. F, Dorsey G, Rosenthal PJ et al. Virologic and immunologic outcomes of HIV- 26. Violari A, Lindsey JC, Hughes MD, Mujuru infected Ugandan children randomized to HA, Barlow-Mosha L, Kamthunzi P et al. lopinavir/ritonavir or nonnucleoside reverse Nevirapine versus ritonavir-boosted lopinavir transcriptase inhibitor therapy. J Acquir for HIV-infected children. N Engl J Med. Immune Defic Syndr. 2014;65:535–41. 2012;366:2380–9.
20. Mulenga V, Musiime V, Kekitiinwa A, Cook 27. United States Department of Health AD, Abongomera G, Kenny J et al. Abacavir, and Human Services Food and Drug zidovudine, or stavudine as paediatric Administration Center for Drug Evaluation tablets for African HIV-infected children and Research. Human immunodeficiency (CHAPAS-3): an open-label, parallel-group, virus-1 infection: developing antiretroviral randomised controlled trial. Lancet Infect drugs for treatment guidance for Dis. 2016;16:169–79. industry. Washington (DC): United States Food and Drug Administration 2015 21. Wason J, Stallard N, Bowden J, Jennison C. A (https://www.fda.gov/downloads/drugs/ multistage drop-the-losers design for multi- guidancecomplianceregulatoryinformation/ arm clinical trials. Statist Methods Med Res. guidances/ucm355128.pdf, accessed 2017;26:508–24. 22 May 2018).
22. Pushpakom SP, Taylor C, Kolamunnage- 28. Wagner C, Zhao P, Arya V, Mullick C, Dona R, Spowart C, Vora J, García-Fiñana M Struble K, Au S. Physiologically based et al. Telmisartan and insulin resistance in pharmacokinetic modeling for predicting
29 the effect of intrinsic and extrinsic SpecialTopics/CriticalPathInitiative/ factors on darunavir or lopinavir exposure CriticalPathOpportunitiesReports/ coadministered with ritonavir. J Clin UCM077254.pdf, accessed 22 May 2018). Pharmacol. 2017;57:1295–304. 38. Guidance for Industry Adaptive Design 29. Samant TS, Mangal N, Lukacova V, Schmidt Clinical Trials for Drugs and Biologics S. Quantitative clinical pharmacology 2010. Washington (DC): United States for size and age scaling in pediatric drug Food and Drug Administration; 2010 development: a systematic review. J Clin (https://www.fda.gov/downloads/Drugs/ Pharmacol. 2015;55:1207–17. GuidanceComplianceRegulatoryInformation/ Guidances/UCM201790.pdf, accessed 30. Zhou W, Johnson TN, Bui KH, et al. 22 May 2018). Predictive performance of physiologically based pharmacokinetic (PB) modeling of 39. Gallo P, Anderson K, Chuang-Stein C, drugs extensively metabolized by major Dragalin V, Gaydos B, Krams M et al. cytochrome P450s in children. Clin Viewpoints on the FDA draft adaptive Pharmacol Ther. 2017. designs guidance from the PhRMA working group. J Biopharm Stat. 2010;20:1115–24. 31. Michelet R, Bocxlaer JV, Vermeulen A. physiologically based pharmacokinetic in 40. James ND, Sydes MR, Clarke NW, Mason preterm and term neonates: a review. Curr MD, Dearnaley DP, Spears MR et al. Addition Pharm Des. 2017. of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in 32. Weiss AR, Hayes-Lattin B, Kutny MA, prostate cancer (STAMPEDE): survival results Stock W, Stegenga K, Freyer DR. Inclusion from an adaptive, multiarm, multistage, of adolescents and young adults in platform randomised controlled trial. Lancet. cancer clinical trials. Semin Oncol Nurs. 2016;387:1163–77. 2015;31:197–205. 41. Parmar MK, Sydes MR, Cafferty FH, 33. Duke T, Mgone CS. Measles: not just another Choodari-Oskooei B1, Langley RE1, Brown L viral exanthem. Lancet. 2003;361:763–73. et al. Testing many treatments within a single 34. Clarke DF, Acosta EP, Rizk ML, Bryson protocol over 10 years at MRC Clinical Trials YJ, Spector SA, Mofenson LM et al. Unit at UCL: multi-arm, multistage platform, Raltegravir pharmacokinetics in neonates umbrella and basket protocols. Clin Trials. following maternal dosing. J Acquir Immune 2017;14:451–61. Defic Syndr. 2014;67:310-315. 42. Cook T, DeMets DL. Review of draft FDA 35. Baiardi P, Giaquinto C, Girotto S, Manfredi adaptive design guidance. J Biopharm Stat. C, Ceci A. Innovative study design for 2010;20:1132–42. paediatric clinical trials. Eur J Clin Pharmacol. 43. Chow SC, Corey R. Benefits, challenges and 2011;67(Suppl. 1):109–15. obstacles of adaptive clinical trial designs. 36. Curtin F, Heritier S. The role of adaptive trial Orphanet J Rare Dis. 2011;6:79. designs in drug development. Expert Rev 44. Bwakura-Dangarembizi M, Kendall L, Clin Pharmacol. 2017;10:727–36. Bakeera-Kitaka S, Nahirya-Ntege P, 37. FDA critical path opportunities report 2006. Keishanyu R, Nathoo K et al. A randomized Washington (DC): United States Food and trial of prolonged co-trimoxazole in HIV- Drug Administration; 2006 (https://www. infected children in Africa. N Engl J Med. fda.gov/downloads/ScienceResearch/ 2014;370:41–53.
30 45. Lallemant M, Amzal B, Urien S, Le Coeur 50. Babiker A, Castro nee Green H, S. Antiretroviral intensification to prevent Compagnucci A, Fiscus S, Giaquinto C, Gibb intrapartum HIV transmission in late comers. DM et al. First-line antiretroviral therapy with 8th IAS Conference on HIV Pathogenesis, a protease inhibitor versus non-nucleoside Treatment and Prevention, 19–22 July 2015, reverse transcriptase inhibitor and switch at Vancouver, Canada (MOAC0204). higher versus low viral load in HIV-infected children: an open-label, randomised phase 46. French N, Nakiyingi J, Lugada E, Watera C, 2/3 trial. Lancet Infect Dis. 2011;11:273–83. Whitworth JA, Gilks CF. Increasing rates of malarial fever with deteriorating immune 51. Penazzato M, Palladino C, Sugandhi N. status in HIV-1-infected Ugandan adults. Prioritizing the most needed formulations AIDS. 2001;15:899–906. to accelerate paediatric antiretroviral therapy scale-up. Curr Opin HIV AIDS. 47. Whitworth J, Morgan D, Quigley M, Smith A, 2017;12:369–76. Mayanja B, Eotu H et al. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study. Lancet. 2000;356:1051–6.
48. Grimwade K, French N, Mbatha DD, Zungu DD, Dedicoat M, Gilks CF. Childhood malaria in a region of unstable transmission and high human immunodeficiency virus prevalence. Pediatr Infect Dis J. 2003;22:1057–63.
49. Moriuchi M, Moriuchi H, Mon HM, Kanbara H. Dichotomous effects ofPlasmodium falciparum antigens on expression of human immunodeficiency virus (HIV) coreceptors and on infectability of CD4 cells by HIV. J Infect Dis. 2002;186:1194–7.
31 MODULE 2: PHARMACOKINETIC MODELLING
©Courtesy of Photoshare
32 1. INTRODUCTION
Two main factors underpin the pharmacokinetic When designing a pharmacokinetic trial, one differences between adults and children needs to consider the method used for data requiring dose adjustments: body size and analysis, since several options are available, each maturation (1). with their own advantages and disadvantages depending on the scenarios. The effect of body size on drug disposition is well described using the theory of allometric scaling, ■■ Non-compartmental analysis is very easy to which predicts a non-linear relationship between implement and summarizes the pharmacokinetic drug clearance and body size. Because of this profiles in terms of the area under the non-linearity, children generally need a larger concentration–time curve and maximum dose in mg/kg than adults. concentration but can only be applied when an intensively sampled pharmacokinetic profile is In addition, the pharmacokinetics for children available for each subject (5). younger than two years and neonates can differ ■■ Population pharmacokinetic analysis is often considerably from that for older children because the preferred analysis when performing of developmental differences in the physiological intensive blood sampling is not feasible, for processes underlying drug absorption, example, in young children, including neonates distribution, metabolism and excretion (2). (6). Population pharmacokinetic analysis In particular, since metabolic pathways are involves a mathematical model-based approach immature, the values of drug clearance tend to suitable with sparse or opportunistically be smaller than body size alone would predict. sampled drug concentration data. Population Although the effect of body size is similar for pharmacokinetic analysis estimates primary all drugs and quite predictable (3), the effects pharmacokinetic parameters such as clearance of maturation depend on the drug and need to and volume of distribution, possibly including be specifically investigated. Thus, before any in the model the effect of individual covariates antiretroviral (ARV) drug can be used among (such as body weight and age) on these neonates, an appropriate neonatal dosing pharmacokinetic parameters. regimen with an appropriate formulation needs ■■ Physiologically-based pharmacokinetics is a to be studied and neonatal safety assessed complex predictive tool integrating into an in (4). Neonates and young infants require ARV silico platform information about both human medicine for both preventing mother-to- physiology and the chemical and physical child transmission of HIV and for treating HIV characteristics of the drug under study infection. The module on trial design and the (7). This tool is designed to work with very module on pregnant and breastfeeding women little or no clinical data but only provides an further discuss issues related to safety and extrapolated prediction. pharmacokinetic studies involving neonates.
33 2. CHALLENGES
Data on pharmacokinetics, safety and efficacy 2.3 Influences on drug bioavailability for adults are needed before drugs can be studied among children. Pharmacokinetic studies Factors unique to infants and other young among children are further delayed when dose- children may influence drug bioavailability. finding studies are performed in sequential age These factors include feeding mode and cohorts (see the module on trial design). schedule, differences in fed and fasted states and modifications to formulations to facilitate 2.1 Establishing initial drug doses drug intake, such as splitting or crushing tablets intended to be swallowed whole. Strategies that avoid having to break tablets across Establishing initial drug doses for neonates and dosing weight bands are advocated. Drug– other children is especially challenging, since the drug interactions among children living with effects of both body size and the maturation of HIV are common, but data cannot be directly metabolic pathways on a drug’s pharmacokinetic extrapolated from adult studies since the extent properties need to be considered. Moreover, of the interaction can differ in children. specific considerations are required when designing pharmacokinetic studies among children, including identifying the optimal drug 2.4 Palatability and changes in drug doses exposure targets, calculating the number of children needed in each age group or weight Poor palatability of ARV drug formulations can be band and ensuring that ethically appropriate a particular challenge for treating children, and blood sampling and volumes are drawn. frequent changes in drug doses are confusing for caregivers and children. Nevertheless, frequent 2.2 Fixed-dose combinations dose changes may be unavoidable for drugs, especially for neonates and other young children, which are metabolized or eliminated through ARV drugs are now commonly co-formulated in pathways with rapid maturation. fixed-dose combinations, which simplifies dosing and enhances adherence to treatment. Creating It is critical to minimize delays in generating fixed-dose combination tablets for children is pharmacokinetic and safety data for novel ARV also desirable but presents several challenges. drugs and/or formulations involving neonates For example, the effect of body size and even and other children. more so that of maturation on each drug within a novel fixed-dose combination often differ, and thus the optimal ratio between the drugs in the fixed-dose combinations may not be equivalent across all weight bands.
34 3. SOLUTIONS
Below are some considerations and solutions by studies among children, starting with the to the common challenges encountered when oldest age group and progressing to younger designing pharmacokinetic trials assessing ARV cohorts once reassuring pharmacokinetic and drugs for children and adolescents. safety data are available for older cohorts.
The choices specific to a pharmacokinetic study 3.1 Identifying ARV drug exposure targets of children include the number of children in each age or weight group and the number of Maintaining ARV drug exposure within blood samples to draw per subject for each therapeutic limits is critical. If ARV drug pharmacokinetic profile. The number of children concentrations are too low, they may fail to in each age or weight group will determine the achieve viral suppression, whereas if they are too precision with which typical values of clearance high, they may be associated with drug toxicity. and volume of distribution parameters in each The pharmacokinetic targets for efficacy and group can be estimated. For example, age bands safety for children are usually extrapolated from are generally smaller for smaller ages (such as <3 studies performed among adults. months, 3–6 months, 6–12 months, 12–24 months, 2–6 years and 6–12 years), to account for the fact In general, ARV drugs are licensed and used that the greatest developmental changes happen for children based on studies of relatively small in the first months and years of life. Similarly, since numbers of children whose primary outcomes the effect of maturation is stronger for younger are drug safety and pharmacokinetics. Dosing children (Fig. 2.1), a larger sample size will be in these studies is designed with the goal of required in the youngest age or weight bands. achieving plasma drug concentration targets equivalent to those established for adults, For the same reason, the lowest degree of although the assessment of viral outcomes variability would be expected among adolescents, among the participating children will provide with the main effect being body weight, and the some evidence that the drug concentration variability would then be comparable to that targets remain appropriate for children. observed for adults. The total number of subjects in each weight and age band will depend on the specific drug and its reported between-subject 3.2 Optimal design of pharmacokinetic variability. An online tool is available to calculate studies involving children this sample size, based on information about the pharmacokinetics of the drug for adults, the information about its main metabolic pathways Unless a drug is intended solely or primarily for and the level of variability observed (9). children, studies involving children cannot be done until data are available on pharmacokinetics, The number of blood samples drawn in each safety and efficacy for adults. The aim of a dose- pharmacokinetic profile will affect the precision finding pharmacokinetic study involving children with which the individual pharmacokinetic is to determine with sufficient precision the parameters are estimated for each subject in the pharmacokinetics for children of different ages, study. Further, ethical constraints limit the total consistent with guidelines provided by regulatory volume of blood that can be collected from a authorities (8). Adolescents are sometimes child (11), so sensitive drug assays are needed that included as part of initial adult studies, followed require minimal plasma volumes (10–50 µL). The
35 Fig. 2.1. Effect of age on drug clearance
2,5
2,0 Renal/GF (Gentamicin) 1,5 CYP3A4 (Alfentanil)
1,0 CYP1A2 (Caffeine)
Clearance/kg Glucuronidation (Morphine) 0,5 (relative to adult value) (relative 0,0
0 5 10 15 20 25 30 Age (years)
Created based on data from: Edginton et al. (10). The lines represent the clearance of drugs through different pathways normalized to body weight and relative to adult reference values.
blood-sampling schedule depends on how the then cover the rest of the curve, aiming to have at data will be interpreted. If non-compartmental least 2–3 samples in the expected terminal phase analysis (5) is planned, a more intensively sampled of the profile. Ideally, the last sample should be profile and strict adherence to the sampling drawn as late after the dose as logistically feasible, schedule are necessary. but avoiding a time range with a high chance of observing values below the lower limit of In addition, the entire dosing interval should quantification of the assay. be covered to accurately calculate the drug exposure (such as area under the concentration– Interim analysis is advised to assess the exposure time curve) at steady state. If a population and determine as soon as possible whether the pharmacokinetic approach is to be used, the observed exposure with the selected dose is in sampling can be more sparse and less rigid, as accordance with the predicted values. long as accurate information is kept about the timing of all samples and doses (even on the days before the blood-sampling visit). Model- 3.3 Model-based approaches to establish based approaches may also have stronger power dosing for initial pharmacokinetics and to determine estimates of pharmacokinetic safety studies among children parameters, because the data from all age bands can be pooled together and analysed jointly. Body size and maturation are the two main factors To optimize the timing of the samples within the causing the difference in pharmacokinetics schedule, a state-of-the-art approach is to apply between adults and children (1)mg/kg. These optimal design theory (12). Briefly, using a model- factors are best accounted for using model-based based approach, software tools are available approaches such as population pharmacokinetics that can provide an optimal sampling schedule or physiologically based pharmacokinetics. The expected to maximize the information collected effect of body size can be predicted well using in the study. Alternatively, a general rule of thumb allometric scaling theory (13), which affects all comprises drawing a pre-dose sample one around drugs in the same way. The volume of distribution the expected time of maximum concentration and is scaled linearly with body weight, whereas
36 clearance (CL) has a non-linear relationship with a drug’s half-life (T1/2) tends to be shorter for body weight (WT) (with an exponent of 3/4), as children, as the ratio between clearance and the outlined in the following equations: volume of distribution will be larger with smaller body size. This may require, for example, splitting what is a single daily dose in adults into two separate doses for children.
The effects of body size on clearance and the volume of distribution, respectively, are expected Given the reference adult values of CLstd and Vstd, which relate to an adult of reference body weight to affect all drugs similarly. Allometric scaling of these parameters is crucial in predicting the WTstd (such as 70 kg), the expected values of CLi suitable dose for children older than two years. and Vi for a person of weight WTi are calculated according to the formulas above. With the For this reason, the use of allometric scaling estimate of clearance for a particular weight, the as a best-guess reasonable assumption has dose can be calculated to achieve a target drug been advocated (3). Allometric scaling can be exposure for adults (such as the area under the applied to simple tools to provide predictions curve using the classic formula area under the of ARV drug exposure across the weight range curve = dose/clearance). of children, such as with the WHO dosing tool to explore optimal drug ratios for fixed-dose Because of this nonlinear relationship between combination tablets for children (14). body weight (a surrogate for size) and drug elimination, children generally need a higher mg/ For children younger than two years, metabolic kg dose than adults, as shown in Fig. 2.2. Thus, if pathways are generally not yet mature and a dose for children is extrapolated from adults to therefore not operating at full capacity compared children using a constant mg/kg, this will generally with those of adults. Because of this maturation cause underexposure in children. In addition, effect, clearance values for infants tend to
Fig. 2.2. Changes in clearance (CL/kg) versus body weight
CL/kg vs. weight 200%
150% A 70 kg adult is chosen as reference Reference Allometry only
100% Allometry and maturarion Fraction of reference of Fraction Small children have larger CL/kg than reference adult
Younger children (generally <2 years) may be immature, with lower CL/kg 50% 0 10 20 30 40 50 60 70 80 90 100 Weight (kg)
The green horizontal line represents the reference clearance/kg for a 70-kg adult. The black dashed line shows the effect of allometric scaling alone, without maturation. The pink line shows the combined effect of allometric scaling and maturation.
37 be smaller than body size alone would predict 3.5 Effect of fed and fasted states on drug (Fig. 2.2). The maturation profile may vary bioavailability among neonates and other greatly between drugs (Fig. 2.1), but if the drug young children elimination pathways are known, one can use literature information about their maturation Generating pharmacokinetic data for novel ARV and use population pharmacokinetics or formulations for children in the fed state by using physiologically based pharmacokinetics to predict healthy adults is standard practice. For neonates a starting dose (15). However, the prediction and other young children, consideration should be of a starting dose will still need to be validated, given to investigating the impact of regional and especially in children younger than one year. age-related infant feeding practices, especially in Since metabolic pathways mature during fetal highly endemic countries. Pharmacokinetic data development, a more accurate description can be in the fasted state are also equally important to obtained using conception age and not postnatal understand the potential impact on drug exposure age, to account for the effect of prematurity. if no or only a little food was provided. Population When determining the optimal dose to use pharmacokinetics or physiologically based for young children, other factors need to be pharmacokinetic modelling may aid in assessing how considered besides the maturation of clearance. food affects drug concentrations, including issues The volume of distribution may also be different of malnutrition, among neonates and other infants. among very young children since body composition changes during the first months of life, and the speed and extent of absorption 3.6 Bioavailability studies of ARV drugs (bioavailability) may also change because among children of differences in the size and motility of the gastrointestinal tract and changes in gastric Bioequivalence of novel formulations to be used pH (16,17) in children must be assessed. Such studies are often performed initially among adults but should also be assessed among children, since adult 3.4 Washout studies in neonates to inform bioequivalence studies of some ARV formulations dose selection for children did not predict bioavailability problems that were revealed when these formulations were Studies in neonates are often performed only administered to children (21,22). after data are available from studies of young infants. Washout studies of the elimination of a drug in neonates that was acquired across the 3.7 Investigating modifications of placenta following administration of the drug novel formulations for adults and children during pregnancy provides an assessment of the is critical rate of drug elimination in the first days of life, informing dose size selection for initial studies The shift from individual liquid formulations with direct neonatal dosing in the first days of life to small dispersible and chewable fixed- (see the module on pregnant and breastfeeding dose combination tablets has been a major women). In vitro studies of the effect of the achievement and has greatly helped families drug on bilirubin binding may also be conducted in low- and middle-income countries in before studies of dosing in neonates to ensure administering complex drug combinations to their that administering the drug to neonates will not children daily. However, it is critical to carefully result in an increased incidence of kernicterus consider how drugs will be administered in a resulting from the displacement of bilirubin from real-life setting across children’s age continuum, albumin (18–20). and efforts to collect pharmacokinetic data
38 following different modes of administration would for children (27). Nevertheless, frequent dose be beneficial. Although less common today, changes may be unavoidable for drugs that are modifying the mode of administering fixed-dose metabolized or eliminated through pathways combination tablets for adults or children has with rapid maturation, such as raltegravir among been necessary to facilitate administration to neonates (see the section on case studies). children, such as splitting or crushing tablets for adults or children that should be swallowed whole (21). Such manipulation of a formulation can 3.10 Giving priority to fixed-dose significantly affect bioavailability(23) . The possible combination formulations for children interactions with excipients should also be considered in the formulations of co-administered The WHO paediatric dosing tool (14) enables drugs (24). In this context, proactively performing the joint display of the exposure of several drugs pharmacokinetic studies of new drug formulations within a fixed-dose combination across weight for adults and children among healthy volunteers bands and allows for graphical comparison. would be beneficial in helping to clarify how the A more sophisticated computer optimization formulations can be safely modified, if at all, in the method selecting both optimal tablet size and clinic and home settings. ratio between the ingredients has recently been proposed for tuberculosis (28). A model-based analysis was recently used to determine the 3.8 Palatability of ARV formulations for optimal drug ratio for a fixed-dose combination children is paramount abacavir + lamivudine + efavirenz tablet for children and is discussed in the section on case Developing solid formulations is favoured over studies (29). developing liquid formulations. For example, the recent introduction of a pellet formulation of lopinavir/ritonavir has helped to simplify 3.11 Drug–drug interactions may differ for dosing, although taste issues remain (25,26). In children versus adults general, flavoured or taste-masked formulations are preferred, and pharmacokinetic and Pharmacokinetic data on drug–drug interactions acceptability studies of these formulations in for adults may be used to inform which drugs children must be undertaken. should not be co-administered to children because of a risk of too high or too low drug exposure. However, drug–drug interactions between ARV 3.9 Dosing strategies should be simplified drugs and commonly prescribed non-ARV drugs when possible that are expected to interact (for example, because of a common metabolic pathway or Simplifying drug-dosing strategies to achieve substrates for the same drug transporters) target drug exposure is of critical importance should be assessed among children as well. Since in successfully administering drugs to children. such interactions may differ between adults and WHO weight-band dosing guidelines have children, dosing adjustments must be investigated helped to simplify dosing, and pharmacokinetic among children. One example of such a difference studies among children living with HIV should be was observed with the reduction in lopinavir undertaken to assess drug exposure and safety exposure with the co-administration of rifampicin with dosing regimens that use these standard as part of tuberculosis treatment. Doubling weight bands. For example, the IMPAACT lopinavir/ritonavir doses when co-administered (International Maternal Pediatric Adolescent with rifampicin resulted in therapeutic lopinavir AIDS Clinical Trials) P1083 study assessed the exposure for adults, but not for children (30,31) WHO weight-band dosing of lopinavir/ritonavir (see section 2.1 of the module on coinfections).
39 4. CASE STUDIES
The following section describes two case studies These data were combined with pharmacokinetic highlighting the pharmacokinetic challenges data for raltegravir from infants older than often encountered when designing clinical trials one month, and a raltegravir population involving children. pharmacokinetic model was developed. Simulations were performed evaluating raltegravir exposure with different dosing regimens during the first six 4.1 Raltegravir for neonates weeks of life, with a goal of selecting a regimen that would provide therapeutic plasma target Raltegravir was the first HIV integrase strand concentrations while avoiding potential toxicity transfer inhibitor to be licensed and the first to throughout the first month of life (33). The be available with a formulation suitable for use suggested regimen (1.5 mg/kg once a day for the among neonates. Raltegravir is metabolized by first week of life, 3 mg/kg twice a day for weeks uridine diphosphate-glucuronosyltransferase 2–4 and 6 mg/kg twice daily during weeks 5–6) (UGT) 1A1, which is also the major enzyme was then evaluated in a study of daily raltegravir responsible for metabolizing bilirubin. Bilirubin dosing among neonates. This study demonstrated glucuronidation is very slow immediately after that this dosing regimen met the raltegravir target birth but accelerates dramatically over the concentrations (34) and led to United States first days and weeks of life, and raltegravir Food and Drug Administration (FDA) licensing of metabolism is expected to follow the same raltegravir for neonates in November 2017. developmental pattern. Raltegravir was the first ARV drug to be licensed Studies were conducted to safely and efficiently for neonates since emtricitabine was licensed investigate the pharmacokinetics of raltegravir in 2005. A study of the pharmacokinetics of among neonates and establish an appropriate raltegravir among low-birth-weight infants is now neonatal dose. An in vitro study of the effect being planned. of raltegravir on bilirubin binding showed that raltegravir would have no clinically significant effect on bilirubin binding at typical therapeutic 4.2 Determining the optimal strength of concentrations but could cause potentially a novel abacavir + lamivudine + efavirenz harmful effects at concentrations 50–100 fold formulation for children higher than typical therapeutic concentrations (18). A study of washout pharmacokinetics of The 2016 WHO consolidated ARV drug raltegravir among neonates following maternal guidelines (35) recommend a combination of dosing during pregnancy demonstrated that abacavir (ABC), lamivudine (3TC) and efavirenz raltegravir elimination was highly variable and (EFV) as the preferred first-line ARV regimen for extremely prolonged in the first days of life(32) . children weighing 10–35 kg (about 3–10 years An initial dosing study of two single raltegravir old). So far, no fixed-dose combination tablet doses during the first week of life, one during of ABC + 3TC + EFV for children is available; the first 48 hours of life and a second at around however, several generic manufactures have seven days of life, confirmed that raltegravir said that they intend to develop this formulation. elimination was extremely slow immediately after The first step in developing this fixed-dose birth but accelerated during the first week of life. combination for children was to determine the
40 optimal dose of each drug within the fixed-dose Recently, population pharmacokinetic analysis combination tablet to provide appropriate dosing was performed using data pooled from multiple of each component across all WHO weight clinical trials and therapeutic drug monitoring bands through simple dose increments. However, datasets from countries around the world the individual dosing recommendations for ABC, (29). Simulations revealed that a fixed-dose 3TC and EFV do not have equal incremental combination of ABC + 3TC + EFV for children of increases in dosing by weight, leading to different 150 + 75 + 150 mg provides the most effective drug ratios across the WHO weight bands. These and safe concentrations across the WHO weight differences in dosing are a consequence of the bands. different rates of maturation of the elimination Manufacturers can now move forward to pathways for the individual drug components. develop this strength tablet, but subsequent Pharmacokinetic data supporting the optimal pharmacokinetic studies are needed to confirm strength of an ABC + 3TC + EFV fixed-dose that optimal drug exposure of each component combination tablet for children are needed. is achieved in the target population of children.
5. SUMMARY
■■ Although efficacy for children can generally ■■ Initial doses in trials for children require be extrapolated from that of adults, understanding the (non-linear) effect of body pharmacokinetic and safety studies are size and maturation. Modelling and simulation necessary to establish appropriate dosing tools are increasingly used to inform initial for children. dose selection.
6. KEY CONSIDERATIONS
■■ Model-based approaches should be used to ■■ Developing robust population pharmacokinetic help inform dosing in young children. Such models using available data in children living data will be critical to support performing with HIV should be prioritized to help determine pharmacokinetic dose-finding studies in which strength and/or ratios of novel fixed-dose children simultaneously across weight and combination tablets for children manufactures age bands rather than using the standard should develop.
‘staggered’ or ‘step-down’ approach. ■■ Pharmacokinetic studies in children should be ■■ Model prediction for infants younger than undertaken to assess drug exposure and safety four weeks are less precise due to the rapid with dosing regimens that use standard WHO maturation of metabolic pathways during the weight bands. first month of life. For newly approved ARVs, performing washout studies in neonates will provide key data to inform dose selection and in turn accelerate dosing-finding studies in this vulnerable population.
41 7. ACKNOWLEDGEMENTS
Authors: Paolo Denti1, Mark Mirochnick2 and Tim R. Cressey3–5
Reviewers: Helen McIlleron1, Brookie Best6 and Adrie Bekker7
1 University of Cape Town, South Africa 2 Boston University School of Medicine, MA, USA 3 Chiang Mai University, Thailand 4 Harvard T.H. Chan School of Public Health, Boston, MA, USA 5 University of Liverpool, United Kingdom 6 University of California, San Diego, USA 7 Stellenbosch University, Cape Town, South Africa
8. REFERENCES
1. Anderson BJ, Holford NHG. Understanding absorption time. J Pharmacokinet Biopharm. dosing: children are small adults, neonates 1980;8:509–34. are immature children. Arch Dis Child. 6. Aarons L. Population pharmacokinetics: 2013;98:737–44. theory and practice. Br J Clin Pharmacol. 2. Smits A, Annaert P, Allegaert K. Drug 1991;32:669–70. disposition and clinical practice in neonates: 7. Zhao P, Zhang L, Grillo J, Liu Q, Bullock JM, cross talk between developmental Moon YJ et al. Applications of physiologically physiology and pharmacology. Int J Pharm. based pharmacokinetic (PBPK) modeling 2013;452:8–13. and simulation during regulatory review. Clin 3. Liu T, Ghafoori P, Gobburu JVS. Allometry Pharmacol Ther. 2011;89:259–67. is a reasonable choice in pediatric 8. Wang Y, Jadhav PR, Lala M, Gobburu JV. drug development. J Clin Pharmacol. Clarification on precision criteria to derive 2017;57:469–75. sample size when designing pediatric 4. Clarke DF, Penazzato M, Capparelli E, pharmacokinetic studies. J Clin Pharmacol. Cressey TR, Siberry G, Sugandhi N et al. 2012;52:1601–6. Prevention and treatment of HIV infection 9. Development of an interactive tool to in neonates: evidence base for existing support paediatric trial design. Brisbane: WHO dosing recommendations and Model Answers; 2018 (https://interactive. implementation considerations. Expert Rev model-a.com.au/development-interactive- Clin Pharmacol. 2018;11:83–93. tool-support-paediatric-trial-design, 5. Riegelman S, Collier P. The application accessed 22 May 2018). of statistical moment theory to the 10. Edginton AN, Schmitt W, Willmann S. evaluation of in vivo dissolution time and Development and evaluation of a generic
42 physiologically based pharmacokinetic 19. Ahlfors CE. Unbound bilirubin associated model for children. Clin Pharmacokinet. with kernicterus: a historical approach. J 2006;45:1013–34. Pediatr. 2000;137:540–4.
11. Howie SRC. Blood sample volumes in child 20. Schreiner C, Ahlfors C, Wong R, Stevenson health research: review of safe limits. Bull D, Clarke D, Mirochnick M. In vitro study on World Health Organ. 2011;89:46–53. the effect of maraviroc and dolutegravir on bilirubin-albumin binding. Pediatr Infect Dis 12. Aarons L, Ogungbenro K. Optimal design J. doi: 10.1097/INF.0000000000002011. of pharmacokinetic studies. Basic Clin [Epub ahead of print] Pharmacol Toxicol. 2010;106:250–5. 21. Chokephaibulkit K, Cressey TR, Capparelli 13. Anderson BJ, Holford NHG. Mechanism- E, Sirisanthana V, Muresan P, Hongsiriwon based concepts of size and maturity in S et al. Pharmacokinetics and safety of a pharmacokinetics. Annu Rev Pharmacol new paediatric fixed-dose combination of Toxicol. 2008;48:303–32. zidovudine/lamivudine/nevirapine in HIV- 14. Denti P, Sugandhi N, Cressey TR, Mirochnick infected children. Antivir Ther. 2011;16:1287–95. M, Capparelli EV, Penazzato M. An easy- 22. Kasirye P, Kendall L, Adkison KK, Tumusiime to-use paediatric dosing tool: one mg/kg C, Ssenyonga M, Bakeera-Kitaka S et al. dose does not fit all. 24th Conference on Pharmacokinetics of antiretroviral drug Retroviruses and Opportunistic Infections, varies with formulation in the target Boston, MA, USA, 4–7 March 2017 (Abstract population of children with HIV-1. Clin 809; http://www.croiconference.org/ Pharmacol Ther. 2012;91:272–80. sessions/easy-use-paediatric-dosing-tool- one-mgkg-dose-does-not-fit-all, accessed 23. Best BM, Capparelli EV, Diep H, Rossi SS, 22 May 2018). Farrell MJ, Williams E et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole 15. Björkman S. Prediction of drug disposition tablets in children. J Acquir Immune Defic in infants and children by means of Syndr. 2011;58:385–91. physiologically based pharmacokinetic (PBPK) modelling: theophylline and 24. Adkison KK, McCoig C, Wolstenholme A, midazolam as model drugs. Br J Clin Lou Y, Zhang Z, Eld A et al. Effect of sorbitol Pharmacol. 2005;59:691–704. on lamivudine pharmacokinetics following administration of EPIVIR solution in adults. 16. Kearns GL, Abdel-Rahman SM, Alander 24th Conference on Retroviruses and SW, Blowey DL, Leeder JS, Kauffman RE. Opportunistic Infections, Boston, MA, USA, Developmental pharmacology – drug 4–7 March 2017 (Abstract 428; http://www. disposition, action, and therapy in infants and croiconference.org/sessions/effect-sorbitol- children. N Engl J Med. 2003;349:1157–67. 3tc-pk-after-administration-lamivudine- 17. Lu H, Rosenbaum S. Developmental solution-adults, accessed 22 May 2018). pharmacokinetics in pediatric populations. J 25. Kekitiinwa A, Musiime V, Thomason MJ, Pediatr Pharmacol Ther. 2014;19:262–76. Mirembe G, Lallemant M, Nakalanzi S et al. 18. Clarke DF, Wong RJ, Wenning L, Stevenson Acceptability of lopinavir/r pellets (minitabs), DK, Mirochnick M. Raltegravir in vitro effect tablets and syrups in HIV-infected children. on bilirubin binding. Pediatr Infect Dis J. Antivir Ther. 2016;21:579–85. 2013;32:978–80. 26. Musiime V, Fillekes Q, Kekitiinwa A, Kendall L, Keishanyu R, Namuddu R et al. The
43 pharmacokinetics and acceptability of Conference on Pharmacometrics, Bellevue, lopinavir/ritonavir minitab sprinkles, tablets WA, USA, 22–27 October 2016. and syrups in African HIV-infected children. J 34. Clarke D, Acosta E, Chain A, Cababasay Acquir Immune Defic Syndr. 2014;66:1. M, Wang J, Calabrese K et al. Raltegravir 27. Pinto JA, Capparelli EV, Warshaw M, Zimmer B, pharmacokinetics and safety in HIV-1 Cressey TR, Spector SA et al. A Phase II/III trial exposed neonates at high risk of infection of lopinavir/ritonavir dosed according to the (IMPAACT P1110). 17th International WHO pediatric weight band dosing guidelines. Workshop on Clinical Pharmacology of HIV Pediatr Infect Dis J. 2018;37:329–35. and Hepatitis Therapy, Washington, DC, 8–10 June 2016. 28. Svensson EM, Yngman G, Denti P, McIlleron H, Kjellsson MC, Karlsson MO. Evidence- 35. Consolidated guidelines on the use of based design of fixed-dose combinations: antiretroviral drugs for treating and principles and application to pediatric anti- preventing HIV infection: recommendations tuberculosis therapy. Clin Pharmacokinet. for a public health approach. 2nd ed. 2018;57:591–9. Geneva: World Health Organization; 2016 (http://www.who.int/hiv/pub/arv/arv-2016/ 29. Bouazza N, Cressey TR, Foissac F, Bienczak en, accessed 22 May 2018). A, Denti P, McIlleron H et al. Optimization of the strength of the efavirenz/lamivudine/ abacavir fixed-dose combination for paediatric patients. J Antimicrob Chemother. 2017;72:490–5.
30. McIlleron H, Ren Y, Nuttall J, Fairlie L, Rabie H, Cotton M et al. Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis. Antivir Ther. 2011;16:417–21.
31. Zhang C, Denti P, Decloedt EH, Ren Y, Karlsson MO, McIlleron H. Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin. Br J Clin Pharmacol. 2013;76:741–51.
32. Clarke DF, Acosta EP, Rizk ML, Bryson YJ, Spector SA, Mofenson LM et al. Raltegravir pharmacokinetics in neonates following maternal dosing. J Acquir Immune Defic Syndr. 2014;67:310–5.
33. Lommerse J, Clarke D, Chain A, Witjes H, Teppler H, Capparelli E et al. Raltegravir dosing in neonates (IMPAACT P1110) – a safe and efficacious regimen for neonates from birth to 6 weeks of age. American
44 MODULE 3: PREGNANT AND BREASTFEEDING WOMEN
©ICAP/Sven Torfinn
45 1. INTRODUCTION
The number of children newly infected with on the safety of ARV drugs during pregnancy HIV has decreased by 47% since 2010, although (8–10). Nevertheless, the data from these 160 000 children acquired HIV in 2016 (1). This studies usually become available years after FDA decline is mainly related to treating women living licensing. Looking at clinical trials reporting on with HIV for their own health and to reduce the the pharmacokinetics and safety of the main risk of vertical HIV transmission (2). Combination ARV drugs during pregnancy, the median time to antiretroviral therapy (ART) is a highly effective first data (the time between FDA approval and strategy for preventing the vertical transmission publication of the first prospective clinical trial) of HIV, reducing the risk from 20–45% to less exceeds six years. than 1% in non-breastfeeding populations (3). However, information on antiretroviral (ARV) Partly depending on treatment alternatives, drug pharmacokinetics and maternal and fetal many pregnant and breastfeeding women and safety during pregnancy, as well as placental potentially their (unborn) infants inevitably transfer, distribution into breast-milk and infant use (or have used) untested ARV drugs. exposure are required before pregnant and Untested here refers to the fact that health- lactating women can safely and effectively use care professionals had no data available on these drugs. pharmacokinetics and safety during pregnancy or breastfeeding to inform treatment strategies Unfortunately, pregnant and breastfeeding (4). Excluding pregnant and lactating women women are generally excluded from pre- from participating in medical research results in marketing clinical drug development a lack of knowledge about the risks and potential programmes (4). In the past decade, the benefits of products that will be available for United States Food and Drug Administration their use once on the market. (FDA) has continued to emphasize the need for including women (pregnant and non- Early data on the pharmacokinetics and safety of pregnant) in development programmes, issuing ARV drugs in pregnancy and lactation gathered guidance for industry on establishing pregnancy under rigorous scientific conditions are critically registries and drafting guidelines for conducting needed. This would place fewer women and pharmacokinetic and pharmacodynamic studies their fetuses at risk compared with the much among pregnant women and draft guidance for larger number of pregnant and lactating women studies among lactating women (5,6). who are exposed when drugs reach the market without evaluation (11). Nevertheless, no current legislation or regulations formally provide incentives for In short, including pregnant and breastfeeding or mandate drug studies among pregnant women in clinical research is critically important, women (7). Several post-marketing surveillance and the period between FDA approval and the initiatives and clinical trial networks (usually first clinical pregnancy and lactation data should in the form of public–private partnerships) be minimized or eliminated (Fig. 3.1). investigate the pharmacokinetics and report
46 Fig. 3.1. Time between approval and the first published pharmacokinetic data in pregnancy for various ARV drugs
Median knowledge gap 6 years
EFV
ETV
DRV, TDF, ABC, MVC
RAL
LPV and FTC
RPV and DTG
ATV
3TC
AZT and NVP
0 2 4 6 8 10 12 14 16 Drug approval Years after FDA approval
2. CHALLENGES
Research involving and treatment of pregnant their infants using ARV agents that have not been and breastfeeding women raises ethical and tested on them. scientific questions. Although regulatory agencies encourage the study of drugs among pregnant and breastfeeding women, they are generally 2.1 Ethical concerns about exposing excluded from drug development programmes, pregnant women and their fetuses to ARV leading to knowledge gaps when drugs come to drugs being developed market. Nearly all drugs are licensed without any data describing their use in pregnancy, including Since the risks to the fetus and the infant posed safety for the mother and child when used by most new chemical entities or approved drugs during pregnancy and breastfeeding, whether cannot be sufficiently ruled out, pregnant and effective exposure is achieved during pregnancy breastfeeding women are generally excluded with standard nonpregnant adult dosing and to from (pre-marketing) clinical trials (12,13). what extent the drug crosses the placenta and Although no one questions the relevance of is excreted in breast-milk. The lack of research these ethical considerations, this leads to the leads to pregnant and breastfeeding women and following point.
47 2.2 ARV drugs are widely used 2.4 Physiological changes in pregnancy “untested” among pregnancy and may affect exposure to ARV drugs, and breastfeeding women these changes may change drug efficacy
Since pregnant women are excluded from Pregnancy is associated with a wide range of clinical trials during the development phase, a physiological, anatomical and biochemical changes substantial knowledge gap remains regarding that substantially influence the pharmacokinetics the pharmacokinetics and safety of ARV drugs of therapeutic agents (15–18). Pregnancy is during pregnancy, placental transfer of agents associated with prolonged gastric transit time, and transfer into breast-milk following drug nausea and vomiting and dietary alterations that marketing. Consequently, many pregnant and may alter drug absorption. Drug distribution may breastfeeding women will inevitably use (or have change in pregnant women because of changes used) “untested” ARV drugs. in body composition, blood volume, protein binding and expression of transporters. Activity of drug metabolizing enzymes may increase during 2.3 Using ARV drugs in pregnancy pregnancy (such as cytochrome 450 (CYP) 3A may be associated with birth defects and uridine diphosphate-glucuronosyltransferase or other adverse birth outcomes: (UGT) 1A4) or decrease (such as CYP 2C19), preterm birth, fetal growth restriction affecting the intrinsic clearance of ARV drugs. and gestational diabetes Increases in cardiac output, renal blood flow and glomerular filtration rate during pregnancy may increase the elimination of renally cleared drugs. An essential element of pregnancy-related clinical pharmacology is the effect on the fetus In combination, these changes may result in of mothers using therapeutic agents. Maternal alterations during pregnancy of the unbound drug effects, such as an increased risk of preterm pharmacologically active concentration of drug labour or impaired maternal glucose homeostasis, at the target site, leading to changes in drug may profoundly affect the well-being of the fetus. response. Studying the pharmacokinetics of ARV Individual drugs cross the placenta to a greater drugs among pregnant women is necessary to or lesser extent, exposing the fetus to potential ensure adequate drug exposure in this vulnerable direct therapeutic and/or toxic drug effects. population (Fig. 3.2). Exposure during the first trimester may impact fetal organogenesis and result in teratogenicity, although to date there is no confirmed association 2.5 Placental transfer, fetal exposure and between exposure to ARV drugs and increased disposition into breast-milk are unknown birth defect rate (10). Physiologically, placental transfer is the main Fetal (or placental) exposure to ARV drugs may determinant of fetal exposure (20). Quantifying provide beneficial effects such as pre-exposure fetal exposure is key for evaluating potential prophylaxis to mother-to-child HIV transmission fetal toxicity and therapeutic effect, since but may also result in fetal toxicity, such as fetal exposure may have benefits in providing bone marrow suppression or mitochondrial pre-exposure prophylaxis against maternal dysfunction (14). virus (14). In general, quantifying human fetal exposure is not straightforward, since the fetus itself is not accessible for sampling throughout
48 Fig. 3.2. Pregnancy, physiology and pharmacokinetics
Gastric pH Gastric emptying and intestinal motility
Total body water Cardiac output Plasma volume CYP2D6 activity Total body fat CYP3A4 activity Albumin concentration
Glomerular filtration rate
Created based on data from: Abduljalil et al. (19). pregnancy, so assessment of fetal drug exposure in regions where formula feeding is not safe, is generally limited to cord blood sampling at affordable or practical. The provision of maternal the time of delivery. Cord-to-maternal plasma ART through the period of breast-feeding has concentration ratios are often computed based been shown to significantly reduce breast-milk on time-matched samples collected at the time HIV transmission by reducing breast-milk HIV of delivery to provide a measure for fetal drug concentrations and/or by providing prophylaxis exposure relative to exposure in the mother. to the infant who ingests the ARV drugs present However, these relationships can be misleading in breast-milk (25). because of the time-dependent distributional Waitt et al. (26) investigated whether infant kinetics of drugs across the placenta (that is, exposure to ARV drugs during breastfeeding is placental transfer may vary during gestation). quantitatively important. They concluded that Cord blood sampling provides the best available this might be the case for some nucleoside proxy for fetal exposure in humans, but the data reverse-transcriptase inhibitors and non- resulting from cord blood sampling are generally nucleoside reverse-transcriptase inhibitors but limited to a single sample collected at one time not for protease inhibitors. point late in pregnancy. This sampling limitation Exposure to ARV drugs during breastfeeding complicates population pharmacokinetic analysis could result in toxicity to the infant. Should the of such data (21,22). Data on fetal exposure from animal models may be informative but of limited infant acquire HIV infection via breast-milk, infant translational value because of interspecies variability exposure to low concentrations of ARV drugs in placental structure and function (23,24). during the breastfeeding period could result in the infant developing ARV drug resistance, Transmission of HIV from mother to child after limiting future therapeutic options (27,28). birth via breast-milk remains a major problem
49 3. SOLUTIONS
Adequate ART for mother and child during and Dedicated clinical pharmacology studies directly after pregnancy is vital in preventing involving pregnant and lactating women can mother-to-child HIV transmission. The following be initiated once initial safety and efficacy have approaches and solutions can be used to been demonstrated among non-pregnant adults ensure adequate treatment. Following these (4). These studies could include the women from recommendations, information will become pre-marketing trials and continue to include available for health-care professionals on more pregnant women for adequate power with adequate treatment regimens during pregnancy respect to a prespecified clinical endpoint, such in a timely, informative and efficient manner. as undetectable viral load at delivery. These studies may be opportunistic (women who become pregnant while receiving a specific drug 3.1 Ethical concerns about exposing can be included without changing treatment) pregnant women and their fetuses to ARV or may be intervention studies (search for the drugs being developed optimal dose in pregnancy) initiated by academia or the pharmaceutical industry. To accelerate Regulatory authorities and ethical committees inclusion rates and include women in the should require and support the inclusion of settings where the disease is most prevalent, pregnant women in pre-marketing clinical trials. these studies should be performed in relevant At the very least, women enrolled in Phase II or populations in both high-income and low- and III clinical trials should not be removed from the middle-income countries. Centres of excellence study drug if they become pregnant during the should be established in the low- and middle- trial, if preclinical reproductive toxicology studies income countries. were negative. Fortunately, the consensus is shifting, and support for including pregnant 3.2 Using ARV drugs in pregnancy women before marketing is growing (11,13). may be associated with birth defects Incentives from regulatory authorities are or other adverse birth outcomes: important to include pregnancy as part of the preterm birth, fetal growth restriction clinical development plan for ARV drugs, given and gestational diabetes the substantial anticipated use among women of childbearing age. This plan should ensure that the necessary data are obtained through studies in The safety of ART and pregnancy outcomes pregnancy and/or breastfeeding to support the should be closely monitored during use of drugs in pregnant women, including: pharmacokinetic studies that include pregnant women. However, clinical studies specifically ■ ■ safety data from both mother and child, with designed to detect safety issues during long-term follow-up after in utero and/or pregnancy require large numbers of study breast-milk exposure; and subjects and are therefore not feasible. Instead, ■■ pharmacokinetic and pharmacodynamic post-marketing surveillance studies are used data: viral load monitoring, CD4 counts, that follow women and newborns exposed pharmacokinetics in pregnancy, placental to ARV drugs during pregnancy, such as the passage, passage into breast-milk and Antiretroviral Pregnancy Registry (http://www. exposure of neonates and other infants. apregistry.com). For sufficient power to detect
50 relevant effects (mainly birth defects), these pregnant women are typically pharmacokinetic studies typically require hundreds of subjects under the assumption that pharmacokinetic exposed to these agents (10). Guidance on parameters such as total drug exposure are designing and executing these studies is informative and predictive for ARV drug efficacy described elsewhere (29). This post-marketing and safety. surveillance should be supported and monitored more closely from a regulatory perspective (see As such, these studies should be powered to the module on pharmacovigilance). detect relevant differences in the primary pharmacokinetic endpoints of interest. These typically include total drug exposure, maximum 3.3 Clinical pharmacology studies of ARV concentration over a dosing interval and/or drugs among pregnant women concentration at the end of the dosing interval and depend on what parameter correlated best with the pharmacodynamics in previous In clinical studies with ARV drugs that include pharmacokinetic and pharmacodynamic pregnant women, the following data should be studies involving non-pregnant adults. These collected: pharmacokinetic parameters can be estimated by ■■ viral loads during pregnancy and postpartum; non-compartmental analysis and, if needed, also ■■ maternal safety during pregnancy; by population pharmacokinetic modelling, with the major advantage that such an approach enables ■■ birth outcome: gestational age, birth weight, interpolation when the dose being investigated is congenital abnormalities and HIV infection deemed inadequate during pregnancy. status;
■■ full pharmacokinetic profiles in the second and This is in accordance with the FDA guidance on third trimesters and postpartum; designing pharmacokinetic studies in pregnancy, in which they recommend that “the dose should ■■ if protein binding is substantial, unbound [be adjusted to] produce a comparable range plasma concentrations should be determined; of unbound plasma concentrations of drug ■■ additional single time-point plasma samples or active metabolites in both controls and can be taken throughout the course of pregnant patients” (5). Pregnancy effects can pregnancy (such as at every visit) to identify be determined by the comparability of exposure temporal changes during pregnancy; of non-pregnant (control) and pregnant people ■■ cord and maternal blood sample at delivery, by means of no-effect boundaries for the ratio ideally for all included subjects; and of a pharmacokinetic parameter, an approach sometimes referred to as the bioequivalence ■■ washout samples of ARV drugs from infants following delivery (see the module on method. For this approach, the null hypothesis is pharmacokinetic modelling). that pregnancy has a clinically relevant effect on the pharmacokinetic parameter of interest. If the Although pharmacodynamics are monitored 90% confidence interval for the ratio falls within and should be reported (such as viral load or the no effect boundaries (typically 80–125%), toxicity), absolute differences are usually small, the null hypothesis can be rejected, and it is and detecting such effects would require more reasonable to conclude that pregnancy has no sophisticated trial design and including much clinically relevant effect and no dose adjustment larger numbers of pregnant subjects. Hence, is needed. pharmacodynamics as the primary endpoint in such studies is generally unfeasible. For The no-effect boundaries are preferably set this reason, the primary endpoints of clinical based on well established pharmacokinetic and pharmacology studies of ARV drugs among pharmacodynamic relationships for efficacy and safety. However, these relationships are
51 not always readily available, and setting these should be used for the analysis, since this is what boundaries can therefore be challenging. Since the infant is ingesting. pregnancy is a temporary condition, boundaries somewhat wider than the conservative bioequivalence boundaries can be acceptable 3.6 Preclinical placental transfer (such as 70–143% or wider), especially if the therapeutic window is relatively wide During the preclinical phases of drug development, and variability is large. Prespecifying these parallel to or shortly after reproductive toxicology boundaries for the primary pharmacokinetic studies, the ex vivo human cotyledon perfusion endpoint and powering the study accordingly model can be used to investigate the placental are crucial. Further guidance on setting the transfer of ARV drugs (14). These experiments use no-effect boundaries and ensuring the inclusion term placentas obtained immediately following of sufficient subjects for adequate statistical delivery and could be outsourced to institutes power is provided elsewhere (30). (typically academic medical centres) that have such models in place. The results of such studies can provide information about the fetal exposure 3.4 Placental transfer and infant washout to the ARV drug of interest, but such studies are limited to late pregnancy. To assess fetal exposure, cord blood samples and maternal samples should be taken at delivery (ideally for all included subjects). In addition, 3.7 Modelling and simulation for compounds with substantial anticipated fetal exposure based on preclinical data, it is Given the limited participation of pregnant recommended to collect serial washout samples women in clinical studies, leading to few data after birth from neonates exposed to the in pregnancy, modelling and simulation may ARV drugs in utero. This sampling is especially facilitate understanding of pregnancy-related important for compounds metabolized by clinical pharmacology. enzymes that are known to be immature in Population pharmacokinetic modelling can be neonates (see the module on pharmacokinetic helpful to quantify the sources of variability, modelling). Depending on the half-life of the handling sparse data, dealing with non-linearity, compound, serial neonatal plasma samples facilitating the pooling of data sets from should be collected, with the duration of studies with unbalanced design, trial simulation sampling based on an estimate of likely half- and interpolation (such as simulation of other life among newborns. Because many neonate dosing regimens in the target population). For enzyme systems are immature, half-life might be this approach to be successful requires certain substantially prolonged (31). clinical data from the target population of pregnant women. These models can then be used 3.5 Disposition into breast-milk for stochastic simulation to evaluate the drug exposure (or other secondary pharmacokinetic When postpartum women included in clinical parameters of interest) during pregnancy, for trials are breastfeeding, simultaneous maternal example, to evaluate the frequency of individual and infant plasma samples and breast-milk drug exposure below a certain target. samples should be collected. In all samples, both If the dose studied appears inadequate, the viral load and concentrations of the ARV drug model can be used for simulating secondary can be assessed. This sampling may be performed pharmacokinetic parameters following at standard postpartum visits, such as at 2, 6, 14 alternative dosing regimens. This can inform and 24 weeks postpartum. Preferably whole milk
52 follow-up studies investigating dose adjustments drug to be simulated in a mechanistic manner, during pregnancy (32). Further, this approach taking molecular processes as a starting-point. can be used for optimizing design and clinical Consequently, it provides comprehensive trial simulation. This enables optimization of and integrated understanding of the sampling schedule throughout the course of pharmacokinetics and pharmacodynamics of a pregnancy, which could provide information drug and can be completed even in the complete about the temporal change of pharmacokinetics absence of clinical data in the target population during pregnancy (33). Further, it could guide (by extrapolation). the plan of analysis for a clinical study, inform the choice of primary outcome measures and For example, fetal exposure can be determine the number of women that should be quantitatively predicted by physiologically based (21,22). Placental included for adequate statistical power. pharmacokinetic modelling transfer can be parameterized using an in Full bottom-up approaches, such as vitro-to-in vivo extrapolation approach based physiologically based pharmacokinetic modelling, on clearance values or rate constants from ex use mechanistic information, including system- vivo human cotyledon perfusion experiments. related parameters (such as organ volumes, blood These parameters can then be integrated in flows and tissue composition) and drug-related fetal-maternal whole-body physiologically parameters (such as intrinsic metabolic clearance based pharmacokinetic models to predict fetal or drug ligand affinity). These parameters are exposure. Following such an approach, recent combined in systems of differential equations studies successfully predicted fetal exposure that are based on a pragmatic compartmental based on human placental transfer (20,33,34). structure describing the anatomy, physiology Later, this can be verified with cord blood and and biochemistry of the pregnant women. This matched maternal blood samples collected at approach enables the way the body processes a birth in clinical studies (Fig. 3.3).
Fig. 3.3. Studies involving pregnant women in developing drugs
Regulatory approval
Preclinical Phase I Phases II and III Post-marketing
Toxicology studies including reproduction toxicology
Placental perfusion studies Ex vivo system
Physiologically based pharmacokinetic models predicting exposure in pregnancy
Pharmacology studies
Safety registry and post-marketing surveillance
Breastfeeding studies
53 4. CASE STUDIES
Currently, most pharmacokinetic studies among systematically reviewed the pharmacokinetic pregnant women living with HIV are conducted studies investigating the transfer of ARV drugs to by two clinical trial networks: 1) the International breast-milk and subsequently to the infant. Maternal Pediatric Adolescent AIDS Clinical The ARIA study (NCT01910402) is a progressive Trial (IMPAACT) Network protocol P1026s example of how to manage women enrolled and 2) Pharmacokinetics of Newly Developed in Phase II trials who become pregnant. In Antiretroviral Agents in HIV-Infected Pregnant this study, sponsored by the pharmaceutical Women (PANNA) network (8,9). These studies follow an opportunistic design and perform industry, women who become pregnant during intensive pharmacokinetic sampling during the study are allowed to continue study drugs pregnancy and postpartum. Together they have with informed consent and are included as a conducted intensive pharmacokinetic sampling separate arm in the study (NCT02075593). on more than 1000 pregnant and postpartum This demonstrates the growing awareness, women receiving more than 25 ARV drugs. implementation and future opportunities for Most recently, these networks reported the (pre-marketing) clinical research that includes pharmacokinetics of rilpivirine and dolutegravir pregnant women. among pregnant women living with HIV Ex vivo human cotyledon perfusion experiments (35,36). Pharmaceutical companies sometimes have also been conducted, and the literature conduct and publish similar studies (37). Such has been reviewed (14). The placental transfer studies routinely conduct cord blood sampling. of the HIV integrase inhibitor dolutegravir Less frequently, washout data from infants is was evaluated in an ex vivo human cotyledon collected. Several neonate washout studies have perfusion model (39). ARV drug placental been performed, especially in case of in utero transfer has been integrated into physiologically exposure to drugs metabolized by UGT. Examples based pharmacokinetic models and fetal are studies performed by the IMPAACT Network exposure has also been predicted (20,33,34). with raltegravir, dolutegravir and elvitegravir (31,36,38). The major database for collecting safety information for ARV drugs during pregnancy Although not yet standard practice, the design is the Antiretroviral Pregnancy Registry, where of these studies would also be ideal for assessing pregnancy exposures and outcomes are reported breast-milk disposition (when national guidelines on a voluntary basis. allow for breastfeeding). Waitt et al. (26)
54 5. SUMMARY
Pregnant and breastfeeding women are mainly The recommendations provided here will assist excluded from clinical research, resulting in the in effectively evaluating all aspects of clinical use of “untested” ARV drugs by pregnant and pharmacology that are required for safe and breastfeeding women and their infants. Including effective treatment of women living with HIV and pregnant and breastfeeding women in clinical their children and to optimize pharmacotherapy research is critical, and the period between FDA during pregnancy. This will facilitate more timely approval and the first clinical pregnancy and and quantitative information on safe treatment lactation data should be minimized or eliminated. strategies for pregnant and breastfeeding women living with HIV.
6. KEY CONSIDERATIONS
■■ Placental transfer should be studied during ■■ Modelling and simulation should be used to the preclinical phases of drug development facilitate understanding pregnancy-related using techniques such as the ex vivo human clinical pharmacology and to inform clinical cotyledon perfusion model. studies involving pregnant women.
■■ Regulatory authorities and ethical committees ■■ Cord blood samples and maternal samples should require and support the inclusion of should be taken at delivery to assess fetal pregnant women in pre-marketing clinical exposure, and washout samples in neonates trials. At the very least, women enrolled in should be taken to assess neonatal elimination.
Phase II or III clinical trials should not be ■■ Postpartum lactating women should be included removed from the study drug if they become in clinical trials, and breast-milk transfer from pregnant during the trial. mother to infant should be assessed. ■■ Clinical pharmacology studies of ARV drugs ■■ The safety of ART and pregnancy outcomes among pregnant and lactating women should should be closely monitored during be executed according to the high standards pharmacokinetic studies that include pregnant and requirements stated in this toolkit. women and by post-marketing surveillance studies.
55 7. USEFUL RESOURCES
FDA and EMA guidance for industry Perinatal guidelines for treating women living with HIV EMA ■■ Recommendations for the use of antiretroviral ■■ The exposure to medicinal products during drugs in pregnant women with HIV infection pregnancy: need for post-authorisation data and interventions to reduce perinatal HIV http://www.ema.europa.eu/docs/en_GB/ transmission in the United States document_library/Regulatory_and_procedural_ https://aidsinfo.nih.gov/guidelines/html/3/ guideline/2009/11/WC500011303.pdf perinatal/0
■■ BHIVA guidelines for the management FDA of HIV infection in pregnant women 2012 ■■ Establishing pregnancy exposure registries (2014 interim review) https://www.fda.gov/downloads/drugs/ http://www.bhiva.org/pregnancy-guidelines.aspx guidancecomplianceregulatoryinformation/ ■ guidances/ucm071639.pdf ■ European guidelines for treatment of HIV-positive adults in Europe ■■ Pharmacokinetics in pregnancy – study design, http://www.eacsociety.org/guidelines/eacs- data analysis, and impact on dosing and labelling guidelines/eacs-guidelines.html https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/UCM072133.pdf) WHO guidelines ■■ Clinical lactation studies – study design, data analysis, and recommendations for labelling ■■ Consolidated guidelines on the use of https://www.fda.gov/downloads/Drugs/ antiretroviral drugs for treating and preventing GuidanceComplianceRegulatoryInformation/ HIV infection: recommendations for a public Guidances/UCM072097.pdf health approach – second edition http://apps.who.int/iris/ bitstream/10665/208825/1/9789241549684_ eng.pdf?ua=1
56 Other ■■ ARIA study at clinicaltrials.gov https:// clinicaltrials.gov/ct2/show/NCT02075593; ■■ Antiretroviral Pregnancy Registry pregnancy substudy https://clinicaltrials.gov/ http://www.apregistry.com ct2/show/NCT01910402
■■ International Maternal Pediatric Adolescent ■■ Guidance for industry: establishing pregnancy AIDS Clinical Trial (IMPAACT) Network exposure registries protocol P1026s http://www.fda.gov/downloads/drugs/ https://clinicaltrials.gov/ct2/show/ guidancecomplianceregulatoryinformation/ NCT00042289 guidances/ucm071639.pdf
■■ Pharmacokinetics of Newly Developed Key publications with open access Antiretroviral Agents in HIV-Infected Pregnant ■■ Pregnancy-associated changes in Women (PANNA) network www.pannastudy. pharmacokinetics: a systematic review com and https://clinicaltrials.gov/ct2/show/ http://journals.plos.org/plosmedicine/ NCT00825929 article?id=10.1371/journal.pmed.1002160 ■■ European Placental Perfusion Network https://www.facebook.com/ EuropeanPlacentalPerfusionGroup
8. ACKNOWLEDGEMENTS
Authors: Stein Schalkwijk1, Angela Colbers1 and Mark Mirochnick2
Other contributor: David Burger1
Reviewers: Gerhard Theron3, Alice Stek4 and Lynne Mofenson5
1 Radboud University Medical Center, Nijmegen, Netherlands 2 Boston University, MA, USA 3 Stellenbosch University, Cape Town, South Africa 4 University of Southern California, Los Angeles, USA 5 Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA
57 9. REFERENCES
1. Fact sheet – latest statistics on the status of 7. Gee RE, Wood SF, Schubert KG. Women’s the AIDS epidemic. Geneva: UNAIDS; 2018 health, pregnancy, and the U.S. Food and (http://www.unaids.org/en/resources/fact- Drug Administration. Obstet Gynecol. sheet, accessed 22 May 2018). 2014;123:161–5.
2. United States Department of Health and 8. Pharmacokinetics of antiretroviral agents Human Services. Panel on Treatment of HIV- in HIV-infected pregnant women (PANNA). Infected Pregnant Women and Prevention Bethesda (MD): National Institutes of Health of Perinatal Transmission. Recommendations Clinical Center; 2008 (https://clinicaltrials. for use of antiretroviral drugs in pregnant gov/ct2/show/NCT00825929, accessed 22 HIV-1-infected women for maternal health May 2018). and interventions to reduce perinatal 9. Pharmacokinetic properties of antiretroviral HIV transmission in the United States. and related drugs during pregnancy and Washington (DC: AIDSInfo; 2017 (http:// postpartum. Durham (NC): IMPAACT; 2015 aidsinfo.nih.gov/contentfiles/lvguidelines/ (http://impaactnetwork.org/studies/p1026s. PerinatalGL.pdf, accessed 22 May 2018). asp, accessed 22 May 2018). 3. Townsend CL, Byrne L, Cortina-Borja M, Thorne C, de Ruiter A, Lyall H et al. Earlier 10. Antiretroviral Pregnancy Registry initiation of ART and further decline in international interim report for 1 January mother-to-child HIV transmission rates, 1989 through 31 Jul 2017. Wilmington (NC): 2000–2011. AIDS. 2014;28:1049–57. Antiretroviral Pregnancy Registry; 2017 http://www.apregistry.com/forms/interim_ 4. Sheffield JS, Siegel D, Mirochnick M, Heine RP, report.pdf, accessed 22 May 2018). Nguyen C, Bergman KL et al. Designing drug 11. Macklin R. Enrolling pregnant women in trials: considerations for pregnant women. Clin biomedical research. Lancet. 2010;375:632–3. Infect Dis. 2014;59(Suppl. 7):S437–44.
5. Pharmacokinetics in pregnancy – study 12. Shields KE, Lyerly AD. Exclusion of pregnant design, data analysis, and impact on dosing women from industry-sponsored clinical and labeling. Washington (DC): United trials. Obstet Gynecol. 2013;122:1077–81. States Food and Drug Administration; 2004 13. Lyerly AD, Little MO, Faden R. The second (https://www.fda.gov/downloads/Drugs/.../ wave: toward responsible inclusion of Guidances/ucm072133.pdf, accessed 22 May pregnant women in research. Int J Fem 2018). Approaches Bioeth. 2008;1:5–22.
6. Draft guidance: clinical lactation 14. McCormack SA, Best BM. Protecting the studies – study design, data analysis, fetus against HIV infection: a systematic and recommendations for labeling. review of placental transfer of antiretrovirals. Washington (DC): United States Food Clin Pharmacokinet. 2014;53:989–1004. and Drug Administration; 2005 (https:// www.fda.gov/downloads/Drugs/ 15. Anderson GD. Pregnancy-induced changes GuidanceComplianceRegulatoryInformation/ in pharmacokinetics: a mechanistic- Guidances/UCM072097.pdf, accessed 22 based approach. Clin Pharmacokinet. May 2018). 2005;44:989–1008.
58 16. Gilbert EM, Darin KM, Scarsi KK, McLaughlin of a model to predict in vivo transfer of MM. Antiretroviral pharmacokinetics therapeutic drugs. Clin Pharmacol Ther. in pregnant women. Pharmacotherapy. 2011;90:67–76. 2015;35:838–55. 24. Carter AM. Animal models of human 17. Colbers A, Greupink R, Burger D. placentation – a review. Placenta. Pharmacological considerations on the use 2007;28(Suppl. A):S41–7. of antiretrovirals in pregnancy. Curr Opin 25. Mirochnick M, Thomas T, Capparelli E, Zeh Infect Dis. 2013;26:575–88. C, Holland D, Masaba R et al. Antiretroviral 18. Pariente G, Leibson T, Carls A, Adams- concentrations in breast-feeding infants of Webber T, Ito S, Koren G. Pregnancy- mothers receiving highly active antiretroviral associated changes in pharmacokinetics: therapy. AntimicrobAgents Chemother. a systematic review. PLoS Med. 2009;53:1170–6. 2016;13:e1002160. 26. Waitt CJ, Garner P, Bonnett LJ, Khoo SH, 19. Abduljalil K, Furness P, Johnson TN, Else LJ. Is infant exposure to antiretroviral Rostami-Hodjegan A, Soltani H. drugs during breastfeeding quantitatively Anatomical, physiological and metabolic important? A systematic review and meta- changes with gestational age during analysis of pharmacokinetic studies. J normal pregnancy: a database for Antimicrob Chemother. 2015;70:1928–41. parameters required in physiologically 27. Fogel J, Li Q, Taha TE, Hoover DR, based pharmacokinetic modelling. Clin Kumwenda NI, Mofenson LM et al. Initiation Pharmacokinet. 2012;51:365–96. of antiretroviral treatment in women 20. De Sousa Mendes M, Lui G, Zheng Y, Pressiat after delivery can induce multiclass drug C, Hirt D, Valade E et al. A physiologically- resistance in breastfeeding HIV-infected based pharmacokinetic model to predict infants. Clin Infect Dis. 2011;52:1069–76. human fetal exposure for a drug metabolized 28. Zeh C, Weidle PJ, Nafisa L, Lwamba HM, by several CYP450 pathways. Clin Okonji J, Anyango E et al. HIV-1 drug Pharmacokinet. 2017;56:537–50. resistance emergence among breastfeeding 21. Zhang Z, Imperial MZ, Patilea-Vrana GI, infants born to HIV-infected mothers during Wedagedera J, Gaohua L, Unadkat JD. a single-arm trial of triple-antiretroviral Development of a novel maternal-fetal prophylaxis for prevention of mother-to- physiologically based pharmacokinetic child transmission: a secondary analysis. PLoS model. I. Insights into factors that determine Med. 2011;8:e1000430. fetal drug exposure through simulations 29. Guidance for industry: establishing and sensitivity analyses. Drug Metab Dispos. pregnancy exposure registries. 2017;45:920–38. Washington (DC): United States Food 22. Zhang Z, Unadkat JD. Development of a and Drug Administration; 2002 (http:// novel maternal-fetal physiologically based www.fda.gov/downloads/drugs/ pharmacokinetic model. II. Verification of guidancecomplianceregulatoryinformation/ the model for passive placental permeability guidances/ucm071639.pdf, accessed 22 drugs. Drug Metab Dispos. 2017;45:939–46. May 2018).
23. Hutson JR, Garcia-Bournissen F, Davis A, 30. Guidance for industry. Bioavailability Koren G. The human placental perfusion and bioequivalence studies submitted in model: a systematic review and development NDAs or INDs – general considerations.
59 Washington (DC): United States Food 37. Crauwels H, Baugh B, Ryan A, Zorrilla C, and Drug Administration; 2014 (https:// Osiyemi O, Yasin S et al. Total and unbound www.fda.gov/downloads/drugs/ pharmacokinetics of once-daily darunavir/ guidancecomplianceregulatoryinformation/ ritonavir in HIV-1-infected pregnant women. guidances/ucm389370.pdf, accessed 22 15th International Workshop on Clinical May 2018). Pharmacology of HIV & Hepatitis Therapy, Washington, DC; USA, 19–21 May 2014 31. Clarke DF, Acosta EP, Rizk ML, Bryson YJ, (Abstract O-15). Spector SA, Mofenson LM et al. Raltegravir pharmacokinetics in neonates following 38. Best B, Capparelli E, Stek A, Acosta E, maternal dosing. J Acquir Immune Defic Smith E, Chakthoura N et al. Elvitegravir/ Syndr. 2014;67:310–5. cobicistat pharmacokinetics in pregnancy and postpartum. Conference on Retroviruses 32. van Hasselt JG, Andrew MA, Hebert MF, and Opportunistic Infections, Seattle, WA, Tarning J, Vicini P, Mattison DR. The status USA, 13–16 February 2017 (Poster 755). of pharmacometrics in pregnancy: highlights from the 3rd American Conference on 39. Schalkwijk S, Greupink R, Colbers AP, Pharmacometrics. Br J Clin Pharmacol. Wouterse AC, Verweij VG, van Drongelen J 2012;74:932–9. et al. Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human 33. De Sousa Mendes M, Hirt D, Vinot C, cotyledon perfusion model. J Antimicrob Valade E, Lui G, Pressiat C et al. Prediction Chemother. 2016;71:480–3. of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models. Br J Clin Pharmacol. 2016;81:646–57.
34. Schalkwijk S, Buaben AO, Freriksen JJM, Colbers AP, Burger DM, Greupink R et al. Prediction of fetal darunavir exposure by integrating human ex-vivo placental transfer and physiologically based pharmacokinetic modeling. Clin Pharmacokinet. doi: 10.1007/ s40262-017-0583-8. [Epub ahead of print]
35. Schalkwijk S, Colbers A, Konopnicki D, Gingelmaier A, Lambert J, van der Ende M et al. Lowered rilpivirine exposure during the third trimester of pregnancy in human immunodeficiency virus type 1–infected women. Clin Infect Dis. 2017;65:1335–41.
36. Mulligan N, Best BM, Wang J, Capparelli EV, Stek A, Barr E et al. Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV. AIDS. 2018;32:729–37.
60 MODULE 4: COINFECTIONS
©WHO/Eduardo Soteras Jalil
61 1. INTRODUCTION
Much of the morbidity and mortality caused by of the potential for combined toxicity and drug– HIV infection is related to immunosuppression drug interactions. Proactively considering what from poorly controlled HIV infection and key coinfections and their treatment imply for subsequent disease from opportunistic developing antiretroviral (ARV) drugs for children coinfections. Coinfections usually require their is therefore prudent. Coinfections of particular own treatment, which may have implications for interest include tuberculosis (TB), hepatitis B the antiretroviral therapy (ART) regimen because virus (HBV) and hepatitis C virus (HCV).
2. COINFECTION WITH TB AND HIV
The global burden from TB, a disease caused is the substantial epidemiological overlap of by Mycobacterium tuberculosis, is enormous, TB and HIV in many settings. There are many with an estimated 10.4 million incident cases reasons for this overlap, including at least in part worldwide resulting in 1.4 million deaths in 2015, the increased risk people living with HIV have of making it the single most deadly infectious developing TB. The highest burden of childhood disease globally (1). The burden of TB among TB remains in sub-Saharan Africa and South- children has been underestimated historially, East Asia, where most children with HIV live, so but more recent attempts have revised the coinfection is likely in many settings (2). estimated number of incident TB cases among Even in settings with a low TB burden, children children substantially upward. As many as 1 million with HIV have a much higher risk of developing children are estimated to develop TB globally TB (3). Although ART reduces this risk each year (1). substantially, people living with HIV receiving Case-fatality rates of untreated TB are as high as ART remain at increased risk of developing TB 44% among HIV-uninfected children older than 5 compared with children without HIV. years and are significantly higher among children living with HIV, even when appropriately treated Second, TB remains one of the most important for TB (2). An estimated 210 000–240 000 causes of mortality among children living children died from TB in 2015, making TB one of with HIV worldwide. HIV infection potentially the top 10 causes of child mortality (2). Notably, complicates the diagnosis of TB among children the children most at risk for poor outcomes and increases the risk of morbidity and mortality. from TB, infants and other young children, are Efforts to reduce mortality among children living also the group for whom predicting drug–drug with HIV must therefore necessarily consider TB interactions is most difficult and for whom child- and work to ensure the optimal co-treatment of friendly formulations are the most important. both infections.
There are several important reasons to Third, co-treatment of TB with ARV drugs specifically consider TB coinfection in developing introduces the potential for additive adverse ARV drugs and formulations for children. First effects. The recommended first-line treatment
62 regimen for drug-susceptible TB is a two- 2.1 Key challenges month intensive phase with rifampicin, isoniazid and pyrazinamide with or without ethambutol The key consideration in developing ARV drugs followed by a four-month continuation phase of for children from the perspective of TB and HIV isoniazid and rifampicin (4). Although children co-treatment is to establish whether the ARV generally tolerate these TB medications well, drug of interest and TB medication, primarily they may cause hepatotoxicity, rash and other rifampicin, have drug–drug interactions. If drug– adverse effects, which overlap with the adverse drug interactions are present, then the extent effects of many ARV drugs. of the interaction should be characterized for Finally, and critically important for drug children. For clinically significant interactions, development, is the potential for drug–drug alternative dosing should be established and interactions (5). Rifampicin, a key TB drug formulations developed that will maintain target uniquely capable of sterilizing TB lesions, exposures of the ARV drug. Safety of the ARV shortening treatment and preventing relapse, drug, at the proposed dose to be used for co- is also a potent inducer of cytochrome p450 treatment, must also be established for children enzymes and important transporter proteins co-treated for TB and HIV. (5–8). These rifampicin-induced interactions may To establish these objectives, studies are needed result in drastically reduced exposure of some among children, such as Phase I and II trials. Data ARV drugs, potentially jeopardizing their efficacy from adults establishing the presence and degree and also increasing risk for acquiring ARV drug of expected drug–drug interactions are highly resistance (5,9). informative for studies of children. However, ARV drugs without clinically significant drug–drug interactions may differ among interactions with rifampicin would be ideal children because of differences in developmental agents, but this is not possible for many ARV pharmacokinetics or formulations. drugs currently in use and in development. An important example is lopinavir/ritonavir Rifabutin, an alternative rifamycin to rifampicin, (LPV/r), the key component of ART for children does not affect concentrations of protease younger than three years. In contrast to adults, inhibitors. However, protease inhibitors potently children given doubled doses of LPV/r combined inhibit rifabutin’s metabolism, and a small with rifampicin-based TB treatment do not study of co-treatment among children was achieve adequate LPV exposure. This appears stopped early because of neutropaenia (10); to result from differences in absorption among this interaction and the safety of co-treatment young children and is potentially related to the with rifabutin and protease inhibitors needs to formulation for children (11,12). This highlights be studied further. In the absence of studies the need to study drug–drug interactions addressing the use of ARV drugs among children among children when developing formulations with TB, this important subpopulation may be for children. Although adding additional receiving suboptimal ART; early inclusion of ritonavir (super-boosting LPV to a 1:1 ratio of children with TB and HIV coinfection in studies of LPV/r) supports adequate LPV concentrations emerging ARV drugs is thus vitally important. for children (13), lack of a suitable ritonavir Because of the epidemiological overlap and formulation limits the adoption of this approach. importance of TB as a cause of morbidity Studies are therefore needed among children and mortality among children living with HIV, living with HIV, but these studies face several the development of ARV drugs for children critical challenges. must ensure that co-treatment with TB is safe and effective.
63 2.1.1 Delays in initiating studies to address the interaction may further complicate involving children formulation issues. If the components of a fixed-dose combination tablet are differentially affected by the interaction, alternative single- There are substantial delays in studying ARV drugs drug formulations of one or more components more generally among children (14). TB is often an may be required. An example is the need for exclusion criterion in early-phase studies of ARV super-boosting LPV/r with additional ritonavir drugs involving children that aim to establish the when co-administered with rifampicin for children dose and safety of these drugs among children. coinfected with TB and HIV. Additional ritonavir is In some ways this is sensible, since drug–drug needed to increase the ratio of LPV/r from 4:1 to interactions with components of TB treatment and 1:1; however, the ritonavir formulation for children the additional safety concerns may be problematic is a poorly palatable liquid requiring refrigeration, for emerging ARV drugs. In fact, trials of ARV which has limited the uptake of this strategy in drugs among children with TB are often not done many low- and middle-income countries. at all, or if they are, it is only after the safety and optimal dosing of a drug has been established among children living with HIV but not TB. This 2.1.3 Challenges of recruiting children leads to very long delays until sufficient experience for studies is accumulated. Since the field is moving rapidly and new and better drugs are constantly being developed, by the time studies of children are Recruiting children to high-quality studies underway or completed, the data are less clinically of TB and HIV co-treatment is increasingly relevant since other newer ARV drugs have already challenging, despite the continued significance taken priority. There is little incentive to include of TB coinfection to morbidity and mortality children coinfected with TB and HIV in early-phase among children living with HIV. As services trials, since manufacturers do not and are not for preventing the vertical transmission of required to seek market authorization for use in TB HIV continue to reach more children in better and HIV co-treatment. functioning health systems, where generally the capacity for implementing the required studies of children is concentrated, fewer children acquire 2.1.2 Lack of appropriate formulations HIV. Children in these studies who do become for children infected with HIV and develop TB are often those who have complicated social situations and have slipped through the existing services, often The lack of appropriate formulations for for the same reasons that make them challenging children is a major barrier to studying drug– participants to enrol and keep in trials. In health drug interactions between TB medications and programmes with gaps in preventing vertical ARV drugs. Suitable formulations are often not transmission and other health services, although available early in the drug development process, more children acquire HIV and TB, the capacity when these studies should be undertaken. In to enrol them into studies is often compromised. addition, the presence or extent of drug–drug interaction may depend on the formulation itself: as described above, for LPV/r, double-dosing 2.1.4 Developmental pharmacokinetics with rifampicin for adults results in adequate LPV and other design considerations concentrations, but the liquid formulation results in low exposure for children (11). The maturation of many physiological processes Even when appropriate ARV formulations are during the first few years of life has the potential available, the altered dosing that may be required to greatly affect the pharmacokinetics of
64 drugs, sometimes in ways that are difficult Potential risks to the participants from this to predict (15,16). Not surprisingly then, approach, such as insufficient viral suppression drug–drug interactions may also vary by age. because of unexpected interactions resulting Pharmacogenomic differences may also influence in low ARV drug exposure, require careful the degree and direction of drug–drug interactions management. The risk would likely be low if the (17). To account for this large potential variability, ARV drug of interest was only given for a short sample sizes must therefore be large enough period after starting TB treatment to perform to characterize pharmacokinetics and establish pharmacokinetic sampling; the time taken for optimal doses across ages. the interaction to mature, because of induction of enzymes and transporters, would need to be Drug–drug interactions between the ARV considered. Other ARV drugs could be added drug of interest and other ARV drugs may also to the regimen so that the drug of interest complicate study design. If the optimal dose is not relied on for viral suppression. Interim of an ARV drug administered with TB drugs pharmacokinetic analyses could inform dosing in is unknown, then it cannot be considered a these trials once they open, further reducing risk. component of a fully active ART regimen. In this case, the ARV drug being studied may be There are other opportunities to accelerate added on to a fully active standard ART regimen. studies among children. Many ARV drug trials However, existing recommended regimens involving children use an age de-escalation contain medications such as efavirenz (EFV) or strategy, starting with older children and with LPV/r, which may also interact with the ARV drug progressively younger children enrolled in a of interest, complicating the characterization of stepwise fashion as data on safety and optimal interactions with TB treatment. dosage emerge. In this case, a trial of the ARV drug for TB and HIV co-treatment could be developed in parallel to a main trial, with age 2.2 Proposed solutions cohorts opening once safety and the optimal dosage have been established among children living with HIV but not TB rather than waiting until 2.2.1 Start studies and develop formulations for the entire trial is completed before opening a trial children earlier among children coinfected with TB and HIV. Delays in evaluating novel ARV drugs among Suitable formulations for children must be children coinfected with TB and HIV must developed much sooner and must consider be reduced. One approach is to enable potential drug–drug interactions among children children living with HIV who develop TB while coinfected with TB and HIV. participating in trials of novel ARV drugs to have pharmacokinetic sampling and short-term safety monitoring after starting antituberculosis 2.2.2 Facilitate more rapid recruitment treatment, rather than immediately going off for studies the study (see section 2.3 on the Odyssey trial). Ensuring more rapid recruitment for studies of Dosing of the ARV drug in such a study can be children coinfected with TB and HIV requires based on the drug–drug interaction studies of continued support for trial and clinical research adults. This opportunistic approach may not be capacity in settings with a high burden of both formally powered to characterize such drug diseases. Multicentre studies involving multiple interactions but may provide meaningful data in study sites in countries with a high burden of an efficient and timely way. The risk of such an TB and HIV coinfection may provide the best approach depends on the degree of expected opportunity to recruit efficiently. Studies should drug–drug interactions based on preclinical and be designed as pragmatically as possible without adult studies.
65 sacrificing safety, to avoid making eligibility estimates down to two years of age. For criteria so strict as to be a barrier to enrolment in children younger than two years, there is more the study. uncertainty because of developmental changes in pharmacokinetics and formulation effects.
2.2.3 Pool data Physiologically based pharmacokinetic modelling Although it has its limitations, pooling data is becoming increasingly sophisticated and may from multiple trials or studies that collect improve dosage estimation among children pharmacokinetic and safety data for co-treated younger than two years. This approach is likely children on the ARV drug of interest may provide to make studies more efficient by reducing the data more rapidly than a single large adequately frequency of dosage adjustments and also by powered trial. This would also make opportunistic requiring fewer participants and fewer sampling collection of data in trials (see section 2.2.1) time points to meet the study objectives. This potentially more useful. A collaborative is critically important, given the challenges mechanism to facilitate such data sharing and of recruiting to these studies. In addition, pooling would be a useful advance. population pharmacokinetic modelling is a powerful tool for pooling data across studies and subpopulations. 2.2.4 Use pharmacometrics
Pharmacometric methods may be very useful in 2.2.5 Consider the data required to make TB and HIV co-treatment. Models can be used recommendations about co-treatment to appropriately scale data from drug–drug interaction studies of adults to better estimate There are clearly challenges to generating optimal doses for co-treatment among children. the relevant data needed to inform treatment This approach is likely to provide reasonable recommendations for infants and other
©Courtesy of photoshare
66 children coinfected with TB and HIV. Even integrase inhibitor increasingly used as a key ARV when suboptimal data are available, health- drug among treatment-naive and -experienced care workers need guidance based on the people living with HIV. It is metabolized by the best available evidence. A pragmatic approach UDPG1 and CYP3A4 enzyme systems, so drug– to developing treatment recommendations drug interactions are expected with rifampicin. is needed, in which generating the highest- quality data is encouraged but the practical A Phase I drug–drug interaction study among challenges in implementing studies in this healthy adult volunteers showed that 50 mg population are considered. For guideline of DTG given twice daily along with rifampicin drafting, such organizations as WHO should resulted in only slightly higher exposure than consider developing a consensus about the with the currently recommended 50-mg once- (18); however, questions highest-priority data and minimum data required daily dose of DTG remain about the optimal dolutegravir dose for to make treatment recommendations. Clear TB and HIV co-treatment (19). Children who are communication of this to researchers and treated with rifampicin for TB when entering the industry could inform choices about how to most trial or who develop TB while in the trial will be efficiently use resources and recruit children eligible for a small TB pharmacokinetic substudy. coinfected with TB and HIV into research studies. While on rifampicin, these children will receive DTG twice daily (rather than once daily) and will 2.2.6 Collaboration and coordination between have pharmacokinetic sampling for DTG while disease areas on rifampicin and then again when rifampicin Both TB and HIV therapeutics are rapidly has been stopped. This efficient approach uses developing. Changes in optimal medications, the opportunity of having children coinfected doses or formulations in either disease area with TB and HIV in an already planned trial to have potentially important implications for generate critically needed data on DTG dosing in children co-treated for TB and HIV. Improved co-treated children. This practical solution should communication between experts and drug be replicated in other trials. developers in these areas will help anticipate potential challenges and develop timely and Pharmacokinetics of LPV/r superboosting effective solutions. Focus on key ARV drugs among infants and other young children that could be combined into 2–3 regimens coinfected with HIV and TB for TB and HIV co-treatment, as identified by This study, sponsored by the Drugs for expert consensus and key organizations such as Neglected Diseases initiative, was a WHO, may help in setting priorities for limited multicentre, open-label, non-randomized, resources. prospective, noninferiority study to compare the pharmacokinetics of LPV administered 2.3 Case studies with superboosting (LPV/r 1:1) and concurrent rifampicin treatment or with standard boosting (LPV/r 4:1) without concurrent rifampicin ODYSSEY trial treatment and to assess the safety, tolerance The ODYSSEY trial is a randomized controlled and viral effect of superboosting among infants trial of dolutegravir (DTG)-based ART versus and other children coinfected with HIV and the standard of care (therapy based on TB weighing >3 kg and ≤15 kg. Preliminary protease inhibitors or non-nucleoside reverse- data from the study, completed in 2016, transcriptase inhibitors) among children demonstrated non-inferiority for superboosting living with HIV (ClinicalTrials.gov identifier with concurrent rifampicin treatment and NCT02259127). DTG is a new, highly potent standard dosing without rifampicin regarding
67 trough LPV/r concentrations below target by CYP3A4. Its primary metabolite DM-6705, values. The trial identified several challenges and responsible for most of its QT-prolonging effect, important lessons: is also metabolized by CYP3A4 (22). Potential
■■ Despite the pragmatic design, enrolment was drug–drug interactions and safety among slow, and strategies to improve study accrual children co-treated with ARV drugs and these are thus needed. medications must be characterized. The trials of bedaquiline involving children have been ■■ Most children were ART naive. substantially delayed, opening only in 2016, ■■ Treatment was failing for many children and the trials of delamanid involving children receiving ART, necessitating additional time and completed enrolment at the end of 2017. resources to be spent on supporting adherence However, neither trial included children living and ensuring that there was no resistance. with HIV. Trials involving children with HIV are ■■ Better strategies are needed to assess beginning to be set up through the IMPAACT adherence. (International Maternal Paediatric Adolescent AIDS Clinical Trials) Network, but this delay has ■■ Tolerability and acceptability should be assessed important implications for children living with proactively (personal communication, Helena HIV, especially for bedaquiline, for which clinically Rabie, Stellenbosch University, Cape Town, significant drug–drug interactions are expected. South Africa, September 2017) (see the module on pharmacokinetic modelling for additional In addition, these and other new and repurposed information on this and related studies). medications have shown the potential in preclinical studies to shorten TB treatment (23–25), and there is thus much work ongoing to 2.4 Future issues develop shorter regimens for drug-susceptible TB with combinations of these medications. Until recently, there has been little change to These medications will therefore probably find TB treatment, with no new TB drugs entering a more prominent role in TB treatment, and the treatment landscape. However, largely as a ensuring that these medications can be used response to the problem of multidrug-resistant safely and effectively for children coinfected TB (defined as resistance to both isoniazid with TB and HIV is even more crucial. Leaders in and rifampicin), this is changing. Repurposed developing both TB and HIV drugs for children medications, such as clofazimine and linezolid, must be aware of the advances in both fields are being introduced into multidrug-resistant that have implications for likely future treatment treatment regimens. Further, two new regimens for both diseases. medications for TB, bedaquiline and delamanid, have conditional approval for treating multidrug- resistant TB among adults. Bedaquiline, a 2.5 Useful resources diarylquinolone that inhibits mycobacterial ATP- synthase, is metabolized by CYP3A4, resulting Chapters 4 and 5. Consolidated guidelines on in significant drug–drug interactions with the use of antiretroviral drugs for treating and EFV (estimated 52% reduction in bedaquiline preventing HIV infection: recommendations for concentrations) and LPV/r (three-fold increase in a public health approach. 2nd ed. Geneva: World bedaquiline exposure) but not nevirapine (20,21). Health Organization; 2016 (http://www.who.int/ hiv/pub/arv/arv-2016/en, accessed 22 May 2018). Delamanid, a nitroimidazole compound that inhibits mycobacterial cell wall synthesis, is not expected to have significant interactions with ARV drugs, but it is partly metabolized
68 3. COINFECTION WITH HBV AND HIV
Chronic HBV infection affects 5–20% of the for the treatment of children coinfected with 36 million people living with HIV worldwide, HIV and HBV. and the burden of coinfection is highest in South-East Asia and sub-Saharan Africa (26). In The recommended first-line nucleoside reverse- countries with high endemicity (seroprevalence transcriptase inhibitors tenofovir disoproxil >8%), where implementation of birth and infant fumarate (TDF) and lamivudine (3TC) (or HBV vaccination has been suboptimal, vertical emtricitabine (FTC)) in adults and adolescents transmission remains the main route of HBV are active against HBV. Among children 3–9 transmission for children, followed by horizontal years old, the first-line nucleoside reverse- transcriptase inhibitors are abacavir (ABC) + 3TC transmission. Horizontal transmission includes or TDF + 3TC. However, ABC + 3TC is preferred from child to child, within the household and because TDF causes significant bone and within the extended family as well as transmission renal toxicity. Further, TDF formulations for through inoculation of minute amounts of younger children are not widely available and, blood or fluid during medical, surgical and to date, there are no TDF-containing fixed- dental procedures through poor injection safety dose combinations for children. Nevertheless, and traditional practices (such as scarification children coinfected with HIV and HBV should or circumcision). In countries with low HBV be treated with a TDF-based regimen, and if endemicity and/or in which the prevention of ARV drugs need to be replaced because of HIV vertical transmission through infant vaccination drug resistance, TDF with 3TC or FTC should be has been widely implemented, HBV infection is continued together with the new ARV drugs. uncommon among children. Tenofovir alafenamide (TAF) has good efficacy The 2016 WHO consolidated guidelines on among adults living with HIV, with much less the use of ARV drugs (27) recommend that children coinfected with HIV and HBV be given bone and renal toxicity. Although limited data priority for ART because of the increased risk of exist on HIV and HBV coinfection, the 2017 (29) fibrosis progression, cirrhosis and hepatocellular European guidelines on HBV infection recommend a TAF-based ART regimen for adults carcinoma. WHO recommends that children coinfected with HIV and HBV. TAF is currently with chronic hepatitis B and clinical evidence of available in the adult formulations of fixed-dose cirrhosis be treated for HBV regardless of alanine combinations for children and adolescents aminotransferase levels, hepatitis B e antigen weighing over 35 kg. status or HBV DNA levels. Antiviral treatment options for children with HBV include interferon α, pegylated interferon-α-2a and the nucleoside 3.2 Proposed solutions and nucleotide analogues lamivudine, adefovir, entecavir and tenofovir (28). Including adolescents in trials involving adults coinfected with HIV and HBV
3.1 Key challenges To speed up the availability of antiviral drugs for HBV, one solution could be including No published studies on HBV treatment among adolescents in trials involving adults coinfected children have included children coinfected with with HIV and HBV. Adolescents can usually HIV and HBV, and no antiviral drugs are labelled take the same dose as adults, since the
69 pharmacokinetics are similar, and there is 3.4 Useful resources therefore no need to wait until trials for adults are completed before starting ones ■■ Guidelines for the prevention, care and for adolescents. treatment of people with chronic hepatitis B infection. Geneva: World Health Organization; Development of TAF for younger children 2015 (http://www.who.int/hiv/pub/hepatitis/ hepatitis-b-guidelines-policy/en, accessed 22 TAF is about to become one of the main May 2018). nucleoside reverse-transcriptase inhibitors ■■ European Association for the Study of the for children living with HIV and HBV in the Liver. EASL 2017 Clinical Practice Guidelines United States and Europe. The development on the management of hepatitis B virus of TAF for children weighing less than 35 kg, infection. J Hepatol. 2017;67:370–98. with appropriate formulations and fixed-dose combinations for children, should be a priority. ■■ Chapter 5. Consolidated guidelines on the This would allow the optimal treatment of HBV use of antiretroviral drugs for treating and among children coinfected with HIV and HBV. preventing HIV infection: recommendations for a public health approach. 2nd ed. Geneva: World Health Organization; 2016 (http://www. Development of TDF formulations for who.int/hiv/pub/arv/arv-2016/en, accessed younger children 22 May 2018). TDF formulations for younger children and TDF- containing fixed-dose combinations for children are needed. However, if the development of TAF for children is given priority, the development of TDF formulations for younger children and TDF- containing fixed-dose combinations for children will be less crucial.
3.3 Case studies
Trial of TAF for HBV among adolescents
A trial is ongoing on TAF among adolescents 12–17 years old monoinfected with HBV (ClinicalTrials.gov identifier NCT02932150).
TAF switch studies among adults
A trial is ongoing on the safety and efficacy of switching from TDF and/or other oral antiviral treatment to TAF among adults monoinfected with HBV (ClinicalTrials.gov identifier NCT03180619).
70 4. COINFECTION WITH HCV AND HIV
In 2016, HCV affected an estimated 5–15% of the are fewer drug–drug interactions between direct- 36 million people living with HIV, rising to 90% acting antiviral HCV regimens and ARV drugs, among people who inject drugs. Low- and middle- and sustained viral response rates with direct- income countries have the highest burden of acting antiviral HCV therapy among people living coinfection. HCV-related liver disease progresses with HIV are higher than 95%, even for those more rapidly among people living with HIV. All with previous HCV treatment failure or advanced adults coinfected with HIV and HCV should fibrosis. People coinfected with HIV and HCV therefore be considered for HCV treatment. therefore no longer need to be considered a special, difficult-to-treat population. The decision to start ART among children and adolescents coinfected with HCV should follow the same principles as in HIV monoinfection. 4.1 Key challenges Potential harmful effects of ARV drugs include their hepatotoxic effects. For most people The United States Food and Drug Administration coinfected with HIV and HCV, including those and European Medicines Agency recently with cirrhosis, the benefits of ART outweigh approved sofosbuvir + ledipasvir, which is concerns regarding drug-induced liver injury. indicated for the treatment of adolescents 12 In treating people coinfected with HIV and HCV, years of age and older or weighing at least 35 considering the potential risk of drug–drug kg with HCV genotype 1, 4, 5 or 6 infections interactions between HIV and HCV treatment without cirrhosis or with compensated cirrhosis. regimens is also very important. People receiving The decision was mainly based on a Phase II, ongoing HIV treatment should have stable viral multicentre open-label study of 100 adolescents control of HIV infection before initiating with chronic genotype 1 HCV infection treated HCV treatment. for 12 weeks with the adult formulation of Children coinfected with HCV and HIV have a sofosbuvir ± ledipasvir (400/90 mg daily). lower rate of spontaneous clearance of HCV, Sustained viral response was documented are more commonly HCV viraemic and have for 98% of participants: the regimen was higher alanine aminotransferase values than safe and well tolerated, with no grade 3 or 4 HCV-monoinfected children (30,31). Treatment adverse events reported. The combination of in the past with interferon-based treatment with sofosbuvir + ribavirin at doses approved for ribavirin was very difficult for children because of adults (400 mg and 15 mg/kg in two divided side-effects such as depression as well as severe doses daily) was tested among adolescents with anaemia, thrombocytopaenia and neutropaenia. chronic HCV genotype 2, receiving 12 weeks of Further, those old regimens yielded low rates of treatment, or genotype 3, receiving 24 weeks of success among children and even lower among treatment. Sustained viral response rates were children coinfected with HCV and HIV (32). 100% (13 of 13) and 97% (38 of 39) in genotype The newer, all-oral direct-acting antiviral HCV 2 and 3 infections, respectively. regimens produce similar and very high rates of This regimen was safe and well tolerated, and sustained viral response among adults regardless the pharmacokinetic properties of sofosbuvir of HIV status. Thus, direct-acting antiviral HCV were equivalent to those among adults. The therapy has substantially simplified the treatment United States Food and Drug Administration and of people coinfected with HIV and HCV . There European Medicines Agency therefore approved
71 sofosbuvir for adolescents 12 years of age and 4.2 Proposed solutions older or weighing at least 35 kg with genotype 2 or 3 chronic HCV infection without cirrhosis or Include adolescents older than 12 years with compensated cirrhosis in combination with coinfected with HIV and HCV in adult trials ribavirin, including adolescents coinfected with HIV and HCV. Adolescents older than 12 years and weighing more than 35 kg can be usually treated with adult At this point, the American Association for the formulations. Adolescents should therefore be Study of Liver Diseases and Infectious Diseases included in trials involving adults coinfected with Society of America guidelines and the European HIV and HCV to speed up the availability of HCV Society for Paediatric Gastroenterology, drugs in that age group. Hepatology and Nutrition guidelines recommend that treatment of children 3–11 years old with A staggered approach is not needed in clinical chronic hepatitis C be deferred until interferon- trials involving children older than three years free regimens are available (33,34). with HCV infection Sofosbuvir + ledipasvir can be used with most A recent expert recommendation on how to ARV drugs. Because this therapy increases speed up research on ARV drugs among children tenofovir levels when given as TDF, concomitant has envisioned the possibility of simultaneously use requires considering renal function. The enrolling different age cohorts by recommending absolute tenofovir levels are highest, and may that children other than infants (<2 years) should exceed exposure with established renal safety be recruited without a staggered approach if no data. There is also insufficient data on safety specific concerns are present(35) . This could also for TDF co-administration with ritonavir- or apply to HCV infection and HCV antiviral drugs. cobicistat-containing regimens. If these drugs are being evaluated, consideration should therefore be given to changing the ARV drug Indication of new drugs for adolescents regimen. If the combined use is unavoidable, coinfected with HIV and HCV renal monitoring is recommended during Indication of new drugs for adolescents coinfected the treatment. with HIV and HCV should be granted if the TAF may be an alternative to TDF during drug has been approved in HCV-monoinfected sofosbuvir + ledipasvir treatment for people adolescents and there is enough evidence on receiving cobicistat or ritonavir as part of their safety in adults coinfected with HIV and HCV. ART. Ribavirin should not be used with zidovudine because the combination has been reported to 4.3 Case study increase the rates of anaemia. Before starting treatment, people should be evaluated for potential drug–drug interactions with selected Example of an adult trial that includes adolescents antiviral medications by consulting the prescribing There are some examples of randomized information and using other resources (such as controlled trials that include adolescents older http://www.hep-druginteractions.org). than 12 years at the same time as adults and with Most of the recent or ongoing studies on HCV the same formulation. For example, an ongoing infection among children still follow a staggered clinical trial of adults living with HIV also includes approach. That approach delays the inclusion of adolescents older than 12 years. The ADVANCE younger children and therefore the approval for trial (ClinicalTrials.gov identifier: NCT03122262) their weight or age band. intends to demonstrate that DTG + TAF + FTC is
72 equivalent to or better than DTG + TDF + FTC or ■■ Chapter 5. Consolidated guidelines on the EFV + TDF + FTC in first-line HIV treatment of use of antiretroviral drugs for treating and adolescents 12 years or older. prevention HIV infection: recommendations for a public health approach. 2nd ed. Geneva: World Health Organization; 2016 (http://www. 4.4 Useful resources who.int/hiv/pub/arv/arv-2016/en, accessed 22 May 2018). ■■ Guidelines for the screening, care and treatment of persons with hepatitis C ■■ Recommendations for testing, managing, and infection. Updated version, April 2016. Geneva: treating hepatitis C. Arlington (VA): American World Health Organization; 2016 (http://www. Association for the Study of Liver Diseases and who.int/hepatitis/publications/hepatitis-c- Infectious Diseases Society of America; 2017 guidelines-2016/en, accessed 22 May 2018 (http://www.hcvguidelines.org, accessed 22 May 2018).
©WHO/SEARO/Gary Hampton
73 5. SUMMARY
■■ Coinfections should be considered in ■■ Overarching major challenges introduced developing ARV drugs and formulations for by coinfections include lack of appropriate children, especially those that have a substantial formulations for children to treat coinfected epidemiological overlap with HIV, those that children, delays in initiating studies involving cause substantial morbidity and mortality among children and challenges with recruiting children living with HIV or those that are likely to coinfected children for these studies. This have overlapping toxicity or clinically significant results in delayed or absent data with which to drug–drug interactions. inform treatment.
■■ Key coinfections to be considered in the process of developing ARV drugs and formulations for children include TB, HBV and HCV.
6. KEY CONSIDERATIONS
■■ To ensure equitable and evidence-informed ■■ Other key solutions include facilitating more treatment of coinfected children, the rapid recruitment for studies through specific development of appropriate formulations and resource investment in sites with a high initiation of trials of ARV drugs among co- burden of coinfected children, pooling data treated children must start much earlier than from smaller studies when appropriate and they do currently. using innovative analytical methods such as
■■ Innovative strategies to retain coinfected pharmacometrics. children in ARV drug studies should be ■■ Close collaboration and improved coordination incorporated into study designs. between disease areas are critical to addressing these challenges.
74 7. ACKNOWLEDGEMENTS
Authors: Anthony J. Garcia-Prats1 and Pablo Rojo2
Other contributors: Giuseppe Indolfi3, Helen McIlleron4 and Helena Rabie1
Reviewers: Mark Cotton1 and Moherndran Archary5
1 Stellenbosch University, Cape Town, South Africa 2 Hospital de 12 Octubre, Universidad Complutense, Madrid, Spain 3 Meyer Children’s University Hospital, Florence, Italy 4 University of Cape Town, South Africa 5 University of KwaZulu-Natal, Durban, South Africa
8. REFERENCES
1. Global tuberculosis report 2016. Geneva: Antiretroviral treatment in HIV-infected World Health Organization; 2016 (http:// children who require a rifamycin-containing www.who.int/tb/publications/global_report/ regimen for tuberculosis. Expert Opin en, accessed 22 May 2018). Pharmacother. 2017;18:589–98.
2. Jenkins HE, Yuen CM, Rodriguez CA, 6. Shehu AI, Li G, Xie W, Ma X. The pregnane X Nathavitharana RR, McLaughlin MM, Donald receptor in tuberculosis therapeutics. Expert P et al. Mortality in children diagnosed with Opin Drug Metab Toxicol. 2016;12:21–30. tuberculosis: a systematic review and meta- 7. Glaeser H, Drescher S, Eichelbaum M, analysis. Lancet Infect Dis. 2017;17:285–95. Fromm MF. Influence of rifampicin on the 3. Turkova A, Chappell E, Judd A, Goodall expression and function of human intestinal RL, Welch SB, Foster C et al. Prevalence, cytochrome P450 enzymes. Br J Clin incidence, and associated risk factors of Pharmacol. 2005;59:199–206. tuberculosis in children with HIV living in 8. Yamashita F, Sasa Y, Yoshida S, Hisaka A, Asai the UK and Ireland (CHIPS): a cohort study. Y, Kitano H et al. Modeling of rifampicin- Lancet HIV. 2015;2:e530–9. induced CYP3A4 activation dynamics 4. Guidance for national tuberculosis for the prediction of clinical drug-drug programmes on the management of interactions from in vitro data. PLoS One. tuberculosis in children. 2nd ed. Geneva: 2013;8:e70330. World Health Organization; 2014 (http:// 9. Reitz C, Coovadia A, Ko S, Meyers T, www.who.int/tb/publications/childtb_ Strehlau R, Sherman G et al. Initial response guidelines/en, accessed 22 May 2018). to protease-inhibitor-based antiretroviral 5. Rabie H, Decloedt EH, Garcia-Prats AJ, therapy among children less than 2 years of Cotton MF, Frigati L, Lallemant M et al.
75 age in South Africa: effect of cotreatment for 17. McIlleron HM, Schomaker M, Ren Y, tuberculosis. J Infect Dis. 2010;201:1121–31. Sinxadi P, Nuttall JJ, Gous H et al. Effects of rifampin-based antituberculosis therapy 10. Moultrie H, McIlleron H, Sawry S, on plasma efavirenz concentrations in Kellermann T, Wiesner L, Kindra G et al. children vary by CYP2B6 genotype. AIDS. Pharmacokinetics and safety of rifabutin 2013;27:1933–40. in young HIV-infected children receiving rifabutin and lopinavir/ritonavir. J Antimicrob 18. Dooley KE, Sayre P, Borland J, Purdy E, Chemother. 2015;70:543–9. Chen S, Song I et al. Safety, tolerability, and pharmacokinetics of the HIV integrase 11. McIlleron H, Ren Y, Nuttall J, Fairlie L, Rabie inhibitor dolutegravir given twice daily with H, Cotton M et al. Lopinavir exposure is rifampin or once daily with rifabutin: results insufficient in children given double doses of of a phase 1 study among healthy subjects. J lopinavir/ritonavir during rifampicin-based Acquir Immune Defic Syndr. 2013;62:21–7. treatment for tuberculosis. Antivir Ther. 2011;16:417–21. 19. Maartens G, Boffito M, Flexner CW. Compatibility of next-generation first- 12. Zhang C, Denti P, Decloedt EH, Ren Y, line antiretrovirals with rifampicin-based Karlsson MO, McIlleron H. Model-based antituberculosis therapy in resource limited evaluation of the pharmacokinetic differences settings. Curr Opin HIV AIDS. 2017;12:355–8. between adults and children for lopinavir and ritonavir in combination with rifampicin. Br J 20. Svensson EM, Aweeka F, Park JG, Marzan Clin Pharmacol. 2013;76:741–51. F, Dooley KE, Karlsson MO. Model-based estimates of the effects of efavirenz on 13. Ren Y, Nuttall JJ, Egbers C, Eley BS, Meyers bedaquiline pharmacokinetics and suggested TM, Smith PJ et al. Effect of rifampicin on dose adjustments for patients coinfected lopinavir pharmacokinetics in HIV-infected with HIV and tuberculosis. Antimicrob children with tuberculosis. J Acquir Immune Agents Chemother. 2013;57:2780–7. Defic Syndr. 2008;47:566–9. 21. Svensson EM, Dooley KE, Karlsson MO. 14. Heidari S, Mofenson LM, Bekker L. Impact of lopinavir-ritonavir or nevirapine Realization of an AIDS-free generation: on bedaquiline exposures and potential ensuring sustainable treatment for children. implications for patients with tuberculosis- JAMA. 2014;312:339–40. HIV coinfection. Antimicrob Agents 15. Hattis D, Ginsberg G, Sonawane B, Smolenski Chemother. 2014;58:6406–12. S, Russ A, Kozlak M et al. Differences 22. Mallikaarjun S, Wells C, Petersen C, Paccaly in pharmacokinetics between children A, Shoaf SE, Patil S et al. Delamanid and adults. II. Children’s variability in coadministered with antiretroviral drugs or drug elimination half-lives and in some antituberculosis drugs shows no clinically parameters needed for physiologically- relevant drug–drug interactions in healthy based pharmacokinetic modeling. Risk Anal. subjects. Antimicrob Agents Chemother. 2003;23:117–42. 2016;60(:5976–85.
16. Kearns GL, Abdel-Rahman SM, Alander 23. Veziris N, Ibrahim M, Lounis N, Andries SW, Blowey DL, Leeder JS, Kauffman RE. K, Jarlier V. Sterilizing activity of second- Developmental pharmacology – drug line regimens containing TMC207 in a disposition, action, and therapy in infants and murine model of tuberculosis. PLoS ONE. children. N Engl J Med. 2003;349:1157–67. 2011;6:e17556.
76 24. Lounis N, Veziris N, Chauffour A, Truffot- 32. Turkova A, Giacomet V, Goetghebuer T, Pernot C, Andries K, Jarlier V. Combinations Miloenko M, Nicolini LA, Noguera-Julian A of R207910 with drugs used to treat et al. HCV treatment in children and young multidrug-resistant tuberculosis have adults with HIV/HCV co-infection in Europe. the potential to shorten treatment J Virus Erad. 2015;1:179–84. duration. Antimicrob Agents Chemother. 33. Recommendations for testing, managing, 2006;50:3543–7. and treating hepatitis C. Arlington (VA): 25. Matsumoto M, Hashizume H, Tomishige American Association for the Study of Liver T, Kawasaki M, Tsubouchi H, Sasaki H et al. Diseases and Infectious Diseases Society of OPC-67683, a nitro-dihydro-imidazooxazole America; 2017 (http://www.hcvguidelines.org, derivative with promising action against accessed 22 May 2018). tuberculosis in vitro and in mice. PLoS Med. 34. Indolfi G, Hierro L, Dezsofi A, Jahnel 2006;3:e466. J, Debray D, Hadzic N et al. Treatment 26. Schweitzer A, Horn J, Mikolajczyk RT, of chronic hepatitis C virus infection in Krause G, Ott JJ. Estimations of worldwide children. A position paper by the Hepatology prevalence of chronic hepatitis B virus Committee of European Society of infection: a systematic review of data Paediatric Gastroenterology, Hepatology published between 1965 and 2013. Lancet. and Nutrition. J Pediatr Gastroenterol Nutr. 2015;386:1546–55. 2018:66:505–15.
27. WHO consolidated guidelines on the use 35. Penazzato M, Gnanashanmugam D, Rojo of antiretroviral drugs for treating and P, Lallemant M, Lewis LL, Rocchi F et al. preventing HIV infection. 2nd ed. Chapter Optimizing research to speed up availability of 5: Clinical guidelines: managing common pediatric antiretroviral drugs and formulations. coinfections and comorbidities. Geneva: Clin Infect Dis. 2017;64:1597–603. World Health Organization; 2016 (http:// www.who.int/hiv/pub/arv/chapter5.pdf, accessed 22 May 2018).
28. Healy SA, Gupta S, Melvin AJ. HIV/HBV coinfection in children and antiviral therapy. Expert Rev Anti Infect Ther. 2013;11:251–63.
29. EASL 2017 Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.
30. Claret-Teruel G, Noguera-Julian A, Esteva C, Munoz-Almagro C, Sanchez E, Jimenez R et al. Impact of human immunodeficiency virus coinfection on the progression of mother-to-child transmitted hepatitis C virus infection. Pediatr Infect Dis J. 2011;30:801-4.
31. Indolfi G, Bartolini E, Serranti D, Azzari C, Resti M. Hepatitis C in children co-infected with human immunodeficiency virus. J Pediatr Gastroenterol Nutr. 2015;61:393–9.
77 MODULE 5: ACCEPTABILITY
©WHO/Sergey Volkov
78 1. INTRODUCTION
In all disease areas, despite the availability of already authorized that are no longer covered effective molecules, formulations adapted for by patents. This includes over-the-counter children are still lacking and their development products for which safety and acceptability may falls behind that of formulations for adults. be problematic. With the incentive of additional Children are often either not treated or, based on data and marketing protection, the paediatric- anecdotal paediatric evidence, treated off label use marketing authorization aims at transforming or off licence with formulations for adults(1–5) . off-label use of drugs into safer and better circumscribed authorized use. Similarly, the Best During the past two decades, new legislation Pharmaceuticals for Children Act in the United and regulation-related guidance from the States provides incentives to encourage the United States Food and Drug Administration performance of studies involving children that (FDA) and the European Medicines Agency provide data on the effectiveness, safety and (EMA) are progressively changing this situation appropriateness of medicines already on the with the mandated concurrent development of market for same or expanded indications. formulations for adults and for children (6–11). Although determining the formulation type, Other countries have introduced policies to dose and intake frequency that provide adequate enhance the labelling of products for children drug exposure across all age or weight bands is (12): in Japan, by extending a product’s re- an essential component of developing drugs for examination period; in Canada, through a six- children, the acceptability of the formulation month extension of data protection providing itself also needs to be maximized, since it partly acceptability and efficacy data for children; and, conditions adherence and ultimately treatment in Switzerland, through the obligation to submit effectiveness and safety (14). paediatric plans and incentives for including data in the medicine label in accordance with The objective of this module is to discuss issues the agreed plans. India and China are becoming around formulation acceptability and to assist important pharmaceutical industry actors, and scientists and organizations confronted with their legislation is being revised to include specific the development of age-appropriate medicines provisions for developing drugs for children. for children. The module focuses on product development strategies for oral dosage forms Pharmaceutical companies are now required to – solid and liquid – although other forms, consider very early in a new drug’s development such as long-acting injectables or inhalants, (13) in terms of the specific needs of children may play an increasing role in therapy for therapeutic indication and the appropriateness children. Importantly, although the theme of of the envisioned drug formulations for the this initiative is developing better antiretroviral relevant target populations. (ARV) formulations for children living with In parallel with regulations mandating the HIV, the scope of the discussion extends to development of formulations for children for new other therapeutic fields, such as antibiotics and or innovative medicines, the EMA paediatric- antituberculosis drugs, medicines for diseases of use marketing authorization is a dedicated the blood and blood-forming organs and cancer marketing authorization covering indications and and malaria therapy, where acceptability may be appropriate formulations for medicines that are key, as well as medications for chronic conditions. developed exclusively for children, for products
79 2. BACKGROUND
The EMA defines acceptability as “the overall In commentary on the EMA guidelines (11), Piotr ability and willingness of the patient to use Kosarevitz (22) states: and its caregiver to administer the medicine As a general rule, acceptability aspects should be as intended” (11). The word “medicine” refers embedded in the development programme and here to the therapeutic entity as it is to be evaluated, (preferably) during the clinical study delivered to the end user. This includes the type (preferably) with patients from all target age of dosage form, its formulation: composition group(s). …The choice of the acceptability testing and appearance (tablet size, shape and colour), method and acceptance criteria (to determine the dose of its specific active substance, dosing whether the medicine dosage form is considered acceptable or not), should be described and justified, frequency, packaging, medical device, dosing taking into account the characteristics of the target devices, container closure system together with age group, the condition relevant to the medicine, written user’s instructions (product label and incidental and multiple use, co-medication and package leaflet) (15) differences between countries
Acceptability, in this context, is essentially a In compliance with regulators’ requirements, characteristic of the product and of how it is pharmaceutical companies must submit their delivered. Acceptability may significantly affect initial paediatric investigation plans (for the EMA) adherence – behaviour rather than a characteristic or paediatric study plans (for the FDA) early of the patient or caregiver – and may secondarily in the drug development process. Paediatric affect efficacy and safety. However, the precise investigation plans are submitted slightly earlier contribution of acceptability to adherence is than paediatric study plans, and both need to difficult to establish(16,17) . However, from an be agreed on with regulators before approval of ethical viewpoint that considers the inherent products for adults. Plans describe and justify vulnerability of children and adolescents, the age appropriateness of the formulations acceptability needs to be maximized regardless envisioned for the relevant children (and justify of how it affects clinical outcomes. waivers for specific groups of children).
Clinical appropriateness is a somewhat broader Although they may be modified during drug concept than acceptability, referring to the development, paediatric investigation plans (and medicine characteristics that determine whether, paediatric study plans) should provide sufficient in their personal environment and life situation, data to enable the assessment of the medicinal children and/or their caregivers can use the product quality (including acceptability), safety medicine as intended. For example, the need for and efficacy in children and thus its benefit–risk refrigeration is a major economic and practical profile for children (23). obstacle to the use of some liquid formulations in Moreover, if formulations already exist for tropical climates. Appropriateness for children is the subsets of the children in question, their discussed in detail in several reflection papers by suitability should be discussed. WHO, the EMA and the International Conference on Harmonisation of Technical Requirements for In its published scientific document template Registration of Pharmaceuticals for Human Use for a paediatric investigation plan application, (10,18–20). The FDA and the EMA (11,18) have also the EMA specifies further its expectations for issued various recommendations on designing formulations adapted for children. age-appropriate medicines for children (21).
80 The section of the paediatric investigation (15), which tend to replace liquid dosage forms: plans and paediatric study plans on developing syrups, solutions, emulsions and suspensions formulations for children should address critical (Table 5.1) (26). issues, such as: To achieve the targeted drug exposure, ■■ the need for a specific formulation, more than one dosage form and/or strength pharmaceutical form, strength or route of may be needed to cover the range of ages and administration in relation to the chosen weight bands as children grow and mature. subsets or age groups of children and Alternative administration strategies with the benefit of the chosen formulation, flexible formulations may be considered for pharmaceutical form, strength or route of children who cannot be accommodated by a administration; specific dosage form: such as segmenting or ■■ potential issues related to excipients and crushing tablets, co-administration with food children’s (anticipated) exposure levels; or liquids or multi-use formulations such as
■■ the administration of the medicine to subsets dispersible chewable tablets (11). of children, including acceptability, use of Although children and caregivers have an specific administration devices, ability to mix opinion about what are the most desirable with food and possible use with a nasogastric types of formulations, preference does not tube; and equal acceptability (27). For older children ■■ the precision of dose delivery and/or dose and adolescents, for example, lifestyle and accuracy for any pharmaceutical form for the peer pressure greatly influence medication anticipated dose for children and indicated preferences. age range.
If, based on scientific justifications, a formulation or pharmaceutical form relevant and acceptable for children cannot be developed on an industrial scale, the applicant should state how it intends to facilitate the industry-verified or extemporaneous preparation of an individual ready-for-use formulation for children.
Despite little empirical evidence, it is generally accepted that the availability of better age- adapted formulations would reduce the risk of medication and dosing errors and increase the overall safety and effectiveness of treatment (14). Although they may still play an important role in the drug development approaches, traditional liquid formulations present important limitations in terms of stability, palatability and costs. For children, the development of liquids has shifted to solid formulations in the past two decades (24,25). Children and caregivers prefer solid oral dosage forms, including tablets, capsules, mini-tablets or pellets and chewable, dispersible and multi-particulate dosage forms
81 Table 5.1. Advantages and disadvantages of various oral formulations for children
Development and Oral dosage forms Dose flexibility Dose preparation Ease of ingestion Tolerability and safety Risk of incorrect dosing Stability – shelf life in use Supply chain Relative cost manufacturing complexity Syrup, solution, High (with limits Need for measuring Easy to swallow; palatability and May require buffers, co-solvents, Incorrect use of Less stable than solids; Simple development, routine Bulky and heavy for Low drops for drops) device volume are possible issues flavours, sweeteners; multidose measuring device microbiological contamination in manufacturing and packaging transport and storage; containers may need preservatives use; compatibility with primary may need refrigeration packaging Emulsion High Requires measuring Easy to swallow; palatability and May require flavours, sweeteners; Incorrect use of Less stable than solids; Development can be complex; Bulky and heavy for Medium to high device and shaking for volume are possible issues multidose containers require measuring device; microbiological contamination; routine manufacturing and transport and storage; homogeneity preservatives and surfactants shaking for homogeneity thermodynamic instability packaging may need refrigeration and dose uniformity Suspension High Requires measuring Easy to swallow, uncertain Multidose containers require Incorrect use of Less stable than solids; Development can be complex; Bulky and heavy for Medium device and shaking for palatability, consider volume, preservatives and may require measuring device; microbiological contamination; routine manufacturing and transport and storage; homogeneity gritty sensation possible buffers, surfactants, flavours or shaking for homogeneity physical instability packaging may need refrigeration sweeteners and dose uniformity Effervescent or Low Suitable volume Easy to swallow; palatability and May require flavours, sweeteners; Need to absorb full Moisture sensitivity; solution or Simple development; routine Easier transport and Low to medium dispersible tablet and quality of water volume are possible issues consider sodium, potassium and dispersion volume dispersion of limited stability manufacturing and packaging; storage for dissolution and bicarbonate content and residue low-humidity conditions and dispersion modified tooling Multi-particulates, Medium to high Appropriate use of Easy to swallow; from birth on if Risk of aspiration or choking Risk of incorrect dosing Good stability; compatibility with Complexity depends on Easier transport and Low to medium granules, powders measuring device or dispersed in liquid, from six months when not dispersed for products requiring food or beverage vehicle to be technology; routine packaging storage packaging; may need on with semi-solid food; dose, dose measurement; verified with standard equipment; can food or liquid vehicle volume, texture and palatability incomplete dosing if serve as intermediate for other require consideration the food or beverage dosage forms vehicle is incompletely consumed; reconstitution errors for powder for suspensions Tablets Low No preparation Difficult to swallow for younger Risk of aspiration or choking; Low risk of incorrect Good stability Not complex; routine packaging Easier transport and Low children, depending on size and ability to swallow limited for dosing, except if tablet with standard equipment storage shape; limited organoleptic issues younger children; lack of data on manipulated age versus suitable size Hard gelatin Low May need preparation Difficult to swallow for younger Risk of aspiration or choking; Low risk of incorrect Good stability Non-complex development Easier transport and Low capsules if administered with children, depending on size; risk of gelatin shell sticking to dosing and incorrect use process; routine manufacturing storage food or liquid limited organoleptic issues gastrointestinal mucosa; gelatin and packaging process may not be acceptable in some cultures – alternatives exist Soft gelatin capsules Low No preparation Difficult to swallow for younger Like hard gelatin capsules; Low risk of incorrect Potentially less stable than Requires specialist development Easier transport and High children, depending on size; potential risk of chewing dosing and incorrect use tablets; may be sensitive to high and manufacturing processes; storage; may be sensitive limited organoleptic issues temperature and humidity routine packaging with standard to high temperatures equipment and humidity Mini-tablets Medium Multiple mini-tabs Easier to swallow than Risk of aspiration or choking, Risk of incorrect dosing Good stability Non-complex development Easier transport and Low (1–4 mm) may require counting; conventional tablets; limited especially for children younger if multiple mini-tablets process; routine manufacturing storage device or packaging – organoleptic issues than two years if coated required per dose and packaging process; content manual dexterity uniformity a challenge Oro-dispersible Low No preparation; water Easier to swallow than Risk of aspiration or choking; may Low risk of incorrect Good stability; may require Complexity depends on Easier transport and Low to high tablet or melt not necessary conventional tablets; taste require flavouring or sweeteners dosing and incorrect use moisture protective packaging technology; routine packaging storage and grittiness are the main with standard equipment; considerations or specialist process and equipment (lyophilizates) Chewable Low No preparation Should be chewed and not Risk of aspiration or choking; may Low risk of incorrect Good stability; may require Complexity depends on Easier transport and Low to medium dosage forms swallowed; palatability may be require flavouring or sweeteners; dosing and incorrect use moisture protective packaging technology; routine packaging storage an issue risk of intestinal obstruction if with standard equipment; swallowed whole or specialist process and equipment (deposited formulations and softgels) Oral films Low No preparation, Easy to swallow May require plasticizers, flavours or Low risk of incorrect Good stability; requires Requires specialist Easier transport and Medium to high (dispersible) water not necessary – sweeteners dosing moisture-protective packaging development, manufacturing storage manual dexterity and packaging processes
Source: reprinted from Int J Pharm., 536, Walsh J, Ranmal SR, Ernest TB, Liu F, Patient acceptability, safety and access: a balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations, 547–62, Copyright (2018), with permission from Elsevier. (26)
82 Table 5.1. Advantages and disadvantages of various oral formulations for children
Development and Oral dosage forms Dose flexibility Dose preparation Ease of ingestion Tolerability and safety Risk of incorrect dosing Stability – shelf life in use Supply chain Relative cost manufacturing complexity Syrup, solution, High (with limits Need for measuring Easy to swallow; palatability and May require buffers, co-solvents, Incorrect use of Less stable than solids; Simple development, routine Bulky and heavy for Low drops for drops) device volume are possible issues flavours, sweeteners; multidose measuring device microbiological contamination in manufacturing and packaging transport and storage; containers may need preservatives use; compatibility with primary may need refrigeration packaging Emulsion High Requires measuring Easy to swallow; palatability and May require flavours, sweeteners; Incorrect use of Less stable than solids; Development can be complex; Bulky and heavy for Medium to high device and shaking for volume are possible issues multidose containers require measuring device; microbiological contamination; routine manufacturing and transport and storage; homogeneity preservatives and surfactants shaking for homogeneity thermodynamic instability packaging may need refrigeration and dose uniformity Suspension High Requires measuring Easy to swallow, uncertain Multidose containers require Incorrect use of Less stable than solids; Development can be complex; Bulky and heavy for Medium device and shaking for palatability, consider volume, preservatives and may require measuring device; microbiological contamination; routine manufacturing and transport and storage; homogeneity gritty sensation possible buffers, surfactants, flavours or shaking for homogeneity physical instability packaging may need refrigeration sweeteners and dose uniformity Effervescent or Low Suitable volume Easy to swallow; palatability and May require flavours, sweeteners; Need to absorb full Moisture sensitivity; solution or Simple development; routine Easier transport and Low to medium dispersible tablet and quality of water volume are possible issues consider sodium, potassium and dispersion volume dispersion of limited stability manufacturing and packaging; storage for dissolution and bicarbonate content and residue low-humidity conditions and dispersion modified tooling Multi-particulates, Medium to high Appropriate use of Easy to swallow; from birth on if Risk of aspiration or choking Risk of incorrect dosing Good stability; compatibility with Complexity depends on Easier transport and Low to medium granules, powders measuring device or dispersed in liquid, from six months when not dispersed for products requiring food or beverage vehicle to be technology; routine packaging storage packaging; may need on with semi-solid food; dose, dose measurement; verified with standard equipment; can food or liquid vehicle volume, texture and palatability incomplete dosing if serve as intermediate for other require consideration the food or beverage dosage forms vehicle is incompletely consumed; reconstitution errors for powder for suspensions Tablets Low No preparation Difficult to swallow for younger Risk of aspiration or choking; Low risk of incorrect Good stability Not complex; routine packaging Easier transport and Low children, depending on size and ability to swallow limited for dosing, except if tablet with standard equipment storage shape; limited organoleptic issues younger children; lack of data on manipulated age versus suitable size Hard gelatin Low May need preparation Difficult to swallow for younger Risk of aspiration or choking; Low risk of incorrect Good stability Non-complex development Easier transport and Low capsules if administered with children, depending on size; risk of gelatin shell sticking to dosing and incorrect use process; routine manufacturing storage food or liquid limited organoleptic issues gastrointestinal mucosa; gelatin and packaging process may not be acceptable in some cultures – alternatives exist Soft gelatin capsules Low No preparation Difficult to swallow for younger Like hard gelatin capsules; Low risk of incorrect Potentially less stable than Requires specialist development Easier transport and High children, depending on size; potential risk of chewing dosing and incorrect use tablets; may be sensitive to high and manufacturing processes; storage; may be sensitive limited organoleptic issues temperature and humidity routine packaging with standard to high temperatures equipment and humidity Mini-tablets Medium Multiple mini-tabs Easier to swallow than Risk of aspiration or choking, Risk of incorrect dosing Good stability Non-complex development Easier transport and Low (1–4 mm) may require counting; conventional tablets; limited especially for children younger if multiple mini-tablets process; routine manufacturing storage device or packaging – organoleptic issues than two years if coated required per dose and packaging process; content manual dexterity uniformity a challenge Oro-dispersible Low No preparation; water Easier to swallow than Risk of aspiration or choking; may Low risk of incorrect Good stability; may require Complexity depends on Easier transport and Low to high tablet or melt not necessary conventional tablets; taste require flavouring or sweeteners dosing and incorrect use moisture protective packaging technology; routine packaging storage and grittiness are the main with standard equipment; considerations or specialist process and equipment (lyophilizates) Chewable Low No preparation Should be chewed and not Risk of aspiration or choking; may Low risk of incorrect Good stability; may require Complexity depends on Easier transport and Low to medium dosage forms swallowed; palatability may be require flavouring or sweeteners; dosing and incorrect use moisture protective packaging technology; routine packaging storage an issue risk of intestinal obstruction if with standard equipment; swallowed whole or specialist process and equipment (deposited formulations and softgels) Oral films Low No preparation, Easy to swallow May require plasticizers, flavours or Low risk of incorrect Good stability; requires Requires specialist Easier transport and Medium to high (dispersible) water not necessary – sweeteners dosing moisture-protective packaging development, manufacturing storage manual dexterity and packaging processes
Source: reprinted from Int J Pharm., 536, Walsh J, Ranmal SR, Ernest TB, Liu F, Patient acceptability, safety and access: a balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations, 547–62, Copyright (2018), with permission from Elsevier. (26)
83 3. CHALLENGES
There are multiple challenges in developing How acceptability is understood and defined better acceptable formulations for children. obviously depends on the question asked. Here Most obvious is the lack of consensus around the essential question is to determine whether what acceptability means and consequently a formulation proposed for registration is the lack of guidance from regulators on how acceptable for the relevant target populations it should be evaluated. Another difficulty of children: can the claim for age-appropriate arises from the fact that acceptability is only medicines for children be effectively one attribute of formulations appropriate substantiated? However, published studies show for children. Other considerations include extreme variation in how acceptability is defined stability, absorption, disease, safety and cost. and assessed. Formulations for children are often considered late in development, when efficacy and safety In the most recent reviews examining various for adults begins to be known and when stability aspects of acceptability of pharmaceutical and pharmacokinetic data have already started dosage forms, the multiplicity of keywords used to be accumulated. Another difficulty is that to identify relevant literature confirms this acceptability is not an inherent property of variation and confusion around the concept the product; it is also defined by the end- of acceptability. Published literature searches users: the children and their caregivers. Finally, most often include such words as acceptance, standardized methods and quality assurance adherence, tolerability, satisfaction, preference, (28). are lacking for assessing the acceptability of palatability, taste and swallowability formulations ranging from solid oral dosage Because paediatric investigation plans and forms such as tablets, capsules, mini-tablets paediatric study plans must be submitted at and pellets, to chewable, dispersible, multi- the very beginning of clinical development of particulate dosage forms and liquid dosage the medication (for adults: Phase I in Europe forms such as syrups, solutions, emulsions and and Phase II in the United States), at the time suspensions. The following sections describe of these first trials, the real constraints of the these difficulties in greater depth and explore formulations for children are not yet known. what solutions can be found. Pharmaceutical companies may therefore not want to or be able to describe the envisioned dosage form for children in a detailed manner. 3.1 Lack of guidance from regulators and varying definitions of acceptability Following the submission of the paediatric investigation plans and paediatric study plans, European and United States regulators require regulators may request clarification about the that pharmaceutical companies describe and target group or the choice of formulation. justify in their development plans the choice Although interactions between regulatory of their formulations for all target populations agencies and pharmaceutical companies and require that they document and report the are not public, a review by the EMA of the acceptability of their formulations, but they paediatric investigation plans submitted to the offer little guidance on what studies should be Paediatric Committee during the first years of performed and reported to comply with this implementation of the paediatric regulations requirement. indicated that in 82% of the cases, the excipients were questioned (their justification, dosage
84 and the possibility of avoiding them through 3.2 Dosage forms for children are a alternative formulations); in half the cases, necessary compromise between stability, testing for palatability and acceptability was absorption, disease, safety, cost and discussed; and in 23% of cases, formulations and acceptability practical issues related to manipulations or small volumes were considered problematic (13). The ideal formulation should have flexible dosage In another review covering 2007– 2011 (29), increments and minimal excipients, be palatable, 150 paediatric investigation plans were examined safe and easy to administer and be stable with (16 therapeutic areas and 220 oral dosage forms regard to light, humidity and heat (Fig. 5.1) (32). in 431 strengths and compositions). One third However, as stated by Walsh et al. (26), “a single of the paediatric investigation plans involved ideal dosage form does not exist”. tablets, 20% liquids and 16% dosage forms stored as a solid but swallowed as a liquid, such as The development of age-appropriate medicines dispersible tablets. According to this report, the for children is constrained (33) by the Paediatric Committee review and interactions characteristics of the target population of children with pharmaceutical companies resulted in an (age group) and by the characteristics of the increase in the number of oral dosage forms molecules (solubility, stability and taste), their age- or a modification of their specific composition and development-dependent pharmacokinetic or strength. For many paediatric investigation profiles (absorption, distribution, metabolism plans, the target age range was widened and and excretion), their pharmacodynamic profiles the excipient composition and usability aspects (therapeutic window, mode of action and modified (30,31). toxicity), the disease and the disease stage
Fig. 5.1. Medicine formulations: a compromise between stability, absorption, disease characteristics, safety and cost
Definition of acceptability, Patients and disease Product formulation data collection and outcome ■■ Age ■■ Molecules: solubility, criteria ■■ Inherent ability stability, taste ■■ Clinical trials: from dose ■ ■■ Prior experience ■ Excipients finding studies to post- ■■ Developmental marketing ■■ Disease type and state pharmacokinetic profile ■■ Sociocultural context of use ■■ Human factor studies –absorption, distribution, ■■ Direct observation of metabolism and excretion children Acceptability dimensions ■■ Pharmacodynamics ■■ Questionnaires and diary ■■ Palatability ■■ Intellectual property entries for children and ■■ Swallowability landscape caregivers ■■ ■■ Dose size and volume and flexibility Manufacturing complexity ■■ ■■ Ease of use, manipulations and device Product shelf life and storage conditions ■■ Impact on lifestyle and dosing frequency ■■ Market size and supply chain ■■ Aspects of packaging ■■ Cost ■■ Transport and storage conditions
85 (forgiveness and acute versus chronic condition), the paediatric investigation plan or paediatric the circumstances of use (clinic, home, nursery, study plan is submitted, and it is only when the school or other), the intellectual property first formulation prototype is available that landscape, the manufacturing and packaging acceptability can be truly evaluated in the target complexity, the product shelf life and storage population and the formulation possibly modified. conditions, the market size and the supply chain The prototype formulation can be intermediate and cost, which ultimately determines access. of the intended final formulation for children or derived from the existing formulation for The characteristics of the final product adults. Using such a prototype often requires therefore represent a compromise between performing a bioavailability study to ensure that multiple constraints (Fig. 5.1). When suboptimal it leads to the same active ingredient exposure formulations are finally obtained, mitigation as the final commercial formulation (unless a strategies can be developed to minimize the biowaiver is granted based on the solubility and impact on acceptability. Risk-based strategic permeability properties of the active ingredient). approaches to innovation could guide the Produced under good manufacturing practice (27,34), but within this selection of formulations standards that ensure reproducible bioavailability, process, acceptability has often been considered it can later be bridged to the final commercial an adjustment variable resulting in pharmaceutical preparation (38,39). products that remain poorly adapted to children.
3.5 Standardized methods and quality 3.3 The influence of the user and the assurance for assessing acceptability medicinal product cannot be studied are lacking separately After almost 10 years of implementation of the The characteristics of the user and those of the paediatric regulations, both in the United States (35,36). medicinal product drive acceptability and in Europe, many experts have investigated Although distinguishing what relates to the user how the acceptability of formulations for children and what relates to the dosage form is useful, is assessed and reported. All reviews stressed the they cannot be disentangled since acceptability lack of standardized methods for assessment and is precisely what links formulation characteristics of quality assurance (13,14,28,36,40–45). with specific target groups. In the studies that are published, the domains of acceptability explored vary considerably, 3.4 Acceptability studies are often carried with palatability being, by far, the most common out late attribute measured. Little to no information is provided about how data capture tools are Although the development of formulations developed and validated or the precautions taken for children can still continue after products to avoid interviewer bias. Hypotheses tested and for adults have been registered along a criteria for acceptability are rarely clearly stated. timeline based on agreed commitment to the Research reports hardly ever define what EMA and FDA, and acceptability questions is considered “acceptable”. Although the can be addressed during the whole duration acceptability threshold used in veterinary of development, in practice the window of research (44) is relatively unambiguous, no such opportunity during which acceptability can be criteria are available for humans. Percentages assessed and the formulation modified is short or scores based on ad hoc summarized or (37). As explained above, the characteristics regrouped direct or proxy measurements of of the product only begin to be known when
86 acceptability reported in published studies However, the more potent option for newborn cannot be readily interpreted. infants, lopinavir/ritonavir solution, was a heat- unstable, foul-tasting solution with 45% alcohol However, most of the acceptability studies for and 17% propylene glycol. It was only in 2015 that a product registration have not been published. better adapted multi-particulate lopinavir/ritonavir In a review of the studies involving children listed solid-pellet formulation received regulatory in the clinicaltrials.gov database in preparation approval. Nevertheless, this formulation cannot be for a symposium, Pinto & Selen (46) note that the given safely to newborns, is difficult to administer results of palatability and swallowability studies by caregivers and is poorly accepted by children are simply not communicated. Of 7259 studies because of its remaining bitter taste. listed, 874 provide study results, but none on swallowability and only two on palatability (46). In a report of the M-CERSI paediatric formulation development workshop in 2016 Published articles report few aspects of through the University of Maryland’s Center of acceptability, with limited evaluation of Excellence in Regulatory Science and Innovation, acceptability dimensions, limited categories Robert Ternik and colleagues have compiled the of information providers and large variation in various approaches used to assess and document assessment approaches and tools (42). palatability and swallowability (34). As explained above, as a result of the incentives and mandatory requirements from stringent Palatability regulatory agencies, the development of drugs Many approaches have been used to assess for children is systematically initiated in parallel palatability in children (47–49). to the development of drugs for adults, and more formulations for children will become available, With the rank order or preferential method, although their acceptability does not or perhaps the subject is asked to place products in order cannot take precedence over other key attributes of preference or choose the one they prefer. such as efficacy, pharmacokinetics or stability. Evaluation is brief and does not involve sustained attention and is therefore suitable for young ARV medicines clearly exemplify this situation. children. The first anti-HIV molecules marketed in the early 1990s had severe toxicity and limited With the facial action coding system, children efficacy and formulations for children comprised are exposed to stimuli and the facial expressions at best liquid forms that were difficult to procure, are videotaped; however, this approach is time store and administer. In many low- and middle- consuming and costly (50). income countries where the HIV epidemic was most severe, the only way to keep children with With scaling methods, subjects older than five HIV alive was to treat them with a mix of syrups years are presented samples and asked to select and solutions and fractions of adult tablets. the likeness of sensation on a scale (51,52).
The first palatable, easy-to-take fixed-dose Scaling methods include: combination became available in 2007. Triomune ■■ facial hedonic scales: these are a scale from 2 Baby® (6 mg stavudine + 30 mg lamivudine + to 10 with pictorial descriptors (43) that can 50 mg nevirapine) and Triomune Junior® (double be used with children as young as three years these concentrations) were the first fixed-dose old, but cognitive maturity may influence the combinations licensed for children younger than results (52,53); 12 years. They were scored so that they could ■■ visual analogue scale: a scale from 10 to 100 easily be broken in half, allowing use within a points on a horizontal 10-cm line, anchored simple weight-band dosing table. with word descriptors at each end (43,52)
87 ■■ Likert scale: it assigns 5–11 points to verbal understand the information in the packaging and descriptors, ranging from “extremely weak” labelling. Formative studies may be conducted to “extremely strong”; and during the iterative product development process
■■ labelled magnitude scale (54), a hybrid scale to assess user interaction with the product and with verbal descriptors on a quasi-logarithmic identify potential difficulties or errors in use. They vertical scale, suitable for describing the taste are followed by human factor (simulated or actual- intensity of highly divergent samples because use) validation studies to demonstrate that the of its broad scaling (54) intended users can use the final product without serious errors or problems under the expected Finally, with verbal response (descriptive use conditions. In situations when understanding methods), children are asked to rate preference the information provided in the labelling of a using verbal descriptors such as “no taste” combination product is critical to using a product to “very strong taste”. This method is more safely and effectively, a study to assess the user’s discriminating than scaling methods (34) but is understanding of such information is appropriate. not suitable for younger children who cannot Knowledge task studies may be carried out as visualize and accurately use the descriptors. part of the formative or validation process. Use- related risk analysis helps to identify the critical Swallowability tasks to be evaluated in a human factor study, inform the priority for testing the tasks and Palatability is subjective, but swallowability is determine whether specific use scenarios should more objective since it describes an ability be included in testing. The analysis should consider of children rather than an appreciation. Most all the intended uses, users and use environments; studies used direct observation, investigating therapeutic or diagnostic procedures associated children’s mouths after administration. Few with the use of the product; similar products studies used questionnaires or diary entries used within the environments; and any associated to provide parents’ reports of the outcomes medical factors that may affect the safe and of swallowing or whether or not a problem in appropriate use of the product. swallowing the product occurred (28,29,55,56. The difficulty lies in defining the outcome: There is considerable need for developing “everything swallowed”, “smooth swallowing”, an operational and pragmatic definition of “swallowing with a choking reflex or cough” and swallowability and palatability and for establishing “biting or chewing followed by swallowing” (34). a simple, standardized method for evaluating For palatability, children’s cooperation highly all dimensions of acceptability, swallowability, influences the assessment. palatability and ease of use. Researchers in the field stress the need to bridge in vitro and in Ease of use vivo data and to develop new technologies for assessing palatability and caution about using adult Ease of use is a third major component of the panels to predict palatability among children. acceptability of a medicine. Human factor studies are designed to evaluate the user interface of a Alignment between stakeholders in defining product (57). Drug development should consider acceptability, assessment methods and criteria the user interface and factors that can reduce would clearly foster much better understanding the risk of medication errors. Since children are of the relationships between acceptability, often dependent on a caregiver for preparing swallowability and adherence to therapy. This and taking the drug, such studies may not involve relationship is essential to understand risks and young children. Human factor studies are typically develop appropriate mitigation strategies to conducted with representative users to evaluate achieving the desired therapeutic outcome. the ability of the user to perform critical tasks to
88 4. SOLUTIONS
This section outlines some potential solutions for Opportunities for scientific advice from the addressing the challenges described. FDA are similar. Most importantly, a parallel mechanism has been put in place for EMA and FDA reviewers to concurrently exchange 4.1 Seek advice from regulators as early with pharmaceutical companies their views on as possible in the process of developing scientific issues during the development phase formulations of new medicinal products. This increases the dialogue between agencies and pharmaceutical Building the much-needed consensus between companies from the beginning of the life cycle of regulators and the pharmaceutical industry a new product, provides a deeper understanding around what is meant by age-appropriate of the basis of regulatory decisions, optimizes medicines for children, what acceptability is product development and avoids unnecessary and how acceptability should be assessed and testing replication or unnecessary diverse testing reported will likely take considerable time. methods. Parallel EMA and FDA advice can be Nevertheless, before and during a marketing obtained at the request of the developer. authorization procedure for a medicinal product, pharmaceutical companies have various 4.2 Clearly define the characteristics of opportunities to discuss critical issues in the drug development process with regulators. users and products
Part of this dialogue is scientific advice, an As explained above, the final formulation opportunity for (early) communication between is necessarily a compromise between the a company and a regulatory authority (the EMA constraints of the molecules and the specific and/or national competent authorities) on quality needs of children. Although at the planning and both clinical and nonclinical aspects of drug stage of developing formulations for children, development, such as study design, choice of when early clinical studies involving adults have endpoint and indication (see http://www.ema. just been completed, little is known of what europa.eu/ema: Scientific advice and protocol these constraints are. Carefully considering assistance). the characteristics of the target populations of The EMA scientific advice is open to children and caregivers in their environment as pharmaceutical companies, academia and other well as those of the medicinal product is very parties developing medicines and is free of important when establishing the target product charge for questions related to children. The profile (59). number of companies requesting scientific The following characteristics of the user should advice related to medicines for children has be considered: increased every year. In 2007, only 7.6% of ■■ age: relative arbitrary characteristic of scientific advice was related to children versus the classically defined age groups given 24.4% in 2016. Companies conducting clinical the variability and non-linearity of body development in accordance with scientific composition and physiological maturation; advice recommendations are more likely to be granted marketing authorization (58). ■■ inherent ability: neurocognitive development and dependence on the caregiver;
89 ■■ previous experience of the child with the ■■ the actual mode of administration that reflects formulation, ability to learn how to take a understanding user instructions and the given product (60) specifically, immunologic feasibility of following them and the device– functioning (CD4+ T-cell%and/or the ability of user interface, such as dial, touch screen, the caregiver to prepare the product or use a indicators, operating instructions, packaging device (short- versus long-term acceptability); etc.; and
■■ disease type and state: acute versus chronic, ■■ associated adverse reactions, tolerability and disease type and state that may affect the risk of misdosing. ability to take the product; need for multiple active pharmaceutical ingredients or co- treatments, such as for HIV, tuberculosis (TB) 4.3 Consider all acceptability attributes or malaria therapy and previous knowledge of simultaneously and study them the dosage form; and systematically ■■ the sociocultural context of medicine use (40,61). All the elements of acceptability should be systematically explored among children of the The following characteristics of a medicinal relevant age groups and appropriately reported. product should be considered: This applies to questions of taste, smell and ■■ palatability: the most frequently measured texture but also the swallowability of less attribute of acceptability; traditional solid forms, such as pellets of different ■■ appearance: for example, colour, shape, sizes with or without coating, granules and mini- embossing etc.; tablets (dispersible or not). ■■ swallowability: size, shape and integrity of the In terms of palatability, it is important to dosage form, such as film coating; determine to what extent the results obtained in ■■ the complexity of modification before the laboratory (such as electronic taste sensing administration if required: determining the systems and cell models), in animal models and dose, weight band width and frequency through adult taste panels or evaluations by of dose adjustment; over time, shift of healthy adult volunteers can be extrapolated to responsibility from caregiver to children; children (17). ■■ fixed-dose combinations; It is also necessary to determine whether ■■ the required dose: for example, the dosing the results of acceptability studies among volume, number of tablets, break marks etc.; children can be extrapolated to children in different age groups, or for different types of ■■ the need for a vehicle: soft food or liquid, diseases, considering the volume of liquid to culturally and financially determined; be administered or the size of multi-particulate ■■ the required dosing frequency and duration of granules, for example (42). The research carried treatment; out in recent years around the acceptability ■■ the selected administration device (62), if any; of mini-tablets or pellets is an example of this approach (63–70). ■■ the primary and secondary container closure system; weight and bulkiness; need Box 5.1 lists acceptability domains, providers of for refrigeration and physical, chemical information and data capture tools, with selected and microbial stability; specific storage articles and reports to which the reader can refer. requirements;
90 4.4 Plan acceptability studies as early Box 5.1. Acceptability domains, providers of information and data capture tools as possible
What aspects and dimensions of At the earliest conception of the strategy for acceptability are measured? developing formulations for children, all the dimensions of acceptability listed above must ■■ Taste, swallowability, other (34,71–74) be considered. The need for data to inform ■■ Ease of use, need for device or for vehicle the biopharmaceutical risk assessment should (62,75–79) be identified early so its collection can be ■■ Accuracy of the dose administered and synchronized with the programme for developing completeness of dose intake (5,80) formulations for adults. For example, these may include evaluating potential taste issues using Who is providing the information on animal models and trained adult taste panels. acceptability? When the adult dosage is being developed, ■■ Health-care professionals (80,81) an exploratory formulation is usually used for the Phase I and IIa studies. Based on these, ■■ Educated panels of adult testers or evaluators (82) a commercial formulation for adults may be developed. The development of a formulation ■■ Caregivers: observational versus proxy for children starts much later (Fig. 5.2). When measures (27,61,83,84) the paediatric investigation plan is submitted to ■■ Children: issue of outcomes reported regulators, the formulation for children can only by children (85) be broadly described based on the exploratory formulation for adults used at the time. What tools are used to capture and report Acceptability for children can first be assessed acceptability? during the initial dose-finding or population pharmacokinetic studies. All components of ■■ Hedonic scales, Likert scales or visual- acceptability in the target populations must analogue scales: the complexity must be be evaluated to minimize the risk of delays in age appropriate (41,53,86–89) developing the final commercial formulation ■■ Direct observation or recorded reaction: for children. closing mouth, pushing the product or vehicle away, crying or spitting out; refusal Acceptability in the target populations can thus to take the medicine; inability to swallow be directly assessed and documented early when (41,85) the formulation is being developed at the time of the initial dose-finding pharmacokinetic studies ■■ Time taken by the nurse or caregiver to involving children. Using prototype formulations administer the medicine may limit the delays incurred if the formulation ■■ Other tools, such as electronic tongue, design needs to be modified based on the animal models, etc. evaluation of acceptability.
Acceptability can still be further assessed in Adherence and effectiveness as indicators pre-registration or in post-marketing studies, but of acceptability (60,81,89,90) this would likely be too late to effectively inform the development of formulations for children. The data generated may only lead to modifying the product labelling or to amending the dosing instructions.
91 Fig. 5.2. Evaluating all aspects of acceptability in the first pharmacokinetic studies involving children
Developing formulations for adults
Preclinical Phase 1 Phase IIa Phase IIb Phase III Registration
Exploratory formulation for adults Commercial formulation for adults
Commercial formulation for children
Preclinical Pharmacokinetics Phase II Phase III Registration
Developing formulations for children
4.5 Capitalize on existing scientific 4.6 Harvest what is already available networks Regulators, in collaboration with both the If several hundred paediatric investigation plans innovator and generic pharmaceutical companies, or paediatric study plans have been submitted, should work to identify opportunities to share it is only now that they start to result in key lessons learned and best practices based registered products. It is therefore too early to on their interactions. The types of information draw the lessons learned from the first decade most valuable to developers should be reviewed of implementation of the regulation of the and discussed, with agreement on the types of development of formulations for children. Issues information that could be shared without disclosing of stability, bioavailability and dose determination the confidential proprietary data. Routinely making and the safety of excipients have largely this information available to companies throughout dominated the scene and taken precedence over the course of developing a paediatric investigation the question of acceptability. Nevertheless, the plan or paediatric study plan would facilitate the regulation of the development of formulations efficient development of a formulation for children. for children has set in motion considerable The publication of best practices for evaluating interest and debate around acceptability, acceptability by regulators would be helpful in as shown by the work of scientific networks planning and implementing the development of regrouping academics and formulation scientists tailored formulations. The publication of best such as the European Paediatric Formulations practices has been applied for Phase I studies, Initiative and the IQ Consortium Drug Product population pharmacology, efficacy and safety, Pediatric Working Group. All stakeholders agree extrapolation of data collected for adults and on the need to systematically incorporate post-registration studies. Similar to the above, acceptability considerations within drug if alignment can be reached on what constitutes development without delaying the availability of precompetitive sharing of best practices, this therapies for children. would greatly facilitate formulation assessments.
92 Although regulators should require that involving children, in pharmacological studies the essential elements that constitute the to determine the dose that ensures optimal acceptability of a product in the various target exposure across all age and weight bands and in groups be evaluated clinically in children, the the subsequent efficacy and safety studies. These pharmaceutical industry should re-evaluate their evaluations are essential to better understand the publication strategies with respect to the clinical longer-term acceptability of the drugs developed results related to assessing the acceptability as well as the impact of acceptability on of drug products and devices in these trials. A adherence and the outcomes of major interest: strategy that mirrors the publication of clinical effectiveness and safety (15,91). safety and efficacy endpoints could serve this Children and their caregivers must be involved purpose (25). This will progress biopharmaceutical science and minimize registration delays. as early as possible in developing the medicines that are safe and designed for them. The Regulatory agencies provide the opportunity participation of children and caregivers in clinical for free scientific advice; pharmaceutical trials can contribute in a meaningful way. In many companies are therefore strongly advised to instances, the lack of children to participate consult with regulators periodically or as needed in trials can slow recruitment and hinder the to ensure strategic and technical alignment. This completion of clinical studies. This reality is a is especially true for the generic pharmaceutical meaningful obstacle to developing products for industry, since it is playing an increasingly children. This same reality makes it even more important role in providing medicines for important that drug product and formulation children. The creation of fixed-dose combinations elements are considered from the earliest stages of several molecules poses problems that of developing formulations for children to avoid transcend the already complex issues of stability, changes late in development that further slow compatibility and bioequivalence. Scientific the registration of medicines for children. advice and early interactions with regulators can help to minimize biopharmaceutical risks and speed up product registration. 4.8 Broaden acceptability studies to include cultural elements and involve social scientists 4.7 Start to collect data systematically Not only children and their parents, but Without unnecessarily increasing the complexity families and the broader community, health and duration of developing formulations for professionals, public health stakeholders and civil children, all the components of acceptability society organizations should be more involved should be evaluated among the relevant users in studying the acceptability of formulations for all paediatric subsets of interest. This requires (see the module on community engagement). that the team in charge of interacting with Geographical and cultural environment should the regulators, the scientists responsible for be considered, especially in countries in developing formulations and the clinical teams which patients have limited access to health within a company work in close collaboration care (15,40). Parents are often not frontline from the onset of the programme for developing caregivers, either because they have health formulations for children. problems themselves or because they are absent. Paediatricians and paediatric research networks The extended family of brothers and sisters or should systematically include in research grandparents are in turn responsible for ensuring protocols a module for assessing the acceptability that children receive the medications they need. of formulations for children in any clinical trial The conditions for delivering and storing drugs and the availability of foods and vehicle types
93 vary considerably from place to place. The design multi-dose studies) and their standardization, the of formulations, packaging and instructions evaluation of the reliability and reproducibility to users must take these circumstances into of the results and the analysis of the data. The account (57,92). tools for collecting acceptability data need to be validated according to age groups, the greater or Social scientists must be involved in this research lesser involvement of parents or guardians and the to better understand the use of drugs in the economic and cultural context in which children economic, geographical and cultural context of live. The methods, strengths and limitations of their use. This goes beyond the supposed but very patient-reported outcome studies that collect data poorly documented variation in taste preferences to support claims in medical product labels need to across cultures. For example, the ability of be assessed. Standardized methods would enable parents or caregivers and children to use a drug comparisons across studies and define which depends in part on the community’s perception products are better accepted in which populations. of the disease in question and the expected role of the therapy and of the health-care system Standardized, universal, objective, simple metrics that makes it available (90). The stigmatization must be developed and validated to evaluate of HIV infection has raised public awareness of the acceptability of existing formulations for these issues, but the same considerations apply to children and optimize that of formulations under managing other diseases, whether TB, malaria or development. This research must necessarily chronic diseases among children. involve the concerned populations, researchers and regulators. Multicomponent referential models to assess acceptability are currently being 4.9 Encourage methodological and evaluated (mapping and clustering models) (80). translational research This research must also be translated to enrich decision-making models that would allow, at the Academia and formulation scientists must planning stage of the development of formulations undertake more primary fundamental and for children, the best options for dose forms for translational research, with the support children to be determined with the best degree of government organizations such as the of reliability. These models should accelerate the United States National Institutes of Health or development of appropriate formulations for philanthropic organizations such as the Bill & children with the effect of increasing efficiency for Melinda Gates Foundation, in addition to or all stakeholders and delivering optimized medical even in collaboration with the work being done outcomes to children. in the pharmaceutical industry.
Methodological research is needed. It should cover the study designs (validated scales for endpoint assessment, children versus adults as assessors, power analyses and sample sizes, use of controls and need for randomization and single-dose versus
94 5. CASE STUDIES
This section describes two examples of situations developing a taste-masked formulation with solid where acceptability was considered in developing granules that associates four drugs LPV, ritonavir, pharmaceutical products. abacavir and lamivudine, a 4-in-1 with the aim of resolving the limitations of the pellets and simplifying therapy for infants (93). 5.1 Developing ritonavir and lopinavir/ ritonavir for treating children with HIV Finally, AbbVie has successfully developed and commercialized a solid powder formulation of ritonavir to replace the liquid formulation, which Ritonavir and lopinavir (LPV) are very potent ARV needs refrigeration for storage and is therefore drugs that have been widely used in combination difficult to use in the tropical climates of Africa, with various nucleoside reverse-transcriptase where more than 95% of children living with HIV inhibitors for treating people living with HIV since reside. Ritonavir is used as a booster for other the early 2000s. One important characteristic protease inhibitors. is that they present a solid barrier to the emergence to resistance mutations. They have The publication of this development by AbbVie therefore been extensively used as a second-line is forthcoming. Indeed, the case of LPV and regimen for adults and as first- and second- ritonavir exemplifies the complexities of line regimens for children whose initial viral developing age-appropriate medicines for load is very high compared with that of adults. children when the chemistry of the active However, both drugs are insoluble and poorly ingredients severely limits formulation options. absorbed. The initial formulations developed by the innovator pharmaceutical company AbbVie were complex solutions presented in soft-gel 5.2 Example of acceptability evaluation capsules for both adults and children or as liquid embedded in a Phase II comparative formulations for children with excipients, which bioavailability study of a generic versus an made their taste difficult to bear. In the late innovator product 2000s, AbbVie subsequently developed a solid formulation using the melt-extrusion technology WHO and national guidelines recommend that resolved taste and excipient issues, LPV/r for children younger than three years presented in the form of tablets for adults and initiating first-line antiretroviral therapy (ART) smaller tablets for older children. and older ones requiring second-line ART. The generic company Cipla has more recently Whereas older children (older than five years) developed a pellet formulation of the LPV/ who can swallow tablets may have minimal ritonavir (LPV/r) combination for infants and problems taking their medications, the younger young children in resource-limited settings (with ones would need a syrup, pellet or mini-tablet tentative approval by the FDA), but as shown or dispersible formulation. Although currently in the study summarized below, taste remains licensed formulations of LPV/r syrup and pellets a significant challenge for younger children, taste bitter, in the CHAPAS-2 trial in Uganda and swallowability creates difficulty in using comparing solid and liquid formulations, the this formulation for infants younger than three pellets were more acceptable than syrup months of age. Cipla in collaboration with the largely because they were easier to store and Drugs for Neglected Diseases initiative is further transport, since they are heat stable and hence
95 do not require refrigeration. However, the formulation remains less than ideal because it acceptability of the pellets waned over time, tastes bitter. In CHAPAS-2, the older children with the reported challenges being the need preferred LPV/r tablets to pellets, and taste was to mask the bitter taste with food, increasingly the main factor. An LPV/r formulation suitable refused by the children, and the caregivers for younger children with improved taste worrying about ensuring that the child is taking masking therefore still needs to be developed. In the whole dose. The requirement that the LPV/r the meantime, ongoing caregiver support needs syrup be refrigerated makes the formulation less to be embedded in national programmes in the acceptable than heat-stable pellets in low- and countries in which the LPV/r pellets have been middle-income countries, although the pellet rolled out (94–96).
6. SUMMARY
The acceptability of a drug formulation to in the drug development timeline, and there the intended users may have a significant is little consensus about how acceptability impact on treatment adherence and ultimately should be defined, measured and reported. safety and efficacy. As a result of recent This may contribute to unnecessary delays in paediatric regulations in the United States making new medicines available to children. The and the European Union, considerable effort considerations below aim to promote clearer and has been made to improve the acceptability more systematic evaluation of the acceptability of drug formulations for children. However, of new formulations for children to facilitate acceptability studies are often carried out late their development.
7. KEY CONSIDERATIONS
■■ Consensus around assessing the acceptability ■■ Regulators should make available existing non- of formulations for children should be proprietary data on acceptability.
established among key experts. ■■ Acceptability data should be collected ■■ Standard criteria for measuring acceptability systematically.
should be developed. ■■ Acceptability studies should be broadened to ■■ Risk-based strategic approaches should be include cultural elements, and social scientists used to guide the selection of formulations. should be involved.
■■ The characteristics of users and products ■■ Methodological and translational research should be clearly defined and considered relating to the acceptability of formulations simultaneously. should be encouraged.
■■ Acceptability studies should be planned early in the process of drug development.
96 8. USEFUL RESOURCES
■■ European Paediatric Formulations Initiative: ■■ Global Research in Paediatrics (GRIP) www.eupfi.org work package 5: Paediatric Formulations:
■■ IQ Consortium Drug Product Pediatric www.grip-network.org Working Group: www.iqconsortium.org ■■ Pediatric Formulations Task Force (American
■■ United States Pediatric Formulations Initiative: Association of Pharmaceutical Scientists) www.bpca.nichd.nih.gov/prioritization/ researchandcollaborations/Pages/pediatric- formulations-initiative
9. ACKNOWLEDGEMENTS
Author: Marc Lallemant1,2
Contributor: Victor Musiime3,4
Reviewers: Janice Lee5 and Diana F. Clarke6
1 Program for HIV Prevention and Treatment, Institut de Recherche pour le Développement, Marseille, France 2 Chiang Mai University, Thailand 3 Makerere University, Kampala, Uganda 4 Joint Clinical Research Centre, Kampala, Uganda 5 Drugs for Neglected Diseases initiative, Geneva, Switzerland 6 Boston Medical Center, MA, USA
The authors are grateful for the input received from the European Paediatric Formulations Initiative and the IQ Consortium Drug Product Pediatric Working Group, especially Catherine Tuleu (University College London, Chair, European Paediatric Formulations Initiative) and David Cheng Thiam Tan (AbbVie, Co-Chair, IQ Consortium) as well as Trupti Dixit (independent), Eleni Dokou (Vertex), Elizabeth Galella (Bristol- Myers Squibb, Co-Chair, IQ Consortium Drug Product Pediatric Working Group), Melissa Keeney (Eli Lilly), John Morris (AbbVie), Yogesh Patil (Amgen), Fabrice Ruiz (Clinsearch), Smita Salunke (University College London), Daniel Schaufelberger (Janssen), Julia Schiele (AbbVie) and Robert L. Ternik (Eli Lilly).
97 10. REFERENCES
1. García-López I, Fuentes-Ríos JE, Manrique- 9. Clinical investigation of medicinal products Rodríguez SM, Fernández-Llamazares C. Off- in the pediatric population. Geneva: label and unlicensed drug use: results from a International Council for Harmonisation of pilot study in a paediatric intensive care unit. Technical Requirements for Pharmaceuticals An Pediatr (Barc). 2017;86:28–36. for Human Use; 2000.
2. Mason J, Pirmohamed M, Nunn T. Off-label 10. Committee for Medicinal Products for and unlicensed medicine use and adverse Human Use. Reflection paper: formulations of drug reactions in children: a narrative review choice for the paediatric population. London: of the literature. Eur J Clin Pharmacol. European Medicines Agency; 2006:45. 2012;68:21–8. 11. Guideline on pharmaceutical development 3. Langerová P, Vrtal J, Urbánek K. Incidence of medicines for paediatric use. London: of unlicensed and off-label prescription in European Medicines Agency; 2013;44:1–23. children. Ital J Pediatr. 2014;40:12. 12. Bucci-rechtweg C. Enhancing the pediatric 4. Magalhães, J. Rodrigues AT, Roque F, drug development framework to deliver Figueiras A, Falcão A, Herdeiro MT. Use of better pediatric therapies tomorrow. Clin off-label and unlicenced drugs in hospitalised Ther. 2017;39:1920–32. paediatric patients: a systematic review. Eur J 13. Turner MA, Catapano M, Hirschfeld S, Clin Pharmacol. 2015;71:1–13. Giaquinto C. Paediatric drug development: 5. Richey RH, Shah UU, Peak M, Craig JV, Ford the impact of evolving regulations. Adv Drug JL, Barker CE et al. Manipulation of drugs Deliv Rev. 2014;73:2–13. to achieve the required dose is intrinsic to 14. van Riet-Nales DA, Schobben AFAM, Egberts paediatric practice but is not supported TCG, Rademaker CMA. Effects of the by guidelines or evidence. BMC Pediatr. pharmaceutical technologic aspects of oral 2013;13:81. pediatric drugs on patient-related outcomes: 6. How to comply with the Pediatric Research a systematic literature review. Clin Ther. Equity Act. Guidance for industry. 2010;32:924–38. Washington (DC): United States Food and 15. Drumond N, van Riet-Nales DA, Drug Administration; 2005. Karapinar-Çarkit F, Stegemann S. Patients’ 7. United States Food and Drug Administration appropriateness, acceptability, usability and and Department of Health and Human preferences for pharmaceutical preparations: Services. Guidance for industry use in results from a literature review on clinical medical product development to support evidence. Int J Pharm. 2017;521:294–305. labeling claims guidance for industry. Clin 16. Baguley D, Lim E, Bevan A, Pallet A, Faust Fed Regist. 2009;1–39. SN. Prescribing for children – taste and 8. Pediatric study plans: content of and process palatability affect adherence to antibiotics: a for submitting initial pediatric study plans and review. Arch Dis Child. 2012;97:293–7. amended initial pediatric study plans. Guidance 17. Squires LA, Lombardi DP, Sjostedt P, for Industry. Washington (DC): United States Thompson CA. A systematic literature Food and Drug Administration; 2016.
98 review on the assessment of palatability and 27. Ranmal SR, Cram A, Tuleu C. Age-appropriate swallowability in the development of oral and acceptable paediatric dosage forms: dosage forms for pediatric patients. Ther Insights into end-user perceptions, Innov Regul Sci. 2013;47:533–41. preferences and practices from the Children’s Acceptability of Oral Formulations (CALF) 18. Development of paediatric medicines: points Study. Int J Pharm. 2016;514:296–307. to consider in formulation. Geneva: World Health Organization; 2012:235 (http://apps. 28. Ranmal SR, O’Brien F, Lopez F, Ruiz F, Orlu who.int/medicinedocs/en/d/Js19833en, M, Tuleu C et al. Methodologies for assessing accessed 22 May 2018). the acceptability of oral formulations among children and older adults: a systematic 19. Report of the Informal Expert Meeting on review. Drug Discov Today. 2018;23:830–47. Dosage Forms of Medicines for Children. Geneva: World Health Organization; 2008;1– 29. van Riet-Nales DA, Römkens EG, Saint- 15 (http://www.who.int/selection_medicines/ Raymond A, Kozarewicz P, Schobben AF, committees/expert/17/application/ Egberts TC et al. Oral medicines for children paediatric/Dosage_form_reportDEC2008. in the European paediatric investigation pdf, accessed 22 May 2018). plans. PLoS ONE. 2014;9:e98348.
20. General principles: EMA-FDA parallel 30. Quijano Ruiz B, Desfontaine E, Arenas-Ló scientific advice (human medicinal products). Pez S, Wang S. Pediatric formulation issues Washington (DC): United States Food and identified in paediatric investigation plans. Drug Administration; 2017;1–4. Expert Rev Clin Pharmacol. 2014;7:25–30.
21. Zisowsky J, Krause A, Dingemanse J. Drug 31. Walsh J. Reflection on the pharmaceutical development for pediatric populations: formulation challenges associated with a regulatory aspects. Pharmaceutics. paediatric investigation plan for an off-patent 2010;2:364–88. drug. AAPS PharmSciTech. 2017;18:250–6.
22. Kozarewicz P. Regulatory perspectives on 32. Sam T, Ernest TB, Walsh J, Williams JL. A acceptability testing of dosage forms in benefit/risk approach towards selecting children. Int J Pharm. 2014;469:245–8. appropriate pharmaceutical dosage forms – an application for paediatric dosage form 23. Tomasi P. Writing applications for paediatric selection. Int J Pharm. 2012;435:115–23. investigation plans and waivers. Med Writ. 2012;21. 33. Montero-Padilla S, Velaga S, Morales JO. Buccal dosage forms: general considerations 24. Orubu ES, Tuleu C. Medicines for children : for pediatric patients. AAPS PharmSciTech. flexible solid oral formulations. Bull World 2017;18:273–82. Health Organ. 2017;238–40. 34. Ternik AR, Liu F, Bartlett JA, Khong YM, 25. Ivanovska V, Rademaker CMA, van Dijk Thiam Tan DC, Dixit T et al. Assessment of L, Mantel-Teeuwisse AK. Pediatric drug swallowability and palatability of oral dosage formulations: a review of challenges and forms in children: report from an M-CERSI progress. Pediatrics. 2014;134:361–72. pediatric formulation workshop. Int J Pharm. 26. Walsh J, Ranmal SR, Ernest TB, Liu F. Patient 2018;536:570–81. acceptability, safety and access: a balancing 35. Venables R, Batchelor H, Hodson J, Stirling act for selecting age-appropriate oral H, Marriott J. Determination of formulation dosage forms for paediatric and geriatric factors that affect oral medicines populations. Int J Pharm. 2018;536:547–62. acceptability in a domiciliary paediatric population. Int J Pharm. 2015;480:55–62.
99 36. Liu F, Ranmal S, Batchelor HK, Orlu-Gul FDA/CDER Office of Pharmaceutical Quality M, Ernest TB, Thomas IW et al. European (Chemistry and Product Performance) Paediatric Formulation Initiatives EuPFI. perspective. M-CERSI Symposium: Challenges Formulation factors affecting acceptability and Strategies to Facilitate Formulation of oral medicines in children. Int J Pharm. Development of Pediatric Drug Products, 2015;492:341–3. Hyattsville, MD, USA, 8–9 June 2016 (http://www.pharmacy.umaryland.edu/ 37. Cram A, Breitkreutz J, Desset-Brèthes S, media/SOP/wwwpharmacyumarylandedu/ Nunn T, Tuleu C. Challenges of developing centers/cersievents/pedsformulation/selen- palatable oral paediatric formulations. Int J presentation-notes.pdf, accessed 22 May 2018). Pharm. 2009;365:1–3. 47. Coldwell SE, Mennella JA, Duffy VB, 38. Purohit VS. Biopharmaceutic planning Pelchat ML, Griffith ,JW Smutzer G et al. in pediatric drug development. AAPS J. Gustation assessment using the NIH Toolbox. 2012;14:519–22. Neurology. 2013;80:S20–4.
39. Ricci BM. Bridging studies in support of oral 48. Mennella JA. Ontogeny of taste preferences: pediatric formulation development. Int J basic biology and implications for health. Am Pharm. 2013;457:323–6. J Clin Nutr. 2014;99:704–11.
40. Flanagan T, Tuleu C. Patient-centred 49. Mennella JA, Spector AC, Reed DR, Coldwell pharmaceutical design to improve SE. The bad taste of medicines: overview acceptability of medicines : similarities of basic research on bitter taste. Clin Ther. and differences in paediatric and geriatric 2013;35:1225–46. populations. Drugs. 2014;74:1871–89. 50. Guinard J-X. Sensory and consumer smiley 41. Mistry P, Batchelor H. Methodology used to face testing with children. Trends Food Sci assess acceptability of oral pediatric medicines: Technol. 2001;11:273–83. a systematic literature search and narrative review. Pediatr Drugs. 2017;19:223–33. 51. Lim J, Wood A, Green BG. Derivation and evaluation of a labeled hedonic scale. Chem 42. Mistry P, Batchelor H. Evidence of Senses. 2009;34:739–51. acceptability of oral paediatric medicines: a review. J Pharm Pharmacol. 2017;69:361–76. 52. Popper R, Kroll JJ. Conducting sensory research with children. J Sens Stud. 43. Squires LA, Lombardi DP, Sjostedt P, 2005;20:75–95. Thompson CA. A systematic literature review on the assessment of palatability and 53. Sjövall J, Fogh A, Huitfeldt B, Karlsson G, swallowability in the development of oral Nylén O. Methods for evaluating the taste dosage forms for pediatric patients. Ther of paediatric formulations in children: a Innov Regul Sci. 2013;47:533–41. comparison between the facial hedonic method and the patients’ own spontaneous verbal 44. Davies EH, Tuleu C. Medicines for children: a judgement. Eur J Pediatr. 1984;141:243–7. matter of taste. J Pediatr. 2008;153:599–604. 54. Mennella JA, Mathew PS, Lowenthal 45. Guideline on the demonstration of ED. Use of adult sensory panel to study palatability of veterinary medicinal products. individual differences in the palatability of London: European Medicines Agency; a pediatric HIV treatment drug. Clin Ther. 2014;44:1–7. 2017;39:2038–48.
46. Pinto J, Selen A. Acceptability of pediatric 55. Kokki H, Nikanne E, Ahonen R. The formulations: palatability and swallowability: feasibility of pain treatment at home
100 after adenoidectomy with ketoprofen 63. Thomson SA, Tuleu C, Wong IC, Keady S, Pitt tablets in small children. Paediatr Anaesth. KG, Sutcliffe AG. Minitablets: new modality 2000;10:531–5. to deliver medicines to preschool-aged children. Pediatrics. 2009;123:e235–8. 56. Els Van de Vijver, Desager K, Mulberg AE, Staelens S, Verkade HJ, Bodewes FA et al. 64. Klingmann V. Acceptability of mini-tablets Treatment of infants and toddlers with cystic in young children: results from three fibrosis-related pancreatic insufficiency. J prospective cross-over studies. AAPS Pediatr Gastroenterol Nutr. 2011;53:61–4. PharmSciTech. 2017;18:263–6.
57. Human factors studies and related clinical 65. Klingmann V. Spomer N, Lerch C, Stoltenberg study considerations in combination product I, Frömke C, Bosse HM et al. Favorable design and development: draft guidance for acceptance of mini-tablets compared industry and FDA staff. Washington (DC): with syrup: a randomized controlled trial in United States Food and Drug Administration; infants and preschool children. J Pediatr. 2016 (https://www.fda.gov/downloads/ 2013;163:1728–33. RegulatoryInformation/Guidances/ 66. Spomer N. Klingmann V, Stoltenberg I, Lerch UCM484345.pdf, accessed 22 May 2018). C, Meissner T, Breitkreutz J. Acceptance of 58. Hofer MP, Jakobsson C, Zafiropoulos N, uncoated mini-tablets in young children: Vamvakas S, Vetter T, Regnstrom J et al. results from a prospective exploratory cross- Regulatory watch: impact of scientific advice over study. Arch Dis Child. 2012;97:283–6. from the European Medicines Agency. Nat 67. Stoltenberg I, Breitkreutz J. Orally Rev Drug Discov. 2015;14:302–3. disintegrating mini-tablets ODMTs – a novel 59. Lopez FL, Ernest TB, Tuleu C, Gul MO. solid oral dosage form for paediatric use. Eur Formulation approaches to pediatric oral J Pharm Biopharm. 2011;78:462–9. drug delivery : benefits and limitations of current platforms. Expert Opin Drug Deliv. 68. Kluk A, Sznitowska M. Application properties 2015;12:1727–40. of oral gels as media for administration of minitablets and pellets to paediatric patients. 60. Garvie PA, Lensing S, Rai SN. Efficacy of Int J Pharm. 2014;460:228–33. a pill-swallowing training intervention to 69. Kluk A, Sznitowska M, Brandt A, Sznurkowska improve antiretroviral medication adherence K, Plata-Nazar K, Mysliwiec M et al. Can in pediatric patients with HIV/AIDS. preschool-aged children swallow several Pediatrics. 2007;119:e893-9. minitablets at a time? Results from a clinical 61. Jefferds MED, Ogange L, Owuor M, Cruz pilot study. Int J Pharm. 2015;485:1–6. K, Person B, Obure A et al. Formative 70. Kekitiinwa A, Musiime V, Thomason MJ, research exploring acceptability, utilization, Mirembe G, Lallemant M, Nakalanzi S et al. and promotion in order to develop a Acceptability of lopinavir/r pellets minitabs; micronutrient powder sprinkles; intervention tablets and syrups in HIV-infected children. among Luo families in western Kenya. Food Antivir Ther. 2016;21:579–85. Nutr Bull. 2010;31:179–85.
62. Walsh J, Bickmann D, Breitkreutz J, 71. Bagger-Sjöbäck D, Bondesson G. Taste Chariot-Goulet M. Delivery devices for the evaluation and compliance of two paediatric administration of paediatric formulations: formulations of phenoxymethylpenicillin overview of current practice, challenges in children. Scand J Prim Health Care. and recent developments. Int J Pharm. 1989;7:87–92. 2011;415:221–31.
101 72. ElChaar GM, Mardy G, Wehlou K, Rubin LG. acceptability: focus on paediatric population. Randomized, double blind comparison of J Pharm Pharmacol. 2017;69:406–16. brand and generic antibiotic suspensions. II. 81. Venables R, Stirling H, Batchelor H, A study of taste and compliance in children. Marriott J. Problems with oral formulations Pediatr Infect Dis J. 1996;15:18–22. prescribed to children: a focus group study 73. Cohen R, de La Rocque F, Lécuyer A, of healthcare professionals. Int J Clin Pharm. Wollner C, Bodin MJ, Wollner A. Study of the 2015;37:1057–67. acceptability of antibiotic syrups, suspensions, 82. Pein M, Preis M, Eckert C, Kiene FE. Taste- and oral solutions prescribed to pediatric masking assessment of solid oral dosage outpatients. Eur J Pediatr. 2009;168:851–7. forms – a critical review. Int J Pharm. 74. Lottmann H, Froeling F, Alloussi S, El-Radhi 2014;465:239–54. AS, Rittig S, Riis A et al. A randomised 83. Adams LV, Craig SR, Mmbaga EJ, Naburi comparison of oral desmopressin lyophilisate H, Lahey T, Nutt CT et al. Children’s (MELT) and tablet formulations in children medicines in Tanzania: a national survey of and adolescents with primary nocturnal administration practices and preferences. enuresis. Int J Clin Pract. 2007;61:1454–60. PLoS ONE. 2013;8:1–7. 75. Walch AC, Henin E, Berthiller J, Dode X, Abel B, Kassai B et al. Oral dosage form 84. Mennella JA, Roberts KM, Mathew PS, Reed administration practice in children under 6 DR. Children’s perceptions about medicines: years of age: a survey study of paediatric individual differences and taste. BMC Pediatr. nurses. Int J Pharm. 2016;511:855–63. 2015;15:130.
76. Slavkova M, Breitkreutz J. Orodispersible 85. Matza LS, Patrick DL, Riley AW, Alexander drug formulations for children and elderly. JJ, Rajmil L, Pleil AM et al. Pediatric patient- Eur J Pharm Sci. 2015;75:2–9. reported outcome instruments for research to support medical product labeling: report of 77. Batchelor H, Kaukonen AM, Klein S, Davit B, the ISPOR PRO good research practices for Ju R, Ternik R et al. Food effects in paediatric the assessment of children and adolescents medicines development for products task force. Value Heal. 2013;16:461–79. co-administered with food. Int J Pharm. 86. Mulla H, Buck H, Price L, Parry A, Bell G, 2018;536:530–5. Skinner R. “Acceptability” of a new oral 78. Martir J, Flanagan T, Mann J, Fotaki N. suspension formulation of mercaptopurine in Recommended strategies for the oral children with acute lymphoblastic leukaemia. administration of paediatric medicines J Oncol Pharm Pract. 2016;22:387–95. with food and drinks in the context of their 87. Thompson A, Reader S, Field E, Shephard A. biopharmaceutical properties: a review. J Open-label taste-testing study to evaluate Pharm Pharmacol. 2017;69:384–97. the acceptability of both strawberry-flavored 79. Abu-Geras, D. Hadziomerovic D, Leau A, and orange-flavored amylmetacresol/2,4- Khan RN, Gudka S, Locher C et al. Accuracy dichlorobenzyl alcohol throat lozenges in of tablet splitting and liquid measurements: healthy children. Drugs R D. 2013;13:101–7. an examination of who, what and how. J 88. van Riet-Nales DA, de Neef BJ, Schobben Pharm Pharmacol. 2017;69:603–12. AF, Ferreira JA, Egberts TC, Rademaker CM. 80. Ruiz F, Vallet T, Pensé-Lhéritier AM, Aoussat Acceptability of different oral formulations A. Standardized method to assess medicines’ in infants and preschool children. Arch Dis Child. 2013;98:725–31.
102 89. Bryson SP. Patient-centred, administration 93. Foissac F, Fauchet F, Burger D, Capparelli friendly medicines for children – an EV, Lallemant M. Lopinavir/ritonavir plus evaluation of children’s preferences and how lamivudine and abacavir or zidovudine they impact medication adherence. Int J dose ratios for paediatric fixed-dose Pharm. 2014;469:257–9. combinations. Antivir Ther. 2015;20:225–33.
90. Nebot Giralt A, Nöstlinger C, Lee J, Salami O, 94. Musiime V, Fillekes Q, Kekitiinwa A, Kendall Lallemant M, Ouma O et al. Understanding L, Keishanyu R, Namuddu R et al. The the acceptability and adherence to pharmacokinetics and acceptability of paediatric antiretroviral treatment in the lopinavir/ritonavir minitab sprinkles, tablets, new formulation of pellets LPV/r: the and syrups in African HIV-infected children. J protocol of a realist evaluation. BMJ Open. Acquir Immune Defic Syndr. 2014;66:148–54. 2017;7:e014528. 95. Kekitiinwa A, Musiime V, Thomason MJ, 91. Eichler H, Abadie E, Breckenridge A, Flamion Mirembe G, Lallemant M, Nakalanzi S et al. B, Gustafsson LL, Leufkens H et al. Bridging Acceptability of lopinavir/r pellets (minitabs), the efficacy–effectiveness gap: a regulator’s tablets and syrups in HIV-infected children. perspective on addressing variability of Antivir Ther. 2016;21:579–85. drug response. Nat Rev Drug Discov. 96. Children with HIV in Africa – Pharmacokinetics 2011;10:495–506. and Adherence of Simple Antiretroviral 92. Comparative analyses and related comparative Regimens (CHAPAS-2). London: ISRCTN use human factors studies for a drug-device Registry; 2011 (http://www.isrctn.com/ combination product submitted in an ANDA: ISRCTN01946535, accessed 22 May 2018) draft guidance for industry comparative analyses and related comparative use human factors studies for a drug-device combination. Washington (DC): United States Food and Drug Administration; 2017.
103 MODULE 6: COMMUNITY ENGAGEMENT
©Courtesy of photoshare
104 1. INTRODUCTION
Since the beginning of the HIV epidemic, 1.1.1. Community community engagement has played an important part in clinical research and drug development. Community is a broad and fluid concept. This is particularly true for adults living with HIV, Individuals are always members of multiple in which activists are strongly involved in clinical communities, with views and perspectives trials and policy decisions – notably through that may have competing interests, potentially community advisory boards. In addition, countries shifting over time with changing priorities. in Europe and the United States of America are starting to include patient perspectives in their Box 6.1. Definiations used in paediatrics health-care systems and decision processes, using value frameworks (1). Trial participant (also called a human subject) – a person who participates in research and is Although community involvement in biomedical observed by researchers research is not only expected but an essential requirement for funding (2), the involvement of Paediatrics – the management of medical children (or their caregivers) and adolescents conditions affecting babies, children and lags behind that of adults. young people Minor – a minor is a person below a certain This module describes the issues and complexity age (usually the age of majority) that legally associated with engaging the paediatric separates a child from an adult; the age community in the process of HIV drug research varies between countries and settings but is and development. It also provides solutions generally 18 years as to how best to involve the community. It aims to help researchers, drug manufacturers Legal guardian – a person who acts as the and regulatory authorities strengthen existing primary caretaker and makes decisions on partnerships and develop new ones. behalf of a child or minor
Despite limited evidence, the recommendations Infant – a child younger than one year of age should facilitate effective engagement of the Child – a person 19 years or younger unless paediatric HIV community, taking into account national law defines a person to be an adult consent procedures, legal and policy frameworks at an earlier age. WHO defines a child as a as well as the geographical and cultural context person 1–9 years of age of the research. Adolescent – a person from puberty to legal adulthood. WHO defines an adolescent as a 1.1 Definition person 10–19 years of age Vulnerable groups – groups of people who This section aims to explain what “community” are particularly vulnerable to HIV infection and “community engagement” mean in clinical in certain situations or contexts. These research involving children and adolescents and include: adolescents (particularly adolescent in the context of this toolkit. girls), orphans, street children, people in closed settings (such as prisons or detention centres), people with disabilities and migrant and mobile populations.
105 The United States National Institutes of Health The balance of power between researchers and defines community as the population in and for participants can affect how communities engage, which the research is being conducted (3). For who represents the different communities and the purpose of this toolkit, community refers to what type and level of interaction exists between trial participants (children and adolescents living the different stakeholders and at what stage of with HIV), their caregivers and advocates as well the research process. Successful engagement as others who may be affected by HIV and/or that considers the research priorities alongside the research being conducted (see the module the needs of the community improves the quality on trial design). Box 6.1 shows other definitions. and outcomes of research (4).
1.1.2 Community engagement 1.1.3 Levels of community engagement
Community engagement in research is a Fig. 6.1 illustrates everyone who represents complex, dynamic and interactive relationship the different communities and their level of between researchers, policy-makers and the engagement in research. community (3). The aim is to involve participants and their advocates as partners in research Scientists, researchers and other stakeholders rather than merely trial subjects or eventual users involved in clinical trials have a critical role to of the drug or intervention. play in how they engage and interact with the paediatric community. Even where the selection Effective community engagement should result of community and community representatives is in the community becoming increasingly critically clear, the way they communicate, the language aware of and involved in research activities, and scientific terms they use, how they perceive processes and decision-making. community involvement and their level of understanding can influence how the community engages in the research process (4).
Fig. 6.1. Levels of community engagement
■■ Trial participants – neonates, infants, children and International adolescents directly involved in the trial civil society ■■ Host community – children living with and affected by HIV, adolescents and their caregivers, advocates and community-based and nongovernmental organizations National (such as community advisory boards) that represent stakeholders the paediatric HIV community directly ■■ National stakeholders – anyone who has a role in the Host political, scientific, social enterprise of developing drugs at the national level, including political decision-makers, community regulatory authorities, ethical review committees, health ministry, national nongovernmental organizations, civil society advocates, donors and funders ■■ International civil society – non-profit, organized, citizen-led groups interested in the goals, processes Trial participants and outcomes of paediatric HIV research and drug development and/or in the rights of communities and research participants (such as WHO and UNAIDS) networks or the media
Source: Slevin et al. (2). Reproduced from the PATH website at www.path.org, 14 June 2018.
106 1.2 The need to engage the community in 1.2.3. Ethical considerations research and drug development Guidelines on ethics in clinical research are well established with the Nuremberg Code and the Once communities have been identified, knowing Declaration of Helsinki as the core foundation. why they should be involved in the research The purpose of ethical conduct in research is process is important. This section examines the both to protect trial participants and to preserve rationale, principles and ethical considerations the integrity of the science (6). Nevertheless, for engaging the community in the research ethical considerations in community-engaged process and drug development. research raise additional questions when community representatives and trial participants 1.2.1. Rationale behind community engagement may take part in relationships among or between in the research process communities, the researchers and research institutions as well as other stakeholders, Engaging the paediatric community in the with principles and codes that are not as well clinical research process may require different defined (5,6). This is especially true in research approaches because of regulatory, cultural, involving children and adolescents, a population political, traditional, religious or socioeconomic dependent on their adult caregivers. factors prevailing in the communities and countries of interest. The Nuffield Council on Bioethics(7) recently published a report focusing on the ethical Community engagement can provide valuable aspects of involving children and young people input in identifying ways to improve clinical in research, providing recommendations about study outcomes, for instance, through helping to the roles and responsibilities of children, their facilitate recruitment and participant retention parents or guardians, researchers and others. (5). Community members are frequently highly motivated and invested in support of the planned The United Kingdom Medical Research Council and ongoing research. One of the benefits (8) and the European Commission (9) have also of community engagement can be increased produced extensive guidance on the ethics of support and investment in the research, and this conducting medical research among children, can improve study success by helping to identify though these documents tend to refer to and address potential issues. children and adolescents as trial participants and less about considering their role as collaborators A collaborative approach and effective in the research process. communication between researchers and the community are paramount to ensure that Researchers must pay particular attention those representing the paediatric community to their role and responsibilities related to truly understand the purpose and procedures child protection and safety when dealing with of research. Such an approach can also help vulnerable groups. Caregivers have an important enhance mutual trust and create a sense of duty as gatekeepers whose informed consent collective ownership. must always be sought when involving minors as participants or collaborators in research. 1.2.2. Principles of community engagement In addition, children younger than the age of in research consent should be able to provide their assent within a safe and non-coercive environment To support researchers in involving communities when working under supervision with adult in the research process, the United States researchers. National Institutes of Health developed a set of principles (Table 6.1) (3).
107 Table 6.1. Principles of community engagement in research
Community engagement must meet the needs of the populations and/or communities affected by the research, strengthening the community’s role and capacity to actively Set clear goals address research priorities and helping to ensure the development and implementation of relevant, feasible and ethical research.
It is important to become knowledgeable about the social and cultural context of the Learn about the community in terms of its economic conditions, political leadership, demographic community trends, history (overall and regarding research) as well as its perceptions of and experience with engagement activities.
Knowledge and understanding of the community’s predominant attitudes, perceptions Develop cultural and practices will help ensure more effective and respectful communication and competence interactions, leading to culturally responsive engagement activities.
The community should be encouraged to express itself independently during the Foster transparency community engagement process.
Partnering with community stakeholders is necessary to create change, build Build partnerships mutual trust and improve health. Toward that end, it is important to seek and trust commitments from community-based organizations and to identify formal and informal leaders in the community.
Provide and promote Sustainable community engagement can only be achieved by identifying and mobilizing capacity-building the community and by developing the capacities and resources within the community.
Maintain a long-term Community collaboration requires an ongoing, long-term commitment by the commitment research organization, its partners and the community.
Source: adapted from Recommendations for community engagement in HIV/AIDS research: a guide for communities and researchers, version 2.0 (3).
©WHO/Stéphane Saporito
108 2. CHALLENGES
The research community can often perceive of working with children and adolescents, as well community engagement in research as as vulnerable groups, can affect researchers’ demanding and time-consuming. This section willingness to engage with this community. highlights some challenges researchers might consider when engaging the paediatric HIV The research community should take on board community in the research process and drug the voices of children and young people that development. have already been captured, such as those published in the Nuffield Council on Bioethics report (7). Asked what qualities they thought 2.1 The paediatric community were important for clinical researchers, young people themselves included “courageous” alongside the more expected descriptors such as Working with children and adolescents “trustworthy” and “openness”. Children and adolescents are not “miniature adults” but a heterogeneous group with unique and complex characteristics, marked by different 2.2 Stigma, disclosure, confidentiality physical and cognitive developmental stages and fear that not only affect the pharmacokinetics and pharmacodynamics of medicines (see the module HIV continues to be stigmatizing beyond on pharmacokinetics) on the body but also the children’s ability to understand the root of such way adults interact and collaborate with them. behaviour. Confidentiality and the parents’ fear of disclosing their own status to their extended Although personal motivation and commitment community, and to their children, can be is key, it is important to recognize that children challenging. Sometimes the children participating and adolescents require age-appropriate in clinical trials have not yet been told their HIV information and support from adults as well as status by their caregivers. The risk that children time, flexibility, patience and additional resources living with HIV could be hurt, misjudged or poorly from the research community to improve their treated because of their health condition causes collaboration in the research process. great anxiety for parents.
Identifying representatives of the Research can also raise parental concern when paediatric community it investigates HIV drugs using data extrapolated from adult clinical studies and for which safety Another challenge with engaging the paediatric and efficacy needs to be proven among children. community in research is identifying those The feeling of personal risk related to treatment who best represent children, from neonates to side-effects and associated interventions as adolescents, alongside their caregivers. well as stringent trial design may deter trial With power inequity (especially for young girls) participation (10). Children and young people compared with adults, children and adolescents participating in research on drug development are usually underestimated in their capacity to may worry about their ability to manage their experience life and make meaningful decisions new treatment or the possible disruption hospital for themselves. Their lack of experience and appointments and treatment side-effects might knowledge of research alongside the ethical issues have on their daily routine and lifestyle.
109 Further, misconceptions, rumours and not directly be included in the community of suspicions can potentially arise about specific interest (such as extended family members and research projects and hinder research progress religious leaders) but who have considerable and drug development (5,11). Particular power and influence over and above local attention should be brought to those who might beliefs and cultural practices.
Table 6.2. Requirements to support children’s participation in the reporting process
Children must receive full, accessible, diversity-sensitive and age-appropriate Transparent and information about their right to express their views freely and to have their views informative given due weight and about how this participation will take place, its scope, purpose and potential impact
Children should not be coerced into expressing views against their wishes and must Voluntary be informed that they can cease involvement at any stage
Children’s views have to be treated with respect, and children should be provided Respectful with opportunities to initiate ideas and activities
Children should draw on their knowledge, skills and abilities to express their views Relevant on relevant issues. Space needs to be created to enable children to highlight and address issues they have identified as relevant and important
Child-friendly Environments and working methods should be adapted to children’s capacity environment (time and resources)
Participation needs to provide for equality of opportunity for everyone, including marginalized children, without discrimination on any grounds, including age, and be Inclusive culturally sensitive to children from all communities. Special measures should be taken to include very young children and other children from marginalized communities
Adults need preparation, skills and support to facilitate children’s participation Capacity-building effectively. Children also require capacity-building to strengthen their skills relevant to the process
Adults have a responsibility towards the children with whom they work and must take Safe and sensitive every precaution to minimize the risk of violence, exploitation or any other negative to risk consequences of their participation.
Child-led organizations, children’s groups and nongovernmental organizations Accountable should ensure that children have a clear understanding of their role and how their views will be interpreted and used.
Source: adapted from Working methods for the participation of children in the reporting process of the Committee on the Rights of the Child (13).
110 3. SOLUTIONS
Although challenges may arise while engaging 3.2 Community advisory boards with the paediatric community, as with any other stakeholders, effective communication A community advisory board engages in a two- and trusting relationships are key to successful way relationship between researchers and the collaboration. The following section proposes targeted community (3,14). Community advisory several ways to improve how scientists and board members commonly include volunteers researchers engage with the community in the from activist and patient groups as well as research process. nongovernmental and sometimes government organizations that best represent the community 3.1 Involving children and adolescents affected by the research. The involvement of community advisory boards in the research in research process can:
■■ improve communication and cooperation According to the United Nations Convention between community representatives and on the Rights of the Child (12), children should researchers; be taken seriously and given every opportunity to express their views and concerns on matters ■■ develop the treatment and research literacy of that affect their lives. Every effort should be community representatives; made to provide children and adolescents a safe ■■ give community participants the opportunity environment to encourage and enable them to to provide input on and help to resolve participate in identifying research priorities and challenges for the trial; and decision-making. Researchers need to ensure ■■ advocate for implementing the trial results in that “an invitation to participate in research national plans and guidelines. constitutes a ‘fair offer’ to children, young people and their parents” (7). A community advisory board aims to ensure community engagement, ensure that the Recent years have witnessed a shift in how research is conducted in the best interests of the scientists and researchers view the paediatric community, develop mutual trust between the community. Children and adolescents are researchers and the community and dispel any starting to be recognized as being extremely myths and rumours that might arise because of lack resourceful and committed to dealing with their of information and understanding fuelled by local own health issues. It is also being recognized beliefs (3,14). Such considerations tend to foster that their input is essential to understanding how transparency and the implementation of culturally to get it right, as evidenced by data showing sensitive strategies that are best suited to the that the HIV response is failing children and setting, local practices and the targeted population. adolescents. Community advisory board activities can also help The United Nations established a set of stimulate the participation of the community at requirements to support children’s participation various stages of the research process, including in the reporting process (Table 6.2) (13). providing input on trial design, informed consent These requirements can also be applied to the forms and other community materials and participation of children and adolescents in participating in study implementation, expanded the scientific HIV research process. access programmes and pharmacovigilance.
111 In addition, community advisory boards can 3.2.2 Community empowerment support partnerships between researchers and the community and the dissemination of research WHO refers to community empowerment as results. This model has also proven to be effective “the process of enabling communities to increase in recruiting and retaining study participants, control over their lives. It assumes that people since it promotes collaboration that leads to are their own assets, and the role of the external practical advice and constructive feedback (3,14). agent is to catalyse, facilitate or “accompany” the community in acquiring power” (16). Although community advisory boards have played an important role in HIV research and Scientists and researchers have a responsibility to drug development, questions are starting to help to empower those directly affected by the emerge about the limitations of their approach, research being conducted. This can mean: shared which may not be entirely independent and ownership on defining priorities, supporting the representative of the overall HIV community process of community–researcher partnership (2). Community advisory boards increasingly and addressing the social, cultural, economic and include young people as established board political aspects of research. members. However, younger children remain Children and adolescents can be supported underrepresented, which constitutes an to take a leadership role in engaging in every important gap in research. step of the research process: for instance, by ensuring adequate information-sharing, ensuring 3.2.1 Children and adolescent advisory transparency and allowing sufficient time for groups or networks critical-thinking. Valuing the voices of children and adolescents in research and understanding In recent years, children and adolescent advisory their lives from their own perspective is an groups or networks have started to arise because important contribution to paediatric studies. of increasing demand and are being solicited to provide valuable input to the research process. It is therefore essential to provide those representing 3.2.3 Capacity-building the community with age-appropriate information Capacity-building is an important part of and the opportunity to develop this. responsible engagement of the paediatric With support, their active community community. Children and adolescents may be from participation and collaboration in clinical trial different socioeconomic and cultural backgrounds discussions can enrich the process. Enabling and at different stages of development, with children and adolescents to share their views on different skills and knowledge. With an emphasis protocol design and ethical issues and welcoming on their existing talents, researchers should their input in developing age-appropriate invest time, resources and logistical support in treatment literacy materials and consent forms training children and adolescents representing can help trial participants to be better informed their community who are committed to becoming when enrolling in drug trials (15). collaborators in the research. Their ability to develop confidence and treatment knowledge will Several paediatric community networks be of immense value to community engagement have recently emerged at the national and and research involving children. international levels, giving children and adolescents a safe space to voice their views and Capacity-building should be tailored and concerns on matters that are relevant to them. appropriate to the age and developmental A non-exhaustive list can be found in the section stage and stage of life of the community being on resources of this module. engaged. This will be very different for young children than for adolescents.
112 Adolescents are transitioning into adulthood, research groups after the drug has been developed and capacity-building should also provide them (17). With limited evidence on the benefits of with transversal skills that will help them in their engaging the community (adults) in health care and personal and professional development. the research process, which is often inconsistent, recommendations on best practice are lacking. The following list is intended to provide examples of training topics that can support the involvement Nevertheless, such patient groups as of children and adolescents as research #PatientsIncluded and PatientsLikeMe are participants and can develop important research increasingly being invited to share their views and social skills: and opinions during decision-making. In addition,
■■ communication; regulatory authorities are proactively taking on patient-centred activities in drug development to ■■ presentation and public speaking; gather patients’ perspectives on various aspects ■■ listening abilities; of health. For instance, the United States Food ■■ information and technology training; and Drug Administration started the Patient- Focused Drug Development Initiative that helps ■■ introduction to HIV, treatment and prevention; evaluate the advantages and disadvantages of ■■ ethics and human rights in clinical research; new therapies (17). ■■ advocacy and peer representation; Pharmaceutical companies are encouraged ■■ introduction to research and clinical trials; to engage with the community, including the ■■ confidentiality; and paediatric community, in a true partnership during the research and drug development ■■ understanding committees and related process, if they want to better understand expectations. the needs and concerns of their customers. Community engagement models and frameworks should be developed with the community, 3.2.4 Confidentiality alongside recommendations based on evidence, Ethical considerations and principles related to to strengthen present and future collaboration confidentiality, anonymity and data protection and community engagement. are the same whether researchers are working with adults or with children and adolescents. 3.2.6 Community engagement plan Age-appropriate information on confidentiality Based on the stakeholder engagement plan and data protection must be provided to those developed by UNAIDS and the AIDS Vaccine involved in research either as trial participants Advocacy Coalition (18), a community or community representatives. This should be engagement plan (Fig. 6.2) provides a structured agreed at the start of the collaboration and approach for researchers to engage with the reiterated when necessary. paediatric HIV community in every aspect of the research process, including planning, designing, 3.2.5 Community engagement models implementing, reviewing and disseminating the and frameworks results of the research being conducted.
Community engagement in research and drug Researchers must identify relevant community development means that innovator manufacturers stakeholders and representatives in a broad, – and researchers – should acquire better multifaceted, inclusive way and develop understanding of the health needs and challenges partnerships that support effective and locally patients experience in their daily lives, beyond acceptable research. This process should seeking the opinion of advocacy and market consider the trial population to be studied
113 Fig. 6.2. Community engagement plan
Community engagement plan
Research question Planning Study design and protocol Recruitment Enrolment Follow-up Results Dissemination of results
Research life cycle
and known stakeholders and understand the using illustrations and cartoons in the design of differences and power relations of potential information sheets and consent forms, is likely to and known stakeholders. boost interest and encourage participation. Involving the community in developing the 3.4 Compensation plan will ensure that research priorities and community needs are included, help determine Compensating children and adolescents for the frequency and methods of engagement and participating in clinical research and those inform the process of reviewing and adopting representing the paediatric community remains community engagement plans. controversial. Although the financial coverage of direct trial-related expenses including transport, meal allowance, accommodation and access to 3.3 A child- and adolescent-friendly health care is commonly accepted in biomedical approach to research research in some countries, the payment of Children and adolescents must feel welcomed children’s and adolescents’ participation as a token and valued if researchers want them to of appreciation for their time and inconvenience is actively engage in clinical trials. Whether as far from straightforward (19–21). trial participants or collaborators working with Compensation for minors to participate in clinical researchers, children and adolescents are not research may influence the decision-making of only sensitive to their environment but also to the the child and/or caregiver, leading to increased approach adults use to communicate with them. acceptance of risk. This could also influence the Ensuring a child- and adolescent-friendly and decisions made by adolescents who are adults safe environment in which they feel comfortable legally (19). expressing their views and ideas is one of the many requirements researchers must consider Nevertheless, the absence of reimbursement when working with the paediatric community. for direct trial-related expenses, as well as time and inconvenience, may interfere with Children and adolescents should also be the opportunity for study participation and presented with information adapted to their enrolment, hindering significant advances in age and in a friendly manner. A family-centred paediatric research (19). approach and age-appropriate communication methods are preferred to encourage their Researchers must recognize the complexity behind involvement while providing a positive and compensating trial participation, considering meaningful experience. Seeking children’s and not only the ethical but also the contextual and adolescents’ contribution to clinical research in individual decisions related to trial participation an innovative and creative way, for instance by during the entire research process.
114 4. CASE STUDIES
Meaningful participation in dissemination for more than one day or it could even be a month without taking drugs. (20-year-old man) Clinical trials involving children significantly You may have something that you do, but when you emphasize informed consent. This occurs at the do not know what you are doing, the progress of opening stages of the trial. A critical element in something that you are doing. We get to know that this ensuring young people’s meaningful participation happens and to know the progress of the study we are in the research process is dissemination towards participating in rather than just coming to have your the end of the trial, which tends to receive far blood tested then you go back. You go without getting less attention. to know anything. (21-year-old man) Yes, it is good to inform us because we are able to We held a dissemination event for participants answer some questions: “you are in the study but (10–21 years old) and their caregivers in a clinical how is it helping?” If you ask me how it has helped me trial in Uganda to explain the findings. The I can respond that the results were positive. It was investigators explained the trial findings and their important and it also helped us. (20-year-old man) implications, answering all the questions posed by Why I clapped my hands is because I saw a great the young people and their caregivers. We then held achievement because I saw a great achievement in focus groups with the young people a few weeks fighting HIV through this research done upon or later to explore their experiences in the trial. reducing or ending HIV. (16-year-old woman)
Those involved highly valued this rare event: This dissemination was useful. In what way? Okay, let us by being informed appropriately, they better assume it is like a journey. If you are on a journey and you understood what they had been part of and why. see where you are heading. When you start seeing there you get the courage to continue walking. But when you Many described understanding for the first time are travelling and you do not know where you are heading why blood tests had been taken so frequently. and you do not see where you have reached, you get This shows the importance of treating informed discouraged. So, this thing gave us strength. It gave us consent as a process, rather than a single event, courage in that when I heard the results, it gave me more and providing regular opportunities to revisit courage to adhere to the drugs and I saw that already young people’s understanding of the trial to we have reached somewhere. We are on track. And it gave me more strength and I got to know that, if this was ensure and develop their understanding. possible, then other things are coming. But if they had not told us about it, we would be there, taking drugs, on Having learned of the potential significance of the study, not knowing how far it has reached, where it is, the trial findings, the participants described pride you just see, they tell us that we are in the study and we in their participation because they considered do not know. So it was vital. (18-year-old man) it to have contributed to the more effective treatment and that their fidelity to their assigned A young person’s experience as a trial participant trial arm had been worthwhile. A 16-year-old was questioned on his experience Many had participated in previous trials, but as a participant in a clinical trial. Asked about the because they were not told about the trial enrolment process and information received, he findings appropriately, some had assumed the experienced some difficulties: “the information trial had been a failure. Understanding the results was clear, but I did not understand some of the of this trial made them feel it was a success, and words, as they were a bit complicated and for this gave them hope for their future health. grown-ups and I was given a month to think about Now hearing that the results were successful gave me getting enrolled”. He shared that research staff a lot of hope that, in future, someone can have a break members were available to answer any questions,
115 although he described the process as being “a “there was an appointment every month for three bit over the top”. He felt very comfortable giving months, and then the appointments were three consent: “I did not feel under pressure. I felt like I times monthly. It was fine because I understood could say no if I didn’t want to do it” though “there why this was and that they had to check I was okay. were too many words and it was hard to read”. For me, everything is really good, it’s going really well”. Although the department was not adolescent- Confidentiality about his HIV status was not an issue, friendly, “No I never got that feeling, it was a very since he clearly said “No, never, I trust them 100%”, adult environment”, he was motivated and keen to referring to the clinical and research staff. Overall, be involved: “I felt good about myself because, if it his experience as a trial participant was good: goes well, I’ll be helping people.”
5. SUMMARY
■■ Community engagement plays an important approaches in different age groups and role in the development of antiretroviral settings.
drugs to treat adults living with HIV, but such ■■ Community advisory boards and children and engagement has lagged behind for children adolescent advisory groups or networks can living with HIV. provide valuable input to the research process. ■■ Innovator manufacturers, researchers and ■■ A community engagement plan provides a other stakeholders involved in clinical trials structured approach for researchers to engage play a critical role in how they engage with the with the paediatric HIV community. paediatric community. ■■ Children and adolescents can contribute to ■■ There are legal and ethical frameworks protocol design and ethical issues and the within which the involvement of children development of age-appropriate treatment and adolescents in clinical research must be literacy materials and informed consent conducted. documents. ■■ Engaging the paediatric community presents ■■ Child- and adolescent-friendly environments many challenges and requires different are critical to their successful engagement.
6. KEY CONSIDERATIONS
■■ Engage community members early in ■■ Provide treatment and prevention literacy designing the study. This might mean working training. To contribute in a meaningful way, with existing national or regional community trial participants and their advocates need advisory boards or youth boards or setting up to understand the science of HIV and the an appropriate advisory board for the study. research interventions. For infants and other young children, involving ■■ Produce informed consent forms in parents and caregivers is critical; for older collaboration with the community. Giving children and adolescents, this should mean truly informed consent on behalf of a child or engaging those from the relevant age groups. yourself requires that protocols be explained in plain language.
116 ■■ Produce age-appropriate, study-related on and trust to discuss any concerns or questions materials in collaboration with the that they have over the duration of the trial. . Ensure that information is shared community ■■ Communicate results in a timely and in a way that is acceptable to those who accessible manner. Participants and/or their need it. This could mean using illustrations, caregivers need to receive results, explained photographs or videos. in an accessible way, before they are widely ■■ Ensure a child- and adolescent-friendly clinic disseminated. . It is environment with continuity of care ■■ Consider appropriate, non-coercive forms important that families have a research nurse or of compensation. This could take the form of other relevant health worker that they can rely vouchers for clothes, telephone airtime etc.
7. USEFUL RESOURCES
Community advisory boards Other community engagement networks
■■ European Community Advisory Boards: ■■ Patients like me: http://www.eatg.org/ecab https://www.patientslikeme.com
■■ African Community Advisory Boards: ■■ Patients included: http://www.afrocab.info https://patientsincluded.org
■■ United Kingdom Community Advisory Boards: http://www.ukcab.net Community engagement projects ■■ National Institute for Health Research: Children and adolescent advisory groups INVOLVE: and networks http://www.invo.org.uk/about-involve
■■ Children’s HIV Association Youth Committee: ■■ Patient-focused drug development https://chiva.org.uk/our-work/youth-committee initiative of the United States Food and
■■ Adolescent HIV Treatment Coalition: Drug Admninstration: http://www.iasociety.org/HIV-Programmes/ https://www.fda.gov/ForIndustry/UserFees/ Programmes/Adolescent-HIV-Treatment-Coalition PrescriptionDrugUserFee/ucm326192.htm ■■ ■■ International Children Advisory Network: Patient-Centered Outcomes Research Institute: www.icanresearch.org https://www.pcori.org/engagement/influencing- culture-research ■■ Youth Trial Board: www.youthtrialsboard.org
■■ Children and Young People Network: National Health Council https://www.ncb.org.uk/children-and-young- ■■ http://www.nationalhealthcouncil.org people-hiv-network ■■ http://www.nationalhealthcouncil.org/sites/ ■■ HIV/AIDS Network Coordination: https://www.hanc.info/Pages/default.aspx default/files/NHC-GA-Patient-Engagement.pdf
■■ Adolescent Medicine Trials Network for HIV/ AIDS Interventions: https://atnweb.org/atnweb
■■ Global Network of Young People Living with HIV: http://www.yplusleadership.org
117 8. ACKNOWLEDGEMENTS
Authors: Djamel Hamadache1 and Polly Clayden2
Other contributors: Sarah Bernays3,4 and Abi Carter5
Reviewers: Marissa Vicari6, Mercy Ngulube5, Gareth Tudor-Williams7 and Janice Lee8
1 Independent consultant, London, United Kingdom 2 HIV i-base, London, United Kingdom 3 Sydney Medical School, Australia 4 London School of Hygiene and Tropical Medicine, United Kingdom 5 Children’s HIV Association, London, United Kingdom 6 International AIDS Society, Geneva, Switzerland 7 Imperial College London, United Kingdom 8 Drugs for Neglected Diseases initiative, Geneva, Switzerland
Special thanks to Sarah Bernays, Abi Carter and Djamel Hamadache for sharing case studies and young people’s experiences as trial participants.
9. REFERENCES
1. Hoo A, Anderson J, Boutin M, Dewulf L, 4. Community engagement: work under the Geissler J, Johnston G et al. Partnering with microscope. London: Wellcome Trust; 2011 patients in the development and lifestyle of (https://wellcome.ac.uk/sites/default/files/ medicines: a call for action. Ther Innov Regul wtvm054326_0.pdf, accessed 22 May 2018). Sci. 2015;49:929–39. 5. Geissler PW, Pool R. Popular concerns about 2. Slevin KW, Ukpong M, Heise L. Community medical research projects in Sub-Saharan engagement in HIV prevention trials: Africa – a critical voice in debates about evolution of the field and opportunities medical research ethics. Trop Med Int Health. for growth. Seattle (WA): PATH; 2008 2006; 11:975–82. (http://www.path.org/publications/detail. 6. The ethics of research related to healthcare php?i=1647, accessed 22 May 2018). in developing countries. Nuffield: Nuffield 3. Community Partners. Recommendations Council on Bioethics; 2002 (http:// for community engagement in HIV/AIDS nuffieldbioethics.org/wp-content/ research: a guide for communities and uploads/2014/07/Ethics-of-research- researchers, version 2.0. Seattle (WA): related-to-healthcare-in-developing- Office of HIV/AIDS Network Coordination; countries-I.pdf, accessed 22 May 2018). 2014 (https://www.hanc.info/cp/resources/ 7. Children and clinical research: ethical issues. Pages/recommendationsInvolvement.aspx, Nuffield: Nuffield Council on Bioethics; accessed 22 May 2018).
118 (http://nuffieldbioethics.org/wp-content/ 14. Principles of community engagement. 2nd uploads/Children-and-clinical-research-full- ed. Atlanta: Agency for Toxic Substances and report.pdf, accessed 22 May 2018). Disease Registry; 2011 (https://www.atsdr. cdc.gov/communityengagement/index.html, 8. MRC ethics guide: medical research accessed 22 May 2018). involving children. London: Medical Research Council; 2004 (https://www.mrc.ac.uk/ 15. Gwara M, Smith S, Woods C, Sheeren E, documents/pdf/medical-research-involving- Woods H. International Children’s Advisory children, accessed 22 May 2018). Network: a multifaceted approach to patient engagement in paediatric clinical research. 9. Ethical considerations for clinical trials on Clin Ther. 2017;39:1933–8. medicinal products conducted with the paediatric population. Recommendations 16. Track 1: community empowerment. 7th of the ad hoc group for the development Global Conference on Health Promotion: of implementing guidelines for Directive track themes. Geneva: World Health 2001/20/EC relating to good clinical Organization; 2009 (Proceedings of the 7th practice in the conduct of clinical trials on Global Conference on Health Promotion, medicinal products for human use. Brussels: accessed 22 May 2018). European Commission; 2008 (https:// 17. Lowe MM, Blaser DA, Cone L, Arcona S, ec.europa.eu/health/sites/health/files/files/ Ko J, Sasane R, Wicks P. Increasing patient eudralex/vol-10/ethical_considerations_ involvement in drug development. Value en.pdf, accessed 22 May 2018). Health. 2016;19:869–78. 10. Walsh E, Sheridan A. Factors affecting patient participation in clinical trials in 18. Good participatory practice: guidelines Ireland: a narrative review. Contemp Clin for biomedical HIV prevention trials, 2nd Trials Commun. 2016;3:23–31. ed. New York: AIDS Vaccine Advocacy Coalition; 2011 (https://www.avac.org/ 11. Nyika A, Chilengi R, Ishengoma D, Mtenga S, good-participatory-practice, accessed 22 Thera MA, Sissoko MS et al. Engaging diverse May 2018).https://www.avac.org/resource/ communities participating in clinical trials: good-participatory-practice-guidelines- case examples from across Africa. Malaria J. biomedical-hiv-prevention-trials-second- 2010; 9:86. edition
12. United Nations General Assembly. 19. Wendler D, Rackoff JE, Emanuel EJ, Grady Convention on the Rights of the Child. New C. The ethics of paying for children’s York: United Nations; 1989 (http://www. participation in research. J Pediatr. un.org/documents/ga/res/44/a44r025.htm, 2002;141:166–71. accessed 22 May 2018). 20. Dobson R. Lump sums for children taking 13. United Nations Convention on the Rights part in research may distort parents’ of the Child. Working methods for the judgment. BMJ. 2002;325:796. participation of children in the reporting 21. Joseph PD, Craig JC, Caldwell PHY. Clinical process of the Committee on the Rights of trials in children. Br J Clin Pharmacol. the Child. New York: United Nations; 2014 2015;79:357–69. (http://www.ohchr.org/EN/HRBodies/CRC/ Pages/WorkingMethods.aspx, accessed 22 May 2018).
119 MODULE 7: TARGET PRODUCT PROFILES
©DNDi/Scholars & Gentlemen
120 1. INTRODUCTION
Target product profiles are key strategic The global community, including WHO, UNAIDS, documents used to communicate summary the Global Fund to Fight AIDS, Tuberculosis requirements for new products that fulfil a and Malaria (Global Fund), the United States priority need. The purpose of target product President’s Emergency Plan for AIDS Relief profiles is to guide industry during the drug (PEPFAR) and the United Nations Children’s Fund development process and serve as a planning (UNICEF), have a responsibility to define the tool that can facilitate discussions with requirements around paediatric medicines and regulatory agencies and be updated as new have clear, transparent communication to industry information becomes available. on the products that are required to meet the unique needs of children. The importance of target product profiles resides in their role in identifying the critical attributes of Some organizations, such as WHO, UNICEF and a product before development begins, to ensure the Drugs for Neglected Diseases initiative, have that the final product is adapted and responds developed target product profiles for specific to the needs of the end-users (Fig. 7.1). Target desired products such as medicines, diagnostics product profiles can help address issues early in and vaccines that have served to guide industry the product development process and prevent in their own product development process.2 The late-stage development failures. target product profile describes how the end- user will use the product and is based on such Fig. 7.1. A target product profile as a strategic attributes as indications, targeted population, planning tool clinical efficacy, safety and tolerability, stability, route of administration, dosing frequency and cost, along with development timelines.
Research and Table 7.1 outlines various properties of target development product profiles and the optimum or ideal characteristics and minimum characteristics. Key properties include the ability to use the product across the age spectrum of children and adolescents, ease of administration, heat stability, Target Regulatory Market palatability and swallowability and acceptable product advice research profile production costs.
Manufacturers and suppliers
2 https://www.dndi.org/diseases-projects/paediatric-hiv/paedhiv-target-product-profile/; https://www.unicef.org/ supply/index_91816.html;http://apps.who.int/iris/bitstream/handle/10665/135617/WHO_HTM_TB_2014.18_eng. pdf;jsessionid=6D9A30EDDBCC978978CF9928FAB921AE?sequence=1
121 Table 7.1. Properties of target product profiles
Property Optimum or ideal target product profile Minimum target product profile Target One dosage form for ages 0–6 years Ages 0–2, 2–6 and >6 years population >6 years: adult Safety, Excipients selected from already used excipients in the Excipients selected in tolerability new drug application or abbreviated new drug application accordance with regulatory and in accordance with the Inactive Ingredients Guide of guidelines on inactive the United States Food and Drug Administration ingredients Limited use of excipients, minimum toxicity and drug interactions Drug attributes Accommodates a wide range of doses and drug A set of 3–5 technologies that properties (such as solubility) accommodate 80% or a majority Durability – high barrier to resistance of drug types and doses and fixed-dose combinations Weight based Possible to administer the same dosage form across Possible to administer the same dosing multiple weight bands dosage form across multiple 1 formulation for children age <6 years; weight bands 1 formulation for age >6 years: adult (or half a dose) Administration Easy to administer – minimum manipulation by the Solid oral dosage forms considerations caregiver preferred Minimal opportunity for child to reject medication If bottle pack, then it should Easy to apply with no irritation (non-oral) have a child-resistant cap Fixed-dose combination, dispersible or small tablet size Administration Product does not need device or appropriate device Minimum instructions necessary device supplied if needed to use device if needed consideration Intuitive – no use instructions necessary Taste and texture Palatable, child-friendly flavour, good mouth feel Palatable, acceptable taste and (oral dosage) mouth feel Manufacturing Accessible development and manufacturing capability in Low technology – easy to low- and middle-income countries manufacture in resource-limited Robust and able to deliver medicines of adequate quality settings at an affordable price Feasibility for technology transfer Cost Acceptable cost to caregivers and funders Low-cost (total cost of goods and landed costs) options Preparation Should not require complex preparation by the end-user Easy to prepare and administer, before before administration such as with water, milk or food administration Include recommendations for extemporaneous Suitable for low-literacy settings compounding in the summary of product characteristics Heat stable, Suitable for all climatic zones, including International Suitable for the supply chain and longer shelf life Council for Harmonisation Zone IVb (30°C and 75% end-user relative humidity) and ≥24 month total shelf life No special transport and See Annex 2, Stability conditions for WHO Member storage handling requirements States by region (5). or No special transport and storage handling requirements Easy to transport and store
122 Property Optimum or ideal target product profile Minimum target product profile Packaging Compact, light weight, easy to open and administer, Same inexpensive, easy and low cost to transport, sustainable packaging Disability For example, Braille labelling or “talking patient information” Due consideration for end-user disabilities Regulatory Clear regulatory approval pathways considered up front Regulatory pathways in end- approval both in source and end-user countries user countries considered up front
Patents Full geographical access, open licences, no data exclusivity Equitable geographical access Feasible to have product monographs in official pharmacopoeia as soon as possible to produce generics
Sources: Special Programme for Research and Training in Tropical Diseases (1), WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-first report (2), Target product profile – paediatric HIV (3), Lopez et al. (4) and Annex 2, Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (5).
Additional considerations in the drug formulation Table 7.2 outlines the advantages and development process include target candidate disadvantages of various formulations. Oral profiles and critical quality attributes. These include liquid preparations and oral solid preparations various drug characteristics that impact what are the most common formulations used for type of formulations can be manufactured and antiretroviral (ARV) drugs. In general, oral solid include: solubility and permeability of the active preparations are preferred to liquids since they pharmaceutical ingredients (Biopharmaceutical require less space and are easier to procure and Classification System classification); bioavailability store. Nevertheless, young children may not be + food effects of the active pharmaceutical able to swallow solid dosage forms. Depending ingredients; polymorphism; particle size; stability on the active pharmaceutical ingredients, of the active pharmaceutical ingredients; taste granules, pellets or chewable tablets may be and potential to “mask” taste during manufacture; difficult to taste mask, and children may refuse content of active pharmaceutical ingredients these products because of poor taste (7–13). per dosage form; dose variability versus age; Liquid formulations allow better accuracy in dose accuracy requirements; manufacturability; dosing but may be less palatable. Refrigeration good technology fit to manufacture the active may be required for some liquid formulations, pharmaceutical ingredients into a finished which will increase the difficulty of storage, pharmaceutical product; possibility to combine both during transport and for the end-user. For several active pharmaceutical ingredients into specialized products, more expensive production fixed-dose combinations (pharmacokinetics, costs or equipment may be required. pharmacodynamics and drug–drug interactions); active pharmaceutical ingredients amenable to age-appropriate simple dosage forms; and environmental pollution with active pharmaceutical ingredients during production (6).
123 Table 7.2. Advantages and disadvantages of various formulations
Active pharmaceutical Special Target age Formulation Procurement Storage Palatability Acceptability Administration ingredients precautions Oral solution Younger age group In principle, easy to Soluble, chemically stable Difficult Difficult Only for acceptable taste Volumes >5 ml Solvents Quality of water (unable to swallow) manufacture or easy-to-mask active problematic for children Measuring device Measurement pharmaceutical ingredients <5 years Only low doses problems Oral Younger age group Other particles can Non-soluble, chemically stable. Difficult Difficult Suspensions allow better Volumes >5 ml Clear information on suspension (unable to swallow) be suspended, like Better than solutions for active taste-masking than problematic for children shaking before use coated pellets… pharmaceutical ingredients that solutions <5 years Measuring device do not taste good Only low doses Oral liquid preparations Oral Syrups Younger age group In principle, easy to Soluble, chemically stable Difficult Difficult Only for acceptable taste Volumes >5 ml Problems measuring Alcohol, sugar (unable to swallow) manufacture or easy-to-mask active problematic for children Only low doses content pharmaceutical ingredients <5 years
Emulsions Younger age group In principle, easy to Non-soluble, chemically stable Difficult Difficult Only for acceptable taste Volumes >5 ml Clear information on (unable to swallow) manufacture or easy-to-mask active problematic for children shaking before use pharmaceutical ingredients <5 years Measuring device Only low doses Effervescent All ages Difficult technology Soluble, non-chemically stable Difficult Difficult Only for acceptable taste Effervescent tablets available or easy to mask active technology pharmaceutical ingredients required Oral powder, Better suited for Can contain beads Palatable and unpalatable active Easy Easy Taste can be an issue if Can be administered Information on food, Risk of granules and young age or mini-tablets pharmaceutical ingredients administered directly or directly in the mouth liquids restrictions aspiration or multiparticulate Technology readily mixed Allows dosing flexibility choking systems available Various strengths needed Tablets Older children (able In principle, easy to Soluble, non-chemically stable Easy Easy Palatable and unpalatable Well accepted May be difficult to swallow to swallow) manufacture active pharmaceutical depending on size ingredients Oral solid preparations Oral Chewable Older children Easy to manufacture. Soluble, non-chemically stable, Easy Easy Only for acceptable taste Well accepted Various strengths tablets Technology readily palatable active pharmaceutical or easy to mask active may be needed available ingredients pharmaceutical ingredients
Oro- All ages In principle, easy to Soluble, non-chemically stable, Easy Easy Taste needs to be Well accepted Various strengths dispersible manufacture palatable active pharmaceutical acceptable or easy to mask may be needed tablets ingredients
Splitting Older children (able In principle, easy to Soluble, non-chemically stable, Difficult Difficult (size) Well accepted Dosing instructions tablets to swallow) manufacture palatable active pharmaceutical (big size) may be difficult ingredients Solids for Younger age group In principle, easy to Soluble and non- soluble, non- Easy Easy Taste needs to be Volumes >5 ml Problems measuring Quality of water reconstitution (unable to swallow) manufacture chemically stable acceptable or easy to mask problematic for children Only low doses <5 years
Oral All ages Requires specific Palatable active pharmaceutical Easy Easy Lyophilization lyophilizates equipment ingredients required Oral films Limitation with Limited quantity of Palatable active pharmaceutical Easy Easy Taste needs to be Equipment high doses ingredients ingredients acceptable or easy to mask required
Source: adapted from: Penazzato et al. (14). © 2015 Penazzato M et al.; licensee International AIDS Society.
124 Table 7.2. Advantages and disadvantages of various formulations
Active pharmaceutical Special Target age Formulation Procurement Storage Palatability Acceptability Administration ingredients precautions Oral solution Younger age group In principle, easy to Soluble, chemically stable Difficult Difficult Only for acceptable taste Volumes >5 ml Solvents Quality of water (unable to swallow) manufacture or easy-to-mask active problematic for children Measuring device Measurement pharmaceutical ingredients <5 years Only low doses problems Oral Younger age group Other particles can Non-soluble, chemically stable. Difficult Difficult Suspensions allow better Volumes >5 ml Clear information on suspension (unable to swallow) be suspended, like Better than solutions for active taste-masking than problematic for children shaking before use coated pellets… pharmaceutical ingredients that solutions <5 years Measuring device do not taste good Only low doses Oral liquid preparations Oral Syrups Younger age group In principle, easy to Soluble, chemically stable Difficult Difficult Only for acceptable taste Volumes >5 ml Problems measuring Alcohol, sugar (unable to swallow) manufacture or easy-to-mask active problematic for children Only low doses content pharmaceutical ingredients <5 years
Emulsions Younger age group In principle, easy to Non-soluble, chemically stable Difficult Difficult Only for acceptable taste Volumes >5 ml Clear information on (unable to swallow) manufacture or easy-to-mask active problematic for children shaking before use pharmaceutical ingredients <5 years Measuring device Only low doses Effervescent All ages Difficult technology Soluble, non-chemically stable Difficult Difficult Only for acceptable taste Effervescent tablets available or easy to mask active technology pharmaceutical ingredients required Oral powder, Better suited for Can contain beads Palatable and unpalatable active Easy Easy Taste can be an issue if Can be administered Information on food, Risk of granules and young age or mini-tablets pharmaceutical ingredients administered directly or directly in the mouth liquids restrictions aspiration or multiparticulate Technology readily mixed Allows dosing flexibility choking systems available Various strengths needed Tablets Older children (able In principle, easy to Soluble, non-chemically stable Easy Easy Palatable and unpalatable Well accepted May be difficult to swallow to swallow) manufacture active pharmaceutical depending on size ingredients Oral solid preparations Oral Chewable Older children Easy to manufacture. Soluble, non-chemically stable, Easy Easy Only for acceptable taste Well accepted Various strengths tablets Technology readily palatable active pharmaceutical or easy to mask active may be needed available ingredients pharmaceutical ingredients
Oro- All ages In principle, easy to Soluble, non-chemically stable, Easy Easy Taste needs to be Well accepted Various strengths dispersible manufacture palatable active pharmaceutical acceptable or easy to mask may be needed tablets ingredients
Splitting Older children (able In principle, easy to Soluble, non-chemically stable, Difficult Difficult (size) Well accepted Dosing instructions tablets to swallow) manufacture palatable active pharmaceutical (big size) may be difficult ingredients Solids for Younger age group In principle, easy to Soluble and non- soluble, non- Easy Easy Taste needs to be Volumes >5 ml Problems measuring Quality of water reconstitution (unable to swallow) manufacture chemically stable acceptable or easy to mask problematic for children Only low doses <5 years
Oral All ages Requires specific Palatable active pharmaceutical Easy Easy Lyophilization lyophilizates equipment ingredients required Oral films Limitation with Limited quantity of Palatable active pharmaceutical Easy Easy Taste needs to be Equipment high doses ingredients ingredients acceptable or easy to mask required
Source: adapted from: Penazzato et al. (14). © 2015 Penazzato M et al.; licensee International AIDS Society.
125 2. CHALLENGES
The development of pharmaceutical products ■■ Since the acceptability of various dosage for children presents additional challenges. These forms varies widely with the age of the child products need to be adapted to a population (see the module on acceptability), how can it that is growing, gaining weight and undergoing be ensured that caregivers will administer the neurodevelopmental changes, has changing correct dose and that the child will receive the elimination pathways (see the module on appropriate dose? pharmacokinetic modelling), relies on caregivers Although information is limited on the safe and to administer medications and requires special appropriate use of ARV drugs for neonates, characteristics such as palatability, swallowability even less information is available for low-birth- and dosing flexibility. Lack of stable electricity weight and preterm neonates (18). About 20% supply, difficulty in supplying and storing of infants born to women living with HIV have medications and additional logistical issues in low birth weight or are preterm, and there is very low- and middle-income countries contribute little pharmacokinetic and safety information on to the challenges in designing medicines for ARV drugs for such neonates. Once a suitable children, especially those more commonly used drug formulation is licensed for use for full-term in low- and middle-income countries. These neonates, the drug is often used for low-birth- requirements and challenges should begin to be weight or preterm neonates, for whom there considered several years before the process of are no safety or pharmacokinetic data (see the product development. module on pharmacokinetic modelling). Questions remain about how appropriate research should be 2.1 Target population: developing supported for such vulnerable populations. formulations across the weight and age spectrum 2.2 Adherence: developing formulations to which people will adhere There is a critical need to develop appropriate formulations of medications suitable for use Adherence to chronic medications is challenging across the weight bands and age groups of for most people, but especially adolescents (19). children and adolescents (15,16). Pharmacokinetic Factors that may influence adherence include and safety information as well as appropriate the following: pill size, pill number, frequency dosing information lags far behind for children, of dosing, volume of solution, palatability, food especially neonates (see the modules on requirement and side-effects attributed to pharmacokinetic modelling and trial design) (17). medications. Although multiclass fixed-dose Key questions include: combination single-dosage formulations have greatly simplified treatment regimens, the actual ■■ How will the limited number of formulations size of the combination tablet may be an obstacle and dosage strengths available provide the to adherence. Many people, including adults, have flexibility required for adjusting the dose for pill aversion and have difficulty swallowing pills. growing neonates, infants, other children and adolescents while drug metabolism and There are limited data on the acceptability of elimination are changing rapidly? different dosage forms for younger children and adolescents (see the module on acceptability), but
126 dispersible tablets, mini-tablets, scored tablets, For example, oral liquids, tablets and capsules are granules and other flexible dosage forms have easier to manufacture and relatively inexpensive. been promoted as preferred by many people. Other more specific formulations such as granules, mini-tablets or oral lyophilizates, The physicochemical properties of the active and 3D printed tablets require dedicated pharmaceutical ingredients determine the range manufacturing equipment and may be more of formulations that can be selected. For instance, expensive to produce. Even manufacturing not all active pharmaceutical ingredients can be dispersible tablets, which are produced using a formulated into all dosage forms. Pharmaceutical well established and frequently used technology, excipients may be needed to mask bitter taste is slightly more expensive than producing and/or to increase solubility, which may also conventional tablets. affect the decision on which formulation is the most appropriate. The quantity of active All these factors increase the manufacturing pharmaceutical ingredients is also an important costs for products that offer less market factor, since it determines the size and volume return in principle (see the module on product of the finished dosage form. The condition to be commercialization). Further, the potentially treated determines the duration of treatment and smaller market for children means that the the dosage requirements. For ARV drugs used for economies of scale needed to mitigate the treating people living with HIV, the decision on the additional costs are difficult to achieve. most appropriate dosage form needs to consider the importance of good adherence and need for lifelong treatment, and acceptability is therefore 2.4 Supply chain issues an important consideration. Medicines for children may need to be shipped to Factors related to administration are key when and stored in low- and middle-income countries, deciding on the most appropriate dosage form. where climatic conditions can be hot and dry Drugs for children need to be formulated in a or hot and humid (5,20). They should be easily dosage form that is easy to administer and that transported, not require refrigeration and be minimizes potential dosing errors. If measuring readily available to the people who need them. administration devices are required, these have Medicines formulated to comply with regulatory to be adapted and easy to use. jurisdictions such as the European Medicines Agency (EMA) or United States Food and 2.3 Costs: development and Drug Administration (FDA) may not have been subjected to stability studies for climatic conditions manufacturing costs for novel medications in countries where they are most needed: hot and formulations and humid tropical zones (International Council on Harmonisation Zone IVa and Zone IVb stability Some medications needed for older children and conditions). This should be considered when for drugs that have no palatability issues can be formulating medicines for children. produced using conventional formulations such as tablets and capsules. However, alternative Factors that are more relevant in low- and pharmaceutical formulations may be required middle-income countries than in high-income to successfully deliver drugs to children in an countries can affect the procurement and storage acceptable, palatable and easy-to-use manner, of medicines, such as the need for cold-chain but these are more expensive than conventional transport and storage. Transporting and storing formulations. They may require specific equipment conventional medicines for children formulated to manufacture, the addition of specific excipients as oral liquids that may require refrigeration can or the use of measuring devices. also be challenging; instead, one could consider
127 developing a tablet for oral solution or suspension 2.6 Product development challenges: or a dispersible tablet. Bulky products, such as oral formulation development issues liquids, increase shipment costs since they take up more space, and the cold chain cannot always Formulation issues innovators encounter during be maintained during transport and storage. The drug development may not be communicated existence of multiple dosage forms for different to the generic manufacturers. The factors that age groups also affects procurement and makes help define the dosage form can be grouped quantifying needs more difficult. into four categories: (1) factors related to the physicochemical properties of the active 2.5 Harmonizing regulatory requirements: pharmaceutical ingredients and excipients used regulatory issues in the formulations, (2) factors related to the condition, dosing and medical need, (3) factors related to transport and procurement and (4) The lack of harmonization of regulatory cost factors. requirements and pathways across regulators is a challenge for drug development. In some The ideal formulations that consider these countries, such as India, the national regulator factors and better respond to these challenges requires clinical trials in their populations even if are characterized in the target product profile a product has already been approved in Europe, but may be difficult to develop for cost or Japan and the United States of America. This feasibility reasons. The innovator or generic can affect access to medicines for children pharmaceutical company may develop the target worldwide since Indian generic manufacturers, product profile as the starting-point of product who supply medicines to most low- and middle- development, but a supplier may also develop income countries, have greater difficulty this. Lack of proper communication between obtaining local approval, which then affects price companies and suppliers to better understand and development timelines. This not only affects the needs, feasibility and costs, as well as India, since most countries require registration the stages of the development process, may in the country of origin before the product is cause delays or even failure when developing authorized for use elsewhere. Regulatory issues formulations for children. can also affect supply and logistics. Differences between regulatory requirements for labelling may lead to a lack of harmonization. Labels with text differing from that required by local authorities may be blocked in customs.
Some regulatory authorities ask for local clinical trials when they consider that existing ones may not demonstrate safety and efficacy specifically in their population. This was the case for India, and although the authorities agreed to grant a waiver for products for children WHO identified as a priority, this may still be problematic for drug development (21).
128 3. SOLUTIONS
This section outlines several solutions and 1. regulatory requirement for safety, ideas for addressing these challenges. Further pharmacokinetic and dosing information references and cross-references to other for life-saving drugs; modules enable more in-depth analysis. 2. incentives for pharmaceutical companies and research networks to collaborate 3.1 Target population: developing on the research needed to obtain this formulations across the age spectrum information; 3. flexible dosage forms that can be safely To ensure that formulations for children and administered to low-birth-weight or adolescents are developed so that these preterm infants; and medications can be used across the age spectrum, additional planning and investigation 4. pressure from organizations and guideline should be undertaken. committees to obtain this information. ■■ ■■ Plan early in the drug development process Investigation of drug stability in breast-milk and the potential need for smaller doses for other solutions and foods should be encouraged infants and other young children. The ideal as part of formulation development (see the formulation should be heat stable, convenient modules on pharmacokinetic modelling and to use, require simple instructions for use and pregnant and breastfeeding women). minimal manipulation to prepare, allow for flexible dosing and not contain potentially toxic 3.2 Adherence: developing formulations excipients such as ethanol or propylene glycol in high concentrations. Excipients should be to which people will adhere selected based on the most recently approved excipient guidelines published by the FDA and In developing formulations for children, factors EMA (22,23). that relate to people’s preferences should be considered. ■■ Neonates are very difficult to study, especially low-birth-weight or preterm ■■ Pill size is important, and manufacturers need infants. A mechanism should be developed to consider acceptability when developing and encouraged so that this information formulations. This is even more important becomes available as more infants receive when formulating fixed-dose combinations empiric therapy, enhanced prophylaxis that combine several active ingredients. and early treatment for HIV infection. ■■ Before deciding on the formulation and the Pharmacokinetic modelling and simulations devices or instructions that it may require, combined with data from older infants and research should be conducted on what are other children can provide an initial potential acceptable formulations in various age groups, dose for medications with good safety both for the patients and caregivers (see the profiles that can be studied in low-birth- modules on acceptability and community weight or preterm infants (see the module on engagement). pharmacokinetic modelling). The following are suggested as potential solutions for obtaining Innovative alternatives, such as long-acting pharmacokinetic and safety data for ARV formulations, could be considered and developed drugs for low-birth-weight or preterm infants: as alternatives to daily oral medications.
129 3.3 Costs: development and ■■ Rapid product uptake helps in mitigating manufacturing costs of novel medications financial risk and recovering investment. and formulations For ARV drugs, this can be done through the Antiretroviral Procurement Working Group, which coordinates the demand of The smaller market for drugs for children and the major purchasers such as the Global Fund, higher manufacturing costs of many formulations UNICEF and the Partnership for Supply Chain for children highlight the importance of limiting Management. the number of formulations. It is important to avoid further reducing the market size, to ■■ Developing a business case for the product correctly quantify the costs in advance and to needed and characterized in the target increase opportunities for leverage incentives, product profile permits measurement of the such as funding for research and development financial risk. Information sharing between and advance market commitments. manufacturers and suppliers is also key in this step, since it enables investment to be adapted The following actions could help in identifying to the expected return. manufacturing costs and limiting the impact of unplanned additional expenditure. 3.4 Supply chain issues ■■ Each specific target product profile should set a target indicative price. The following actions could avoid supply-related ■■ Accurately quantifying and estimating the problems for formulations for children. size of the market may help in planning the investment needed to develop ■■ Stability studies must demonstrate the formulations for children and ensure financial stability of the medicinal product throughout sustainability (see the module on product its intended shelf life under the climatic commercialization). conditions prevalent in the target countries. For global supply, product stability should be ■■ If a supplier, buyer or other stakeholder systematically conducted in the most stringent develops the target product profile, sharing this conditions (climatic zone IVa, 30±2°C and information with the pharmaceutical companies 65±5% relative humidity or IVb, 30±2°C is important to understand potential obstacles and 75±5% relative humidity) unless the to product development that may increase characteristics of the active pharmaceutical cost. Input from manufacturers needs to be ingredient typically do not support such considered in the final target product profile. conditions (5,20). This can be done through an open consultation process to develop the target product profile, ■■ Products should be labelled with actual online publication of a draft for comment, storage temperatures. Stating that a product industry and stakeholder consultations and, does not require special storage conditions is if needed, face-to-face meetings. The target unacceptable for use in countries where these product profile and all product information, products are most needed. including timelines, should be shared in ■■ Heat-stable products that do not require cold advance with teams and organizations in chain or end-user refrigeration are ideal. charge of procurement, to accelerate product ■■ Age-appropriate solid oral dosage forms or introduction. Procurement of drugs should medicines in appropriate packaging greatly be based on identifying the desired drugs and reduce weights and volumes and thereby dosage forms, estimating the requirements shipping and storage costs. for each drug product for a given period and determining what resources are available (24).
130 3.5 Harmonizing regulatory requirements: 3.6 Product development challenges regulatory issues that affect supply and logistics The following product development challenges should be considered. ■■ Efforts to ensure harmonized regulatory ■■ Regardless of whether a manufacturer requirements should be increased. These or a supplier develops the target product efforts include the following. profile, communication between the parties ■■ Efficient collaboration between regulatory involved is important, to understand whether agencies and manufacturers would greatly the proposed target product profile covers reduce the costs and delays involved in both the requirements and whether it is feasible drug development and supply and logistics. industrially. Precise knowledge of the costs
■■ Improving the harmonization of regulatory associated with product development enables requirements and pathways and regulatory proper planning. interpretation of stability studies across ■■ Planning properly, establishing timelines and regulators can positively affect drug outlining product development benchmarks development and supply and logistics. are also key. Face-to-face meetings, mainly
■■ Specific country regulatory requirements when the process starts and the target need to be considered early in the drug product profile is established, are needed for development process to avoid additional this purpose. The target product profile can hurdles and obstacles to importation and in- be adapted over time to incorporate new country approvals. information or to reflect important changes in product development. ■■ WHO and other global health agencies should consider how to leverage influence to encourage the regulatory agencies to better harmonize their requirements.
©DNDi/Anita Khemka
131 4. CASE STUDIES
This section provides examples of products from birth and weighing ≥2 kg. Raltegravir is developed by adopting some of the solutions available for use for children as oral granules outlined in this module. for suspension, chewable tablets and film- coated tablets (18,26,27). The bioavailability of raltegravir varies by formulation, and the 4.1 Lopinavir/ritonavir 40 mg/10 mg pellets dosing recommendations for the solid tablets are different and not interchangeable from Based on the results of IMPAACT (International those for the chewable tablets or oral granules Maternal Paediatric Adolescent AIDS Clinical for suspension. Preparing the oral granules for Trials) P1060, WHO recommended lopinavir/ suspension requires that caregivers receive ritonavir as the preferred treatment for infants proper training, since several steps are involved newly diagnosed with HIV (25). Lopinavir/ in reconstituting the granules and measuring the ritonavir 40 mg/10 mg pellets were launched appropriate dose. A study is currently underway in 2015 and have been rolled out in several to assess the acceptability and feasibility of the countries in Africa, where acceptability studies raltegravir oral granules for suspension in low- are underway. Cipla developed these heat- and middle-income countries. stable pellets to avoid problems with the oral solution, which requires refrigeration and does The use of raltegravir chewable tablets, although not taste good, thus helping to increase uptake not yet approved for children younger than and implement WHO treatment guidelines. two years, has been recently investigated to Cipla designed and developed the formulation determine whether these may be dispersed following recommendations from organizations and administered to infants and other young working in the field and in close communication children (27). In vitro evaluation was conducted with suppliers. The product characteristics were demonstrating stability in various liquids, discussed in advance, which contributed to its including breast-milk. Several studies using acceptability (see the module on acceptability). chewable tablets as dispersible tablets are planned among young children, since the The Drugs for Neglected Diseases initiative chewable tablets are anticipated to be easier to is working with Cipla to develop a 4-in-1 use in low- and middle-income countries. fixed-dose combination product including abacavir + lamivudine + lopinavir/ritonavir that will be easier to administer to young children who 4.3 Excipients in neonatal formulations cannot swallow pills. Taste masking has been a major challenge in developing the 4-in-1 product. Unanticipated toxicity has been observed when drugs licensed for older children are used for neonates and low-birth-weight or preterm 4.2 Raltegravir infants. Experience with lopinavir/ritonavir has taught the need for extreme caution among Many national and international guidelines now these vulnerable children. FDA labelling includes prefer the integrase inhibitors as first-line agents a black-box warning that lopinavir/ritonavir in combination with other ARV drugs. Raltegravir should not be used in the immediate postnatal is the first in this class the FDA has approved period for premature infants because an for use for infants and other children starting increased risk of toxicity has been reported.
132 This toxicity includes: transient symptomatic 4.4 Long-acting formulations adrenal insufficiency(28) ; life-threatening bradyarrhythmia and cardiac dysfunction, There is considerable interest in developing long- including complete atrioventricular block, acting formulations for both prophylaxis and bradycardia and cardiomyopathy (29); and treatment of HIV and other infectious diseases. lactic acidosis, acute renal failure, central However, no information is currently available nervous system depression and respiratory as to what types of long-acting formulations depression. This may be caused by the drug itself (injectable, patch or implants) are acceptable to and/or by the inactive ingredients in the oral different age groups or caregivers. solution. Transient asymptomatic elevation in 17-hydroxyprogesterone levels has been reported among term newborns treated at birth with lopinavir/ritonavir (28).
Extreme caution must be used when including excipients in formulations designed for neonates and other young children.
5. SUMMARY
Target product profiles are key strategic A target product profile should consider: documents used to communicate summary target population, safety and tolerability, requirements for new products that fulfil the drug attributes, weight-based dosing, ease priority needs of children and adolescents. The of administration, need for administration purpose of the target product profiles is to devices, taste and texture of oral dosage forms, guide industry during the drug development manufacturing capability and technology, cost, process and serve as a planning tool that can drug preparation before administration, heat facilitate discussions between regulatory stability and shelf life, packaging, adaptations agencies, manufacturers, suppliers and global for end-user disabilities, regulatory approval and health organizations. patent issues.
133 6. KEY CONSIDERATIONS
■■ The target product profile should capture ■■ The decision on the type of formulation for key attributes so that the end product meets children affects the development process.
the needs of the target population (including ■■ The formulation developed needs to be neonates and other young children), facilitates adapted to the age for which it is intended good adherence and avoids supply chain issues and to be usable across weight bands for this and regulatory challenges. target population; small-size tablets, fixed- ■■ Additional considerations, including dose combinations and any other dosage physicochemical characteristics and forms developed need to maximize adherence; bioavailability, are part of the target candidate development costs that may negatively affect profiles and critical quality attributes. the final price need to be minimized when
■■ Potential challenges in product development possible; the final product should be stable in and manufacturing costs need to be addressed the most stringent climatic conditions; specific early, and strategies need to be in place to country regulatory requirements need to be address these issues. addressed; and strict and clear timelines and suggestions from suppliers in the development ■■ Several formulations respond better to plan and the target product profile need to children’s needs, such as dispersible tablets. be incorporated. However, all properties need to be properly assessed through the target product profile to ensure that the final formulation is appropriate.
7. USEFUL RESOURCES
■■ Reflection paper: formulations of choice for ■■ Paediatric Antiretroviral Drug Optimization the paediatric population. London: European (PADO) meeting 3. Geneva: World Health Medicines Agency, Committee for Medicinal Organization; 2017 (http://www.who.int/ Products for Human Use; 2006 (http://www. hiv/pub/meetingreports/paediatric-arv- ema.europa.eu/docs/en_GB/document_ optimization-pado3/en, accessed 22 May library/Scientific_guideline/2009/09/ 2018). WC500003782.pdf, accessed 22 May 2018).
134 ACKNOWLEDGEMENTS
Authors: Diana F. Clarke1, Fernando Pascual2 and Atieno Ojoo3
Reviewers: Marc Lallemant4,5, Vinod Arora6, Paul La Barre3, Jonathan Howard Brand3 and Nandita Sugandhi7
1 Boston Medical Center, MA, USA 2 Medicines Patent Pool, Geneva, Switzerland 3 UNICEF, Copenhagen, Denmark 4 Program for HIV Prevention and Treatment, Institut de Recherche pour le Développement, Marseille, France 5 Chiang Mai University, Thailand 6 Medicines Patent Pool, Gurgaon, Haryana, India 7 Texas A&M Health Science Center, College Station, USA 8 ICAP at Columbia University, New York, NY, USA
REFERENCES
1. Special Programme for Research and Training 4. Lopez FL, Ernest TB, Tuleu C, Orlu Gul M. in Tropical Diseases. Health product research Formulation approaches to pediatric oral & development fund: a proposal for financing drug delivery: benefits and limitations of and operation. Geneva: World Health Organi- current platforms. Expert Opin Drug Del. zation; 2016 (http://apps.who.int/iris/bitstream/ 2015;12:1727–40. handle/10665/204522/9789241510295_eng. 5. Annex 2, Stability testing of active pdf;jsessionid=C12BA0E88127D0348DFEB- pharmaceutical ingredients and finished CE916117FC4?sequence=1, accessed 22 May pharmaceutical products. Geneva: World 2018). Health Organization; 2010 (http;//www.who. 2. WHO Expert Committee on Specifications int/areas/quality_safety/quality_assurance/ for Pharmaceutical Preparations: fifty-first StabilityTable2.pdf, accessed 22 May 2018). report. Geneva: World Health Organization; 6. Inter-Agency Agreement between the 2017 (http://www.who.int/medicines/areas/ Eunice Kennedy Shriver National Institute quality_safety/quality_assurance/expert_ of Child Health and Human Development committee/WHO_TRS_1003_full-version. (NICHD) and the U.S. Food and Drug pdf, accessed 22 May 2018). Administration (FDA). Bethesda (MD): 3. Target product profile – paediatric HIV. United States National Institutes of Geneva: Drugs for Neglected Diseases Health; 2014 (https://bpca.nichd.nih.gov/ initiative; 2018 (https://www.dndi.org/diseases- collaborativeefforts/initiatives/Documents/ projects/paediatric-hiv/paedhiv-target- Formulations_Platform_Report2.pdf, product-profile, accessed 22 May 2018). accessed 22 May 2018).
135 7. Committee for Medicinal Products for 15. Penazzato M, Gnanashanmugam D, Rojo Human Use. Reflection paper: formulations P, Lallemant M, Lewis LL, Rocchi F et al. of choice for the paediatric population. Optimizing research to speed up availability of London: European Medicines Agency; pediatric antiretroviral drugs and formulations. 2006 (http://www.ema.europa.eu/docs/ Clin Infect Dis. 2017;64:1597–1603. en_GB/document_library/Scientific_ 16. Penazzato M, Palladino C, Sugandhi N. guideline/2009/09/WC500003782.pdf, Prioritizing the most needed formulations to accessed 22 May 2018). accelerate paediatric antiretroviral therapy 8. Strickley RG, Iwata Q, Wu S, Dahl TC. scale-up. Curr Opin HIV AIDS. 2017;12:369–76. Pediatric drugs – a review of commercially 17. Clarke DF, Penazzato M, Capparelli E, available oral formulations. J Pharm Sci. Cressey TR, Siberry G, Sugandhi N et al. 2008;97:1731–74. Prevention and treatment of HIV infection 9. Nunn T, Williams J. Formulation of in neonates: evidence base for existing medicines for children. Br J Clin Pharmacol. WHO dosing recommendations and 2005;59:674–6. implementation considerations. Expert Rev Clin Pharmacol. 2018;11:83–93. 10. Committee for Medicinal Products for Human Use Paediatric Committee. 18. Clarke D, Acosta E, Chain A, Cababasay Guideline on pharmaceutical development M, Wang J, Teppler H et al. Raltegravir of medicines for paediatric use, Rev 2. pharmacokinetics and safety in HIV-1 London: European Medicines Agency; exposed neonates: dose-finding study. 2013 (http://www.ema.europa.eu/docs/ 2017 Conference on Retroviruses and en_GB/document_library/Scientific_ Opportunistic Infections, Boston, marketing guideline/2013/07/WC500147002.pdf, authorization, USA, 13–16 February 2017 accessed 22 May 2018). (http://www.croiconference.org/sessions/ raltegravir-pharmacokinetics-and-safety- 11. Liu F, Ranmal S, Batchelor HK, Orlu-Gul hiv-1-exposed-neonates-dose-finding-study, M, Ernest TB, Thomas IW et al. Patient- accessed 22 May 2018). centred pharmaceutical design to improve acceptability of medicines: similarities 19. HIV medication adherence. Washington and differences in paediatric and geriatric (DC): United States Department of Health populations. Drugs. 2014;74:1871–89. and Human Services; 2018 (https://aidsinfo. nih.gov/understanding-hiv-aids/fact- 12. Batchelor HK, Marriott JF. Formulations for sheets/21/54/hiv-medication-adherence#, children: problems and solutions. Br J Clin accessed 22 May 2018). Pharmacol. 2015;79:405–18. 20. Stability testing of active pharmaceutical 13. Lopez FL, Ernest TB, Tuleu C, Gul MO. ingredients and finished pharmaceutical Formulation approaches to pediatric oral products. Geneva: World Health drug delivery: benefits and limitations of Organization; 2009 (http://apps.who. current platforms. Expert Opin Drug Deliv. int/medicinedocs/documents/s19133en/ 2015;12:1727–40. s19133en.pdf, accessed 22 May 2018).
14. Penazzato M, Lee J, Capparelli E, Essajee S, 21. Draft guidance on approval of clinical trials Ford N, Ojoo A et al. Optimizing drugs to & new drugs. New Delhi: Central Drugs reach treatment targets for children and Standard Control Organization, Directorate adolescents living with HIV. J Int AIDS Soc. General of Health Services, Ministry of 2015;18:20270. Health & Family Welfare 2011 (http://www.
136 cdsco.nic.in/writereaddata/Guidance_ 28. Simon A, Warszawski J, Kariyawasam D, Le for_New_Drug_Approval-23.07.2011.pdf, Chenadec J, Benhammou V, Czernichow P accessed 22 May 2018). et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal 22. Annex to the European Commission dysfunction among uninfected infants of guideline on “Excipients in the labelling and HIV-infected mothers. JAMA. 2011;306:70–8. package leaflet of medicinal products for human use”. London: European Medicines 29. Lopriore E, Rozendaal L, Gelinck LB, Agency; 2017 (http://www.ema.europa.eu/ Bökenkamp R, Boelen CCA, Walther FJ. docs/en_GB/document_library/Scientific_ Twins with cardiomyopathy and complete guideline/2009/09/WC500003412.pdf, heart block born to an HIV-infected accessed 22 May 2018). mother treated with HAART. AIDS. AIDS; 2007;21:2564–5. 23. Guidance for industry: nonclinical studies for the evaluation of pharmaceutical excipients. Washington DC): United States Food and Drug Administration; 2005 (https://www. fda.gov/ohrms/dockets/98fr/2002d-0389- gdl0002.pdf, accessed 22 May 2018).
24. 24. Management of drugs at health centre level – training manual. Geneva: World Health Organization; 2004 (http://apps. who.int/medicinedocs/en/d/Js7919e/7. html#Js7919e.7, accessed 22 May 2018).
25. Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha L, Kamthunzi P et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. 2012;366:2380–9.
26. Nachman S, Alvero C, Acosta EP, Teppler H, Homony B, Graham B et al. Pharmacokinetics and 48-week safety and efficacy of raltegravir for oral suspension in human immunodeficiency virus type-1- infected children 4 weeks to 2 years of age. J Pediatric Infect Dis Soc. 2015;4:e76–83.
27. Teppler H, Thompson K, Chain A, Mathe M, Nachman S, Clarke D. Crushing of raltegravir (RAL) chewable tablets for administration in infants and young children. 9th International Workshop on HIV, Paris, France, 21–22 July 2017.
137 MODULE 8: PRODUCT COMMERCIALIZATION
©WHO/Sergey Volkov
138 1. INTRODUCTION
Successful product development and securing (ART) in low- and middle-income countries. of regulatory approval does not guarantee that However, the market for many drugs for children a product will be commercialized and available is much smaller than that for adults and as a to the people who need it. The successful result, developing a clear business case for development of a new drug for children must industry to develop, manufacture and supply also consider its commercial viability to ensure medicines for children at an affordable cost can that it reaches the populations for which is it be challenging. In the absence of consolidated is intended. global forecasts and demand planning, there may be no clear incentive or indication for The impact of new products on the lives of manufacturers to initiate the development of children living with HIV relies on upstream formulations for children. activities related to drug development and regulatory approval to bring a new product Careful procurement planning and clear to market, but downstream activities are communication between procurers, national just as important to ensure that the market programmes and suppliers can ease the launch for antiretroviral (ARV) drugs for children is of a new formulation for children. In the absence sustainable and products are accessible in the of this, suppliers can be hesitant to take on settings in which they are most needed. Both inventory risk and commit production resources supply and demand considerations must be to the new products until larger orders are considered beginning early in the process of received. Thus, lead times may become very drug development. long, risking loss of interest from programmes to adopt new products, shortages of ARV drugs or The majority of ARV drugs, including those even stock-outs, which may result in treatment used in infants and other children, are used in interruption. low- and middle-income countries, and cost is therefore a significant consideration. Generic manufacturing, which relies on economies of scale to achieve affordable pricing, has been critical for scaling up antiretroviral therapy
139 2. CHALLENGES
The market for ARV drugs for children is in the higher weight bands before eventually relatively small and fragmented across multiple transitioning into adult cohorts. In addition, formulations, and the uptake of new formulations since ART is a lifelong need and previously used in countries can be slow. These factors make the regimens were often suboptimal, it is important commercialization of new ARV drug formulations to consider the sequencing of new drugs, since for children much more challenging than for ARV an increasing proportion of children receiving drug formulations for adults. ART will eventually require second- or even third-line ART. Finally, the increasing use of more potent ARV drugs in first-line ART, which have a 2.1 Small market size higher genetic barrier to resistance, could result, over time, in more durable first-line regimens and The market for many medications for children is lower demand for products needed for future typically much smaller than that for adults; this lines of ART for children. is particularly true for ARV drugs, since children make up only 5% of the people receiving ART (1). A clear business case must be available to give 2.2 Fragmentation across incentives to industry to develop, manufacture duplicative products and supply medicines for children. Despite the relatively small size of the market A first step in developing a business case for for ARV drugs for children, there are multiple developing a new ARV product for children dosage forms for the limited number of ARV is to anticipate the number of children who drugs that have been approved for children. will benefit (the market size). There are many However, generic manufacturers rely on variables to consider when estimating the market accumulating order volumes that achieve a size for a new ARV drug for children. First, ART minimum production batch size as a threshold to coverage among children is growing – ambitious determine when production should be initiated. targets set by the Start Free, Stay Free, AIDS Free initiative are expected to continue to The minimum batch sizes may be on the order of increase the number of children living with thousands or even tens of thousands of packs, HIV receiving ART (2). At the same time, with but when procurement orders are divided across the success of campaigns for preventing the small volumes of duplicative drug dosage forms, vertical transmission of HIV, fewer infants are consistently reaching the threshold necessary newly infected with HIV each year, leading to a to maintain a reliable supply of products may relatively smaller population of infants and other be challenging. Too many ARV drug choices young children requiring ART. produce a limited demand for each and decrease the likelihood of sustained supplies and adequate Another key dynamic is that the increasing access to care for children. success of ART for children means that infants and other young children are more likely to survive long term on treatment, which means more children and adolescents will need ART
140 2.3 Slow uptake at the country level ■■ uncertainty about how a new product aligns with or replaces other products for children Even after the product is developed, delays in that are already being procured and are introducing new products for children may occur widely used; for several reasons, including but not limited to: ■■ delays in commercialization by suppliers because the product for children has low ■■ lack of awareness from global buyers and/or in-country decision-makers of the availability priority and/or low volume for them relative to and benefits of the new drug; other new products in their portfolio; and ■■ limited production capacity and/or uncertainty ■■ limited visibility into development and filing timelines may discourage programmes from about supply security that may diminish incorporating new products into national demand-side enthusiasm for the new product. policies and programme plans;
3. SOLUTIONS
Partner coordination, rationalization of for children by sharing market intelligence and paediatric formularies and proactive scaling up coordinating the procurement of ARV drugs for of production capacity are strategies to stabilize children and other low-volume ARV products (4). the market for ARV drugs for children and to The Antiretroviral Procurement Working facilitate the entry of newer products. Group serves as an excellent resource for both programmes and manufacturers for clear, 3.1 Coordination consistent and reliable market intelligence about new and existing products. This allows the global Although early efforts such as the Unitaid–Clinton community to better anticipate and mitigate Health Access Initiative Paediatric HIV/AIDS potential supply issues. In addition, placing orders Treatment Project (3) supported the scaling up according to timelines recommended by the of ART for children, ongoing efforts to improve Antiretroviral Procurement Working Group can supply security through a process of coordinating minimize lead times when low-volume individual procurement and strategically managing demand orders may not meet a supplier’s minimum have reduced the risks of supply disruption. batch size.
The Antiretroviral Procurement Working In collaboration with Unitaid and other key partners, Group (formerly known as the Paediatric ARV WHO has established a forecasting working group Procurement Working Group) brings together with the objective of consolidating criteria and 2 major buyers of ARV drugs for children, including different models used by various organizations donors, funders, country programmes and to estimate future needs. The work of this group, implementing partners. It was established in which is expected to deliver prototype forecasting 2011 to support coordination at the global level tools by the end of 2018, will also help better to improve the supply security of ARV products quantify the size of the market.
2 The group consists of Avenir Health, the Clinton Health Access Initiative (CHAI); the Global Fund to Fight AIDS, TB and Malaria; the Medicines Patent Pool (MPP); the Partnership for Supply Chain Management (PFSCM); PEPFAR; UNICEF; USAID and its Global Health Supply Chain-Procurement and Supply Management (GHSC-PSM) project, and several others.
141 3.2 Rationalization of formularies target product profile and simplify supply chain for children management (Table 8.1). The optimal paediatric ARV formulary includes The WHO essential medicines group developed the minimum number of dosage forms for optimizing formularies for essential medicines children necessary to enable all WHO- as an approach to facilitate the rational usage of recommended preferred first- and second-line drugs and promote equitable access to critical regimens and neonatal prophylaxis for preventing drugs. Optimizing formularies is especially critical vertical transmission of HIV to be administered for relatively fragmented markets such as that across all appropriate weight bands for children. for ARV drugs for children, since the inherent In addition, the limited-use list provides for small volumes make drug companies less likely to dosage forms of drugs that may be needed for invest, making the market vulnerable and highly special circumstances, such as third-line ART, cost sensitive. neonatal treatment and drugs that are being phased in or out of use. The optimal and limited-use paediatric ARV formularies, established in 2011, took this Since new ARV products enter the market and approach to develop a focused list of products guideline recommendations are updated, the for children that are needed to deliver ART optimal paediatric ARV formulary and limited- across all age groups and weight bands of use lists are revised to ensure that they remain children using a set of criteria to identify current, with updates released in 2013 (6), dosage forms that most closely align to the 2015 (7) and 2016 (8); an updated version is
Table 8.1. Criteria for selection of optimal ARV drug dosage forms for children
Criterion Definition Meets WHO requirements Included in the latest WHO guidelines for treating children Enables the widest range of dosing options Enables flexible dosing across multiple weight bands and ages Approved by the stringent regulatory authority or Availability of at least one product approved by the WHO prequalification stringent regulatory authority User-friendly Easy for health-care workers to prescribe Easy for caregivers to administer Supports adherence Optimizes supply chain management Easy to transport Easy to store Easy to distribute Available for low- and middle-income countries Product is licensed or registered for use in low- and middle-income countries Reliable supply of product Comparative cost Cost should not be a deciding factor, but the comparative cost of formulations of the same combination of drugs should be considered
Source: adapted from: Penazzato et al. (5). © 2015 Penazzato M et al; licensee International AIDS Society
142 anticipated in mid-2018. Programmes have been Some of the dynamics described earlier around encouraged to refer to this list to guide the preventing vertical transmission and improving selection and procurement of ARV products formulations are compounded by limited for children. reliable data available from countries about true breakdowns of children receiving ART by age, A focused list of products increases the volume weight and line of ART. All this, with different orders of particular products, thus providing appetites for change or early adoption across incentives for production on a regular basis, country programmes, makes creating accurate which stabilizes supply. This also makes the global demand forecasts several years out overall market more attractive to manufacturers difficult if not impossible. and encourages continued investment in developing new products. Procurement and However, based on the intended use (such as implementation are also easier at the programme children younger than three years), the relative level if a limited number of formulations are scale and ranges of possible demand can be available for use across weight and age bands. determined using modelled epidemiological data from UNAIDS (9). One can get a sense of the maximum potential market size (assuming every 3.3 Scale-up planning eligible child is receiving treatment with the product in question) and work backwards from From the early stages of development of ARV that to real-world scenarios of demand over time. drugs for children, it is critical to consider the settings in which the finished drug product Whereas suppliers generally initiate actual will be used. This includes supply chain production only on receiving confirmed orders, considerations for the finished dosage form to with a sense of the maximum potential market ensure successful implementation in low- and size, suppliers can and should have proactive middle-income countries, where most children plans and commitments in place to increase living with HIV receive treatment, in addition to production capacity concomitant with various the characteristics of the finished dosage form scenarios for scaling up demand (Fig. 8.1). (see the module on target product profiles).
Fig. 8.1. Illustrative proactive (pre-launch) production scale-up planning
Maximum potential Maximum potential Initial planned Scalable capacity Further capacity demand (global) demand from capacity with orders placed changes in response 2–3 high-volume (no orders (1–2 months of to demand early-adopter placed yet) turnaround time (within one year countries in response to after the first actual demand) orders are placed)
143 Such a proactive plan can help suppliers in production capacity (such as process variation balancing capital investment risk, inventory risk and additional manufacturing sites) that may and production line opportunity costs while become bottlenecks in product availability if minimizing delays in access to drugs should pursued in a reactive manner. a scenario with rapidly scaled up demand materialize. Otherwise, suppliers will simply For such an exercise to be useful, suppliers have hedge their risk with lower capacity and only to be forthcoming about what relative ranges increase it reactively, leading to long delays in are relevant for their production planning based product availability. This is especially important on the product in question (such as material when additional regulatory approval may be differences in demand being 10 000 versus 100 needed to be able to increase commercial 000 packs per month or 10 000 versus 15 000 packs per month).
4. CASE STUDY
Abacavir + lamivudine 120 mg/60 mg combination tablet of ABC + 3TC 60 mg/30 mg was available to dose across all weight bands. Since 2013, the WHO consolidated guidelines on However, the pill burden for older children was of the use of antiretroviral drugs for treating and concern, since they would require up to six tablets preventing HIV infection (10) have recommended of ABC + 3TC 60 mg/30 mg daily, with additional using abacavir (ABC) and lamivudine (3TC) as tablets needed to complete a three-drug regimen. a preferred nucleoside reverse-transcriptase In response to the need for a stronger tablet for inhibitor backbone for children three years and children, generic manufacturers developed an older and as one of two preferred options for ABC + 3TC 120 mg/60 mg scored tablet that children younger than three years. At the time could still be used across all weight bands but had it was included in the guidelines, a fixed-dose a far lower pill burden (Table 8.2).
Table 8.2. Dosing of ABC + 3TC 60 mg/30 mg for weight bands for children
Weight band (kg) Daily dosing of ABC + 3TC Daily dosing of ABC + 3TC 60 mg/30 mg 120 mg/60 mg scored
3–5.9 2 1 6–9.9 3 1.5 10–13.9 4 2 14–19.9 5 2.5 20–24.9 6 3 25–34.9 1 adult tablet (600 mg/300 mg) 1 adult tablet (600 mg/300 mg)
Source: Consolidated guidelines on the use of antiretroviral drugs for treating and prevention HIV infection. Recommendations for a public health approach – second edition (10).
144 The United States Food and Drug Administration programmes expressed interest, it was not until tentatively approved the new ABC + 3TC a country with a high burden of HIV infection 120 mg/60 mg tablet in October 2014 (11) placed a large order for the product that and subsequently added it to the 2015 optimal ABC + 3TC 120 mg/60 mg was commercialized. paediatric ARV formulary (7). However, Since then, uptake has been rapid, with the despite the increased uptake of ABC + 3TC- forecast for ABC + 3TC 120 mg/60 mg now containing regimens for children, the first outstripping that for 60 mg/30 mg (12). order for ABC + 3TC 120 mg/60 mg was not placed until October 2016, two years after The example of ABC + 3TC 120 mg/60 mg approval. Several factors contributed to the demonstrates that, even when a more optimal delay between stringent regulatory approval dosage form that is in high demand is developed and commercialization, including issues related and receives approval by a stringent regulatory to national registration and country concerns authority, additional steps are needed to about supply security, since the product was ensure successful commercialization and only initially available from a single supplier. uptake. This includes consideration for national drug registration, ensuring communication of In addition, the availability of the product may not availability of the product to buyers and inclusion have been communicated to programmes in time in procurement plans. to be included in procurement plans. Although
SUMMARY
Significant strides have been made in consolidating A high level of coordination is already occurring and stabilizing the ARV drug market for children between various stakeholders across the upstream through such efforts as those of the ARV and downstream components of new product Procurement Working Group. Careful procurement introduction through various initiatives such as planning and clear communication between the Unitaid-funded Paediatric HIV Treatment procurers, national programmes and suppliers can Initiative and the Global Accelerator for Paediatric ease the launch of a new formulation for children. Formulations (13).
KEY CONSIDERATIONS
■■ National programmes should rationalize their ■■ Suppliers should have a proactive and formularies to the most optimal formulations as transparent production capacity scale-up plan much as possible while proactively transitioning before filing their dossier to be able to react children to WHO-recommended and age- quickly to demand. appropriate regimens and formulations.
■■ Global partners should collaborate to ensure that clear and consistent messages about new products are being sent to national programmes and suppliers.
145 ACKNOWLEDGEMENTS
Authors: Nandita Sugandhi1, Fernando Pascual2 and Vineet Prabhu3
Other contributors: Diana F. Clarke4 and Atieno Ojoo5
Reviewers: Carolyn Amole6 and Victor Musiime7,8
1 ICAP at Columbia University, New York, NY, USA 2 Medicines Patent Pool, Geneva, Switzerland 3 Clinton Health Access Initiative, Boston, MA, USA 4 Boston Medical Center, MA, USA 5 UNICEF, Copenhagen, Denmark 6 Clinton Health Access Initiative, New York, NY, USA 7 Makerere University, Kampala, Uganda 8 Joint Clinical Research Centre, Kampala, Uganda
Generous support from Unitaid enables the work of the Clinton Health Access Initiative on optimal ARV drugs for children.
REFERENCES
1. Dongmo-Nguimfack B. Major ARV regimens Fund to Fight AIDS; Tuberculosis and Ma- used among adults and children and trends laria; 2016 (https://www.theglobalfund.org/ as impact of policies on ARV regimens since media/6492/psm_paediatricarvprocure- 2010–2017. Joint WHO/UNAIDS Annual mentworkinggroupcasestudy_report_en.pd- Consultation with Pharmaceutical Companies, f?u=636597505830000000, accessed 22 Partner Organizations and Stakeholders, May 2018). Geneva, Switzerland, April 2018. 5. Penazzato M, Lee J, Capparelli E, Essajee S, 2. A super-Fast Track framework for ending AIDS Ford N, Ojoo A et al. Optimizing drugs to in children, adolescents and young women by reach treatment targets for children and 2020. Geneva: UNAIDS; 2018 (https://free. adolescents living with HIV. J Int AIDS Soc. unaids.org, accessed 22 May 2018). 2015;18:20270.
3. Paediatric HIV/AIDS project. Paris: Unitaid; 6. Interagency Task Team on Prevention and 2015 (https://unitaid.eu/project/paediat- Treatment of HIV Infection in Pregnant ric-hiv-aids-project/#en, accessed 22 May Women, Mothers and Children. Update 2018). to the optimal list of paediatric ARV formulations. IATT meeting report. Geneva: 4. Antiretroviral Procurement Working Group. World Health Organization; 2013 (http:// 2016. Sustaining paediatric ARV supply apps.who.int/medicinedocs/en/m/abstract/ security with the PAPWG. Geneva: Global Js21435en, accessed 22 May 2018).
146 7. Interagency Task Team on Prevention and 2018 (https://www.theglobalfund.org/me- Treatment of HIV Infection in Pregnant dia/6589/psm_arvprocurementworkinggrou- Women, Mothers and Children. Update panticipateddemandforecast_table_en.pdf, to the optimal list of paediatric ARV accessed 22 May 2018). formulations. Geneva: World Health 13. New product introduction toolkit. Organization; 2015 (http://apps.who.int/ Washington (DC): Clinton Health Access medicinedocs/en/m/abstract/Js22094en, Initiative; 2017 (https://www.newhivdrugs. accessed 22 May 2018). org, accessed 22 May 2018). 8. Interagency Task Team on Prevention and Treatment of HIV Infection in Pregnant Women, Mothers and Children. 2016 IATT paediatric ARV formulary and limited-use list: 2016 update. Geneva: World Health Organ- ization; 2016 (http://apps.who.int/medicine- docs/documents/s23120en/s23120en.pdf, accessed 22 May 2018).
9. Prabhu VR, McGovern S, Domanico P. Estimating the size of the pediatric antiretroviral (ARV) market in 26 low- and middle-income countries (low- and middle-income countries) through 2025 as prevention of mother to child transmission (PMTCT) initiatives continue to succeed. 9th IAS Conference on HIV Science, 23–26 July 2017, Paris, France (Abstract WEAD0203; http://programme.ias2017.org/Abstract/ Abstract/2724, accessed 22 May 2018).
10. Consolidated guidelines on the use of antiretroviral drugs for treating and prevention HIV infection: recommendations for a public health approach. 2nd ed. Geneva: World Health Organization; 2016 (http://www.who.int/hiv/pub/arv/arv-2016/ en, accessed 22 May 2018).
11. Tentative approval for abacavir and lamvidine tablets for oral suspension, 120mg/60mg. Washington (DC): United States Department of Health and Human Services; 2014 (https:// www.accessdata.fda.gov/drugsatfda_docs/ appletter/2014/204915Orig1s000TAltr.pdf, accessed 22 May 2018).
12. ARV Procurement Working Group. Antic- ipated demand forecast. Geneva: Global Fund to Fight AIDS, Tuberculosis and Malaria;
147 MODULE 9: REGULATORY FILING
©ICAP
148 1. INTRODUCTION
Although the end result is almost always similar, (EMA). The centralized procedure foresees the approaches for new antiretroviral (ARV) drug a single marketing authorization application approvals and the development of ARV drugs for (marketing authorization application). The EMA children differ somewhat between the European is responsible for scientific review through its Union (EU) and the United States of America. Committee for Medicinal Products for Human This module describes the approval processes in Use. If the Committee comes to a positive the EU and United States and regulatory steps opinion following the assessment, the proposal toward approving drugs for children on a more to grant a marketing authorization for the expedited timeline. It also describes procedures concerned medicines is sent to the European specific to the product quality reviews Commission, which grants the marketing conducted by WHO. authorization for the EU as a whole.
In the United States, new drugs, including ARV Afterwards, the launch for individual European drugs, are approved after a new drug application national markets must be applied to the dossier is submitted and the United States Food corresponding national authorities. A central and Drug Administration (FDA) reviews it. The marketing authorization is automatically valid time frame for reviewing new drug applications in all 28 EU countries plus the three EEA-EFTA is established in United States law and allows countries (Iceland, Liechtenstein and Norway). for either “standard” or “priority” review. Each Applications for marketing authorization of new new drug application must contain sufficient ARV drugs must include the results of studies information to demonstrate that the drug is carried out as part of a paediatric investigation safe and effective when used as indicated and plan agreed by the EMA Paediatric Committee to describe the processes for manufacture, and or information on a paediatric investigation plan each must contain either a paediatric assessment deferral or waiver. ARV drugs authorized across or a request for deferring or waiving the the EU based on the results of studies complying requirement for studies involving children. with a completed paediatric investigation plan are eligible for an extension of their supplementary The paediatric assessment summarizes the basis protection certificate by six months. for evaluating the drug among children of all ages and any clinical data on children submitted Through specific laws, both the FDA and the in the new drug application; a waiver or deferral EMA require pharmaceutical innovators to study of studies involving children may be requested drugs among children whenever a new drug is if these studies have not been completed at the likely to be needed for children. As part of this time the new drug application is filed. Of note, requirement, innovators are required to submit the United States laws and regulations relevant a paediatric study plan to the FDA (1) and a to developing drugs for children refer to age paediatric investigation plan to the EMA (2–4). groups and not weight bands. The EMA requires submission of the paediatric investigation plan at the end of Phase I drug In Europe, new ARV drugs placed on the market development (after initial dose finding and have to be authorized according to centralized safety); the FDA mandates submission of the marketing authorization procedure, for which paediatric study plan at the end of Phase II manufacturers submit the dossier with the drug development (after preliminary evidence evaluation of quality, safety and efficacy of of efficacy). the drug to the European Medicines Agency
149 Both paediatric investigation plans and paediatric EMA and FDA will lead to the same conclusions study plans must provide a summary of the or that it will lead to similar labelling of the drug. nonclinical and clinical evidence available to support the study of the drug among children, Regulatory approval of novel formulations of an outline of the proposed studies among approved drugs (without a reference product), children, including the expected population (such especially fixed-dose combination products as the ages and weights to be studied and key specifically intended for use in low- and middle- enrolment criteria), a rationale for any request to income countries, was previously outside the scope waive studies in specific subgroups and a timeline of stringent regulatory authorities. To address this for completing the proposed studies. gap, the WHO Prequalification Programme was formed in 2001 to assess the quality of products Despite submitting these plans for developing and inspect manufacturing plants for HIV drugs drugs for children, studies involving children may in low- and middle-income countries. The WHO take up to 8–10 years to complete after the drug Prequalification Programme has subsequently has been approved for adults. These regulatory expanded their assessments; they not only assess processes apply to all drugs, and extended lag a range of finished pharmaceutical products in times are not unique to ARV drugs but can be several therapeutic areas but also assess active identified in many programmes for developing pharmaceutical ingredients and quality control drugs for children. Expediting the regulatory laboratories. It also provides technical assistance processes could improve access to products and conducts extensive training activities. for children for other diseases of public health importance such as tuberculosis (TB), malaria In 2006, as part of the United States President’s and viral hepatitis. Emergency Plan for AIDS Relief (PEPFAR), the FDA described a regulatory path to To address the lag in approvals of drugs for receive tentative approval specifically for ARV children, collaboration between the FDA and products intended for use in low- and middle- EMA, with the participation of Health Canada, income countries while maintaining patent Japan’s Pharmaceuticals and Medical Devices protection within the United States (6). This Agency and Australia’s Department of Health, was process followed the review model used by established to help support global development the FDA Office of Generic Drugs but added in plans for medicinal products for children and to components of the 505(b)2 new drug application exchange information on applications and topics process of the FDA Office of New Drugs for related to development. These regular meetings novel products that relies on information owned by phone or videoconference among regulators by other sponsors, previously reviewed by the in clusters or areas of cooperation focus on FDA or in the public domain (Table 9.1). special topics, such as developing medicinal New products for which there is a marketed products for children (5). reference product use the standard generic These meetings can result in issuing a non- drug abbreviated new drug application filing binding common commentary to inform the and review process (such as a generic Truvada, sponsor of the discussion of their product at emtricitabine + tenofovir disoproxil fumarate the meeting. The cluster teleconferences can tablet) through the FDA Office of Generic be used to align the requirements in paediatric Drugs. New products for which no reference investigation plans and paediatric study plans listed product exists (such as lamivudine + and in overall paediatric development plans. tenofovir disoproxil fumarate) are submitted to However, they do not guarantee, even if an early the FDA Division of Antiviral Products of the dialogue between regulators is established, that Office of New Drugs for review. Should there the assessment of the same set of data by the be questions regarding a product’s dossier or
150 the appropriate filing approach, the Division of with analysis and information to support their Antiviral Products offers pre-submission advice own registration decisions rather than making through an active programme available before this decision for them. filing an investigational new drug application (the pre-investigational new drug programme) (7,8). Under Article 58, the Committee for Medicinal Products for Human Use conducts a regulatory The PEPFAR review team has committed to review that is identical in all aspects to standard completing their reviews on a priority review EMA regulatory review and requires submitting schedule for the first three manufacturers for a full regulatory dossier. Article 58 enables each PEPFAR product, but successful review participation by WHO experts and the national depends on the FDA receiving a complete regulatory authorities of target countries in application at the time of submission and the the review process. This includes advice on manufacturers passing the required inspections. the risk and benefit in low- and middle-income Products approved or tentatively approved by the countries and on whether the drug is needed FDA are co-listed on the WHO Prequalification and appropriate for these settings. Importantly, Programme product list but may not be eligible the Article 58 process does not culminate in for the Collaborative Registration Procedure. regulatory approval but in the scientific opinion by the Committee for Medicinal Products for The EMA, in collaboration with WHO, can give an Human Use on the product. Article 58 has the opinion to manufacturers for products intended strength to offer a superior standard to most for non-EU markets through the mechanism regulatory alternatives in low- and middle- of EUM4All (Article 58 of Regulation (EC) income countries since it not only provides a No. 726/2004 procedure) (9). The European regulatory assessment at the same level afforded Commission established the Article 58 to any product for use in the EU but also mechanism in 2004 to facilitate registration by incorporates an informed assessment of risk and low- and middle-income countries of medicines benefit from experts in endemic countries. to prevent or treat diseases of major public health interest, including neglected infectious Nevertheless, alternative pathways and incentives diseases, such as HIV infection. This procedure have been developed, and some core barriers was intended to assist regulators in low- and remain to Article 58 realizing its full potential. middle-income countries by providing a Manufacturers are unclear about or unconvinced scientific assessment of a dossier for a medicinal of its benefits and are reluctant to use it because product for use outside the EU. This assessment successful precedents are lacking. The fees are is intended to provide national regulatory considered burdensome or prohibitive (especially authorities in low- and middle-income countries the annual maintenance fees).
Table 9.1. Recognized FDA regulatory pathways
FDA pathway Filings acceptable for using the pathway Typical sponsor of the filing New drug application New molecular entities Innovators New drug application New formulations, fixed-dose combinations and Innovators and generics 505(b)2 new product strengths under PEPFAR Abbreviated new drug Generic drugs Generics application Pre-investigational new First in human studies, new clinical or modelling data Innovators, generics, third drug or investigational to support additional dosage forms or strengths party for ease of reference new drug
151 Many national regulatory authorities are unaware consumes scarce regulatory resources but also of Article 58 or consider it a lower-grade review, extends the time needed to make them available. since it does not confer EU marketing approval. Poor coordination between the EMA and WHO, WHO has therefore designed a collaborative both in terms of general logistics and the procedure that enables national regulatory management of variation and pharmacovigilance, authorities to use work already carried out by limits the potential impact of their collaboration WHO and to strengthen their own regulatory for both national regulatory authorities and oversight processes, in accordance with manufacturers. international best practices. Of greatest interest to manufacturers is that application of In addition, since the FDA PEPFAR route typically the procedure enables faster registration. The confers some procurement eligibility using donor Collaborative Registration Procedure is open funds, manufacturers more commonly use the to national regulatory authorities in all WHO FDA route. Products that have been positively Member States and holders of prequalified assessed through the Article 58 procedure finished pharmaceutical products, on a voluntary are co-listed on the WHO Prequalification basis, and its principles are a model for other Programme product list. Manufacturers can regulatory collaborative initiatives. also request participation in the Collaborative Registration Procedure based on the EMA or In addition to the Collaborative Registration WHO Prequalification Programme reviews. Procedure, WHO has implemented a collaborative registration pilot for medicines Only 10 product applications have completed approved by a stringent regulatory authority. This the Article 58 process since 2004, all from pilot was initiated in 2012 as an extension of the multinational pharmaceutical companies. Three of WHO Collaborative Registration Procedure and these were label extensions or new formulations aims at facilitating the registration of essential of existing HIV drugs: Aluvia® (lopinavir/ medicines approved by a stringent regulatory ritonavir) has a public assessment report, whereas authority in countries that may have limited Lamivudine ViiV® (lamivudine) and Lamivudine/ regulatory resources. Since November 2014, Zidovudine ViiV® (lamivudine + zidovudine) were the EMA has participated in developing and withdrawn (10). implementing the pilot (five products related to HIV, TB and malaria), resulting in more rapid WHO has implemented a Collaborative approval by national regulatory authorities in Registration Procedure: a collaborative procedure participating countries. between the WHO Prequalification of Medicines Programme and national medicines regulatory In this context, EMA’s scientific assessment authorities in the assessment and accelerated reports are shared with regulators in other national registration of WHO-prequalified countries by companies holding EU marketing pharmaceutical products (11). This addresses the authorizations that want to market their products issues of significant delays in national registration in these countries. Unfortunately, the FDA does in low- and middle-income countries. Finished not yet have a corresponding review-sharing pharmaceutical products reviewed by the mechanism and does not participate in the WHO Prequalification Programme team have Collaborative Registration Procedure, although been evaluated and inspected according to efforts are underway to determine whether international standards. However, the national there may be a viable pathway for data sharing. regulatory authorities of the countries for which WHO Prequalification is not required to use market entry is sought must still approve them the stringent regulatory authority Collaborative for use. Repeating assessment and inspection of Registration Procedure route for filing. these finished pharmaceutical products not only
152 For in-country registration in low- and middle- Applying for a registration waiver for new income countries through national regulatory products of public health interest is therefore authorities, each manufacturer must submit a common practice. Nevertheless, applying dossier and any associated fees for each country for and obtaining a waiver is a short-term in which they would like to register for marketing solution to access to medicines and, ultimately, approval. Although some of the pathways manufacturers must obtain registration in all (primarily the WHO Collaborative Registration countries in which they intend to market. More Procedure) are designed to allow manufacturers information on the waiver process is available to obtain more rapid registration in multiple (12). It is beyond the scope of this document to countries at the same time, not all countries describe the regulatory procedures of all national participate in these processes. regulatory authorities approving ARV drugs.
2. CHALLENGES
The regulatory reasons drug developers most a lag in developing and approving generic ARV often cite for delay in approving initial (innovator) products, including fixed-dose combinations, for drugs for children include: use in low- and middle-income countries include:
■■ lack of alignment of requirements in paediatric ■■ uncertainty regarding what specific products investigation plans and paediatric study plans; are most needed or desired in the market (and
■■ different processes and processes perceived for fixed-dose combinations in what ratios); to be cumbersome to revise paediatric ■■ uncertainty about converting age- or weight- investigation plans and paediatric study plans; based dosing approved in markets with stringent
■■ difficulties in designing and conducting clinical regulatory authorities to the simplified public trials across the age range of children (see the health approach of weight-band dosing module on trial design); endorsed by WHO (13); ■■ ■■ difficulties in developing suitable age- unwillingness to pay recurring regulatory fees; appropriate formulations for younger children and (see the module on acceptability); and ■■ concern regarding the small size and relative
■■ the desire of drug developers for additional instability of the commercial market for drugs safety data in adults before initiating trials for children. involving children. For both innovators and generic suppliers, After the first few ARV drug approvals in the changes in the knowledge base leading to 1990s, clinical trials involving children have changes in product labelling post-marketing can begun well after the clinical trials involving adults slow the development of ARV drugs for children and have progressed stepwise from older to since the new information must be incorporated younger children, a process that is often unduly into studies involving children or labelling of the conservative and time-consuming. drugs, often as these studies are in progress. In addition, the FDA has noted significant Following initial approval of an ARV drug for deficiencies in many dossiers submitted to the children, the reasons most often expressed for PEPFAR review programme.
153 3. SOLUTIONS
Regulators and other stakeholders have already of extensive product review and prioritization. begun working together to identify solutions to The priority ARV drug recommendations of the long timeline typical of most programmes the Paediatric Antiretroviral Drug Optimization for developing drugs for children. The FDA, group might need to be provided earlier in drug EMA and other stringent regulatory authorities development if the goal is to influence EMA have undertaken a series of regular conference Paediatric Committee and FDA decisions, since calls to discuss and reduce differences in the the agencies review products at a very early requirements for studies involving children. The stage in development. In addition, further staging stated goal of these calls is to bring programmes to identify which of the priority ARV drugs are for developing drugs for children reviewed by the most critical might allow better coordination stringent regulatory authorities into alignment with generic suppliers. so that a company can focus on a unified global programme of drugs for children. 3.2 Earlier development of formulations The following considerations are expected to expedite the development of drugs for children, As soon as Phase II trials involving adults and many have been accepted in principle by demonstrate evidence of effectiveness and a stringent regulatory authorities (14,15). decision is made to proceed to Phase III trials, development of an age-appropriate formulation 3.1 Giving priority to products for children should be initiated. Early discussions about the paediatric investigation plan and paediatric study plan between sponsors, regulators and In both the United States and the EU, the other stakeholders should include discussion of obligation to develop a product that is expected formulation needs in low- and middle-income to be safe and effective for children can only be countries. waived if there is lack of significant benefit over an existing (authorized) product or if good-faith attempts at developing a formulation have failed 3.3 Simplifying paediatric investigation and not because a potentially better product plans and paediatric study plans exists in the developmental pipeline. However, the development of drugs for children may be Both the EMA and FDA agree that paediatric deferred for a period of years and can be waived investigation plans and paediatric study plans at a later time if public health needs change. written early in the product life cycle should be If the stringent regulatory authorities adopted concise and contain less of the technical detail recommendations of an external priority-setting the agencies already know. When applicable, process that addressed the public health needs toxicology data and safety and efficacy data for of children, it could help shorten the timelines of adults that are already filed could be incorporated development for priority ARV drugs, especially via references or briefly summarized. However, fixed-dose combinations, and minimize resources when the paediatric investigation plan is spent on products that do not meet a public submitted early in development, few clinical health need. data may be available and the description of The Paediatric Antiretroviral Drug Optimization nonclinical data may become more important. group convened by WHO provides this kind Descriptions of proposed clinical trials could be
154 very limited, with caveats that the final study Saharan African countries for children younger design and the doses to be studied will be agreed than 18 years. on when adequate information is available. The applicant can always request to modify Simultaneously enrolling all age and weight the paediatric investigation plan and paediatric cohorts of children instead of sequentially study plan and the studies included. Using an enrolling older then younger children agreed protocol template (a master protocol) could assure all parties that clinical trials would Regulatory agencies have agreed, in principle, meet regulatory requirements and public health with the proposal to enrol age groups of children needs. Keeping the paediatric investigation plan simultaneously, but the rate-limiting step is and paediatric study plan concise would allow usually formulation development for younger more flexibility for innovators to incorporate children who cannot swallow tablets. Acceptance new information, as needed, since previously of this proposal assumes there are no safety included details would not become outdated as a concerns that might affect the willingness to programme progressed. administer the drug to infants and other children.
Using standardized weight bands for dosing in 3.4 Streamlining clinical trials involving clinical trials involving children corresponding children to WHO recommendations for ARV drug dosing for children Stringent regulatory authorities are moving Stringent regulatory authorities have agreed in toward alignment in areas that will improve the principle to this proposal if there are adequate efficiency of clinical trials involving children (see data to support dosing in all age and weight the module on trial design). groups. Using standardized weight bands in the original trials involving children precludes Simultaneously developing products for adults the need for retrofitting pharmacokinetic data and adolescents collected in other cohorts or for additional The inclusion of adolescents in trials involving studies to validate WHO dose recommendations adults is considered acceptable, since adolescents that might differ from approved labelling. In generally use the formulation and dose for adults 2015, the EMA convened a meeting to discuss and no major differences in safety and efficacy ways to expedite the development of fixed-dose are generally expected between adults and combination drugs for children and endorsed the adolescents. Separate but concurrently conducted use of WHO weight bands as part of the solution. studies involving adults and adolescents may be In many cases, national regulatory authorities more practical and still provide the necessary in low- and middle-income countries have data to include adolescents in the initial marketing embraced this type of dosing, since it is easier authorization for adults. for health-care providers to implement in busy clinics than individualized dosing. However, not all national regulatory authorities agree with this approach, and the approval of some Maximizing the use of all available pharmacokinetic ARV drugs for adolescents has lagged behind data collected through modelling and simulation approval for adults in Africa even as concurrent approvals by stringent regulatory authorities have Innovator sponsors can use pharmacokinetic data become more common. For example, the FDA for adults and their knowledge of physiological approved dolutegravir (Tivicay®, ViiV Healthcare) changes among infants and other children to for both adults and adolescents (weighing >40 kg) perform modelling to select initial doses for study in 2013 but has not yet approved it in some sub- in younger and smaller children. Similar exercises
155 can be performed to convert age-based dosing 3.5 Waiving regulatory fees to weight-band dosing, if necessary. Both industry and paediatric stakeholders such as the Paediatric There are specific circumstances in which an Antiretroviral Working Group can use modelling innovator sponsor may request a user fee waiver and simulation to predict the optimal ratio of when submitting a new drug application to the component drugs in fixed-dose combinations for FDA. However, these conditions are unlikely to children. The 2015 EMA meeting on fixed-dose apply to the innovator sponsors who develop combinations for children also endorsed the use new ARV drugs. In contrast, the PEPFAR review of modelling and simulation to support the dosing process allows generic suppliers to apply for a recommendations submitted to the EMA (see the user fee waiver, and these are frequently granted. module on pharmacokinetic modelling). An FDA guidance document (16) outlines the In some cases, post-approval modelling to criteria for eligibility and the request process. As support a novel fixed-dose combination for of its most recent reauthorization, the FDA no children can be submitted to the FDA for longer charges a fee for submitting supplements review and agreement through the Division of to an already approved new drug application (a Antiviral Products pre-investigational new drug supplemental new drug application). Data on programme (7,8). This programme was originally children submitted for an approved new drug developed to provide advice to pharmaceutical application would therefore incur no user fee. sponsors during early drug development but can Drug developers may request scientific advice also be used by nongovernmental organizations from the EMA Committee for Medicinal Products or academic groups seeking regulatory advice. for Human Use on the appropriate tests and For example, pharmacokinetic modelling studies for developing a medicine. This advice will to support proposed dosing for an be free of charge for questions related to children. abacavir + lamivudine + efavirenz fixed-dose Applicants may choose to request scientific advice combination for children was provided to the first to help in preparing a paediatric investigation FDA pre-investigational new drug programme plan or may submit a paediatric investigation plan after collaborative work among paediatric first and follow it up with a request for scientific stakeholders led by the Medicines Patent advice on specific questions, for example, Pool to ask the FDA whether this modelling combined development of formulations for adults could be used to support a future paediatric and for children given the requirements of the application. The Paediatric Antiretroviral Working paediatric investigation plan. Group used innovator pharmacokinetic data The Article 58 process through the EMA also has to evaluate different component doses for the fees associated with it, and this has been noted as abacavir + lamivudine + efavirenz fixed-dose a barrier to using this route for filing. The process is combination for children given priority by the perceived to have high costs (up front and annual) Paediatric Antiretroviral Drug Optimization group. that can be prohibitive for small manufacturers, The FDA provided a preliminary assessment of and the possibility and criteria for fee waivers the dosing and modelling and indicated that this are largely unknown to manufacturers. The EMA would be an acceptable approach to justify the has recently clarified these issues and created dosing for the abacavir + lamivudine + efavirenz a range of regulatory tools to support applicants in fixed-dose combination. FDA acceptance developing and submitting applications (17). will allow multiple generic suppliers to use the modelling provided by the Medicines In 2013, WHO implemented a user fee structure Patent Pool to support registration of an to balance external and internal funding for the abacavir + lamivudine + efavirenz product WHO Prequalification Programme (18). In 2017, for children. the fee structure changed, and the fee for an
156 initial application was increased substantially Additional recommendations to improve the (19). There are, however, options to apply for quality of dossiers submitted to the FDA’s and receive a waiver based on specific products PEPFAR review programme include: and product categories in the WHO guidance ■■ ensuring that adequate stability data are document annex (20). Pharmaceutical products included with the application, including stability formulated specifically for children are listed as a data collected at 30°C and 75% relative product category for which a manufacturer may humidity to enable worldwide distribution; apply for a waiver. To receive information on the ■■ ensuring that tablet size and scoring correspond waiver process, manufacturers should contact to approved dose recommendations; the Prequalification Programme team for advice. ■■ ensuring that an approved reference listed drug is used for bioavailability and 3.6 Submission of complete dossiers with bioequivalence studies; appropriate cross-references ■■ responding to any questions from the FDA promptly and completely; and For generic suppliers submitting dossiers ■■ to obtain pre-submission guidance for PEPFAR for PEPFAR programme review that rely on original new drug applications, use the Division information in the public domain or previously of Antiviral Products’ pre-investigational new reviewed by FDA, appropriately referencing drug consultation programme; the programme that information is critical to a timely review. is useful to discuss specific questions on Abbreviated new drug applications and 505(b) product quality. (2) new drug applications must reference the nonclinical and clinical development programme of relevant innovator products. Labelling must match that of the referenced innovator products. In addition, if proposed dosing for children differs from the original approved dosing, the submission must include justification for that dosing.
For example, if the proposed dose leads to higher or lower exposure, rationale and supportive data or a summary must be included outlining why the lower (or higher) exposure would not compromise safety or efficacy. Such justification can include copies of or electronic links to WHO treatment guidelines, pharmacokinetic modelling (as mentioned above), the Paediatric Antiretroviral Drug Optimization group or Paediatric Antiretroviral Working Group reference documents and priority lists and any other relevant clinical information (such as publications, letters of reference to submitted data, etc.).
157 4. SUMMARY
In summary, attempts to coordinate innovator steps that should expedite the development companies’ required drug development and of products for children with the greatest studies related to children into unified, globally potential for public health benefits. Continued relevant programmes are underway. Regulators collaboration among innovators, regulators, are committed to improving communication generic suppliers, and other stakeholders is and harmonization. Paediatric stakeholders necessary to eliminate the current delays in the and representatives of stringent regulatory availability of ARV drugs for children. authorities have agreed in principle to many
5. KEY CONSIDERATIONS
■■ Programmes for developing drugs for children ■■ Manufacturers should enquire as to whether should focus on priority products most likely to products might be eligible for a fee waiver or be useful in low- and middle-income countries. reduction.
■■ The development of formulations for children ■■ For PEPFAR products (especially novel fixed- should begin early in the product life cycle. dose combinations), all information necessary
■■ Clinical trials involving children should be to justify proposed dosing for children should streamlined, and modelling and simulation be provided, and manufacturers should should be used to identify initial dosing. ensure that chemistry, manufacturing and control information is complete at the time ■■ When doubt arises regarding paediatric of submission. investigation plans and paediatric study plans, alignment and advice should be sought from regulatory authorities (the FDA and the EMA).
©Deidre Schoo
158 6. ACKNOWLEDGEMENTS
Authors: Linda Lewis1, Melynda Watkins1 and Francesca Rocchi2,3
Reviewers: Yodit Belew4, Andrea Ecker5 and Victor Musiime6,7
1 Clinton Health Access Initiative, Boston, Massachusetts, MA, USA 2 Bambino Gesù Children Hospital, Rome, Italy 3 PENTA Foundation, Padua, Italy 4 United States Food and Drug Administration, Washington, DC, USA 5 European Medicines Agency, London, United Kingdom 6 Makerere University, Kampala, Uganda 7 Joint Clinical Research Centre, Kampala, Uganda
Comments were also provided by the Division of Paediatric Committee, are their own and may not Antiviral Products of the United States Food and be understood or quoted as being made on behalf Drug Administration and by representatives of of or reflecting the position of the United States the European Medicines Agency and members Food and Drug Administration or of the European of the European Medicines Agency Paediatric Medicines Agency or any of its committees or Committee. Any views expressed in this publication working parties. by employees of the United States Food and Drug Administration or the European Medicines Agency, Generous support from Unitaid enables the or members of the European Medicines Agency work of the Clinton Health Access Initiative on optimal ARV drugs for children.
7. REFERENCES
1. Draft guidance for industry: pediatric study (EC) No 726/2004. Brussels: European plans: content of and process for submitting Commission; 2006 (https://ec.europa.eu/ initial pediatric study plans and amended health//sites/health/files/files/eudralex/vol- initial pediatric study plans: guidance for 1/reg_2006_1901/reg_2006_1901_en.pdf, industry. Washington (DC): United States accessed 22 May 2018). Food and Drug Administration; 2016 (https:// 3. Regulation (EC) No 1902/2006 of the www.fda.gov/ucm/groups/fdagov-public/@ European Parliament and of the Council of fda.gov-drugs-gen/documents/document/ 20 December 2006 amending Regulation ucm360507.pdf, accessed 22 May 2018). 1901/2006 on medicinal products for 2. Regulation (EC) No 1901/2006 of the paediatric use. Brussels: European European Parliament and of the Council of Commission; 2006 (https://ec.europa.eu/ 12 December 2006 on medicinal products health//sites/health/files/files/eudralex/vol-1/ for paediatric use and amending Regulation reg_2006_1902/reg_2006_1902_en.pdf, (EEC) No 1768/92, Directive 2001/20/ accessed 22 May 2018). EC, Directive 2001/83/EC and Regulation
159 4. Information from European Union HowDrugsareDevelopedandApproved/ institutions, bodies, offices and agencies. ApprovalApplications/ Guideline on the format and content of InvestigationalNewDrugInew drug applications for agreement or modification applicationpplication/Overview/ucm077776. of a paediatric investigation plan and htm, accessed 22 May 2018). requests for waivers or deferrals and 9. Article 58 applications: regulatory concerning the operation of the compliance and procedural guidance. London: check and on criteria for assessing significant European Medicines Agency; 2016 studies. Brussels: European Commission; (http://www.ema.europa.eu/ema/index. 2014 (https://ec.europa.eu/health//sites/ jsp?curl=pages/regulation/document_ health/files/files/eudralex/vol-1/2014_ listing/document_listing_000157. c338_01/2014_c338_01_en.pdf, accessed 22 jsp&mid=WC0b01ac05800240d1, accessed May 2018). 22 May 2018). 5. Principles of interactions: between EMEA and FDA pediatric therapeutics. 10. Opinions on medicines for use outside London: European Medicines Agency; the European Union. London: European 2007 (http://www.ema.europa.eu/docs/ Medicines Agency; 2016 (http://www.ema. en_GB/document_library/Other/2009/12/ europa.eu/ema/index.jsp?curl=pages/ WC500017969.pdf, accessed 22 May 2018). regulation/general/general_content_000312. jsp&mid=WC0b01ac058001d12c, accessed 6. Guidance for industry: fixed dose 22 May 2018). combinations, co-packaged drug products, 11. Accelerated registration of prequalified and single-entity versions of previously finished pharmaceutical products. Geneva: approved antiretrovirals for the treatment World Health Organization; 2016 (https:// of HIV. Washington (DC): United States extranet.who.int/prequal/content/ Food and Drug Administration; 2006 collaborative-registration-faster-registration, (https://www.fda.gov/downloads/Drugs/ accessed 22 May 2018). GuidanceComplianceRegulatoryInformation/ Guidances/UCM079742.pdf, accessed 22 12. HIV new product introduction toolkit: May 2018). registration. Washington (DC): Clinton 7. Getting started with the division of Health Access Initiative; 2017 (https://www. antiviral products pre-investigational new newhivdrugs.org/registration, accessed 22 drug process. Washington (DC): United May 2018). States Food and Drug Administration; 13. WHO generic tool for assessing paediatric 2017 (https://www.fda.gov/Drugs/ ARV dosing. Geneva: World Health DevelopmentApprovalProcess/ Organization; 2018 (http://www.who.int/hiv/ HowDrugsareDevelopedandApproved/ paediatric/generictool/en, accessed 22 May ApprovalApplications/ 2018). InvestigationalNewDrugInew drug applicationpplication/Overview/ucm077546. 14. Draft guidance for industry: pediatric HIV htm, accessed 22 May 2018). infection: drug development for treatment. Washington (DC): United States Food and 8. Division of Anti-Viral Products’ (DAVP) pre- Drug Administration; 2018 (https://www. investigational new drug letter of instruction. fda.gov/ucm/groups/fdagov-public/@ Washington (DC): United States Food and fdagov-drugs-gen/documents/document/ Drug Administration; 2016 (https://www.fda. ucm607416.pdf, accessed 22 May 2018). gov/Drugs/DevelopmentApprovalProcess
160 15. Guideline on the clinical development of medicinal products for the treatment of HIV infection. London: European Medicines Agency; 2016 (http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_ guideline/2016/07/WC500209918.pdf, accessed 22 May 2018).
16. Guidance for industry: prescription drug user fee act waivers for fixed combination antiretroviral drugs for the President’s Emergency Plan for AIDS Relief. Washington (DC): United States Food and Drug Administration; 2018 (https://www.fda.gov/ ucm/groups/fdagov-public/@fdagov-drugs- gen/documents/document/ucm610019.pdf, accessed 22 May 2018).
17. Support for applications on Article 58. London: European Medicines Agency; 2017 (http://www.ema.europa.eu/docs/ en_GB/document_library/Regulatory_ and_procedural_guideline/2017/02/ WC500221119.pdf, accessed 22 May 2018).
18. WHO Prequalification of Medicines Programme – application fees. Geneva: World Health Organization; 2016 (http:// apps.who.int/medicinedocs/documents/ s20307en/s20307en.pdf, accessed 22 May 2018).
19. WHO/PQT Guidance Document. WHO prequalification fees. Geneva: World Health Organization; 2016 (https://extranet.who.int/ prequal/sites/default/files/documents/PQ_ Fees_092017_1.pdf, accessed 22 May 2018).
20. Annex to WHO prequalification fees. Geneva: World Health Organization; 2016 (http://apps.who.int/medicinedocs/ documents/s20307en/s20307en.pdf, accessed 22 May 2018).
161 MODULE 10: PHARMACOVIGILANCE
©WHO/Petterik Wiggersn
162 1. INTRODUCTION
This section introduces the concepts of The global system of pharmacovigilance was first pharmacovigilance and adverse drug reactions, developed following the thalidomide tragedy in the discusses the burden of adverse drug reactions 1960s, where thalidomide was used to treat nausea for children and explains the importance of in pregnancy, resulting in serious teratogenic pharmacovigilance in the context of antiretroviral events among infants exposed in utero (6). Ideally, therapy (ART). pharmacovigilance systems take a life-cycle approach, focusing not only on the properties of the prescribed medicine but also on how it is 1.1 Defining pharmacovigilance formulated, dispensed and administered (7,8). This approach is a continuum throughout the process WHO defines pharmacovigilance as the “science of drug development, from initial research and and activities related to the detection, assessment, development activities to final consumer use and is understanding and prevention of adverse effects commonly divided into two stages (Fig. 10.1): or any other possible drug-related problem” ■■ pre-marketing surveillance: adverse drug (1). It focuses on investigating and monitoring reactions from preclinical screening and adverse drug reactions after medicinal products Phase I, II and III clinical trials; and are licensed (2). Adverse drug reactions are a response that is noxious and unintended and that ■■ post-marketing surveillance: adverse drug occurs at doses normally used in humans for the reactions from the post-approval stage and prophylaxis, diagnosis or therapy of disease or for throughout a drug’s market life. modifying physiological function (2). They may vary Pre-marketing safety assessment is generally in presentation and occurrence and are commonly limited for children. This commonly results from divided into type A (augmented pharmaceutical few children enrolled in paediatric clinical trials response) and type B (bizarre or hypersensitivity) and/or the long latency between exposure to the adverse drug reactions (3). medicinal product and the onset of the reaction, An example of a type A reaction in relation to and less common adverse reactions may therefore antiretroviral (ARV) drugs for treating HIV is the not be detectable during this phase. The amount of negative effect of tenofovir on bone mineral dedicated information on the safety of medicines density, which may increase fracture risk (4). An for neonates, children and adolescents at the example of a type B reaction is efavirenz-related time of marketing authorization is therefore very hypersensitivity in the form of a skin rash with limited, which poses even more reliance on proper systemic symptoms (5). pharmacovigilance in the post-marketing stage (9).
Fig. 10.1. Timeline of pharmacovigilance for a drug from development (pre-market) to post-marketing use
Pharmacovigilance life cycle: pre- and post-marketing
Pre-market research and development Post-market real world use
Regulatory Benefit–risk and risk Preclinical Clinical Clinical Clinical Pricing review and management activities: animal toxicity Phase I Phase II Phase III and access approval pharmacovigilance
163 The module on trial design covers issues children by regulatory agencies in recent years concerning efficacy and safety data from Phase has resulted in an increased number of trials I to III studies, including the implications of involving children. Following the Paediatric relatively short follow-up times in drug approval Regulation in Europe, the European Medicines trials and restricted entry criteria into trials. Agency (EMA) issued the Guideline on the Conduct of Pharmacovigilance for Medicines Post-marketing pharmacovigilance can Used in the Paediatric Population, which was be conducted through passive and active recently updated (15). surveillance systems.
In passive surveillance, health-care professionals or patients send spontaneous reports describing 1.2 Burden of adverse drug reactions an adverse drug reaction after one or more among children and available studies medicinal products are administered to the marketing authorization holder or regulatory Age-specific pharmacovigilance is required authority. Sometimes such first case reports among children, since they differ from are published, which may stimulate subsequent adults because of ongoing neurobehavioural reporting. An example is the case report development and physical growth, including of efavirenz-induced gynaecomastia in a internal organ maturation (9). Further, different prepubertal girl with HIV, published in 2013 (10). maturation milestones are likely to alter the A case series is a series of such reported cases, susceptibility of children at different ages to and these can help to generate hypotheses specific adverse reactions and how they react about an association between drug exposure and to them, from (pre)term neonates to toddlers an outcome. An example is the case series of at one end of the spectrum to postpubertal gynaecomastia cases reported to the National adolescents at the other. HIV & Tuberculosis Health Care Worker Hotline Factors influencing the susceptibility of children in South Africa and published in 2016 (11). to adverse reactions for a given medicine include:
Active surveillance involves enhanced or ■■ changes in the maturation of organ targeted monitoring for certain events or drugs systems (such as skin, airways, kidney, liver, and seeks to ascertain completely the number gastrointestinal system, brain and blood-brain of adverse drug reactions through a pre-planned barrier as well as drug transporters) during process. Active surveillance is also commonly growth and their development (ontogeny) known as toxicity monitoring (such as the WHO leading to a different pharmacodynamic and ARV programme) or safety monitoring (12). pharmacokinetic profile of a medicine to what An example is a cohort study that evaluated is known in adults; the prescribing of, adherence to and adverse ■■ rapid changes in body mass and shape that drug reactions associated with ART in a large can reduce the therapeutic window, leading programme in Lagos, Nigeria (13). to increased susceptibility to dose-related Pharmacovigilance (passive or active) was not adverse drug reactions; specific to drugs for children until the beginning ■■ the immaturity of many organ systems that of the new millennium, when the Pediatric Rule might lead to different vulnerability to adverse (United States) and the Paediatric Regulation drug reactions in some subpopulations of (European Union) were implemented (14). children, such as preterm neonates; Aspects related to children are now integrated ■■ the presence of specific pharmaceutically early in the process of developing a new drug active excipients that may have unintended (pre-marketing). Stronger enforcement of effects for children (such as alcohol), leading requirements to obtain safety information for to a risk of adverse reactions; and
164 ■■ the impact of short- and long-term effects published over time, as Fig. 10.2 demonstrates. on the developing organs and organ systems, Rather concerning was the great disparity such as the nervous system, skeletal growth between the number of studies involving and sexual maturation; such effects may children compared with adults, as represented in only become obvious, visible or identifiable the right vertical axis of Fig. 10.2, showing about in the long term, with remarkable delay, in 25–30 published studies involving children adolescence or adulthood. versus about 3500 studies involving adults per year in recent years. The following section These considerations highlight the importance explores some of the challenges related to of taking into account aspects related to organ conducting pharmacoepidemiological studies maturation and developmental pharmacology involving children exposed to and living with HIV, when performing pharmacovigilance activities and this helps to understand the causes of the for children and imply that the value of low level of evidence for adverse drug reactions long-term follow-up should be considered among children. systematically (16). For children exposed to HIV and children living A recent meta-analysis of the incidence with HIV, ART provides enormous benefits, of adverse drug reactions in paediatric including dramatically reduced mortality risk, observational studies demonstrated that the improved growth, immune recovery and viral rates of all adverse drug reactions that resulted suppression and improved cognitive development in hospital admission ranged from 1% to 10% (20). However, similar to any drug, ARV drugs among children (pooled estimate 3%). For have been associated with adverse drug hospitalized children, these rates were higher, reactions. Short-term adverse drug reactions ranging from 1% to 17% among children exposed after initiating ART may include dizziness and (17). Anti-infective drugs (including to a drug gastrointestinal disorders as well as cognitive ARV drugs) and anticonvulsants were the and sleep disorders. Longer-term adverse drug most frequently reported therapeutic classes reactions associated with ARV drugs include associated with adverse drug reactions among changes in body fat distribution (lipodystrophy) hospitalized children. and negative effects on bone health(20) .
Although the evidence is limited, the burden of In some studies of ARV drugs, the rates of adverse drug reactions among children appears ART discontinuation have been higher in post- to be similar in high-income countries and low- marketing observational studies than in the (5). Besides the and middle-income countries clinical trials that led to regulatory approval. impact of adverse drug reactions on morbidity For example, for dolutegravir (DTG), about 10% and mortality and the associated direct costs of of adults in a large cohort study discontinued managing them, adverse drug reactions also have DTG during the first year of treatment versus other significant costs in terms of the loss of only 2–4% of adults in regulatory clinical trials confidence in the health system, financial losses (21). In addition, data on the efficacy of specific of the pharmaceutical industry, increased non- combinations of ARV drugs from Phase I to III adherence to treatment and the development of studies may be limited to specific populations (18). drug resistance to anti-infective drugs and/or have smaller sample sizes, limiting the Another systematic review focused on studies ability to evaluate adverse drug reactions. These quantifying the association between drug challenges highlight the ongoing need for long- exposure and adverse drug reactions among term pharmacovigilance of ART across different children and adolescents younger than 18 years populations of HIV-exposed children and (19). Surprisingly, only 268 relevant articles children living with HIV to ensure that the drugs were retrieved, with an increase in the number are safe and effective.
165 Fig. 10.2. Number of pharmacoepidemiological safety studies involving children
Drug and vaccine Vaccine Drug All pharmacoepidemiological safety studies in Embase and Medline, 1979-2013
35 4000
3500 30
3000 25
2500 20 2000
15 1500
10
pediatric pharmacoepidemiology) pediatric pharmacoepidemiology) 1000 Number of retained papers (pertaining to papers (pertaining retained of Number
5 500
0 0 and Medline in Embase indexed that were population) the general Total number of pharmacoepidemiological safety studies (pertaining to studies (pertaining safety pharmacoepidemiological of number Total
1991 2011 1979 1982 1985 1988 1993 1995 1997 1999 2001 2003 2005 2007 2009 2013
Year of publication
Source: Osokogu et al. (19). © 2016 The Authors. Pharmacoepidemiology and Drug Safety, published by John Wiley & Sons Ltd.
1.3 Importance of pharmacovigilance in two key public health programmes has resulted the era of expanded access to ART in substantial exposure of fetuses in utero and children to ARV drugs: initiatives to prevent the perinatal transmission of HIV and initiatives to Post-marketing pharmacovigilance is essential improve the survival of children with HIV. to monitor the longer-term safety of drugs, especially in specific populations and/or situations that are not normally included in Initiatives to prevent the perinatal transmission pre-marketing studies. Underlying this is the of HIV importance of appropriately collecting and Current WHO and national guidelines recommend reporting safety data to provide information that all pregnant women living with HIV receive for clinical decision-making. The expansion of lifelong ART to prevent the perinatal transmission
166 of HIV and to improve maternal health. Global well controlled studies of pregnant women have coverage of ART for preventing perinatal failed to demonstrate a risk to the fetus in the transmission and maternal HIV treatment is high, first trimester of pregnancy (and no evidence with UNAIDS estimating that coverage of ART exists of risk in later trimesters). This FDA among pregnant women living with HIV was 76% classification system has now been replaced in 2016 (22). Consequently, HIV transmission with more informative labelling to enable the rates are now less than 1% in many high-income health-care provider and patient to better countries and less than 5% in several low- and assess risk, although all ARV drugs classified middle-income countries (23,24), and estimates while the system was in use were category B or suggest that 2 million children avoided acquiring lower, demonstrating the moral duty to collect HIV infection globally from 2000 to 2015 because adequate safety data (28). of the roll-out of ART for pregnant women (25).
With the successful scale-up of maternal ART, an Initiatives to improve the survival of children estimated more than 1 million infants are exposed with HIV to ART in utero and/or in early life through short- Children living with HIV, who may or may not term prophylactic ART (26). Although ART is have been exposed to ART in utero and/or highly effective in reducing perinatal transmission, during breastfeeding, and who are prescribed and preventing children from become newly lifelong ART, need proper monitoring to assess infected is unquestionably beneficial, there is the short-term and longer-term effects of ART. also global recognition of the potential negative ARV drugs have greatly improved the survival of impact of exposure to ART during fetal and children living with HIV in high-income countries postpartum growth and development on the and low- and middle-income countries, even morbidity, mortality and developmental outcomes though coverage among children continued for millions of children (26,27). to lag behind that among adults, at 43% versus In addition, the roll-out and scaling up of ARV 53%, respectively, in 2016 (29). Children living drug pre-exposure prophylaxis to pregnant and with HIV are exposed to lifelong ART throughout breastfeeding HIV-negative women will result in critical developmental stages of childhood, ongoing exposure to these drugs among their including the metabolic and hormonal changes of offspring, in utero and during breastfeeding, puberty during adolescence. UNAIDS estimates further increasing the number of children that, in 2016, 2.1 million children younger than 15 years were living with HIV globally, and 160 000 exposed to ART globally. The current size of the children were newly infected, with projections HIV-uninfected population exposed to pre- suggesting that the number of children acquiring exposure prophylaxis is likely to be relatively small, HIV will only decline to 100 000 by 2020 (25). since in many countries pre-exposure prophylaxis is only available to key populations at higher risk such as men who have sex with men and sex workers but this population may be substantially larger in the future.
To sustain the uptake of these programmes and to reduce uncertainty around safety issues related to ARV drugs, post-marketing surveillance of pregnant women exposed to ART is of utmost importance. This is because no ARV drugs have been categorized as United States Food and Drug Administration (FDA) category A in pregnancy, indicating that adequate and
167 2. CHALLENGES
This section discusses the challenges of ■■ a national pharmacovigilance centre with conducting pharmacovigilance of ART among designated staff and at least one full-time staff children in low- and middle-income countries. member;
■■ the existence of a national spontaneous 2.1 General pharmacovigilance challenges adverse drug reaction reporting system, incorporating a national individual case safety report form (an adverse drug reaction This subsection describes the challenges relevant reporting form); to the safety of all medicine, and the next subsection describes those specific to ART. ■■ a national database or system for collating and managing adverse drug reaction reports; and
2.1.1 Regulatory challenges in low- and middle- ■■ a national pharmacovigilance advisory income countries committee to provide technical assistance on causality assessment, risk assessment and There have been significant advances in management, case investigation and crisis pharmacovigilance activities in recent decades, management, including crisis communication. and systems are considered well established in most high-income countries. Regulatory Fortunately, the number of low- and middle- developments have supported these advances, income countries conducting passive and the absolute number of paediatric safety surveillance and reporting to the WHO studies has increased since the introduction of Programme for International Drug Monitoring the Best Pharmaceuticals for Children Act in has steadily increased. For example, in a review the United States in 2002 and the Paediatric of pharmacovigilance systems in sub-Saharan Regulation in the European Union in 2007 (19). Africa, 72% of countries participated as an The implementation of pharmacovigilance in low- official or associate member of this Programme and middle-income countries, however, is highly (30). However despite a rise in the number of variable. Some countries have no systems at all, spontaneous adverse drug reaction reports from whereas a few have more established programmes low- and middle-income countries (7), very few that are comparable to those in high-income countries have reached the desired target of countries, such as South Africa (7). A review of 100 reports per million inhabitants. Reported the general pharmacovigilance systems of 46 challenges to improving the reporting of adverse countries in sub-Saharan Africa in 2010 concluded drug reactions in low- and middle-income that the capacity for regulating health products countries include (7): was inadequate in sub-Saharan Africa (30). ■■ busy clinics, high patient volumes and few health-care professionals, with no time to focus Given the importance of pharmacovigilance on reporting suspected adverse drug reactions; among children and adults across all settings, WHO has defined the minimum requirements for ■■ health-care professionals being uncomfortable any routine national pharmacovigilance system, reporting adverse drug reactions because focusing on the least resource-demanding they fear perceptions of professional error passive surveillance methods that can be or culpability, lack of clear legal provisions to implemented without major investment (31). guarantee confidentiality of submitted reports, These requirements include: lack of trust in the integrity of authorities and lack of proper training; and
168 ■■ postal services and Internet being unreliable, The priority in low- and middle-income complicating reporting to national centres (7). countries in recent years has been to establish access to essential medicines to reduce The review highlighted several gaps in morbidity and mortality. In this light, investing (30). pharmacovigilance in sub-Saharan Africa in pharmacovigilance systems was considered Although most (74%) of the 46 countries in sub- an unaffordable luxury (7), thus impeding the Saharan Africa had a national medicine regulatory allocation of time and resources to developing authority and 78% had a national medicine policy, sustainable global pharmacovigilance. This is less than half (41%) had a national policy related especially true for HIV, with the rapid roll-out to pharmacovigilance and medicine safety, and of ART through the Global Fund to Fight AIDS, only one third (30%) had a legal mandate to Tuberculosis and Malaria and the United States monitor adverse drug reactions. Further, less President’s Emergency Plan for AIDS Relief than one third (28%) of the countries had legal (PEPFAR) in early 2000 being aimed primarily at provisions requiring marketing authorization saving millions of lives. Consequently, access to holders to report all serious adverse drug essential medicines for treating such common reactions to the national medicine regulatory health conditions as malaria, pneumonia, HIV authority, and only 17% of countries required and diabetes mellitus has increased substantially marketing authorization holders to conduct post- in low- and middle-income countries, and global marketing pharmacovigilance. coverage of ARV drugs for people living with HIV On the positive side, most (74%) of the countries increased to 53% in 2016 (33). had a pharmacovigilance centre with a clear The consequence of this success is an increasing mandate and formal organizational structure, 39% number of people globally at risk of adverse had national pharmacovigilance guidelines and a drug reactions, especially in communities with safety advisory committee and 45% had a drug limited education and fewer trained health-care information service providing drug information to professionals to guide the safe and appropriate use health-care professionals and the public. of medicines. Increased global medicine exposure, Coordination among all stakeholders was, however, lack of information on drug safety and ongoing minimal – only 28% of countries had a platform significant presence of comorbidities emphasize or strategy to coordinate pharmacovigilance the need for efficient pharmacovigilance systems activities at the national level. A pharmacovigilance in low- and middle-income countries, especially database existed in half (50%) the countries, but for large-scale treatments such as ART and among coordination and collation of pharmacovigilance vulnerable populations such as pregnant women data from all sources was inadequate. The review and children. did not focus on pharmacovigilance involving children, which has only relatively recently gained 2.2 Specific ART-related pharmacovigilance attention in high-income countries. challenges
Beyond general challenges to passive and active 2.1.2 Competing resource and capacity surveillance in low- and middle-income countries, challenges several specific challenges exist for passive and Pharmacovigilance activities involving adults and active surveillance of ARV drugs. We first discuss children have historically been underdeveloped in challenges for case reports and subsequently low- and middle-income countries, partly because the challenges for conducting retrospective and of some stakeholders perceive that the cost of prospective epidemiological studies. pharmacovigilance infrastructure competes with the distribution of scarce resources for direct care delivery (32).
169 2.2.1 Challenge in assessing the causality of 2.2.2 Challenge to distinguish between adverse case reports drug reactions and dosing errors
The challenge in assessing causality for suspected The risk of medication dosing errors (under- or adverse drug reactions from case reports is that overdosing) is high for children and especially they are rarely specific to the individual drug, among young children receiving ARV drugs, who diagnostic tests are usually absent, a re-challenge require frequent dose changes in response to (such as reintroducing the drug to the patient rapidly changing body weight. Use of formulations after an adverse drug reaction) is rarely ethically for children, such as granules and sprinkles, liquids and clinically justified, and there are frequently and small tablets, requires proper training and no denominators of patients at risk. support of the caregiver by the skilled health-care worker and, if not implemented, may result in Assessing causality for ARV drugs is even more dosing errors causing adverse drug reactions and challenging, since multiple drugs are taken drug–drug interactions. together in the form of fixed-dose combinations for ART or HIV prophylaxis, and many may Case reports of medication dosing errors produce similar adverse events. The presence of involving infants who received up to 10 times the comorbidities and concomitant treatments (such recommended dose of zidovudine prophylaxis or as for tuberculosis or malaria) further complicate treatment and the subsequent adverse events the assessment of causality. (34) highlight the risk for such errors and helped stakeholders advocate for appropriately sized In practice, few adverse drug reactions have a administration vehicles such as syringes for certain or unlikely relationship with a specific children (35). drug, and most are somewhere in between these extremes, such as possible or probable. Recognizing the presence of adverse drug 2.2.3 Challenge in generalizing results from reactions may also be more difficult since they high-income countries may present with a different pattern or severity Currently, pharmacovigilance studies involving because of environmental or behavioural factors children originating from high-income countries or comorbid conditions and concomitant dominate the field, but many high-income medications. Higher incidence rates of drug– countries have relatively few children living with drug interactions and adverse drug reactions are HIV compared with low- and middle-income therefore naturally expected in low- and middle- countries. For example, the European Pregnancy income countries (12). and Paediatric HIV Cohort Collaboration has In addition, late initiation of ART, frequently with conducted post-authorization safety studies advanced HIV disease and malnutrition, limited on behalf of pharmaceutical companies for the health-care provider expertise and drug stock- EMA. These studies involve secondary analyses outs may result in treatment interruptions and of prospective cohort data, supplemented by restarts or drug substitutions, both for HIV and questionnaires on outcomes specific to adverse (36). Of the five ARV drugs with comorbidities, that can also contribute to higher drug reactions findings published to date(36–40) , two were for rates of adverse drug reactions. Compared with drugs used relatively infrequently in Europe and the common comorbidities in low- and middle- correspondingly had sample sizes of less than income countries, providers in high-income 200 in each study, highlighting the challenges of countries face a different array of confounding conducting pharmacovigilance studies with small health conditions and concomitant drugs used, sample sizes (37,40). such as illicit drugs, psychotropic drugs and lipid-lowering agents, which can also complicate The availability of newer ARV drugs differs by pharmacovigilance activities. income setting. Children in low- and middle-
170 income countries are frequently prescribed ability to investigate the real-world adherence, generic first-generation individual ART drugs and effectiveness and safety of specific ARV drugs. generic fixed-dose combinations, which may no Adverse drug reactions and medication use are longer be considered preferred regimens in high- often not documented because of lack of time income countries. Thus, new evidence for the and lack of awareness of their importance. drug safety of older regimens will no longer be generated from high-income countries with well 2.2.5 Heterogeneity of exposure and populations: developed pharmacovigilance systems, leading effect modification versus power to an even larger disparity in safety information between low- and middle-income countries and Children with ART exposure are not a high-income countries. homogeneous group but comprise distinct populations of HIV-negative children and children living with HIV, all with ART drug exposure 2.2.4 Challenges based on the quality of differing by duration and the combination of source data drugs given. These differences may all affect Retrospective epidemiological studies in low- the rates of adverse drug reactions, and studies and middle-income countries may rely on need to distinguish these factors and study safety extracting data on the outcome and exposure by the type of regimen and population. Only if from paper medical records, and the quality effect modification is absent may exposure be of these is likely to vary widely depending on pooled. The need to evaluate effect modification the study context. Treatment records may be affects the power. ART exposure should be well incomplete or missing and difficult to retrieve, documented, including maternal and infant and a lack of recorded viral load data in many exposure, although this proves to be difficult low- and middle-income countries restricts the even in high-income countries (41).
A good example is the West Cape Province of South Africa, which has an electronically linked health record system linking maternal and infant records, including pharmacy ART records with a range of health records, including hospital admissions, death and cancer registries. Such surveillance systems may provide a critical foundation for well powered pharmacovigilance systems.
2.2.6 Challenges from selection bias and loss to follow-up
The surviving and ageing perinatally infected children living with HIV make pharmacovigilance studies difficult to conduct. Challenges include how to select representative samples of children and the appropriate duration of follow-up. Because of dropout or loss to follow-up, the analysable amount of person-time may be low, limiting the power to investigate longer-term safety. This affects the confidence in the findings ©Courtesy of photoshare of different studies.
171 2.2.7 Multiple outcomes of interest exposure range from effects on physical growth to rare remote events such as malignancies Paediatric safety outcomes of interest range in adulthood, and all need to be investigated. from prenatal, perinatal and neonatal to longer- Studying such a broad range of health outcomes term outcomes. Many outcomes may require will require varied study design approaches and diagnostics that are not generally available in proper assessment of outcomes over a long clinics in low- and middle-income countries, lifespan, which is challenging because of the such as dual-energy X-ray absorptiometry and lack of automated and linked health records, neurological and psychiatric assessment. Longer- migration and loss to follow-up. term outcomes of short-term and lifelong ART
3. SOLUTIONS
The safety of ART has improved considerably ■■ implementing medication review into the over time but, similar to any active compounds, standard of care to identify the potential for vigilance is required, especially in vulnerable drug–drug interactions; and
populations (such as pregnant women, children ■■ training health-care providers and patients and immunocompromised people). Solutions to promptly recognize, treat and document to improve pharmacovigilance in its broader adverse drug reactions. context start with preventing or minimizing risks. Having data available to identify and minimize the risk requires comprehensive signal detection 3.2 Improving the regulatory framework and evaluation studies being in place, to generate to create a safety culture actionable information. A key reason for the lack or limited 3.1 Minimizing the risks implementation of pharmacovigilance in low- and middle-income countries is a lack of national regulations to enforce the responsibilities Pharmaceutical adverse drug reactions (type of the pharmaceutical industry, including A) may be prevented through an array of risk- generic drug manufacturers, regarding minimizing activities such as: safety reporting of adverse drug reactions ■■ providing access to up-to-date information to national pharmacovigilance centres (18). on the safety of ARV drugs in different With a pharmaceutical market in sub-Saharan populations to health-care providers in high- Africa estimated to be worth US$ 3.8 billion to income countries and low- and middle-income 4.7 billion, the pharmaceutical industry, both countries so that well informed decisions can innovator and generic, is a major stakeholder be made; in pharmacovigilance activities. The industry ■■ pretreatment screening to identify people at should replicate the standard pharmacovigilance high risk of specific adverse drug reactions; practices they undertake in high-income countries and implement similar activities in ■■ avoiding prescribing concomitant medicines low- and middle-income countries to safeguard with a shared risk for similar adverse drug patients and protect the public health of the reactions, such as multiple nephrotoxic agents; communities in which they market their products.
172 Generic drug manufacturers provide a significant Building and sustaining the required human proportion of ARV drugs for low- and middle- capacity to identify adverse drug reaction income countries, and the lower pricing ensures signals and manage them requires introducing greater access to drugs among the affected pharmacovigilance in undergraduate- and populations. However, historically, generic drug graduate-level teaching for all health professionals companies may have devoted fewer resources globally. The WHO Collaborating Centre for for pharmacovigilance and may perceive that Pharmaceutical Policy and Regulation in Utrecht, monitoring adverse drug reactions is not Netherlands, which conducts academic research relevant for generic drugs with well known at the interface of pharmacoepidemiology and safety profiles (18). Generic drug manufacturers policy analysis, has been charged with developing may not see it as their responsibility to support such programmes (42). pharmacovigilance on market entry even when The establishment of a WHO Collaborating the innovator company is not marketing the Centre for Advocacy and Training in compound. However, in the era when increasingly Pharmacovigilance in Accra, Ghana has large proportions of the population living with been a major step towards consolidating the or exposed to HIV globally are receiving generic establishment of pharmacovigilance in Africa ARV drugs, there are increasing calls for regional (7). Since 2009, this Centre has been providing and national regulations and an increased role for pharmacovigilance training, building capacity, the generic pharmaceutical industry to share the promoting advocacy and strengthening adverse responsibility for pharmacovigilance with other drug reaction reporting, with a focus on passive global and national stakeholders. surveillance, in African countries. WHO is also building capacity in sub-Saharan Africa through 3.3 Strengthening capacity the Global Training Network on vaccine quality and the through the WHO Collaborating Centre A 2010 review of existing pharmacovigilance for International Drug Monitoring in Uppsala, systems in sub-Saharan Africa demonstrated that Sweden, with courses on adverse events there was existing capacity in the WHO African following immunization (passive surveillance). Region to conduct medicine safety research that The Pharmaceutical Industry Association of South can help identify, evaluate and confirm medicine- Africa organized pharmacovigilance training related risks (30). Active surveillance, including in South Africa with a focus on pre-marketing Phase IV studies to evaluate the safety and clinical safety research or post-marketing adverse effectiveness of medicines, had been or were events following immunizations. Courses and being conducted by academic institutions, public training on pharmacovigilance are also available health programmes, hospitals and international from other academic institutions and centres of organizations in 22 African countries, although excellence (see the section on useful resources). most studies were related to malaria treatment. Teaching institutions with centres of excellence To improve the coordination of existing research within their own countries also conduct many capacity and resources, regional groups in Africa active surveillance studies, providing the potential could be supported to develop networks that link for mentorship to non-teaching hospitals to research institutions and regulatory authorities build the capacity of health-care workers in to increase medicine research capacity. pharmacovigilance at the local level. Pharmacovigilance centres in sub-Saharan Africa In the European Union, the Eu2P programme was could also collaborate on a more global level, developed through funding from the Innovative since many training courses and opportunities Medicines Initiative. It is currently offering for remote collaborations exist and are available innovative web-based education and training in remotely (see the section on useful resources).
173 pharmacovigilance and pharmacoepidemiology, 3.5 Pooling existing data from active including master and PhD programmes that can surveillance studies be conducted alongside day-to-day work and are available for applicants from low-income Merging or pooling data from multiple studies countries, including regulatory staff and health- increases the statistical power of analysis and care workers. Internships are available in WHO can be a relatively cost-efficient approach. collaborating centres in Uppsala (Sweden), Standardized data exchange protocols are Accra (Ghana), Utrecht (Netherlands) or Rabat available to aid data mergers, including the (Morocco) (see the section on useful resources). HIV Cohorts Data Exchange Protocol (43) and The pharmaceutical industry can assist national the International Epidemiology Databases to pharmacovigilance programmes by limiting their Evaluate AIDS Data Exchange Standard. employment of national qualified personnel A recent example of a large-scale data merger from pharmacovigilance centres and investing in is the Collaborative Initiative for Paediatric HIV pharmacovigilance training. To retain well trained Education and Research cohort collaboration, personnel, salaries in the public sector may need which has conducted a data merger on 93 351 to be increased to avoid a drain into the private children younger than 18 years across 12 HIV sector. Joint PhD programmes with high-income observational cohort networks globally to countries and private companies may facilitate investigate the incidence and predictors of the retention of personnel in research settings. switching to second-line ART (44). Among other findings, children starting ART with non- 3.4 Focus on active surveillance nucleoside reverse-transcriptase inhibitor-based regimens have been found to have a higher incidence of switching compared with those In the presence or absence of functional starting with protease inhibitor–based regimens. passive surveillance systems, the primary focus should be on setting up active surveillance. Such collaboration can be a key source of One of the benefits of active surveillance over pharmacoepidemiology data, especially in passive surveillance is the ability to generate settings with weak underlying pharmacovigilance information that may inform decision-making, systems. The existence of electronic health since there is a higher probability of evaluating records comprises another available resource and quantifying the relationship between the for pharmacoepidemiological pharmacovigilance adverse drug reaction and the related drug. safety studies (19). Active surveillance may be implemented using existing capacity: for example, through demographic surveillance networks and public 3.6 Developing standardized methods health programmes, which exist in many low- and protocols and middle-income countries. Collaboration can be initiated between pharmacovigilance experts Using standard protocols and definitions for and public health officials. outcomes, exposure and confounders for active surveillance studies may increase validity and ease the pooling of data from disparate settings. Common data models for data collection may be created, facilitating pooling and the use of common analytical data scripts, especially in areas with limited capacity.
174 3.7 Pooling of spontaneous reporting data 3.8 Harnessing WHO technical support
A crucial aspect of pharmacovigilance is the To support the safe introduction of new ARV ability to easily pool data from disparate sources drugs for children and address the gaps in safety to inform the global community of emerging data within national programmes, WHO provides trends in adverse drug reactions. National technical support to countries to implement both pharmacovigilance systems should establish routine toxicity monitoring via the HIV patient and maintain adverse drug reaction databases monitoring system and active adverse drug that are compatible with the international reaction surveillance for ART. WHO has developed standard format for adverse drug reaction and disseminated patient monitoring tools that reports, known as individual case safety reports. capture and enable reporting of treatment limiting The International Council for Harmonisation of adverse drug reactions. WHO also supports the Technical Requirements for Pharmaceuticals implementation and the strengthening of data for Human Use developed this international quality to encourage the generation of reliable standard, known as the ICH-E2b, which allows data and maximize the utility of collected data. easy exchange of adverse drug reaction data WHO works with health ministries and technical between countries, regulatory authorities and partners to adapt the minimum datasets, tools the pharmaceutical industry. and protocols to individual country settings and is supporting the implementation of surveillance of Low- and middle-income countries can use the drug safety among pregnant women in Malawi and VigiFlow data management system from the South Africa. WHO Collaborating Centre for International Drug Monitoring at low cost, in which the ICH- Moreover, WHO has developed an ARV drug E2b is fully integrated. Further, international toxicity monitoring tool that provides step data sharing is necessary to support global by step instructions and reporting tools for pharmacovigilance, especially given international countries to implement both routine monitoring trade and traffic in pharmaceuticals, and of toxicity and active adverse drug reaction specifically, the small numbers of specific monitoring at selected sentinel sites for new ARV adverse drug reactions involving children. drugs among children. WHO aims to produce additional tools and annexes for new ARV drugs, The power to detect adverse drug reaction including new ARV drug formulations for children signals is greatly enhanced when a data for in-country implementation and adoption. management system can receive and collate For example, a standardized reporting form is pharmacovigilance data from all sources, available for countries to report DTG-associated including routine adverse drug reaction adverse drug reactions, together with training monitoring integrated within public health materials and an adaptable data dictionary. ART programmes, clinical trials, immunization WHO is also developing a central database for programmes, active surveillance and periodic safety evaluation of DTG to enable pooling of safety updates from the pharmaceutical industry. data and inform global guidance. Countries are also being supported with the adaptation of tools, approaches and data analysis, to facilitate the implementation of adverse drug reaction monitoring in their own context.
175 4. CASE STUDIES
Active surveillance designs typically follow rely on consent and self-reported exposure. standard epidemiological study designs. In The advantage is that they cost less and enable epidemiology, populations are studied and the multiple exposure patterns to be studied. occurrence of disease is compared between exposure groups. An essential epidemiological In recent years, other case-based studies have concept is that if a drug causes disease, the been developed that are suitable for brief drug drug must be administered before the disease exposure or vaccine safety. They start with the developed and must alter the frequency of that cases with a specific outcome and compare disease. Frequency of disease can be measured exposure during case occurrence with periods by risk (cumulative incidence over a specific of time for the same person before the case period) or incidence rates (number of cases for a occurred (case crossover) or in unexposed certain number of people and a certain amount periods (self-controlled case series). These of time). The following are the key observational studies inherently control for all confounding designs and can be applied for safety and factors that are stable (environment and effectiveness studies (Table 10.1). genetics) and are very cost-efficient.
In cohort studies, the population is divided into Cross-sectional studies provide a snapshot at one exposure groups and the incidence (cumulative point in time of the co-occurrence of exposure or rate) is calculated and compared between and disease and are suitable for generating the exposure groups. The advantage of cohort hypotheses, but since the temporal association studies is that multiple outcomes can be studied between the exposure and disease is unknown at the same time. Cohort studies are usually this design cannot be used to evaluate causality. expensive, since large populations need to be Case-based studies only provide measures of followed over time to monitor the occurrence association (relative risk) between exposure and of disease. For ARV drugs, cohorts may also outcome (odds ratio). Cohort studies do that as be complex since treatment may change and well (relative risk) but also provide an absolute many covariates also change over time, all of measure of risk or incidence. which need to be measured and considered in any analysis. As an aside, experimental studies (randomized controlled trials) have a cohort 4.1 Tenofovir and renal toxicity design, except that exposure does not follow real-world practice but is randomly assigned by A series of spontaneously reported cases (case the investigator. series) from passive surveillance often provides the first indication of a safety signal. For example, An alternative to cohort studies is case-based in the mid-2000s, single case reports and case studies, which start with the outcome (cases). series highlighted instances of proximal renal In case–control studies, the past frequency tubular dysfunction and other renal toxicity in a of exposure to a drug in cases is compared few children with HIV taking tenofovir disoproxil with the frequency of exposure to the drug in fumarate (45,46). This led to the EMA requiring controls (people without the outcome). Since post-authorization safety studies to assess the outcome is the entry point into the study and whether the recommended patient monitoring exposure needs to be assessed retrospectively, laboratory tests and evaluations are adhered these designs are efficient but susceptible to to in routine care (36). Various study designs selection and information bias, especially if they
176 Table 10.1. Examples of important pharmacovigilance issues in paediatrics and study design approaches
Pharmacovigilance Study design issue in paediatrics Optimal choices Less optimal choices Prenatal exposure Cohort of ART-exposed and -unexposed women and Case series of women to ART and maternal specific investigations of maternal health and birth receiving a specific outcomes and birth outcomes (provides rates and associations) ART regimen (no good defects Case–control study of infants with birth defects (cases) reference group) and without (controls) (efficient design; provides a Cross-sectional measure of association) (no temporal association) Nervous system and Cohort study of children initiating ARV drugs on various Cross-sectional mental effects of ART regimens (provides rates and associations) (no temporal association) specific ARV drugs on Case–control study of children with nervous system and children mental effects (cases) and without (controls) (efficient design; provides a measure of association) Self-control case series (efficient design; adjust for confounders within each person) have investigated this relationship between grade 3 and 4 adverse events by treatment arm exposure and outcome, such as cohort (47) and were compared, suggesting good tolerability case–control designs (48), randomized trials of abacavir and also lamivudine (52). Follow- (49) and, more recently, a systematic review up continued beyond the primary endpoint, to (50). Together, these and other reports have evaluate longer-term outcomes, including safety. highlighted clinically relevant adverse renal and In ARROW, hypersensitivity related to abacavir bone effects of regimens containing tenofovir was found to be rare, being experienced by disoproxil fumarate among children. 0.3% of trial patients (53). This finding was later confirmed in a systematic review of the evidence from trials and observational studies (54). 4.2 Abacavir and hypersensitivity
Abacavir is a nucleoside reverse-transcriptase 4.3 Safety of ARV drugs among inhibitor recommended by international HIV-exposed and uninfected children guidelines and available in Africa. However, there have been concerns about its toxicity, Although surveillance studies in low- and middle- including hypersensitivity reactions, which are income countries are evaluating the safety more likely for people with the HLA B5701 of ART in pregnancy and effects on infants at genotype. Studies of adults with HIV receiving delivery (55), including in Botswana (56) and abacavir-based ART have reported an increased South Africa (57), these studies are not following risk of hypersensitivity reactions and myocardial up ART-exposed infants subsequently. infarction (51). In high-income countries, the Surveillance One key study investigating hypersensitivity Monitoring for ART Toxicities Study in HIV- among children taking abacavir was the uninfected Children Born to HIV-infected Antiretroviral Research for Watoto (ARROW) Women is a cohort study measuring the safety trial, which investigated new ART strategies of exposing HIV-uninfected children born to for children living with HIV in Africa and had an mothers living with HIV to ART in utero, using active surveillance component. In the main trial,
177 an active surveillance approach (58). Areas Other cohorts and studies use novel data of interest include effects on metabolism and linkage designs to ascertain very long-term growth, the heart, the nervous system and its outcome measurements from national cancer development, behaviour, language and hearing. and death registries in cohort studies of children A novel trigger-based design provides efficient born to mothers living with HIV. For example, use of study and patient resources, in which in France, children born to women living with trigger thresholds dictate additional prespecified HIV are linked to the National Cancer Registry evaluations rather than randomly selecting (59). Findings from France’s registry cohort subgroups of patients to study with detailed suggested a strong association between assessments. didanosine exposure in the first trimester and transplacental oncogenicity, which led to the avoidance of didanosine during pregnancy.
©WHO/Harry Anenden
178 5. SUMMARY
A huge number of children globally have been Issues that need to be addressed include the cost exposed to ARV drugs during early life, and of pharmacovigilance, difficulty in attributing this trend will continue for the foreseeable causality, dosing errors, the generalizability future. In addition, many children living with of findings, data quality, the heterogeneity of HIV are expected to continue to need ART for exposure and populations, loss to follow-up lifelong HIV treatment (5,51,60). In recent years, and multiple outcomes of interest. However, appreciation has increased of the importance many recent developments have strengthened of generating safety data specific to children and improved reporting, and there is a need to since they are exposed to ARV drugs throughout further capitalize on progress by improving the critical growth and development phases in regulatory framework, building capacity, focusing addition to differing from adults in absorption, on active surveillance, pooling existing data and distribution, metabolism and excretion of ARV harnessing WHO technical support. drugs and concomitantly administered drugs (61). All of these aspects are important for the future, The poor level of evidence for adverse when focus is likely to be increased on the role drug reactions among children reflects of DTG as a priority for children, as well as two- some of the challenges of conducting drug regimens and long-acting formulations. pharmacoepidemiological studies involving These new trends demonstrate a clear need for children exposed to HIV and ARV drugs. In more robust pharmacovigilance monitoring to low- and middle-income countries in particular, better understand the risks and safety profile of regulatory systems are commonly weak, with ART for children, especially in low- and middle- the main focus being on passive surveillance. income countries.
6. KEY CONSIDERATIONS
■■ Pharmacovigilance of adverse drug reactions ■■ Training opportunities are available, and WHO is key to ensuring that medicines are safe. provides technical support to implement both
■■ Pharmacovigilance studies can range from passive and active surveillance approaches. passive surveillance, which can be relatively ■■ Issues of drug safety in HIV will continue simple and cheap to implement, to active for the foreseeable future, and approaches surveillance, which may be more costly but therefore urgently need to be implemented, generates more informative results. strengthened and scaled up.
■■ Major challenges of pharmacovigilance in low- and middle-income countries include a lack of robust regulatory systems that enforce manufacturer commitments to support longer- term approaches to pharmacovigilance and competing resources and capacity challenges.
179 7. USEFUL RESOURCES
WHO links WHO collaborating centres
■■ Technical guidance for Global Fund HIV ■■ Uppsala, Sweden: https://www.who-umc.org
proposals: treatment – pharmacovigilance for ■■ Accra, Ghana: http://apps.who.int/whocc/ antiretroviral drugs (http://www.who.int/hiv/pub/ Detail.aspx?cc_ref=GHA-1&cc_region=afro& toolkits/3-2-8_Pharmacovigilance_3Nov.pdf) ■■ Utrecht, Netherlands: http://www. ■■ Pharmacovigilance: ensuring the safe use of pharmaceuticalpolicy.nl medicines (http://apps.who.int/medicinedocs/ ■■ Rabat, Morocco: http://www.capm.ma/pv- pdf/s6164e/s6164e.pdf) pharmacovigilance ■■ A practical handbook on the pharmacovigilance of antiretroviral medicines (http://www.who.int/medicines/areas/quality_ Data exchange formats safety/safety_efficacy/HIVhandbook.pdf) ■■ International Epidemiology Databases to ■■ Venter WDF, Ford N, Vitoria M, Stevens W. Diagnosis and monitoring of HIV programmes Evaluate AIDS Data Exchange Standard; http:// to support treatment initiation and follow up iedea.github.io and improve programme quality. Curr Opin ■■ HIV Cohorts Data Exchange Protocol: http:// HIV AIDS. 2017;12:117–22 (http://www.who.int/ www.hicdep.org hiv/pub/journal_articles/diagnosis-monitoring- hiv-programmes/en) Other links
Training courses ■■ Eu2P programme: https://www.eu2p.org ■■ International Society for Pharmacoepidemiology ■■ WHO adverse events following immunization Pediatric Special Interest Group: https://www. (https://www.who-umc.org/global- pharmacoepi.org/communities/sigs/pediatrics pharmacovigilance/communication-in- ■■ INDEPTH network: http://www.indepth- pharmacovigilance) network.org ■■ Uppsala Monitoring Centre education and training opportunities (https://www.who-umc. org/education-training/education-training)
■■ Uppsala Monitoring Centre internships (https://www.who-umc.org/about-us/contact- us/career-page)
180 8. ACKNOWLEDGEMENTS
Authors: Ali Judd1, Intira Jeannie Collins1, Hiwot Haile-Selassie2, Natella Rakhmanina3 and Miriam Sturkenboom4
Other contributors: Françoise Renaud2
Reviewers: Andy Stergachis5 and Karen Cohen6
1 University College London, United Kingdom 2 World Health Organization, Geneva, Switzerland 3 Elizabeth Glaser Paediatric AIDS Foundation, Washington, DC, USA 4 University Medical Center Utrecht, Netherlands 5 University of Washington, Seattle, USA 6 University of Cape Town, South Africa
9. REFERENCES
1. The importance of pharmacovigilance – antiretroviral therapy regimen. Expert Rev Clin safety monitoring of medicinal products. Pharmacol. 2016;9:1493–1503. Geneva: World Health Organization; 2002 6. Kim JH, Scialli AR. Thalidomide: the tragedy (http://apps.who.int/medicinedocs/en/d/ of birth defects and the effective treatment Js4893e, accessed 22 May 2018). of disease. Toxicol Sci. 2011;122:1–6. 2. International drug monitoring: the role of national centres. Geneva: World Health 7. Olsson S, Pal SN, Dodoo A. Organization; 1972 (http://apps.who.int/iris/ Pharmacovigilance in resource-limited handle/10665/40968, accessed 22 May 2018). countries. Expert Rev Clin Pharmacol. 2015;8:449–60. 3. Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, 8. Aronson JK, Hauben M, Bate A. Defining editor. Textbook of adverse drug reactions. “surveillance” in drug safety. Drug Saf. Oxford: Oxford University Press; 1977. 2012;35:347–57.
4. Bedimo R, Rosenblatt L, Myers J. 9. Guideline on good pharmacovigilance Systematic review of renal and bone safety practives (GVP). Product- or population- of the antiretroviral regimen efavirenz, specific considerations. IV. Paediatric emtricitabine, and tenofovir disoproxil population. EMA/572054/2016 draft for fumarate in patients with HIV infection. HIV public consultation. London: European Clin Trials. 2016;17:246–66. Medicines Agency; 2017.
5. Mouton JP, Cohen K, Maartens G. Key toxicity 10. van Ramshorst MS, Kekana M, Struthers HE, issues with the WHO-recommended first-line McIntyre JA, Peters RP. Efavirenz-induced gynecomastia in a prepubertal girl with
181 human immunodeficiency virus infection: a Health Organization; 2011 (http://apps.who. case report. BMC Pediatr. 2013;13:120. int/medicinedocs/en/d/Js19152en, accessed 22 May 2018). 11. Njuguna C, Swart A, Blockman M, Maartens G, Chisholm B, Stewart A et al. Cases of 19. Osokogu OU, Dukanovic J, Ferrajolo antiretroviral-associated gynaecomastia C, Dodd C, Pacurariu AC, Bramer WM reported to the National HIV & Tuberculosis et al. Pharmacoepidemiological safety Health Care Worker Hotline in South Africa. studies in children: a systematic review. AIDS Res Ther. 2016;13:40. Pharmacoepidemiol Drug Saf. 2016;25:861–70.
12. Surveillance of antiretroviral drug toxicity 20. Barlow-Mosha L, Musiime V, Davies MA, within antiretroviral treatment programmes. Prendergast AJ, Musoke P, Siberry G et al. Geneva: World Health Organization; 2013 Universal antiretroviral therapy for HIV- (http://www.who.int/hiv/pub/arv_toxicity/ infected children: a review of the benefits technical-brief-surveillance/en, accessed 22 and risks to consider during implementation. May 2018). J Int AIDS Soc. 2017;20:21552.
13. Oreagba IA, Usman SO, Olayemi SO, 21. Elzi L, Erb S, Furrer H, Cavassini M, Calmy Oshikoya KA, Opanuga O, Adeyemo TA et A, Vernazza P et al. Adverse events al. Pharmacoepidemiology of antiretroviral of raltegravir and dolutegravir. AIDS. drugs in a teaching hospital in Lagos, Nigeria. 2017;31:1853–8. Ghana Med J. 2014;48:194–203. 22. UNAIDS data 2017. Geneva: UNAIDS; 2017. 14. Zisowsky J, Krause A, Dingemanse J. Drug development for pediatric populations: 23. Townsend C, Byrne L, Cortina Borja M, regulatory aspects. Pharmaceutics. Thorne C, De Ruiter A, Lyall H et al. Earlier 2010;2:364–88. initiation of ART and further decline in mother-to-child HIV transmission rates, 15. European Parliament and the Council of 2000–2011. AIDS. 2014;28:1049–57. the European Union. Regulation (EC) No 24. 2015 progress report on the Global Plan. 1901/2006 of the European Parliament and Geneva: UNAIDS; 2015. of the Council of 12 December 2006 on medicinal products for paediatric use and 25. Children and AIDS: statistical update 2017. amending Regulation (EEC) No 1768/92, New York: UNICEF; 2017. Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Offic J 26. Thorne C. The HIV-exposed and uninfected Eur Union. 2016;L 378:1–19. child: what’s to worry? 24th Conference on Retroviruses and Opportunistic Infections, 16. Tayman C, Rayyan M, Allegaert K. Neonatal Seattle, WA, USA, 13–16 February 2017. pharmacology: extensive interindividual variability despite limited size. J Pediatr 27. Slogrove A, Johnson L, Powis K. The population Pharmacol Ther. 2011;16:170–84. effect of HIV exposure in HIV-uninfected children on infant mortality in Botswana and 17. Smyth RM, Gargon E, Kirkham J, Cresswell South Africa. 9th International Workshop on L, Golder S, Smyth R, Williamson P. Adverse HIV Pediatrics, Paris, France, 21–22 July 2017. drug reactions in children – a systematic review. PLoS ONE. 2012;7:e24061. 28. Jose KM, Wallace MR. FDA pregnancy categories for antiretroviral therapy. In: 18. Safety of medicine in sub-Saharan Africa: Anand J, Bartlett J, editors. New York: assessment of pharmacovigilance systems Medscape; 2014 (https://emedicine. and their performance. Geneva: World
182 medscape.com/article/2039748-overview, of fosamprenavir in HIV-infected children accessed 22 May 2018). in Europe. Pharmacoepidemiol Drug Saf. 2013;23:321–5. 29. ARV market report, Issue 8, September 2017. Boston: Clinton Health Access Initiative; 2017. 38. European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study 30. Strengthening Pharmaceutical Systems (SPS) group in EuroCoord. Safety of darunavir and Program. Safety of medicines in sub-Saharan atazanavir in HIV-infected children in Europe Africa: assessment of pharmacovigilance and Thailand. Antivir Ther. 2015;21:353–8. systems and their performance. Arlington (VA): Management Sciences for Health; 2011. 39. European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study 31. Minimum requirements for a functional group in EuroCoord. Safety of zidovudine/ pharmacovigilance system. Geneva: World lamivudine scored tablets in children with Health Organization; 2010 (http://www.who. HIV infection in Europe and Thailand. Eur J int/medicines/areas/quality_safety/safety_ Clin Pharmacol. 2017;73:463–8. efficacy/PV_Minimum_Requirements_2010_2. pdf, accessed 22 May 2018). 40. Lyons A, Collins I, Chappell E, Tostevin A, Thompson L, Ramos-Amador J et al. Safety 32. Bakare N, Edwards IR, Stergachis A, Pal of etravirine (ETR) in young people with HIV: S, Holmes CB, Lindquist M et al. Global patient characteristics, adverse events and pharmacovigilance for antiretroviral drugs: discontinuation. 9th International Workshop on overcoming contrasting priorities. PLoS Med. HIV Pediatrics, Paris, France, 21–22 July 2017. 2011;8:e1001054. 41. Slogrove AL, Archary M, Cotton MF. 33. Ending AIDS. Progress towards the 90– Optimizing research methods to understand 90–90 targets. Global AIDS update 2017. HIV-exposed uninfected infant and child Geneva: UNAIDS; 2017. morbidity: report of the Second HEU 34. Chiappini E, Galli L, Gabiano C, Gattinara Infant and Child Workshop. Front Immunol. GC, Martino A, Scolfaro C et al. Preventable 2016;7:576. zidovudine overdose during postnatal 42. Bamford A, Turkova A, Lyall H, Foster C, Klein N, prophylaxis in healthy children born to HIV-1- Bastiaans D et al. Paediatric European Network positive mothers. AIDS. 2008;22:316–7. for Treatment of AIDS (PENTA) guidelines for 35. Livshits Z, Lee S, Hoffman RS, Nelson LS, treatment of paediatric HIV-1 infection 2015: Esteban-Cruciani N. Zidovudine (AZT) optimizing health in preparation for adult life. overdose in a healthy newborn receiving HIV Med. 2018;19:e1–42. postnatal prophylaxis. Clin Toxicol. 43. Kjaer J, Ledergerber B. HIV cohort 2011;49:747–9. collaborations: proposal for harmonization of 36. Turkova A, Collins IJ, Lyons A, Ramos data exchange. Antivir Ther. 2004;9:631–3. Amador JT, Rojo Conejo P, Ene L et al. Use 44. Collins IJ, Collaborative Initiative for Paediatric and safety of tenofovir disoproxil fumarate HIV Education and Research (CIPHER) Cohort (TDF) in children and adolescents with Collaboration Duration of First-line Team. HIV in paediatric cohorts in the European Switching to second-line antiretroviral therapy Union. 9th International Workshop on HIV (ART) in HIV-infected children: a CIPHER Pediatrics, Paris, France, 21–22 July 2017. cohort collaboration global analysis. 21st 37. Judd A, Duong T, Galli L, Goetghebuer T, International AIDS Conference, Durban, South Ene L, Julian AN et al. Post-licensing safety Africa, 18–22 July 2016.
183 45. Hussain S, Khayat A, Tolaymat A, Rathore 53. Nahirya-Ntege P, Musiime V, Naidoo B, MH. Nephrotoxicity in a child with perinatal Bakeera-Kitaka S, Nathoo K, Munderi P et al. HIV on tenofovir, didanosine and lopinavir/ Low incidence of abacavir hypersensitivity ritonavir. Pediatr Nephrol. 2006;21:1034–6. reaction among African children initiating antiretroviral therapy. Pediatr Infect Dis J. 46. Hawkins S, Ball C. Adverse events 2011;30:535–7. experienced by three children taking tenofovir and didanosine in combination. HIV 54. Jesson J, Dahourou DL, Renaud F, Penazzato Med. 2007;8:411. M, Leroy V. Adverse events associated with abacavir use in HIV-infected children and 47. Vigano A, Bedogni G, Manfredini V, adolescents: a systematic review and meta- Giacomet V, Cerini C, di Nello F et al. Long- analysis. Lancet HIV. 2016;3:e64–75. term renal safety of tenofovir disoproxil fumarate in vertically HIV-infected children, 55. Zash RM, Williams PL, Sibiude J, Lyall H, adolescents and young adults: a 60-month Kakkar F. Surveillance monitoring for safety follow-up study. Clin Drug Investig. of in utero antiretroviral therapy exposures: 2011;31:407–15. current strategies and challenges. Expert Opin Drug Saf. 2016;15:1501–13. 48. Judd A, Boyd KL, Stohr W, Dunn D, Butler K, Lyall H et al. Effect of tenofovir disoproxil 56. Zash R, Jacobson DL, Diseko M, Mayondi fumarate on risk of renal abnormality in G, Mmalane M, Essex M et al. Comparative HIV-1-infected children on antiretroviral safety of antiretroviral treatment regimens in therapy: a nested case-control study. AIDS. pregnancy. JAMA Pediatr. 2017;171:e172222. 2010;24:525–34. 57. Dheda M. Decentralized HIV/AIDS 49. Della Negra M, de Carvalho AP, de Aquino pharmacovigilance in South Africa: MZ, da Silva MT, Pinto J, White K et al. A Mpumalanga as pilot province for national randomized study of tenofovir disoproxil roll-out. J AIDS HIV Res. 2013;5:357–65. fumarate in treatment-experienced HIV-1 58. Williams PL, Hazra R, Van Dyke RB, infected adolescents. Pediatr Infect Dis J. Yildirim C, Crain MJ, Seage GR 3rd et al. 2012;31:469–73. Antiretroviral exposure during pregnancy 50. Okonkwo RI, Weidmann AE, Effa EE. Renal and adverse outcomes in HIV-exposed and bone adverse effects of a tenofovir- uninfected infants and children using a based regimen in the treatment of HIV- trigger-based design. AIDS. 2016;30:133–44. infected children: a systematic review. Drug 59. Hleyhel M, Goujon S, Delteil C, Vasiljevic Saf. 2016;39:209–18. A, Luzi S, Stephan J-L et al. Risk of cancer 51. D:A:D Study Group. Use of nucleoside in children exposed to didanosine in utero. reverse transcriptase inhibitors and risk of AIDS. 2016;30:1245–56. myocardial infarction in HIV-infected patients 60. Calmy A, Hirschel B, Cooper DA, Carr enrolled in the D:A:D study: a multi-cohort A. Clinical update: adverse effects of collaboration. Lancet. 2008;371:1417–26. antiretroviral therapy. Lancet. 2007;370:12–4. 52. ARROW Trial Team. Routine versus clinically driven laboratory monitoring and first-line 61. Dubrocq G, Rakhmanina N, Phelps BR. antiretroviral therapy strategies in African Challenges and opportunities in the children with HIV (ARROW): a 5-year open- development of HIV medications in pediatric label randomised factorial trial. Lancet. patients. Paediatr Drugs. 2017;19:91–8. 2013;381:1391–403.
184 CONCLUSION
©WHO/TDR/Andy Craggs
185 1. CONTEXT
This toolkit is part of a wider global initiative to required for optimal treatment of children and raise awareness of the historical and ongoing coordinating the procurement of antiretroviral delays in developing and commercializing HIV (ARV) drugs in low- and middle-income drugs in formulations suitable for children and countries (2). adolescents and to find innovative ways to Building on these ongoing initiatives, this toolkit accelerate this process (1,2). Efforts in recent years have focused on promoting intersectoral brings together the knowledge and experience collaboration, giving priority to the most of key experts on HIV to suggest pragmatic ways needed formulations for children, establishing to further accelerate the drug development a formulary of existing drug formulations time scale.
2. SUMMARY OF KEY CONSIDERATIONS
The key considerations arising from this toolkit research studies, which should include key centre around: population groups from the start.
■■ earlier planning and coordination to facilitate ■■ Early communication between all stakeholders the design and conduct of key research is needed to facilitate timely planning of studies; studies of novel drugs involving children and
■■ including key population groups (young children, pregnant women. adolescents and pregnant and breastfeeding ■■ The development of age-appropriate women) in the research process; formulations suitable for low- and middle-
■■ more efficiently using the available data to fill income countries should be initiated as soon knowledge gaps and minimize the need for as reassuring safety and efficacy data are additional studies; and available from Phase II trials involving adults. ■■ ■■ increasing collaboration and coordination For this to happen, clinical trials, among key stakeholders throughout the key pharmacokinetic studies and acceptability stages of drug development. studies involving children should be designed alongside research studies involving adults and in close collaboration with regulatory 2.1 Earlier planning and acceleration of authorities to establish what data are needed research studies early on. ■■ Community engagement should occur as This toolkit provides many examples of ways to early as possible in designing clinical trials and accelerate the development of drugs for children acceptability studies. Community groups should by establishing communication channels between be engaged throughout the process of drug key stakeholders early in the drug development development, including during the planning and process and accelerating appropriately designed design of clinical trials involving children.
186 ■■ Target product profiles should be developed III clinical trials should not be excluded from early in the drug development process, to the study or taken off the study drug if they enable formulations to be adapted if needed. become pregnant during the trial unless there
■■ Specific country regulatory requirements need are specific reasons to do so. to be considered early on to avoid additional hurdles and obstacles to importation and in- 2.3 Efficient data collection and country approvals. data sharing ■■ Generic drug manufacturers also need to be involved early in the drug development process. More carefully planning studies of novel ARV drugs for children and more efficiently using 2.2 Including pregnant women, children existing data can accelerate and streamline the and adolescents in clinical trials drug development process. ■■ Pharmacokinetic data for adults can be used A more inclusive approach to clinical trial in modelling and simulation studies, along with eligibility should be embraced, with more knowledge of physiological changes among widespread inclusion of pregnant and infants and other children, to establish starting breastfeeding women, adolescents and children doses for trials involving children. of all ages, including those with coinfections. ■■ Clinical trials should be carefully designed
■■ Novel drugs with well established safety to maximize efficiency and make best use of and metabolic profiles should be evaluated resources, by employing innovative designs concurrently across weight and age ranges, and statistical methods. taking advantage of pharmacodynamic and ■■ Early planning and intersectoral pharmacokinetic modelling to estimate communication should ensure that the data starting doses. The age groups or weight bands generated in clinical trials involving children should be staggered only if there is a specific are fit for purpose; for example: safety concern. −− that the weight bands used for dosing ■■ Adolescents should be included in clinical within the trial are in accordance with trials involving adults, since they usually use WHO ARV drug dosing recommendations the formulations and doses for adults, and no for children; and major differences in safety and efficacy are −− that the results generated are sufficient for expected compared with adults. regulatory approval to be granted. ■■ Adolescents coinfected with hepatitis B or ■■ Washout data obtained from neonates C virus should be considered for inclusion in exposed to ARV drugs in utero should be used coinfection studies of adults. to support the design of neonatal trials. ■■ Children and adolescents coinfected with ■■ Acceptability data should be collected tuberculosis or hepatitis B or C virus should be systematically as part of clinical trials involving included in clinical trials and pharmacokinetic children. If data on acceptability of formulations studies. Innovative strategies to retain are already available, regulatory authorities coinfected children in ARV drug studies should should routinely make them available. be incorporated into study designs. ■■ Pooling of data, potentially through large ■■ Regulatory authorities and ethics committees paediatric HIV networks, can maximize the should require and support the inclusion of use of existing data on subpopulations such as pregnant women in pre-marketing clinical coinfected children. trials. Women enrolled in Phase II or Phase
187 ■■ Pharmacovigilance data on pregnant women ■■ Collaboration is also needed between receiving novel drugs and their exposed formulation scientists, the paediatric HIV infants should be routinely collected, and research community and social scientists to pharmacovigilance systems in low- and middle- establish consensus around the assessment of income countries should be expanded. acceptability of ARV formulations for children, including standard criteria for measuring acceptability. 2.4 Intersectoral communication and ■■ Target product profiles should be used to coordination communicate product characteristics and anticipate potential problems and should be In the past few years, the need for intersectoral developed with input from manufacturers, collaboration to facilitate the process of suppliers and regulatory agencies. developing ARV drugs for children, including ■■ Improved harmonization of regulatory supply and logistics, has become increasingly requirements and pathways and regulatory apparent. Several initiatives have emerged, interpretation of stability studies across linking drug manufacturers, research networks, different regulators would positively influence regulatory agencies, funding bodies and policy- drug development and supply and logistics. makers (1). This toolkit highlights approaches for further improving intersectoral communication ■■ Both the United States Food and Drug at various stages of the drug development Administration and the European Medicines process, including the following. Agency are already committed to improving communication across stakeholders, and such ■■ In designing clinical trials, all potential efforts should be expanded. stakeholders should be involved at an early stage, to ensure that trials are aligned as ■■ Donors, funders, country programmes and closely as possible with the objectives of implementing partners should continue to funders, regulators and clinicians. work together, for example through the Antiretroviral Procurement Working Group, ■■ Drug manufacturers should work closely to anticipate and coordinate the procurement with clinicians, expert groups and stringent of ARV drugs for children. regulatory authorities to ensure that collection of key data is feasible and that the data ■■ Overall, the approach to drug development generated are clinically relevant and meet needs to be harmonized, with efficient regulatory requirements. communication between policy-makers, the paediatric HIV research community, the ■■ Close collaboration and improved coordination pharmaceutical industry, regulatory agencies between disease areas is also critical to and funders. ensure that issues relating to the treatment of coinfected children are considered and that data on these subpopulations are collected in a timely way.
188 CONCLUSION
This toolkit contributes to a global programme The recommendations outlined in this toolkit of work encompassed by the Global Accelerator aim to simplify, unify and accelerate research for Paediatric Formulations to ensure faster, and development of drug formulations for more efficient development of optimized children and, ultimately, to expand access to treatment options for infectious diseases such as safe, effective and well tolerated ARV drugs tuberculosis, viral hepatitis and HIV (2). Although for children living with HIV in low- and middle- it focuses on HIV, many of principles discussed income countries. This is an essential step within this toolkit can be extended to other towards ensuring that WHO universal treatment disease areas with similar delays in obtaining guidelines can be adopted and that the Start treatment options for children. We therefore call Free, Stay Free, AIDS Free targets of ending on drug manufacturers, researchers, regulatory AIDS among children, adolescents and young agencies, funders and other stakeholders to women by 2020 can be achieved (3). strengthen intersectoral partnerships and work together to incorporate these recommendations into standard practice.
REFERENCES
1. Penazzato M, Gnanashanmugam D, Rojo 3. UNAIDS and United States President’s P, Lallemant M, Lewis LL, Rocchi F et al. Emergency Plan for AIDS Relief (PEPFAR). Optimizing research to speed up availability of Start free, stay free, AIDS free: a super-fast- pediatric antiretroviral drugs and formulations. track framework for ending AIDS in children, Clin Infect Dis. 2017;64:1597–1603. adolescents and young women by 2020. Geneva: UNAIDS; 2018 (https://free.unaids. 2. Penazzato M, Lewis L, Watkins M, Prabhu org, accessed 22 May 2018). V, Pascual F, Auton M, Kreft W et al. Shortening the decade-long gap between adult and paediatric drug formulations: a new framework based on the HIV experience in low- and middle-income countries. J Int AIDS Soc. 2018;21(Suppl. 1).
189 For more information, contact: World Health Organization Department of HIV/AIDS ISBN 978-92-4-151436-1 20, avenue Appia 1211 Geneva 27 Switzerland
E-mail: [email protected] www.who.int/hiv