Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations

Abstract

Globally 1.8 million children are estimated to be living with HIV, yet only 51% of those eligible actually start treatment. The completion of research and development (R&D) for paediatric antiretrovirals (ARVs) is a lengthy process and licensing of new paediatric ARVs continues to lag considerably behind adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up of paediatric treatment globally. In this manuscript we review current approaches to R&D for paediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including enrolment of multiple age-cohorts concurrently and the early introduction of dosing approaches for both single and fixed-dose combination (FDC) drug formulations (preferably scored and dispersible) that match WHO weight-bands. Efforts to speed up development of optimal drugs and formulations for children should focus on a limited number of prioritised formulations. This work should build upon existing partnerships and collaborations to ensure that paediatric investigation plans are developed early in the drug development process but can be modified in a streamlined manner as more information becomes available. In addition, simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more efficient and sustainable. Registration, implementation, and strategic use of drugs should not be seen as a sequential process, with research designed to address multiple questions simultaneously to respond to the needs of HIV-infected children where they live. It is imperative that lessons learned from HIV should be shared to support progress in developing paediatric formulations for other diseases with similar treatment challenges, including tuberculosis and viral hepatitis.

The HIV drug optimization agenda: promoting standards for earlier investigation and approvals of antiretroviral drugs for use in adolescents living with HIV

“…The Paediatric Antiretroviral Working Group led by the World Health Organization (WHO), has proposed optimizing research approaches for children and adolescents to speed-up the availability of ARVs and formulations for these groups [1]. Recently, the United States Food and Drug Administration (US FDA) recommended that ARV drug trials include adolescents (aged 12 to <18 years) in phase 3 clinical trials along with adults, or that a separate phase 3 clinical trial among adolescents be conducted in parallel [2].…”

Inclusion of pregnant women in antiretroviral drug research: what is needed to move forwards?

“…In both treatment and prevention studies, drug exposures in the infant may also be "opportunistically" measured, by doing "washout PKs, " where infants are exposed to maternal ARVs. This provides data which can be modelled before formal PK studies, depending on the suitability of the new ARV to be used for treatment or prophylaxis in this age group [97].…”

Propelling the Pediatric HIV Therapeutic Agenda With Science, Innovation, and Collaboration

“…The pediatric therapeutic agenda has generally lagged behind advances in the adult population, resulting in substantial delays in new medications, formulations, and approaches to treat HIV infection in infants, children, and adolescents. 12 – 14 Historically, a number of well-described obstacles have thwarted drug development as well as intervention and pathogenesis research. 12 , 13 The rapid growth and physical development that characterize the trajectory of childhood generally necessitates dose changes as well as unique formulations that can easily be administered to infants and young children.…”

“… 12 – 14 Historically, a number of well-described obstacles have thwarted drug development as well as intervention and pathogenesis research. 12 , 13 The rapid growth and physical development that characterize the trajectory of childhood generally necessitates dose changes as well as unique formulations that can easily be administered to infants and young children. Traditionally, new drugs have been studied by age group, advancing from older to younger children, resulting in complex study designs with long timelines.…”

“…Other impediments have included regulatory hurdles, cautious engagement and investment of pharmaceutical companies, limitations on blood volumes that can be obtained from small children, and ethical conundrums around participation of children and adolescents in research. 12 …”