Current landscape of clinical development and approval of advanced therapies

Abstract

Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. The uncertainty about the product's benefit-risk balance at the time of approval, the limitations of nonclinical development, and the complex quality aspects of those highly individualized advanced therapies are playing a key role in the clinical development, approval, and post-marketing setting for these therapies. This article reviews the current landscape of clinical development of advanced therapies, its challenges, and some of the efforts several stakeholders are conducting to move forward within this field. Progressive iteration of the science, methodologically sound clinical developments, establishing new standards for ATMPs development with the aim to ensure consistency in clinical development, and the reproducibility of knowledge is required, not only to increase the evidence generation for approval but to set principles to achieve translational success in this field.

Methodological Characteristics of Clinical Trials Supporting the Marketing Authorisation of Advanced Therapies in the European Union

“…On the other hand, the difficulties of conducting standard clinical developments with orphan drugs are well-recognised, and single small trials using alternative approaches have been the basis for numerous MAA in the recent years ( Blin et al, 2020 ; Micallef and Blin, 2020 ; Picavet et al, 2013 ; Pontes et al, 2018 ). This regulatory flexibility sometimes comes at the cost of having a less comprehensive clinical data, and in consequence, greater uncertainty about the product’s benefit-risk balance at the time of MA ( Iglesias-Lopez et al, 2021b ). In addition, since the introduction of the adaptive pathway concept, the shift towards accelerated clinical developments has also been associated with an intrinsic uncertainty on effectiveness and safety, which can result in promising Phase II results but an unsuccessful Phase III or post-marketing studies ( Pharma Intelligence, 2019 ; Novartis press release, 2021a , b ).…”

Análisis estratégico para la implementación de las terapias avanzadas en España

“…Desde el año 2009, la EMA ha aprobado 24 terapias avanzadas 1,19,20 , aunque en la actualidad solamente 17 de ellas cuentan con una autorización de comercialización vigente en la Unión Europea 1, 20 . El 76% de estas terapias son consideradas medicamentos huérfanos (MMHH), y un 35% cuenta con una aprobación condicional de comercialización.…”

“…Fuente: Iglesias-López (2021) 20 Para hacer frente a esta problemática, se llevan a cabo distintas acciones que busquen disminuir los riesgos y la incertidumbre sobre los resultados de los ensayos clínicos. Por ejemplo, recientemente el Instituto de Salud Carlos III ha aprobado una subvención de 10 millones de euros a proyectos de I+D vinculados a la Medicina Personalizada y Terapias Avanzadas dentro de la actuación coordinada para el fomento de la colaboración público-privada y la transferencia de I+D+i académico al sector industrial.…”

Gene transfer and genome editing for familial hypercholesterolemia

“…In recent years, gene therapy has emerged as a promising therapeutic option for monogenic diseases, as witnessed by the ever-growing number of clinical trials and approved drug products (Iglesias-Lopez et al, 2021). Gene therapy offers the attractive prospect of being a "one-and-done" treatment by inducing a permanent genetic modification in the host for a therapeutic purpose.…”