Uncertainty management in regulatory and health technology assessment decision-making on drugs: guidance of the HTAi-DIA Working Group.

OBJECTIVES: Uncertainty is a fundamental component of decision making regarding access to and pricing and reimbursement of drugs. The context-specific interpretation and mitigation of uncertainty remain major challenges for decision makers. Following the 2021 HTAi Global Policy Forum, a cross-sectoral, interdisciplinary HTAi-DIA Working Group (WG) was initiated to develop guidance to support stakeholder deliberation on the systematic identification and mitigation of uncertainties in the regulatory-HTA interface. METHODS: Six online discussions among WG members (Dec 2021-Sep 2022) who examined the output of a scoping review, two literature-based case studies and a survey; application of the initial guidance to a real-world case study; and two international conference panel discussions. RESULTS: The WG identified key concepts, clustered into twelve building blocks that were collectively perceived to define uncertainty: "unavailable," "inaccurate," "conflicting," "not understandable," "random variation," "information," "prediction," "impact," "risk," "relevance," "context," and "judgment." These were converted into a checklist to explain and define whether any issue constitutes a decision-relevant uncertainty. A taxonomy of domains in which uncertainty may exist within the regulatory-HTA interface was developed to facilitate categorization. The real-world case study was used to demonstrate how the guidance may facilitate deliberation between stakeholders and where additional guidance development may be needed. CONCLUSIONS: The systematic approach taken for the identification of uncertainties in this guidance has the potential to facilitate understanding of uncertainty and its management across different stakeholders involved in drug development and evaluation. This can improve consistency and transparency throughout decision processes. To further support uncertainty management, linkage to suitable mitigation strategies is necessary.

Adaptation through Collaboration: Developing Novel Platforms to Advance the Delivery of Advanced Therapies to Patients.

For the nascent field of advanced therapies, collaboration will be a game-changer, turning scientific progress that was once unimaginable into transformative medical practice. Despite promise for lifelong management and even cure of disease, skepticism remains about the feasibility of their delivery to patients, fueling investment risks. With the potential for long-term effectiveness in need of frequent reassessment, current approaches to predict real-life drug performance bear little relevance, necessitating novel and iterative schemes to monitoring the benefit-risk profiles throughout the life span of advanced therapies. This work explains that reinventing an adoption route for Advanced Therapy Medicinal Products is as much about the scientific and clinical components, as it is about the organizational structures, requiring an unprecedented level of interactions between stakeholders not traditionally connected; from developers and regulators, to payers, patients, and funders. By reflecting on the successes and lessons learned from the growing space of global precompetitive consortia and public-private partnerships, as well as a number of emerging accelerated development pathways, this work aims to inform the foundations for a future roadmap that can smooth the path to approval, reimbursement, and access, while delivering value to all stakeholders. Echoing the growing demands to bring these transformative products to patients, it provides critical insights to enhance our capacity in three fundamental domains: deploying the operational flexibilities offered by the growing space of collaborations, utilizing emerging flexible and accelerated pathways to tackle challenges in quantifying long-term effectiveness, and building the necessary digital and clinical infrastructure for knowledge development.

Curing consortium fatigue.

The complex pathology of consortium fatigue provides diagnostic data on how to improve collaboration in biomedical innovation.

A foamy virus vector system for stable and efficient RNAi expression in mammalian cells.

The promise of the RNA interference (RNAi) technology is equally dependent on the efficiency and stability of gene silencing. The aim of the present study was the development of foamy virus (FV) vectors for stable RNAi, utilizing two potent RNA polymerase III (Pol III) promoters. Using green fluorescent protein as a target gene, we examined the efficiency of mouse U6 (mU6) and human H1 Pol III promoters in different human cell lines and mouse hematopoietic stem cells (HSCs) ex vivo and in vivo, following bone marrow transplantation. Both our mU6 and H1 FV vectors mediated very efficient gene silencing with as low as one vector copy per cell. However, transduction of human cell lines with FV vectors expressing short hairpin RNA from mU6 led to the gradual elimination of cells in culture, as opposed to H1-harboring cells, underscoring the importance of the expression system or cellular context in the evaluation of the overall RNAi effects. The efficiency and stability of the H1 vectors were further shown by the successful silencing of BCR-ABL in K562 cells. Accordingly, mU6 vectors induced efficient and stable gene silencing in mouse HSCs following bone marrow transplantation. Our work is the first in vivo study on the efficiency and stability of RNAi gene silencing in HSCs with FV vectors, currently a safe alternative for viral gene transfer.

Splice-variant- and stage-specific RNA editing of the Drosophila GABA receptor modulates agonist potency.

The molecular diversity of many gene products functioning in the nervous system is enhanced by alternative splicing and adenosine-to-inosine editing of pre-mRNA. Using RDL, a Drosophila melanogaster GABA-gated ion channel, we examined the functional impact of RNA editing at several sites along with alternative splicing of more than one exon. We show that alternative splicing and RNA editing have a combined influence on the potency of the neurotransmitter GABA, and the editing isoforms detected in vivo span the entire functional range of potencies seen for all possible edit variants expressed in Xenopus laevis oocytes. The extent of RNA editing is developmentally regulated and can also be linked to the choice of alternative exons. These results provide insights into how the rich diversity of signaling necessary for complex brain function can be achieved by relatively few genes.