The national blueprint for future factor VIII inhibitor clinical trials: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors

Abstract

Introduction Inhibitor formation is a major complication of haemophilia for which clinical trials are planned. Despite emerging novel haemostatic agents, challenges of rare disease trials are limited subjects and lack of an organized research organization with strategic resources and partnerships. Aim The charge to Working Group 1 was to establish scientific priorities and innovative implementation strategies to conduct inhibitor prevention and eradication trials. To determine feasibility of trial design and strategic resources and partnerships to be leveraged, two clinical trial concepts were considered. Results For the Inhibitor Prevention Trial, we considered adaptive design with early stopping rules, dynamic randomization and Master Protocol models to reduce sample size; and registries to provide concurrent controls and natural history data. For the Inhibitor Eradication Trial using gene therapy, an adaptive design was considered in a small number of subjects, and, if safe and meeting regulatory requirements, enrolment would be expanded. A Haemophilia Clinical Trials Group (HCTG) infrastructure was envisioned, with uniform procedures and standardized outcomes, data collection and assays, within which trial concepts would be developed, vetted and prioritized by a Steering Committee, and submitted to NIH and other research sponsors for review and funding. Mechanistic studies would be embedded within the trials, early stage investigators trained and mentored, and the research infrastructure established within the haemophilia centre (HTC) network and supported by partnerships with foundations, community, federal partners and industry. Conclusion The success of inhibitor trials will depend on innovative trial design and an organized HCTG research infrastructure, leveraged through community partnerships.

The national blueprint for future basic and translational research to understand factor VIII immunogenicity: NHLBI State of the Science Workshop on factor VIII inhibitors

“…Individual clinical centres that receive funding from other community studies would be expected to contribute as many types of samples as possible given their available resources. Given recent advances in gene therapy as a potential cure for haemophilia, it would be most advantageous to also incorporate analysis of immune responses to FVIII in gene therapy trials and work, potentially with industry partnerships, towards a clinical trial on reversal of inhibitors by gene therapy (Figure ) . This will also help prepare gene therapy trials that aim to induce tolerance in patients with inhibitors.…”

The national blueprint for 21st century data and specimen collection and observational cohort studies: NHLBI State of the Science Workshop on factor VIII inhibitors

“…The future US infrastructure model for seamless data and biospecimen collection across the lifespan of an individual emerged from the NHLBI‐sponsored SOS workshop, characterized by the fluid movement of registered individuals from observational cohort to clinical trial and back with capture of longitudinal clinical and laboratory phenotyping, including personalized ‐ omics. These data would be informed by and support basic/translational and clinical research priorities in haemophilia and in FVIII immunogenicity and tolerance . Outcomes from basic/translational science, observational studies and clinical trials would then inform subsequent mechanistic, clinical and observational research priorities.…”

Executive summary of the NHLBI State of the Science (SOS) Workshop: Overview and next steps in generating a national blueprint for future research on factor VIII inhibitors

“…The blueprints for future basic, translational and clinical research in FVIII immunogenicity, and in the prevention and eradication of FVIII inhibitors has been detailed in each of the full Working Group reports . This paper will serve to highlight and integrate several key points from each body of work.…”

“…A Haemophilia Clinical Trials Group (HCTG) concept was proposed from Working Group 1 which would provide the resources for clinical trial infrastructure. This would facilitate funding for personnel, data acquisition, sampling, processing and shipment; set up a single IRB for protocol submission; drive trial implementation; and assure appropriate clinical trial design and biostatistical support for trial concept development.…”