Title: Regulatory bench-testing of a transformational polymeric heart valve: a key step toward a first-in-human trial to benefit patients aged 18-80 with one valve type
Funder: Department of Health and Social Care

Abstract: Research Question: Can we achieve design freeze of a new polymeric heart valve? Background: Worldwide 1.3 million patients with heart valve disease require valve replacement surgery annually. With the geriatric population growing rapidly and rheumatic valve disease affecting 35 million younger patients in undeveloped countries, valve replacement surgeries will increase by 4-5 times by 2050. Existing biological valves (trans-catheter plus surgical devices) are used in 90% of cases. They are biocompatible with excellent functional performance but used only in elderly patients as they last only 10-12 years. Mechanical valves are used in younger patients due to excellent durability but require life-long anticoagulation, which triggers 3-4% thrombo-embolic/haemorrhagic events/year and teratogenicity during pregnancy. These obvious limitations involve poor health outcome and many expensive readmissions. Therefore, we have developed a transformational polymeric heart valve, using a proprietary technology, for patients of any age, that combine excellent durability and biocompatibility with no need for long-term anticoagulation. Bench testing at ISO standards of 19-21mm aortic valves has demonstrated >35 years of durability with function being similar to the best-in-class biological valve. Short-term in-vivo testing in sheep has confirmed feasibility, function and biocompatibility. Six mitral valves made with the same technology have just been implanted at IMMR-Paris preclinical facility with study design based on FDA and tier 1 company guidance to assess structural integrity, calcification, dynamic performance, biocompatibility, and toxicity at 6-month (results due in April 2022). A spin-out, Cambris Cardiac Ltd, created by Universities of Cambridge and Bristol has secured &pound;450k in seed funding to accelerate the route to adoption and oversee non-clinical/clinical testing required by regulators. Aims/objectives: To achieve design freeze using methods conforming with ISO 5840:2015 and to progress the device toward NHS adoption. Methods: The research plan includes 3 milestones over 9 working packages (WPs) with Go/No-go criteria: WP1.Material safety validation; Milestone 1: Acceptable material properties; WP2.Design optimisation; WP3.Standardisation of manufacturing and quality control; WP4.Device validation; Milestone 2: Design freeze; WP5.Clinical grade coating, sterilisation, packaging and storage; WP6.Development of valve holders and sizers; Milestone 3: In vitro regulatory compliance; WP7.Device description, labelling, performance, and shelf-life specifications; WP8. Health Economics; WP9.Public and patient involvement, engagement and participation (PPIEP). Surveys among 20 patients and 20 heart surgeons/cardiologists/healthcare professionals confirmed clinical need and willingness to receive or implant/assess the new valve and NHS adoption. The Bristol NIHR BRC PPIEP group have provided feedback captured in the application and we have pre-defined clear PPIEP deliverables. For risk mitigation we have established partnerships with CamBris Cardiac Limited (co-applicant), Biointeractions-UK (heparin-coating), IMMR-Paris-France (preclinical studies, not funded here), Biomerics LCC-US (material safety/manufacturing, not funded here), Tower Mains Ltd-UK (regulation / quality management system), CardioMed Device Consultants-US (FDA/MHRA regulatory approvals) and Arterius-UK (packaging and shelf life). Timelines: Design freeze by end 2023; preclinical regulatory hurdles cleared by mid 2025; start a FIH trial within 1-year after that. Anticipated Impact, and Dissemination: the new valve could replace existing artificial valves on a global scale, with major patient/societal/economical benefit. Dissemination will be in line with NIHR practice.

Lay abstract: Aim: To develop the final version of a new heart valve for use in patients Why do we need this? Worldwide 1.3 million patients with heart valve disease require valve replacement surgery every year. With the older population predicted to increase to 83 million by 2050 in the US only and rheumatic heart valve disease affecting 35 million younger patients in undeveloped countries, heart valve replacement surgeries are likely to increase by 4-5 times by 2050. Existing metal valves are used in younger patients as they last longer, but they require mandatory life-long blood thinning, which in turn is associated with serious blood clotting or bleeding complications. Biological valves, made from cow/pig tissue have excellent function and do not require life-long blood thinning, but are used only in elderly patients as they last only 10-12 years. Why do we need this? We have developed a transformational heart valve for patients of any age made from safe special plastic that function like a biological valve but last more than 35 years at bench-testing like a metal valve with no need for blood thinning tablets. Hence, this could markedly increase patient benefit and reduce hospital costs. Are there any risks to the new valve? Short-term testing in sheep has confirmed feasibility, function and no need for blood thinning. Six new implants have just been completed in Paris in keeping with regulatory safety standards to confirm safety and non-toxicity at 6-month after surgery with results available by April 2022. Conclusive safety checks will be undertaken if this study is funded. We will be considering environment impact and will be using environmentally sustainable resources where possible, The study: If all proceeds according to plan, it will take 12-15 years to see this new valve used in the NHS. We have already completed 8 years of this. The current study will last 3 years and will allow us to obtain the very final version of the new valve and confirm safety and efficacy before it is used in patients. The study will focus on standardisation of manufacturing of the final version, conclusive bench-testing, quality control, material safety, effective sterilisation, packaging and storage. Patient and Public Involvement, Engagement and Participation (PPIEP) will be involved in every possible stage of this research and PPIEP training on all aspect of developing and testing a new device will be provided to ensure continued education and contribution to decision-making on safety aspects and risk mitigation via representation on the Steering Committee and regular workshops. We will also be carrying out an economic assessment to make sure the valve is good value for money. We hope to share the results with as many people as possible.

Research activity codes: 5.4 SURGERY
Health categories: CARDIOVASCULAR