Osteoarthritis (OA) represents a high-burden non-communicable disease (NCD) and is a principal cause of chronic disability in adults. It is the most common inflammatory and degenerative disease of synovial joints. More than 500 million people worldwide suffer from its debilitating clinical symptoms and ~80% of the elderly population shows radiographic signs. The incidence of OA is further rising because of an aging population and the epidemic of obesity, especially in more economically developed countries. The total age-standardized disability-adjusted life-years (DALY) rates considerably rose by 35% and age-standardized DALY rates by 4% between 1990 and 2015, attesting to the ever-growing epidemiological and socioeconomic priority of OA.
Early phases of OA are probably the most relevant to be treated with gene therapy approaches since the structural destruction and erosion just begin.
As early OA mainly affects the articular cartilage, this tissue is a key target for a chondroanabolic gene therapy in early OA. However, altered inflammatory and immunological patterns contribute to the progressive damage in early OA and thus are also targets for current gene therapy approaches. The accessibility of different gene transfer techniques has successfully focused on chondrocytes in vitro and in situ/in vivo when their impermeable extracellular matrix (ECM) encompasses the cells. Such methods depend on either nonviral compounds or viral contaminant vehicles that utilize normal passage pathways in cells. Recombinant adeno-associated viral (rAAV) vectors are the only known class of gene vectors that can penetrate the dense cartilaginous ECM with high efficiency, making them particularly suited for approaches to improve the articular cartilage structure. The major tactics of gene therapy for OA are in vivo and ex vivo approaches. Direct gene transfer strategies have been tested by either systemic delivery or intraarticular vector administration via injection or direct application of the gene vector. The first clinical trial for OA was performed in patients with end-stage knee OA using an ex vivo approach to intraarticularly provide TGF-b1. Other ongoing gene therapy trials use an rAAV vector carrying an IL-1Ra transgene or plasmid DNA encoding a variant of human IL-10.
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The outcome of the translation of basic knowledge into a clinical application is often covered by specific legislations and thus associated with regulatory requirements linked to them. Broadly speaking, legal, procedural and scientific issues need to be considered.
While scientific issues might be more globally aligned, procedural and legislative frameworks differ approaches between regions. The presentation will focus on the EU and provide considerations to ensure compliance, usability and robustness of data generated in development. In addition, innovative developments frequently bridge the interface between multiple legislations, which adds scientific and regulatory complexity to their development. With a focus on Advanced Therapy Medicinal Products (ATMPs), the presentation will give a brief overview on issues to consider and support available.
The first regulatory consideration is whether a certain development falls under the legal definition of a medicinal product, medical device or other, considering indication and mechanism of action. Procedural requirements for clinical trial submissions are revised at the beginning of 2022 with the practical application of the EU Clinical Trials Regulation (Regulation (EU) 536/2014), further information is available in EudraLex Volume 10 (https://ec.europa.eu/health/documents/eudralex/vol-10_en), where dedicated guidance is also available according to the nature of the investigational medicinal product (e.g. small molecule, biologic, ATMP). Guidance for later development stages and requirements for marketing authorization can be found on the webpage of t he European Medicines Agency (EMA, www.ema.europa.eu).
For developments incorporating device elements or codevelopment of in-vitro diagnostics, the Medical Device Regulation (Regulation (EU) 2017/745, MDR) and the In Vitro Diagnostics Regulation (Regulation (EU) 2017/746, IVDR) need to additionally be considered. Where a product has a device element, procedural requirements during development differ depending on whether the device is considered as integral or not. Intregral devices need to comply with the general performance and safety requirements of annex I of the MDR, but procedurally, a clinical trial with such a product falls under the medicines legislation only. In contrast, where a medicinal product and a non-integral medical device are being co-developed, the procedural requirements for clinical trials according to both legislations need to be considered. The latter also applies for the co-development of in-vitro diagnostics including companion diagnostics. The legislative framework currently does not provide for a single procedure investigating both medicines and medical devices/IVDs.
Efforts are ongoing to clarify interface issues between medicines and medical device legislations with guidance to follow. Guidance on the consultation procedure for Companion diagnostics has recently been published on the EMA website. Further, for cell-based approaches, the ongoing revision of the EU Tissues and Cells Legislation is to be considered for donation and procurement requirements.
Support for developers is available through the Innov ation Network, which includes Innovation offices at National Competent Authorities and EMA. In addition, scientific advice is provided on both National and EMA level, where EMA scientific advice focuses on marketing authorization requirements.
The presentation will highlight regulatory requirements during early development of a biological medicinal product, give a brief guide on the regulatory system and highlight interface issues for medicinal products combining drug and device elements, including in vitro diagnostics
https://ec.europa.eu/health/documents/eudralex/vol-10_en
www.ema.europa.eu
www.who.int/groups/expert-committee-on-biological-standardization