Issues with Tissues: Trends in Tissue-Engineered Products in Clinical Trials in the European Union

Abstract

Tissue-engineered products (TEPs) consist of engineered cells or tissues produced to regenerate, repair, or replace a dysfunctional, diseased, or absent human tissue. TEPs make up <5% of all advanced therapeutic medicinal products (ATMPs) in clinical trials and received 5.1% of ATMP-designated funding in trials in the European Union (EU) in 2019, highlighting the relatively low proportion of TEPs being developed. The realization of TEPs being marketed has yet to be fulfilled, with few products being approved. Since 2009, 90 TEP-based clinical trials have been undertaken in the EU. Of these 90, 25 were Phase I/II trials, 35 were Phase II, 28 were Phase III, and two were Phase IV trials. This review provides an overview of TEPs in development, identifying musculoskeletal, cardiovascular, and skin/connective tissue disorders as the main therapeutic areas of interest. Commercial sponsors have funded most trials, and a significantly higher proportion of late-phase trials. Furthermore, this study has identified a shift toward the use of allogeneic cells in TEPs and increased activity in the proportion of early phase trials listed. This indicates a renewed interest in TEP development as sponsors adapt to the new regulation, with prospects of more TEP market authorization applications in the future. Impact Statement Tissue-engineered products (TEPs) consist of engineered cells or tissues produced to regenerate, repair, or replace a dysfunctional, diseased, or absent human tissue. This article evaluates the regulatory landscape of TEPs and identifies the trends in clinical trial activity in the European Union (EU) since the introduction of Regulation (EC) No 1394/2007. This article identifies trends in TEP development, highlighting the most active member states, commercial involvement, a shift toward the use of allogeneic cells and a renewed interest in TEP development in recent years.

Keywords: European Union; advanced therapeutic medicinal products; clinical trial; tissue-engineered product.

FIG. 1.

Geographical overview of clinical trial activity investigating TEPs in each Member State according to the EU Clinical Trials register, analyzed on January 22, 2022. The geographical map represents all trial sites across EU states, where some trials contain multiple sites across states. “No. of trials by sponsor state/union” represents the number of individual trials funded by a sponsor in each named jurisdiction. Sponsor state, trial phase, sponsor status, and trial status reflect individual trials with unique EudraCT numbers. Funding sources for TEP clinical trials are divided into sponsors located in EU and non-EU states. Two trials sponsored by the EU through the European Commission and Horizon 2020 listed the EU as the sponsor and thus no state is given. However, while UK is no longer in the EU, it has been included in this graph to accurately represent clinical activity over the last 12 years. Trial-phase status is based on the most recent updated list in the EU Clinical Trials Register. Phase I trials are not publicly available in the EudraCT database, except those including pediatric populations. “Other” in trial status includes two halted trials and one restarted trial. EU, European Union; TEP, tissue-engineered product; UK, United Kingdom. Color images are available online.

FIG. 2.

Medical conditions under investigation summarized by therapeutic area and trial phase. The number of trials in various therapeutic areas (left) is matched to the trial phase (right), providing an overview of the proportion of therapeutic areas in early- and late-phase trials. The EMA provides updates and opinions on therapeutic areas for approved medicines. Many entries have been revised and corrected due to sponsor errors and inaccuracies. Errors include the sponsors listing therapeutic area as “Analytical, Diagnostic and Therapeutic Techniques and Equipment—Surgical Procedures, Operative,” “Body processes—Cell Physiological Phenomena,” and “Not possible to specify” for TEPs that repair focal cartilage defects, which should be listed as “Musculoskeletal Diseases.” EMA, European Medicines Agency. Color images are available online.

FIG. 3.

Distribution of autologous and allogeneic cell use across sponsor types and trial phase. Commercial status is self-reported by sponsor input. (A) Commercial sponsors fund a great proportion of trials using allogeneic cells versus autologous cells. In contrast, noncommercial sponsors funded a greater proportion of trials using autologous cells. (B) Overview of the number of trials in each phase using autologous and allogeneic cells, further divided by sponsor status. (C) Distribution of cell origin in the trial phase. Autologous cells have been used in a greater proportion of late-phase trials. (D) Commercial sponsors have funded a greater proportion of late-phase trials over noncommercial sponsors. Statistical analysis of these data is presented in Table 1. Color images are available online.

FIG. 4.

Details of the IMPs used in TEP trials. Autologous and allogeneic cells were used in all trials. The “Standard Terms Database” generated by the EDQM is used to describe the pharmaceutical form and route of administration of IMPs. EDQM, European Directorate for the Quality of Medicines; IMPs, investigational medicinal products. Color images are available online.

FIG. 5.

Trends in trial characteristics from 2009 to 2021, inclusive. Characteristics from the first 6 years since regulation introduction (2009–2015) (n = 43) were compared to the last 5 years of trial entries to date (2016–2021) (n = 47). Two different time frames were used to capture a similar number of studies. A significant relationship was identified between time period and cell source (X = 5.02, p = 0.0251) and trial phase (X = 4.36, p = 0.037). No relationship was observed for the time period and commercial status (p = 0.9288). Color images are available online.