Clinical development of gene- and cell-based therapies: overview of the European landscape

Abstract

In the last decade, many clinical trials with gene- and cell-based therapies were performed and increasing interest in the development was established by (national) authorities, academic developers, and commercial companies. However, until now only eight products have received marketing authorization (MA) approval. In this study, a comprehensive overview of the clinical development of gene- and cell-based therapies in Europe is presented, with a strong focus on product-technical aspects. Public data regarding clinical trials with gene- and cell-based therapies, obtained from the European Union (EU) clinical trial database (EudraCT) between 2004 and 2014 were analyzed, including product-technical variables as potential determinants affecting development. 198 unique gene and cell therapy products were identified, which were studied in 278 clinical trials, mostly in phase 1/2 trials and with cell therapies as major group. Furthermore, most products were manufactured from autologous starting material mostly manufactured from stem cells. The majority of the trials were sponsored by academia, whereas phase 3 trials mostly by large companies. Academia dominated early-stage development by mainly using bone marrow derived products and stem cells. Conversely, commercial sponsors were more actively pursuing in vivo gene therapy medicinal product development, and cell therapies derived from differentiated tissue in later-stage development.

Figure 1

Gene- and cell-based therapy landscape. CTMP, cell therapy medicinal product; GTMP, gene therapy medicinal product; SME, small and medium-sized enterprise; TEP, tissue-engineered product. (a) Distribution of the indication areas for the gene- and cell-based therapy, showing absolute numbers derived from the public domain of the EudraCT database*; (b) Absolute numbers of clinical trials with the of gene- and cell-based therapy product types per year; (c) Numbers (represented in percentages, n = 278) of different clinical trials study phases performed with gene- and cell-based therapy products. * Since phase 1 clinical trials are not in the public domain of EudraCT and processing of trials in EudraCT can be delayed, clinical trials may be missing.

Figure 2

Country-specific variations in gene- and cell-based therapy development. (a) Percentage of clinical trials with gene- and cell-based therapies per country derived from the public domain of the EudraCT database* depicted in color and absolute numbers of clinical trials performed per country (written in country). (b) Ratio of the number of clinical trials with gene- and cell-based therapy products performed in a country per the total amount of clinical trials in that country derived from the public domain of the EudraCT database. The white colored countries did not perform any studies with gene- and cell-based therapy products or do not belong to the European Union. (European map adjusted from http://www.youreuropemap.com/). * Since phase 1 clinical trials are not in the public domain of EudraCT and processing of trials in EudraCT can be delayed, clinical trials may be missing.

Figure 3

Sponsor type variations in gene- and cell-based therapy development. CTMP, cell therapy medicinal product; GTMP, gene therapy medicinal product; SME, small- and medium-sized enterprise; TEP, tissue-engineered product. (a) Distribution of the different sponsors that performed clinical trials with gene- and cell-based therapies. (b) Absolute numbers of clinical trials performed with gene- and cell-based therapy types per sponsor and the total absolute number of clinical trials with the different gene- and cell-based therapy types. (c) Absolute numbers of clinical trials in different clinical phases per sponsor and the total number of clinical trials per clinical phase. (d) Starting material per sponsor type.

Figure 4

Database record selection and arrangement. (a) A schematic overview of the EudraCT data record selection. Trial data records from the EudraCT queries were reduced towards product records with corresponding clinical trials. (b) A schematic overview on how the database ProMISe was built, by coupling of clinical trials to the product and coupling of the countries in which the clinical trials have been performed.