Trends in clinical development of tissue-engineered products in the EU
While gene therapies are currently on the rise, few tissue-engineered products (TEPs) are being developed. TEPs consist of engineered cells or tissues that are produced to regenerate, repair, or replace a dysfunctional, diseased, or absent human tissue.
From a regulatory perspective, TEPs are covered under the framework for advanced therapy medicinal products (ATMP regulation, (EC) No 1394/2007).TEPs make up less than 5% of all ATMPs in clinical trials and received 5.1% of ATMP-designated funding in trials in the EU in 2019.
In a recently published paper, authors conducted an overview of TEPs under development, identifying musculoskeletal, cardiovascular, and skin/connective tissue disorders as the main therapeutic areas of interest. The review further identified a trend towards development of allogeneic cells in TEPs and increasing interest in early phase clinical trials.
Commercial sponsors have funded most of the clinical trials with TEPs, with a significantly higher proportion of late-phase trials. Commercial sponsors also fund about one-third more Phase I/II and II trials than noncommercial sponsors. It can be assumed that some of these commercial sponsors in early phases are small Biotech Companies, including spin-offs from universities.
To date, of the 25 total ATMPs that have been granted marketing authorization by the European Medicines Agency (EMA), only 4 were TEPs. Two of those have since been withdrawn from the market, leaving just two TEPs on the market: Spherox, which is used to repair cartilage defects of the knee and Holoclar, a stem-cell treatment used to replace damaged cells on the surface of the cornea.
Uncovering the trends
To better understand trends in TEP research, we — a group of scientists and regulatory experts with expertise in the field — conducted a review of TEPs in clinical development via a search of the EudraCT database. The research found 90 clinical studies involving TEPs at sites across the EU in all phases of clinical research (it needs to be noted, however, that Phase 1 studies are not included in the analysis as they are not listed in the EudraCT database). Some of these studies have been concluded, most are ongoing and a couple of them have been halted or ended prematurely. It Is also interesting to note that, while the majority of the clinical studies (60%) use autologous cells, 40% now investigate allogeneic cells. Indeed, the trend toward allogeneic cells has been gathering pace over the past two years. The review found that more autologous cells are in later phases of development than allogeneic, which we believe might be due to preference for autologous cells in earlier years, partly including products that have been on the EU market since before the EU ATMP regulation came into force.
While allogeneic cells raise concerns over immunogenicity to the recipient, since they involve healthy donor material immunologically distinct from patients’ immune system, they benefit from the possibilities for producing larger batch sizes at lower production costs, the availability of off-the-shelf products and greater control over variability.
There are also shelf-life issues to overcome since TEPs usually can’t be provided frozen, and therefore shelf life is typically very short, usually no more than four days or even less. Currently because it is not possible to freeze TEP products full sterility testing at time of release to the patient is not possible, which adds the risk of microbial contamination. Therefore, the product manufacture needs to be accompanied by a robust aseptic manufacturing process with a reasonable sterility testing strategy starting from the tissue biopsy up to final product as well as a risk mitigation in case of post-transplant positive results. This underscores the need for developing rapid sterility methods.
Therapeutic areas of research
The largest majority of trials (32) are conducted in patients with musculoskeletal diseases, another 16 in cardiovascular diseases and 14 in skin disorders. The remaining are in a broad range of various disorders such as eye diseases, ear, nose and throat, urinary and reproductive system, metabolic, respiratory and congenital, hereditary and neonatal disorders. The review elaborated that studies in musculoskeletal and cardiovascular diseases have been increasing since 2009, which the authors attributed to emerging interest in these areas.
However, advancing products to the next stage will require solutions for immunogenicity and shelf-life challenges, managing the regulatory pathway, and addressing costs including. reimbursement considerations.
Still there is cause for slight optimism with TEPs. As the paper shows, research trends and greater focus on allogeneic TEPs could pave the way for more products to receive marketing authorization and reach patients in need.
About the author
Dr. Zaklina Buljovcic is Director, Principal Consultant Innovative Therapies, Biopharma Excellence by PharmaLex. She is a regulatory specialist for innovative therapies, especially advanced therapy medicinal products (ATMPs) with 14 years of experience in the field and 18+ years in regulatory. She has also broad experience and knowledge with other innovative products such as biotech, tissue, blood, and microbiota transplantations. Zaklina’s main focus includes regulatory strategy, project management, and pharmaceutical quality.