The development of innovative therapies starts with translating discoveries from basic research. This section explores the steps from fundamental to pre-clinical and clinical research underpinning the development of innovative gene and cell therapies.
Recent advances in biotechnology and medicine have initiated a shift from the traditional one-size-fits-all medicine towards a more personalised approach. Advanced Therapy Medicinal Products (ATMPs) are part of this new class of innovative and complex biological medicinal products. ATMPs are biological medicinal products under European Union law. They can be sub-classified as gene therapy medicinal product (GTMP), somatic cell therapy medicinal product (sCTMP), tissue engineered product (TEP) and combined ATMP (cATMP). Learn more in Therapy Classification. These therapies are developed by targeting the cause of diseases at the molecular level or the cell level.
The principle of gene therapy is to correct a faulty or missing gene that causes an inherited condition to alleviate symptoms. Scientists have developed various methods, including viral vectors (Adeno-Associated Virus, Adenovirus, Lenitvirus), bacterial plasmid vectors, and non-biological gene delivery systems to deliver therapeutic genetic materials into cells to restore their normal functions. Tools that directly modify or edit the cellular genome are also being actively developed, including zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs), and more recently CRISPR (see Jinek et al 2012, Cong et al 2013, and Adli 2018).
Cell therapy includes a wide range of treatments in which somatic cells (body cells not involved in reproduction) are used to heal the patient. The cells are manipulated to change their biological characteristics, and are administered to humans to treat diseases through pharmacological, immunological, or metabolic actions of the manipulated cells. An EMA-approved example is using properties of MSCs (mesenchymal stromal cells, or mesenchymal stem cells) to reduce inflammation and to facilitate the growth of new tissues (see Alofisel). More cell therapies using stem cells are also under active development, regenerating and repairing damaged tissues and organs.
Tissue engineered products function by regenerating, repairing, and replacing diseased tissue. An example of approved TEP uses spheroids (spherical aggregates) of chondrocytes (cells found in patient’s own healthy cartilage) to repair defects in knees by producing new tissues (see Spherox)
Combined advanced therapy medicinal product (cATMP) is a gene therapy medicinal product, or a somatic cell therapy medicinal product or a tissue engineered product that incorporates one or more medical devices or active implantable medical devices. One example of approved combined TEP uses matrix-applied characterised autologous cultured chondrocytes to repair symptomatic cartilage defects of the knee (see Maci). However, the marketing authorisation for Maci has expired following the marketing-authorisation holder’s decision not to pursue the renewal of the marketing authorisation as well as its previous decision to close the EU manufacturing site for the medicine due to commercial reasons (read more here).
Other approved ATMPs notably include: Holoclar, which uses a patient's own stem cells found in corneal epithelial cells, to replace damaged cells on the surface of the cornea caused by burns. Kymriah and Yescarta, which use a patient's own T cells, genetically engineered, to express chimeric antigen receptors (CAR). These modified T cells recognise antigens on a patient's atumour cells, attacking and killing the cancer cells. This type of therapy is also known as CAR-T therapy (Larson and Maus 2021, June and Sadelain 2018).
All gene and cell therapies are characterised by a high degree of complexity. Underlying the development of these novel therapies are decades of research in fundamental biology and medical science, especially on studying the biological targets and biological processes that cause diseases. Biotechnology development for the characterisation of these complex therapies is essential to facilitate therapy development and is equally challenging.
Innovative gene and cell therapies present the opportunity to address unmet clinical need, but due to their novel mechanisms of action, they may bring new risks such as immunogenicity, tumorigenicity, and viral safety to patients. Researchers are working on new technologies, such as non-viral gene delivery and tissue-targeting methods, to lower such risks. Research and innovations in the field will also enable treatments of diseases that affect a larger population, such as Parkinson's or diabetes.
The path towards bringing these innovative therapies from bench to bedside is long and full of challenges. Follow our research pathway to learn more about the development process for gene and cell therapies.
The goal of the pre-clinical (or non-clinical) development phase is to identify the lead (most promising candidate) product, and to study its efficacy and safety before it can be tested on humans. The results from pre-clinical studies provide information for a safe and efficacious product dosage to be used in clinical trials.
Pre-clinical studies should be carried out in compliance with Good Laboratory Practice (GLP). GLP is a set of principles on how laboratory studies are planned, performed, recorded, monitored, and reported to ensure the quality and validity of data generated.
Pre-clinical studies are usually performed in animals. They are first conducted in animals without the disease of interest for testing toxicity, then in animal models of the disease to assess its disease-modifying effects. In cases when there are no relevant animal models available, in vitro and/or ex vivo studies may replace animal studies. Perfect models that mimic human disease may not exist, but results from these studies provide information for regulatory agencies to determine whether the product should be further developed.
During the pre-clinical stage, the product must be well-characterised to reduce batch-to-batch variability. Expected product function, and its stability must also be confirmed. These activities are part of the process development that lays the foundation for manufacturing.
Developers who wish to continue to clinical trials for medicines for human use in the EU/EEA need to apply for a clinical trial application (CTA) by submitting information on the investigational medicinal product (IMP) through an Investigational Medicinal Product Dossier (IMPD) to a Clinical Trial Information System (CTIS) managed by EMA.
The investigational medicinal product (IMP) is next tested in clinical trials in humans if its clinical trial application (CTA) is approved based on pre-clinical data, and the clinical research protocol. Clinical trials are an important part of medicine development, with the purpose to evaluate an IMP by finding the appropriate dosage range and identifying the side effects. It must comply with many regulatory requirements to protect the fundamental rights, safety, and well-being of clinical trials’ participants.
To establish the safety and effectiveness of medicinal products, their clinical research needs to be conducted according to Good Clinical Practice (GCP). GCP is an international ethical and scientific quality standard for designing, recording, and reporting trials that involve human participants. Compliance with GCP ensures that the rights, safety, and confidentiality of participants in clinical research are protected, and the data reported from trials are credible.
Clinical trials are generally carried out in three phases, phase I, II and III. In an ideal scenario, the IMP would first be tested in phase 1 trials for general safety on a small group of healthy volunteers, followed by phase II trials on a larger group including patients for dose-related safety and proof-of-concept (PoC) studies of the therapeutic mechanism, further followed by phase III trials for confirmatory studies on a large group of subjects. If, after the first three phases of clinical trials, the IMP is found to be safe and effective, the European Commission, taking into account the scientific assessment of the EMA, can authorise its wide commercialisation for therapeutic use, and continues to monitor its effects. See also: Commercialisation.
Clinical trials for many ATMPs are more difficult to conduct, for example, those targeting rare diseases have a small patient population. As another example, autologous products cannot be tested on healthy volunteers for ethical reasons. In these cases, phase I clinical trials are conducted in a small group of target patients, and the evaluation of safety is often combined with an early evaluation of efficacy in phase II. In subsequent trials, safety data and efficacy data continue to be collected to demonstrate that the ATMP has a beneficial therapeutic effect in increasing patient numbers.
Early interactions with regulators
Gene and cell therapy products are complex and face unique regulatory challenges. EMA has early advice procedures in place to facilitate early dialogue with applicants on therapy development. These include: EMA Innovation Task Force Briefing meetings, EMA Scientific advice and Protocol Assistance, Parallel advices (EMA/HTA, EMA/FDA) . There are also early support regulatory schemes from national competent authorities, including a pilot for simultaneous national scientific advice.