Safety studies are scientific investigations which evaluate the safety of a substance, product, or process. These studies generally involve comparing estimated risk levels with science-based safety standards.

Typically, safety evaluation for gene therapy is divided into nonclinical and clinical stages:

•    Study Design
•    Preliminary Research
•    Animal Testing
•    Human Clinical Trials

Gene therapies and genome editing have complex impacts. There are some key risk categories that safety studies often focus on: 

Key Considerations in Nonclinical Safety Study Design

• The design and conduct of studies should be able to identify and address any potential toxicity of the therapy
• The length of the study needs to capture any short-term, long-lasting or delayed onset side effects or toxicities. The length of the study has to be adjusted based on the specific characteristics of the therapy being tested.
• For animal testing, the dose which is safe and effective in animals may not directly translate to humans. Therefore, the model animal used for testing must be carefully selected, taking into account many factors including how the therapy will be administered and which tissues it has to reach. 

(This answer was contributed by Siang Li, a GetRADI fellow based at the University of Copenhagen, Biotech Research & Innovation Centre)

Examples of traditional therapies and treatments include drugs, chemotherapy or surgery. Gene and cell therapies represent cutting-edge approaches in modern medicine, and they differ from traditional therapies in several key ways across biological mechanisms, delivery procedures, availability and accessibility, and regulation. 

(This answer was contributed by Xiubin He, a GetRADI fellow based at the University of Copenhagen, Biotech Research & Innovation Centre)

Embryonic stem cells (ESCs) for therapies and research come from the inner cell mass of the human blastocyst, an early stage of the developing embryo lasting from the 4th to 7th day after fertilization. The blastocyst cells are pluripotent, meaning they can differentiate into any cell type in the human body.

Most commonly, human ESCs used in research are sourced from excess embryos created during in vitro fertilization (IVF) procedures that are not used for implantation in the uterus. Instead, they are donated for research purposes, with the consent of the donors.

In some cases, embryos may be created specifically for research purposes through techniques like somatic cell nuclear transfer (SCNT),  where the nucleus of a somatic (body) cell is inserted into an egg cell to create a genetically identical embryo. However, this is a controversial and less common source due to ethical concerns.
 

Learn more about ESCs

Learn about the ethics of ESCs in research 

Traditional treatments or drugs often help with symptoms, but do not address the root cause. Making these treatments is relatively straightforward; there are clear rules set by lawmakers about how to make them safely and scale up production to commercial levels. Government health agencies have set up guidelines that companies must follow when developing and manufacturing these medicines.

Gene and cell therapies are a new generation of medicines, and work completely differently. They aim to fix or replace the root cause of the problem. These treatments can be highly personalised -  often, they're made just for one person, using a patient’s own cells or genetic material. For example, in once cancer treatment called CAR-T Cell therapy, the patient's immune cells are collected from the body and modified in the lab to better recognise and fight cancer cells, then returned to the patient's body. Each time this treatment is used, it is prepared specifically for an individual patient. 

This means that making gene and cell therapies is much more complicated than making regular medicines. It is like creating a custom-made, perfectly tailored suit instead of buying one off the rack. As a result, it costs much more money and takes much more work, energy and time. Usually, these treatments are made in small amounts, often just enough for one person at a time. Because of their experimental approach and unique nature, they need extra safety checks to make sure they are safe and effective.

The rules for approving gene and cell therapies are also different from regular medicines. For example, in Europe they are classified as Advanced Therapy Medicinal Products (ATMPs). These treatments must go through several steps of validations and testing before they are allowed to be used in patients. This means it takes longer for them to become available to patients compared to regular medicines.

Despite the challenges, gene and cell therapies offer exciting possibilities. They could potentially cure diseases that we can only manage with traditional medicines. However, their complexity and cost mean that right now, they are mostly used for serious conditions where other treatments have not brought a desired outcome, or as a last resort.

(This answer was provided by Aleksander Nowak, a GetRADI fellow based at Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine)

Gene and cell therapies are needed because they offer solutions for diseases and medical conditions that traditional treatments and medicines cannot effectively address. These advanced therapies fill an unmet need in treating diseases caused by genetic mutations, or those requiring the regeneration of damaged tissues or cells. 

Traditional treatments and medicines primarily manage symptoms, but they do not correct the underlying cause of disease. Therefore, patients may require lifelong treatment and medication, sometimes with side effects and limited success. However, gene therapies could potentially cure diseases caused by genetic mutations, by correcting, reversing, or replacing the defective gene of interest. In some cases, this can be a single treatment resulting in a life-long cure. 

Some diseases are caused by or result in damage to cells or tissues. Once cells or tissues have been lost, there is often no way to restore it, and sometimes transplant is the only treatment. Here, cell therapies aim to promote repair of the damaged tissue, or to replace it. Currently, this is only possible with a handful of cell types and conditions. However, scientists hope that cell therapies may be used in lots of other ways in the future; to repair damage after a heart attack, or replace spinal cord cells after injury. 

Gene and cell therapies also offer potential for new treatments for other diseases, like cancers and autoimmune disease. For example, one type of therapy called CAR-T Cell therapy modifies the cells of a patient’s own immune system to allow it to identify and attack blood cancer cells. 

While significant challenges remain, ongoing research is addressing many of these challenges, and advances in gene editing and tissue engineering hold promise for overcoming some of these obstacles. Gene and cell therapies can fill critical gaps in the medical landscape, offering new hope for previously untreatable conditions. 

(This answer was provided by Louise Bomholtz, a GetRADI fellow based at Max-Delbrück-Centrum für Molekuläre Medizin (MDC).)

What is genetic testing? 

Genetic testing is a method used to ‘read’ a person’s DNA, which carries the instructions for the structure and function of every cell in the body. Genetic testing can detect specific genetic changes (mutations) which may cause illness or disease. A sample of cells (typically from blood, saliva, or tissue) is collected, and advanced technologies such as DNA sequencing or microarray analysis are used to determine whether specific gene variants or chromosomal abnormalities are present.

Genetic testing can be used to look at single genes known to cause disease, entire chromosomes, or even the whole genome. 

Different types of genetic testing are performed for different reasons. 

Diagnostic testing can be used to confirm the diagnosis of a disease or condition caused by genetic mutations. For example, genetic testing could be used to confirm the presence of the single-gene mutations responsible for disorders like cystic fibrosis or sickle cell disease, or larger chromosomal abnormalities, such as missing or duplicated regions, which lead to conditions like Down syndrome or Turner syndrome. 

Predictive or presymptomatic testing helps assess an individual’s likelihood of developing certain diseases later in life, especially if they have a family history of the condition. For instance, testing for BRCA1/BRCA2 mutations can help identify individuals at higher risk of breast or ovarian cancers. In more complex diseases such as heart disease or diabetes, multiple genes contribute to risk;  looking at multiple genes can help estimate an individual’s risk of developing disease.

Carrier screening plays an important role in family planning, by determining whether a person carries a genetic mutation that could be passed on to their child and cause disease, even if they have no symptoms themselves. Prenatal screening during pregnancy allows early detection of genetic disorders in a developing fetus, often through non-invasive prenatal testing (NIPT), which analyzes foetal DNA present in the mother’s blood. After birth, newborn screening can identify metabolic, hormonal, or genetic disorders that, if treated early, can prevent serious health complications. 

Pharmacogenetic screening can help tailor treatment for specific health conditions by evaluating how an individual’s genes affects their response to specific medications, determining which medication and dosage will be most effective. 

Receiving a genetic diagnosis can provide significant benefits. It allows people to access specialized medical care, provides eligibility for certain support programs, therapies, and financial benefits, and improves quality of life. It can offer families important information for reproductive decision-making, helping them plan for potential risks and explore available options such as prenatal testing or assisted reproductive technologies. Knowing one’s genetic risks can also build connections with patient advocacy groups and support networks, providing emotional and practical assistance to individuals and families navigating genetic conditions. 

Genetic testing has its limitations. A positive result from genetic testing does not always guarantee disease, and a negative result does not always rule it out, as environmental factors and gene expression also play a role in some cases. There are also complex ethical considerations around genetic screening regarding privacy and confidentiality, potential discrimination, psychological impact, and reproductive decisions (particularly in case of prenatal screening). Therefore, the immense potential that genetic screening holds for improving health outcomes must be balanced with careful ethical reflection to prevent harm, ensure fairness and respect individual rights.

(This answer was contributed by Aurora Giometti, a GETRADI Fellow based at Miltenyi Biotech)

Animals are often used in research as ‘models’, to understand what causes a disease, how it affects the body, or whether a treatment works. This is controversial; some people feel that animals should not be used in this way. 
Some of the ethical arguments against using animal models in research are:

Is it humane or fair to use animals for experiments? Experiments can cause pain or stress to animals, and some people question if it's right to put animals through this. Many believe animals have a right to live without harm, just like humans do.

Are animals the best models for understanding human disease? Animals are not perfect substitutes for humans, so some question if using them is always helpful, but the biology of humans and other animals, particularly mammals, is surprisingly similar. Many animals even suffer from the same diseases as humans, and can be used to study those diseases. In other cases, researchers use a genetic 'animal model' of a disease, which mimics the human condition.

Are animals still required for research? With new technologies, like computer models, people wonder whether we can stop using animals entirely . However, while modern research tools like organoids are creating new ways to study disease, the current status of the science does not yet allow full replacement of animals in the discovery and development of new therapies.

Who decides how animals are used in research?
Governments have rules about when and how animals can be used in experiments . Special ethics committees at universities and research centres decide if animal experiments are necessary, and make sure that any animals involved are treated humanely. Animal advocacy groups and the public have also influenced the treatment of animals in research, by pushing for stricter rules on the treatment of lab animals and encouraging the use of non-animal methods.

Guidelines to Protect Animals 
In the EU, researchers are committed to the ‘3 Rs’ principle:

• Replace animals with other methods when possible
• Reduce the number of animals used
• Refine experiments to make them more humane

Animals are only used in research when there is no available alternative. The goal is to balance the potential benefits of animal research for humanity against treating animals as humanely as possible. Laws, experts, and public opinion all play a role in finding that balance.

Learn more about the ethics and requirements for animal research: 

ABPI Animals and Medicines Research | EuroGCT

Various types of regulators play vital roles in all stages of gene and cell therapy (GCT) development. The medicines agencies such as the European Medicines Agency (EMA) in the European Union (EU) and The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom (UK) are heavily involved in facilitating the development and patient access to GCTs and other medicines.

The EMA is a decentralised agency of the European Union (EU), and is responsible for the scientific evaluation, supervision and safety monitoring of medicines. EMA protects public and animal health in EU/EEA by ensuring that all medicines available on the EU market are safe, effective and of high quality. Based on EMA's recommendation, the European Commission (EC) makes a legally binding decision for all the centrally authorised medicinal products. If granted by the EC, the centralised marketing authorisation for the medicine is valid across the entire EU/EEA.

While many of the gene and cell therapies, especially those that are classified as Advanced Therapy Medicinal Products (ATMPs), are regulated centrally by the EMA, some may be regulated by national medicines agencies and through different regulatory pathways. The term “regulators” in fact, has a very wide meaning – it includes any competent authorities, including but not limited to the Medicines Agencies, National Competent Authorities, Health Technology Assessment (HTA) Bodies, Ethics Committees, Payers, and more. To learn about who they are and what other types of regulators are involved in medicines development process, please see EuroGCT’s Actors and Networks database. 

Which regulator determines the prices of medicines? 

The EMA does not make decisions on the pricing, reimbursement and the accessibility of medicines. 

Decisions about pricing and reimbursement take place at member states and regional level, taking into account the health system of the respective country or region and through a series of processes. In the EU, regional and national Health Technology Assessment (HTA) bodies evaluate the new medicine by assessing its relative effectiveness compared to the existing medicines. The result is then used to inform reimbursement decisions made by national bodies and/or payers. The EU healthcare payers look at the medicine’s cost effectiveness, its impact on the country or region’s healthcare budgets and the seriousness of the disease, and use this information to decide whether they cover a medicine and under what conditions. The payers also negotiate the price of medicines with their manufacturers. 

Genes, proteins and cells

Our bodies are composed of cells, with different cells performing different functions. Genes contain information for the production of proteins, acting like blueprints or instructions. Proteins are the components or building blocks of our cells. A cell’s function and behaviour depend on which proteins are produced. 

A change in a gene that causes a change in the protein is called a mutation. Many mutations are harmless, but some can be damaging. This can mean that an important protein is under- or over-produced, or that it is produced incorrectly and cannot fulfill its role in the body. Either outcome can result in illness. 

Gene Therapy 

Gene therapy is a technique that uses or manipulates genetic material like DNA to treat, prevent or cure a disease or disorder. This may mean adding a copy of the functional gene, or 'correcting' a gene so that it produces the functional protein. 

Cell Therapy

Cell therapy is the use of living cells to treat diseases, intervening at a cellular rather than genetic level. Stem cells are often used in cell therapy, as they can produce a range of different cell types to repair the affected tissue. 

Therapy Classification

Classifying a therapy can be very complicated, as it may depend on many different factors.  

Read about gene and cell therapy in more detail
 

Advanced therapy medicinal products (ATMPs) are medicines for human use based on cells, genes or tissues. ATMPs are a subset of gene and cell therapies; not all gene and cell therapies are medicines or correspond to the legal definition of ATMPs. 

 ATMP Sweden discuss the different categories of ATMP here.

In our in Research Pathways section, Therapy Classification and the entries within provide information regarding the different legal classifications of gene and cell therapy (including ATMPs) and their subsequent pathways to clinic.

Animal models are essential for assessing the safety and effectiveness of therapies before they reach human clinical trials. They allow researchers to understand how a treatment works in a living organism, providing insights that laboratory studies alone cannot offer.

Risk Assessment 

One key advantage of using animal models is the ability to evaluate potential risks associated with gene therapy. Researchers can observe how the therapy behaves within a living system, identifying possible immune responses, which tissues are affected, and unforeseen biological interactions before moving to human trials. Animal studies also offer a way to predict potential side effects. This predictive capability is crucial for refining therapies and improving patient safety.

Investigating Long-Term Safety 

Long-term safety assessments are another important aspect of preclinical research. Observing the effects of gene therapy over extended periods, sometimes across multiple generations, helps identify delayed or cumulative consequences that may not be detectable in shorter studies. Such findings contribute to a deeper understanding of a therapy’s long-term impact.

Evaluating Therapeutic Effectiveness

Beyond safety considerations, animal models play a crucial role in testing how well a therapy works. They allow researchers to study how a gene therapy works in practice, offering valuable insight into its potential success in humans. For example, Duchenne muscular dystrophy (DMD) is caused by a loss of a protein called dystrophin.  Researchers use mdx mice, a well-established disease model, to test gene therapies aimed at restoring dystrophin production. Efficacy is tested by measuring dystrophin levels in muscles and evaluating muscle strength and function. If treated mice show restored dystrophin expression and improved muscle performance, it suggests the therapy could be effective in human patients. This step is fundamental in determining whether a treatment is worth pursuing further. 

Optimising Delivery and Dosing 

Animal models can also help optimize delivery mechanisms. Scientists can test and refine different gene delivery approaches, such as selecting the most effective viral vectors or exploring alternative non-viral methods. This is crucial for ensuring that the therapy reaches its target cells efficiently, while minimizing off-target effects, which could lead to unintended genetic modifications or immune responses. Animal studies help researchers assess how well the therapy is distributed throughout the body, whether it reaches the intended tissues, and if it produces the desired level of expression without causing harmful side effects. By fine-tuning these delivery methods in preclinical models, researchers can improve the safety and effectiveness of gene therapies before they are tested in humans. 

Why do we need animal data?  

With the insights gained from animal models, researchers can refine gene therapies to improve both safety and efficacy in human testing, paving the way for successful clinical applications. Regulatory bodies, such as the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), actually require detailed preclinical data before approving human clinical trials. These preclinical studies often rely on animal models to demonstrate safety, efficacy, and appropriate dosing. While the use of animals remains a necessary step in many cases, significant efforts are now made to minimize their use through alternative methods such as advanced cell-based models, organ-on-a-chip technology, and computational simulations. Ethical considerations and the principles of the 3Rs (Replacement, Reduction, and Refinement) guide researchers to ensure that animal testing is conducted responsibly and only when absolutely necessary. 

Learn more about how stem cells are being used to model diseases 

(This answer was contributed by Matilde Vale, a GETRADI Fellow based at the Institute of Molecular Genetics of the Czech Academy of Sciences)  

Preclinical and clinical trials are important steps in the process of developing gene therapies, as they protect the safety of the patients. These trials provide a structured, stepwise approach for evaluating safety, efficacy, and risks over the long term for a new gene therapy before approval for general use in humans.

Preclinical Trials 

Before any gene therapy reaches human testing, it undergoes preclinical trials, which involve lab-based tests on cell cultures (in vitro) and animal models (in vivo). These early studies aim to predict how the therapy might behave in humans, and to identify major risks that could affect patient safety.

One key focus of preclinical trials is toxicity testing. Researchers use animal models like mice or rats to observe how different doses of the therapy impact cells, tissues, and organs. This provides details of the safe dose range and early signs of toxicity, which plays an essential role in setting the dosing guidelines during clinical trials.

Another critical aspect of preclinical testing is biodistribution, as gene therapies must target specific tissues or organs while avoiding off-target effects. These studies track where the gene therapy vector travels and accumulates in the body, ensuring it reaches the intended site—like the liver or brain—while avoiding non-targeted tissues that could lead to harmful side effects.
By understanding the therapy’s distribution and persistence, researchers can refine its safety profile and reduce the risk of toxicity before advancing to human trials.

Preclinical studies also assess genotoxicity and tumorigenesis to evaluate the risk of the gene therapy causing harmful genetic changes. Researchers investigate whether the therapy could accidentally integrate into the host’s genome in a way that might activate cancer-causing genes or disrupt tumor-suppressing genes, both of which could lead to cancer. These tests help minimize the risk of tumor formation, ensuring the gene therapy is as safe as possible before moving to clinical trials.

Preclinical trials also evaluate immunogenicity, which refers to the potential of the gene therapy to trigger an immune response. This is important because an overactive immune reaction can lead to serious side effects, such as cytokine storms or immune-mediated tissue damage. By identifying these risks early, researchers can adjust the therapy to reduce its immunogenicity and help prevent severe immune reactions during human testing.

Clinical Trials 

Once preclinical studies confirm that the gene therapy appears safe, it goes on to clinical trials in humans. Clinical trials are conducted under strict ethical standards and regulations aimed at protecting participants. These would include checks by Institutional Review Boards, informed consent processes, and ongoing monitoring for safety during the time of the trial.
Clinical trials are divided into phases, each with an important role to play in ensuring patient safety.

Phase 0 trials are optional trials in which a very low dose of the therapy is given to a small number of subjects in order to learn more about how the body processes the therapy (known as pharmacokinetics). 

Phase I trials, sometimes referred to as "first-in-human studies",  are more often the first stage of testing in human subjects. These test the safety of the therapy and define safe doses for further testing.

If Phase I results are promising, the therapy progresses to Phase II trials, which confirm its safety in a larger population and provide data on the potential benefits of the therapy. This phase will help identify other risks that may not have appeared in Phase I.
In Phase III, the therapy is tested on an even larger and more diverse group of patients. The large sample size detects adverse events that are rare and may not have been visible in earlier phases. At this point, the therapy may be approved for use in the general population.

However, the process doesn’t end with approval. Phase IV trials, also known as post-approval monitoring, continue to track the therapy’s long-term effects in the general population. Ongoing monitoring for safety is particularly vital in gene therapies, as this might have very long-term or even permanent effects on the body.

The data gathered from both preclinical and clinical trials play an important role in protecting patients. These trials help minimize risks by identifying potential hazards early in development, ensuring only the safest therapies move forward. They also provide the scientific evidence required for regulatory approval by agencies like the FDA or EMA, which demand proof of safety and efficacy before allowing a therapy to reach the market.

(This answer was provided by Maryam Taghdiri, a GETRADI Fellow based at Freiburg University Medical Center) 

Genreally speaking, a medicine can only be placed on the market when its quality, safety and efficacy has been assessed by the Regulatory Authority (EMA for EU and MHRA for UK), met the standards for its intended use, and granted a Marketing Authorisation (MA). Here we compile reliable sources, databases and registries for these approved medicines in EU and UK: 

For medicines approved in EU countries:  

• EMA's Medicine finder can help you find information on centrally authorised medicines - medicines that EMA evaluated and approved for human (or veterinary) use. All Advanced Therapy Medicinal Products (ATMPs) fall under this category.  
• The medicine may be authorised in individual Member States via national procedures. Information for these authorised medicines can be found in the respective national registers: Member States registers of nationally-authorised medicinal products or National registers of authorised medicines. Please note that information in these national registers may not be available in English. 
• Medicinal products can also be approved through Mutual recognition information. Such products can be found at MRI - Product search.  

For medicines approved in UK: 

• MHRA products page hosts the most up-to-date information for MHRA-approved medicines. 

How are medicine developed?

Medicines development, often used interchangeably with drug development, refers to the scientific and regulatory processes involved in bringing a new medicine to the market. Medicine development is costly and time-consuming. It takes an average of 10-15 years and more than US$2 billion before it can reach the pharmacy shelf. 

It starts from the pre-discovery phase during which researchers try to understand the mechanisms underlying diseases and propose possible biological targets for treating them. In the discovery phase, scientists look for potential small molecules or biologics, the “leads”, that will modulate this target and possess a therapeutic effect. Scientists then chemically modify the lead to further improve the lead's properties and therapeutic effects.  

The resulting lead, now an optimised drug candidate, then moves to pre-clinical testing for studying how effective (the efficacy) and safe it is using different testing approaches. These testing approaches include in vitro testing (in a controlled environment outside a living organism like a petri dish) and in vivo testing (in a living organism) 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.   

The drug candidate is next tested in clinical trials in humans if its clinical trial application is approved by regulatory authorities based on pre-clinical data, and the clinical research protocol. Clinical trials are an important part of medicine development, with the purpose to evaluate the active ingredient by finding the appropriate dosage range and identifying the side effects. Clinical trials are generally carried out in three phases, phase I, II and III. In an ideal scenario, the active ingredient 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, further followed by phase III trials for confirmatory studies on a large group of subjects.  

How are medicines approved?

Upon completion of the phase III trial, the sponsor submits a marketing authorisation application file to the regulatory authority (EMA for Europe) to demonstrate drug safety and efficacy. For a medicine to be authorised, the sponsor needs to show that it is effective, safe, and good quality. This requires preparing and submitting a marketing authorisation dossier that contains information drawn from pre-clinical/clinical studies and the manufacturing process description, prepared in accordance with regulatory, scientific, and procedural guidelines. After EMA’s scientific evaluation, EMA will provide a recommendation to the European Commission, which decides on granting the marketing authorisation. If granted, this results in one Marketing Authorisation that is valid in the entire EU/EEA, this means an approval for a medicine to be marketed for commercial use in the entire EU/EEA. In EU, another possible route for medicines’ approval is through a national route in which the medicine is assessed and approved by one Member State only.

After the medicine is authorised, it may be used in patients. During clinical trials, the safety and efficacy of a medicine has only been evaluated on a carefully selected small group of patients in controlled conditions for a limited amount of time. After authorisation, however, the medicine may be used in a larger number of patients and for a longer period of time. Through monitoring these activities, some previously unidentified adverse effects may be observed. To ensure patient safety, EMA and the EU Member States will constantly monitor the medicine’s safety and take according actions if new information indicates that the medicine is no longer as safe and effective as previously thought. 

Further reading

How are medicines developed and approved?