Evolution in the landscape of non-clinical safety testing for advanced therapies

Cell & Gene Therapy Insights 2024; 10(2), 39–44

DOI: 10.18609/cgti.2024.007

Published: 19 January
Michaela Sharpe

Abi Pinchbeck, Assistant Editor, Cell & Gene Therapy Insights, speaks to Michaela Sharpe, Senior Nonclinical Director at Moare Solutions Ltd, about the evolving regulatory guidance surrounding non-clinical safety assessments for cell and gene therapies, as well as enabling the transition into the clinic and beyond.

What are you working on right now?

MS: I am working on a range of projects in the cell and gene therapy space, supporting products as they move through their non-clinical development. I work on projects in the early stages of preclinical development, all the way through to those close to transitioning into clinical trials. I enjoy having the opportunity to work on such a variety of different products. It is great to have a small part in helping to realize the potential of these cutting-edge therapies.

Over your 18 years of experience in the biotech and pharma sector, can you distill any key learnings and advice for therapy developers working on the translation of cell and gene therapies into the clinic and beyond?

MS: First and foremost, the goals of non-clinical programs are the same as ever—to acquire data to support efficacy, to select potential clinical dosages, and to establish product feasibility and safety. This remains the same for all types of products in development. For cell and gene therapies, it is likely that a standard set of non-clinical studies will not be used, so one must consider how to design the non-clinical program to obtain the information needed to support clinical translation. For a number of these products, this can pose challenges and in vivo studies might not be feasible for specific assessments of efficacy and safety, so any models used must be carefully considered.

One must have a strong scientific rationale for choosing a particular approach. Many people believe that regulators expect an in vivo model. In reality, regulators expect that you are performing the right study to address a specific question. An in vivo model may not be the right study. It is critical to think about how to maximize the information gained from the development studies, in order to move through the preclinical phase as efficiently as possible.

Another point to consider is that your product may change. When starting to perform the non-clinical program for a given product, in an ideal world this will be your final clinical product, but the reality is that it probably won’t be. You need to consider how any changes in manufacturing may affect what you have been doing in a non-clinical program and how you can use the data you have already generated. It is not necessary to repeat your studies if you have a sound scientific rationale not to. In vitro approaches can be particularly helpful. If you have tests that can show product comparability, there may not be the need to repeat all or any of the studies.

The most important thing is to engage with regulators early because having regulatory input is key, particularly if you are using novel methods or approaches. In addition, it helps to understand if there are any aspects that the regulators want you to look at or are unsure of so you can make sure these requirements are fulfilled.

Can you outline the current key considerations for the non-clinical safety assessment of cell and gene therapies?

MS: The safety factors fall into several broad categories related to the biology of products and how they function. This includes their biodistribution, immunogenicity/immunotoxicity, safety, and persistence, and in the case of gene therapy, where their gene expression is being observed and the risk of insertional mutagenesis. These factors will not be the same for each therapy, so it is necessary to determine the specific risks for each particular product. When thinking about the key safety considerations, a scientific data-based approach can be taken. There is no one-size-fits-all strategy so you must consider how your product is made, its biological characteristics, the target patient population, and the available models to assess product risks.

A risk-based approach to designing your non-clinical package is also recommended, as it allows you to assess whether alternative in vitro or in silico testing could be scientifically justified. The risk-based approach is a series of generic scientific questions that apply to any advanced therapy medicinal product based on factors relating to the quality, manufacturing of the product, biological activity, and clinical application. By determining the risks for each product based on these characteristics, one can begin to determine the extent of the non-clinical package needed, including the relevant studies and the mechanisms for acquiring data. This may be through in vivo studies, in vitro studies, or paper-based exercises from existing knowledge in the literature. Published literature can be underestimated as a valuable tool here—there is a lot of data out there to be used. There are also opportunities for the replacement of animal studies with well-designed in vitro alternatives.

How are non-clinical in vivo testing requirements evolving?

MS: Fundamentally, the development of any program is about doing the right study to address a specific issue. Regulators are looking for well-designed, appropriate studies to address a specific risk. Within the cell and gene therapy space, how non-clinical studies are evolving is about how much data is acquired from a study. Historically in pharmaceutical development, there has been a distinct delineation between the different non-clinical phases but for many advanced therapy medicinal product studies, we are not separating efficacy, pharmacokinetics, and safety, and instead potentially testing all of these within a given study. Acquiring more information from one study will limit the number of animals needed, and biologically relevant models can be used where possible.

There is also the challenge, particularly with gene therapies, that a product may only be active in humans and potentially primates. The risk is that we begin to do more non-human primate studies. Investigating whether you can obtain the same information from an animal equivalent product or an in vitro assessment is important. As a field, we need to limit the use of non-human primates to only those studies where there is no alternative.

Do you see regulators coming around to less animal testing in practice? If so, in what specific circumstances?

MS: Yes—there has been clarification that non-animal testing methods can be accepted. It has always been the case that regulators would consider non-animal testing, but they have become more explicit about it. In 2021, the European Medicines Agency implemented new measures to minimize animal testing during medicines development, and specifically measures sought to promote the 3R principles. In 2022, legislation was enacted in the US to replace a stipulation that drugs had to be tested in animals as part of the US FDA Modernization Act 2.0. Other regulatory agencies are either bringing in similar measures or providing greater clarification and being more explicit on the topic. Regulators will look to developers to use the most appropriate study to assess patient risk, whether in vitro or in vivo.

The key driver is that the tests must be relevant and must be shown to work. The measures must be in place to show that that test can address the questions asked and that the sensitivity and robustness of the assay have been established. There are a variety of tests that are coming into development to do this, such as organ-on-chip technologies, novel genomic technologies, and in silico modeling methods. There are potentially many biologically relevant surrogates out there.

One challenge is that some safety aspects are complex and are the result of multi-parameter, multi-organ effects. There is the risk that some in vitro tests will not detect specific safety issues, but it is also true to say that animal studies do not always identify safety issues either. We must always be aware there may be knowledge gaps and consider model limitations. This may mean additional monitoring may be needed to go into clinical trials, and/or a panel of tests may be needed to address different safety aspects.

What does the ‘umbrella IND’ mean for cell and gene therapy non-clinical development? How much can you leverage from one advanced therapy product or platform to another?

MS: The umbrella IND allows a sponsor to evaluate multiple versions of an investigational product. The similarities in terms of the products and biology will determine which non-clinical data could be considered for a platform. I certainly think there is great potential but it will be product specific.

If you have a gene therapy that is similar to another except for some small differences in sequences, you may be able to develop a scientific position on the commonality of the products and hence determine that existing studies are relevant, which could reduce animal use in testing. This is also not limited to the umbrella IND. There is the potential for opportunities to utilize published data for related products, potentially both preclinical and clinical data to assess risks, and thus minimize the required studies.

As an example, extensive data has been published on the distribution and persistence profile of multiple routes of administration of mesenchymal stem cells. There may be a strong scientific case for not repeating a study with a new product that is perhaps for a different indication but uses a standard route of administration. It may be possible to utilize existing published data on specific aspects, such as clinical dose levels or safety risks, without repeating the studies. In general, looking at what has been published and sharing safety information will help to minimize animal use in some of these programs.

What will the non-clinical safety space for advanced therapies look like in a decade?

MS: The space will evolve due to the acquisition of knowledge of the long-term risks of products. Hopefully, some of the risks that are currently considered theoretical will not materialize. In addition, we will know of any risks that do develop as reality and their risk-benefit profile. As we get more long-term data with gene therapies, we will understand any long-term potential risks and the longer-term efficacy of the products. Based on that, the types of non-clinical programs will evolve.

I also believe we will see an increase in the use of alternative testing methods due to recent advancements, particularly organ-on-a-chip and genomic technologies that enable more specific assessments. An example of this is the change in the way to assess the potential for teratoma formation for pluripotent stem cell-derived products. This involves looking for the presence of residual pluripotent cells, which could be a teratoma risk. Previously, this was done in 6 to 12-month studies in immune-compromised mice. Now, technologies like qPCR and flow-based assays to look for the presence of rare cells will allow you to do these assessments in days, utilizing no animals.

Within the industry, groups are working together to identify where the needs are for some of these alternative methods. Organizations such as the Health and Environmental Sciences Institute and others are looking to collaboratively develop these types of technologies. Supporting information from collaboration studies that show that these technologies work will lead to greater acceptance to enable the rapid deployment of some of these alternative technologies in valid circumstances. The general principle of the right study to address the right question will remain. We will become more confident within the field that in some cases, the right study may be an alternative in vitro approach.

What are your own goals and priorities in your work for the next 12–24 months?

MS: My goal is primarily to help the programs I am working on, that are currently in their preclinical development phase, move into clinical trials. As I move forward, my priority will be to continue to work with new and innovative products and keep abreast in terms of the methodologies and ways to assess these types of products.

I would like to bring in these new technologies to help accelerate programs as they move forward and continue to work with peers across the industry to bring the technologies and the knowledge surrounding them to a wider audience going forward.


Michaela Sharpe is a Senior Nonclinical Director at Moare Solutions Ltd. She has specialized in the nonclinical development of cell and gene-based therapies, and has designed and implemented nonclinical development programs for a broad range of cell and gene therapy products. She has supported numerous academic teams through the nonclinical development pathway, as well as global small and medium-sized enterprises, and pharma organizations.


Michaela Sharpe
Senior Nonclinical Director,
Moare Solutions Ltd

Authorship & Conflict of Interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given their approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: The author has no conflicts of interest.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & Copyright Information

Copyright: Published by Cell & Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2024 Sharpe M. Published by Cell & Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Revised manuscript received: Jan 17, 2024; Publication date: Jan 18, 2024.