Preclinical research is one of the most critical (and often underestimated) stages of ATMP development.

Only a small percentage of therapies that show promising results in the laboratory ever reach patients. In advanced therapy medicinal products (ATMPs), the transition from early research to clinical development is particularly complex due to the scientific, technical and regulatory challenges involved.

Preclinical development goes beyond demonstrating efficacy

In many early-stage projects, the initial focus is placed on demonstrating therapeutic efficacy in laboratory models. However, advancing towards clinical evaluation requires much more than positive experimental results.

Preclinical development must also establish product quality, safety, mechanism of action, biodistribution, and the overall regulatory framework supporting future clinical use.

One of the major challenges in advanced therapies is that many researchers begin development without a clear understanding of the regulatory expectations that apply to their product. As a result, potentially promising therapies may struggle to progress beyond experimental stages.

Classification determines the regulatory pathway

One of the first key steps in ATMP development is defining the regulatory classification of the product.

This classification is not always intuitive and has a direct impact on the studies and documentation required during development.

For example: therapies using cells may be classified as tissue engineering products if their therapeutic effect is based on tissue regeneration, while products involving genetic modification are not always classified as gene therapies, depending on the characteristics of the final administered product.

Because regulatory requirements differ significantly between categories, establishing the correct classification early can help avoid unnecessary studies, delays and development costs.

Why advanced therapies are more complex than conventional drugs

Compared with conventional small-molecule drugs, advanced therapies involve a much higher level of biological complexity.

A chemical compound may involve a limited number of mechanisms or interactions. By contrast, cell-based therapies involve living systems composed of large numbers of molecules interacting simultaneously with tissues, organs and immune responses.

This complexity increases further in areas such as tissue engineering, where interactions occur between multiple biological structures at the same time.

As a result, demonstrating efficacy and safety in ATMPs often requires more sophisticated experimental approaches and broader datasets than those used for conventional medicines.

The role of experimental models in preclinical research

Preclinical evaluation can involve multiple levels of investigation, including animal models, organoids and tissue explants, cell cultures, and molecular or biochemical analyses.

Each model provides different types of information regarding efficacy, safety and biological behaviour.

In therapies such as CAR-T treatments, for example, researchers may analyse anti-tumour activity in vivo, tumour cell killing capacity in vitro, or molecular parameters such as vector copy number and genomic integration sites.

Selecting appropriate models depends not only on the therapy itself, but also on whether reliable disease models already exist for the condition being studied.

Regulatory frameworks continue to evolve

Advanced therapies are supported by an extensive and continuously evolving regulatory framework, particularly in Europe.

Over the past two decades, regulations, directives and international harmonisation guidelines have progressively defined the requirements applicable to gene therapies, cell therapies and tissue engineering products.

In addition to European Medicines Agency (EMA) guidance, developers often work within international frameworks such as ICH guidelines related to biotechnology products and preclinical safety evaluation.

Because multiple regulatory documents may apply simultaneously, understanding how these frameworks interact becomes an essential part of development planning.

Common gaps in early-stage development

One of the most frequent challenges in early preclinical projects is the lack of sufficiently documented safety data.

Researchers naturally tend to focus on therapeutic efficacy, while more subtle secondary effects may go unrecorded if they are not actively investigated.

In some cases, observations that could support safety evaluation are simply not documented because they were not originally considered relevant within exploratory research studies.

Another major challenge involves biodistribution studies. Tracking how cells or biological products move through the body remains technically difficult in many advanced therapies. Detecting small numbers of cells in specific tissues or monitoring cell migration without altering biological behaviour continues to require highly specialised methodologies.

For this reason, regulatory agencies often accept combinations of complementary analytical approaches rather than relying on a single technique.

Why regulatory planning should start early

One of the main conclusions highlighted throughout the discussion is the importance of integrating regulatory and preclinical strategy from the earliest stages of development.

As soon as a therapy begins to show promising efficacy data, developers benefit from understanding which studies will eventually be required, how regulatory expectations apply to their product and which data should already begin to be generated during exploratory research.

Early regulatory guidance can help structure development more efficiently and increase the likelihood of successful progression towards clinical stages.

Preclinical development ultimately plays a critical role in enabling future clinical development. The quality and relevance of early-stage data often determine whether a promising therapy can realistically advance towards patient use.