Advanced therapies provide novel opportunities to correct physiological functions but they may cause unpredictable risks to patients. A risk-based approach can be used to ensure patient safety and data quality throughout product development.

Being a ‘living drug’, advanced therapies are very complex and diverse, and are significantly different from how conventional drugs are developed. Standard procedures to assess safety and efficacy of an advanced therapy may not be applicable or have limited value, making the step from bench to bedside challenging to predict. There is no fool proof way on how to deal with the inherent uncertainties when developing advanced therapies, but a risk-based approach can be your best bet of a successful outcome. 

Advanced therapies may deviate from the traditional development path when it comes to non-clinical assessment, manufacturing, clinical development, and post-market monitoring.  It can be especially challenging to find the appropriate laboratory experiments and animal testing in the non-clinical phase making it challenging to transfer the lab results to outcomes in humans. Due to the specific characteristics of advanced therapies, there need to be extensive non-clinical safety data available before the drug’s first administration to humans.

How much data is determined on a case-by-case basis taking the collected knowledge of every known risk into consideration. Non-clinical development aims to study the safety and efficacy of the drug. This assessment include studies on how the drug behaves, what dose is presumed safe while still generating the desirable effect, and how the drug should be administered for best possible outcome. The data package should provide clear insights of the benefit-risk ratio of the product under development before it is greenlighted to proceed to clinical studies.  

Stepwise risk assessment

The risk-based approach is a strategy to determine the extent of quality, nonclinical and clinical data that needs to be included in the Marketing Authorisation Application (MAA). In this step-by-step approach, each decision depends on the outcome of earlier investigations. Every advanced therapy developed is very specialised and differs from other products that might already be available, therefore the quality, non-clinical and clinical data required is highly product specific. However, risk-based approach should not be used to address risk-based quality management and risk factors, which are subject to principles of GMP, GLP and GCP.

For a drug that differs from the conventional development process, the risk-based approach provides a structured way of identifying and assessing each individual risk. The collection of data should be an on-going process, starting at the beginning of product development, maturing over time as the knowledge of the product and its characteristics increases.

Identifying the risks

The European Medicinal Agency defines risk as a potential unfavourable effect that can be attributed to the clinical use of the advanced therapy and is of concern to the patient and/or to other populations (e.g., caregivers and offspring). During the development of an advanced therapy, it is key that the developer systematically integrates all available information and obtain a profile of every risk associated with their product.

Risk factors that can be associated with the development of cell therapies could stem from:

  • the origin of the cells or tissues used (autologous vs. allogenic)
  • how the cells divide and differentiate
  • how the cells drive the immune reaction
  • the level of cell manipulation
  • mode of administration (lotion, pills, infusion)
  • the duration of the effect (short or life-long)

Risk factors that can be associated with the development of gene therapies could origin from:

  • The vector used to correct the gene
  • If/how much of the vector genome integrates in the patient’s chromosome
  • Immunogenicity – when the immune response is provoked by the therapy
  • The duration of the expression of the corrected gene (effect)
  • Off target effects – the gene ends up in the wrong type of cells


Advanced therapies provide novel opportunities to restore, correct or modify physiological functions but due to their novelty and complexity they may cause unpredictable risks to patients. A risk-based approach during product development can be used to adapt the development program and to a greater extent ensure patient safety and data quality. With that said, advanced therapies have demonstrated enormous therapeutic benefits to patients by directly targeting the underlying cause of disease. This is a major shift from a “one size fits all” tactic to tailor-made treatment so patients receive the highly individualised therapies that work best for them.

To find out more about how to de-risk your advanced therapy development, contact our experts.


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