The effect of a living drug does not necessarily decrease over time in the way conventional treatments do. Many gene therapies are integrated in the DNA and will be expressed over years if not a lifetime. Due to the long-term risks potentially associated with these products, they are as a rule subject to specific regulatory requirements for safety monitoring for many years after regulatory approval.   

The human genome is composed by over 20,000 genes and serves as an operating manual telling the cells how to create a human being. Genes encode proteins and proteins dictate cell function. A genetic disease is caused by a change in the DNA sequence, a mutation that occurs during cell division. As the DNA is copied, some of its building blocks can be replaced, deleted, or even added in. The majority of the changes have no effect, but sometimes an alteration can lead to a damaged protein, an extra protein, or no protein at all, which can have serious consequences.  

Gene therapies have the ability to target the root cause of a disease caused by an error in the DNA by inserting new genetic material directly into the affected cells by using a viral vector – a virus engineered to not carry any disease. It is in the nature of a virus to enter (infect) a cell, unload its genetic material and hijack the cells machinery to make new viral proteins. In gene therapy, the virus instead unloads a therapeutic gene, instead of a viral gene, which has the potential to remedy the disease.  

In general, advanced therapies have specific safety issues due to their novelty and complexity and may therefore cause unpredictable risks to patients. Throughout the development, a risk-based approach can be used to adapt the program and to a greater extent ensure data quality and most importantly - patient safety. Gene therapies are designed to achieve therapeutic effects through permanent or long-lasting changes in the human body and may therefore be subjected to the risk of undesirable and unpredicted outcomes beyond the clinical trial and the approval of the product.  

To understand and mitigate the risk of adverse events, patients treated with gene therapies may be monitored for an extended amount of time. However, not all types of gene therapies will require years of observation and the safety aspects of the follow-up strategy is based on the product and the vector used as well as the individual preconditions of the patient such as disease, potential comorbidities, or concomitant treatment.  

The follow-up of the patients who received gene therapy aims to detect delayed adverse reactions, to prevent clinical consequences and to ensure timely treatment of those consequences. Risks can be related to the type of vector used, to faulty insertion of the genetic material, or if the gene expression somehow is unpredictably altered.  

Potential risks of delayed adverse events are for example: 

• Unwanted immune reaction. The immune system may react to the viral vector.  
• Infection.  The virus used as a vector might get reactivated.  
• Tumour formation. If the new genes get inserted in the wrong spot in your DNA. If the vector DNA integrates in the cells.  

The duration of clinical follow-up observations should be sufficient to monitor the patients for risks that may be due to the characteristics of the product, the nature and extent of the exposure, and the anticipated time of occurrence of delayed adverse reactions.  The duration of the follow-up is therefore established on a case-by-case basis, and can range from 5 to 15 years, depending on the nature of the gene therapy. With respect to everyone involved, the approach to long-term monitoring must be carefully considered and should only be extended as long as necessary and clinically relevant. 

Genetic therapies hold promise to treat many diseases, but these new approaches to treatment are complex and come with uncertainties and risks such as immune reactions and tumour development. Because gene therapy techniques are relatively new and evolving, some risks may be unpredictable; however, drug developers and regulatory agencies are all working hard to ensure that research, clinical trials, and the approved therapies are as safe as possible. 

If you have safety concerns or questions regarding follow-up and risk management for advanced therapy medicinal products, contact @ndareg.com