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Madhavi Lakkaraja, MD, MPH
Fred Hutch Cancer Center
United States

Roundtable Title: If You Knew Then What You Know Now: Balancing Risk/Benefit for Cell Therapies Post Regulatory Approval
Roundtable Date: Friday May 09, 2025
Roundtable Time: 15:00 - 16:00

Key Learning Objectives: 

•    Review of the current regulatory guidance for data and sample collection on long-term follow up (LTFU) studies
  • For long term follow post administration of a cell or gene therapy is risk-based depending on the vector/modality used for gene transfer (for example, lentivirus and retrovirus for 5 to 15 years).
    •  Per risk-based approach, follow up for integrating viruses is five years, though the product can be assessed in one-year increments to determine if longer follow up is needed.
  •  Goal is to look for late reactions, oncogenesis, tumorigenesis, by assessing clinical exams and labs tests that gauge the persistence, expansion and patient safety post product administration. 
• Identify potential solutions for gaps in long-term follow up data collection and reporting (non-efficacious product, loss of funding, etc)
  • As the amount of data collected over 15 years is extensive, as a field we should decide on when the data should be interrogated and when it should be published.
    • Lot of groups don’t publish long term data if it is benign, but it is necessary to push the field forward as there is nothing in literature that will modify reporting requirements in the current form.
  • While the goal is to look for safety signals, persistence or secondary malignancies to determine and ensure patient safety, LTFU studies also need to balance follow-up requirements from patient perspective.
    • Sometimes there are really engaged families that want to and do participate in LTFU as scheduled. After a certain time, a subset of those families will find the LTFU requirements burdensome and/or reminders of times when they were ill and therefore stop participation.
    • Patients should be offered the option to follow up locally to decrease the burden to families.
  • From a financial perspective, we also need to be smart about the process. What data do we need from a scientific and safety perspective, balanced by what data will patients want as they are transitioning towards a “normal” life.
  • Some centers have developed their own LTFU studies for patients that have participated on cell and gene therapy trials where grant or company funding has ended to ensure subjects continue to receive comprehensive medical follow-up.
• Extent of data needed to change the benefit/risk ratio from the perspective of the provider, regulatory agencies, and patients
  • Patient perspective is fundamental as these are new therapies and families are concerned about long-term side effects. Families want to know if a child’s or patient’s health will be okay, and nothing was compromised by a caregiver’s choice.
  • With new data, it is assessing the potential risks with the known natural history of the disease.
  • Involving patient advocacy groups early can help with understanding and communicating any updates to the community in a timely fashion.
  • Once new warnings or safety communications are made available, many academic centers will review the new guidance, their experience with the agents, and alternative treatment options to determine if a product will still be offered in the post-approval setting.
• Any other notes:
  • Gene therapy is a better and excellent treatment option for some patients and their families.
  • In cases where data is good, but side effects are being seen, is there a way to systematically determine the issue and fix it (for example, use of a new vector) without removing the treatment option from patients?
  • Long term follow up should be patient centric, data driven and financially responsible. One must balance the information we need versus what we want. A risk-based approach, with flexibility to adapt as we get additional information, is a potential LTFU solution. It is important to work remotely with primary providers and look at alternative methods of follow-up such as tracking persistence and if no adverse events are seen, then move to phone calls and surveys to determine long-term outcome and safety profile. 
• Why are LTFU studies important?
  • Gene therapy is still new, and it is hard to do large gene therapy studies. From an academic standpoint, costs are high and there are limited number of patients. However, we owe it to the field and to patients to learn as much as we can.
  • We have made tremendous strides in the last 30-years with the goal of providing safe and effective cell and gene therapy options for patients and their families. While everything is not known, for many, a chance of something vs nothing is huge; therefore, it is important to collect and communicate as much information as possible to allow patients and families to make informed and timely treatment decisions.