In this unit, Dr. Amy Waldman gives a closer look at what lies ahead for someone participating in an investigational clinical trial and, in particular, what is still unknown.
Listen to Quick Takes from experts in the community on the following questions (Time: 19 min):
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Why aren’t all drugs given open label as opposed to a double-blind design?
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What are some of the more realistic expectations that a person participating in a gene therapy trial could expect?
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What are the biggest unknowns and potential risks, both now and in the future, for individuals participating in these trials?
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Once a patient receives gene therapy how are they monitored over time, and why is long-term follow-up important?
Key Takeaways
Why aren’t all drugs given open label as opposed to a double-blind design?
Not all gene therapy trials use an open label design because double blind, placebo-controlled trials are often the most reliable way to assess a treatment’s true effectiveness. While open label designs allow all participants to receive the therapy, it can be harder to understand the outcomes. The choice of trial design depends heavily on the nature of the disease, including its rate of progression. For slow progressive diseases, a staggered approach can be effective, where some participants receive the therapy immediately and others after a delay. This allows for meaningful comparison while eventually giving all participants access to treatment. The goal is to make sure the research measures what it supposed to and the results are accurate while being ethically responsible for patient safety and outcomes.
What are some of the more realistic expectations that a person participating in a gene therapy trial could expect?
Gene therapy responses often take time to appear and may not lead to immediate improvement in symptoms. Unlike typical medicines that provide quick relief, gene therapy may require a period (weeks or months) before its effects become noticeable. Because of this, there is a concern that the disease might continue progressing while waiting for the therapy to take effect. Realistically, the goal is often disease stability rather than symptom improvement. Meaning patients may expect to maintain their current abilities and avoid further decline. Significant improvements, such as regaining lost functions like walking or speech, are less likely, especially if the disease has progressed. Early intervention, particularly in young children, may offer better chances to alter disease progression. Overall, the expectation is cautious with a primary outcome looking to prevent the disease from worsening, and in the best case to see improvement of functions.
What are the biggest unknowns and potential risks, both now and in the future, for individuals participating in these trials?
Gene therapy carries both short-term and long-term risks that individuals and families should understand before participating in clinical trials. In the short term, especially within the first three months, patients may experience their immune system working harder, and a specific part of their defense, called the complement system, could also be triggered which can cause side effects like vomiting or discomfort. Liver toxicity is also a concern within the first one to two months, potentially leading to liver failure. To mitigate this, patients are often treated with steroids or other immunosuppressants, which carry their own risks. While these issues may happen early on, there can still be unexpected effects six months or more after treatment. Long-term risks include uncertainty about how long the therapy’s effects will last.
Once a patient receives gene therapy how are they monitored over time, and why is long-term follow-up important?
Currently, getting an AAV gene therapy more than once is not possible due to immune system memory, which could reject a second dose. Although today’s AAV-based therapies have not been shown to cause cancer or cell overgrowth, the very long-term effects—10 to 15 years out—are still unknown. Because of this, lifelong monitoring is essential, with care transitioning over time to a coordinated team that includes a primary care provider, a disease expert (such as a neurologist or metabolic physician), and ideally, a gene therapy specialist.
Final Thoughts
Participation in gene therapy trials is a deeply personal choice with no pressure to join. Gene therapy remains experimental, with unknown safety and efficacy, so families should make decisions based on what feels right for them. Those who participate take on significant risks as “unsung heroes” paving the way for future treatments, while those who choose not to participate or cannot access trials deserve equal respect. Communities are encouraged to support each other, recognizing the complex challenges and hopes shared by all. Ultimately, understanding the nuances of these trials helps families make informed choices and contributes to advancing treatments for rare diseases.
Continuing the Journey
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