MARCH 2026 TECH OUTLOOK8IN MY OPINIONBy Haichen Yang, MD, MA, MBA, Vice President, Clinical Research, Amicus Therapeutics IncCurrently, most gene therapies are being developed for rare and serious diseases. In vivo gene therapies tend to be one treatment only and many use invasive delivery methods. On the other hand, ex vivo gene therapies involve complicated and lengthy preparation processes. These and other complications made it very difficult to design placebo-controlled trials. So far, all the approved gene therapy products have used historical data as control groups, either data from a natural history study (e.g., Zolgensma, Libmeldy) or historical data prior to treatment (e.g., Roctavian, Luxturna, Zynteglo). FDA opens to use historical (external) controls in specific circumstances. "FDA regulations recognize historical controls as a possible control group... however, inability to control for certain biases could limit the ability of externally controlled trials to demonstrate substantial evidence of effectiveness. However, bias may be mitigated in certain situations where the disease course is predictable and the treatment effect dramatic." (FDA Draft Guidance "Rare Disease: Natural History Studies for Drug Development") HISTORICAL CONTROL IN GENE THERAPY CLINICAL DEVELOPMENTHaichen Yang
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