Comment from American Brain Tumor Association

To Whom It May Concern: This letter is in response to the request for comments for the FDA issued draft guidance titled “Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause” (Docket ID: FDA-2026-D-1256). For over 50 years, the American Brain Tumor Association (ABTA) has worked to advance the understanding and treatment of brain tumors with the goals of improving, extending and ultimately saving the lives of those impacted by a brain tumor diagnosis. Supporting the brain tumor community for over five decades comes with an intrinsic understanding of this unforgiving and life-stealing disease. It is from this perspective that the ABTA has some concerns about the unintentionally limiting language in the guidance as submitted. Glioblastoma (GBM) is an incurable brain cancer with less than five percent overall survival at five years. As if this staggering statistic weren’t enough, GBM patients suffer from a number of severe symptoms including seizures, confusion, personality changes, as well as vision, balance, mobility challenges, and other types of decline in brain function. Simply put, GBM is a dire diagnosis in need of urgent treatments. We appreciate that the FDA Draft Guidance is an important step toward more efficient development of therapies for this complicated and challenging disease. The draft guidance is a needed step forward because it is designed for rare diseases with serious unmet need, well-understood natural history, and infeasible or unethical randomized trials. Also, it includes eligibility criteria requiring that disease abnormalities (genetic, cellular, or molecular) can be targeted with personalized therapies. However, there is a particular emphasis on genome editing and RNA-based approaches. Here is the specific wording from the FDA guidance, where we are suggesting a change to be more impactful: "While this guidance specifically discusses genome editing (GE) and RNA-based therapies (e.g., 41 antisense oligonucleotides (ASOs)), the general concepts may apply to other types of 42 individualized therapies. Specifically, this guidance applies when clinical evidence from a 43 limited number of patients will be available to support the individualized product’s safety or 44 efficacy in the intended patient population." As currently written, this language may be unintentionally restrictive. Stating “may apply to other types of individualized therapies” introduces ambiguity by implying conditional applicability without defining the conditions. Also, the term “other types” is very vague. We strongly recommend changing the language from “other types” to “any types” to broaden the use of this pathway for other therapeutic approaches. That way, as long as it meets scientific criteria and also meets evidence of safety and efficacy in the patient population, it can reach patients sooner. Thank you for considering these changes to the guidance that will broaden the potential therapies for patients like the GBM population we serve. We need to decrease barriers for access to these treatments so that every option can be considered. You can help make this happen. We appreciate your consideration of our comments and look forward to your final decision.