Эксперт Polaryx: для редких заболеваний FDA — партнер, а не регулятор

How FDA discussions evolve in rare disease program Clinical development and regulatory affairs VP discusses regulatory touchpoints, placebo challenges and the value of proactive agency engagement. In this Q&A, Minsu Kang, vice president of clinical development and regulatory affairs at Polaryx Therapeutics, shares his insights from his firsthand experience engaging with the FDA in the context of rare disease therapies. Kang has over 10 years in CNS development, and extensive experience working on late-stage clinical trials and regulatory affairs for a number of neurodegenerative diseases. Polaryx, a publicly-traded, clinical-stage biotech is developing novel, disease-modifying therapies for rare, pediatric lysosomal storage disorders (LSD). Recent funding will allow the initiation of its Phase II SOTERIA trial, evaluating its lead compound across multiple LSD indications. BioXconomy (BX): Given the current uncertainty surrounding the FDA, can you walk us through how FDA interactions typically unfold during rare disease drug development programs? What are the key touchpoints, and how has the process evolved in your experience? Minsu Kang (MK): Companies should engage with the FDA as early as possible. The pre-IND meeting sets the tone for the clinical development program, followed by the remaining typical touchpoints like end of Phase I, end of Phase II/pre-pivotal, pre-NDA/BLA, and so on. While those key touchpoints are still in place and expected, the process has been evolving from a milestone-based model of engagement to a more iterative and focused model that encourages more frequent touchpoints between the big milestone meetings. The addition of Type D meetings is a good example of this approach, where companies can engage the FDA with very specific, narrow regulatory questions for rapid feedback. BX: Are there critical inflection points during FDA interactions where the nature of the dialogue shifts, and how do you prepare for those transitions? MK: Each transition from one development stage to the next is, of course, always critical. Beyond the expected discussions for those transitions, the dialogue can shift when there’s a signal in either the efficacy or safety of the drug, especially in rare disease drug development. Unexpected serious adverse events such as malignancies or deaths can completely derail the program, while remarkable efficacy data may shift the conversation to exploring expedited approval pathways. Whichever the case is, companies should focus on establishing a solid scientific foundation to explain the results as much as possible. Any data or clinical considerations that may explain the serious adverse events, whether they are related to the study drug or whether there’s a way to mitigate the risk, can potentially rescue the program. Similarly, any additional data beyond the positive clinical endpoints that can further demonstrate the target engagement or mechanism of action using biomarkers and other exploratory datasets can elevate the engagement with the FDA and avoid any surprises down the line if the FDA does not share the same excitement for the data or has concerns about the data. BX: What specific challenges have you encountered when trying to align with the FDA on study design and regulatory expectations for rare disease therapies? Conversely, what strategies or approaches have worked particularly well in achieving regulatory alignment? MK: A common challenge in rare disease drug development is the use of a placebo. In many cases, using a placebo may be unethical or make the study impossible to enroll despite the scientific justification. Many factors go into achieving alignment with the FDA on this topic, such as off-label uses of existing medications, disease severity, and availability of natural history data that may serve as an external control arm. Having a good scientific foundation and supporting data, beyond simply referring to the unmet medical needs, can be helpful in achieving regulatory alignment. BX: In your experience, has this alignment caused any friction with the clinical development plans or maybe trial amendments? MK: Yes, it is not uncommon to see both clinical development plans and trial designs to be adjusted based on ongoing regulatory discussions. I don’t see it as friction necessarily, but more of an iteration of the development plan and trial design to ensure continued regulatory alignment. You don’t want to finish the program and then find out that the FDA doesn’t agree with your development plan or trial design. It pays to be proactive, even if it means you are having to make changes, which can sometimes be costly and often labor-intensive. BX: How do you balance the FDA’s requirements for scientific rigor and robust evidence with the inherent challenges of rare disease development—such as small patient populations and limited natural history data? MK: The FDA is willing to work with sponsors and find a path forward, but they still need some assurance that there’s a reasonable level of scientific rigor. Sponsors should do extensive research on patient populations, enrollment barriers, and all available data to highlight what is possible and what the challenges are. Any way to enhance the totality of the data such as careful selection of endpoints and meaningful biomarkers can help with the discussions with the FDA. BX: Given the ongoing discussions about FDA uncertainty, what advice would you give to companies currently developing or planning to develop rare disease therapies? MK: Companies should really see the FDA as a partner in drug development, especially in rare disease where regulatory alignment during the early development stage is critical. Sponsors can utilize mechanisms like INTERACT to get early scientific advice for novel therapies even before a pre-IND meeting and definitely should pursue regulatory designations such as Fast Track Designation that can enable more frequent and expedited touchpoints with the FDA. Despite the uncertainty at the FDA, or in fact, because of the uncertainty at the FDA, earlier, more frequent discussions are critical for successful development programs. Sponsors should rigorously prepare for those interactions to help the FDA understand the reality of a specific disease and provide sound scientific evidence to show that the sponsor is committed to upholding the scientific standards of the FDA as much as possible while ensuring that the clinical development program remains feasible.