Comment from Josh Bonkowsky

I am making these comments on behalf of myself.The Plausible Mechanism Framework (PMF) is an important step forward, with special importance for rare and orphan diseases. I am a pediatric neurologist, physician-scientist; and Director of the Center for Personalized Medicine (Primary Children's Hospital/University of Utah Department of Pediatrics; Salt Lake City, Utah). I would encourage a process for conditional approval, even in the absence of "robust" natural history data. This is because the natural history data is difficult and slow to obtain; whereas treatment with a therapeutic that has safety is much more important. Instead, clinical outcome metrics such as mortality, hospitalizations, Emergency department visits, etc., could be used over a 2-3 year period, and compared to these same outcomes. These clinical outcome metrics I have listed are more easily obtainable, such as from national databases (such as PHIS, or insurance administrative databases). The reason to take this approach is because the burden of harm from untreated disease outweighs the risks of therapies that have had safety established.