LAUSR

We all know the proverbial story of the committee attempting to agree on the description of an elephant. Now, more than 200 years on from James Parkinson’s codification of his now-eponymous syndrome, with his hopeful statement predicting the discovery of diseasemodifying therapies, 145 years after the publication of Charcot’s teachings (reviewed by Goetz), 50 years since the advent of effective means of using levodopa to treat the motor symptoms of the disease, and 20 years into the synuclein era, the elephant that is PD still sits in the room with us. And that elephant has a mate, the proof-of-concept (PoC) clinical trial. Elephant #1 intrudes itself in our thinking by reminding us that as much as we think we know about the etiopathogenesis of PD, we still lack crucial information linking genetic and protein abnormalities to the myriad intracellular pathways affected in multiple cell types that ultimately lead to neuronal dysfunction and neurodegeneration. We lack efficient techniques to account for the clinical heterogeneity of patients, impeding our ability to adequately differentiate and stratify patients most appropriate for enrollment in clinical trials, as well as tools to directly measure the impact of underlying brain pathology in relation to patients’ functional impairments and disabilities. Thus, in our current state of knowledge, there are critical gaps that we must do our best to fill. Elephant #1 gets a lot of attention, as elegantly described by Lang and Espay in this issue of the journal. Elephant #2, the PoC beast, gets a lot less attention. But what exactly constitutes “proof”? And of what “concept”? So how should we define these terms? On Wikipedia, the definition of “PoC” reads: “Proof of concept (PoC) is a realization of a certain method or idea in order to demonstrate its feasibility, or a demonstration in principle with the aim of verifying that some concept or theory has practical potential. A proof of concept is usually small and may or may not be complete.” However, in drug development, we need to be concerned not just with the potential of an approach, but also with its utility, as we will be investing many dollars and years, demanding much of our colleagues and patients and their families, and possibly asking them to participate in an endeavor to the exclusion of others that may have greater promise. So for the purposes of describing “proof of concept” in pharmaceutical development, we might want to consider a more directed construct, for example, the idea that: