Authored by Christopher Nabel

There are certain aspects of translational research that cannot be taught in a standardized curriculum and, instead, are more amenable to sharing through discussion that reveals common themes.  Many of the lectures at the Society for Translational Oncology Fellows’ Forum fall under this classification but perhaps none quite as much as Dr. Keith Flaherty’s lecture on what comprises an effective Phase I clinical trial.  The early investigational space is highly interdisciplinary, as basic science, medicinal chemistry, pharmacology, and clinical trial design all converge in an attempt to test a hypothesis.  Navigating these issues is critical for the success of a trial and the potential to achieve long-term clinical benefit for patients.

Dr. Flaherty’s talk communicated two major messages.  In the first portion, he demystified the major stepping stones in an early-phase trial, primarily based on his professional experiences.  The first step involves having a clear hypothesis that guides the scientific rationale of the clinical trial.  Once the hypothesis is in place, it needs to be tested—specifically with a drug (or, for the purposes of framing with regards to the hypothesis, a tool compound to test the biology of interest).  A lot of iterative target validation and medicinal chemistry then go into the next two questions: Does the drug act like a drug?  And does the drug do its molecular effect?  While these questions feel like somewhat of an oversimplification given the tremendous amount of work that goes into these two elements, the simplistic reality is that the drug has to work if there is any potential for further success.  Beyond these foundational questions, the matter of whether the drug has any clinical effect requires additionally favorable pharmacokinetics and pharmacodynamics.  Additional investigation regarding factors that account for variable effects or loss of effect of the drug can drive ancillary studies on resistance.

While there are tangible “hard stops” that need to be met as described in the prior paragraph, there are additional intangibles that are harder to quantify.  Specifically in this regard, Dr. Flaherty discussed the importance of finding alignment between the trial sponsor and the study team to ensure that both parties advocate towards a common, successful endpoint for the trial.  I had not considered many of the stressors that early-stage biotechs may face that provide competing interests in trials.  In particular, the time pressure that comes with a limited budget was not something I would intuitively anticipate in determining the endpoints for a trial.  Additionally, a company without a medically-trained representative within their leadership may lack critical insight into the implementation of a trial or recruitment of patients.  Making sure that the two parties truly understand each other is critical to ensure that the early stage clinical trial is in the best position to succeed.

I lastly appreciated Dr. Flaherty’s enthusiasm in sharing his work for the translational process.  What came across in his presentation is his real passion for this translational process and his desire to share it with others.  By distilling a complicated, somewhat nebulous process into general themes, he made it feel accessible—and I feel slightly more empowered for having heard him talk.