Hormesis, biological plasticity, and implications for clinical trial research

Area of Science:

• Pharmacology
• Clinical Trials
• Biological Plasticity

Background:

• Randomized human drug trials can yield false negative results, failing to detect beneficial agents.
• Human performance enhancement is limited by biological plasticity, typically between 30-60%.
• High variability in clinical trials often necessitates large effect sizes (2-3x control) for statistical significance.

Purpose of the Study:

• To identify a critical factor causing false negatives in human drug trials.
• To explain how biological plasticity limits impact trial outcomes.
• To propose a novel methodology for addressing these limitations in clinical trial design.

Main Methods:

• Analysis of the hormetic dose response model to define limits of biological plasticity.
• Examination of variability in human epidemiological and clinical trials.
• Proposal of a weight-of-evidence methodology.

Main Results:

• Biological plasticity imposes a maximum enhancement limit on human performance.
• Clinical trial variability can obscure the efficacy of agents within these biological limits.
• Potentially beneficial agents may be missed due to failure to account for plasticity.

Conclusions:

• The hormesis-biological plasticity-clinical trial interaction is a significant source of false negatives.
• A weight-of-evidence approach, similar to EPA's environmental assessments, can successfully address this conundrum.
• This methodology can improve the detection of efficacious agents in drug development.