The US Food and Drug Administration (FDA) on Thursday released draft guidance to help sponsors understand the evidence necessary to demonstrate the effectiveness of new drugs, including biologics, or new drug uses intended for slowly progressive, low-prevalence rare diseases that are associated with substrate deposition and are caused by single enzyme defects.
In addition to the recommendation that sponsors perform genetic testing for the defect(s) of interest in all clinical trial subjects, FDA explains how in the absence of a way to “directly characterize the clinical response to the drug of interest (i.e., how a patient feels, functions, or survives), the nonclinical and, in particular, the clinical pharmacology components of the drug development program become the main source of data that 1) support a safe dose that can be used to initiate human studies, and 2) inform dose exploration, which is essential to final dose selection for clinical trials.”
Animal models, FDA says, can provide evidence of enzyme activity by demonstrating the reduction or disappearance of disease-specific substrates.
“Some animal models of single-gene human storage disorders display phenotypes that mimic to a large extent the clinical manifestations and overall course of the human disease (e.g., tripeptidyl peptidase (TPP) null dachshund dog model for TPP deficiency) and offer unique opportunities for evaluating the effect of human enzymes in situations where there is significant structural and functional conservation of the missing enzyme across species,” the draft says.
FDA calls on sponsors to discuss plans to generate evidence of substrate reduction in clinical trials.
“Such evidence should be generated in tissues where changes in substrate deposition can be readily measured, and the relevance of changes in these tissues to the overall disease process must be well understood and clearly justified. The sponsor should also address how the treatment effect size relates to the variability in the test measure,” the draft says.
And FDA notes that this guidance does not apply to low-prevalence rare diseases with rapidly progressive clinical courses, as “such conditions can be evaluated by traditional approaches (i.e., using clinical endpoints such as survival, preservation of function, etc.)” and low-prevalence rare diseases “with previously characterized endpoints predictive of clinical benefit.”
Slowly Progressive, Low-Prevalence Rare Diseases with Substrate Deposition That Results from Single Enzyme Defects: Providing Evidence of Effectiveness for Replacement or Corrective Therapies Guidance for Industry