A new guidance from the U.S. Food and Drug Administration (FDA) provides direction to sponsors on the evidence necessary to demonstrate the effectiveness of investigational new drugs (INDs) 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. However, the guidance applies only to those low-prevalence rare diseases with well-characterized pathophysiology, and in which changes in substrate deposition can be readily measured in relevant tissue or tissues.
There are many reasons that make demonstrating effectiveness extremely challenging for drugs intended to treat slowly progressive, low-prevalence rare diseases that result from defects in a single enzyme, FDA says in the guidance. Examples include:
- Given the slow progression of the disease, demonstrating clinical stability or clinical improvement may require an extremely long time—even decades—in some conditions.
- Developing new disease-specific instruments and endpoints to assess clinical response (e.g., patient-reported outcomes, observer-reported outcomes, new biomarkers) may not be feasible because of the rarity of the disease, geographical distribution of patients, or slow progression of disease manifestations.
- Information on the natural history of the disease may be insufficient to inform the selection of a historical comparator or to inform clinical endpoint selection in future clinical trials.
- In rare circumstances, conducting clinical trials may be impossible because of the extremely low number of patients with a specific disease or with a clinical manifestation of interest for a given disease.
Sponsors should take several factors into consideration when developing a rational approach to drug development, including:
- A genetic defect affecting a single enzyme can result in either the absence of, or a low level of, enzyme activity, with subsequent accumulation of substrates that may be toxic to various tissues. Residual enzyme activity often inversely correlates with substrate accumulation.
- An increase in enzyme activity resulting from the administration of an exogenous enzyme product, by reducing the amount of substrate accumulated and/or by slowing substrate accumulation, may alter the rate of disease progression or, over time, shift the disease phenotype to a milder one.
Author: Michael Causey
