September 11, 2023
We appreciate the opportunity to comment and support FDA’s proposed rule regarding: “Inborn Errors of Metabolism That Use Dietary Management: Considerations for Optimizing and Standardizing Diet in Clinical Trials for Drug Product Development; Draft Guidance for Industry; Availability.”
The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
As improved screening methods and technologies emerge for diagnosing inborn errors of metabolism (IEM), the incidence of IEM continues to increase. Dietary management is a central treatment modality for many IEM conditions as dietary control reduces toxic metabolite formation and prevents organ damage. NCHR agrees that when drug products are studied as a treatment modality for IEM, they should be studied as a supplement to dietary management in an effort to improve data interpretability, reduce confounding, and produce reliable data regarding drug efficacy.
While NCHR generally supports the draft guidance, we propose several recommendations to improve study design, feasibility, and ultimately drug efficacy:
- We recommend that the FDA propose standardized protocols in circumstances where a) a study participant is non-adherent to their standardized diet, b) a study participant has an acute flare-up of their disease, and/or c) a study participant experiences an acute illness that changes their metabolic demand.
- We recommend that the FDA propose specific guidance for crossover clinical study design within this population as this may introduce diet variability and result in poor data interpretability.
- We recommend that the FDA include more objective measures for dietary compliance, such as enzymatic or metabolite testing, rather than rely on participant documentation and diet diaries to reduce confounding and improve the understanding of drug efficacy results.
While NCHR supports the overall perspective of FDA’s draft guidance, these recommendations would strengthen the quality of the clinical trials performed among the IEM patient population, reduce the effects of confounding, and improve data interpretability on drug efficacy.