FDA revises IEM drug draft guidance to clarify food standards, use of control groups

The US Food and Drug Administration (FDA) has issued a revised draft guidance on developing drugs to treat inborn errors of metabolism (IEM) to offer clarification on how such treatments should be evaluated in conjunction with dietary management, considerations regarding trial subjects from different countries and on the use of control groups.

IEM are a group of disorders where the metabolic pathways fail to properly break down or store carbohydrates, fatty acids or proteins. The disorders can be inherited or result from spontaneous mutations.

To help sponsors developing drugs for such disorders, FDA published a draft guidance in 2018 outlining its thinking on topics such as clinical trial design, taking into consideration some of the challenges of running clinical trials in the IEM patient population, and other considerations, such as changes in dietary management. After reviewing the comments it received on the earlier draft guidance, FDA issued a revised draft guidance on 11 July to offer some additional clarifications. (RELATED: Diet in Clinical Trials: FDA Drafts Guidance, Regulatory Focus 23 July 2018)

In the updated guidance, FDA clarifies that all drugs being studied for IEM should be studied in conjunction with the patient’s dietary management for conditions where their dietary management is the current standard of clinical care.

“Optimizing and standardizing dietary management in patients diagnosed with inborn errors of metabolism before they enter clinical trials and during clinical trials reduces an important source of bias and variability, improves interpretability, and may allow for smaller and more efficient clinical trials,” the agency added.

In the original draft guidance, FDA only said patients should enter the treatment phase of the trial during a period of stable metabolic control as evaluated by appropriate biochemical analytes and clinical assessments, and sponsors should document baseline dietary information such as total daily protein, lipid, carbohydrate and total daily caloric intake over an appropriate time period. Now, the agency adds that metabolic control may be evaluated by biochemical analytes and clinical assessment as substantiated by current clinical standards of care.

In the revised guidance, FDA also takes into consideration that patients’ diets may vary from country to country, and their baseline dietary management standards should take that into consideration and be stated in the trial protocol.

“Given the global nature of rare disease trials, sponsors should have an awareness of and clearly state the differences in standards in baseline dietary management among patients from different countries,” the agency added.

The guidance notes that efficacy comparisons of historical controls were unlikely to be informative for various reasons, including changes in dietary management standards, differences in patient and trial characteristics and differences in the types and performance characteristics of the assays used.

While FDA still emphasizes that the best type of clinical trial for evaluating IEM drugs are double-blind randomized clinical trials, the agency clarifies in the updated draft guidance that the most informative trial designs also include a concurrent control group with either an approved drug or placebo arm.

“Dietary management should be consistent across all trial arms such that regardless of treatment arm, all patients should be receiving optimized standard of care, including dietary management,” the agency added.

Revised Draft Guidance

FDA revises IEM drug draft guidance to clarify food standards, use of control groups

Related topics

Recommended content

Welcome to the new RAPS Digital Experience