A new draft guidance document released by the US Food and Drug Administration (FDA) instructs industry on the nonclinical evidence needed to identify potentially harmful effects of an investigational drug on the endocrine system prior to the initiation of testing in humans.
The endocrine system is responsible for the secretion of hormones, a process which can be disrupted by an aptly named class of chemicals known as endocrine disruptors. This disruption occurs in three primary ways:
- A chemical mimicking a hormone (or enhancing an existing one), resulting in the release of fewer hormones
- Blocking hormone receptors
- Affecting the synthesis, transport, metabolism or excretion of a hormone
FDA notes in its guidance that a "wide variety" of adverse events are associated with endocrine disruptors, including developmental problems resulting from the inadequate uptake of hormones. Some of these effects can be permanent, affecting everything from organ function to behavior, nervous system function and even appearance.
Even more alarming, these effects can persist for several generations by producing epigenetic modifications.
A New Understanding
Calling efforts to understand safety "critical," FDA's says that it has recently "gained an understanding of how to identify these potential endocrine effects in drugs not intended to possess those activities."
The result of that understanding, it said, is a data-backed approach that calls for nonclinical test batteries. "To date, no examples of endocrine toxicities have been noted after marketing that would not be identified using the current standard battery of nonclinical tests," FDA wrote. "This experience suggests that in the vast majority of cases, data derived from the FDA's standard nonclinical test paradigm will successfully identify human endocrine disruption risks and that only in rare instances will follow-up testing be necessary." Some additional tests could be necessary depending on the outcome of the initial battery, FDA added.
These tests should conform with the International Conference on Harmonization's (ICH) M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals guideline. Five studies in particular are useful to conduct, said FDA:
- Receptor-Binding and Enzyme Assays
- Pharmacology Studies
- Repeat-Dose Toxicity Studies (for drugs used chronically)
- Developmental and Reproductive Toxicity Studies (for drugs used chronically)
- Carcinogenicity Studies (for drugs used chronically)
The guidance also calls on companies to conduct further testing based on the following questions:
- Are there other data on the compound or from related compounds indicating the drug or related compounds may have endocrine disrupting activity?
- Is the drug proposed for use in a population particularly susceptible to endocrine effects such as pregnant women or pediatric patients?
- Is the clinical systemic exposure to the drug at levels near or above the no observed adverse effect level (NOAEL) for endocrine effects in animals?
- Is exposure to the drug likely to occur throughout an entire lifetime from multiple sources such that cumulative systemic exposure will be unknown?
Further testing may also be warranted if data from the original studies are inconclusive, including alternative animals models, nonclinical DART studies, nonclinical juvenile studies, nonclinical multigenerational studies and, rarely, clinical studies. The latter should be planned in close consultation with FDA.
Draft Guidance for Industry: Endocrine Disruption Potential of Drugs; Nonclinical Evaluation