FDA Guidance Calls for Drugmakers to Determine Endocrine Effects Before Starting Clinical Trials
Before wasting time and money on a clinical trial, sponsors should determine whether additional preclinical studies are needed to rule out a drug candidate’s potential for encodrine-related adverse effects, the FDA says.
The agency notes, for example, that while standard animal studies can detect harm to the endocrine system following in utero exposures and exposures to adults, they might not detect adverse effects from early postnatal exposure. Further studies — such as direct dosing during the early postnatal period — should be designed to evaluate adverse effects in juvenile animals, according to guidance released last week.
The guidance addresses public comments on a 2013 draft seeking clarity on when additional nonclinical studies of endocrine-related drug toxicity are required.
The FDA notes that nonclinical safety assessments for most new drugs include repeat-dose toxicology studies in two animal species, which can identify endocrine-related activities and potential adverse effects. In assessing those results, drugmakers should ask the following questions to determine if further studies are needed:
- Are there data on related compounds indicating that the drug or related compounds may have adverse endocrine-related effects?
- Is the drug proposed for use in a population not studied in standard toxicity studies?
- Is the clinical systemic exposure to the drug near or above the exposure at the no observed adverse effect level for endocrine effects in animals?
Endocrine activities that occur in animals only at exposures greater than 50 times the human exposure typically don’t require further study, the FDA says. Additional tests are generally necessary only if human exposure is comparable to or greater than the exposure level at which endocrine-related activity is seen in standard nonclinical studies and the relevance to humans is not known.
Drugmakers should also consider possible exposure to multiple drugs containing the same active ingredient or having similar endocrine effects, as this could raise the risk compared with a single drug, the guidance explains.
When further studies are warranted, the FDA suggests:
- Mechanistic studies. If standard studies indicate adverse endocrine effects and the relevance to humans is important for a regulatory decision, then studying the mode of action in alternative animal models may be useful, the FDA says.
- Nonclinical juvenile studies. Studies in young animals may clarify a drug’s long-term effects in infants and children when that can’t be predicted from adult animal studies, according to the guidance.
- Clinical studies. Including endocrine endpoints, such as hormone levels, in clinical trials may confirm adverse activity seen in nonclinical studies, the FDA notes, adding sponsors should discuss this with agency staff.
With the exception of the sections on additional studies, the final guidance hues closely to the draft version. It discusses nonclinical tests sponsors should conduct to support the safety of their drug candidate, including receptor-binding and enzyme assays, nonclinical pharmacology studies, repeat-dose toxicity studies, development and reproductive toxicity studies and carcinogenicity studies.
Read the final guidance, Nonclinical Evaluation of Endocrine-Related Drug Toxicity, at www.fdanews.com/09-09-15-toxicity.pdf. — Meg Bryant