FDA Finalizes Testicular Toxicity Guidance

Regulatory NewsRegulatory News | 24 October 2018 |  By 

The US Food and Drug Administration (FDA) on Wednesday finalized guidance for drugmakers on identifying and evaluating early signals that could indicate whether a drug might have adverse effects on the testes and when clinical trials are necessary to assess those risks.
Specifically, the 14-page guidance lays out recommendations for identifying nonclinical signals that suggest risk of testicular toxicity; conducting nonclinical assessments to further evaluate the risk; clinical monitoring; and study design for clinical trials primarily aimed at evaluating drugs for testicular toxicity.
The guidance, which finalizes a draft version released in 2015, includes revised recommendations for nonclinical study design, including species selection, chronic study design, histopathology assessment, sperm quality and what findings increase concerns for impaired fertility.
The guidance has also been revised to stress that “to the extent possible, subjects enrolled in the dedicated clinical safety trial represent the intended population.”
According to the guidance, evaluating a drug for testicular toxicity is challenging as there are only a few clinical markers that can track potential changes in testicular function and because there is a latency period of several months between the time a drug-related injury occurs and when it can be detected using semen analysis.
As such, FDA says it is standard for drugmakers to conduct nonclinical studies to look for evidence of adverse effects on the male reproductive system in animals.
When designing nonclinical studies, FDA says sponsors should “provide a rationale for the choice of doses, duration of exposure, and species used to investigate male reproductive toxicity” and that all studies should feature a control group. Early safety evaluation studies should also include both a rodent and non-rodent species.
“For chronic studies where nonhuman primates are the only relevant species based on pharmacology, the sponsor should ensure when assessing reproductive toxicity that male animals have attained sexual maturity by the end of the study,” FDA writes, noting that this is not always feasible.
According to FDA, sponsors should be looking for evidence of factors that could indicate impaired fertility, such as atrophy, degeneration, necrosis or hypocellularity of the testes; increased seminiferous tubule degeneration or necrosis; germ cell depletion; or other factors that suggest impaired reproductive function.
Certain factors can also increase the significance of such findings, such as whether the incidence or severity of the findings increase with dose or duration; the findings occur in multiple species; or if the findings occur in tissues bilaterally.
The guidance also provides input on risk minimization and monitoring strategies for testicular toxicity in clinical trials and study design recommendations in the event that a dedicated clinical safety trial assessing testicular toxicity is needed.
For oncology drugs covered under the International Conference on Harmonisation’s S9 Nonclinical Evaluation for Anticancer Pharmaceuticals guideline, FDA says sponsors should contact the Office of Hematology and Oncology Products before launching follow-up studies to evaluate testicular toxicity.
FDA, Federal Register Notice


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