From the "Pink Sheet" Daily
Testicular Toxicity In Drug Trials: An ‘Uncommon But Persistent Challenge’
By Brenda Sandburg
Article # 14150729005 / Posted: July 29 2015 9:40 PM
How do you craft a safety study to assess a product's impact on the male reproductive system? First, randomize 200 men, FDA says.
FDA provides detailed advice on designing a clinical trial to assess drug-related testicular toxicity in draft guidance for sponsors.
The draft guidance, “Testicular Toxicity: Evaluation During Drug Development,” describes standard nonclinical studies used to assess the effects of pharmaceuticals on the male reproductive system and the findings that may raise concern about testicular toxicity. The guidance then suggests ways to monitor the drug when it is initially administered to people and if warranted, how to design a clinical safety trial.
The agency recommends a randomized, double-blind, placebo-controlled, parallel-arm trial that randomizes approximately 200 men in a 1:1 ratio to receive either the investigational drug or placebo. For drugs intended for chronic use, FDA recommends that the drug should be administered for at least two human spermatogenic cycles, which is 26 weeks. Drugs indicated for short-term or intermittent use should be administered according to the maximum intended duration of use.
The guidance says the primary endpoint should be percentage of subjects in each group who experience a 50% or greater decline in sperm concentration, compared to baseline, 13 weeks after starting the investigational drug (intended for short-term use or intermittent re-treatment) or after 26 weeks of drug exposure (for chronically administered drugs). The secondary endpoints are changes from baseline in sperm concentration, ejaculate volume, total sperm ejaculate, motility, and morphology.
Acceptability of Adverse Effect Depends on Particular Drug
Subjects who experience a 50% or greater decline in sperm concentration should be re-evaluated after at least a 13-week drug-free interval to assess the recovery following drug exposure, the guidance states.
“The purpose of the clinical semen trial is to evaluate human testicular function based on nonclinical findings of testicular toxicity that cause concern,” the document states. “The trial does not directly evaluate drug effect on human male fertility.”
FDA says that in general, it is not possible to stipulate firm guidelines for interpretation of these trial results and specify results that would resolve the concern of testicular toxicity.
“Each drug, its intended use, and the results of a semen trial as outlined in this guidance should be individually evaluated,” the guidance states. “Ultimately, the acceptability of the adverse effects of a drug on testicular function should be based on the overall risk-benefit assessment of the particular drug and indication being sought.”
Comments on the draft guidance are due Oct. 15.
‘Uncommon but Persistent Challenge’
A few years ago, representatives from eight pharmaceutical companies reported the results of a survey of the incidence of testicular toxicity, stating that testicular toxicity is a “sporadic and challenging issue in pharmaceutical drug development.”
Their 2011 article, “Incidence and nature of testicular toxicity findings in pharmaceutical development,” was published in Birth Defects Research Part B: Developmental and Reproductive Toxicology. It describes highlights from a survey sponsored by the International Life Sciences Institute-Health and Environmental Sciences Institute. The authors were from Johnson & Johnson, Pfizer Inc., Eli Lilly & Co., Boehringer Ingelheim Pharmaceuticals Inc., Merck Research Laboratories, Abbott Laboratories Inc., Bayer HealthCare LLC and AstraZeneca PLC.
They noted that although preclinical testicular toxicity was encountered relatively infrequently, half of 16 respondents observed repeated problems with testicular toxicity (TT) during pharmaceutical development.
“TT remains a relatively uncommon but persistent challenge in pharmaceutical development,” they concluded. “Although current preclinical TT approaches appear to be effective in limiting the occurrence of pharmaceutical candidate attrition in clinical trials, improved biomarker or screening platforms would allow companies to identify TT at an earlier stage, thus decreasing the time and resources expended on safety evaluation of pharmaceutical candidates.”