Comments of Members of the Patient, Consumer, and Public Health Coalition on “Testicular Toxicity: Evaluation During Drug Development – Guidance for Industry” [Docket No. FDA-2015-D-2306-0001]
We appreciate the opportunity to provide feedback to the FDA on the evaluation of testicular toxicity during drug development. The recommendations in the draft guidance are very important and we support the FDA’s effort to better characterize drug-induced testicular toxicity.
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As recognized by the FDA, the effects of many medications on male infertility are either unknown or inconclusive. Testicular toxicity (TT) is a sporadic and challenging issue in pharmaceutical drug development. Although the incidence of TT in pharmaceutical development is typically lower than the incidence of hepatic and renal toxicity, TT presents a challenging issue due to the lack of accurate and precise screening methods. The standards proposed in the Draft Guidance will advance the FDA’s ability to protect the public from drugs with the potential to cause testicular toxicity.
In an effort to strengthen the proposed safeguards, we suggest the following changes to the Draft Guidance:
Section III: Nonclinical Evaluation
The Draft Guidance recommends repeat-dose toxicology studies with at least 4 weeks of drug exposure in two species. We suggest a study duration of at least 3 months based on evidence reported in the literature. For example, a recent survey found that, while TT was generally identified in studies of short duration (less than or equal to 4 weeks), two sponsors indicated that TT had been identified only in studies of greater than or equal to 3 months duration: one detected TT in a 3-month rat study and the other saw TT in a 6-month rat study and in a dog study of more than 6 months in duration.[1]
We also recommend that sponsors be required to submit all data from all species tested for testicular toxicity, and that discordant results from different species be transparent. Furthermore, if rodent studies are concerning but studies in large animal species do not raise the same level of concern, the sponsor should be expected to provide additional studies to help clarify the toxicity profile if the discrepancy cannot be explained. Sasaki et al. noted that it is frequently the case that testicular findings attributable to toxicity are recognized in only one of the two species used for preclinical toxicity testing. And, importantly, experience has shown it is usually not possible to dismiss findings in rodents based solely on the absence of similar observations in the large animal species.[2] Despite this fact, about half of the sponsors in the study would dismiss worrisome rodent findings, if the toxicity was not corroborated in the second species tested.[3]
While the Draft Guidance recommends demonstration of the reversibility of an adverse finding after cessation of dosing, we recommend the sponsor be required to explain the rationale for the timing and length of the recovery period. The justification should include consideration of the drug’s half-life and time required to achieve off-drug pharmacokinetic and pharmacodynamic steady state. Data provided in the survey by Sasaki et al. note the importance of a suitable duration of recovery. One sponsor reported worsening of testicular changes during the 28-day recovery period following a 28-day rat study. Another sponsor noted that, for one project, TT was only conclusively identified in a 3-month dog study after similar findings in the 1-month dog study had been dismissed as background lesions. The findings in the 3-month dog study suggested that mature germinal cells were affected, which may be why the lesion appeared to significantly worsen after 1 month.[4] Because a drug may have lingering effects on upregulation or downregulation of receptors and other biochemical processes, the recovery period parameters (timing, length, etc.) must be transparently explained in the context of the drug’s biochemical effects.
Section IV. Monitoring of the Testes During Clinical Trials
The Draft Guidance recommends semen analyses be completed at baseline and at 13 weeks (one spermatogenic cycle) after initiation of the investigational drug. If adverse effects are seen during the first 13-week period, another 13-week evaluation, at one spermatogenic cycle (13 weeks) after final exposure to the investigational drug, is recommended to assess for recovery of changes in semen parameters. We recommend specifying that the first 13-week analysis must occur after the drug reaches steady-state concentrations, or at least 3 half-lives after initiation of the investigational drug. Likewise, if an analysis is completed after the final exposure, the Guidance should specify that it occur at least 3 half-lives after the end of dosing. This recommendation would be particularly critical for drugs with long half-lives, where the drug would not have reached its steady-state concentration at the end of only 13 weeks. For example, amiodarone, with a half-life of 58 days, would not be expected to reach steady state concentrations until about 25 weeks after its initiation.
In fact, the Final Guidance should require all preclinical and clinical analyses to occur on a timeline that can be justified based on the particular investigational drug’s unique pharmacokinetic and pharmacodynamic parameters.
Section V. Design of a Clinical Trial to Evaluate the Effect of a Drug on the Testes
The primary endpoint suggested in the Draft Guidance is a 50% decline in sperm concentration from baseline. A 50% decrease is a very large decrease and, at this time, no standard percent decline that predicts testicular toxicity has been identified. A smaller change may be relevant on a clinical and population level. We recommend substantially reducing the minimum decrease required as a primary endpoint or providing solid documentation to justify the use of such a large change in sperm concentration as a primary endpoint.
If you have any questions, please contact Tracy Rupp, PharmD, MPH, RD at tr@center4research.org or 202-223-4000.