FDA Guidance: Testicular Toxicity

Posted by Tracy Hendershott on Nov 26, 2018 9:29:00 AM
Tracy Hendershott
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Testicular Toxicity

After being in the draft stages for approximately three years and continuing to receive industry feedback, the FDA CDER has just released final Guidance for Industry Title Testicular Toxicity: Evaluation During Drug Development in October 2018. There are numerous challenges with conducting multi-center clinical trials focusing on testicular toxicity and yet remaining within the realm of guidance from the FDA per their statement:

"A single central laboratory should process and analyze all semen samples for the purposes of consistency and quality assurance."

The primary challenge with this is the stability of semen specimens themselves (<1 hour), as well as the lack of trained semen analysis technologists/andrologists at clinical trial sites and significant inter-laboratory, as well as intra-laboratory variability with processes and procedures.

Eurofins Central Laboratory has been providing the industry a solution to these challenges for over three years now with our Mobile Laboratory Technician service offering. This allows our clients a pathway for compliance with the FDA Guidance document, by having certified Eurofins Laboratory Technicians perform standardized and qualified semen analysis within the stability time window, at sites located globally.

But first, let's explore the significant elements of the final Guidance Document surrounding Testicular Toxicity.

 

Nonclinical Findings that May Indicate the Requirement for
Testicular Toxicity Study Design in the Clinical Stage

The FDA has highlighted the following outcomes in nonclinical trials, that would increase the likelihood of testicular toxicity monitoring in the clinical phase protocols:

  • Findings occur at clinically relevant exposures or small multiples of the clinical exposure
  • Findings occur in multiple species
  • Findings increase in incidence and severity with increasing duration of exposure
  • Finding does not resolve, or at least show partial recover, after one or two spermatogenic cycles or after five half-lives following the last drug dose
  • Finding occurs bilaterally in paired organs
  • Finding is rare in healthy untreated animals
  • Reproductive organ weight change (increased or decreased weight) correlates with adverse histology
  • Decreased male fertility and impaired mating behavior
  • Sperm quality adversely affected (count, motility or morphology)
  • Signs of hormonal perturbation:
    • Anti-Androgenic Signs: Decreased weight and maturation of male sexual organs, including seminal vesicles and ventral prostate when weighed with their secretions, clinical signs suggestive of reduced aggressiveness (e.g. lethargic or reduced mating behavior, feminization of males)
    • Androgenic Signs: Masculinization of females (decreased fertility, female sexual organ pathology or estrus cyclicality), decreased testes size and impaired spermatogenesis

 

Clinical Study Design Recommendations by FDA

If any of the above mentioned criteria are observed during nonclinical phases, the FDA Guidance document recommends the following for clinical phase study design:

  • Semen analysis should be based upon average of two specimens, collected several days apart:
    • At baseline
    • At one spermatogenic cycle (13 weeks) after starting the investigational drug
    • At one spermatogenic cycle (13 weeks) after drug discontinuation or following complete drug elimination
  • Subjects should abstain from ejaculating for at least 48 hours (maximum 7 days) before each semen collection
  • Inclusion criteria based upon 5th percentile value of World Health Organization (WHO) reference values (2010 values)
    • Semen volume - 1.5 milliliters (mL)
    • Total sperm per ejaculate - 39 million spermatozoa per ejaculate
    • Sperm concentration - 15 million spermatozoa per mL
    • Sperm progressive motility - 32 percent
    • Sperm morphology - 4 percent normal forms using strict "Tygerberg" method
  • Potential for utilization of other biomarkers in Testicular Toxicity - serum analysis of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH)
  • A single central laboratory should process and analyze all semen samples for the purposes of consistency and quality assurance

 

Solution with Eurofins Mobile Laboratory Technician for Testicular Toxicity Focused Clinical Trials

To overcome the challenges with limited specimen stability, lack of qualified semen analysis technicians at majority of clinical trial sites and significant variability with both inter- and intra-site laboratory results, Eurofins Central Laboratory has been providing our Mobile Laboratory Technician solution to the industry. Emulating the CRA model abundant within the clinical trial industry, we have built a department of Mobile Laboratory Technicians (MLT) that are available on-call for those patients wth upcoming screening visits for baseline analysis, as well as the planned follow-up visits during week 13 and end-of-drug treatment. Our dedicated MLTs bring the standardized and certified analysis required by the FDA, to each of your clinical site locations globally via our staffed locations in:

  • Lancaster, PA, USA
  • Breda, Netherlands
  • Singapore
  • Shanghai
  • China

Relevant highlights of our program are as follows:

  • Licensed and certified Laboratory Technicians worldwide

  • Performs standardized analysis at clinical trial site, under Eurofins CAP/CLIA certifications from our four global locations

    • Includes CAP/CLIA required oversight from Eurofins Laboratory Supervisor, Director and Medical Director ensuring submission ready data results

    • Proficiency testing at defined intervals based upon Sponsor criteria

  • Travels with calibrated equipment to each clinical site, reducing costs for hardware placement and calibration at each clinical site globally 

To learn more about our Mobile Laboratory Technician solution for short stability specimen analysis (semen, PBMC processing), please reach out to our scientific team here and we can explore your requirements and Eurofins Central Laboratory solutions together.

 

 View the FDA Guidance Document

 

Tags: FDA, Testicular Toxicity, Central Laboratory, Clinical Trial