When it comes to conducting auditory safety studies on drugs, the wise choice is to keep it in-house
Certain medications can damage the ear, resulting in hearing loss, ringing in the ears, hyperacusis, or balance disorders. Thus, many drugs should be tested for auditory safety prior to going to market, ideally at a laboratory that can do all of the GLP-required studies in-house.
In 2015, the US Food and Drug Administration (FDA) issued its guidance document for nonclinical safety evaluation of reformulated drug products and products intended for administration by an alternate route. This is the first guidance to give specific endpoints for testing drugs administered into the ear, including Auditory Brainstem Response (ABR) Evaluation, cytocochleograms, and auditory histopathology. In addition to these safety endpoints, dermal sensitization and otic distribution assessments are required.
When conducting these tests, it is important to work with an organization that has the necessary breadth and depth of experience to support your mission. Ototoxicity studies deal with highly complex tissues and structures that require significant training to extract and test without causing harm:
- Clear observation and pathological review of middle ear conductive mechanisms must be part of every ototoxicity study submitted to the drug approval regulatory agency. Only skilled, steady hands of qualified and trained necropsy technicians can ensure preservation of these structures. There is only one shot at tissue harvest following successful bone decalcification.
- The cochlea is a complex three-dimensional coiled bundle of neural tissue that requires specialized skills, processing, and articulation to achieve the standard of finalized, fixed, and oriented tissue expected by the FDA for histopathological evaluations.
- Cytocochleograms are required on auditory safety studies to support or refute any potential test article related to ABR changes. There are graphic representations of the actual numerical count for inner and outer hair cells along the length of the cochlea. Drug-induced hair cell toxicity produces permanent hearing loss, making the cytocochleogram a critical endpoint on auditory safety studies that requires extremely technical skills.
Experienced organizations with more expansive of ototoxicity studies covering thousands of animal models is also helpful. An extensive database helps determine if an abnormality can be ruled out based on natural background or if it is a drug-related issue. Also helpful is if the lab is GLP-certified. Organizations that adhere to these guidelines are audited on a regular basis, and this certification requires that staff undergo extensive training to ensure consistent quality and compliance. While it can depend on the situation, the FDA often prefers to see studies that are performed in GLP-certified labs due to the consistent oversight, uniformity, and excellence in science.
Lastly, working with an organization that conducts these studies in-house allows more precise planning for reporting, as the CRO sets the timelines for all endpoints of the study. Working directly with one experienced CRO from the beginning to end mitigates risk for delays and ensures quality data for Sponsors. By limiting the study to one laboratory you are also ensured a single point of study control and advocacy that is present throughout the development of the study, in-life conduct, post-life functions, and tissue pathology reviews. Engaging a single Study Director to be your eyes and ears throughout the process increases the rigor of study control and execution.
One Study Director, one phone number, one email address, and almost immediate feedback on study progress are essential elements provided by in-house study control.