Pure-tone thresholds have long served as a gold standard for evaluating hearing sensitivity and documenting hearing changes related to medical treatments, toxic or otherwise hazardous exposures, ear disease, genetic disorders involving the ear, and deficits that develop during aging. Although the use of pure-tone audiometry is basic and standard, interpretation of thresholds obtained at multiple frequencies in both ears over multiple visits can be complex. Significant additional complexity is introduced when audiometric tests are performed within ototoxicity monitoring programs to determine if hearing loss occurs as an adverse reaction to an investigational medication and during the design and conduct of clinical trials for new otoprotective agents for noise and drug-induced hearing loss. Clinical trials using gene therapy or stem cell therapy approaches are emerging as well with audiometric outcome selection further complicated by safety issues associated with biological therapies. This review addresses factors that must be considered, including test-retest variability, significant threshold change definitions, use of ototoxicity grading scales, interpretation of early warning signals, measurement of notching in noise-induced hearing loss, and application of age-based normative data to interpretation of pure-tone thresholds. Specific guidance for clinical trial protocols that will assure rigorous methodological approaches and interpretable audiometric data are provided.

Pure-tone thresholds have long served as a gold standard for evaluating hearing sensitivity and documenting hearing change related to treatments, exposures, disease, genetic disorders, and normal aging. Interestingly, nationally representative population studies have revealed hearing to be improving over time with this long-term beneficial trend speculated to perhaps be influenced by declines in manufacturing jobs, better hearing protection device (HPD) use in noisy workplaces, decreases in the prevalence of smoking, and better medical management of diabetes, hypertension, and dyslipidemia (Campbell and Rybak, 1996; Hoffman et al., 2010; Hoffman et al., 2017). Data from the large, regional, longitudinal Beaver Dam and Beaver Dam Offspring studies show a similar improvement in hearing as a function of generation (Zhan et al., 2010). The identification of individual hearing levels (HLs) for clinical purposes (diagnosis, rehabilitation, and ototoxic monitoring) as well as research purposes (epidemiological reports and factors influencing hearing) and clinical investigations (development of drugs or devices that protect or restore hearing) rely on the pure-tone audiogram for insights and conclusions such as those above.

Although the use of pure-tone audiometry is basic and standard, interpretation of thresholds obtained at multiple frequencies in both ears over multiple visits can be complex. In this paper, we address factors that must be considered during audiometric testing and how these considerations may vary across diagnostic, research, and clinical trial applications. The emphasis of this review is use of the audiogram and testing considerations when determining if hearing loss occurs as an adverse reaction to a new drug in clinical trials or if hearing loss is prevented during clinical trials evaluating investigational agents targeting prevention of noise-induced hearing loss (NIHL) and drug-induced hearing loss (DIHL). Whereas the focus of this paper is on pure-tone thresholds, some material will be presented in the context of other tests likely to occur in conjunction with the pure-tone threshold data.

In the early 1900s, hearing testing was based on or dominated by tuning fork tests with the Weber test, Rinné test, and Schwabach test being commonly used (for review, see Huizing, 1973; 1975a,b). Tuning fork tests still see significant clinical usage, particularly in otology clinics (see, for example, Ungar et al., 2021), but there are limitations to these tests (Miltenburg, 1994; Behn et al., 2007; for systematic review, see Kelly et al., 2018). Comprehensive audiometric testing is, therefore, the gold standard in the diagnosis of hearing loss.

One of the first prototype audiometers was the Iowa Pitch Range Audiometer in 1922 (Bunch, 1922), although the Hughes audiometer was developed beforehand (Hughes, 1879). These early devices were followed by the first commercial audiometers, such as the Western Electric 1A audiometer (Rossville, GA), after the development of the vacuum tube (Miles, 1956; for comprehensive review, see Vogel et al., 2007). Advances over the course of time included the addition of masking capabilities, the addition of microphones for live voice testing, and the onset of computer testing interfaces (for discussion, see Staab, 2017). Cordia Bunch, a key contributor to the development of the Iowa Pitch Range Audiometer, moved to Washington University School of Medicine with otolaryngologist L. W. Dean and collected a wealth of audiometric data from patients, leading to the publication of Clinical Audiometry (Bunch, 1943). The birth of audiology as a profession, however, is largely considered to have occurred in the 1940s, subsequent to World War II, driven by the large number of veterans with NIHL and auditory rehabilitation needs.

In addition to pure-tone detection thresholds, detection thresholds for speech are also of interest. Raymond Carhart advocated that functional assessment should include the speech reception threshold (SRT) measurement, as well as word identification at sound levels above the SRT. This ultimately resulted in the development of the “Carhart method” for hearing aid selection, which emphasized functional outcomes as part of the selection of a device providing maximum benefit to the patient (Carhart, 1946). Although this specific procedure is no longer used in clinical practice or research, pure-tone and speech audiometry are integral to the practice of clinical audiology, hearing research, and clinical trials designed to evaluate drugs or devices.

Degrees of hearing loss are formally based on a pure-tone average (PTA) and typically based on frequencies such as 0.5, 1, and 2 kHz (PTA512) or 0.5, 1, 2, and 4 kHz (PTA5124). The PTA does not specify audiometric configuration, which is usually further described as “flat,” “sloping,” etc., or may be described by specific frequency regions (for review, see Baiduc et al., 2013). The categories of degree of hearing loss, based on PTA512 as established by Goodman (1965), include −10–26 dB HL, within normal limits; 27–40 dB HL, mild loss; 41–55 dB HL, moderate loss; 56–70 dB HL, moderately severe loss; 71–90 dB HL, severe loss; and 91+ dB HL, profound loss. An alternative common strategy is to subdivide the “within normal limits” category as follows: –10–15 dB HL, normal; 16–25 dB HL, slight hearing loss; and 26–40 dB HL, mild hearing loss (Clark, 1981). Other grading strategies are also available (Olusanya et al., 2019). Thus, the definitions must be clearly stated to avoid ambiguity and confusion in reporting.

All of the above threshold levels within the classification schemes are specified using American National Standards Institute (ANSI) or International Organization for Standardization (ISO) references for signal intensity, which provide a conversion from decibels sound pressure level (dB SPL) to decibels hearing level (dB HL). The calibration of audiometers with specific transducers is performed by measuring dB SPL output, whereas patient hearing is specified in dB HL, which is the dB difference relative to the dB SPL measurement that is deemed “normal” for a reference population. From 1951 to 1964, American Standards Association (ASA) references were used (American Standards Association, 1951). After adoption of new standards (ISO, 1964; ANSI, 1969), any audiograms obtained from those earlier times had to be converted using the updated 0 dB HL reference before direct comparisons with current audiometric data (Davis and Kranz, 1964; Campbell, 1998). As reviewed in Davis and Kranz (1964), the levels specified in American Standards Association (1951) were based on threshold measurements in normal ears tested during the 1937 U. S. Health Survey (Hall, 1938; Weisz, 2011), and the data were observed to be systematically different from other data collected with more modern technology and procedures in European countries in the 1950s. These discrepancies prompted the ISO to create a new international standard based on review of normative data from 18 to 25 year old participants tested in studies using (then) modern acoustic and psychoacoustic criteria. The normative data derived from approximately 15 studies conducted in 5 countries were adopted by the ISO (1964) and ANSI (1969; for detailed review, see Davis and Kranz, 1964; Michael, 1968).

Campbell et al. (2016) recommended guidelines for auditory threshold measurement in clinical trials on NIHL prevention. Their recommendations included case history assessing relevant risk factors, otoscopic examination, tympanometric testing to assess the functional status of the middle ear, and pure-tone threshold assessment at 0.5, 1, 2, 3, 4, 6, and 8 kHz with testing completed prior to noise exposure to establish a baseline, after the noise exposure to document any immediate changes in hearing, and at 2–4 weeks post-noise to establish the permanence of any documented changes in hearing. Threshold elevation that recovers prior to the end of a 2–4 week post-exposure window is a noise-induced temporary threshold shift (NITTS) and threshold elevations that remain at 2–4 weeks post-exposure are a noise-induced permanent threshold shift (NIPTS). Data from animals suggest little additional recovery beyond the first 2 weeks but up to 4 weeks of recovery time can be provided to assure that there is no additional recovery of any remaining threshold shift. Initial changes are often described as a compound threshold shift (CTS) because the relative mix of temporary threshold shift (TTS) and permanent threshold shift (PTS) cannot be determined until the end of the recovery period when the permanence of the shifts are established. Campbell et al. (2016) recommend that test-retest reliability be established at each test time by verifying that responses are within ±5 dB at 1 and 2 kHz, following protocols used by Fausti et al. (1999) and Campbell et al. (2003). Per Campbell et al. (2016), equipment calibration in compliance with relevant ANSI or ISO standards is necessary.

The U.S. requirements for trained personnel are discussed in Campbell et al. (2016). Licensed audiologists familiar with rigorous adherence to research protocols are recommended personnel with the possible additional inclusion of technicians who are certified by the Council for Accreditation in Hearing Conservation (CAOHC) or have equivalent military training (per the criteria specified in Instruction 6055.12; see Department of Defense, 2019). State-licensed and/or professionally certified audiology assistants are another possible category of personnel. For example, the State of Texas now allows licensed audiology assistants to complete assigned otoscopy, tympanometry, otoacoustic emission test procedures, and pure-tone air conduction threshold testing (although they are not permitted to diagnose or make statements about the severity of any measured hearing loss; see Texas Department of Licensing and Regulation (2018). Audiology assistant licensure regulations and training requirements may vary from state to state; therefore, one possibility is to require audiology assistant certification (C-AA) from the American Speech-Language Hearing Association (ASHA), a new certification category which became effective July 1, 2020, if audiology assistants are to participate in clinical trial test administration. Although the training requirements and regulations described above are those of the U.S., adherence to similar requirements in other countries is imperative.

In the U.S., some clinical trial publications do not specify personnel qualifications (Kil et al., 2017) and others specify certified audiologists (Kopke et al., 2015) or licensed audiologists and supervised Doctor of Audiology students (Le Prell et al., 2016). If technicians, assistants, or graduate students participate in testing, it is incumbent on the study leadership to provide adequate supervision, and vigilance can be necessary even with clinician-administered intervention studies. In the multisite aging and cognitive health evaluation in elders (ACHIEVE) randomized controlled trial, Arnold et al. (2021) followed a rigorous protocol, including online training for participating clinicians, testing on the protocol, an in-person pre-study meeting with role playing, and routine video conference meetings to prevent “drift” from the standard protocol over time.

The definition of significant threshold shift (STS) varies across organizations and diagnostic applications. In the U.S., one of the definitions for STS is the standard threshold shift as defined by the Occupational Safety and Health Administration (OSHA), who defined a significant change in hearing as an average threshold shift of 10 dB or greater at 2, 3, and 4 kHz (Occupational Safety and Health Administration, 1983). Later, a reportable work-related hearing loss was defined for regulatory purposes as including three criteria: (1) the average threshold shift at 2, 3, and 4 kHz is 10 dB or greater (i.e., a STS as defined in the 1983 statute); (2) the average threshold at 2, 3, and 4 kHz is 25 dB HL or poorer; and (3) a physician or other licensed health care professional deems workplace noise to have caused or contributed to the hearing loss or to have aggravated a preexisting hearing loss (Occupational Safety and Health Administration, 2001; see, especially, 29 CFR 1904.10, “Recording criteria for cases involving occupational hearing loss”). As per 29 CFR 1904, the goal of workplace injury reporting regulations is to “compile accurate statistics on work injuries and illnesses which shall include all disabling, serious, or significant injuries and illnesses, whether or not involving loss of time from work, other than minor injuries requiring only first aid treatment and which do not involve medical treatment, loss of consciousness, restriction of work or motion, or transfer to another job.” Thus, STS definitions used by OSHA are intended to identify hearing loss that is disabling, serious, or significant as per the statutory language.

The OSHA (1983) definition of STS has been adopted within Department of Defense (DoD) Instruction 6055.12 as well (Department of Defense, 2019) with STS defined as an average shift of 10 dB or more at 2, 3, and 4 kHz. OSHA regulations allow but do not require retesting the employee to determine the permanence of the measured STS (Occupational Safety and Health Administration, 1983). DoD regulations, in contrast, require follow-up testing with at least 14-h noise-free time prior to the audiometric test repetition (Department of Defense, 2019). As per a recent systematic review of 31 clinical trials investigating NIHL prevention (Le Prell, 2022), the preliminary report to the Army by Campbell (2016) is the only report that appears to include the OSHA criterion, and the OSHA criterion was one of several reported study outcome measures. Thus, OSHA STS has not been used as a primary outcome measure in any NIHL otoprotection studies and has not been routinely used as a secondary outcome measure. A major issue is that OSHA STS develops over years, and clinical trials have to date been active for much shorter periods of time than would be necessary for OSHA STS to develop in a sufficient proportion of participants.

For NIHL, the most common early warning signal for noise injury is the “red flag” advocated by the National Institute for Occupational Safety and Health (NIOSH). In their 1998 Practical Guide, NIOSH advocated that a STS be defined as a 15-dB threshold shift at 0.5, 1, 2, 3, 4, or 6 kHz (i.e., any of the OSHA-required test frequencies). They also recommended retest subsequent to reinstruction and repositioning of the earphones to assure that the shift is not spurious. If the 15-dB threshold shift is repeated at the initial test time, then an additional test is required within 30 days with a 12-h quiet period to precede the follow-up test to assure that test results are not confounded by TTS (NIOSH, 1998). The DoD similarly employs a 15-dB red flag, but it is limited to 1, 2, 3, and 4 kHz, and serves as an early warning requiring counseling and HPD check but with no requirement for follow-up testing to establish the permanence of the single-frequency shift (Department of Defense, 2019). Several clinical trials assessing NIHL prevention have included (or are including in the case of ongoing trials) a single-frequency 15-dB shift criterion as one of the reported outcomes (NCT04768569; NCT04774250; Joachims et al., 1993; Campbell, 2016) but these represent only 13% (4/31) of the NIHL otoprotection trials identified in the review by Le Prell (2022).

The observation of a “notched” audiogram in combination with documentation of significant noise exposure history is generally considered the gold standard for NIHL identification, although there are a variety of audiometric features to consider (Kirchner et al., 2012; Mirza et al., 2018). The understanding of the notched audiometric configuration has been based on data such as the audiograms from workers employed at a jute-weaving factory (Taylor et al., 1965). Those data, as plotted by Dobie (2013), clearly show a notched configuration. Data collected across industries and published by OSHA during the promulgation of the hearing conservation regulations (Occupational Safety and Health Administration, 1981) also clearly show notched configurations emerging with increasing duration or level of occupational noise exposure (see Fig. 1). In the OSHA data tables, the “expected” contributions of aging to hearing loss have been subtracted from individual participant thresholds in an effort to reduce confounding of the effects of aging and noise on hearing. As will be discussed in Sec. II F, there are multiple age-correction strategies and issues with the correction of individual audiograms that must be considered. Age-corrected data, such as those shown in Fig. 1, therefore, should be interpreted with caution.

FIG. 1.

Audiometric data tables from Occupational Safety and Health Administration (1981) are plotted to illustrate the increasingly notched shape of the audiogram as workplace exposure levels (85, 90, 95, and 100 dBA) and years of employment (10, 20, 30, or 40 yr) increase. The range in degree of noise-induced hearing loss is reflected through illustration of the 10th percentile, median, and 90th percentile. In the OSHA data tables, the expected contributions of aging to hearing loss have been subtracted from each individual participant's thresholds based on the individual participant's age as cumulative effects of aging confound NIHL that increases over time simultaneous with but not parallel to changes in hearing expected with aging.

FIG. 1.

Audiometric data tables from Occupational Safety and Health Administration (1981) are plotted to illustrate the increasingly notched shape of the audiogram as workplace exposure levels (85, 90, 95, and 100 dBA) and years of employment (10, 20, 30, or 40 yr) increase. The range in degree of noise-induced hearing loss is reflected through illustration of the 10th percentile, median, and 90th percentile. In the OSHA data tables, the expected contributions of aging to hearing loss have been subtracted from each individual participant's thresholds based on the individual participant's age as cumulative effects of aging confound NIHL that increases over time simultaneous with but not parallel to changes in hearing expected with aging.

Close modal

Separate from age correction, there are fundamental issues relevant to the discussion of notched audiograms, including the basic definition that is used to identify the presence of a notch (for review, see Le Prell et al., 2011; Bhatt and Guthrie, 2017). Of the more common definitions, Niskar et al. (2001) defined a noise notch as (1) thresholds ≤15 dB HL at 0.5 and 1.0 kHz; (2) 3, 4, or 6 kHz thresholds at least 15 dB worse than thresholds at 0.5 and 1 kHz; and (3) 3, 4, or 6 kHz threshold at least 10 dB worse than the 8 kHz threshold. In contrast, Coles et al. (2000) defined a noise notch as a hearing threshold at 3, 4, or 6 kHz that is at least 10 dB greater than that at 1 or 2 kHz and 6 or 8 kHz. Additional detail about other notch definitions, including those of Mahboubi et al. (2013), Phillips et al. (2010), Agrawal et al. (2009), Hoffman et al. (2006), McBride and Williams (2001), and Lees et al. (1985), is provided in Bhatt and Guthrie (2017). In general, all of the definitions reviewed by Bhatt and Guthrie (2017) included either a 10 or 15-dB notch depth with recovery at 6 or 8 kHz. Just as some ototoxicity grading scales for DIHL are more sensitive than others, resulting in higher rates of observed ototoxicity for some grading scales than that of others, the notch definition will affect the measured prevalence of audiometric notches with more notches observed when using a 10-dB criterion than a 15-dB criterion. It must also be remembered that not all individuals identified as having an audiometric notch report a positive history of noise exposure, and not all individuals reporting a positive history of noise have an audiometric notch (Hong, 2005; Nondahl et al., 2009; Osei-Lah and Yeoh, 2010).

A cautionary note has emerged regarding use of a notched audiometric configuration as a metric for the prevalence of NIHL in military personnel. Moore (2020) and, more recently, Lowe and Moore (2021) reported a significant prevalence of 8 kHz threshold deficits in military personnel, resulting in an audiometric configuration that does not produce a notch according to many of the definitions noted above. They proposed a military noise-induced hearing loss (M-NIHL) definition that importantly differs from other notch definitions in its use of the age-related hearing loss (ARHL) data tables published by ISO (2017b). As per Lowe and Moore (2021), the criteria for M-NIHL include (1) the hearing threshold at 3, 4, 6, or 8 kHz is at least 10 dB poorer than that at 1 or 2 kHz; (2) the difference between the 6 and 8 kHz thresholds is at least 5 dB smaller than would be expected based on age alone, or the difference between either 3 and 8 kHz or 4 and 8 kHz thresholds are at least 10 dB smaller than would be predicted based on age alone, using ISO (2017b) median values; and (3) the hearing threshold at 4, 6, or 8 kHz is at least 20 dB poorer than the median threshold for that age, using ISO (2017b). Using the M-NIHL strategy of Moore (2020), Lowe and Moore (2021) found a higher incidence of noise injury within a population that had served in the British military than was revealed using the Niskar et al. (2001), Coles et al. (2000), or Phillips et al. (2010) notch metrics.

The observation that M-NIHL patterns in soldiers with weapons fire exposure deviate from the expected notched audiometric configuration may explain at least some previously reported discrepancies in which notching was not as expected. As a newly emerging measure, M-NIHL has not been included in any clinical trials at this time. None of the clinical trials identified in Le Prell (2022) evaluated the prevalence of notched audiometric shifts or prevention of new audiometric notches in trial participants.

The nature of the interaction between the effects of aging and those of noise on hearing have been the subject of considerable interest (for review, see Bielefeld, 2012). Some human studies suggest additivity with the total hearing loss reflecting the sum of the threshold shifts occurring during aging and from noise exposure. For example, veterans with existing NIHL developed approximately the expected amount of additional ARHL when followed longitudinally (Macrae, 1971; 1991). Thus, the consensus of several expert working groups is that NIHL does not progress after cessation of the offending exposure (Humes et al., 2005; Kirchner et al., 2012; Mirza et al., 2018). In other words, individuals with existing NIHL lose hearing at the expected rate as they grow older.

Data from rodent models (Mills et al., 1997; Kujawa and Liberman, 2006), however, have raised questions about whether ARHL will progress more rapidly than expected even if the noise exposure is not ongoing. Longitudinal changes in audiograms from middle-aged men participating in the Framingham Heart Study showed that men who had 4 kHz notches developed larger threshold shifts at 2 kHz in subsequent years than men whose audiograms were not notched at the start of the study (Gates et al., 2000). As per the commentary by Dobie (2013), however, there was no documentation of noise exposure history in participants with audiometric notches and no documentation that participants without audiometric notches did not have a significant noise exposure history. In addition, Dobie (2013) noted that many participants were below the age of retirement at their initial audiogram with no documentation that noise exposure ceased at the time of this initial audiometric test. If noise exposure was ongoing, interpretation of the longitudinal data as reflecting accelerated ARHL would be confounded. Several other studies thought to reflect accelerated human hearing loss subsequent to the termination of noise exposure have similar shortcomings. For example, Rosen et al. (1962) and Goycoolea et al. (1986) estimated noise exposure based on time spent living in cities with no other documentation of the specific type or amount of noise exposure in those reports. A more recent longitudinal study that did document noise exposure history compared the progression of hearing loss in retirees with previous noisy careers and those with previous quiet careers (Lee et al., 2005). No difference in the progression of hearing loss over time was noted, a finding that is consistent with assumptions that hearing loss was additive rather than synergistic (see, also, Dobie, 2013). Whether or not early noise exposure predisposes individuals to increased risk for greater than expected hearing loss during aging is certain to be an ongoing question of interest and topic for additional research as it has significant implications not only for those exposed to military or civilian occupational noise but also for those exposed to recreational (leisure) noise.

As noted above, there are several considerations in the subtraction of the expected effects of aging from the audiogram when an estimate of NIHL is of interest. Multiple databases provide “expected” ARHL values that can be used to “age-correct” the audiogram. These databases are typically based on the median hearing loss measured in different screened or unscreened populations (ANSI, 1996; ISO, 2013; ANSI, 2016; ISO, 2017b).

The ANSI (1996) standard included three databases, termed Annex A, Annex B, and Annex C; this standard was updated in 2006 and again in 2016. The current versions of Annex A and Annex B, found in ANSI (2016), are equivalent to Database A and Database B in ISO (2013). Each Annex includes 10th percentile, median, and 90th percentile thresholds from a specific population. In the case of Annex A, the predictive equations were derived from Robinson and Sutton (1979), who combined data from multiple screened populations drawn from various countries (ANSI, 1996). Annex A is, thus, generally assumed to represent “pure” presbycusis because individuals with a history of noise exposure and other risk factors for hearing loss have been excluded. Annex B was originally based on United States Public Health Service (USPHS) data (U.S. Department of Health Education and Welfare, 1965); however, ANSI (2016) has been updated using data from three unscreened populations drawn from Sweden (Johansson and Arlinger, 2002), Norway (Engdahl et al., 2005), and the United States (Hoffman et al., 2010; 2012). Annex C, published in ANSI (1996) but not in ANSI (2016), included race as an additional factor and a more limited screening with individuals excluded from the database calculation if they had occupational noise exposure but not if they had other risk factors for hearing loss. NIOSH (1998) recommended the use of Annex C unless a better database became available. In contrast, Dobie and Agrawal (2011) recommended unscreened databases for age-corrected calculations of NIHL as individuals with noisy jobs, who are excluded from Annex C, are also more likely to be smokers, diabetics, poorly educated, white, and exposed to nonoccupational noise, all of which are risk factors for hearing loss.

An additional database that must be noted is Appendix F of 29 CFR 1910.95 (Occupational Safety and Health Administration, 1983). When age correction is used to subtract out the effects of age from an individual worker's audiogram prior to the calculation of threshold shift within the occupational hearing conservation program, Appendix F must be used. Age correction is allowed but not required by OSHA. In contrast, DoD Instruction 6055.12 (Department of Defense, 2019) does not permit age correction. Arguments against age correction are largely based on the significant variation across individuals. An individual at the tenth percentile (i.e., having better hearing than 90% of the reference population) will likely be overcorrected when median ARHL values are subtracted from their audiogram, attributing too little hearing loss to noise injury after subtracting the median ARHL values. An individual at the 90th percentile (i.e., having better hearing than only 10% of the reference population) will, in contrast, likely be undercorrected when median ARHL values are subtracted from their audiogram with all of the remaining hearing loss attributed to noise after subtracting median ARHL values. Thus, the accuracy of insights generated via age correction will vary across individual patients/workers, a problem that is specifically noted in ANSI (2016), which states: “For a single individual, it is not possible to determine precisely which changes in hearing threshold level are caused by noise and which changes are caused by other factors, although, in doubtful individual cases, the data in this American National Standard might provide an additional means for estimating the most probable causes in audiological diagnosis.” In medical legal cases, allocation strategies that are based on a proportional analysis of both the expected ARHL and expected NIHL, described in detail in Dobie (2015), might be considered instead of using fixed age-correction factors from any of the above databases.

If age correction is going to be applied to the audiogram, selection of an appropriate reference database is important. Given the ongoing epidemiological National Health and Nutrition Examination Survey (NHANES) study, NIOSH (1998) suggested that NHANES data could, in the future, provide a better age-correction database. Indeed, an alternative median-based age-correction table has now been proposed using normative population data from NHANES (Dobie and Wojcik, 2015). A second set of NHANES-based age-correction factors are also available and notable in that they are based on 25th percentile data rather than median data (Flamme et al., 2020). The 25th percentile was selected by Flamme et al. (2020) based on the close correspondence of the 25th percentile data with longitudinal threshold measurements from a population of firefighters working for the Federal District of New York.

The differences between age-correction factors are significant. The NHANES is an ongoing nationally representative survey with new population cohorts recruited every 2 yr. The age-correction factors proposed by Dobie and Wojcik (2015) were based on NHANES data collected from 1999 to 2006, whereas the age corrections proposed by Flamme et al. (2020) were based on NHANES data collected from 2005 to 2012. Because of the differences in hearing across NHANES cycles and the differences between the 25th percentile and median HL data, the age corrections are smaller in Flamme et al. (2020) than in Dobie and Wojcik (2015), OSHA Appendix F, and ANSI appendices. Thus, relatively more hearing loss will be attributed to noise if using Flamme et al. (2020) (because of the smaller age-correction factors), and relatively less hearing loss will be attributed to noise if using age corrections that have larger age-correction factors.

For DIHL, the most common definition of STS is found in the criteria used to identify significant ototoxic change (SOC), put forward by ASHA (1994) and adopted by the American Academy of Audiology (AAA; American Academy of Audiology, 2009). ASHA and AAA define the early warning for SOC as hearing threshold shift meeting one of the three criteria: (1) 20 dB decrease at any one test frequency; (2) 10 dB decrease at any two adjacent frequencies; or (3) loss of response at three consecutive test frequencies where responses were previously obtained. As noted above, the ASHA and AAA definition of SOC has not been broadly used within clinical trials investigating the development of drugs for NIHL prevention. However, a broad review of inner ear medication trials for various auditory indications revealed that the ASHA SOC criteria were included in 20% (6/30) of the identified DIHL clinical trials (Le Prell, 2021). Given that the ASHA and AAA SOC criteria are explicitly recommended for early warning DIHL identification, it is not surprising to see a higher rate of inclusion in DIHL prevention studies than in studies investigating other auditory indications.

For drug-induced ototoxicity adverse event determination in clinical trials, scales that grade the severity of the hearing loss are available. One of the most familiar is the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE), which is currently available in version 5.0. CTCAE versions 2–5 are available online in the NCI Division of Cancer Treatment and Diagnosis (DCTD) Cancer Therapy Evaluation Program (CTEP). CTCAE is used for adverse event reporting for all body systems throughout the clinical trial. As discussed in King and Brewer (2018), when pre-treatment thresholds are available, the severity of the ototoxicity is documented based on changes in hearing thresholds and when pre-treatment thresholds are not available, subjective changes in hearing and severity of hearing deficit are used. CTCAE grading scales exist for pediatric patients as well as adults.

A variety of additional ototoxicity grading scales have been developed for classifying the severity of hearing loss in patients receiving ototoxic drug agents. These are reviewed in detail in Crundwell et al. (2016), King and Brewer (2018), and Campbell and Le Prell (2018). TUNE, described by Theunissen et al. (2014), is the only adult ototoxicity scale that includes high frequencies (8–12.5 kHz) and subjective complaints in the absence of threshold shift, but it also appears to have a higher rate of false positives (for discussion, see King and Brewer, 2018). Three additional pediatric scales include the Brock (Brock et al., 1988; Brock et al., 1991), Chang (Chang and Chinosornvatana, 2010), and International Society of Pediatric Oncology (SIOP) scales (Brock et al., 2012). These scales all grade measured hearing thresholds, irrespective of baseline HL, and they are generally designed to identify minimal hearing loss and/or higher-frequency hearing loss based on the unique hearing needs of children (for review, see King and Brewer, 2018). The Muenster scale, developed at Muenster University Hospital, is based on World Health Organization classifications (Schmidt et al., 2007) and appears to provide the earliest identification of hearing loss relative to other scales, based on review of 3799 audiograms from 654 pediatric patients receiving required treatment with cisplatin and/or carboplatin (Clemens et al., 2019). King and Brewer (2018) provide a comprehensive discussion of grading scale selection based on whether the monitoring goals are early identification versus early intervention. Grading scales that are sensitive to smaller changes are better suited for early identification of ototoxic effects, whereas grading scales that require larger changes at frequencies that impact speech understanding are designed to identify hearing loss with a functional impact. Grading scale selection issues are highly relevant to clinical trial outcome selection in addition to their relevance to ototoxicity monitoring.

As discussed above, the SOC criteria defined by American Speech-Language-Hearing Association (1994) and American Academy of Audiology (2009) are designed for early detection of ototoxic change. To meet the ASHA SOC criteria, changes must be retested and confirmed within 24 h, and there must be no indication of middle ear abnormality. Baseline tests are essential. Patients serve as their own controls for ototoxic change with the threshold shift computed relative to baseline measures for each test.

The two goals for early identification of ototoxic change using the SOC criteria are to enable conversations about changes in ototoxic drug treatment if such changes are medically feasible (for insights into physician perspectives, see Garinis et al., 2018) and assure that auditory rehabilitation is provided in a timely way, protecting the patients' ability to communicate with medical providers and loved ones. The SOC criteria were not designed to define an adverse event of ototoxicity or measure reductions in ototoxic hearing change, although they have been used in this way in clinical trials assessing ototoxic change (Campbell et al., 2003) or prevention of DIHL (Knight et al., 2017). The SOC criteria do not provide a grading scale for ototoxic adverse events; the CTCAE, Tune, Brock, Chang, SIOP, or other rating scales must be used to grade the severity of the observed ototoxicity. With the exception of the TUNE classification scheme, which includes hearing thresholds through 12.5 kHz, all of the above grading scales are limited to frequencies through 8 kHz. The ASHA SOC criteria are the only criteria that broadly include high frequency hearing. For the SOC and grading schemes, there is a potential for false positives, particularly if the subject is inattentive or the testing has less than optimal replicability (for detailed discussion, see King and Brewer, 2018). The SOC criteria are nonetheless very useful in early detection of possible ototoxicity, can serve as an early warning flag for subjects that need particularly careful follow-up, and can serve as an alert to quality control concerns if a specific clinic has a higher rate of ASHA SOC changes.

With respect to test-retest reliability, the possibility of reverse ASHA SOC criteria, which are defined as an improvement rather than a worsening by the same amount of change, should be recognized. Reverse SOC criteria are important to document as they provide a measure of variability or possible learning effects as the patient becomes more experienced in the test procedures. If the clinical trial data examining the effects of a potentially ototoxic drug demonstrate as many reverse SOC changes as standard SOC changes, the data would not suggest ototoxicity but rather some variability in the data (Campbell et al., 2017). In the context of monitoring for noise injury, Dobie (1983) suggested the rate of positive hearing changes meeting the specified change criteria should be subtracted from the rate of negative hearing changes meeting the specified change criteria to control for spurious changes. This strategy could be considered in the context of clinical trials assessing ototoxicity and otoprotection (for discussion, see Le Prell, 2022) and in cases of potential hearing improvement after drug cessation (e.g., furosemide).

Some of the most common causes of hereditary hearing loss are pathogenic variants of the GJB2, SLC26A4, and MT-RNRI genes, affecting the Connexin 26, Pendrin, and 12S ribosomal ribonucleic acid (rRNA) proteins, respectively (Green and Raphael, 2015). However, human hereditary hearing loss is heterogeneous with over 120 nonsyndromic hearing loss genes identified to date (Van Camp and Smith, 2000; Morton and Nance, 2006). Additionally, the patterns of human hereditary hearing loss are complex; it can be dominant, recessive or sex-linked, syndromic or nonsyndromic, influenced by environment or modifier genes, congenital or late-onset, stable or progressive, and range from the high frequencies only to a profound hearing loss across the test frequency range. Accurately capturing the audiometric phenotype, including degree and configuration of hearing loss, age of onset, and rate of progression over the lifespan, is important for prognosis, patient and family counseling, rehabilitative decision-making, and evaluating the success of interventions. In some cases, audiometric profiles that capture age-related changes in hearing for specific hearing loss genes are available (Hildebrand et al., 2009).

Gene therapy is predicted to have significant promise for patients with hereditary hearing loss (Yoshimura et al., 2021). Goals of gene therapy include correction of pathogenic mutations, prevention of cell death in the cochlea, preservation of hearing, and possibly regeneration of hair cells (Chien et al., 2015). Currently, gene therapy for hearing loss is an experimental technique that uses genes to treat or prevent disease. It is intended to introduce genetic material into cells, and viral vectors are used to insert the gene into the target cells. Gene therapy can replace mutated genes with intact copies, inactivate (“knock-out”) a mutated gene, or edit a mutated gene using CRISPR/Cas9 techniques (for review, see Ahmed et al., 2017).

As reviewed by Ahmed et al. (2017), targets for gene therapy in the inner ear have included hair cells (via genes that influence stereocilia and the hair cell body), stria vascularis (via genes that mediate potassium recycling), supporting cells (via genes that target the connexin family), and the spiral ganglion neurons (via genes that control trophic growth factors). Review of the preclinical literature by Zhang et al. (2018) highlights mixed success across preclinical studies using the mouse as a model for human hearing. However, successes in the mouse and other rodent models (such as the guinea pig; see Kawamoto et al., 2003) have enabled planning for human clinic trials (for discussion of translational issues, see Hickox et al., 2021; Hinton et al., 2021; Lewis, 2021). Staecker et al. (2016) provided comprehensive discussion of the challenges planning first-in-man studies with particular emphasis on the audiometric criteria for enrollment, recommending that participants have sufficient residual hearing to allow measurement of significant hearing threshold shift but enough hearing loss that they would qualify for cochlear implants if unexpected adverse effects of cochlear gene therapy worsened their hearing.

No gene therapy trials for auditory indications were discovered in the comprehensive review by Ginn et al. (2013). Ahmed et al. (2017), which specifically focused on gene therapies for genetic hearing loss, similarly, did not identify any clinical trials. However, Crowson et al. (2017) identified a clinical trial recruiting participants into a study assessing CGF166 for auditory indications, reflecting the initiation of the first gene therapy trial for auditory indications. Gene therapy for auditory indications sharply contrasts with gene therapy trials for other indications. When Ginn et al. (2018) did a comprehensive review of all human gene therapy trials around the globe, they reported that almost 2600 gene therapy clinical trials had been completed, were ongoing, or had been approved in 38 countries. At the time of that review, at least one hearing loss trial was identified as hearing loss was included under “other diseases,” which comprised 2.2% (58 trials) of the total sample (Ginn et al., 2018). As per Schilder et al. (2019a), there were four commercial entities developing regeneration therapies for the inner ear not only for hereditary hearing loss but also for acquired hearing loss indications. Updated review of the commercial pipeline by Isherwood et al. (2022) showed growth in the overall preclinical pipeline, including gene replacement therapies, but with only three regenerative therapies identified as being in active phase 2 trials (OTO-413, LY-3056480, and PIPE-505).

Table I summarizes a variety of clinical trials using gene therapy and other small molecule therapies for regenerative auditory intervention that can now be found in ClinicalTrials.gov, including CGF166, OTO-413, LY-3056480, PIPE-505, and FX-322. Primary outcomes across the studies shown in Table I routinely included both safety measures, typically using CTCAE v5.0, as well as efficacy measures based on auditory tests, including conventional and high frequency thresholds. Other commonly included outcome measures included (a) speech in quiet; (b) speech-in-noise tests, such as the Bamford-Kowal-Bench sentences in noise (BKB-SIN (Bench et al., 1979) and the Words-in-Noise (WIN) test (Wilson et al., 2003); (c) tinnitus (commonly assessed using the Tinnitus Functional Index; Henry et al., 2016); and (d) patient reported outcome measures, such as the Hearing Handicap Inventory for Adults (HHIA; Newman et al., 1990; 1991) and Hearing Screening Inventory (HSI; Coren and Hakstian, 1992). An initial publication describing promising results with FX-322 in a small number of human patients enrolled in a phase Ib study (McLean et al., 2021), design considerations for the OTO-413 trial (Foster et al., 2022), and some limited information on the development of CGF166 (Pannirselvam et al., 2017) are available.

TABLE I.

Gene therapy and other small molecule regeneration therapy trials listed in ClinicalTrials.gov as of 2/27/2022. BAER, Brainstem auditory evoked response; BKB-SIN, Bamford-Kowal-Bench speech-in-noise; C-SSRS, Columbia-suicide severity rating scale; CTCAE, Common Terminology Criteria for Adverse Events; HHIA, Hearing Handicap Inventory for Adults; HSI, Hearing Screening Inventory; HIT, Head Impulse Test; SVV, Subjective Visual Vertical; TFI, Tinnitus Functional Index; WIN, Words-in-Noise Test; VEMP, vestibular evoked myogenic potential.

Clinical trial identification Study title Inclusion criteria Primary outcome Status
NCT02132130    Safety, Tolerability and Efficacy for CGF166 in Patients with Unilateral or Bilateral Severe-to-profound Hearing Loss  Ages 21–75 years old; Eligible patients required to have documented, nonfluctuating severe-to-profound unilateral or bilateral hearing loss  Adverse events, conventional audiometry, bone conduction audiometry  Completed 
Secondary outcomes include BAER, vestibular function (HIT, VEMP, and SVV), and speech recognition 
First posted May 7, 2014 
NCT03300687    First in Human Safety Study of FX-322 in Adults Undergoing Cochlear Implantation  Ages 18 years old or older; severe–to-profound SNHL of 80 dB HL or poorer at 500 Hz, meets criteria for cochlear implantation, and has chosen cochlear implant surgery  Number of adverse events (tinnitus, vertigo, and perforation)  Completed 
Secondary outcomes include plasma pharmacokinetics over 24 and 72 h; perilymph pharmacokinetics within 24 h 
First posted October 3, 2017 
NCT03616223    FX-322 in Sensorineural Hearing Loss  Ages 18–65 years old; stable hearing loss due to NIHL or sudden SNHL; PTA5124 better than 70 dB HL  Number of CTCAE v5.0 adverse events  Completed 
Secondary outcomes include drug concentration in plasma within first 24 h 
First posted August 6, 2018 
NCT04120116    FX-322 in Adults with Stable Sensorineural Hearing Loss  Ages 18–65 years old; stable hearing loss due to NIHL or sudden SNHL; PTA5124 26–70 dB HL in the injected ear  Speech in quiet, speech-in-noise (WIN), conventional audiometry, CTCAE v5.0 adverse events, abnormal otoscopic changes; abnormal change in tympanometry  Completed 
First posted October 9, 2019 
Secondary outcomes include high frequency audiometry, tinnitus assessment (TFI), and multiple patient reported outcome measures (HHIA, HIS) 
NCT04129775    OTO-413 in Subjects with Speech-in-Noise Hearing Impairment  Ages 21–64 years old; eligible patients required to have documented normal or up to moderately severe hearing impairment, self-reported difficulty hearing in noise for at least 6 months, and a speech-in-noise deficit in at least one ear  Number of adverse events; abnormal otoscopic changes; abnormal change in audiometry  Recruiting 
First posted October 17, 2019  Secondary outcomes include speech-in-noise, auditory brainstem response and patient global impression of change 
NCT04462198    Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects with Hearing Loss  Ages 66–85 years old; eligible patients required to have documented age-related sensorineural hearing loss; PTA5124 of 26–70 dB HL in the ear to be injected  Treatment emergent adverse events  Completed 
Secondary outcomes include pharmacokinetics 
Other outcomes include speech-in-noise, audiometry, auditory brainstem response 
First posted July 8, 2020 
NCT04601909    FX-322 in Adults with Age-Related Sensorineural Hearing Loss  Ages 66–85 years old; eligible patients required to have documented age-related sensorineural hearing loss; PTA5124 of 26–70 dB HL in the ear to be injected  Number of CTCAE v5.0 adverse events; abnormal otoscopic changes; abnormal change in tympanometry; suicide risk (C-SSRS)  Active, not yet recruiting 
First posted October 26, 2020 
Secondary outcomes include speech in quiet, speech-in-noise (WIN), conventional and high frequency audiometry, tinnitus (TFI) 
NCT04629664    FX-322 in Adults with Severe Sensorineural Hearing Loss  Ages 18–65 years old; eligible patients required to have documented, acquired, nongenetic, severe sensorineural hearing loss; PTA5124 of 71–90 dB HL in the ear to be injected  Number of CTCAE v5.0 adverse events; abnormal otoscopic changes; abnormal change in tympanometry; suicide risk  Completed 
First posted November 16, 2020 
Secondary outcomes include speech in quiet, speech-in-noise (BKB-SIN), conventional and high frequency audiometry, tinnitus (TFI) 
NCT05061758    A Trial of LY3056480 in Patients with SNLH (VESTA)  Ages 18–65 years old; eligible patients required to have minimum of 6 months documented, stable, hearing loss (±5 dB) and documented stable word recognition test (±6%) for approximately 6 months  Number of responders with at least 2 dB improvement in an adaptive sentence in noise test (international matrix test) compared to placebo  Not yet recruiting 
First posted October 20, 2021 
NCT05086276    FX-322 in Adults with Acquired Sensorineural Hearing Loss  Ages 18–65 years old; eligible patients required to have documented, acquired, adult onset, sensorineural hearing loss (NIHL or sudden SNHL); PTA5124 of 35–85 dB HL in the ear to be injected  Speech perception  Recruiting 
Secondary outcomes include standard and high frequency audiometry, tinnitus assessment, and multiple patient reported outcome measures 
First posted October 20, 2021 
Clinical trial identification Study title Inclusion criteria Primary outcome Status
NCT02132130    Safety, Tolerability and Efficacy for CGF166 in Patients with Unilateral or Bilateral Severe-to-profound Hearing Loss  Ages 21–75 years old; Eligible patients required to have documented, nonfluctuating severe-to-profound unilateral or bilateral hearing loss  Adverse events, conventional audiometry, bone conduction audiometry  Completed 
Secondary outcomes include BAER, vestibular function (HIT, VEMP, and SVV), and speech recognition 
First posted May 7, 2014 
NCT03300687    First in Human Safety Study of FX-322 in Adults Undergoing Cochlear Implantation  Ages 18 years old or older; severe–to-profound SNHL of 80 dB HL or poorer at 500 Hz, meets criteria for cochlear implantation, and has chosen cochlear implant surgery  Number of adverse events (tinnitus, vertigo, and perforation)  Completed 
Secondary outcomes include plasma pharmacokinetics over 24 and 72 h; perilymph pharmacokinetics within 24 h 
First posted October 3, 2017 
NCT03616223    FX-322 in Sensorineural Hearing Loss  Ages 18–65 years old; stable hearing loss due to NIHL or sudden SNHL; PTA5124 better than 70 dB HL  Number of CTCAE v5.0 adverse events  Completed 
Secondary outcomes include drug concentration in plasma within first 24 h 
First posted August 6, 2018 
NCT04120116    FX-322 in Adults with Stable Sensorineural Hearing Loss  Ages 18–65 years old; stable hearing loss due to NIHL or sudden SNHL; PTA5124 26–70 dB HL in the injected ear  Speech in quiet, speech-in-noise (WIN), conventional audiometry, CTCAE v5.0 adverse events, abnormal otoscopic changes; abnormal change in tympanometry  Completed 
First posted October 9, 2019 
Secondary outcomes include high frequency audiometry, tinnitus assessment (TFI), and multiple patient reported outcome measures (HHIA, HIS) 
NCT04129775    OTO-413 in Subjects with Speech-in-Noise Hearing Impairment  Ages 21–64 years old; eligible patients required to have documented normal or up to moderately severe hearing impairment, self-reported difficulty hearing in noise for at least 6 months, and a speech-in-noise deficit in at least one ear  Number of adverse events; abnormal otoscopic changes; abnormal change in audiometry  Recruiting 
First posted October 17, 2019  Secondary outcomes include speech-in-noise, auditory brainstem response and patient global impression of change 
NCT04462198    Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects with Hearing Loss  Ages 66–85 years old; eligible patients required to have documented age-related sensorineural hearing loss; PTA5124 of 26–70 dB HL in the ear to be injected  Treatment emergent adverse events  Completed 
Secondary outcomes include pharmacokinetics 
Other outcomes include speech-in-noise, audiometry, auditory brainstem response 
First posted July 8, 2020 
NCT04601909    FX-322 in Adults with Age-Related Sensorineural Hearing Loss  Ages 66–85 years old; eligible patients required to have documented age-related sensorineural hearing loss; PTA5124 of 26–70 dB HL in the ear to be injected  Number of CTCAE v5.0 adverse events; abnormal otoscopic changes; abnormal change in tympanometry; suicide risk (C-SSRS)  Active, not yet recruiting 
First posted October 26, 2020 
Secondary outcomes include speech in quiet, speech-in-noise (WIN), conventional and high frequency audiometry, tinnitus (TFI) 
NCT04629664    FX-322 in Adults with Severe Sensorineural Hearing Loss  Ages 18–65 years old; eligible patients required to have documented, acquired, nongenetic, severe sensorineural hearing loss; PTA5124 of 71–90 dB HL in the ear to be injected  Number of CTCAE v5.0 adverse events; abnormal otoscopic changes; abnormal change in tympanometry; suicide risk  Completed 
First posted November 16, 2020 
Secondary outcomes include speech in quiet, speech-in-noise (BKB-SIN), conventional and high frequency audiometry, tinnitus (TFI) 
NCT05061758    A Trial of LY3056480 in Patients with SNLH (VESTA)  Ages 18–65 years old; eligible patients required to have minimum of 6 months documented, stable, hearing loss (±5 dB) and documented stable word recognition test (±6%) for approximately 6 months  Number of responders with at least 2 dB improvement in an adaptive sentence in noise test (international matrix test) compared to placebo  Not yet recruiting 
First posted October 20, 2021 
NCT05086276    FX-322 in Adults with Acquired Sensorineural Hearing Loss  Ages 18–65 years old; eligible patients required to have documented, acquired, adult onset, sensorineural hearing loss (NIHL or sudden SNHL); PTA5124 of 35–85 dB HL in the ear to be injected  Speech perception  Recruiting 
Secondary outcomes include standard and high frequency audiometry, tinnitus assessment, and multiple patient reported outcome measures 
First posted October 20, 2021 

As gene therapy (and other small molecule regenerative approaches) progress to interventions aimed to prevent or slow the progression of hereditary hearing loss, it will be imperative that outcome measures, such as pure-tone thresholds, are obtained with rigor and defined with the same considerations given to ototoxic changes in hearing. A number of questions must be answered in advance of labeling a hearing change as an improvement or slowing of the rate of progression. These include (1) how much of a change in hearing can be considered an improvement versus a learning effect?, (2) how much improvement in pure-tone thresholds can be attributed to maturation and improved attention in pediatric patients?, (3) can existing ototoxicity scales be applied in reverse to capture improvement?, (4) what is the natural history of hearing loss progression for different genetically based hearing impairments?, (5) does the rate of progression vary across mutations or mutation types within a single gene?, (6) how do we define efficacy of an intervention?, (7) how much does hearing need to improve to have a functionally significant impact?, and (8) how do we advise Institutional Review Boards regarding risk:benefit ratios attached to gene therapy for hearing loss?

An additional investigational approach to inner ear therapy is that of stem cell therapy. Stem cell therapy is an experimental technique in which stem cells are guided to become specific cells that can then replace diseased cells. Progress has been made with respect to the identification of stem cells in neonatal cochlear tissue in animal models with less success identifying such cells in the mature cochlea (for review, see Xia et al., 2019). Stem cells transplanted into rodent cochleae have been induced to develop into spiral ganglion neurons (Chen et al., 2012) and hair cells (Chen et al., 2018). Significant challenges for translation to humans has included a low survival rate for stem cells transplanted into the inner ear, although three-dimensional (3D) biomaterials and neurotrophic support may alleviate some of these challenges (Chang et al., 2020; Bergman et al., 2021). Only a small number of clinical trials using stem cell therapies as investigational interventions for inner ear indications are listed in ClinicalTrials.gov as shown in Table II, and none have involved direct transplant into the inner ear. Instead, stem cells derived from umbilical cord blood have been delivered intravenously with two reports of subsets of study participants (ages 6 months–6 years old) having no infusion-related toxicities and reductions (improvements) in auditory brainstem response (ABR) threshold greater than expected test-retest differences (Baumgartner et al., 2018; Baumgartner et al., 2021). Of three identified trials, audiometric tests and development of age-appropriate speech language skills were included as primary or secondary outcomes in two of the clinical trials. All of the issues relevant to tracking improvements in hearing or a slowing of the hearing loss progression with gene therapy/small molecule therapy are directly relevant to stem cell therapy interventions as well.

TABLE II.

Stem cell therapy trials listed on ClinicalTrials.gov as of 2/27/2022. CTCAE, Common terminology criteria for adverse events.

Clinical trial identification Study title Inclusion criteria Primary outcome Status
NCT01343394 (2014)    Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children  6 week–18 months of age; moderate to profound acquired sensorineural hearing loss; must not be genetic/syndromic  Physiologic outcomes  Suspended 
Secondary outcomes include age-appropriate speech-language outcomes 
First posted April 28, 2011 
NCT02038972 (2018)    Safety of Autologous Stem Cell Infusion for Children with Acquired Hearing Loss  6 weeks–6 years of age; moderate to profound hearing loss (40–90 dB) in at least one ear; acquired hearing loss developing within past 18 months  Safety (hemodynamic stability, chest x ray)  Completed 
Secondary outcomes include inner ear function, audition, and language acquisition 
First posted: January 17, 2014 
NCT02616172 (2018)    Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss  2–6 years of age; bilateral moderate to profound hearing loss (40–90 dB) diagnosed 2–4 yr ago; hearing loss must be acquired and not genetic or syndromic  Blood pressure, pulmonary endothelial damage, hepatic injury and neurological adverse events scored using CTCAE v3.0, blood-oxygen saturation  Completed 
First posted November 26, 2015 
Secondary outcomes include audiometry, otoacoustic emissions and auditory brainstem response 
Clinical trial identification Study title Inclusion criteria Primary outcome Status
NCT01343394 (2014)    Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children  6 week–18 months of age; moderate to profound acquired sensorineural hearing loss; must not be genetic/syndromic  Physiologic outcomes  Suspended 
Secondary outcomes include age-appropriate speech-language outcomes 
First posted April 28, 2011 
NCT02038972 (2018)    Safety of Autologous Stem Cell Infusion for Children with Acquired Hearing Loss  6 weeks–6 years of age; moderate to profound hearing loss (40–90 dB) in at least one ear; acquired hearing loss developing within past 18 months  Safety (hemodynamic stability, chest x ray)  Completed 
Secondary outcomes include inner ear function, audition, and language acquisition 
First posted: January 17, 2014 
NCT02616172 (2018)    Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss  2–6 years of age; bilateral moderate to profound hearing loss (40–90 dB) diagnosed 2–4 yr ago; hearing loss must be acquired and not genetic or syndromic  Blood pressure, pulmonary endothelial damage, hepatic injury and neurological adverse events scored using CTCAE v3.0, blood-oxygen saturation  Completed 
First posted November 26, 2015 
Secondary outcomes include audiometry, otoacoustic emissions and auditory brainstem response 

All clinical trials must have rigorous study design standards established prior to implementing any data collection protocols to ensure replicable, standardized data that are consistently obtained across multiple clinical trial sites. Additional considerations may apply, depending on the purpose of the clinical trial. Clinical trials for DIHL may be conducted for the purpose of determining if a new drug in development for another medical purpose (e.g., cancer, infectious disease, or osteoporosis) is accompanied by auditory or vestibular adverse reactions. Alternatively, the purpose may be to assess whether an investigational otoprotective agent effectively prevents or mitigates the adverse auditory or vestibular effects of a known ototoxin, such as an aminoglycoside antibiotic or cisplatin. Clinical trials on NIHL prevention might investigate prophylactic treatment administered prior to exposure to loud sound if the exposure is expected as for daily occupational exposure, participation in firearm training activities, etc. Alternatively, they may assess the potential for a rescue therapy to be administered after an unexpected noise exposure as might occur with firecrackers, firearm use in the line of duty, or equipment malfunction resulting in alarms or other unexpected sound increases.

The clinical trials to determine if a newly developed drug has auditory adverse events and those to determine if an otoprotective agent mitigates ototoxicity or noise injury can have special challenges. If the new drug is for a rare disorder, data collection likely must occur at multiple sites and possibly even in multiple countries to accrue the necessary number of affected patients. Multiple sites might also be used to shorten the timeline to study completion. If data collection occurs at multiple sites and, in particular, if data collection occurs in multiple countries, extra care must be taken to standardize equipment, personnel, and procedures across all clinical trials sites to ensure that all data can be collapsed across sites to obtain adequate power for analysis. Often the clinical trial sites have been selected based on the availability of the target patient population and test equipment and medical expertise specializing in that particular disorder. Particularly, in the case of a drug that is not intended for an auditory indication but which may have auditory adverse events, it is possible that not all of the clinical trial sites will have audiology resources on site with the appropriate equipment and personnel. Referring patients out “for a hearing test” may lead to uninterpretable and poorly controlled data. Further, when referred out, the timing of the audiometric testing may, then, greatly vary relative to the study drug administration yielding uninterpretable data for the drug's relationship to any adverse events.

The following considerations for equipment, personnel, test-retest reliability protocols, and participant selection are important in designing clinical trial protocols and vetting audiology clinics as possible study sites. Although the focus of this final section is on drug-induced ototoxicity and its prevention, many of the following comments are also directly applicable to NIHL prevention study design and gene therapy trials.

For thresholds in the conventional frequency range (0.25–8 kHz), also called “the speech frequency” range, audiometers meeting current ANSI S3.6 (ANSI, 2018b) or ISO 389-1 (ISO, 2017a) standards should be used. Compliance with professional standards will assure audiometers are calibrated in the same fashion even if using a variety of audiometer makes and models at various clinics and further guarantee that the same reference thresholds for dB HL are used across sites. The make and model of audiometers and transducers used in the clinical trial at each site should be explicitly vetted for each site prior to initiation of the clinical trial and recorded into the clinical trials database. Although this may be impractical in some settings, to reduce variation as much as possible, the same patient should be tested and retested on the same audiometer in the same booth with the same stimulus transducer and, preferably, by the same audiologist. At each testing, in addition to the subject number, audiologist, and booth, the audiometer and transducers used should be recorded on the case report form (CRF). That type of record keeping will allow early identification of the source of highly variable or suspect findings.

Because drug-induced ototoxicity frequently starts in the high frequency range (9–20 kHz) and then progresses into lower frequencies needed for human communication, monitoring in the high frequency audiometric range is critical for early detection of ototoxicity in clinical trials (for recent discussion, see Konrad-Martin et al., 2018; Paken et al., 2019). However, high frequency audiometry can require some special considerations in clinical trials. One of the first considerations is that not all audiology clinics have high frequency audiometry available. Thus, each clinic must be queried regarding the audiometer in use, and if high frequency audiometry is not available, whether or not the current equipment can be upgraded to include high frequency audiometry. Most transducers used in general clinical audiometry do not cover the high frequency audiometry range, although there are some circumaural headphones that are able to be used for conventional frequencies through 8 kHz and the higher frequencies without switching transducers during the tests (e.g., Sennheiser HDA 200, Sennheiser HDA 300, Old Lyme, CT). High frequency reference equivalent threshold sound pressure levels (RET SPLs) are available in ANSI S3.6 (ANSI, 2018b). However, ISO 389-5 (ISO, 2006) only includes RET SPLs for a small number of specific earphones. Thus, there is continued interest in international standards for the calibration of audiometric equipment in the 8–16 kHz frequency range (for discussion, see Rodríguez Valiente et al., 2014). The transducers for high frequency audiometry need to be matched to the audiometer and calibrated, and a record of the audiometer and transducers for all clinical trials sites must be maintained, along with the annual or semiannual calibration records. Detailed record keeping is recommended as calibration of audiometers in the high frequency region can vary with microphone configuration (Barham, 2016).

Some clinics report high frequency audiometry thresholds in dB HL (RET SPL) and others in dB SPL. To be able to collapse the data across all clinical trial sites, all of the measured thresholds will need to be converted to the same dB reference. However, unlike the conventional frequency range where the dB SPL to dB HL conversion is the same for every ANSI/ISO audiometer and matched transducer, the conversion factors between dB HL and dB SPL for high frequency audiometry vary by audiometer model, the affiliated transducer, and calibration coupler/adaptor. The conversion factors for each transducer approved for use with a specific audiometer can be found in the manufacturer's manual. Each site must promptly report any audiometer or transducer change that occurs and submit the new calibration records.

Each site must also be vetted for the sound booths used. Each booth should be calibrated to ensure that it meets ANSI S3.1 or ISO 8253–1 standards for ambient noise levels within the booth (ISO, 2010; ANSI, 2018a). Although double-walled sound booths are preferred, single-walled booths can be used if the surrounding ambient noise levels are sufficiently controlled. An on-site visit to each audiology clinical site can help determine if the area surrounding the booth is sufficiently quiet, but the visit must be evaluated during peak traffic hours. If an in-person visit is not possible at each site, photos of the booth and surrounding area may be used for remote qualification.

The selection of appropriate testing personnel may vary by country, but carefully selecting the most qualified audiologists or the country's equivalent for efficiently and accurately testing patients who may be ill or fatigued will yield the most accurate and reliable data. Scheduling sufficient time for clinical trial audiometric assessments is critical as adequate time must be allowed for each study subject. Too often clinical trial sites will try to “work in” study subjects on top of a busy clinical schedule and may require audiologists to work in the study subjects during lunch or after regular work hours. Poor scheduling practices will increase variability in the data through fatigue of the study subject or audiologist. Further, insufficient time allowances by schedulers may result in study subjects not receiving the audiologic assessments at the precise times needed relative to the study drug/placebo administration, weakening the study. Indeed, scheduling barriers are one of the major hurdles even for routine ototoxicity monitoring programs (Konrad-Martin et al., 2018), highlighting the urgent need to appropriately schedule study staff.

Unless the clinical trial is a phase 1a study employing healthy subjects (e.g., Campbell et al., 2003; Lynch and Kil, 2009), the disease may potentially impact the ability of the patient to attend to the careful listening required for accurate audiometric threshold testing. In addition, many drugs have cognitive adverse events which can affect performance on audiometric tests (DiSogra, 2019). For example, in a study of a pain medication to control moderate to severe back pain, patients on placebo could potentially be distracted by unrelieved pain, rendering it difficult for them to sit through the audiologic assessment and concentrate, or patients receiving the experimental treatment may be sedated by the pain-relieving medication, reducing focus on the auditory signals (Campbell et al., 2017). Thus, extra time in the schedule may be needed for the evaluations, patients may need breaks during testing, and replicability at each test must be even more carefully monitored. Investigations that recruit patients with cancer have additional special considerations as patients receiving chemotherapy may be nauseous, have “chemobrain,” or be scheduled tightly for multiple evaluations. Consequently, testing may need to be abbreviated to a limited number of frequencies (Campbell et al., 2021).

In summary, except in phase 1 clinical trials (e.g., Campbell et al., 2003), by definition, the subjects enrolled in ototoxicity monitoring and inner ear intervention studies have a medical disorder which needs to be considered for possible effects on every aspect of testing, including test personnel. Many clinical trial subjects will have very full treatment schedules, which may limit the time available for audiologic assessments. The use of students, technicians, and any audiologist that is not experienced at quickly and efficiently providing diagnostic threshold testing should be carefully considered and will be inadvisable in many clinical trials. As noted above, if students, technicians, or other personnel perform audiometric testing, it is incumbent on the principal investigator to assure appropriate supervision.

As introduced above, replicability is frequently measured to assure within session reliability. Fausti et al. (1999) required reliability within 5 dB at 2, 8, and 12.5 kHz, and Campbell et al. (2003) have similarly used a 5 dB criterion to document the subject is capable of replicable, reliable responses within the accepted test-retest range. Testing the subject at the qualification and/or baseline visit until replicability is within ± 5 dB at every test frequency will further document that subjects are capable of replicable, reliable responses within the accepted test-retest range but will also significantly increase the test time. Assuring reliability at enrollment can prevent a later “learning effect,” a phenomenon of hearing threshold improvement over time (frequently around 5 dB) that results from learning and improved skill in responding to signals at threshold. Replicability across sessions is obviously confounded by changes in hearing; however, within session replicability can be documented at every study session and the additional time required should be balanced against the potential that replicability will be different from session to session due to disease, medication, or other differences across the study.

Attention to threshold replicability at frequencies above 8 kHz is warranted if the audiologists at the site are using high frequency audiometry for the first time. The test procedures for determining high frequency audiometry thresholds are the same as those for the conventional frequency range, i.e., modified Hughson-Westlake procedure (Carhart and Jerger, 1959; American Speech-Language-Hearing Association, 2005); however, the earphone placement is more critical because of the increased possibility of standing waves. The earphones for high frequency audiometry are usually circumaural and patients may “readjust” the earphones as soon as the audiologist leaves the booth unless the audiologist carefully instructs them otherwise. If the audiology team does not have a strong history of working with high frequency audiometry, it is advisable to have them test other individuals until competency with the test procedure is established and prior to testing subjects enrolled in the clinical trial. Replicability within ± 5 dB at each test frequency is desired; however, Frank and Dreisbach (1991), Frank (2001), and Schmuziger et al. (2004) all report test-retest reliability within 10-dB for participants tested with a variety of high frequency transducers, making this goal potentially difficult to achieve. Sources of variability include participant reliability and earphone fitting variance (Stelmachowicz et al., 1989). Additional discussion of the use of high frequency hearing measures in clinical trials is provided in Lough and Plack (2022).

Another cross-check for threshold reliability is the SRT. The SRT is the lowest level at which bisyllabic words with equal emphasis on each syllable (Spondee words) can be correctly identified 50% of the time. The SRT, measured using the American Speech-Language-Hearing Association (1988) procedures, should correlate to and be within 6 dB of the average air conduction threshold for the frequencies of 0.5, 1, and 2 kHz. If the SRT does not agree with the PTA at those three frequencies, the participant needs to be reinstructed and retested because they may not have understood the instructions or may have been distracted (e.g., by pain, nausea, tinnitus, or cognitive adverse events) and not adequately attending to low level auditory stimuli presented at threshold. If the SRT is substantially lower than the average of those three frequencies, however, the hearing loss may be nonorganic, which can be a possible concern in cases where compensation for hearing loss is involved (Rickards and De Vidi, 1995).

In clinical trials designed to detect drug-induced ototoxicity, it may be tempting to restrict subjects to those with normal hearing at baseline to avoid any effects of preexistent hearing loss. It is possible that preexistent hearing loss may predispose a subject to DIHL if the hearing loss is due to patient factors that produce a more fragile auditory system (i.e., genetics, diabetes, or vascular disease). However, it may alternatively be the case that preexisting hearing loss is “protective” in that the most vulnerable components of the cochlea are already absent. Given the high prevalence of sensorineural hearing loss in diverse international samples (Agrawal et al., 2008; Hoffman et al., 2012; Turton and Smith, 2013; Dawes et al., 2014; Mulwafu et al., 2016; Gong et al., 2018; Newall et al., 2020; GBD 2019 Hearing Loss Collaborators, 2021), restricting the subject pool to only those with normal hearing will not only impede recruitment, but it could later confound clinical use of the drug if it is approved for general use. For most medical disorders in adults, a substantial percentage of patients will have preexistent hearing loss as demonstrated across age-related hearing tables (discussed above), and physicians will need to know whether hearing-impaired patients can safely use new medications. The best approach is simply to ensure that the experimental and placebo groups have similar hearing thresholds at baseline. Correction for ARHL is not necessarily needed for studies of DIHL because they are shorter term studies in general; nonetheless, if longitudinal data were collected over multiple years, adjustment for effects of aging may be necessary.

A number of exclusion criteria should be considered during participant selection, however, and some audiologic exclusion factors may be advisable. For example, participants who have received a known ototoxic drug (e.g., an aminoglycoside antibiotic or platinum-based chemotherapeutic) in the last 6–12 months should probably be excluded because those drugs may cause progressive hearing loss, potentially confounding the data from the current study (for discussion, see Campbell and Le Prell, 2018). In addition, participants with otitis media or other middle or inner ear diseases that cause fluctuating hearing loss should be excluded because the fluctuating nature of the hearing loss may confound interpretation of the drug's effect on hearing, if any. Participants with actively progressive or asymmetric sensorineural hearing loss may have disorders associated with unpredictable rates of hearing loss progression. When this occurs during the clinical trial, disease-related hearing changes may be misinterpreted as a drug-related adverse event. Consequently, it is advisable to exclude subjects with fluctuating or actively progressive hearing loss from the study unless these types of hearing loss are the target of the therapeutic intervention. Patients with asymmetrical hearing loss may be considered for participation, provided that their pure-tone thresholds are stable and they are referred for otologic consultation if they have not obtained it previously.

Within the clinical trial population, it is important that male and female participants be included. Nationally representative data sets reveal a higher prevalence of hearing loss in males than in females (Agrawal et al., 2008) and, as discussed above, it is not clear if existing hearing loss will significantly influence either ototoxicity or otoprotection. With respect to noise injury, NIHL strikes males and females, but males have been described as more likely to suffer from NIHL than females (Beckett et al., 2000; Hwang et al., 2001; Bohnker et al., 2002; Brink et al., 2002). Part of this seemingly gender-related difference could be associated with differences in nonoccupational exposures which appear to begin during adolescence (Widen et al., 2006; Warner-Czyz and Cain, 2016) and may include differences in firearm exposure (Marlenga et al., 2012).

Data from animals do not resolve questions related to potential differences in vulnerability. Whereas a study in gerbils did not reveal gender-related differences in vulnerability to NIHL (Boettcher, 2002), data from mice indicated that females were more vulnerable to NIHL across a range of frequencies (Milon et al., 2018). Interestingly, data from noise-exposed chinchillas revealed female chinchillas to be more sensitive to high frequency NIHL and less sensitive to low frequency NIHL (McFadden et al., 1999). Estrogen signalling may underlie differences in vulnerability (Shuster et al., 2019; Shuster et al., 2021) and has also been hypothesized to underlie the gender-related difference in outcomes subsequent to stapedoplasty in patients with otosclerosis (Ricci et al., 2022).

Within the clinical trial population, it is important that racial and ethnic minorities be represented. Differences in ARHL are associated with race and ethnicity (Lin et al., 2012) with significantly lower prevalence of hearing loss in Black than in White participants within the nationally representative NHANEs data set (Agrawal et al., 2008). Related questions have recently been investigated by Bishop et al. (2019), who reported that hearing loss, tinnitus, and balance dysfunction commonly affected adult African Americans participating in the Jackson Heart Study but the observed rates were consistent with a lower prevalence of hearing loss in African Americans compared to non-African American populations. Flamme et al. (2020) discuss the important implications of these results for assessing noise injury. Because non-Hispanic Blacks have less ARHL than other groups, the effects of noise on hearing may be significantly underestimated as too much of the observed hearing loss will be counted as expected age-related change if race-blind adjustments are used.

In addition to associations with ARHL, race and ethnicity also appear to be significantly associated with NIHL with White participants being found to be more susceptible to the effects of noise than members of other racial groups in several investigations (Jerger et al., 1986; Ishii and Talbott, 1998). Similar results have been observed in animal subjects with albino animals showing greater noise-induced deficits than pigmented animals (Conlee et al., 1986; 1988).

This paper discussed the use of the audiogram in clinical trials assessing possible ototoxic effects of medicines being investigated for nonauditory indications and the use of the audiogram in clinical trials investigating possible prevention or treatment of hearing loss using investigational inner ear medications. Across auditory indications, by far the most common study outcome in clinical trials evaluating investigational inner ear medications is reduction in average threshold shift. Reductions in average threshold shift at one or more frequencies were a study outcome in 78% of NIHL studies (7/9), 47% of DIHL studies (14/30), 62% of stable sensorineural hearing loss (SNHL) treatment studies (8/13), and 100% of acute sudden SNHL treatment studies (9/9), according to the review of studies by Le Prell (2021). However, as reviewed in this paper, reductions in average threshold shift are not the only possible clinical trial outcome and, perhaps, not even the best audiometric measure as small but statistically significant threshold improvements may not be clinically significant.

Diverse criteria for STS exist, allowing either the rate of STS to be reported or the severity of STS to be graded. The rate of STS is routinely included in studies of DIHL prevention (20/30, although the specific grading scale varied across studies) with little use of STS rate in studies on NIHL prevention (1/9), sudden SNHL treatment (0/9), or treatment of stable SNHL (1/13; Le Prell, 2021). One can readily envision the use of scales paralleling CTCAE, TUNE, Brock, Chang, SIOP, or Muenster for scaling the severity of NIHL at frequencies where deficits typically first emerge (3, 4, and/or 6 kHz), as well as the development of more severe hearing loss impacting lower frequencies. The OSHA or NIOSH criteria used to identify occupational noise injury could also be considered, although they will only be appropriate for use in long-term studies in which a significant incidence of STS injuries is anticipated to accrue (for additional discussion, see Le Prell et al., 2019; Le Prell, 2022). For any clinical trial, consideration of the study goals with respect to prevention of early injuries [which could be documented using DPOAE amplitude or extended high frequency (9–20 kHz; EHF) hearing, in addition to the conventional audiometric test battery] versus the prevention of more severe deficits impacting the lower frequencies and communication ability is critical.

Multiple issues in the design of rigorous clinical trials have been raised, including study personnel, study equipment, and inclusion/exclusion considerations. With the large number of investigational inner ear pharmacologics, biologics, and gene therapy approaches currently under development (for review, see Schilder et al., 2019a; Isherwood et al., 2022), these are critical issues receiving increasing attention (see, for example, Schilder et al., 2019b; Le Prell, 2021, 2022). The audiogram is the clinical gold standard with widespread use since the development of the first commercial audiometers and the birth of modern audiology in the mid 1900s. Despite its widespread use, there is significant variability in the use of the audiogram and the definition of audiometric change within clinical trials completed to date. This significant heterogeneity across trials creates challenges for those seeking to compare relative effectiveness of different agents evaluated using different audiometric criteria. It is not clear what the “best” outcome measures would be either broadly or within specific auditory indications, but rigorous scientific design elements are clear and multiple suggestions have been provided. Standardized measures are a long-standing and important goal. The recommendations put forward by Gurgel et al. (2012) are not ideal for DIHL and NIHL as they emphasize speech frequencies in quiet (for discussion, see Carlson, 2013), but they do provide an important model that could be followed in developing minimum reporting requirements that would be sensitive to DIHL, NIHL, and their prevention.

An additional issue that may need to be considered moving forward is the potential impact of “decentralization” of clinical trials. Decentralized clinical trials (DCTs) leverage telemedicine, digital applications (“apps”), wearable devices, such as smart watches, and patient reported outcome measures (PROMs) to reduce participant visits to study sites. DCTs have benefits when participants live in remote areas (Sundquist et al., 2021), and there was a dramatic increase in prevalence of DCTs in response to the COVID-19 pandemic (for discussion, see Anderson, 2021; Banks, 2021; Chiamulera et al., 2021; Sessa et al., 2022; Ahern and Lenze, 2022; Deplanque et al., 2022). This has driven multiple recent efforts to identify barriers to DCTs and understand risk management and quality control in DCTs (Dunlap et al., 2020; Coert et al., 2021; De Brouwer et al., 2021; Rogers et al., 2022; Van Norman, 2021; Coyle et al., 2022; Stansbury et al., 2022).

The implications of DCTs for investigations of NIHL and its prevention are significant. App-based sound level meters are widely available (Roberts et al., 2016; Jacobs et al., 2020), and smart watch environmental sound measurements are not only being used to gain insight into sound exposure but also in combination with audiometry apps (Smith et al., 2020; Neitzel et al., 2022). Audiometry apps are of high interest (Barczik and Serpanos, 2018; De Sousa et al., 2018; Masalski and Morawski, 2020). Recent reviews raise concerns regarding calibration, background noise, and other sources of variability that may confound accurate threshold measurement with smartphone-based apps (Bright and Pallawela, 2016; Irace et al., 2021), but there are tablet based automated test systems that incorporate headphones with enhanced sound attenuation (Meinke et al., 2017). It is even possible to imagine the inclusion of remote testing as part of ototoxicity monitoring, including DIHL prevention, particularly with high frequency hearing test capabilities becoming available with tablet-based systems (Rieke et al., 2017). Given that ototoxicity is a reported adverse event for a number of drugs being used as investigational therapeutics in settings with limited access to technology and diseases with high transmissibility (e.g., COVID-19; see Little and Cosetti, 2021), opportunities for remote monitoring would be advantageous if data quality issues can be satisfactorily resolved.

In conclusion, the pure-tone audiogram is the gold standard in clinical audiology and clinical trials evaluating investigational medications for the inner ear. Despite widespread use of the audiogram, the operational definitions for audiometric change vary significantly across clinical trials. Given the above, end point selection requires careful consideration. Selection of a hearing loss end point that neither the placebo nor the experimentally treated participants meet will result in a failed clinical trial even if the investigational agent has benefits; thus, this is a major issue in the successful development of novel medications.

C.G.L. is currently supported by United States Army Medical Research Acquisition Activity Grant Nos. W81XWH-19-C-0054, JPC-8/SRMRP W81XWH1820014, National Institutes of Health (NIH)-National Institute on Deafness and Other Communication Disorders (NIDCD) Grant No. 1R01DC014088, and the Emilie and Phil Schepps Professorship in Hearing Science and has previously received contract funding and/or clinical trial material from industry partners, including Sound Pharmaceuticals, Inc. (Seattle, WA), Edison Pharmaceuticals, Inc. (Mountain View, CA), and Hearing Health Science, Inc. (Ann Arbor, MI). K.C.M.C. has previously received funding from NIH [NIDCD and National Institute on Aging (NIA)], DoD, and numerous industry laboratory and clinical trial consulting contracts. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. DoD or the NIH. This work was supported, in part, by the Division of Intramural Research, NIDCD at the NIH (C.C.B.).

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