The impact of COVID-19 on otolaryngology research: a cross-sectional analysis of discontinued trials

Context: The COVID-19 pandemic has reduced the capacity to conduct medical research due to recruitment difficulties, supply chain shortages, and funding deficits. The clinical practice of otolaryngology was especially impacted due to a reduction in elective procedures, such as facial plastic surgeries and vocal fold injections. Objectives: The primary objective was to examine the extent of clinical trial (CTs) disruption secondary to the COVID-19 pandemic in the field of otolaryngology. Methods: On August 1, 2021, we conducted a systematic search utilizing ClinicalTrials.gov for CTs related to common otolaryngologydisorders. We utilizedthe date range January 1, 2020 through August 1, 2021 to identify all trials potentially affected by the COVID-19 pandemic. Investigators performed screening and data extraction in a duplicate, masked fashion. Trials resulting from the search were extracted for trial status, condition treated, enrollment number, funding, study type, study design, last update posted date, and trial location. Trials that explicitly mentioned COVID-19 as a reason for discontinuation or suspension were coded as such. For trials that did not explicitly mention COVID-19, we coded the reason provided from ClinicalTrials.gov. The Oklahoma State University Center for Health Science Institutional Review Board determined that this project did not qualify as human subject research. Results: A total of 1,777 CTs met the inclusion criteria, and 223 CTs were discontinued between January 1, 2020 and August 1, 2021. Thirty-three (14.8%) of the 223 CTs reported discontinuation explicitly due to the COVID-19 pandemic. The 33 studies had 1,715 participants enrolled in total. Among the primary interventions, 11 (33.3%) were devices, 10 (30.3%) were drugs, 5 (15.2%) were behavioral, 4 (12.1%) were diagnostic tests, 1 (3.0%) was dietary, and 2 (6.1%) were labeled as “ other. ” Regarding the CT location, 20 (60.6%) were conducted in the United States, and 13 (39.4%) were conducted internationally. Of the 33 CTs, 19 (57.6%) were suspended, 9 (27.3%) were terminated, and 5 (15.2%) were withdrawn. The overall most common reason for trial disruption was recruitment difficulties (24.2%). Median enrollment for discontinued trials due to COVID-19 was 37 (interquartile range [IQR], 19 – 71) and for other reasons was 6 (IQR, 0 – 27), for which the Mann – Whitney test showed a statistically significant difference between the two (z= − 3.913, p<0.001). There were no signi ﬁ cant associations between trial location, funding source, randomization, or whether a study involved masked vs unmasked participants. Conclusions: The COVID-19 pandemic has incited an impact on clinical research in the field of otolaryngology. To preserve trial continuation amid future threats to participant interaction and communication, we recommend further exploration of remote monitoring practices and virtual procedures — those that will maintain the effectiveness and accuracy needed to establish novel therapeutics. We encourage future trials to gauge which remote assessments show the greatest validity, with the long-term goal of establishing innovative study designs resilient to future pandemics.

The practice of evidence-based medicine combines clinical knowledge gained from experience with robust scientific evidence often provided by clinical trials (CTs) [1]. Findings from CTs are valuable to otolaryngologists, because they provide evidence for treating medical conditions such as tinnitus, rhinosinusitis, head and neck cancers, and many other ENT-related conditions [2]. The COVID-19 pandemic has reduced the capacity to conduct medical research by disrupting the progress of ongoing CTs in several fields of medicine [3][4][5][6]. In response to the pandemic, the United States Food and Drug Administration updated guidance on conducting CTs, prioritizing patient safety by limiting travel and accessibility of participants to study visits and follow-ups, minimizing interactions with social distancing, and halting drug supply chains [7]. Further, sponsoring institutions have introduced restrictions on developing trials, because funding has remained uncertain amid the unpredictable pandemic [3]. Together, many safety measures, while necessary, have hindered the progress of CTs.
The practice of otolaryngology also shifted dramatically during the COVID-19 pandemic. For example, ENT surgeons have been inundated with patients requiring tracheostomy tube placements due to prolonged intubation from COVID-19 complications, which has detracted from their usual focus of practice [8]. Additionally, procedures such as facial plastic surgeries, vocal fold injections, and other nonemergent procedures have been stalled after having been deemed "elective" by some institutions [9]. The shifting focus of otolaryngology practice brought about by the pandemic may have profound effects on CTs as well as other research studies in the field of otolaryngology. Moreover, ENT-related osteopathic techniques that can be utilized to combat upper respiratory infections, such as cervical myofascial release, cervical articulation, and lymphatic drainage techniques, declined due to the highly pathogenic nature of the coronavirus [10,11]. In fact, a survey through the American Osteopathic Association revealed that 95% of osteopathic physicians experienced a decline in practice revenue as a result of the COVID-19 pandemic.
Gauging the long-term impact of the pandemic on otolaryngology research will depend on having first assessed the immediate impacts of the pandemic on otolaryngology-related CTs. Although protecting trial participants from COVID-19 has remained of the utmost importance, the effects of the pandemic on ENT CT progress remains unknown. Thus, we sought to examine the extent of otolaryngology CT disruption secondary to the COVID-19 pandemic. Findings from this study may highlight the importance of developing strategies for safely continuing clinical research amid the possibility of future global emergencies.

Methods
On August 1, 2021, we performed a systematic search of ClinicalTrials. gov, an international registry of both privately and publicly funded interventional studies [12], for trials related to otolaryngology disorders. Our search included the following terms: Acoustic Neuroma, Adenoidectomy, Ageusia, Allergic Rhinitis, Anosmia, Cochlear Implants, Craniofacial  We included interventional trials in any phase and in any country that were recruiting, active but not recruiting, enrolling by invitation, suspended, withdrawn, or terminated. The "last update posted" date was utilized as a proxy for trial status change. We utilized the date range January 1, 2020 through August 1, 2021 to identify all trials potentially affected by the COVID-19 pandemic. The search string is presented in Figure 1.
The trials resulting from the search were extracted for trial status, condition treated, enrollment number, funding, study type, study design, last update posted date, and trial location. Trials were then screened for relevance to the field of otolaryngology utilizing the "conditions treated," and irrelevant studies were excluded. In a blinded, duplicate manner, two authors (B.M.R. and N.B.S.) manually extracted the reasons for discontinuation or suspension provided on the ClinicalTrials.gov website. Trials that explicitly mentioned "COVID-19" as a reason for discontinuation or suspension were coded as such. For these trials, study intervention was additionally extracted. For trials that did not explicitly mention the COVID-19 pandemic, we coded the reason provided from ClinicalTrials.gov. If a reason was not provided, the reason for discontinuation was coded as "not provided." A Mann-Whitney U test was utilized to examine whether significant differences in enrollment existed between trials discontinued due to the COVID-19 pandemic vs all other discontinued trials. We utilized a Mann-Whitney U test because enrollment numbers were nonnormally distributed among trials in our sample. We utilized Fisher's exact tests to examine associations between trials that were canceled due to the COVID-19 pandemic and the funding source and trial location (US and non-US-based). If a study had multiple sites and any of them were listed in the United States, they were coded as US studies. Funding source was coded as either US Government (if any US Federal agency, Veterans Affairs, Department of Defense was reported), Industry (if any industry involvement was reported), or Other for registered CTs receiving funding from neither industry nor government. Other is a "funded by" category that investigators can select on ClinicalTrials.gov, and we applied this term as defined on ClinicalTrials.gov. If a study included US Government and Industry, it was coded as US Government due to superseding reporting guidelines, with the same hierarchy for studies with Industry and Other.
Statistical analyses were performed utilizing Stata 16.

Statistical associations
Median enrollment for discontinued trials due to COVID-19 was 37 (IQR, 19-71) and for other reasons was 6 (IQR, 0-27), for which the Mann-Whitney test showed a statistically significant difference between the two (z=−3.913, p < 0.001; Table 1). There were no significant associations between trial location, funding source, randomization, or whether a study involved masked vs unmasked participants. The association of reasons for discontinuation by trial characteristics is displayed in Table 1.

Discussion
We found that at least 14.8% of registered otolaryngologyrelated CTs discontinued since the pandemic began were halted due to the COVID-19 pandemic, with the majority of these trials reporting recruitment problems. These trials discontinued due to the pandemic represent 1,715 participants who could not receive novel and potentially beneficial treatments because of the pandemic. A statistically significant association was found between COVID-19-related trial discontinuation and median enrollment number, suggesting that larger trials were more likely to be discontinued as a result of the pandemic. This disruption could have resulted from social-distancing protocols that placed limitations on the maximum capacity of facilities and social gatherings. Although no significant associations were found between COVID-19 discontinuation and trial location, randomization, funding source, or masking strategy, any trial disruption poses important implications. Moreover, it is possible that reporting trial discontinuation due to the COVID-19 pandemic was underreported. The most common reason overall for trial discontinuation was recruitment difficulties, which may have been a consequence of shutdowns, stay-at-home orders, or social distancing policies. The lack of various associations with the likelihood of trialists reporting discontinuation due to the COVID-19 pandemic may simply suggest that all discontinued otolaryngology trials were impacted equally, regardless of differences in these measured variables.
The COVID-19 pandemic brought on new challenges to CT progress. For example, social distancing policies threatened trial discontinuation, especially for interventions involving person-to-person contact. Selfisolation policies can interfere with all phases of CTs, which warrants the exploration of novel protocols for use in pandemic situations. Virtualization, telecommunication, and at-home collection of data could all serve as possible solutions going forward [13]. In a systematic review assessing the impact of the COVID-19 pandemic on trial progress, Sathian et al. [14] suggested alternative methods of obtaining data amid self-isolation protocolstelephone-mediated questionnaires and at-home data collection. In addition, Xue et al. [15] surveyed CT investigators utilizing ClinicalTrials.gov data in May 2020 to determine the extent to which the pandemic altered the progress of ongoing trials. Investigators in the study reported that 57% of patient interactions and 79% of interactions between sponsors and contract research organizations took place remotely [15]. However, the integration of telemedicine poses its challenges; trial developers must consider the additional costs of technology, and they have to establish amendments protecting patient rights and procedure operations [16].
Premature trial discontinuation is often necessary for ethical reasons. Compromised patient safety, the presence of severe adverse events, and interventional futility are a few of the justifiable considerations for trial discontinuation [17]. If a trial exposes human subjects to more risks than benefits, the justification to continue research markedly diminishes. However, trials are often discontinued due to preventable circumstances, which greatly contributes to research waste [18]. In a retrospective cohort study utilizing randomized controlled trial (RCT) protocols approved between 2000 and 2003, Kasenda et al. [19] found that approximately one quarter of planned RCTs are prematurely discontinued primarily due to recruitment issues. RCTs have also been shown to be at a higher risk for discontinuation compared to nonrandomized controlled trials, single-arm trials, and cohort studies [20]. These findings, as well as our own findings, suggest the need for improved contingency plans and strategies aimed at continuing trials that fail to adequately recruit participants, especially in the setting of a pandemic or other global emergency. By preventing trial discontinuation, or mitigating its impact, valid data and progress could be preserved and utilized as evidence for subsequent systematic reviews, meta-analyses, and other forms of medical evidence. It is important to note the potential benefit that osteopathic treatment holds for diseases like COVID-19. Although hands-on osteopathic manipulation may have been hindered by the contact precautions and social isolation policies in place during the pandemic, videoinstructed at-home exercises and techniques could hold some benefit to patients that are otherwise unable to access care. However, we encourage future studies to assess the impact of osteopathic treatment to nonhospitalized patients during the pandemic because manipulative therapy requires person-to-person interactions.

Limitations
By the nature of our study design, trials were labeled as "COVID-19-related discontinuation" if COVID-19 was explicitly mentioned in the "Recruitment Status" box provided on ClinicalTrials.gov. This does not rule out the potential for other trials found in our search to have been disrupted from the COVID-19 pandemic. Therefore, our results could be underrepresenting the true impact of the COVID-19 pandemic on ENT research. Also, we cannot claim causality due to the nature of cross-sectional analysis, and our results should be interpreted accordingly. There may have been additional factors contributing to trial disruption, even among trials explicitly reporting the COVID-19 pandemic as a factor. For example, many CTs in otolaryngology may have been modified to support COVID-19 research efforts. Principal investigators may have reallocated funds to support COVID-19 research efforts when the National Institutes of Health (NIH) allowed for grant revisions at the start of the pandemic. However, we were not able to assess the extent of funding reallocation with the current methodology, limiting the ability to discuss the possibility of grant revision and protocol restructuring. Future studies are needed to assess the impact of funding reallocation on the progress of ENT trials during the pandemic. With many ENT trials discontinued during the pandemic period, it is likely that researchers could also reallocate time to write manuscripts. Thus, future research may investigate whether the number of ENT manuscripts submitted or published showed significant changes during the pandemic. Lastly, our results are indicative only of the current pandemic time period and would benefit with further analysis of discontinued studies both prepandemic and postpandemic. We encourage the implementation of future studies to explore CT discontinuation statistics to aid in establishing a baseline for the data obtained in this study.

Conclusions
Overall, the COVID-19 pandemic has incited an impact on clinical research in the field of otolaryngology. We believe that this manuscript is important for osteopathic students and resident physicians pursuing otolaryngology as a profession, especially in academic settings where clinical research occurs. Our study demonstrates the susceptibility of ENT CT design to global emergencies. We hope that the findings of this study inspire osteopathic students and residents entering otolaryngology to develop resilient CT methods that allow ENT research to continue safely during global health crises. Further, to preserve trial continuation amid future threats to participant interaction and communication, we recommend further exploration of remote monitoring practices and virtual procedures-those that will maintain the effectiveness and accuracy needed to establish novel therapeutics. We encourage future trials to gauge which remote assessments show the greatest validity, with the long-term goal of establishing innovative study designs resilient to future pandemics.