In response to the COVID-19–related public health emergency, clinical research regulatory authorities have recognized the potential challenges posed by COVID-19, including site closures, travel restrictions, quarantines, investigational product availability, and staff and patient infections. Such occurrences may hinder and complicate meeting protocol requirements, including treatment administration, clinic visits, laboratory tests, and imaging studies. In response to this unprecedented situation, the FDA issued guidance suggesting consideration of telephone or video visits, performance of laboratory tests and imaging studies at local sites near patients’ homes, delaying certain assessments, alternative sites for treatment administration, and remote monitoring. The NIH Central Institutional Review Board (CIRB) allowed for remote informed consent procedures and use of electronic signatures. The NCI Cancer Therapy Evaluation Program (CTEP) issued provisions for nonstudy local healthcare providers to perform study follow-up procedures, as well as shipment of oral study therapy directly to patients’ homes.
These COVID-19–related allowances represent one of the greatest shifts in clinical research practice in recent history. For decades, professional organizations and patient advocacy groups have called for greater flexibility in the design and conduct of cancer clinical trials, with the intent of increasing access to trials and decreasing demands on trial participants, thereby improving trial enrollment, completion, and result generalizability.1 –3 Additionally, the FDA and other regulatory authorities have identified the importance of “real-world” data in the evaluation of new therapeutic entities.4 –6 Despite these efforts, until COVID-19, cancer clinical trials continued to increase in complexity, with more numerous and stringent eligibility criteria, and greater numbers of screening and on-study procedures required to be performed in shorter time intervals.7,8
To determine the impact of COVID-19–related changes, and whether some changes could potentially be continued after the COVID-19 emergency ends, we performed a survey among clinical research professionals at an NCI-designated comprehensive cancer center. Given their detailed familiarity with protocol requirements and regular and close contact with patients, sponsors, investigators, and regulatory agencies,9,10 these individuals are uniquely and ideally positioned to provide key feedback on these considerations.
Methods
Study Setting
The Harold C. Simmons Comprehensive Cancer Center is an NCI-designated comprehensive cancer center affiliated with UT Southwestern Medical Center in Dallas, Texas. Clinical trials are conducted at the primary university clinic site, two satellite clinic sites, and at affiliate sites of Parkland Health and Hospital System (the safety-net medical provider for Dallas County) and Children’s Health Dallas. Clinical research is overseen by a clinical research office with a staff of >100, including nurses, coordinators, managers, and regulatory personnel, which are largely organized according to tumor site.
On March 16, 2020, in response to the emerging COVID-19 pandemic and an institutional stay-at-home order, new enrollments to clinical trials were put on hold. Patients previously enrolled were continued on study. Adjustments covered in FDA and NIH guidance, including remote consent, telehealth visits, and shipment of oral study therapy to patients’ homes, were instituted. On April 27, 2020, therapeutic clinical trials were reopened to enrollment in a phased fashion, with almost all trials reopened by June 1, 2020. These restrictions did not apply to pediatric cancer clinical trials conducted at Children’s Health Dallas.
Survey Design and Administration
On May 22, 2020, clinical research office personnel attended a 15-minute webinar reviewing FDA- and NIH-based COVID-19–related clinical research adjustments. The content presented is summarized in supplemental eAppendix 1, available with this article at JNCCN.org. Immediately following the session, an anonymous survey was distributed to the participants via email. Research personnel who were only affiliated with Children’s Health Dallas were not included, because conduct of trials at that site was not impacted by COVID-19 to the same extent as adult cancer clinical trials. Electronic reminders were sent twice before the survey was closed on June 1, 2020. Survey questions are shown in supplemental eAppendix 2. The survey was designed by coauthors with expertise in clinical oncology (D.E.G. and M.S.B.), clinical trial design and implementation (D.E.G., M.S.B., E.L.W.), and survey methodology (S.J.C.L.).
Survey data were collected and managed using REDCap electronic data capture tools hosted at UT Southwestern.11 REDCap is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources.
Statistical Analysis
Mean survey response scores were computed by assigning a point scale ranging from −4 (“Very negative”) to 4 (“Very positive”) for the survey questions about impact of COVID-19–related clinical trial adjustments and from −3 (“Much worse”) to 3 (“Much better”) for survey questions about perceptions of specific COVID-19 adjustments, then taking the mean of those scores, ignoring “Unsure/No opinion” responses. Whether a respondent had experience with a given adjustment was determined using the answers to a question regarding “Types of COVID-19–related clinical trial adjustments experienced” in the background section of the survey. Those who had experience with either remote initial consent or remote re-consent were counted as having experience with remote consent. P values were computed by applying the Fisher exact test to contingency tables.
Results
A total of 94 of 108 (87%) survey recipients completed the survey. Characteristics of these individuals are shown in Table 1. As would be expected given the high response rate, there was broad representation across disease-related groups and position type within the clinical research office. Table 2 displays respondents’ direct experience with COVID-19–related clinical trial adjustments. Approximately half of the individuals were following patients on trials at the time of the COVID-19 pandemic, consistent with the distribution of professional positions; research nurses, research coordinator, and data specialists directly follow patients enrolled on trials and accounted for approximately half of respondents. Fewer than 20% of respondents had personal experience enrolling patients to trials during the COVID-19 pandemic. This distribution reflects the timing of the survey, which was administered less than 1 month after selected trials began reopening to enrollment at the center. The number of COVID-19–related deviations per patient was relatively low, with only rare cases having >5. The most frequently encountered COVID-19–related clinical trial adjustments were telehealth visits, remote monitoring, delayed study-related procedures, and shipment of therapy directly to patients’ homes. By contrast, only a single respondent had experience with off-site administration of study treatment.
Respondent Characteristics
Experience With COVID-19–Related Clinical Research Adjustments
Table 3 shows the perceived impact of COVID-19–related clinical trial adjustments on a number of parameters. These adjustments were rated as having the most positive impact on patient safety, staff experience, and patient communication. Data quality was the only variable thought to be impacted negatively by COVID-19–associated changes, with an average assessment between “slightly negative” and “somewhat negative.” The particularly favorable assessment of impact on patient safety may indicate respondents’ considering not only general clinical research scenarios but also the particular circumstances surrounding the COVID-19 pandemic, during which measures supporting social distancing may be especially beneficial for oncology populations.
Perceived Impact of COVID-19–Related Clinical Trial Adjustments
Respondents provided their assessments of various COVID-19–related clinical trial adjustments, as well as their perception of patients’ and clinician/investigators’ assessments (Figure 1). On average, respondents’ own impressions were positive for all adjustments, with most favorable scores for telehealth visits and therapy shipment. Enthusiasm appeared lowest for remote consent and off-site treatment. Among the 3 groups, clinician/investigators were felt to have the least favorable response to telehealth visits, shipment of oral therapy, off-site diagnostic procedures, off-site treatment, and remote monitoring. Patients were perceived as having particularly favorable responses to telehealth visits, therapy shipment, off-site diagnostic, and off-site treatment. Perceptions of COVID-19–related clinical trial adjustments according to whether the respondent had personal experience with the adjustment are shown in supplemental eTables 1 and 2.
Perceptions of COVID-19-related clinical research adjustments for (A) remote consent, (B) telehealth, (C) therapy shipment, (D) off-site diagnostic/monitoring procedures, (E) off-site treatment, and (F) remote monitoring.
Citation: Journal of the National Comprehensive Cancer Network 19, 5; 10.6004/jnccn.2020.7643
In general, there was clear support for sustaining positive COVID-19–related clinical research adjustments after the pandemic ends, with responses regarding the importance of sustaining the changes reported as follows: very important (49%), pretty important (22%), important (20%), somewhat important (9%), and not important (0%). Despite this enthusiasm, with the exception of remote monitoring, only a minority of respondents felt sufficiently comfortable with specific adjustments to recommend their continuance: remote consent (37%), telehealth (44%), therapy shipment (35%), off-site diagnostic procedures (26%), off-site treatment (14%), remote monitoring (51%). Notably, individuals with greater experience (defined as either personal experience with a specific COVID-19–related clinical trial adjustment or years of experience as a clinical research professional) were more likely to recommend continuation of adjustments (Tables 4 and 5). Specifically, among those experienced with specific adjustments, most recommended continuing remote consent, telehealth, therapy shipment, and remote monitoring. Among those with >5 years’ professional experience, most recommended continuing telehealth and remote consent.
Recommendation to Continue Trial Adjustments by Experience With Adjustment
Recommendation to Continue Trial Adjustments by Experience as a Clinical Research Professional
Respondents rated the organization’s ability to respond to crisis as follows: very strong (39%), strong (52%), average (9%), weak (0%), and very weak (0%). Ratings of the organization’s ability to learn from crisis were as follows: very strong (41%), strong (41%), average (15%), weak (2%), and very weak (2%).
Representative open-ended comments from respondents are provided in supplemental eAppendix 3. Of the 6 open-ended items inviting written comment, 2 received comments from approximately 20% of participants: comment on your experience with COVID-19–related changes (20%), and comment on the impact of these changes to the future of clinical trial practice (21%). The remaining open-ended items received comments from ≤10% survey respondents. Overall, respondents with >5 years of professional clinical trial experience tended to offer longer and more frequent written comment. Additionally, those responding to the initial query about changes were notably more likely to have provided written comments subsequently. Interestingly, only 1 of 10 research nurses responded with written comments; other roles were equally as likely to comment as not.
Discussion
Over time, cancer clinical trials have become more complex, and eligibility criteria are expanding.7 The number of screening procedures is also increasing, whereas the permitted time for their completion is decreasing.8 Trial complexity limits which centers may participate, a trend that disproportionately affects institutions providing care to medically underserved populations, including racial and ethnic minorities.12 Ultimately, these factors may discourage participation, limit enrollment, prolong study duration, and reduce generalizability of results.
The recent COVID-19 public health emergency offers an unprecedented opportunity to evaluate major shifts in clinical research policy. In response to the numerous challenges arising from this pandemic, regulatory authorities and study sponsors have permitted profound adjustments to the care of patients on cancer clinical trials. With the goals of limiting exposure and risk for patients, study staff, and other personnel, many of these changes may also address longstanding concerns surrounding clinical trial design and conduct. For the present study, we surveyed a large group of clinical research professionals to determine their impressions of COVID-19–related clinical trial adjustments. To our knowledge, this report represents the first systematic assessment of experience, perceptions, and recommendations related to COVID-19–associated trial changes.
In general, response to these adjustments was favorable and enthusiastic. Patient safety, treatment efficacy, patient and staff experience, and communication with patients, investigators, and sponsors were perceived as improved by COVID-19 adjustments. Notably, >90% of respondents felt that positive changes should be considered after the COVID-19 pandemic. They also reported that patients viewed multiple changes positively, including remote consent, telehealth visits, therapy shipment, and off-site diagnostic procedures and treatment. The perceived reaction of clinicians/investigators was somewhat less enthusiastic, particularly for off-site procedures and treatment administration.
Our study also identifies an area of concern for research professionals. Overall, respondents felt that COVID-19–related clinical trial adjustments had a somewhat negative impact on data quality. With procedures delayed, skipped, or performed off-site, it is not difficult to envision more frequent information gaps. The obvious next question—and one that has already received considerable attention—is which data are truly needed to protect patient safety and optimize treatment efficacy. For instance, an analysis of >8,500 electrocardiograms performed in a phase I research program found that none identified a clinically significant abnormality.13 Similarly, an FDA study of Investigational New Drug (IND) safety reports found that >85% were uninformative.14 Such observations suggest that these practices may be draining resources and adding unnecessary work, without contributing meaningfully to the well-being of participants.
We found that more experienced individuals were more likely to support continuing COVID-19–related trial adjustments in the future. For all adjustments, except off-site treatment administration (with which only a single respondent had experience), respondents with personal experience with the specified change were more likely to support incorporation into future practice after the pandemic ends. In contrast, only a minority of those without personal experience expressly supported such policy modifications. One potential explanation is that the research staff who favor certain changes are more likely to incorporate them into their clinical research activities. However, this seems unlikely given the current clinical research oversight structure. The allowance of adjustments initially comes from regulatory authorities. Whether such changes are permissible on a given clinical trial reflects the preferences of the study sponsor. At the level of the individual patient, it is typically the treating clinician/investigator and/or the site principal investigator who decides if and how an individual patient’s treatment and monitoring will be modified. Additionally, the staff with more years in the clinical research profession were more likely to recommend extending COVID-19–related clinical trial adjustments, suggesting that those most familiar and comfortable with clinical trials see the greatest potential benefit in such modifications.
It is not difficult to envision the potential benefits of continuing certain COVID-19–related clinical trial adjustments beyond the duration of the pandemic. Remote consent, telehealth visits, therapy shipment, and performance of study procedures at local sites near patients’ homes may render trials more accessible to patients. In the United States, approximately half of individuals with advanced breast, prostate, colorectal, and lung cancer live at least a 60-minute drive from a clinical trial site,15 rendering travel for clinical research time-consuming, fatiguing, and costly. Earlier studies have demonstrated satisfaction with video-based telehealth communication for routine clinical care among patients with cancer,16 which suggests feasibility for research visits. The decentralization of cancer clinical trials might also increase referrals and partnerships, because referring physicians may be able to maintain relationships with and billable services from trial patients who can undergo study-related procedures at their local oncologist’s practice. Such changes could also have broader benefits. Clinical trials represent a key reason for the increasing costs of drug development, which now exceed inflation by almost 10%.17 Reduced number and frequency of protocol-specified assessments will decrease costs. Remote monitoring eliminates both the expense and environmental impact of regular air travel and lodging.
A key strength of the study is an exceptionally high response rate nearing 90%, thereby reducing potential response bias. By comparison, national surveys of oncology professionals usually have response rates <30%.18 –23 Additionally, because responses were anonymous, respondents may have felt more comfortable providing honest answers than if their identity were linked to their responses. Limitations include the single-center setting, because institutional practice in the setting of COVID-19 may vary across centers. Our survey participants had highly favorable views of the institution’s response to and ability to learn from COVID-19, which may influence their perceptions of specific policies. Because this survey was conducted relatively soon after the implementation of COVID-19–related clinical trial adjustments, relatively few respondents had experience with some aspects of these changes, in particular remote informed consent. The clinical research professionals targeted for this survey represent a broad range of job descriptions—from finance to education to administrative management to research coordinators and nurses. Because their personal experience with individual COVID-19–related adjustments varied widely, there were multiple “unsure” responses for many of the questions. Nevertheless, we were still able to identify trends for and significant associations with perceptions and recommendations. Although clinical research professionals may have frequent contact with both patients and clinicians, research personnel impressions of these individuals’ reactions to COVID-19–related adjustments do not substitute for direct assessment of patient and provider perceptions and preferences.
Conclusions
COVID-19–related clinical research adjustments have led to marked changes in trial implementation and conduct. In a single-center setting, the clear majority of clinical research professionals view these modifications favorably. In particular, those with greatest professional experience support extending these policies after the pandemic ends. Given longstanding and repeated calls to simplify cancer clinical trials, further research to determine the impact of COVID-19–related clinical trial changes is imperative.
Acknowledgments
The authors wish to thank Ms. Dru Gray for assistance with manuscript preparation.
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