key: cord-0742510-wy7p8uwg authors: Tolaney, Sara M; Lydon, Christine A; Li, Tianyu; Dai, Jiale; Standring, Andrea; Legor, Kristen A; Caparrotta, Caryn M; Schenker, Matthew P; Glazer, Daniel I; Tayob, Nabihah; DuBois, Steven G; Meyerhardt, Jeffrey A; Taplin, Mary-Ellen; Johnson, Bruce E title: The Impact of COVID-19 on Clinical Trial Execution at the Dana-Farber Cancer Institute date: 2020-09-22 journal: J Natl Cancer Inst DOI: 10.1093/jnci/djaa144 sha: b3c02cd424f2724c6fc33623a2543beb62201640 doc_id: 742510 cord_uid: wy7p8uwg Interventions designed to limit the spread of COVID-19 are having profound effects on the delivery of healthcare, but data showing the impact on oncology clinical trial enrollment, treatment, and monitoring are limited. We prospectively tracked relevant data from oncology clinical trials at Dana-Farber Cancer Institute (DFCI) from January 1, 2018 to June 30, 2020, including the number of open trials, new patient enrollments, in-person and virtual patient visits, dispensed investigational infusions, dispensed/shipped oral investigational agents, research biopsies, and blood samples. We ascertained why patients came off trials and determined on-site clinical research staffing levels. We used two-sided Wilcoxon rank sum tests to assess the statistical significance of the reported changes. Nearly all patients on interventional treatment trials were maintained, and new enrollments continued at just under half the pre-pandemic rate. The median number of investigational prescriptions shipped to patients increased from 0-74 (range: 22-107) per week from March-June 2020. The median number of telemedicine appointments increased from 0-107 (range: 33-267) per week from March-June 2020. Research biopsies and blood collections decreased dramatically after DFCI implemented COVID-19-related policies in March 2020. The number of research nurses and clinical research coordinators on-site also decreased after March 2020. Substantial changes were required to safely continue clinical research during the pandemic; yet, we observed no increases in serious adverse events or major violations related to drug dosing. Lessons learned from adapting research practices during COVID-19 can inform industry sponsors and governmental agencies to consider altering practices to increase operational efficiency and convenience for patients. A previously unknown respiratory illness emerged in Wuhan, China in December 2019. The causative agent was identified as the novel coronavirus SARS-CoV-2, and the associated disease was named coronavirus disease 2019 [1] [2] [3] . The first verified patient in the United States became ill in January 2020 in Washington State [4] . The virus has now spread rapidly throughout the United States, and caused more than 5.6 million cases and nearly 176,000 deaths by late August of 2020 [5] . The spread of this deadly virus has led to substantial changes in public policies throughout the United States that have impacted travel, public gatherings, and access to medical care in the inpatient and outpatient settings, including elective procedures and non-emergent clinical services [6] . Oncology care is commonly critical, and most of the care is administered in the outpatient setting. This has led members of the oncology community to provide guidance for managing the treatment of cancer patients during this pandemic [7, 8] . Clinical trials are essential for advancing cancer treatment and also provide access to novel and potentially effective treatments for patients. The public policies enacted around the United States to reduce the spread of COVID-19 have prompted the National Cancer Institute [9] and the Food and Drug Administration [10] to issue guidelines around the conduct of clinical trials. Dana-Farber Cancer Institute (DFCI) and Brigham Health (BH) are in Massachusetts, which had the 12th highest number of COVID-19 cases and the 4th highest number of deaths in the United States by early August 2020 [5] . As the threat emerged, the Commonwealth of Massachusetts enacted a series of public health policies to protect its citizens and visitors. Governor Charles Baker issued a State of Emergency to Respond to COVID-19 on March 10, 2020, when there were 91 known cases of COVID-19 in the state [11] . DFCI and BH followed the policies set forth by the Commonwealth of Massachusetts, including a stay-at-home advisory 6 on March 23, restrictions on gatherings of 10 or more people, and other policies that are impacting the methods and the ability to deliver healthcare to our patients. In addition, DFCI and BH had to ensure that there were adequate resources to care for the anticipated surge in COVID- 19 admitted inpatients in April of 2020 [12, 13] . On May 18, 2020, Governor Baker instituted Phase I of the stepwise reopening of businesses and other organizations in Massachusetts. Phase II, Step 1 was subsequently initiated on June 1, 2020, followed by Phase II, Step 2 on June 19. In response, DFCI and BH instituted a phased recovery plan beginning on May 18, 2020 [11-13] . Although the cancer community has provided guidance for managing patients with cancer, and federal agencies have issued guidelines for clinical trials, there are little objective data to assess the impact of public and institutional policies for patients who are considering or already enrolled onto clinical trials. The Office of Clinical Research at DFCI monitors clinical trials by assembling pertinent data and providing feedback to study teams. In the months following the enactment of the public policies meant to limit the spread of COVID-19, as well as policies to ensure access to acute medical care for patients who contracted the virus, we assessed the ability to carry out interventional treatment clinical trials in this challenging environment. The Office of Clinical Research has prospectively tracked metrics for clinical trials from 2015 to the present. We retrieved the dates and specifics of the COVID-19-related institutional policies that impacted clinical care and clinical trials at DFCI from online staff communications. The number of patients accrued to clinical trials by month was retrieved from January 1, 2018 through June 30, 2020 from the OnCore CTMS Enterprise Research system. The information on other parameters was gathered by the study teams from January 1, 2020 to June 30, 2020, with a few exceptions as noted below. The number of studies that were open but were not able to enroll, and the number of patients and reasons for coming off the clinical trials were ascertained. The number of research biopsies performed each month (from January 1, 2018 to June 30, 2020) was prospectively monitored and enumerated. The number of research blood samples collected was retrieved by monitoring the kits used for drawing the research blood. The number of in-person patient visits and virtual visits by week was retrieved from the electronic medical records. The number of investigational infusions (from January 1, 2018 to June 30, 2020), oral agents dispensed in the outpatient pharmacy, and oral agents shipped to subjects were prospectively monitored and retrieved from the electronic investigational drug accountability system (nCoup). Research management provided research nursing and clinical research coordinator (CRC) staffing levels from March 16, 2020 to June 30, 2020, the number of trials that held accrual due to COVID-19, and the number of patients who came off trials due to COVID-19. The statistics team used various statistical methods and models to assess the clinical research changes over time. The Wilcoxon rank sum test (two-sided) was used to evaluate the 8 time effect on the following factors: the number of patients enrolled to interventional treatment studies; the number of patients enrolled to interventional, non-treatment studies; the number of patients enrolled to non-interventional studies; the number of interventional treatment trials; the number of infusions of investigational agents; the number of biopsies for research purposes; the number of research blood collections associated with therapeutic trials. The time factor was trinary, with 2018, 2019, and January/February 2020 collapsed into one group, March-May 2020 coded as another group, and June coded as the third group as DFCI and BH instituted a phased recovery plan coordinated with the State of Massachusetts policies. Linear spline regression models were fit to assess the following associations: the proportion of investigational agents dispensed weekly by mail from January to June 2020; the proportion of patients (adult or pediatric) evaluated by telemedicine appointments over the weeks from March 16 to June 28, 2020; the number of missed appointments either in-person or via telemedicine over the weeks from March 16 to June 28, 2020; the proportion of research nurses working remotely over the weeks from March 16 to June 28, 2020; the number of CRCs working on-site over the weeks from March 16 to June 28, 2020. The week of May 31, 2020 was picked as the spline knot for all the linear spline models. We wanted to examine whether the recovery policy issued on May 28, 2020 at DFCI had any effect on the clinical practices previously described. The statistics team performed all analyses using SAS 9.4. P-values less than 0.05 were considered statistically significant. The ongoing guidance from the Commonwealth of Massachusetts, the National Cancer Institute, and the Food and Drug Administration prompted DFCI to enact progressively restrictive guidelines for clinical research operations from March through April 2020 (Box 1). 9 Operational restrictions at BH made in preparation for the COVID-19 patient surge further impacted clinical research at DFCI. Specifically, the procurement of image-guided percutaneous biopsies for research purposes was temporarily limited to only support research that had the potential to be lifesaving or disease-altering in circumstances where no alternative clinical treatments were available. These policies necessitated adjustments to our staffing models and delivery of care to patients enrolled and screened for clinical trials. The Office of Clinical Research worked with DFCI to provide guidance to study teams, and we assessed the impact on patients and compliance by our staff. As of March 20, 2020, the DFCI was at Level 4 research (Box 1). In addition to other changes, Level 4 restrictions limited the number of research nurses and study coordinators who could be on-site, all monitoring of trials was required to be conducted remotely, and biospecimen collection was restricted due to the reduction in on-site staff available to collect and process samples. On May 18, 2020, the DFCI initiated Stage 1 of recovery, which involved preparing to resume seeing patients in person and collecting biospecimens for therapeutic and non-therapeutic trials. Collection of biospecimens for therapeutic clinical trials resumed when Stage 2A of recovery was implemented on May 28, 2020 in which the minimum number of CRCs needed to collect samples were permitted on site. Stage 2B was initiated on June 11, which allowed for study patients to be seen in person whenever possible, with up to five CRCs per disease center and one research nurse for every 10 trial patients were allowed on site per day (Box 1). Trials with eligibility criteria and study requirements for on-study biopsies, frequent clinic visits, extended pharmacokinetic (PK) assessments, and other research blood collections were particularly affected by Level 4 restrictions. In addition, sponsors' decisions to pause enrollment also had an impact. For each clinical trial, the principal investigator was asked to ensure the resources needed to enroll and safety maintain the participants on the study were available, and the sponsor agreed to adapt the protocol requirements to existing conditions brought on by the pandemic. A median of 205 patients per month (range 157-241) enrolled onto medical oncology interventional treatment studies from January 2018 to February 2020. The number fell dramatically between March and May 2020, to a median of 86 patients (range 83-140), before beginning to recover in June 2020, with 138 accrued ( Figure 1A ). In general, the trend was decreasing (p = 0.007). The recovery from March-May to June was not statistically significant (p = 0.65). Although new enrollments declined, only seven of the 2295 (0.3%) active patients already on interventional treatment trials came off study, either due to concerns about contracting COVID-19 or international travel restrictions. Similar decreasing trends were observed for patients enrolled onto interventional, non-treatment studies ( Figure 1B ; p = 0.08) and noninterventional, non-treatment studies ( Figure 1C ; p = 0.007) ( Table 1) . Table 1 , the median number of interventional treatment trials accruing patients at DFCI by month remained largely stable between February and June 2020. Nevertheless, since the COVID-19-related policies were instituted, 49 of the 568 enrolling trials (8.6%) were closed (temporarily or permanently) and 154 (27.1%) were put on hold (many of which were put on hold due to restrictions on biospecimen collection). Additionally, 41 IRBapproved trials were not activated as of the end of June 2020 due to COVID-19 restrictions. The enactment of COVID-19-related policies also resulted in a statistically significant reduction in the monthly infusion of investigational agents, collection of biopsies for research purposes, and blood collection for research purposes (Table 1) . 11 The research pharmacy at DFCI dispensed a median of 272 outpatient oral investigational prescriptions per week (range 225-324) from January 5, 2020 through March 22, 2020 ( Figure 2A ). The guidance from the National Cancer Institute and Food and Drug Administration called for increased flexibility in shipping investigational agents directly to patients. In response, in March 2020, the research pharmacy, with the assistance of research nursing and CRCs, began a program to mail investigational prescriptions to participants rather than requiring in-person pickup at the DFCI outpatient pharmacy. Ten sponsors provided blanket approval to ship investigational oral agents, while two sponsors did not provide this approval. The total oral investigational agents dispensed ranged from 232 to 276 (median= 251) Figure 2B ). The percentage of telemedicine appointments for adults from March to the end of May was stable (p = 0.30), but we report a statistically significant decrease beginning in the month of June (p = 0.02). The number of pediatric telemedicine research-related appointments peaked at 11 during the weeks of April 12 and May 3 ( Figure 2C ). There was no statistically significant change in the percentage of telemedicine appointments for pediatric patients either from March to May, or in June (p = 0.95, p = 0.75, respectively). We also tracked missed appointments for patients on clinical trials each week from January to June 2020. Missed appointments spiked during the week of March 15, 2020 ( Figure 2D ), as DFCI was rapidly transitioning from Level 1 to Level 4 research restrictions (Box 1). As providers began seeing patients through telemedicine appointments, a roughly equal proportion of patients missed in-person and telemedicine appointments from late April to early June 2020. Finally, we reviewed patient complaints, and did not observe any complaints specific to the execution of clinical trials under the COVID-19-related restrictions. The ongoing COVID-19 pandemic is placing tremendous strain on the healthcare system. Medical and pediatric oncology programs have been particularly impacted, due to the ongoing need to provide optimal care to cancer patients while limiting their potential for contracting COVID-19 [14, 15] . In addition to routine care, therapeutic clinical trials have also been affected by policies designed to protect patients and staff from COVID-19. Despite the limitations imposed by social distancing requirements, travel restrictions, remote work policies, and limited support staff for correlative studies, DFCI was able to continue enrolling patients onto therapeutic clinical trials at approximately half the pre-COVID-19 rate; moreover, nearly all the patients previously enrolled were able to stay on the studies. This continued new enrollment and treatment for existing participants were mostly due to practice modifications that allowed patients to participate remotely as recommended by our state and federal agencies. These include performing adverse event assessments via telehealth visits and mailing investigational agents to patients' homes. Also, more than half of the research nurses and the majority of CRCs began 15 working remotely once the COVID-19 policies were implemented. This allowed DFCI to maintain a full research staff, albeit under modified working conditions. As businesses and other organizations in Massachusetts began to reopen in late May and throughout June, DFCI began a staged recovery process to resume scheduling of study patients for on campus visits and collection of biospecimens for therapeutic and non-therapeutic trials. It is important to point out several limitations of this prospective study. Prior to the institution of the COVID-19-related policies, the research pharmacy did not ship oral medications directly to patients unless it was an emergency situation and approved by the sponsor and principal investigator. However, the precise number of shipped medications was not centrally tracked; this means that the baseline number of investigational agents shipped to patients prior to the week of March 29, 2020 is not clearly known but was very rare. Second, the number of CRCs and research nurses on-site was obtained by surveying clinical research managers in each disease center and nursing leadership in medical and pediatric oncology. However, it is possible that not all schedule changes were captured by the managers' records. It is important to consider that the experience at DFCI might not reflect the situation at all cancer centers around the country, since policies and resources differ by center. A recent American Society of Clinical Oncology survey of 32 cancer centers (14 academic centers and 18 community programs) revealed that 64% of the centers had developed formal policies related to the delivery of cancer care and conduct of clinical trials during the COVID-19 pandemic. The policies at many of the sites included provisions such as telehealth visits for patients (87.5%), remote work by research staff (75%), and remote monitoring by sponsors and/or contract research organizations (71.9%), which are also part of the COVID-19 policies at DFCI and BH. Even with these modifications, 59.4% of the surveyed centers had halted screening and/or 16 enrollment for clinical trials and had ceased research-only visits, except for those providing cancer treatment. In addition, roughly half of the responding centers had ceased research-only blood draws and/or tissue collections, similar to our institutions [16] . The continued enrollment to therapeutic clinical trials at DFCI and other cancer centers around the country during COVID-19 demonstrates that cancer clinical research is robust and can be adapted to changing circumstances. Additionally, these changes can be adopted without compromising safety, as seen by a lack of increase in serious adverse events and major violations. However, it is prudent to consider the changes that are taking place not only as stopgap measures to respond to a temporary health crisis, but perhaps also as considerations in long-term improvements in clinical trial design to reduce the burden on study participants and research staff [17] . Many of the modifications made to ensure the safety of patients and staff during COVID-19, including telehealth visits, remote monitoring, and shipping of investigational agents, could benefit cancer patients in general as the pandemic wanes. Frequent traveling to the clinic in particular has been identified as a source of difficulty for cancer patients and a barrier to participation in clinical trials [18, 19] , particularly for ethnic and racial minorities [20, 21] . 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BWH = Brigham and Women's Hospital CSIR = cross sectional interventional radiology PFT = pulmonary function test RRN = research registered nurse Impacted Metric Median (range) p-value a a These p-values still show a decreasing trend across time in general The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.