key: cord-0818607-i400ynjp
authors: Milner, Ross; Donington, Jessica; Matthews, Jeffrey; Posner, Mitchell; Turaga, Kiran; Angelos, Peter
title: Is it Ethically Appropriate to Continue Surgical Clinical Trials During the COVID-19 Pandemic? EDITED BY DR SARR
date: 2020-04-27
journal: Surgery
DOI: 10.1016/j.surg.2020.04.024
sha: 8aac9169348eae970ed0c141484b935b55dbbb19
doc_id: 818607
cord_uid: i400ynjp

COVID-19 has greatly impacted surgical care and decision-making. The status of surgical clinical trials during this pandemic has not been addressed. We provide a framework and recommendations for the management of patients involved in surgical clinical trials.

The COVID-19 pandemic has greatly impacted both clinical care and its underlying ethical basis, shifting from the traditional patient-centered approach to a public health strategy. 1 As surgeons, we have been challenged to balance the risk of proceeding with planned operations ith the cncerns to the patient and to the health care system against the risk of delay. For the first time in the United States, we have found it necessary to consider the availability of appropriate hospital resources, the potential for increased adverse outcomes in occult COVID-19-positive patients, and limitations in pre-operative testing, as well as potential health dangers posed not onoy to the patients but also to hospital staff including the entire operating room staff-nurses, anesthesiologists, physicians, etc. At the University of Chicago, we introduced a scoring system to assist in the ethical triage of medically-necessary, timesensitive (MeNTS) procedures given that the imperative to halt all "elective" surgery does not adequately capture the nature or define the types of non-emergency procedures that may still need to proceed. 2 We have found this approach to be particularly useful with respect to the constantly changing pressures on peri-operative resources (anesthesiologists, nursing, personal protective equipment, blood, ventilators) and hospital inpatient capacity otherwise diverted to dedicated COVID units and ICUs during different phases of the pandemic. The timing of surgery for cancer patients has been particularly thorny, and a number of groups have proposed thoughtful frameworks for these clinical decisions. 3, 4, 5 So far unaddressed during this pandemic has been the status of surgical clinical trials.

Specifically, is it ethically appropriate to continue enrollment and treatment of patients in clinical trials that include surgical intervention? If we continue such clinical trials, are we putting patients at greater risk of COVID19-related complications? Could the pandemic inappropriately skew the results? If we expedite and prioritize surgical treatment for those patients who are part of a trial, are we unduly pressuring them to participate (a form of coercion)? In contrast,, is it ethical to suspend future enrollment or active participation if it would potentially deny patients the benefit of novel therapeutic interventions or improved outcomes associated with the clinical trial? Although the ethical debates might apply across a broad range of clinical studies during the pandemic, we sought to focus specifically on surgical trials. We discuss here the ethics of clinical trial care within the surgical specialties and the the pros and cons of participation in clinical trial during the COVID-19 pandemic, with a specific focus on surgical oncology and vascular surgery.

The clinical trial portfolio is the core of any comprehensive cancer center. Oncologic therapeutic clinical trials offer patients access to exciting new treatments. These trials are designed typically to answer specific questions regarding treatment and outcomes and not the timing of surgical procedures or the frequency of visits and invasive procedures (at least not as primary objectives). The current need for social distancing and limitations of health care resources has shifted priorities appropriately, but completely halting clinical trials would hinder dramatically the delopment of novel treatment sand leave patients currently enrolled in these trials without access to potentially life-saving medications.

The Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute (NCI) recognizes these issues and encourage sponsors, investigators, and institutional review boards to revise existing policies and procedures to mitigate risk and to protect trial participants while keeping clinical trials open. This program includes steps to alter the informed consent process, study visits and procedures, data collection, and the reporting of adverse eventz. For example, local treating physicians can perform a majority of study-related activities and administer all medications except investigational agents. 6 The issues related to surgery in a clinical trial during the COVID pandemic are more challenging.

Many of the proedyres ypically cannot be performed by the surgeon at the local hospital, have strict time constraints dictated by inclusion/exclusion criteria in the trial protocol, and carry the potential to place an undue strain on limited inpatient resources and the health care workforce. Futhermore, cancer patients undergoing complex surgical procedures are inherently immunosuppressed and are at risk for superinfection by the COVID-19 virusn and the associated increase in morbidity and mortality.

Therapeutic clinical trials that involve oprative intervention tend to focus on locally advanced tumors and often involve induction therapies (chemotherapy, radiation therapy or both) that increase the potential for post-induction fibrosis, which may increase the technical difficulty of an operative procedure and prolong the postoperative hospital stay due to peri-operative complications. In the end, the decision to proceed with a planned cancer resection for a patient enrolled in a clinical trial is highly dependent on the institution's phase in the pandemic and availability of peri-operative resources. The decision to proceed with an operationthat is governed by stict time-dependent guidelines is often somewhat arbitrary and that time interval can likely be prolonged without adversely affecting the There are cities and hospitals where only urgent surgery is possible and others where resources still allow for high priority, oncologic resections. At the University of Chicago, we have attempted to maintain patients already enrolled in clinical trials, butwehave curtailed new enrollment dramatically due to the uncertainty of available resources and have focused our research efforts on COVID-centric issues. Only low risk trials with novel agents and unique therapies remain open to enrollment, but, as expected, accrual has slowed tremendously. Trials that include surgery do not fall into this category. Surgical trials typically require multiple different therapies on rigid time schedules and are not deemed prudent in our current environment. It is unclear how these decisions will impact cancer care for individual patients and the advancement of our science, but in a time of limited resources, we do not want to embark on a treatment strategy that we cannot potentially safely complete. But, it is not lost on us that clinical cancer trials that do or do not involve surgery are invaluable in defining new treatment paradigms that lead to improved outcomes for cancer patients, and it is known that just by participating in a clinical trial, derivative benefits in patient outcomes are the rule. Therefore, striking the correct balance between these two conflicting concepts is the essence of the ethical dilemma we are facing.

The majority of clinical trials in vascular surgery involve the use of medical devices or a surgical procedure to treat peripheral artery disease, carotid artery disease, or aortic aneurysms/dissections. At the University of Chicago, we participate in a number of such trials. Many of these large, multiinstitutional device trials are sponsored by industry. In light of the COVID-19 pandemic, all vascular clinical trials have been halted. One of the large device trials that was scheduled to start in March has delayed its start during the COVID-19 pandemic due to the need to eliminate "elective" cases for the well-being of individual health care systems. The decision on the part of industry to suspend such clinical trials has been met largely with support from vascular surgeons.

What is the ethical basis for supporting this decision even though it means that some patients are not getting the latest and potentially more effective devices to treat their vascular disease? The care and focus of linical trials in vascular surgery are both resource-intensive and time-sensitive. Using our current framework of MeNTS procedure prioritization, we have focused attention on patient care issues related to critical limb ischemia, symptomatic carotid artery disease, and symptomatic or ruptured aortic aneurysms. As such, vascular surgeons should not utilize scarce operating room time or clinic time to investigate novel devices with unknown outcomes. It is our belief that this same prohibition on vascular clinical trials should also apply to FDA-approved devices that are being investigated under a registry designation. By halting the nenrollment of patients into such trials, we relieve the pressure placed on surgeons to enroll patients in a clinical trial that could negatively impact the timely care of other patients whose needed procedures have greater medical urgency. Most importantly, we believe that in the present environment, surgeons should provide care that is the best known "standard of care" and that can provide the most benefit to our patients and minimize the impact on our hospital and health care systems with unknown outcomes from devices. Finally, patients should not feel pressured to participate in clinical trials in the hope that by enrolling they may be given an advantage to have surgery sooner.

The COVID-19 pandemic has created both clinical and ethical dilemmas for surgeons. We believe that continuing surgical clinical trials at the present time poses unique ethical concerns. Before continuing to enroll patients in surgical trials, we believe that surgeons must carefully consider the type of trial, the institutional status with respect to scarce resources, and the potential risk/benefit ratio to patients and health care workers involved. We have decreasedour clinical trial efforts mzarkedly during the pandemic to minimize patient coercion and to maximize the use and avialablity of patient care resources for evidence-based procedures.

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COVID-19 has greatly impacted surgical care and decision-making. The status of surgical clinical trials during this pandemic has not been addressed. We provide a framework and recommendations for the management of patients involved in surgical clinical trials