The Need to Balance Basic and Clinical Research with the Safety of the Research Environment and Personnel in the Time of COVID-19 in the United States

To limit the potential of medical surges overwhelming hospital systems in the United States during the Coronavirus Disease 2019 (COVID-19) pandemic, most states implemented stay-at-home orders [1], affecting non-essential personnel at healthcare institutions. Academic medical centers had essentially “shut down” research programs to de-densify campuses. These unprecedented moves stalled basic science research and limited clinical research. At the same time, researchers mobilized to study the novel coronavirus, its mechanism of pathogenicity, the host response to the virus, and treatment options. Scientists are faced with obstacles not previously considered since it is imperative that we advance scientific knowledge of this emerging virus and ensure the safety of personnel involved in the research of this highly contagious virus, while limiting the use of scarce personal protective equipment (PPE).

In this commentary, we address issues researchers in the United States are facing in balancing the desire to advance our understanding of COVID-19 while maintaining the safety of bedside and research personnel, as states begin to lift restrictions and COVID-19 cases are on the rise.

Informed Consent

Informed consent, often referred to as consent, is a process to obtain permission for research study participation and is required for most studies unless the institutional review board (IRB) grants a waiver. Consent is obtained from the research participant or their legal authorized representative (LAR). In critical illness, consent is often obtained from a LAR because the patient lacks capacity (e.g. intubated or highly sedated). Later, when the patients are awake and able, they are approached for assent to ensure they understand what study participation entails.

Obtaining informed consent frequently requires multiple discussions between research personnel, patients, and their LAR to ensure an understanding of the risks and benefits of participation. Many hospitalized with COVID-19 are critically ill with high mortality rates [2]; therefore it may seem too burdensome to discuss elective research options with patients or their LAR. This may lead to lower enrollment rates, higher withdrawal rates or lack of understanding of the process. Research personnel must be mindful of which patients to approach for consent by considering their clinical trajectory and the benefits of the study to the patient.

To limit the spread of COVID-19, hospitals have limited the number of visitors, thereby complicating the consent process. Furthermore, the Centers for Disease Control (CDC) recommends screening of all visitors for symptoms [3], which may limit the availability of family at the bedside for consent. The CDC also recommends targeted COVID-19 nasal PCR testing of hospitalized patients [3]. Patients awaiting testing results or with confirmed COVID-19 are placed under special isolation, requiring personnel entering the room to wear PPE. Even for pediatric patients whose legal guardians are at the bedside, it may be unsafe to bring the guardian out of the room to discuss research options. With a national PPE shortage, institutions are restricting PPE use to only clinical care and prohibiting use for research unless participation is directly linked to the subject’s clinical care. There also remains uncertainty of when patients with confirmed COVID-19 can be removed from isolation and are no longer considered infectious, leading to potentially long isolations times and PPE use, thereby further complicating the process of obtaining consent. Fortunately the CDC has provided guidance to when isolation can be removed, but concerns about continued infectious/carrier status remain [4].

These barriers in obtaining informed consent make it difficult to implement well-designed studies, especially randomized controlled trials. It is important to uphold the highest of ethical standards and remain accountable to the scientific community and our patients by obtaining informed consent even if it may slow down knowledge advancement. The COVID-19 pandemic has inadvertently brought to light the ethical dilemma of off-label use of potential therapeutic options. Specifically, with repurposed agents approved by the Food and Drug Administration, clinicians are struggling between using drugs off-label vs enrolling into a blinded study where their patients could be randomized to not receive a potentially lifesaving therapeutic option. Guidelines by both the Infectious Diseases Society of America and World Health Organization have discouraged the use of off-label practice, with treatments only recommended if part of an ongoing clinical trial [5–7]. The use of off-label therapies is commonplace in medicine, especially in pediatrics since many clinical trials reflect adult populations and assumptions are made in the pediatric population. The use of off-label therapies, when data are supportive in other populations, is not unreasonable to consider, but may leave patients uninformed about the potential risks or benefits that would have been reviewed in the informed consent of a clinical trial.

To conserve PPE and limit in-person interaction between patients and research personnel, consent can be obtained remotely. While phone calls may suffice for initial discussions, reading materials may need to be provided by email to allow participants who are visual learners to be fully informed and for documentation purposes. Participants or LARs may prefer consent to be done over video to allow for interactive communication with the use of visuals to enhance understanding. Researchers must ensure that the video format is Health Insurance Portability and Accountability Act (HIPAA) compliant. Many institutions have telehealth capabilities but use of the technology may be prioritized for clinical care. Implementing electronic consent has limitations. Redcap has previously been used for electronic consent but has not been widely adopted since RedCap can be prohibitively costly for institutions without a license [8]. Additional training is also necessary to develop an electronic consent process.

Essential Personnel

While specific details of stay-at-home orders vary state-to-state and restrictions are being lifted, academic health centers continue to urge that only essential personnel travel for work. These recommendations have been made due to the high transmission rate of COVID-19 even among asymptomatic persons [9], and to reduce PPE use since many institutions have universal masking policies [10]. Essential personnel include frontline healthcare providers and select research personnel who maintain murine colonies or provide other vital laboratory functions. Many non-clinical academic faculty, research nurses, and clinical research coordinators do not qualify for essential personnel status. Thus, new studies including those focused on COVID-19 need to adapt their clinical research process. Instead of relying on clinical research coordinators to obtain consent and collect samples, institutions may require frontline healthcare providers to perform these activities to limit the number of employees in the hospital. However, this may be too time consuming and impractical for bedside personnel given high censuses and acuity. It may create tension within each provider and between stakeholders regarding obligations towards clinical care versus towards research, as previously experienced during Ebola outbreaks [11], and currently being experienced in the COVID-19 pandemic [12]. These tensions were not commonly experienced in the United States during the 2003 SARS pandemic [13] or Middle Eastern Respiratory Syndrome (MERS) epidemic [14] given their limited spread within the country compared to the current COVID-19 pandemic. Institutions should provide guidance on how to mitigate these conflicts. In addition, finding affordable and approachable ways for COVID testing employees may allow more non-essential personnel to participate in research without increasing risk.

Sample and data collection

For studies of patients with suspected or proven COVID-19, obtaining biological specimens may prove challenging. Certain studies, such as drug pharmacokinetic studies, are ideally conducted with specifically timed samples. However, requesting research personnel or bedside nurses to enter the rooms of patients with COVID-19 more frequently than needed for clinical care would increase their risk for infection and require PPE use. Researchers must evaluate the necessity of obtaining perfectly timed samples while considering the risks of exposing personnel to the disease.

Opportunistic sampling allows for the collection of specimens, such as blood, without increasing the exposure to patients with COVID-19 [15] . In the sparse opportunistic sampling approach, bedside nurses obtain additional tubes of blood at the same time that blood is being drawn for tests ordered by the clinical team, and thus do not enter patient rooms unnecessarily. Scavenged opportunistic sampling utilizes the remaining blood after clinical laboratory tests are completed for research purposes. Clinical laboratories often store residual blood for further testing or for research. A benefit of using the scavenged approach is that some IRBs may grant a waiver of consent, further reducing contact between research personnel and patients with COVID-19. With this latter approach, it is important to know whether the drug, biomarker, cell or genetic material is stable under the storage conditions and over time.

Additional considerations when handling and processing patient samples with potentially live virus and conducting preclinical, in vivo, and in vitro studies are appropriate laboratory environments and PPE use for research personnel in the laboratory. The CDC recommends that a Biosafety Level (BSL) 2 laboratory be used when handling suspected or confirmed COVID-19 patient specimens [16]. For procedures with high likelihood to generate aerosols or droplets, biological safety cabinets are recommended, as well as additional PPE such as surgical masks or face shields. Personnel should consider processing samples in bulk when possible to minimize PPE use.

Research Priorities

Many institutions have created biorepositories of clinical specimens from patients with COVID-19. These specimens are highly sought by multiple investigators and institutions must prioritize who has access to the specimens. Questions to consider for prioritizing are: Should research focused on optimizing therapeutic dosing affecting outcomes of current COVID-19 patients take precedence? Conversely, should research that may benefit thousands of patients in the future (e.g. investigating targets for new therapies or evaluating outcomes of interventions) take priority? Should priority be based on seniority of principal investigators or grant funding status in the distribution of limited samples? Using these criteria may limit contributions from junior investigators who have likely faced declines in productivity during the pandemic and are concerned about the faculty promotion timeline [17]. These questions of justice, a basic principle of medical ethics, must be considered in research utilizing biological specimens from patients with COVID-19.

Conclusion

Most research has been halted due to the aggressive measures needed to limit COVID-19 spread and reduce the potential of medical surges. Many scientists have admirably refocused their research efforts and materials to understand the novel coronavirus. However, conducting research during a pandemic and restarting halted research as restrictions are lifted have presented challenges that have not been faced in in the United States in our lifetime. While it has always been necessary to protect our bedside and research personnel from the risks of working with contagious infectious materials, the nationwide PPE shortage introduces additional obstacles. Clinical research in the post-pandemic world will need to be reevaluated to ensure optimal efficiency balancing safety and study goals through effective collaboration between institutions, government and public health agencies.