key: cord-102456-6jt4ksha authors: Taylor-Cousar, Jennifer L.; Maier, Lisa; Downey, Gregory P.; Wechsler, Michael E. title: How I Do It: Restarting Respiratory Clinical Research in the Era of the COVID19 Pandemic date: 2020-11-13 journal: nan DOI: 10.1016/j.chest.2020.11.001 sha: doc_id: 102456 cord_uid: 6jt4ksha The clinical research we do to improve our understanding of disease and development of new therapies has temporarily been paused or delayed as the global healthcare enterprise has focused its attention on those impacted by COVID-19. While rates of SARS-CoV-2 infection are decreasing in many areas, many locations continue to have a high prevalence of infection. Nonetheless, research must continue and institutions are considering approaches to re-starting non-COVID related clinical investigation. Those restarting respiratory research must navigate the added planning challenges that take into account outcome measures that require aerosol generating procedures. Such procedures potentially increase risk of transmission of SARS-CoV-2 to research staff, utilize limited personal protective equipment, and require conduct in negative pressure rooms. One must also be prepared to address the potential for COVID-19 resurgence. With research subject and staff safety and maintenance of clinical trial data integrity as the guiding principles, here we review key considerations and suggest a step-wise approach for resuming respiratory clinical research. Clinical research is critical to our understanding of disease mechanisms and leads to life-saving therapies. During the time that worldwide efforts have been appropriately focused on describing and treating disease caused by the SARS-CoV-2 virus, most non-COVID19 clinical research has paused and or pivoted to a COVID-19 research focus. However, now that we have navigated the initial surge of SARS-CoV-2 cases, many are considering how to reintroduce non-COVID-19 clinical research conduct while protecting participants, staff and ensuring data integrity. Because of the many aerosol generating procedures (AGP) that are necessary to generate critical outcomes in respiratory research (e.g. lung sampling with bronchoscopy, nasal brushing, spirometry, administration of nebulized medications, and sputum induction amongst others), the challenges to resuming clinical research in pulmonary disease are numerous, and potentially more complicated than in other areas. Here we review key considerations and suggest a step-wise approach for resuming clinical research including observational research, registry trials, and interventional trials, as well as potential data confounding related to COVID-19 infections that are important to consider as research studies restart and data are analyzed. In January 2020, a 63-year-old woman enrolled in an 8 week, phase 3 randomized trial with planned open label rollover. Based on the increasing number of cases of COVID-19 in her state, clinical research conduct was put on hold with the exception of studies that were deemed to have potential benefits to subjects. Because the subject was scheduled to roll-over to open label study drug at the end of March 2020, her continued participation was agreed to have benefit. The subject's local government issued a shelter-in-place notice on March 25, 2020. This ordinance, in combination with the potential risk of infection, decreased the subject's enthusiasm to travel to the research site. Development of a new process was deemed necessary to ensure her access open label study drug. To resume clinical research in the era of COVID-19, several guiding principles should be followed. -Research subjects must be kept safe -Clinical research staff must be kept safe -The integrity of protocols, data, and outcomes must be maintained. -The process of resuming research should be flexible and dynamic, varying over time and by geography as dictated by the prevalence of COVID-19, the availability of testing and personal protective equipment (PPE), and by local institutional and governmental policies. Clinical research inherently has certain risks, due to either procedures or investigational agents. In the spirit of "Do No Harm", it is critical that institutional policies and processes are in place to ensure that there is no significant additional risk of contracting viral respiratory or other infections in the normal course of participation in research studies; now during the COVID-19 pandemic, these principles are even more critical. Careful consideration should be given regarding screening, enrollment, and continued protocol participation for high-risk participants. Equally important, it is imperative that clinical research staff are protected from potential risks of contracting respiratory tract infections including SARS-CoV-2 from research subjects or individuals accompanying them. Maximizing safety of all can be addressed by adopting several strategies to reduce potential exposure to those infected. COVID-19 Screening/Testing: The first line of protection is preventing subjects and staff at risk of infection from contracting and propagating disease. While there is some risk associated with asymptomatic individuals spreading disease, the vast majority of COVID-19 transmission is from symptomatic people. In that vein, all staff must self-monitor and self-report any symptoms daily. If these symptoms occur, staff must remove themselves immediately from work and from serving as vectors of infection. Similarly, research subjects should be screened for symptoms in the 2-14 days before each visit to evaluate whether the subject has symptoms of COVID-19, or is otherwise at high risk of being infected or infectious. This evaluation is particularly important for immunocompromised patients as they may shed virus longer. Screening for symptoms should also be repeated upon arrival at the institution with both survey questions and temperature checks. Symptomatic or febrile subjects must undergo COVID-19 testing with research visits postponed until test results have returned and/or symptoms have resolved. Whether all subjects, including asymptomatic subjects, should be tested prior to participation in research depends on several factors including local community standards of care, prevalence and testing availability including rapid turnaround time (2) . Testing of some individuals before J o u r n a l P r e -p r o o f they undergo a procedure that is likely to produce a high level of aerosol generation such as bronchoscopy, should be strongly considered and has been implemented at many academic institutions (3) . At this time, Sars-CoV-2 antibody testing has significant limitations due to sensitivity and specificity depending on the platform, and is currently not recommended. However, as testing characteristics improve in the future, this may be helpful in evaluating the safety of research participation and potential for confounding due to COVID-19 as noted below. Reducing exposures with administrative and engineering controls and personal protective equipment (PPE). Other measures should be taken to reduce potential exposure, including directing access of participants strictly to entrances where monitoring stations are present, limiting or avoiding visitors accompanying participants, minimizing the number or duration of participant visits, using remote monitoring such as telehealth if possible, and staggering participant visits to reduce exposures. Additional administrative measures to reduce exposures include limiting non-essential/non-research staff interactions with participants and research areas, and limiting research staff from directly interacting with participants; the latter will also conserve PPE. These preventive measures can be done by managing access to research units, developing one way hallways for 6-minute walk testing and using Plexiglass/plastic barriers and good ventilation in areas when staff and or participants are in close proximity. Furthermore, staff and participants should be safely positioned in workplaces and research areas to optimize social distancing. Adherence to Centers for Disease Control (CDC), professional society and/or local and state guidelines and policies should be followed for allocation of PPE for research, with priority of allocation for use in clinical care. As outlined by the CDC, central purchase and storage of PPE may be considered to ensure adequate supplies as well as conservation of PPE, especially for face masks and protective eyewear (e.g. face shields, safety glasses and goggles). Participants and research staff should be educated in the appropriate use of PPE, including donning and doffing and exposure reduction measures. All must be required to wear face masks or surgical masks as well as protective eyewear for study personnel if available to reduce the spread of infectious droplets and aerosols. Aerosol generating procedures, including pulmonary function testing, exhaled nitric oxide measurement, sputum induction, nasopharyngeal sampling, laryngoscopy, and bronchoscopy require additional PPE, inclusive of at least an N95 filtering facepiece respirator (FFR) and a face shield or a controlled air purifying respirator (CAPR), gown and gloves. While the Occupational Safety and Health Administration (OSHA) has currently waived the yearly fit testing requirement for FFRs, this testing is necessary if it has not been done recently. The AGPs should be performed with appropriate engineering controls, including negative pressure and increased air exchanges and filtration, allowing appropriate time for air clearance between procedures, as well as donning and doffing of PPE. Scheduling patients' visits must include consideration of PPE, as well as air clearance, required intensified sanitization of the room and or equipment; consideration should be given to limit the number of visits occurring at any given time and to space out participant visits. Environmental sampling for SARS-CoV2 virus should be considered to evaluate exposures and cleaning and disinfection processes. As an example, surface sampling based on World Health Organization (4) or other methods could be considered in potential areas of exposure, including rooms in which AGPs are performed as well as the equipment used for testing. Viral sampling of air in examination and J o u r n a l P r e -p r o o f procedure rooms, and UV light decontamination of rooms and surfaces may be considered using routine industrial hygiene techniques depending on available resources and expertise. A key principle of clinical research is ensuring protocol and data integrity to maximize the generalizability of clinical trial/study results including the endpoints, efficacy, and safety of studied interventions. Research goals include timely recruitment, proper adherence to protocolspecified procedures, high retention of participants, and proper statistical analyses to avoid undue loss of statistical power and increased risk of bias due to informative missing data. Fleming et al recently recommended several strategies to protect scientific integrity (5). These approaches include potentially delaying or pausing enrollment, pre-specifying analyses to address effects of the pandemic on trial integrity, and addressing analytical issues such as missing data with validated statistical approaches. Considerations for remote study visits: Another consideration is to modify protocols to accomplish study goals without interfering with the spirit of the study. These modifications may involve reconsideration of the necessity of all study visits and procedures. In that regard, one could consider implementing telehealth, home health visits and smart technology to facilitate clinical research. Prior to the pandemic, the use of telehealth and home outcome assessment (e.g. spirometry, sputum collection and even patient reported outcomes) were limited. The rapid deployment of these clinical tools has allowed their application to clinical research studies, and in some cases ensuring the continued conduct of study consent, safety visits and assessments, and collection of outcome measurements. Based on the positive reception from trial participants, it is anticipated that, as in clinical care, telehealth and home assessment options will continue to be incorporated into clinical trials subsequent to the pandemic. The standardization of acquisition and reproducibility of home measurements for cross-sectional and longitudinal studies will need to be established. For example, increased variability in home spirometry measurements may lead to the need to increase sample size to maintain adequate study power to detect differences in outcomes. Use of research coordinator tele-coaching for the maneuver could improve reproducibility. As another example, collection of a sputum sample at home by the participant could be inadequate, or the sample could be lost in transit, thus increasing the work of study statisticians to account for missing data points. Furthermore, assessment of physical exam findings is limited to those that can be ascertained by observation, and may limit recording of study-related adverse events. On the other hand, use of telehealth for clinical research may increase access to research for potential participants who have previously avoided participation because of time and/or distance from the research site. Sponsors and investigators will need to find the balance between access to study participation and the current limitations of telehealth and accuracy of home outcome measures. 1). The impact on other assays, such as genomic, epigenetic or immunologic and the duration of the impact is unknown, but is likely to occur with the potential for extensive impact on the immune system (7) and needs to be considered in analyses. Finally, for multi-center studies, the variance in regional allowance of on-site visits and study procedures will need to be considered and the resulting bias adjusted for in data analysis. In addition, consideration may be given to modifying the study procedures to minimize risk. For example, if repeated AGPs are required to obtain specimens from bronchoscopy, induced sputum or nasopharyngeal sampling, limiting the number of these procedures if required over multiple time points, or pairing with blood specimens to allow comparisons and or allowing studies to substitute collection of specimens with lower risk of viral transmission more frequently might be an option. Ensuring use of leftover specimens from procedures being done for clinical purposes and limiting control participant procedures or number are other possibilities. The processing of the specimens needs to be considered as a risk of exposure to staff and some centers have used heat or UV light inactivation of biofluid samples or chemical inactivation (e.g. placement of blood, nasal or bronchial epithelial cells directly into acid-guanidinium-phenol based reagent such as Trizol or other virus-inactivating medium) for genomic studies to minimize the possibility of viral exposure. Propagation of respiratory epithelial cells collected from a SARS-CoV-2 infected individual in submerged or air-liquid interface culture may result in generation of high viral titers and should be done under Biosafety Level-3 (BSL-3) conditions. Ideally participants and/or their cells should be tested for SARS-CoV-2 prior to propagation of respiratory cells in culture. J o u r n a l P r e -p r o o f As each clinical research unit contemplates the approach to re-starting non-COVID clinical research at its institution, guidelines from the national, regional and local level should be considered well in advance to allow appropriate preparations to be completed ( Figure 1 ). As described above, Center for Disease Control (CDC) (8) recommendations should be considered in establishing return to clinical research approaches in the health care setting and or other setting. Institutional and local mandates: The establishment of crisis standards of care in hospitals (e.g. temporary restrictions on elective procedures), as well as at-home isolation orders and travel restrictions for state citizens are impacted by regional variation in leadership and rates of SARS-CoV-2 infection. Similarly, the rescinding of such mandates is not uniform across the country and must be considered to determine not only when participants may travel to the research site for visits, but also when research sponsors and monitors can begin study initiation and oversight. The interpretation of city/state mandates by each institution will also dictate the revision of pandemic policies that restrict clinical study activity, including the conduct of outcome measures that result from AGPs and require PPE. Changes made to protocols must be passed by local and central IRBs/ethics committees as well as granting agencies and or sponsors as appropriate. Federal guidance: Both the FDA and National Institutes of Health (NIH) have issued publicly available recommendations (1,9) regarding conduct of research in the setting of the COVID-19 pandemic. In the midst of the pandemic, the NIH suggested limitation of study visits to those needed for participant safety or those that would be coincident with clinical care, to consideration of the conduct of virtual visits, use of local laboratories for safety monitoring, limitation of unnecessary travel and the cancellation of large gatherings. In acknowledgement of the potential pandemic-related delays in research progress and the incurrence of unanticipated costs, the NIH will allow for project extensions and requests for administrative supplements in some cases. Similar to the approach of the NIH, the FDA guidance has used patient safety as the overarching principle to guide recommendations. Adherence to good clinical practice (GCP) and minimizing risks to trial integrity are also required. FDA guidance encourages sponsors to work closely with investigators and independent ethics committees to determine in which situations subjects' participation in a trial will continue or be paused. Furthermore, sponsors and investigators are advised to work closely with institutional review boards to address urgent or emergent changes to the protocol or informed consent that resulted from the pandemic, and to prospectively define procedures to prioritize reporting of protocol deviations that may impact participant safety. Necessary protocol modifications that will impact efficacy assessments, data management and statistical analysis plans, should be discussed with the applicable review division. As with all FDA research conduct, documentation of changes and their rationale remains critical during the pandemic including changes that "impact on the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting, and changes in investigator(s), site staff, and/or monitor(s) secondary to travel restrictions, quarantine measures, or COVID-19 illness itself." With the restart of clinical research, reversal of temporary changes must occur and be documented, including updates to study status on clinicaltrials.gov. Finally, when submitting clinical trial study reports to the FDA, sponsors will need to address the impact of the COVID-19 pandemic on the reported safety and efficacy results. In order to re-start clinical trials/studies put on hold as a result of the pandemic, and to prepare for the start of new trials, one should consider implementing a multi-stage, risk-based approach that continues to emphasize participant and staff safety ( Table 2 ). In each stage, one should consider the pre-pandemic status of the trial (active or in the study initiation phase), the location of the participant (local versus out of state requiring travel), and most importantly, the procedures that will be associated with the visit. Unlike research in many other fields, respiratory clinical trials often include a large number of potential and known AGPs that are used as primary or secondary efficacy measures and outcomes, including spirometry, induced sputum, nasal potential difference, cardiopulmonary exercise tests, laryngoscopy and bronchoscopy amongst others. As outlined above, the availability of negative pressure rooms, PPE fit-tested staff, adequate well-ventilated space for social distancing of returning staff, safe specimen processing areas, disinfection protocols, and availability of PPE must be established before progression to subsequent re-opening stages. To insure that each of the guiding principles has been considered prior to re-starting clinical research, we created the following checklists: Research participant and staff safety Establish guidelines for location of specimen processing based on source (lowrisk versus known Sars-CoV-2 infected subjects and their bodily fluids) Ensure laboratory processing space meets safety guidelines for processing of biological specimens Re-design 6MWT area to ensure social distancing between subjects/staff Re-evaluate study design and ability to use lower risk procedures and/or samples such as peripheral blood cells versus bronchoalveolar lavage cells or change in study timepoints Protocol Integrity Discuss all potential protocol modifications with sponsor, whether federal and or industry, as well as the institutional review board Report any pandemic-related unanticipated events and protocol deviations to the sponsor/IRB Establish SOP for conducting research telehealth visits Establish process for shipping of investigational product, home testing kits (e.g. urine, sputum) Submit protocol modifications to institutional review board/data monitoring committee/FDA/NIH Update clintrials.gov with protocol modifications/enrollment holds (if indicated) Contact sponsor (NIH, foundation, etc.) to establish impact on study funding Flexibility Weekly COVID planning/update meetings with research managers and medical director to review local case data, changes in state/federal/institutional guidelines Weekly review of environmental testing of clinical research areas by medical director Adjust newly established SOPs as indicated by changing case data and state/federal/institutional guidelines Clear plan for regular communication to investigators regarding the move forward through stages of re-opening (or cessation of research based on increased infection rates/lack of PPE and/or testing capabilities) This year has taught all of us that flexibility and adaptability are critical aspects of navigating the uncertainties caused by the pandemic. Thus, timelines for progressing to the next stage must be adjusted for subject and staff safety based on successful transition through the previous stage. Successful transition will include objective measurements, such as the absence of positive SARS-CoV-2 environmental testing on the clinical research unit, absence of COVID related adverse outcomes in research subjects (e.g. positive testing for SARS-CoV-2 after contact with an asymptomatic but subsequently positive member of the research staff), or local outbreaks of disease in the community. Changes in the availability of adequate PPE could also delay the transition from one stage to the next. Other considerations moving forward will include the criteria that would lead to another clinical research pause if there is a substantial resurgence of SARS-CoV-2 infections. This may include rates of COVID-19 positive infections, hospital and ICU capacity, availability of PPE, participant willingness to continue to be involved in research, and movement to crisis standards of care to name a few. These measures should be discussed and outlined ahead of time so that reversion to a prior stage or staying at a current stage can be clear and transparent for staff and participants. This pandemic has taught us that we may need to consider not just SARS-CoV-2 infection, but also more closely scrutinize the impact of confounding by other respiratory viruses and infections in many of our vulnerable patient populations as the 'cold and flu season' comes upon us. In order for the subject to remain in the study and continue in the open label arm, the sponsor was contacted to discuss and approve the plan to obtain the minimum required safety tests (urine pregnancy test, complete metabolic panel and complete blood count) at the subject's home, to conduct consent by telephone, and to ship the investigational product to the subject's home. The sponsor reviewed Federal Drug Administration (FDA) COVID-19 guidelines (1), and submitted the necessary changes to the central institutional review board. At the time of the subsequent scheduled follow-up safety visit, telehealth was in place and the subject accepted the option of a visit via telehealth with a home nurse visit to draw safety laboratory values versus an on-site visit. After the sponsor was notified that research spirometry could not be performed per institutional policy, the subject was provided with a home spirometer from the sponsor. If aerosol generating procedures are able to be performed at the time of her next scheduled safety visit, the subject will be given the option of a remote visit, with blood draw and home spirometry, or an on-site visit with spirometry performed in office or at home prior to the visit. Throughout the subject's participation in clinical research during the pandemic, she expressed her appreciation for the opportunity to continue in the study from which she believed she was benefiting, with minimal risk of exposure to infection from SARS-CoV-2. In sum, while the world has appropriately focused on combating COVID-19 for the last several months, we are all now shifting our focus to the resumption of clinical care and clinical research under new circumstances. The main priority in clinical research conduct should continue to be the safety of participants, while also considering the safety of staff and data integrity of trials. Flexibility, creativity, vigilance and resilience will be critical aspects of restoring and reinventing clinical research participation, and of designing and conducting the trials of the future. Public Health Emergency Guidance for Industry, Investigators, and Institutional Review Boards Recommendation from European Respiratory Group 9.1 (Respiratory function technologists/Scientists): Lung function testing during COVID-19 pandemic and beyond The Use of Bronchoscopy during the COVID-19 Pandemic: CHEST/AABIP Guideline Surface sampling of coronavirus disease (COVID-19): A practical "how to" protocol for health care and public health professionals. Version 1 Conducting Clinical Research During the COVID-19 Pandemic Protecting Scientific Integrity Pulmonary fibrosis secondary to COVID-19: a call to arms? Immunology of COVID-19: current state of the science Guidance for NIH-funded Clinical Trials and Human Subjects Studies Affected by COVID-19 Clinical trials press on for conditions other than COVID-19. Will the pandemic's effects sneak into their data? CAPR-controlled air purifying respirator CDC-Centers for Disease Control FDA -Federal Drug Administration GCP-good clinical practice FFR-filtering facepiece respirator MBW-multiple breath washout NIH-National Institutes of Health NO-nitric oxide NPD-nasal potential difference, OSHA-Occupational Safety and Health Administration