Managing oncology clinical trials during COVID-19 pandemic

Abstract

São Paulo city is the epicenter of the Brazilian COVID-19 pandemic. The Instituto do Cancer do Estado de São Paulo is currently conducting 161 multinational sponsored trials plus 116 in house studies in the oncologic population. There are 242 currently active participants and 180 patients in follow-up. The management of the tightly controlled environment of clinical research becomes a challenge, and the Food and Drug Administration set of priority recommendations for patient safety while maintaining study integrity. Fast adaptations are necessary, and actions coalesce to participant protection from COVID-19. We pointed out critical processes for adjustments, and we believe that our experience may help other academic health centers.

The COVID-19 pandemic is jostling established processes in academic health centers resulting in a profound reorganization of its clinical operations. The management of resources to prioritize COVID-19 patients raises concerns such as those with chronic diseases, including cancer. Cancer is a potentially life-threatening disease, and, to many patients, particularly in developing and emerging countries, participation in clinical trials represents an alternative means of treatment. The environment to conduct clinical trials requires well-controlled procedures regularly performed in in-person visits. Contrasting, social distancing, and the isolation of infected individuals have long been the primary strategy to fight infectious diseases. The complexities of the pandemics are moving the clinical research toward a high level of uncertainty, and resolute alternatives such as halting research activities are neither feasible nor desirable.

The Food and Drug Administration (FDA) published guidance to industry, investigators, and institutional review boards (IRB) on conducting clinical trials during the COVID-19 pandemic [1]. The orientations prioritize participant safety and study activities could be adapted to achieve the best possible level of patient welfare, otherwise recommending to decision-makers to discontinue study participation if risks outweigh potential benefits. Modern drug clinical trials run in multiple sites worldwide, which have been drastically affected by the COVID-19 pandemic, particularly with couriers’ logistics for sample shipping, delivery of investigational products to centers, and to import and export study materials.

Withholding or deferring recruitment temporarily during the COVID-19 pandemic could prevent potential risks of candidates to participate in studies that might end up unfinished. It may be necessary to reorganize infrastructure, reestablish logistics, and normalize lockdowns to permit in-person visits. From the participants’ perspective, unavoidable non-compliance with study schedules and procedures may be anticipated. Practical obstacles like patient consent withdrawal due to fear of COVID-19 exposure, missed appointments due to lack of transportation, and treatment-toxicity related examination constraints (i.e., shortage of ophthalmologists and otolaryngologists to evaluate immunologic treatment-associated adverse events) require adaptations (Table 1). Upon efforts on adjustments, clinical trials should be conducted at a reasonable safety level. In our institution, we interrupted recruitment of all protocols for eight weeks, and 107 days after the 1st death occurred in March 18th [2], no dropouts or discontinuation due to COVID-19 were registered. The participants continue to receive experimental treatment during contingency according to protocols, and the primary objectives were successfully assessed.

Table 1.

Adjustments of oncology clinical trials.

Guarantee of treatment availability and logistics
•Postponement of the activation of sites that have not yet been initiated until logistics normalization.
•Make 4–6 months planning for drug supply to included patients.
•Consider home delivery of medications, especially oral drugs.
Keep participant well informed and safe
•Inform the participants of all study changes and adaptations immediately.
•Confirm the availability of infrastructure supporting clinical research and related supply.
•Consider enrolment interruption temporarily if minimum safety support requirements are not met or are in potential risks.
Reduce the risk of COVID-19 exposure
•Limit in-person visits to safety check-ups and primary endpoint assessments and use telemedicine for non-complex procedures such as laboratory check-ups.
•Grouping all the labs, imaging, and drug infusions on the same day of medical visits to reduce the total number of hospital visits.
•Use the phone, and online platforms for video conferences with participants to respond to questionnaires.
•Offer transportation alternatives for home-site and site-home travels to avoid mass public transportation.
Keep the validity of data and sample collection
•Expand the use of a risk-based monitoring (RBM) approach and remote monitoring as much as possible.
•Update Case Report Forms (CRF) and informed consent to add information regarding COVID-19 infection.
•Consider COVID-19 disease as a potential confounder during analyses of results.
•Consider maintaining in-person monitoring visits with hygiene protocols in handling documents and social distancing with physical barriers among monitors and site staff. Adaptations in the infrastructure might be necessary.
•Confirmed COVID-19 cases should be tested until negative results. Tests should be reimbursed by the sponsors. Clinical trial participation interruption should be evaluated individually.
•Consider adaptive efforts in biological sample handling according to WHO COVID-19 guidelines to continue functional biobanking.
Improve principal investigator, sponsor, and IRB communication
•Maintain and improve the communication with sponsors for adaptations of protocol schedules and procedures prioritizations
•Immediately communicate the IRB regarding any urgent adjustments for safety purposes

The local site workforce responsible for managing study requirements is multidisciplinary, and an expert team typically requires months of training to achieve an adequate level of experience. The new coronavirus outbreak may cause substantial staff infection and reduction, which may impact the ability to coordinate all corrective and preventive actions. Also, there is a growing possibility of research team reallocation to life-saving pandemic mitigation efforts. Replacement in a clinical trial team is problematic because of specific personnel background and study-related credentials. Leaders should work at different shifts to reduce the risk of simultaneous infection. Virtual meetings and safe desk distances between coworkers may be part of the contingency plan to maintain a minimum organizational structure to coordinate the adjustments. The use of telehealth modalities, including video conferences and telephone calls are efficient distancing tools to research nurses that are engaged in actively calling participants to update them in new schedules and adaptation of research protocols. The pandemic pushes urgent implementation of telemedicine to reduce in-person check-ups [3].

The study integrity is of great concern as the overall survival is the most critical endpoint in oncology. A UK report estimates a COVID-19 case-fatality ratio of 28% in cancer patients with symptomatic COVID-19, with mortality increasing with age and associated non-cancer comorbidities [4]. COVID-19 testing is not part of screening in current clinical trial protocols, and investigators could inadvertently enroll asymptomatic patients. There is a significant risk of the introduction of bias in survival estimates. Even in a randomized allocation, one may expect COVID-19 to imbalance results toward the less toxic treatment, thus breaking the principle of equipoise. In addition, potential virus-related pulmonary, hepatic, and cardiac toxicity may jeopardize data analysis.

Participants with confirmed COVID-19 should be oriented according to the World Health Organization (WHO) guidelines and if possible remain in quarantine for 14 days [5]. A specific confirmatory test should be performed with RT-PCR and serology assessments may corroborate to the diagnosis. In cases of suspected pneumonia, a thorax CT may be useful to assess pulmonary involvement. The decision to interrupt the trial participation for 14 days should consider the participants' individuality and the severity of the COVID-19, the overall clinical status, the potential toxicity of the investigational product, the cancer stage, and the time point of the study. It remains controversial to adopt a positive PCR test as a paramount criterion to halt or resume trial participation since aggressive tumor types must have no treatment gap [6]. The conflicting shreds of evidences indicating whether or not anticancer treatments increase the COVID-19 mortality risks [4] takes patients to a great vulnerability in managing stress under high level of uncertainty. A personalized approach is always crucial in sharing decisions with the participant about the potential risks and benefits to clinical trial participation [7], and during COVID-19 pandemic, this approach should be strengthened. As there are no comparable precedents in recent history, unpredictable impacts are expected in data interpretation on modern-era clinical trials.

Biobanking has been critical for exploratory studies such as those investigating prognostic and predictive markers in precision oncology trials or studies addressing concomitant viral infections such as HIV or HPV [8]. During (and after) the pandemic, a set of specific precautions would require controlled areas compatible with biosafety level 2 (BSL-2) and standardized pre-analytical processes of handling potentially contaminated samples. Interim biosafety guidance of the WHO related to coronavirus recommends that all procedures must be performed only by personnel with proven capability [9]. Although many biobanks interrupted activities according to UKs' Tissue Directory and Coordination Centre (TDCC), it's vital for research efforts to maintain or reestablish functional biobanks [10]. The WHO recommends that each institution should conduct a local risk assessment to ensure appropriate risk control measures. In Brazil, additional requirements would be necessary, such as notifying the National Ethics Committee (CONEP) to permit infected samples in the biobank, and the National Biosafety Technical Commission (CTNBio) to register BSL-2 areas for safe handling of infectious samples. The pandemic's legacy would improve the safety conditions of research, specifically those involved in tissue sample procurement.

The decision-making to recruit and maintain the participant in oncology clinical trials is stressful as the pandemic influences the reasonability of balancing the risks and benefits. Sharing decisions with sponsors and IRBs would be necessary for choosing the best possible compromise of participants' safety while maintaining data quality. As COVID-19 continues to spread, the pandemics' duration and severity will dictate further difficulties requiring immediate adaptations that may eventually be permanent. Quarantines and lockdowns programs are used to control disease propagation, but participants might be infected. A dedicated COVID-19 pavilion and operators for confirmed cases can maintain virus-free areas for cancer patients. Still personalized patient-centered care in clinical research will change toward community care where the pandemic solutions are necessary for the entire population. Participants’ safety is paramount and efforts to prevent contamination should be the primary objective while fast operational adjustments contribute to the study integrity.