Adaptive and Pragmatic Approach to Clinical Research: The Silver Lining of a Global Pandemic

In response to the evolving COVID-19 pandemic, most local and national governments and professional bodies endorsed the cancellation of elective surgery. This action was in an effort to free up hospital bed capacity for possible admission of COVID patients and to preserve supplies of personal protective equipment (PPE).

Our institution also experienced cancellation in elective orthopedic surgery for a few months in line with the strategy mentioned above. The adult reconstruction division, which performs over 5,000 hip and knee arthroplasty per year, came to a complete halt for a few months. During this time, numerous patients with disabling arthritis of the hip and knee had to endure hardship while waiting for openings of elective surgeries. As a complementary and essential activity, our institution's clinical research division also halted operations from March to July 2020. Employees in research were instructed to work from home while clinical trials came to a complete halt. At the time, the research division had 12 active clinical trials, two bench-based projects, and a large number of other research projects in progress. Numerous research personnel were then partially or fully furloughed.

Despite all, the research staff focused on ways to continue the essential work of clinical research. Instead of meeting with patients eligible for studies in person, telemedicine technologies, including Zoom, GoToMeeting, and Webex, were used to improve efficiency and safety while maintaining high monitoring standards. Additionally, where in-person visits were required, research staff was provided with appropriate personal protective equipment and clear instruction to minimalize exposure and possible risk of transmission. Although most of the studies are still ongoing, we believe that the measures put in place were well-received by both patients and researchers. Further evaluation should look at differences (if any) in dropout rates and short-term and long-term monitoring.

The use of remote monitoring is vital for the continuation of non-COVID-19 clinical trials. Understanding the detrimental downstream sequelae of these delays, the FDA encouraged flexible ways of restarting trial monitoring efforts through remote visits. For some trial sponsors, setting up the remote monitoring infrastructure was possible despite an interruption in the study period. These adjustments have not been financially feasible for others, unfortunately resulting in the clinical trials' termination altogether.

COVID-19 changed the shape of academic surgery as nothing before. As a sizeable academic institution and leader in orthopaedic research, the research and academic work disruption can profoundly affect many people's lives and careers. First and foremost, our patients had to endure for months musculoskeletal pain quarantined at home. Secondly, the career of the research staff, students, and fellows were affected in quality and quantity, and last but not least, every day of delay in our research can potentially halt the future health of many. However, despite any prediction, there is no exact way to measure what the future impact will be on patients.

These unprecedented events made clear that the common approach to clinical research should and can be improved. New ways were needed, and international efforts were made to 'adapt' to the COVID-19 pandemic by altering the process of clinical and translational research at our institution. As a result, adaptive, pragmatic designs were used to accelerate the process of investigating treatments for COVID-19. Large trials such as the NIAID-sponsored Adaptive COVID-19 Treatment Trial (NCT04280705) and the WHO-sponsored SOLIDARITY trial (ISRCTN83971151) are leveraging adaptive clinical trial designs, in which multiple, prespecified, investigational therapies can be compared with placebo to identify subgroups of patients who respond best to them. Pragmatic trial designs have also been proposed to evaluate therapies on a broader array of patients with the disease and increase the success of clinical trials.

Platform and adaptive trials have been known to trialists and researchers for years, but only recently are making the first few steps in the clinical research world. The reason mainly lies in regulatory pathways and funding agencies' unresponsiveness to adapt to Bayesian statistics. Thus, researchers and industry were hesitant to leave the safe harbour of frequentivistic statistics and 'traditional' trial design...