Operational Considerations for Designing and Setting up a Site-less Decentralised Clinical Trial (DCT)

Study Design

Tactics

• Expertise in Decentralised Trials:
  Bionical Emas are founding members of the Decentralised Trials and Research Alliance (DTRA) and are committed to driving decentralised clinical trials (DCTs) forward and ensuring patient centricity in our clinical trial strategy. Given the nature of the treatment pathway and limitations during the COVID-19 pandemic, a site-less DCT was the only option for this clinical trial. Our experience as leaders in the DCT space meant that we were well placed to design and implement this novel and highly decentralised clinical trial.
• Home health nursing team:
  Patients with asymptomatic/mildly symptomatic COVID-19 are required to self-isolate at home and must not leave the house for any reason other than to go to a test centre for a PCR test. Without home healthcare, this patient population would otherwise be inaccessible, therefore, home health nursing was pivotal to the success of this study. The home health nursing team are central to navigating the operational complexities of ensuring that all nurses visits occur per protocol, IP shipments arrive at the participants house on time, unblinded nurses are available to prepare the IP at each participants home within 2 hours of administration, and couriers are available to collect samples.
• National Recruitment:
  The UK COVID-19 landscape is ever changing, and so for COVID-19 studies, it is important to be able to constantly move and adapt to target areas with high cases numbers. A specialist recruitment team was a key part of the study strategy and they developed robust and UK wide digital and community out-reach campaigns. Campaigns were developed to be instantly adaptable and flexible to move to areas of high and/or increasing waves of local cases, and they were also tailored towards the communities within each local area. The specialist recruitment and home health nursing teams needed a joined-up strategy, to ensure that nurse teams were available in the areas that were being targeted for recruitment at each stage of the study.
• Sample Collection:
  With typical UK study start-up timelines, approvals and site level activities are usually on the critical path. However, due to the expeditious approval timelines and the Sponsor desire to start the study rapidly, central laboratory set-up was identified as a potentially limiting processes on the critical path for this study. It was important that we identified a central laboratory that could be flexible to this need, and the selected central laboratory committed to an expedited 4-week set-up process to support same-day collection of samples from participants homes via a specialist courier, including shipments of dry ice where frozen samples are required. The nursing team will use mobile centrifuges to prepare samples for collection as required.
• Direct-to-patient IP Distribution:
  IP labelling and direct-to-patient IP distribution is provided by a company who are UK experts in this area. As they have an on-site pharmacist, they were able to obtain a temporary license to act as the central pharmacy for the study which meant that IP could be distributed directly to the participants home and did not need to go via another pharmacy. Following randomisation, the IP distributors package the appropriate vials into a temperature controlled shipping container that will arrive at the participants house on the day of treatment. We also developed a highly complex processes to allow for same-day IP deliveries where required. This study was the US Sponsor’s first study in Europe, and we also had to rapidly factor in audit and qualification steps at their manufacturing sites to ensure compliance to UK/EU GMP standards. Our project team scheduled and completed remote audits, responded to findings, completed an audit report, and turned around a QP declaration within a record time of 10 business days.
• Flexible and Agile Operational Team:
  To make this study design work, our operational teams had to constantly think outside of the box and find new ways to work. To enable this, we empowered our operational teams to act in a way that facilitates a decentralised design. The team resourced to the study also had a wealth of experience working on other COVID-19 studies and so excelled in this type of environment. Highly flexible teams and processes allowed us to adapt quickly to meet specific needs, without compromising patient safety or data integrity. Daily scrum calls, which included the project’s oversight team, were also important to keep the focus and drive start-up forward.
• Industry Leading Electronic Systems:
  Due to the novel study design, it was important that we identified systems that met the needs of the study, rather than needing to adapt systems to fit the study requirements. This was important to ensure operational activities were streamlined and not overly complicated. IBM Clinical Development (IBM CD) was chosen as the most appropriate eDC for the study. As certified IBM CD builders, we build databases quickly. Utilising our eCRF library of standardised forms allows an expedited build process for many of the eCRFs needed, providing time to focus on the study specific forms. Modules available within IBM CD allowed us to have an eDC, electronic diary (ePRO), and randomisation all within one system, allowing consistency and ease for such an innovative study design. Furthermore, the Data Migrator module allowed easy processes to be set up to enable source data to be uploaded directly from outputs from our nursing teams system into the eCRFs, removing the need for transcription, which is critical for a decentralised study.
• Audit Ready TMF and ISF:
  Another hurdle to overcome was how to maintain an Investigator Site File (ISF) in a site-less design when our systems are set up to manage traditional site-based designs. Although this study is ‘site less’, the documentation requirements for the study team are the same as for a site based design, and so we are able to consider the study as having one ‘virtual’ site. We used Trial Interactives eTMF and eISF solutions to streamline collection of traditional site facing documents such as training and delegation of authority logs. Also, we are using a Learning Management System which will provide training for Investigators and Nurses working on this study. This solution allowed us to implement a streamlined solution to the problem, and maintain one ISF for the entire study.
• Virtual Investigator Oversight:
  Without clinical trial sites, we had to find a way to ensure Investigator oversight for the study. We identified two Key Opinion Leaders to support the study; a Chief Investigator to support the protocol design and ethics submission; and a Principal Investigator to maintain primary responsibility for the conduct of the study. We also identified a team of Sub-Investigators who had both clinical trial experience and were appropriate for the trial, such as GPs. Rather than having site level Investigators, we have a study level virtual Investigator team, which has an added benefit of consistency in oversight activities. The team of Sub-Investigators support the Principal Investigator with the day-to-day running of the study and complete traditional Investigator tasks such as reviewing serious adverse events and assessing abnormal laboratory results for clinical significance. They work on a rostered shift system, managed by the project team, and provide continuous cover throughout the trial.
• Public Engagement:
  This study is a relatively new and novel design for the UK, and so it was important for us to engage with the public to ensure the design would be acceptable for the target population. We harnessed feedback from a public group on the participant information sheet, and by carefully managing timelines and expectations, we collected and responded to their feedback within 5 business days. In line with their feedback, we implemented a summary participant information sheet to provide a simple-to-read document that gave an overview of the study information considered to be most important to potential participants.

Outcome

• Bionical Emas estimated a set-up of less than 6 weeks from final protocol to first patient in, and recruitment of 350 participants in a further 6 weeks. To date, Bionical Emas completed the writing of essential documents (protocol, IB, IMPD), completed early engagement with the MHRA on the study design, and have received full MHRA and REC approvals.
• A cost comparison of this site less design vs. a traditional site based model showed a 20% reduction in costs for the site-less design. Cost savings were predominantly due to shorter study timelines, particularly with regards to study start-up and recruitment.
• We welcome future opportunities to offer our expertise in the design of novel and decentralised clinical trials.