operational considerations for designing and setting up a

Outline.

Operational Considerations forDesigning and Setting up a Site-LessDecentralised Clinical Trial (DCT)

Case Study

Bionical Emas are providing full-service CRO support for a Phase 2 study to evaluate

the safety and efficacy of an intranasal antibody in patients with asymptomatic or mild

COVID-19 in the UK.

Challenges.

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.

Successful 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.

Develop. Access. Innovate.+44 (0)1462 424 400 | info@bionical-emas.com | bionicalemas.com

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.

Design a study to expedite the development of potential and much needed COVID-19 treatments.

Working in an evolving and rapidly-changing COVID-19 landscape where cases appear in difficult to predict waves.

Recruiting and treating an outpatient population of COVID-19 positive patients with asymptomatic or mild disease, that are not routinely seen in primary or secondary care in the UK.

Nurse Home VisitsCo-ordinate and complete in-person

visits and administers treatment in

the participant’s home

Participant Support24/7 access to Investigator /

nurse and technical support

call center

Virtual Study VisitsDaily ePRO, regular check-ins

from Investigator

ParticipantIdentification

National recruitment

through digital advertising

and community outreach

Clinical Contact CentrePre-screens, gets participant ‘buy

in’ and books the screening visit

StudyCompletion

Expedited recruitment

Higher retention of

patients

Increased compliance

Trial Aspect Traditional Site-less DCT

Recruitment

In-Person Protocol Visits

Telephone Protocol Visits

ID Dispensing

IP Delivery

Laboratory Assessments

ePRO Completion

Investigator Oversight

Investigator and site team led

On-site

Via telephone

IP distributed to site pharmacy, dispensed by

site pharmacist

Administered at the site

Samples taken on-site and results available

through a local or central laboratory depending

on the same type

Participant completes at home on their own

(or provisioned) device

Site-level on-site Investigator team

Self-referral via advertising

At the participant’s home

Via telephone or virtual call

IP distributed direct-to-participant’s home by

central dispensary

Administered in the participant’s home

Samples taken a visit at the participant’s home,

posted directly to the central laboratory and results

available centrally

Participant completes at home on their on own

(or provisioned) device

Study-level virtual Investigator team