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Outline.

Bionical Emas are currently actively involved in designing and implementing several COVID-19 studies, one of which is an ongoing Phase IIa open-label study of an immunomodulator therapy in patients with severe COVID-19 pneumonia. Here, we describe how we were able to rapidly set-up this clinical trial at two US sites in five business days utilising:

  • Our experience and expertise in designing and implementing critical care studies in patients with severe respiratory diseases (e.g. viral pneumonia, acute respiratory distress syndrome [ARDS]) and in the use of immunomodulators to assess efficacy and safety of a novel therapy at this early stage of development (i.e. Phase IIa)
  • Standard operating procedures (SOPs) that allow flexibility to develop new processes rapidly without compromising patient safety or data integrity
  • Adaptive and agile approach to data capture and rapid set up of the case report form (CRF) and electronic data capture (EDC) system
  • Rapid study start-up methodologies, including:
    • Our understanding of the accelerated approval pathways for COVID-19 treatment studies
    • Close collaboration with the Sponsor
    • Involvement of all company departments, including peripheral teams such as quality assurance, legal and commercial
  • Flexible and novel approaches to clinical monitoring

Tactics.

Expertise in this area: Our knowledge and understanding of how complicated intensive care unit (ICU) studies can be reliably and efficiently run, the severe pneumonia patient journey and how patients are managed on the ICU, and how immunomodulators may be best tested in this setting and at this early stage of development, was crucial to our success. It was also critical to understand the different aspects of the disease and its progression, so that study design and efficacy parameters could be optimised to define optimal patient benefit. Prior experience of running these types of clinical trials in patients with severe pneumonia on the ICU is therefore critical, and we were able to resource this study with our specialised critical care project team (Project Manager and CRAs).

Highly flexible SOPs: These were key to the rapid set-up as they allowed us to adapt and develop processes in real time to meet the specific needs of this study, without compromising patient safety or data integrity. A general statement was added to study plans to confirm they should be followed if SOPs conflicted. As an example, we adapted our Clinical Supplies Release and Site Activation approval forms to allow IP release for shipment as early as possible, which meant no lag time between collection of the last essential document and commencement of screening.

Adaptive and agile approach to CRF and EDC set-up: The EDC was ready to go live with pages required for the first patient visit within 5 business days, compared to the industry standard of 8 to 12 weeks. We also reacted to a protocol amendment requested by the FDA and updated the EDC to go live on the 7th business day, following FDA approval. Our data management (DM) team combined COVID-19 specific data-points from the publicly available World Health Organization (WHO) novel COVID-19 CRF, with templates from our CRF page library. IBM Clinical Development was chosen as the EDC platform due to its ease and speed to build and allowed the sponsor to benefit from IBM’s offer that the platform can be used at no-cost. Our DM lead was exempt from study calls and other tasks to allow them to focus on the build, and reviews were strictly limited to one per page. CRF completion guidelines were developed to provide reference and support for the screening/randomisation visit which was essential to start enrolling, with the rest of the CRF guidelines to be developed as the remaining part of the EDC goes live.

Rapid start-up methodologies:

  • Understanding of accelerated approval pathways. FDA approval was obtained using the Coronavirus Treatment Acceleration Program (CTAP), which aims to review protocols within 24 hours.
  • Central vs. local IRB approval. Whilst central IRBs are generally regarded as the most expeditious, since it requires an additional step of local IRB approval for the study which we considered to be an unnecessary delay, we targeted a local IRB process. Both IRBs had put a hold on routine reviews but convened a virtual meeting to specifically review this protocol and were able to provide approval within three days, subject to FDA approval.
  • Sponsor and CRO alignment. We had previously worked with this Sponsor and so had developed relationships between our CRO project team and the Sponsor, which allowed us to work together and make decisions quickly.
  • All key team members attended the kick-off meeting (KOM). All key team members from the Sponsor and Bionical Emas attended the KOM and were completely aligned and focused on efficient and effective delivery of the protocol and study. Tasks were assigned based on expertise, and everyone left the meeting with their priority tasks for the next 24 hours.
  • Daily Scrum calls. These were held to review tasks and plan work for the next 24-hours. Sites were selected where we had previous successful experience and had recently negotiated a budget and contract template, which expedited the contracting process significantly.

Flexible clinical monitoring: Since sites were known to us, we waived the qualification visit. Remote SIVs were used, and the training was recorded and made available to any staff pulled onto front line emergency work who could not attend. Sites were SIV’d and training completed rapidly to ensure sites were ready to go as soon as FDA approval was granted. Sites were instructed not to begin recruiting until they received written authorisation to do so, and this was reiterated by monitors on a daily basis until activation. Also important was selection of sites that allow monitors to log into their electronic Medical Record (eMR) systems remotely, and we implemented a new Work Instruction (WI) for remote source data verification (SDV).

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Successful Outcome.

In these unprecedented circumstances of the COVID-19 pandemic, Bionical Emas and the study Sponsor worked very closely and tirelessly to ensure that this important clinical study could be efficiently designed and implemented in just five business days. From KOM to first SIV, Bionical Emas were able to rapidly set-up and start this critical first wave, Phase IIa, open-label study, with a novel immunomodulator therapy in patients with severe COVID-19 pneumonia. The study is now enrolling these critically ill patients, desperately in need of an effective treatment, at a number of key US sites, and plans are developing for a much larger patient expansion study.

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