ICON supported a phase 1/2/3, single-arm, open-label, multi-site, single dose in patients with transfusion-dependent ß-thalassemia. Patient population age ≥18 and ≤35 years and later expanded to adolescent population. The drug product was composed of an autologous CD34+ human hematopoietic stem and progenitor cells (hHSPCs) modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene.

• The study covered myeloablative HSPC transplant using the investigational product delivered cryopreserved in vials and the entire dose was given through a central venous catheter
• The primary efficacy endpoint was the proportion of subjects achieving sustained transfusion independence for at least 6 months starting 3 months after the investigational drug infusion
• Sites had limited experience with CRISPR-Cas9 modified gene therapy. They were selected for their experience with Apheresis and Bone Marrow transplant. It was also complex to accurately plan recruitment rates, project recruitment or timelines.
• The submission package submissions were lengthy, difficult to compile and complex which affected the approval timelines as some documents, for example, some ICFs were rejected by competent authorities. Site contracts were complicated and had long negotiation turnaround timelines due to the complexity of the procedures.
• The volume of the training specially for sites was very high, taking up to 2 weeks to complete and certify; This had an impact on staff turnaround and sometimes impacted the site activation.
• Due to the study design and treatment plan, it was necessary to plan for ovarian and sperm preservation. Some sites did not have these facilities and required external vendors and contracts which was the cause for some delays and some countries had to be replaced with back up countries.
• The CRF volume was sometimes more than1,200 pages per subject as data from hospitalised patients had to be collected daily for the duration of 1-2 months. When several patients were recruited during the same period, this created a heavy data backlog which generated high peaks of activity which had to be addressed, especially due to the frequently planned safety data cuts.

Patients’ successful treatment was dependent of the manufacturing slots for the stem cells. Stem cells were collected via apheresis and sent to the manufacturing facility where cells were modified, sent to the site and kept cryopreserved until they were re-infused into patient. Several issues were identified that delayed the entire process, for example, cell destruction and low cell concentration required that the whole apheresis process had to begin again.

The protocol was amended several times to subsequentially increase the patient sample size from 10 to finally 55 patients and included the adolescent patient population. These changes lengthened the timelines initially planned and has prolonged the overall study duration.

Numerous client audits and FDA and EMA mock inspections were conducted to ensure patient safety, reliability of the data, and confirmation of inspection readiness, which was an expectation from the client due to the numerous data cuts, and participation in congresses with interim results.

The COVID pandemic impacted the monitoring strategy, recruitment, and the data cleaning.

Very frequent communication with the key stakeholders at a site and sponsor level was required, which helped to prioritise the tasks, and to work as a cohesive team with prompt escalation of communication related issues as early as possible.

Resources are managed very carefully to avoid frequent team changes, ensuring team motivation and fatigue were addressed specially during the peaks of activity related to patient enrollment and data cuts.

A forecast for data cleaning was conducted 3 months in advance of when the data cleaning activities were required. ICON assigned back up CRAs and scheduled monitoring visits with a 3–4 day duration and included several CRAs for each visit to cover all monitoring and data cleaning needs.

To manage COVID related restrictions, a full remote monitoring strategy was planned well in advance. Several CRAs who were able to monitor in parallel were appointed, as were back up CRAs in case recruitment increased at a certain timepoint.

Patient drug preparations were tracked carefully to avoid drug supply issues, and a call with sites was scheduled at the pre-collection and pre-treatment visits to ensure each case was closely monitored and risks managed.

Special efforts were made to ensure patient retention to ensure the data from the patient follow up period was collected after the modified cells Infusion.

Very frequent communication with the key stakeholders at a site and sponsor level was required, which helped to prioritise the tasks, and to work as a cohesive team with prompt escalation of communication related issues as early as possible.

Resources are managed very carefully to avoid frequent team changes, ensuring team motivation and fatigue were addressed specially during the peaks of activity related to patient enrollment and data cuts.

A forecast for data cleaning was conducted 3 months in advance of when the data cleaning activities were required. ICON assigned back up CRAs and scheduled monitoring visits with a 3–4-day duration and included several CRAs for each visit to cover all monitoring and data cleaning needs.

To manage COVID related restrictions, a full remote monitoring strategy was planned well in advance. Several CRAs who were able to monitor in parallel were appointed, as were back up CRAs in case recruitment increased at a certain timepoint.

Patient drug preparations were tracked carefully to avoid drug supply issues, and a call with sites was scheduled at the pre-collection and pre-treatment visits to ensure each case was closely monitored and risks managed.

Special efforts were made to ensure patient retention to ensure the data from the patient follow up period was collected after the modified cells Infusion.

Once ICON`s involvement started all milestones planned were met and first patient randomised was per plan. Due to the different amendments issued throughout the study, last patient treated which was planned in October 2022 has been pushed to February 2023.

Last patient in was achieved in September 2021 and last patient is expecting to complete the trial in February 2025 with a the data base locked in April 2025.

Overall recruitment planned against the current recruitment can be seen below.