Successes in phase 2 autologous cellular therapy Oncology programme

ICON was awarded two early development cancer immunotherapy studies from a biotherapeutic company for a potentially ground¬breaking autologous cellular therapy in the treatment of two tumour types. These studies transitioned from an outgoing CRO without a clear plan for logistics management of cell shipping and processing. Because a number of target sites were already active, ICON needed to work rapidly in its implementation strategy so as not to delay patient enrollment. While the Sponsor initially intended to contract ICON for logistics management of only one of the two studies, ICON’s strategies were ultimately so successful that logistics management was rapidly transitioned to ICON for the second study as well.

While logistics support varies with each sponsor product platform and study design, critical areas of focus include the following: precise definition of roles/responsibilities during the entire personalised manufacturing life cycle, restricted site selection, Tissue Establishment (TE) licensure in startup, robust logistics management and communication for each patient, and the reduction of pre-infusion dropout rates through additional medical checkpoints.

Tissue Establishment (TE licensure in startup)

Only adoptive cell therapy accredited sites can be used for these studies and per EU regulations, site-specific licensure (Tissue Establishment (TE) License) was also required for sites to be permitted to ship and receive personalised cellular product to and from the manufacturing facilities. A critical consideration for the TE licensure was the lengthy submission/approval timeline required, often up to 12 months, and the need to cross check the EU compendium for list of sites with valid TE numbers and initiate the relevant discussions with sites from the time of site selection.

Logistics management

Comprehensive collaboration and communication between all parties along the product chain of custody are critical in cell therapy logistics. Failures along this pathway could lead to product management and/or serious patient safety issues.

Leveraging medical checkpoints to reduce dropout rates

Pre-infusion dropout rates were increasingly high at the start of the study.

During the site selection process, sites were requested to state whether they had a valid Tissue Establishment License. Sites identified as not having a valid license, or as having an expired license, were supported by the ICON clinical team and sponsor with identifying the submission or renewal process and assisted through the completion of the submission documentation in various ways. Often, the ICON team facilitated sharing of knowledge between sites on the Licensure submission/renewal process. On some occasions, external on-site support was required to provide assistance with navigating through the submission process and with liaising between institution departments and government authorities.

In parallel, the ICON logistics team maintained oversight of the site TE numbers as these appeared in the EU compendium. The logistics team implemented reminders to the site study teams with information on their TE number, as obtained from the EU compendium, to facilitate their completion of the tissue shipment forms to the manufacturing facilities.

Due to the complex study design, multiple forms of documentation required at all stages of the manufacturing process, and time-sensitive nature of all stages of this process, ICON created a bespoke Logistics Plan so as not to impact or delay patient treatment. Key clarifications included but were not limited to:

• Key ICON, sponsor, manufacturer, courier, and site stakeholders, with responsibility delineated for all key stages
• Pre-site initiation requirements (equipment delivery, procurement of site contacts/key
  stakeholders for all key stages)
• Dry-run (test) shipment instruction; test shipments were completed prior to site activation and patient enrollment to mitigate any issues and provide re-training prior to any of these actual shipments
• Detailed scheduling processes for tumour harvest and product infusion; coordinated
  between site and manufacturer based on manufacturing slot and patient scheduling availability
• Patient and site level documentation; detailed instruction for what forms were required when, and who was responsible for them

Other critical considerations for logistics management included:

• Resourcing: Due to the specific qualities required of logistics coordinators on these studies, such as proactivity, excellent communication skills, resourcefulness amidst challenges, high attention to detail, dedication, and commitment to ensuring coverage during specific business hours, the team established these standards for careful resourcing of this role
• Backup: ICON logistics coordinators were assigned to each study and in each time zone to ensure backup within each region and a central ‘logistics mailbox’ was implemented to ensure nothing was missed. This provided site staff in the EU and the US with immediate access to logistics coordinatorsduring their work day, and ensured coverage by trained ICON team members for vacation coverage. Strict guidelines were implemented for logistics coordinators’ vacation time to ensure multiple absences did not occur simultaneously. In addition, each study and region had its own clinical team manager (CTM) as well as backup CTM, who were also trained for backup emergencies.
• Site tools and ongoing training: Due to multiple repeat protocol amendments, often with critical changes to inclusion/exclusion criteria, all study documents and key logistics documentation needed to be updated frequently and sites retrained accordingly. The studies required white glove CRA service, with frequent communication and availability of ICON and sponsor support at all times.
• Logistics calendars: With multiple procedures occurring simultaneously and the associated high volume of email traffic and required documentation, ICON logistics coordinators maintained their own Outlook calendar in which all required steps were documented by date to ensure nothing was missed and patient treatment was not delayed.
• Site communication: Experienced Oncology CRAs were chosen for these studies. Due to the high volume of site communication related not only to logistics, but to frequent protocol amendments, document amendments, and sponsor’s need for near-real time SDV, ICON staff assignments were made carefully based on experience, communication style, and proactivity. Teams worked hard not tooverload sites and to maintain site morale.

In order to circumvent pre-infusion dropout rates, eligibility was completed at two time points on each study; once in screening/prior to tissue collection (enrollment), and again following tissue collection/prior to lymphodepletion to ensure patient stability on multiple levels prior to treatment (infusion). Reconfirmation of eligibility prior to lymphodepletion required detailed medical review, including ECOG score, confirmation of prior therapy washout, confirmation of no brain metastases, scans, con-med review, labs, ECG, radiology, and results for multiple inclusion/exclusion criteria. Due to the 28-day washout period and the length of time on study prior to treatment (infusion), MDs were also required during the reconfirmation step to confirm that patients’ cancer did not require immediate attention and they would not otherwise suffer a disadvantage during this timeframe by participating in these trials.

While the complexity of these studies increased significantly over time, ICON adapted quickly in an ever-changing environment and capitalised on the trust built early-on with the sponsor by having implemented successful processes which were maintained throughout. Strategic operational approaches to site set-up, resourcing, logistics management, and communication enabled enrollment milestones to not only be met but in some cases exceeded, even when one study was ultimately fast-tracked for registration.