By Andi DeStefano, Director of Project Management at Veracity Logic, LLC.
To see why flexibility is important to keeping a clinical trial on track, let’s explore the Clinical Trial Supply Lifecycle using a fictional Sponsor named Pharzm, who will be running Phase 3 trials for a new drug.
Pharzm has a new two-year trial, which includes 200 subjects. They plan to manufacture 5,280 bottles of the new drug, which includes only a 10% overage. They aim to limit the number of shipments to each site to only one per month. The drug is in powder form and can only be used for six months before it expires; therefore, four campaigns will be scheduled. Each subject has one visit per month; one bottle is needed per subject per visit. The drug will need to be reconstituted and prepared by an Unblinded Pharmacist at the site.
The Unblinded Supply Manager at Pharzm is working with their IRT (Interactive Response Technology) Project Manager to help manage inventory. All the information mentioned can be included in the User Requirements (URS) and the configured into the IRT system.
The IRT is modular, so a Predictive Inventory Module has been included to ensure the optimal quantity of drug is delivered to the site in time for the subject’s next visit.
The Expiry Management Module has also been included, so the IRT system will not assign the drug within 30 days of the batch expiry date. This module will prevent any drug being shipped once the drug is within 44 days of the expiry date. An alert will be sent to Pharzm 90 days before the existing batch approaching the expiry date that a new batch needs to be loaded into the IRT. The system will automatically generate shipment requests using the new batch to replace batches approaching the expiry date.
Also, while standard notifications are sent to the site staff, the system sends specific notifications for the unblinded pharmacist to maintain the blind. These notifications can be configured to include treatment arms, dose levels, and dose calculations.
The team at the IRT partner also works cooperatively with either the statistician or supplier who is creating the clinical trial material (CTM) list and incorporates all the requirements into the system.
Once all the requirements are configured into the system, the Project Manager (PM) at the IRT vendor demonstrates and reviews the first build of the system. The Pharzm team has the opportunity to make some changes to the formatting or how the questions are worded. The IRT system partner provides a thorough Validation Summary Report (VSR) and shows which errors have been fixed, so Pharzm User Acceptance Testing proceeds quickly and smoothly. The average time to build an IRT is 4 to 6 weeks, depending on complexity and approvals.
Once the system goes live, the shipment requests can be automatically generated when the first site is activated or when the first subject is screened. The shipment requests are emailed to the warehouse/depot based on the programming requirements. The warehouse/depot typically updates the system as soon as they dispatch a shipment to a site.
The site acknowledges receipt of the shipment in the system as soon as it is delivered. Once the site has acknowledged receipt of the shipment, the system can start assigning study medication per the system requirements.
The team at Pharzm are pleased with the progress, but some common errors arise:
- Multiple pending shipments for one site, the site acknowledges the incorrect shipment.
- Warehouse/depot forgets to include a packing slip.
- Problems with individual kits at warehouse/depot/site (damaged, missing, or unusable).
- Problems with Return Shipments back to the depot (more kits were physically sent back then accounted for in the system).
- Shipments are not dispatched by warehouse/depot on time.
- Shipments needed to be canceled (for various reasons — including when Pharzm needs to combine multiple shipments into one, and a site has closed and the resupply was not turned off).
These are just minor hiccups; when the above happens, the user calls the IRT’s help desk and helps resolve the issue.
That’s how it would work, ideally.
But it’s the nature of scientific discovery to make changes to experiments as new information is learned, resulting in a protocol amendment.
The Pharzm clinical team realizes this; they know there will always be changes; the IRT needs to adapt and be flexible to support the trial.
In Pharzm’s selection of partners for the study, they feel confident that the IRT has additional modules, so capabilities can be added as needed.
If changes occur, they know from experience that they can add capabilities for:
- Temp Deviation – when clinical trial material must be stored under controlled conditions, this allows clinical sites to indicate when a temperature deviation is reported during shipping. When a shipment experiences a temperature deviation, all kits in that shipment are marked “Temp Deviation” to prevent them from being assigned to subjects.
- Drug / Kit Accountability (with or without drug destruction at site and or depot)
- Tracking of Ancillary Supplies
- And even changes in the type of randomization – to accommodate site-blocking randomization, skipped doses, titrations, adding cohorts, or any other changes requiring a protocol amendment.
The typical time for a major change to a system requiring changes or additional coding is 2-4 weeks after a signed approval of the scope change.
To expedite the trial and meet the sponsor’s budget, they also ensured that an interface was available for authorized Pharzm team members to make certain updates (that did not require reprogramming) to the IRT’s Static Resupply/Predictive Algorithm throughout the study. The IRT offers training on how to access the system and which changes can be made. To avoid errors, the system only allows team members access to these functions if their job requires it.
Once the study commences, Pharzm finds they must do several system changes over the course of their two-year study:
- Comparators are changed due to new scientific and logistic issues.
- The scientists learned that temperature affects the drug adversely, and it must be maintained in a certain environment, requiring the addition of the temperature deviation module.
- A sister study’s findings show that the dosage plan is too high, so the dosage included in the protocols must be removed and lower doses inserted.
- The sponsor is unable to receive the regulatory approval needed for a country outside of the US and therefore needs to add a substitute kit type that will meet the regulatory requirements and allow them to start recruiting subjects in all countries.
- Slow enrollment necessitated a protocol amendment enabling subjects from another study to enroll in the new study.
- A protocol amendment specified that different patient populations follow a different treatment schedule. In this case, the IRT had to include unique visit schedules based on the protocol’s new rules.
- Due to the COVID-19 pandemic, drug distribution during monthly visits with the doctor was disrupted by the “stay at home” order. The vendor contracted to distribute the drug could not quickly gear up to ship the drug to individual subjects, so another firm was hired to ship the drugs. The IRT had to be reconfigured to accommodate this change and allow the new vendor to log in to enable shipment tracking.
In all these examples, the IRT partner’s ability to quickly adapt – working cooperatively to either add functions or change programming, was important for the clinical team to overcome the challenges and meet their milestones.
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