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Applied Clinical Trials
eGSP-driven approach focuses on overcoming operational challenges through data integration.
The current global economical and regulatory environment has led the biopharmaceutical industry to transform the clinical supply from oversight of a domestic, linear process into management of a complex network of global demand and supply lines, addressing additional challenges. New adaptive study designs, new target diseases, and global studies require on-demand packaging and labeling methods in order to keep operating costs under control.
These challenges create significant opportunities for clinical supply chain to drive efficiency, lower costs, and reduce lead times for drug launches. There is an urgent need to set up and deploy integrated management solutions from investigative center opening to study closeout in order to streamline the entire clinical supply chain.
Electronic good supply practices (eGSP) ensure that the supply chain, supported by integrated e-platforms, is safe and meets its intended use while guaranteeing full traceability and accountability. This article aims at simplifying some critical steps of parallel logistics processes to optimize operational challenges faced by clinical trial stakeholders and to achieve significant savings through process rationalization and data integration.
Clinical research logistics have not evolved to keep pace with the outsourcing of activities to contract manufacturing organizations (CMOs), contract research organizations (CROs), central laboratories, centralized ECG, and bio-imaging providers. Even though the logistics processes for clinical trial materials do not vary significantly from study to study, the supply chain remains fragmented among various subcontractors and suppliers. This results in increased complexity, redundancy, higher costs,1 and even confusion at investigator sites.
Despite the success of interactive voice/web response services (IXRS) facilitating the logistical issues surrounding the conduct of clinical trials, no efforts have been made to integrate the supply chain of investigational medicinal products (IMPs), sampling kits, and ancillary supplies. The eGSP approach is the turnkey to streamline the clinical trial supply chain and to provide all stakeholders with the required tools to manage a specific part of the supply chain or to give the complete overview and status of all aspects of the study.
Beyond the business process and complexity issues, a lack of software integration and functionality/gaps also causes difficulties. Packaging operations are managed through an independent control system. The IXRS systems generating orders for clinical trial kits are not usually integrated with the planning processes, which are distinct from the systems used to manage internal and third-party production and distribution operations.
New technologies are emerging to help pharmaceutical companies distribute medicines. E-platforms help share data securely and economically with suppliers around the world, analyze the data very rapidly, and respond to sudden changes in supply and demand, while advanced tracking technologies enable them to monitor products from the factory gate to the patient.2
While several solutions are available, such as clinical trial management systems (CTMS), clinical data management systems (CDMS), enterprise resource planning (ERP), laboratory information management systems (LIMS), manufacturing execution systems, business intelligence, IXRS, and SAS business analytics software applications used in clinical development, most of these are isolated applications that do not share data, resulting in delay and poor data accuracy and data availability.
Forecasting and inventory visibility challenges can also be attributed to the fact that the CRO—to which most of the trials are outsourced—usually does not share the same platform of applications and depends more on the IXRS to provide dynamic forecasts. Thirty-five percent of businesses recently surveyed by Gartner Inc. identified the inability to synchronize end-to-end business processes as an issue, which will increase demand for supply chain management application convergence.3 In the clinical research supply chain, we struggle with functional and application silos of each stakeholder, that make orchestrating and synchronizing business processes across the stakeholders nearly impossible.
The key success factor to streamline the collection and exchange of data is the development of secure e-platforms for capturing, gathering, consulting, sharing, and tracking all study data. The real added value, therefore, comes from the development of the e-platform best suited to support each trial. eGSP incorporates the good practices of integrating electronically all information systems related to the supply chain in clinical trials.
A range of internal stakeholders, including clinical operations, regulatory affairs, clinical quality, manufacturing and supply, and the qualified person (QP) are all involved in various aspects of ensuring adequate supply. Involvement of the right people who know the business is critical in the setup of an eGSP approach. Those from clinical operations, clinical supply chain, regulatory, and workers in the plants should be involved in the early stage of trial development to review process maps and gather feedback on how the new system would operate. Typical stakeholders who should be involved in eGSP implementation are:
Such stakeholders must have a clear operational view on their own business as well as a proven experience in the collaboration with other involved departments/vendors/CROs.
The design of the clinical study protocol is a mandatory first step in the application submission and approval process of a clinical trial. It is the starting point and reference document throughout the entire duration of the study and details the background of the study, the objectives, the clinical design, Inclusion/exclusion criteria, treatment of subjects, reporting, data collection, and many other topics. Surprisingly, none of the topics from the protocol describe logistics, although one can consider the development of the study as a huge logistical process. While logistics operations might be out of sight, logistics is under significant pressure to deliver near-perfect performance under more complex, risky, and difficult business conditions. Many reconsiderations based on previous experiences demonstrate the importance of defining the logistics design sooner, if not already during the development of the clinical study protocol. This path becomes increasingly critical with the adoption of new study designs such as adaptive trials.
When considering the percentage of logistics in the total cost of a project and knowing the current financial pressure on the pharmaceutical industry to reduce costs, it is urgent that all parties involved in the practical implementation of a study join their efforts in achieving the most cost efficient and seamless clinical supply chain. The eGSP is the best approach in this strategy, but how can it be ensured that this e-platform is set up in such a way that it allows for each specific clinical trial to collect and centralize the appropriate information at the right moment and in the most appropriate way? There is need to outline the supply chain processes of all materials (i.e., IMPs, sampling kits, biological specimens, ECG, bio-images, ancillary supplies) and to determine the roles and responsibilities of all parties involved in the "clinical supply protocol." The clinical study protocol brings together the clinical expertise and the logistics expertise and will allow the design of the optimal supply process for a study, ensuring operational and financial efficiency.
For every item in the clinical study protocol, the supply chain implications are identified and fully described. This process should not be unilateral or separate, but should ideally be done in parallel with the clinical study protocol. Supply chain aspects could also influence some aspects from the protocol.
The structure of the clinical supply protocol should be clear and practical:
Data to be used by different parties throughout the logistics processes should be outlined in the clinical supply protocol. Typical supply chain aspects consist of production, warehousing, distribution/transport, and returns. For all these activities, specific quantifiable information (volumes, timelines, etc.) should be collected. Specific software tools used by the different subcontractors should be listed and their interface requirements with the e-platform identified. Finally, the roles and responsibilities of all stakeholders involved in the protocol supply chain should clearly be assigned and validated by each party.
Based on such information summarized in a well-elaborated clinical supply protocol, the set-up of the project in the integrated e-platform will be an easy and smooth process. The framework of the clinical supply protocol provides a single, integrated landscape to manage the complete clinical supply chain by addressing all challenges faced by the different logistics stakeholders.
In an eGSP approach, upon availability of the clinical supply protocol, operational processes must be delineated step-by-step in order to ensure appropriate interaction between the following stakeholders involved:
There are three essential processes that are supported by integrated e-platforms to allow these stakeholders to best interact with an innovative eGSP approach:
The clinical supplies process supported by an e-platform is very comprehensive. According to their access rights, the e-platform will involve the related stakeholder to ensure clinical supplies, but also sampling kits and ancillary supplies are available on-site. The supply process starts with the involvement of the project manager (from the CRO or sponsor) to give a "green light" through the e-platform in order to release shipping orders.
Once green light is given for an investigator site, a shipping order (built in a suitable format and according to a predefined structure) is sent to the CMO for automated integration into its system. A shipment date is associated with each shipping order and the site is immediately notified when the shipment will be performed. Just-in-time packaging and labeling is then carried out as well as the connote (air waybill) preparation. Shipment information (content and connote number) is confirmed in the e-platform that will promptly notify involved parties (sponsor/CRO and site). Shipment confirmation will also trigger a notification to the parties as well as the proof-of-delivery confirmation. The person on site responsible for receiving the shipment will be prompted to confirm shipment content and integrity (received in good state or damaged, correct quantities, etc.) by accessing the e-platform and completing the necessary online form. This will allow the CMO and project manager to be notified accordingly. Should some actions be required following the confirmation performed by site (e.g., goods received damaged), the e-platform will trigger appropriate notifications to the CMO and project manager, allowing a timely follow-up with the sites.
This process will only be enabled if all e-systems are fully used and integrated and if all steps are first thoroughly identified to ensure smooth and efficient implementation in the custom-made e-platform; this is the essence of an eGSP solution.
Patient material/record collection is a critical step in eGSP implementation as well. Building an e-platform should not be restricted to the management of IMPs; sampling kits, ancillary supplies, and any other material deemed necessary to conduct a clinical trial should also be considered when building the e-platform. This enables a direct link between investigating staff and the whole supply chain. After linking the patient material/record with the patient demographics collected in the eCRF, the e-platform will generate a consistent e-requisition form to each supply chain vendor. In addition, the e-platform will automate stock level checks on-site and generate, when needed, re-supply orders. After processing of collected material by the central lab and core lab, their outputs (e.g., lab results) are integrated into the e-platform (e.g., after upload), so that both project manager and site staff are notified about the results.
The IMP prescription (and re-supply) process is involved at the critical study phases of patient randomization and follow-up.
Depending on the study activity, one of the processes just described will be involved. The typical study conduct phases are:
Site opening: Consists in given access to the sponsor or CRO project manager to give the site regulatory green light through the e-platform. Once confirmed, the site will be virtually opened and all study stakeholders will be notified accordingly. Site opening will automatically trigger the clinical supply process.
Patient recruitment/screening: Is performed by investigational staff through the eCRF section of the e-platform, triggering notifications to the project manager and allowing a tight link with the patient material/record collection process.
Patient randomization: Allows site staff to allocate a patient to the right treatment arm. For an enhanced interactive eGSP approach, the use of an eCRF with embedded IWR system will be preferred. Once the patient has been randomized successfully, automatic notifications to the project manager and to the supply chain as well as a seamless link with IMP prescription and patient material/record collection processes will be enabled.
Patient follow-up: Under a eGSP approach, this consists of granting site staff access to the eCRF module for the recording of follow-up data. At given time points, a narrow check will be performed by the e-platform to allow for appropriate links with the IMP prescription and patient material/record collection processes. Throughout these processes, the system will be checking the stock levels and will issue new order requests to the clinical supply chain after project manager approval.
Patient close-out: Allows site staff to confirm and sign off patient data through the eCRF. Balance between IMP intake and returned to site is done at this level.
Site close-out: Is usually requested by the project manager through the site management page of the e-platform. At this point, automated notifications ensure that both site and supply chain stakeholders are kept updated of site close-out by the CRAs. The carrier will then initiate the return of remaining IMPs and ancillary supplies still available on-site. Since the e-platform provides up-to-date information about dispensed and collected IMPs and ancillary supplies, the CMO will be able to perform the full reconciliation and trigger the site close-out.
Study close-out: With eGSP, there is no need to perform manual generation of e-mails or faxes to service providers involved or to carry out manual accountability. Inventories of IMPs and ancillary supplies are immediately available on the e-platform and the study close-out notifications will inform all stakeholders in a seamless way. Once this step accomplished, database locking, archiving, and destruction tasks will be led in a timely manner.
In a first global Phase III cardiovascular study, 186 sites spread over three continents (Europe, Australia, and South America) were going to recruit 520 patients. The ECG supplier was located in Canada, the Holter supplier in the United States, and the sampling kits were assembled in Belgium, while the IMPs were manufactured in France. In order to optimize the supply chain and minimize the number of shipments, it was decided when preparing the clinical supply protocol to centralize all supplies in a single warehouse in Belgium, which would be responsible for worldwide distribution. The central warehouse did assemble and integrate the IMPs, sampling kits, ECG, and Holter materials, including a single Investigator manual. The total logistics budget was reduced by 43%, despite the extra costs of central warehousing for three years and assembly of all clinical trial materials. In addition, the investigators were very pleased, as they were supplied by a single source rather than having to mail or fax their orders to the four original suppliers.
In a Phase III CNS trial aiming at randomizing 350 patients in 30 sites spread over six countries, the e-platform integrated the eCRF, IWRS, and drug supply management in order to streamline interaction between all involved stakeholders (i.e., study manager, the CMO, investigators, pharmacists) at each site. After reshaping the conventional supply chain, the production and the supply of drugs was optimized to reach €500,000 savings. How was this possible? Initially, the sponsor planned to provide each site with a large box containing all treatment combinations in the different dosages. Thanks to the implementation of a study-specific drug supply management strategy, each individual combination in each arm was managed by the e-platform so that stock available on sites was minimized.
The two described case studies show how significant savings can be achieved by optimizing the clinical trial supplies process through a comprehensive eGSP strategy. Overall, the implementation of an eGSP approach leads to measurable cost savings reaching up to 30% of each clinical trial budget.
E-platforms developed in an eGSP approach are fully interactive, streamline the clinical research process, and bring together the clinical and logistics expertise simultaneously during the design process of a clinical study. This ensures the ultimate operational and financial efficiency of a trial. eGSP is an integrated approach towards best-in-class internal and external clinical trial supply management processes supported by state-of-the-art technology, which will result in higher compliance, shortened study timelines, and reduced R&D costs.
Christophe Golenvaux is Director of Sales and Marketing, Lambda-Plus, email: [email protected] Benoit Cloquet is Director of Operations, B&C Group, email: [email protected].
1. T. Applebaum and B. Blake, "Roche Beats Complexity by Building End-to-End Clinical Trial Supply Chain." Gartner Research, ID:G00229768 Published: 5 April 2012.
2. PwC "Pharma 2020: Supplying the Future – Which Path Will You Take?," www.pwc.com/pharma2020/.
3. Gartner, "Gartner's Top Predictions for Global Logistics Organizations to 2016," Gartner's Supply Chain Executive Conference, 17-18 September 2012 in London.
4. P. Bielmeier, G. Crauwels, and J. Williams, "Stretched to the Limit," European Pharmaceutical Contractor, December 2011.
5. P. Bielmeier and G. Crauwels, "Managing the Extended R&D Supply Chain," Pharmaceutical Engineering, July-August 2012.