A common challenge for sponsors and distributors is ensuring that clinical supplies are available where and when needed, while maintaining maximum supply-chain flexibility in order to mitigate risks of future stock-outs and control costs associated with manufacturing, labeling and shipping of clinical supplies. Interactive response technology (IRT) systems offer many benefits in overall clinical supply management and manufacturing. These benefits include ordering algorithms that reduce waste; the ability to adjust (decrease) supply strategy ceiling and floor levels as the trial reaches full enrollment as well as to cap the maximum number of visits predicted for ordering; real-time product release, country approval, expiry and status management for rapid product updates; just-in-time (JIT) ordering (where this is supported by the protocol design (e.g., placing initial orders upon site enrollment or screening of first subject rather than at site activation where the minimum window between screening and randomization is longer than the lead time required to order dispatch and deliver a shipment); JIT labeling or JIT product manufacture at the point of dispatch; as well as forecasting reports and supply-chain simulations.
Pooling can be an effective strategy in some cases (1) to significantly reduce the quantity of supplies required to conduct trials. Supply pooling uses the same product batch across multiple protocols or development programs. In the pooled supply scenario, product is manufactured and labeled for a program of studies instead of a single trial. The product is not assigned to a specific study until ordering to site (for depot pooling) or at the site at the point of allocation (for site pooling). Pooling techniques can be used with investigational medicinal products (IMPs) as well as concomitant or comparator medications and devices. Supply pooling maintains flexibility in the clinical supply chain and can be conducted at a depot or site level. At the depot level, supplies are released for multiple protocols. The consignment generator runs against these protocols, identifying supply needs for new and existing subjects within a prediction window and matching the identified needs with product batches that meet can fill those needs. This pooled ordering process can significantly cut down on manufacturing quantities required to support a clinical development program covering multiple trials.
Pooling also has an impact on labeling requirements. For example, depot-level pooling does not require that sites are approved for multiple protocols within a program. Rather, orders are placed independently for each study. The IRT assigns a protocol to the product at the point of ordering. This typically requires a JIT over-labeling capability as the protocol is added to the product label at the point of picking for dispatch to the receiving location. Expiry may also be added to the label at the point of dispatch (as there could be different expiry dates for each country release, or for storage and shipping such as with product that is stored frozen and thawed prior to shipment). Another approach consists of adding multiple protocols to the product label, though they must be individually approved for each destination country (2). This approach requires careful planning and does not account for any unknown protocols at the point of label creation or the risk that some protocols could be subsequently suspended.
Site-level pooling represents another strategy. Here, product is ordered to sites that could fill requirements for multiple protocols. The product is available for multiple protocols but is assigned to a single protocol at the point of subject allocation. Depending on the label language, additional label content may be required, for example, over-labeling with the protocol where the base label includes only a program or product identifier. However, sponsors may also add multiple protocols to the label. The limitation of this approach applies to both depot and site product pooling, in that it does not account for unknown protocols or the risk that some protocols may be suspended. One possible solution is to employ JIT over-labeling at the site, an approach that requires careful control. However, site pooling offers the ability to maintain a common buffer stock at a site for multiple protocols, thus potentially reducing the net quantity of product required to be on site (adjusted for overall site activity) while maintaining adequate stock on hand to prevent stock-outs. Of course, this approach offers little benefit if receiving sites are not participating in multiple protocols. Also, the product may require a supplemental label at site at the point of allocation via IRT. However, where and when this method is appropriate, it can reduce overall product quantity requirements.
Typical IRT system requirements for supply pooling include:
- Lot release
- QP management (or country release)
- Expiry management per protocol/country
- Program and protocol level inventory reporting
- Program and protocol level ordering availability
- Flexible product approval options for study, country, and depot
- Ease of use in selecting and modifying changing supply strategies
- Integrated drug accountability application
- Program level forecasting and simulation options
- IRT system scalability and flexibility to adopt additional protocols.
Planning is especially important when considering pooled clinical supply manufacturing and management. Sponsors should ask questions to determine, product, process, and organizational readiness. Factors to consider before pooling include:
- Do formulation, packaging, and stability data support a pooled approach?
- Is there a common packaging and global labeling platform? (3)
- Anticipated protocols countries, sites, and subjects participating in the pool
- Cost/benefit analysis—pooling may not be a benefit for every trial
- Stakeholder acceptance and readiness
- Protocol design
- Protocol timing vs. current product stability data
- Shipping units vs. allocation units
- Implications of variable pack life across protocols
- Regulatory acceptance
- Labeling strategy and capabilities
- Impact of dose adjustments and titrations
- Drug accountability requirements
- Additional training needs
- Compliance issues
- Risk management.
Additional IRT systems
Careful consideration should also be given to other IRT configurations that maximize efficient stock utilization and extend supply chain flexibility. JIT ordering is based on site enrollment activity rather than approval. Another option is “rancode look ahead” for trials with site stratified rancode. Here, the consignment generator will select kit quantities and types matching the next available entries in the rancode rather than using static buffer requirements for every site. Another technique involves implementing allocation substitution rules. For example, a sponsor could allocate 2 x 20-mg packs in lieu of a 40-mg pack. Clearly this approach has practical limitations and must not be used in cases where the study blind could be compromised. For some protocol designs, however, it could be a viable option. Additional options include use of e-label smart device applications to verify product expiry, status, protocol availability, and usability on-site or point of allocation or during storage. There is also some interest in using such applications by subjects to improve compliance. These applications may rely on a BYOD (bring your own device) model and should work with various operating systems such as IOS, Android, or Windows Mobile.
Product pooling has implications for product manufacture and labeling as well as IRT design. When used appropriately, however, a pooled supply approach for the right product, at the right stage of the development lifecycle can improve supply chain flexibility when managing large development programs through a reduction of required product quantities and product types. One method will not work for every scenario. It is important for sponsors to work with an experienced IRT provider to define program requirements and ensure that system design aligns with program goals and to effectively mitigate the “unknown unknowns” as much as possible through careful planning and risk management.
1. D. Reige and E. Tourtelotte, Applied Clinical Trials (April 1, 2008), http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/Articles/Drug-Pooling-Power-and-Pitfalls/ArticleStandard/Article/detail/506849, accessed May 14, 2014.
2. MHRA, Good Manufacturing Practice: Investigational medicinal products (IMP) FAQs, Question 23, http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/FAQ/IMP/#q23 , accessed May 14, 2014.
3. C. Hall, Pharma Focus Asia, Issue #8 (2008), http://www.pharmafocusasia.com/clinical_trials/clinical_trial_supplies.htm, accessed May 14, 2014.