Expansion Cohort Clinical Trials and Your Cryogenic Supply Chain

Posted by Cheryl Robinson, RPh, MS on Aug 17, 2016 10:30:00 AM

Clinical_Site_72-resized-600.jpgOne advantage to the traditional phase 1, 2, and 3 format of clinical trials is that it allows reasonable forecasting with regard to the clinical supply chain. This phase 1-2-3 format is rapidly changing, however, especially with regard to biological therapies, as more and more clinical trials include expansion cohorts. If you are planning clinical trials for a cell-based therapy that must be maintained in liquid nitrogen, and may potentially take the expansion cohort route, you should consider the impact on your distribution capabilities as soon as possible.

The concept of the “expansion cohort” clinical trial began in 2011, with Merck and the PD-1 inhibitor pembrolizumab. The first-in-human trial of the agent, intended for the treatment of metastatic melanoma, was initiated with the usual goal of defining dosage for phase 2 trials. However the response to the immunotherapy, all in patients with advanced stage solid tumors, was stunning, and the phase 1 cohort was rapidly expanded, both to include additional melanoma patients as well as patients with other tumors with a similar molecular subtype.

To date, most clinical trials adopting the expansion cohort design are still in oncology and are typically used for breakthrough therapies [defined as both a) intended to treat a serious or life-threatening condition, and b) as with penbrolizumab, preliminary clinical evidence shows the treatment offers substantial improvement over existing therapies]. This clinical trial design is great news to patients, as it allows much faster access to these therapies compared with traditional clinical trials. However, what does this change in clinical trial design do to your clinical supply chain?

The breakthrough therapies tested in this innovative clinical trial design are typically biopharmaceutical agents that require maintenance at specific temperatures. Manufacturing can be a limiting factor with regard to the number of patients enrolled, and those running the clinical trial are critically aware of the production limitations. However, the time required to expand shipping and distribution capabilities in order to keep up with patient enrollment can escape notice.

Adding 10 to 20 patients at a time will typically not overwhelm shipping department staff. The issue is not manpower, but the availability of the specialized shippers, which must be purchased and qualified/validated for use. Purchasing and validating the dry shippers for distribution of these therapies can take time—from four to seven weeks, and this assumes that the pack-out (the racks used to hold the doses, and the number of doses shipped) and validation protocol does not change.

If the clinical trial began with US sites only, and the expansion cohort includes new sites overseas, shippers may need to be re-qualified to account for the additional time needed for transit and to clear customs, as well as seasonal variations at the additional sites. These changes in number and location of patients enrolled can potentially require an overhaul in your distribution system, which can take months instead of weeks.

The number of patients and location of the clinical sites are not the only variables you need to consider. Additional factors that will challenge your distribution infrastructure:

  • Sites that do not have liquid nitrogen storage capabilities will need to keep the dry shipper for storage of a patient dose until it is administered.
  • Clinical staff may not consider returning shippers a priority, resulting in additional delays.
  • Autologous therapies may require patient-specific shippers, increasing the number of units needed.
  • Shippers may be returned damaged and have to be repaired and re-validated or replaced.

All of these elements take valuable time that can result in delays in your clinical trials. At the same time, taking shortcuts with shipping and distribution can result in temperature excursions, which can threaten patient safety, treatment efficacy, and the integrity of the entire protocol. Bottom line—as you plan additional enrollment, don’t forget to keep your shipping department in the loop.

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