If you’re running a clinical or preclinical study, there are many components that you need to think about, plan, and execute. One is “what the heck do I do with these samples we’re collecting” – especially if they’re rare or limited. But even if samples are not rare or limited, you still want it to go well. We’ve seen our fair share of shipments go sideways, and want to impart some tips to make your job easier and your study go smoothly. I’ll talk about coordinating between the Bioanalytical/Biomarker (BA/BM) and Central Labs, Pharmacokinetic/Pharmacodynamic (PK/PD) collection kits and lab manual/instructions, chain of custody, temperature control, documentation, and permits for domestic and international shipping for preclinical and clinical single-site and multi-site trials.
Whether you have samples sent directly from the clinical site to the BA/BM lab or routed first through a Central Lab depends on a few factors – single-site vs. multi-site, budget, sample stability and the team’s past experience. For an early clinical study being conducted at a Phase I Clinical Research Unit (CRU), the staff at the CRU is likely well experienced with handling a variety of types of samples and are familiar with coordinating shipments going to multiple analytical labs. Even for some multi-site studies, it may be preferred to have samples shipped directly from the site to the BA lab because of stability concerns or the cost of a middle-lab acting as depot is prohibitive. Either way, a few things to think about are:
(1) Which lab will draft the sample processing instructions/manual,
(2) Who will obtain sample processing materials (vacutainers, cryovials) and shipment materials,
(3) When/how often will the shipments occur to the analytical lab, and
(4) When will the analysis occur (immediately upon receipt or batched).
SAMPLE HANDLING INSTRUCTIONS
The PK/PD Laboratory Manual describes who does what and how it should be done. It’s particularly important in multi-site trials so that there’s consistency between sites. The qualification or validation experiments the BA/BM lab performs on the assay investigates a number of variables which can influence the processing done at the site, therefore the BA/BM lab should provide the instructions.
The manual is specifically designed for each study protocol and includes instructions and documents required for notification, sampling, storage and shipment of samples from the collection site to the analytical site, including the:
- Instructions for the collection and processing of samples
- Details and instructions regarding labels
- Storage requirements
- Sample shipment instructions
- Shipping Materials (shipping containers, DOT labels, sample manifest form, packaging materials)
You’ll want to be sure the laboratory at the clinical site is well prepared and capable of performing all of the tasks involved in the processing and shipment of the samples. The manual should also include instructions on the sample manifests so that samples can be easily inventoried and to limit queries after the samples arrive at the BA/BM lab. As is the same with many things in life – doing it right the first time is much easier than trying to fix it after the fact.
PK/PD COLLECTION KITS
Whether the site or the BA/BM lab, or the Central Lab is providing the collection supplies, kit materials need to be on-hand to process the samples. KCAS typically includes the following items in the PK/PD collection kits:
Sample collection supplies (depends on matrix), example for plasma/serum:
Study specific labels
Sample collection sheets
Training and on-call support
Instructions and preferred logistics carriers
Additional information can be found at KCAS’ virtual lab manual
TEMPERATURE CONTROL / COLD CHAIN
You’ll want to think about making sure the samples are not compromised as they’re transported from the patient to the lab bench. This cold chain of custody instructions should be driven by the BA/BM lab. Things to think about are:
- Is the clinical site and every facility the sample will be held capable of not only storing the samples at the right temperature, but the temperature is tracked and monitored during the entire storage duration?
- Will you use tracking devices (sometimes called temperature maps) in the boxes to measure and record the temperature as samples are shipped from site to the lab?
- What shipper will you use? KCAS has preferred shippers that we recommend, depending on the origin of the samples and budget.
- How will you mitigate risks and ensure the temperature remains constant during shipment? What happens if the samples are hung up at Customs offices or delays occur during shipment due to weather?
DOCUMENTATION AND PERMITS
Different countries require different import and export permits. Studies conducted around the globe require a well versed Clinical Sample Logistics group to coordinate and limit delays or rejected shipments.
Many Sponsors apply for permits to import their Drug and/or Device, but fail to realize that an import permit is required for PK/PD Collection Kits as well. Permits vary within each country so it’s important to investigate what permits are required in each (and every!) country. Applying for permits can be quite a timely process… plan accordingly. In addition to the permits, most countries in the EU are now specifying clinical collection supplies (vacutainers, phlebotomy supplies, cryovials etc.) are required to have CE Marking. Accompanying the CE Marked items, a Certificate of Conformance is required to be provided as part of the customs entry. These certificates are provided by the manufacturer of these goods and can be located on the manufacturer’s website.
To import the supplies, the Sponsor or managing CRO acts as Importer of Record in each country. This can be the clinical site in single-site studies, but rarely in multi-site trials. The Importer of Record completes paperwork in the language spoken in the country. This paperwork can be simple or complex – every country is different. In some cases, hiring a broker to clear the shipments, while more costly, can be effective at expediting shipments, especially in challenging countries. These brokers use the sponsor’s VAT and EORI number to facilitate the clearance process. In any case, whether or not a broker is used, having a VAT and/or EORI number is necessary to clear customs. The countries in which the Sponsor is importing supplies requires this. Taxes need to be collected. If there is not a designated person or entity assigned with a VAT/EORI number, taxes will not get paid and shipments will not get released.
Alright, you’ve gotten your supplies into the sites, and have collected your samples. Now you want to get them out to your BA/BM lab. Depending on what is being sent and the originating country, the importing lab may need an Etiologic & Agent Import Permit from the CDC or Fish & Wildlife Permits for CITES listed animal studies. KCAS’ Clinical Sample Logistics team is IATA trained for the shipment of dangerous goods and manages everything from study specific sampling manuals to detailed labels to ensure that these and FDA/GLP/OECD regulatory compliance is met.
We have customers that, for reasons of patient availability or regulatory efficiencies, conduct studies in (as example) Mexico, Eastern Europe, Central/South America, or Australia. These are sometimes “one and done” studies, returning to the US for later phase studies. Sometimes sponsors prefer to have the Bioanalytical and Biomarker testing done in the US to ease communication and to facilitate long-term sample storage. It’s important to KCAS that we support our clients throughout the entire drug development timeline – discovery through NDA and beyond. We’ve positioned ourselves to be both nimble and efficient, yet experienced in providing kits and receiving samples from around the globe. Our clients appreciate that our Clinical Sample Logistics team is just down the hall from the scientists analyzing the samples. It saves time and preserves the sample integrity from collection from the patient through the dataset delivered to the statistician.