Considerations for Clinical Trial Packaging Logistics

Plan for the complete package: Considerations for clinical trial packaging logistics

It’s no secret that clinical trials require rigorous attention to detail. When discrepancies or deviations in trial execution can mean the difference between a drug’s regulatory approval and rejection, it’s essential to ensure consistency and stability across all study components.

Clinical trial packaging and kitting are no exception. Understanding the variables that impact packaging is the first step to ensuring that this logistical element will support, rather than detract from, the validity of a clinical trial. This blog will explore key considerations in clinical trial packaging logistics, and how to address them to ensure consistency throughout your study. 

Labeling

The labeling of any drug provides important information, including instructions for use, expiration dates, and warnings and safety information. For clinical trials that utilize a placebo, labels play another role: ensuring that the trial remains perfectly blinded. The validity of double-blinded clinical trials relies on neither the patient nor the physician knowing who is receiving an investigational drug or a placebo.

As a result, these two products must be labeled and packaged identically, with no discernable differences. Elements as simple as a slight difference in label color or a pattern in serial numbers — for example, placebo serial numbers always starting with the same digit — could be enough for a perceptive physician to uncover which of their patients is receiving the true drug. Packaging companies must pay close attention to detail in an effort to produce truly identical labels and packaging. Further, rather than relying on a discernable pattern in serial numbers, the labeling company should utilize a key to keep track of which doses are the drug and which are the placebo.

One consideration for labeling is when the label should be applied to a study product. Clinical trials can change quickly, especially where dynamic trial formats, such as decentralized trial designs (DCTs), are incorporated. This dynamic nature can create shifting elements in study drug labeling. Participant enrollment is unpredictable during DCTs, and which sites will require larger or smaller numbers of study drugs or kits is constantly fluid. If shifts in participant enrollment occur after labels have already been applied, products must be relabeled with the updated site information, usually at significant cost. Instead, just-in-time labeling — or waiting as long as possible before applying labels — can conserve resources and reduce the need for relabeling.

Packaging for double-blind studies

There are a number of further packaging considerations for double-blind studies. In some cases, clinical trials will be comparing a branded drug already on the market with a placebo or an investigational drug. In these instances, it may be necessary to repackage both to obscure which product is which. This adds the further need to consider what packaging will support a drug’s stability. Because often the only drug stability data available is for the original packaging, it is critical to ensure that equivalently or more protective packaging be used, or the drug’s expiry date may be reduced.

Another challenge that may fall to the packaging company is ensuring the drugs themselves cannot be distinguished from one another. There are a number of approaches to accomplishing this, depending on the drug’s mode of administration. One such method is the use of over-encapsulation, in which identical capsules are used to mask each individual pill for both the investigational drug and placebo. Other forms of therapeutic use alternative methods, such as shells to mask the color and opacity of liquids in glass containers, but the end goal is the same: maintaining the blind.

Patient compliance

One of the key roles of packaging in clinical trials is to support patient compliance, which is critical to a trial’s success. When designed well, packaging can make it easier for patients to follow trial protocols appropriately. The investigational product can be packaged in a way that makes it clear to patients what a single dose is — such as through the use of blister packs for pills or pre-loaded syringes for injectables. This clarity is particularly important for studies that involve taking multiple drugs, in which it may be hard to remember how much of each to take and when. Studies have shown that prepackaged doses, particularly blister packs, can improve patients’ adherence to a multi-drug regimen.¹ In a clinical trial, packaging can take this even further by bundling the appropriate dose of multiple drugs that are meant to be taken at the same time in the same pouch or blister.

Further, the needs of the target patient demographic should be considered. For example, elderly patients may have difficulty reading small text, so any instructions and labeling should be evaluated to ensure that it is easy for all patients to read and follow directions.

Because patient compliance cannot be assumed, smart packaging can be used to track and inform adherence to clinical trial protocols. Near-field communication (NFC) tags, which use a type of low-power, wireless radio frequency identification, can communicate with an application on the patient’s smartphone to monitor the patient’s use of a drug, such as by sensing the removal of the drug from packaging. NFC tags, as well as QR codes that can be scanned by a smartphone, are also able to provide the patient with instructions for use and guidance on the timing or dose of the medication.

Additionally, if the clinical trial involves DCT elements — meaning they do not take place at a single central trial site — direct-to-patient kits contribute to compliance. Specifically, it is critical to include all necessary materials for at-home administration and testing. Items that may be commonly available in a clinical setting, such as a blood pressure monitor, may not be in a patient’s home, meaning that adherence to clinical trial protocol can be compromised should any materials be missing. And whether the kit is provided for at-home or in-clinic use, it should be specific to the protocol, and include clear, detailed directions on how to complete each step, and in what order. 

Ensuring integrity during shipping

Protecting the investigational product. For example, drugs that are shipped as a liquid may require protective secondary packaging to prevent breakage. On top of the typical considerations for safely transporting a drug product, clinical trial kits can contain a number of materials that may shift and impact one another while they are being transported if they are not carefully secured. To prevent damage, these kits should be designed in a way that minimizes breakage and contamination. Securing kit contents is also a safety concern. For instance, without care, a needle may become uncapped during transport and present a stick hazard.

Some investigational products are sensitive to temperature, and must be kept in a refrigerated environment — including temperature-controlled shipping, as well as a preconditioned certified shipping box and temperature monitor. This means that it can be more beneficial to package and ship the investigational product separately from kits with ancillary materials. The certified shipping boxes can significantly add to the size and weight of a shippable unit. Separating the investigational product from ancillary materials (which can be shipped normally) maximizes the use of temperature controlled shipping containers, so that more units of the investigational product can be fit in one container. The drug product and the kit will arrive at the same location, and can be dispensed together. As an additional consideration, manufacturers should ensure that labels are suitable for cold transport and storage, as low temperatures can impact the effectiveness of adhesives or make some label materials brittle. 

Global trials

At a time when international clinical trials have become common practice for many drug developers, it is necessary to account for the different packaging standards and regulations of various regions. For instance, different countries may have distinct requirements of materials approved for drug packaging, or different standards for the biocompatibility of packaging materials. This can be seen in the US, Europe, and Japan’s varied classification and presentation of different types of plastic for medical use.

Labeling also falls under distinct requirements, depending on the region in which clinical trials are taking place. One example of this is the European Union Clinical Trial Regulation, Annex VI, which requires that primary and secondary packaging be labeled with the expiry date, except in specific circumstances. In the event that this information changes after packaging has been labeled, relabeling and repackaging becomes a significant undertaking — again making the case for just-in-time labeling. As another example, labels may require printing in different languages, so that they are accessible to patients in varied locales and cultures. In vitro devices have further unique labeling requirements in different regions, as seen in the new EU in vitro diagnostic medical devices regulation, better known as IVDR. 

Logistics to meet complex needs

As clinical trials grow in scope and complexity, with sponsors increasingly interested in multinational data, so too do the required logistics for these trials become more complex. This makes it more imperative than ever to have a plan in place for such elements as packaging and product sourcing and supply, reliable transportation even to potentially remote areas, and navigating import/export regulations. With multiple variables that can influence the best approach for a given trial, packaging and kit design only scratch the surface of necessary logistical considerations — but provide an important foundation for the ever-expanding needs of clinical research.

1. Shah, Gautam, et al. “Impact on Patients’ Compliance with Medication Using Prepacked Blisters for Multidrug Medical Therapy: I-COMPLY Study.” American Journal of Health-System Pharmacy, vol. 78, no. 18, Sept. 2021, pp. 1713–19, https://doi.org/10.1093/ajhp/zxab193.