For a large part of the 20th century, clinical trials were disorganised and fragmented, making it difficult to obtain a truly global representation of how a medicine could perform under regular conditions. The goal of any clinical trial is to support the marketing authorisation of new drugs globally, with trial findings going worldwide.
While such moves have increased the efficiency and speed of clinical drug development, they also present a whole new set of challenges to sponsors and pharmaceutical companies, including how to harmonise the process across the world in order to ensure that frameworks and requirements across all regions are met – adding another layer of operational complexity and expense to already costly trials. The process is complicated enough when running over several regions, because each area has its own detailed regulatory frameworks or ethical needs that might dictate approval and conduct of trials at a national level.
Regulators are therefore required to work together to synchronise requirements on a protocol-by-protocol basis, and regulatory and procedural requirements must be aligned to enable concurrent trial initiation across regions and introduce common processes to reduce operational intricacy. A delicate balance must be struck between maintaining the clinical trial’s efficiency and satisfying regional regulatory requirements, while also adhering to good manufacturing practices (GMP).
Of course, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, and the Clinical Trials Transformation Initiative (CTTI) has worked towards achieving this. Its aim has been to progress and drive the adoption of practices that will increase the value and efficacy of clinical trials. The CTTI in particular seeks to create a patient-centred system that is efficient and reliable, and allows timely access to evidence-based therapeutics prevention and treatment options.
More than meets the eye
How an investigational medicinal product (IMP) looks can be incredibly important in a clinical trial; after all, a pharmaceutical company or sponsor wants trial participants to see the test through from start to finish to see exactly how the drug performs and whether it has any side effects. Not only does the packaging have to be user-friendly – easy to open and labelled with clear, precise directions on how to take the medication – it must also display a professional appearance, while adhering to the rules and regulations governing medicines and clinical trials.
The packaging needs to be designed for function, keeping in mind the end user – specifically the trial participant. The IMP needs to be accessible, so it may be necessary to offer different types of packaging to cater to a range of different users and their abilities; a blister pack or vial/bottle depending on the dexterity of the participant, for example. It is also important to choose the correct material for constructing the packaging: one with the ideal characteristics – for example, moisture permeability – to avoid adversely affecting the trial drug.
The global nature of today’s clinical trials means that medicines are directed to multiple countries, each with their own requirements and regulations for packaging and labelling. Some regions within a country even have specific labelling requirements and wording, meaning that flexibility is needed in terms of what is printed on the label, as well as what that label is stuck to.
But it isn’t just the bottle or blister pack that an IMP arrives in; how these are packaged, stored and transported is also significant. What if the medicine is temperature-sensitive, and could be destroyed by either too cold or too warm a temperature? Greater numbers of trials are using biopharmaceuticals, or advanced cellular and gene therapies, and in such cases the environmental conditions must be carefully and stringently controlled to preserve the IMP’s efficacy. Variations in temperature during their storage, handling or distribution could not only affect the quality and efficacy of the product, but the data created for clinical trial evaluation, too – while at the same time presenting a substantial safety risk to the trial participant.
“Given that the primary aim of investigational drug intervention is to provide the right drug to the right participant at the right time, it’s not surprising that drug shipment and delivery play a critical role in achieving this intention,” explains Dr Wynand Smythe, Investigator for Lead Projects at the Clinical Research Centre at the University of Cape Town, South Africa. “At our research centre, the most noticeable changes in IMP packaging and shipment have been observed in the supply of cold chain products.
“Packaging material used to maintain cold chain has changed from the typical single-use frozen gel packs through to the reusable solid-plastic ice packs and currently to the new-generation phase-change materials,” he continues.
Packaging has an increasingly important role to play in maintaining the temperature of shipments. It can vary from a passive and custom-designed container for a specific application to an active container able to heat or cool an IMP when necessary.
Products might also be shipped in different forms of packaging material, such as dry ice, liquid nitrogen or a phase-changing material, depending on what is most suitable.
“Similarly, temperature data-loggers accompanying the cold chain products have changed over time,” explains Smythe. “Initially we received single-use loggers that required shipment back to the supplier to download and confirm IMP stability. Presently, we receive loggers that our site uses to download data and confirm IMP receipt and integrity with the supplier – for instance, when there is no need to ship the logger back to the supplier.”
Get physical
Storage and transit temperature records are two of the many details that need to be maintained in order for suppliers to show adherence to the trial protocol, and ensure the credibility and truthfulness of data. The packaging of an IMP during shipment needs to maintain the integrity of an IMP prior to dispensing to participants, states Smythe, adding that typically, the primary, secondary and tertiary packaging maintain the “physical” integrity of the IMP, while ancillary packaging typically maintains the environmental conditions such as temperature and/or humidity of the IMP that it carries.
In order to maintain the stability of an IMP, Smythe believes the most logical solution to the problem would involve manufacturing a more stable IMP, not necessarily relying on packaging that protects its physical and environmental properties.
The increased globalisation of clinical trials, and the subsequent problems in distributing it worldwide, can cause delays in participants receiving medicines on time.
Global trade regulations can be a challenge as they can prevent movement of supplies between sites, delay deliveries and even unblind trial supplies. The problem could be the result of delays in customs-clearance processes, a lack of distribution capacity and poorly established distribution lanes.
“Notably, our site’s greatest challenges in supplying participants with an IMP unexpectedly involve administrative challenges such as transit times through customs – for instance, on occasions an IMP may be held up at customs, resulting in it being exposed to conditions compromising its stability,” says Smythe.
Smythe also notes, “the interactive web-response systems that some of our sponsors use to supply an IMP to our study site: the automated systems ensure that our site is resupplied with an IMP either when the IMP is dispensed [used] or about to expire”. Such a system could ensure a suitably adequate supply of an IMP throughout the trial period.
But the work is by no means complete. Clinical trials, and how they are conducted, are still evolving, and the need for novel adaptive trial designs, platform trials and other forms of novel trial design continues.
Of the future, Smythe says: “I hope to see sustainable, reusable and lightweight cold-chain packaging used to maintain physical and environmental properties of the IMP during shipment. Similarly, I see ‘stable’ IMP manufacture neglecting the requirement for specialised shipment conditions.”
