Packaged for research purposes only, drugs for clinical supply escape the need for the same aesthetics associated with commercial packaging, making functionality and usability the primary objectives. The complexities of packaging drugs for clinical trials centre on the risks associated with numerous products being packed for different markets and clinical sites, meaning that a full understanding of global regulations, the inner workings of clinical trial protocols, as well as the specifics of varying study designs, is fundamental in ensuring the right packaging strategy is adopted for every product.
Colin Newbould, director of regulatory affairs and QP services at the Wasdell Group, addresses the main considerations for sponsors in packaging drugs for clinical trials. He also summarizes the challenges that are faced relating to blinding, randomizations and patient adherence, as well as discussing how new approaches, such as just-in-time labeling, are providing welcome solutions to some of the industry’s challenges.
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Blinding and randomization
In 2002, the World Health Organization (WHO) [1] published guidance on clinical trial packaging which highlighted the major differences when compared to the development of commercial packaging. These included aesthetics vs usability, high vs low volume and the variances in storage and logistics when a product is not being created for market. Another significant difference is the need to manage the process of blinding and randomization across multiple trial sites. This is made more complex when sites are spread across different countries and subject to different regulations.
Blinding is an important process to ensure that patients, study teams and the physicians involved in a trial are unable to differentiate between placebos and the active drug. It is a prerequisite that packaging suppliers keep accurate records of the placebo drugs that can be quickly accessed should a medical emergency occur (‘unblinding’). This comprehensive data should be stored in an effective system that can be updated by different users as necessary, without compromising the security or validity of the data.
The task of hiding a product’s identity is a complex process. For example, if the product is an injectable in a double-blinded study, the sponsor would be required to develop pre-filled syringes with two identical liquids that behave in very different ways. Packing of these products would also need to be the same and the packaging in comparator studies also needs to be matched.
The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [2] emphasises that modifying packaging or implementing repackaging is an efficient approach, although this does create significant waste.
Another vital step in clinical trial packaging is the process of randomization. This step prevents selection bias occurring between patient groups which could lead to inaccurate results and could compromise an entire study. Most widely used in later stage trials, companies are required to deal with larger volumes [3] while still ensuring that they are dispatched to sites in a way that protects their identity.
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Planning for patient compliance
The WHO advises that the packaging of drug products for clinical trials plays a fundamental role in making sure that patients remain compliant for the duration of a study, while also delivering important information to study teams [1]. Its guidance states that packaging should make administration as safe as possible for patients. Patient-specific instructions, such as when a medicine needs to be taken, can be added to packaging, while trials that involve particular groups of patients, such as the elderly, can use packing designs that are easy to access and feature clear instructions that assist the patient to take their medication at the right intervals. As the use of smart technology and virtual trials increase, this type of packaging looks set to become more commonplace.
Smart technology varies from wearable devices such as the Apple watch to smart devices like mobile phones, tablets and sensors. Smart technology allows for real world data, such as time and movements, to be captured and used in a trial. Using this technology alongside specifically developed apps makes it possible to run trials outside of a medical or clinical research environment, and potentially allows the trial to be run from the patient’s home. The information provided from smart technology can assist in patient compliance and ease of access to medicines, which are fundamental to the success of a trial.
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The emergence of ‘just-in-time’ approaches
Deciding to embark on a clinical trial is a huge investment for pharmaceutical companies. One way of strategically negating unexpected costs is to ensure that trial supplies are prepared, packaged and shipped to trial sites more efficiently.
It is not always the most cost-effective option to have products packaged and stored far in advance of when they will be needed. Packaging largely differs depending on the conditions of the trial and the product itself. For example, the shelf life and stability of a solid dosage form when compared to a liquid formulation highlights the difficulties that sponsors encounter. Small molecule drugs can often endure temperature changes while in transit and are easier to store than large molecule products, which usually need cold chain transportation and storage. With the introduction of more biotech products, this is becoming an increasingly important consideration.
Additionally, defining the number of placebos, comparators and doses needed for each site is both complicated and time-consuming. While all trials try to forecast supply and establish the ideal participation rate, it is unlikely that patient targets will be met. It is also unlikely that all patients will remain in the trial for its duration. These factors make it complicated to determine the exact volumes required, and therefore, make it difficult to pinpoint how many doses will need to be packaged and stored in advance.
When enrolment rates differ at a site to those originally intended, a more flexible approach to drug supply needs to be adopted. Many sponsors are now opting to use a just-in-time supply chain strategy where partially packaged products are stored and then finalized for a specific trial.
The approach requires the implementation of a clinical protocol design that can use partially finished packaging. Labelling can be left until a product is about to be shipped to site, with the correct language, patient numbering data and expiration date all added at the last minute. This makes adapting to changes in country authorization, local patient recruitment and the application of expiration dates much simpler. However, in the absence of the full information needed for the label, companies must ensure that they can still adequately track and identify medicines.
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Additional considerations for the industry
Packaging design is another important consideration. While simple packaging designs for clinical study drugs generally makes them easy to blind, this becomes increasingly difficult during later trials, especially Phase III [4]. At this stage, consideration needs to be given to commercial packaging in order to gather feedback from study teams and patients. For example, in a trial involving a children’s medication, the bottle must be childproof. To avoid any costly mistakes, problems must be identified and addressed early on.
Batch size is another central consideration as the volumes of products needed for trials are often much smaller. Efficient packaging relies on companies being able to provide packaging to scale.
In addition, with serialization strategies now in place for commercial products in many counties, and with more due to come into force, regional regulators are increasingly developing their own tracking and serialization processes for clinical trials. This is to support near-commercial packaging for later phase trials, offering manufacturers the opportunity to ensure that their designs have enough space to include information such as serial numbers.
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Finally, in-depth knowledge of varying global regulations is a must for all teams working on clinical trials. This is especially vital when medicines are packaged in a centralized depot, which is often the case with just-in-time approaches.
Final thought
One of the major challenges for today’s sponsors is that the requirements of a trial may develop very differently to those originally set out in the study protocol. Having a mechanism for packaging to adjust to changes in enrolment, regulatory requirements and localization issues is becoming more vital if sponsors want to avoid these hurdles impacting on their budgets and timelines.
As every trial is different, flexibility is a primary factor in making all modern trials a success. Partnering with packaging vendors that have expertise in working with different protocols and within different markets is essential to ensure that products are in the right place, at the right time, while meeting the necessary regulatory guidelines of a specific market. Equally important is patient adherence, which can be supported by effective packaging. It is the patient data that will prove the viability of a drug and keeping patients on trial from day one through to study close is key in avoiding costly delays.
If implemented effectively, the just-in-time approach can bring greater flexibility to any clinical program. With intense pressure for better management of the clinical supply chain, it can help to scale back the amount of time and resources needed to repackage products and offer more control over clinical trial supplies, ultimately making the pathway to market more efficient.
References
[3] http://www.who.int/medicines/publications/druginformation/issues/WHO_DI_31-2_Placebo.pdf
[4] https://www.ncbi.nlm.nih.gov/pubmed/26908540