Packaging
randomisation across different sites and international borders, and the importance of a detailed packaging strategy becomes clear. Bruce Hastings, managing principal at De Mi Tierra Consulting and a former director of process technology at Amgen, highlights three fundamental mistakes often seen during packaging design for clinical trials. “A lack of planning, combined with tight time restraints, can often lead to research teams accepting a less than optimal design,” he says. “Secondly, a basic lack of understanding of the users, their needs and a failure to design for them can affect outcomes. “Thirdly, there is often a lack of optimal packaging – in terms of volume – that is qualified and production-ready.”
Protecting trial integrity
Helping to preserve the integrity of a trial should be a fundamental objective of packaging. Poor packaging can inadvertently ‘unblind trials’ and put years of research and investment at risk. A slight variation in the colour of a placebo packet compared with the product packet, different adhesives, or shortcuts on labelling can all affect trial outcomes. Hastings says trial participants often go to extraordinary efforts to identify whether they are being given a placebo or the trial drug. “You would be amazed how they try to defeat efforts to keep them in the dark,” he says. Sub-standard labelling or using a label and adhesive combination that is not aggressive enough is a common error. To protect trial integrity, however, medication must not only be blind to patients, but also to medical practitioners dispensing the drug and placebos, and to researchers analysing the results. Medications and placebos, along with all components and materials used in packaging – including blister packs, bottles, closures, caps, vials and ampoules – must be identical. Supplementary materials used during modes of administration, such as syringes or injection pens, must also be foolproof. “The packaging demands typically depend on the trial phase you are in,” explains Hastings. “In the phase 1 – and sometimes into phase 2 – packaging tends to be very basic, and typically based on the manufacturer’s existing capabilities and pack options.”
Hastings says that while there is no obligation to progress or develop packaging as a trial advances, phase 3 can provide sponsors with an opportunity to road-test commercial primary packaging in real- world environments.
“This is a marvellous opportunity to gain some insight from users, and it can be invaluable in
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Trade-off between blinding and efficiency in clinical trials
There is a trade-off between ensuring the blind and kit efficiency. To illustrate this, consider the task of supplying kits in single dispensation trials – such as trials in which a single drug kit contains a subject’s drug for the entire study. Antibiotic and vaccine trials are often single dispensation trials. Two simple supply methods, naive replacement (NR) and waste-one-kit (WOK), illustrate the extremes of this trade-off.
Naive replacement (poor blinding, high efficiency)
After a kit at the site is given to a subject, this method sends a replacement kit to the site. Because the replacement kit is of the same kit type as the kit that was used, the investigator is partially unblinded when the replacement kit is used to dose a subject. That is, the investigator can conclude that the subject who is dosed with the replacement kit and the subject who was dosed with the kit that initiated the shipment of the replacement kit are on the same treatment arm.
Waste-one-kit (excellent blinding, low efficiency)
This method protects the blind at the expense of wasting one kit per subject. It sends kits to sites in pairs: one active and one placebo. After a subject is randomised to receive either active or placebo kit, the unused kit in the pair is deactivated and a new pair of kits is sent to the site. Deactivating and not assigning the unused kit to a future subject eliminates any information regarding the used kit. A good supply strategy will fall between these extremes and ensure the blind, while minimising the
number of kits that are needed. Source: Contemporary Clinical Trials Communications
the design of the secondary packaging in terms of facilitating intuitive or correct use,” he says. “The big difference in phase 3 is that it is about user interface – do we need a design to assist in titration? What are the needs in terms of blind- testing, serialisation or comparative studies? These can all change the secondary look.” He says these requirements in a clinical space can be very different to the demand of a future commercial space.
Serial offending
Serialisation is another core consideration during each of the trial phases, and is key to tracking medication use and recording test results. Without a protocol to safeguard data, it is impossible to safeguard trial integrity. Hastings says missing serialisation numbers or the misinterpretation of numbers can often be linked back to poor packaging design and printing.
“A lack of planning, combined with tight time restraints, can often lead to to research teams accepting a less than optimal design.”
Attention to consistency and accuracy – especially across batches or in preparation for expanded trials – during the design and manufacturing process can help eliminate these concerns. Packaging can also differ depending on the trial requirements and goals. Labelling – and its influence on functionality – is of particular concern when combination products are being tested.
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