Kit-form clinical trials

Two decades ago, the largest clinical studies would have included around 1,000 patients in two or three countries, lasting several months. Today, many studies are in the tens of thousands in patient size and span the globe, incorporating 40-50 countries simultaneously and progressing for several years. As the global marketplace continues to expand, the demands and complexities of planning and managing these studies will continue to increase.

The challenges are immense and, with the ever-changing regulatory requirements that must be negotiated across regions, varying import regulations, control of expiry dating and comparator supply issues, the level of complexity appears almost insurmountable.
Much of the success in managing supplies for large clinical trials has been due to the improvements in information technology along with other key developments. However, to successfully work with these technologies and manipulate them requires experienced and highly trained individuals, attributes not typically accounted for, due to the fact that outside of these teams, very few understand what is required of the clinical supply manager or how the supply chain is maintained.

The challenges, although they appear as individual components, are very much related and interactive. They can be categorised as follows:

• planning: communication with internal and external partners
• drug supply: availability of drug and comparators, consideration of blinding requirements, associated stability, and patient kit design and packaging
• technology: interactive response technologies (IRT), and forecasting and simulation software
• labelling: multilingual booklet labels and supply flexibility
• distribution: import andexport requirements, and temperature monitoring.

At the outset, the relationship with internal and external teams is critical to develop a clear plan to support the supply chain, and communication is key. The importance of effective collaboration with regulatory, quality, CMC and clinical departments, for example, is fundamental in obtaining the information that drives and supports the planning of an effective supply strategy. Additionally, and no less importantly, communication with vendors in translating the information into patient supplies is paramount.

In the case of relatively large studies, it is likely that drugs will be available in limited quantity, and understanding these limitations in communications with CMC and/or formulations is crucial. In dealing with the clinical groups, the requirement for reasonable recruitment forecasts then becomes imperative. A poorly forecasted recruitment rate for a study may result in the limited drug supply being shipped to countries where recruitment is low, while the real areas where there are patients being actively recruited leaves such areas in short supply. Hence, while having absolutely accurate forecasting is not the expectation, it should be expected that some form of reasonable recruitment forecast should be available to provide for an initial ramp-up of patients into a study. It is just as important for clinical supply teams to ensure all parties understand that their needs and time impacts on decision changes or late changes in strategy.

Once a study is underway and initial recruitment has begun, it then becomes critical to ensure that the planned clinical supply strategy not only maintains existing patient supply but allows for ongoing recruitment, new site initiations and even dose amendments or study extensions as the trial progresses. The method of monitoring the study and communicating amendments and production requirements both internally and with vendors to ensure the supply chain is maintained is very often a significant challenge and highlights the importance of having highly skilled project managers.

Too often, important information is missed due to lack of communication or lack of understanding of the importance of what may be perceived as minor details. As an example, the types of comparators that may be required in head-to-head studies may take significant time to source in the marketplace. Additionally, such comparators may be required to be multisourced from various regions because formulations can differ from one region to the next. The overall timeline to source these supplies, potentially blind them, package and convert them into patient kits, along with the requirement to supply supporting stability data, may be so long that the expected time to initiate the study becomes problematic. The impact on studies, especially those that have seasonal variations, could cause significant delays if start dates are not met, not to mention the damage to the company's desired strategy and increased expense.

The shortage of comparator supplies in the industry has gained the attention of the health authorities as well as industry in general as it adds to the challenge in supporting clinical programmes and many conferences have focused on this because it continues to present a significant problem to the industry.

The kit parade

Often the patient kit itself can present a huge challenge, but when it comes to designing the optimal kit, the model I always use is to place myself in the shoes of the patient. What would be acceptable with regard to portability of supplies? How easy will it be to comply with taking the medication? Is the dispensing practice amenable to the patient's condition? And I always keep in mind the regulatory requirements.

The rule of thumb is, if the patient kit can fit into a handbag or a coat pocket, then it becomes much more user-friendly. The types of packaging materials to use are dictated by the characteristics of the investigational compound and the stability of the product itself. For blinded comparator use, additional stability must be performed to demonstrate compliant product/material interaction.
The earlier the involvement of the clinical supply teams in the strategy and information flow, the better the chance of providing optimally designed supplies to support compliance and efficiencies.

Blinding supplies may be as simple as over-encapsulation, commonly used with oral formulations. For other dosage types, the blinding process and supply of matching placebo may be much more demanding, for instance meter dose inhalers have been blinded in the past by use of snap-on devices (not always the best solution, as they can be snapped off) and for other products such as syringes and vials, label removal and application of new labels has been achieved. However, in some cases, the preparation of a matching placebo becomes more difficult where a syringe or vial is patented for a particular product, hence the supply of a truly matching placebo becomes a much more difficult task. These issues, along with the need for long-term stability required to support expiry dating, makes the time line much longer, impacts study start times and can even effect the overall protocol design.

An added complexity when running blinded studies is maintaining the blind in the study throughout the duration of the trial. Because the blinded study is built around statistical analysis, any possibility of bias introduction can impact study results, hence, even the print quality of labels and their position on the kits can present a significant issue. The last kit produced in a study should exactly match the first kit produced even though they may have been prepared several years apart from each other, and one could be the active supply while the other is the opposing placebo.

Much of the operational work runs in parallel but the challenge to meet timelines is dictated by multiple issues. Looking at oral solid products and the tooling requirements for blister-packaging equipment for instance, can only occur once there is an overall kit design. This will be based on criteria such as the draft protocol design, agreed patient dispensing visits, stability and patient considerations, to name a few. Once tooling designs are in place, the acquisition of tooling can vary from 2-4 months. Any blister card designs and cartons will be additionally required, and purchased in parallel. In consideration of the blistered supplies, the US requires child resistant, senior friendly packaging, which can add to the complexity, cost and lead time. Where titration kits are required, or where mixed feeding of multiple products (all identical in appearance) into the same blister strips is required, then the complexity increases by a significant order of magnitude.

There are many challenges associated with the distribution of clinical supplies around the globe. As an example of some of the issues the importation requirements vary from country to country. Brazil requires each shipment to that country to have a pre-notification on the physical characteristics of the shipment including weight and dimensions. After a two to three-week period, following the submission, the shipment may then be approved. Once approved, the shipment period to Brazil can then be as much as ten days and this only gains access to the country depot. From there, the shipment must be broken down to accommodate site shipments.

All told, this can amount to a two-month transit time, hence accurate forecasting requirements of how much supply is needed, and where and when it is required, in order to maintain patients in the study, is essential, and leads us back to the overall clinical supply plan and strategy. Of course not all countries have this importation requirement, some are much more complex, with periodic renewals of import licences and long processing times, while others have no import restrictions, but while all of this must be built into the supply plan countries can, and have, changed their requirements during the course of a study, and such changes may include no legacy period.

Additionally one needs to consider the temperature control of the shipment between depots, sub depots and sites, and proper storage and monitoring at those sites. Certainly the health authorities are becoming more interested in how drug supplies are controlled during transit and storage, and the use of recording systems in the industry, while a common practice, is not always used. Hence, justification of not using such items will be required. However it has often been the case that the failure to follow temperature-controlling procedures has resulted in loss of drug supply following transit, or at sites due to poor monitoring of storage requirements.
Then we have to consider the labelling of supplies. In the past, single panel labels with one or two languages were the norm.

Nowadays, as we are simultaneously treating tens of thousands of patients across the globe, there is a need to have full flexibility of each patient kit such that any kit can be shipped anywhere in the world and dispensed to the right patient in the right dose at the right time. In order to support this need, the booklet label was born. By having all languages on one label, in a booklet form, the label provides the flexibility needed in the drug supply chain. The difficulty in obtaining booklet labels in time to support the drug supply need is in having all the languages accurately translated and all regulatory statements that are required for each country.

Time and again

Typically, four to six months is required just to have labels available, although often the initial supplies may commence with a single panel label then switch to the booklet form due to lead times and accelerated study plans. After performing this immense task, what can possibly go wrong? Lots. For instance, a regulatory authority may make changes, in which case the label must change or the clinical team may decide that a few extra countries should be added to the study after initiation. The latter may be dealt with without having a change to the existing label, in that a second set of labels can be generated; however, now control of inventory becomes more complex because there is a need for segregation of supplies and a more complex supply strategy.

Technology has played an important role in the globalisation of studies. Interactive response technologies (IRT) sometimes referred to as IXRS or IWRS refer to the use of computer and/or telephone systems to support drug supply and drug dispensing at the site level. The advantage of such technology in the supply chain is in supporting the control of product such that no expired or expiring patient kit supplies should ever be in a patient's possession. Additionally, because the IRT system controls and records dispensing at the site, the feedback to the supply chain allows recognition of which kits are required at each site and the numbers of patients, leading to better inventory control and drug supply management to assist in controlling overages in the study and streamlining distribution lines across the globe. The challenge when setting up such systems is in generating the user specifications that form the process by which the logic of the system operates. It is a case of rubbish in, rubbish out (RIRO), and requires technically competent staff to set up and qualify the system. Because the system controls dispensing and records patient dosing, significant savings and efficiencies can be gained.

However, because it is a reactive tool, the CS team must use reports in order to assist in forecasting the downstream requirements of the study and hence contribute to the overall strategy. While the IRT system cannot forecast, other systems are available in the marketplace that can assist in forecasting strategy and integrate with the IRT systems. These systems are often referred to as simulation and forecasting software and, although they can be very useful, this is only true if data is first available for uploading. Where it can be of huge assistance is in identifying the impact of various changes, providing forecasted risk analysis and identifying opportunities for improved distribution to support the needs of the study. Again, the simulation and forecasting tools are subject to RIRO, so educated and trained staff members are hugely important.

The majority of studies require labels to have expiry dates updated on labels while the supplies are at depot or site, due to ongoing stability data. This is a huge task, given that supplies could be at hundreds or thousands of sites across the globe. Notwithstanding the regulatory control, the requirement to label (a GMP process) at clinical sites (GCP controlled) is a significant undertaking. In recent years many companies have been able to obtain approval to remove the need for expiry dating and demonstrate control through IRT, however this is not an automatic allowable process. Indeed where it has been successfully allowed in the past the same companies have had subsequent requests rejected.

Slowly, however, it appears that the authorities are warming to the process and further enhancements to efficiencies such as pooling of supplies across multiple studies are gaining momentum. Pooling allows patient kits to be available across multiple studies, but be controlled by whichever study they are assigned at the time of dispense. These two initiatives not only save on costs and effort, but are also arguably able to provide better control over dispensing and accountability.

While these are broadly the issues faced by clinical supply organisations, they are really a very light flavour of the problems being dealt with on a daily basis. Hence, there is a need for constant development of supply management strategies and ongoing improved relationships with health authorities, as well as the provision of education to improve mutual understanding.