The constant drive for efficiency has become an essential element of any business process, across all industries. In the development of pharmaceuticals and biologics, where target patient populations are often decreasing and the cost of developing a drug increasing, such initiatives are familiar, including quality by design (QbD) and advanced product quality planning (APQP). Each place increased emphasis on upfront planning, which although may be viewed as costly in both time and money, can lead to multiple time and other resource savings later in the drug’s development.

Planning for the efficient and accurate supply of clinical trial material as the study progresses is one area where upfront planning is becoming more important. This reflects the growing number of trials, their increased complexity, and the flexibility that is more commonly being built into trial design. Later stage trials are often global in nature, and due to their scope and scale require thoughtful planning. For studies involving sensitive biologics or that target very narrow patient populations such as in the case of rare diseases, the distribution of the necessary supplies to the clinical sites may be especially time critical and can often face additional challenges such as the need for specialty handling or proactive management of very short expiry dated materials.

As a molecule progresses through clinical phases, diligent upfront planning can assist in ensuring that challenges and potential pitfalls can be addressed quickly and that resources are used efficiently.

The number of clinical trials underway, in all phases, continues to increase year-over-year, with particularly robust growth over the past two years in phase 1 trials. This rise is fueled by more and more companies becoming involved in drug research and development; many of these are small start-up or spin-out companies that are now ready to take their potential therapies beyond phase 1 studies but often lack the necessary experience, infrastructure or internal expertise to do so.

A 2017 Pharmaprojects report¹ showed how the number of development companies engaged in clinical trials had doubled in the period 2007-2017, to a total of nearly 4,000; the number of molecules being investigated in clinical trials had risen from nearly 8,000 to 15,000. There were over 2,250 companies with only one or two molecules in the clinic, suggesting these to be small start-up organizations, who may only take their drugs only as far as phase 1 before seeking a partner or licensing them for further trials and on to commercialization.

Efficient planning and management of clinical supplies can be challenging for trial sponsors, especially those with smaller internal teams or fewer resources. Challenges can include understanding and managing the increased pressure from government regulators, like the U.S. FDA and the European Medicines Agency (EMA), on quality requirements, and how to move clinical supplies between countries.

In 2017, Catalent undertook a survey² to assess the perspectives of executives and key stakeholders within the trial sponsor arena, as well as clinical research organizations (CROs), healthcare institutions, research institutions and consulting firms. This revealed that sponsors and service providers alike all face challenges in understanding and effectively managing the clinical supply aspect of their studies, regardless of the size of the organization.

The most difficult aspects of clinical supply for respondents were the regulatory challenges of importing/exporting materials, including understanding the role of the Qualified Person (QP)³ in the UK and Europe, followed closely by manufacturing/blinding challenges and supply planning and forecasting. Other important issues rounding out the list of challenges include maintaining timelines, budget concerns, and having clear, consistent and effective communication among all stakeholders.

As clinical trials progress through the various phases they become increasingly complex as the number of patients rise, sometimes from fewer than one hundred to thousands, and the number of clinical sites expands from a few to several hundred across multiple regions and countries. As new clinical sites, regions and patients are added, further planning uncertainties are introduced, import/export regulations may change and complex temperature controlled supply chains may be required. But implementing an optimized clinical supply strategy can help to eliminate, or at least reduce, many of these concerns which is why preparations should ideally start at the earliest planning stages of the trial.

There are many factors that influence the complexity of clinical trials, and some of the more common ones can be summarized as follows:

• Number of treatment arms and dispensing kit types;
• Complex study design (e.g., blinded, titration, dose escalation, cross-over, cohort expansion, adaptive);
• Number of clinical sites, patients and supply depots;
• Shelf life of shortest dated product;
• Comparator drug and value of dispensable unit;
• Number of ancillary supplies to be managed;
• Controlled substances, potent or dangerous goods hazard status; and
• “Just-in-time” or “on-demand” packaging and distribution.

Phase 1, first-in-human trials are relatively small, and at this stage the manufacturing quantities are generally not an issue. Even if kits need to be manually assembled the task is usually manageable because of the small quantities involved. Also, since the duration of this phase is relatively short, proper planning can ensure that the shelf life of the investigational medicinal product (IMP) is not as much of a challenge as in later phase trials. But a low volume of kits with many variations could mean that the cost per dispensing unit could be higher than some sponsors expect which can place considerable pressure on often already tight budgets.

During Phase 1, the dosage form may bear little resemblance to the final commercial form. Several considerations will greatly influence the design of the clinical packaging, including the availability of stability data, which may require sponsors to be cautious and adopt more tightly controlled storage conditions, than may be needed once the product is approved and commercialized. Though Phase 1 trials are smaller in size, they may have complicated dosing schemes, which then in turn can introduce complicated packaging schemes. Because of the smaller scale of the trial in geographic reach as well as size, many sponsors choose to forego the use of a Randomization and Trial Supply Management (RTSM) system. Site-specific randomization schemes are often employed to manage the randomization of subjects to multiple sites in a decentralized approach. Depending on the supply strategy, an unblinded site pharmacist may also be utilized to manage subject randomization and dispensing at each clinical site. It is advisable to plan up front for additional clinical sites and changes to or expansion of the trial when randomization schemes and packaging plans are generated to avoid potential delays and additional costs that will need to be accommodated later. The optimal packaging to suit the trial will depend on the study design, the number of sites, the randomization, and how the drug is to be administered to patients.

Dosing schemes in Phase 2 studies can be very complex, and the majority will involve titration or dose escalation. These studies will often cover dozens of clinical sites across multiple countries and regions, making the strategy to use unblinded pharmacists unfeasible, so trials will usually employ central randomization commonly using RTSM systems. Depending upon their capabilities and configuration, these systems can manage treatment allocation in accordance with the randomization scheme, as well as subject (patient) enrolment at sites, automate shipments of clinical supply from depots to clinical sites, and manage the restocking levels at participating clinical sites. The newer generation of RTSM systems can also integrate with electronic data capture (EDC) and clinical trial management (CTM) systems that manage patient data, and most can also be set up to manage temperature monitor deviation reporting, facilitate workflow, and hold data for returns and reconciliation of clinical supplies.

Using a RTSM system that can manage the supply allocation and randomization has become the industry norm to effectively manage a complex trial; but sponsors should allow for adequate time at the planning stage for the development, build, and validation of the RTSM system.

The challenges will only get bigger
Expanding into multiple countries with varying regulatory requirements and timelines for both importing and exporting, as well as labelling, will require careful planning if timelines are not to slip. For example, lead times for translating and manufacturing booklet labels into multiple languages can be around three months on average.

Furthermore, the duration of the study will often exceed the retest date of the IMP, so multiple packaging campaigns should be planned, as well as the possibility of having to do at least one expiry update during the trial. Regulations governing expiry update labelling require that the additional label should state the new date and repeat the batch/lot number. The additional label can cannot cover the original lot number, so sufficient space must be available on the labelling to meet this requirement, which can potentially be a problem if the primary packaging is a small vial or syringe.
The challenges facing sponsors in Phase 2 are generally amplified in Phase 3, as more patients are enrolled across wider geographies, and when the duration of the study lengthens. Retest dating will continue to be a concern. Also of concern, is the risk of a supply shortage if planning has not taken into account the need to scale up manufacturing of the IMP in line with the requirements of the study. Other complications will be the likely inclusion of a comparator arm with concomitant sourcing and blinding challenges, the need to maintain a temperature-controlled cold chain, and the need for an end-of-study lot reconciliation that could include tens of thousands of unique kits.

Comparators
Before approval, a new drug usually must be compared against the current standard of care available, but obtaining supplies of the required commercial product to use in the comparator arm of the trial can be difficult. Effective and efficient sourcing commercial products can be one of the most challenging, stressful and expensive aspects of supply chain planning and execution and failure to obtain the necessary product can delay or even cause a study to be cancelled altogether.

Quite often the commercial drug will still be under patent protection and therefore not be available in a generic form. In this instance, not only is the drug likely to be expensive, it may be very difficult to obtain as well, especially in large quantities or in certain countries. Central sourcing may appear to be the easiest and most efficient method to manage sourcing and supply; but export restrictions by certain manufacturers, or import restrictions imposed by some countries may make this impossible. Careful research on the markets where the trial will be conducted must therefore be carried out in advance to thoroughly understand the regulatory requirements and constraints, and so to identify the best sourcing strategy.

Whether it be a central, regional, local or combination sourcing strategy, or one purchasing direct from the manufacturer or through an intermediary, each solution presents its own advantages and disadvantages. For example, clinics and hospitals will typically impose a mark-up if they procure locally. Innovators and manufacturers who supply these comparator products will already have their own forecasting and production schedules in place, and may impose limits on access to the product if the commercial market supply could be disrupted due to an unforecasted commercial need, which could be other clinical trials competing for the same supply. An alternative may be to use a wholesaler, but with the caveat that supplies will likely be limited to what is available at the time and the product’s period of use remaining may be less than desirable. Additionally, there is the risk of shortages once the finite supply has been exhausted.

The blinding of comparators can be extremely challenging, and the possibility needs to be considered that the innovator may change components or other presentation aspects of the product during the trial, thereby compromising the blinding solution employed. The supply chain in a Phase 3 trial is likely to require external resources to enable effective planning, packaging and distribution strategies that can be flexible as the clinical trial goes through inevitable changes. Expert support for import, export, regulatory and commercial product sourcing challenges can prove vital to a trial’s successful execution.

Planning for a continuous supply of the IMP should take into account the variability of clinical site start-up speed, patient enrolment rates, and the remaining shelf life of the products being used. If enrolment is slower than originally envisaged, it could result in excessive waste due to over-stocking and product expiration, which in turn puts pressure on the overall manufacturing requirement and can have a detrimental effect on the cost of the study. On the other hand, if the trial proceeds quicker than expected, the sponsor must ensure there are no supply-related issues such as regional shortages or shortages for the trial overall. A mitigation plan should always be in place at the start of the study to address both contingencies should they occur.

In some countries, lengthy lead times for import licenses may need to be considered, as well as the physical transportation of the drug around the globe, sometimes to remote locations with little in-situ infrastructure to maintain, for example, the required controlled temperatures. Besides the varying import and export requirements of different countries, it may be necessary to have more supply depots outside the primary packaging depot to move supplies closer to a region or within a country; adequate supplies need to be in place at all times during the trial to ensure that patients are dosed according to schedule. This again makes it difficult to calculate how much product is needed to keep the regional depots and clinical sites appropriately stocked.

The returns, reconciliation and destruction management is something that sponsors often overlook early in the study planning process. These study end procedures should be defined at the beginning of the study so that the final reconciliation required for regulatory submission does not delay the close-out at the end of the trial. Countries vary in their regulations regarding waste disposal. There is no “one size fits all” method for site destruction of materials: some sites will have standard operating procedures in place, while others will not, so a contingency plan must be in place for sites that cannot carry out the destruction.

Overall reconciliation of the product is a requirement under both good clinical practice (GCP) and good manufacturing practice (GMP), and all the IMPs must be accounted for at the conclusion of the study. As it is not yet an approved drug, regulators will require proof that unused product has been retrieved and appropriately destroyed. This can be a large task if there are thousands of patients, and tens of thousands of kits out in the field.

Conclusion
There are a significant number of factors that affect the complexity of planning and managing clinical supplies: from maintaining a reliable supply of IMPs to sites to ensure that no patient misses a dose or has to drop out of the trial, to planning for retest dating and relabeling; from cost-effective sourcing of comparators to ensuring appropriate handling of product with a view to minimizing waste; and from understanding differences in national and regional regulations and requirements to accounting for all product at the end of the trial. Many of these issues can be avoided, or at least managed, with proper planning and the use of external support where required. A totally risk-free supply chain would be prohibitively expensive, but with effective management, forecasting, and planning it is possible to strike a proper balance between overall cost and risk. 

References

1. Pharmaprojects Pharma R&D Annual Review 2017.
2. https://www.clinical.catalent.com/expert-content/webinars/clinical-supply-trial-perspectives-challenges-facing-small-mid-sized-and-large-biopharma-companies/
3. Qualified Person (QP). The person defined in Article 48 of Directive 2001/83/EC, as amended, and Article 52 of Directive 2001/82/EC.