By Christopher Ohms, director, supply chain, Rigel Pharmaceuticals Inc.
Whether you are a company of two or 20,000 people, clinical studies are an important part of drug development. By the end of 2019, there were nearly 320,000 clinical studies registered globally. Ensuring that enough study drug supplies are available at study sites is a requirement of every clinical trial. Equally, it is important to provide study drugs as quickly as possible to prevent early subject withdrawals as well as to provide patient/subject convenience. This article discusses five fundamental tools and techniques for effective planning, execution, monitoring, and inventory control of clinical trial material (CTM) from the manufacturing, packaging, and distribution perspectives. These “pillars” of clinical supply chain management are: a production forecast, a project plan or tracking tool, a re-supply plan, a distribution schedule, and a risk mitigation register. Each of these can be designed and built in an Excel workbook or maintained in software systems aimed to support chemistry, manufacturing, and control (CMC) and/or clinical materials supply chain.
1. Production Forecast
In the absence of a clinical forecast, it is important to generate some type of production forecast from which to plan for excipients, API, packaging components, and third-party resources. A forecast serves as a tool from which to plan the requisite operations to support one or a multitude of studies. The forecast is also an instrument to be used among internal and external stakeholders, so all parties agree on the current and future inventory positions. In the absence of a production forecast, everything centered around CTM becomes inactive and/or reactive. The forecast provides a basis for reacting as needed to the ever-changing landscape of the clinical setting.
As a company’s clinical strategies become better defined, the forecast can be updated and detailed to include consideration of program or study-specific lead times, kit designs, country-specific challenges, and operational assumptions associated with manufacturing, packaging, and distribution of the test articles. For example, in a double-blind, dose-escalation, placebo-controlled, multi-country, Phase 3 study involving DEA Schedule II API and senior-friendly, child-resistant packaging, it is imperative that the forecast be prepared to consider (a) dose escalation and de-escalation as defined by the protocol(s), (b) storage limitations at the sites to hold surplus inventory, and (c) how much to send each site based upon the indication or expected number of patients per site (and the total number of sites planned for the study). From a CMC perspective, an effective forecast is derived by knowing how much of any given treatment type is to be produced. As a rule, it is a good idea to maintain QA-released inventory of API, excipients, and brite-stock (i.e., unlabeled product in a primary container-closure system) materials to remain as nimble as possible to support the changing landscape of the clinical world.
2. Project Plan Or Tracking Tool
A plan or project file is vital to the successful supply of most studies. This generally includes all the pre- and post-production activities needed to deliver supply to the site(s). In most cases, a generally acceptable project management tool (i.e., project plan, tracking tool, etc.) can be used and modified as needed based upon the particulars of the study. As a template, this tool can help to socialize and aid other departments in understanding the drivers of GMP-compliant CTM.
While this may include many tactical activities, the plan may also include strategic elements, too. For example, it may include the sourcing of secondary or tertiary vendors, material inventory lots, and even internal resources. The plan incorporates information for ongoing and planned studies to ensure that clinical demand, clinical supply, manufacturing, and procurement are all aligned. Outcomes of completed plans and the act of strategic planning are extremely useful if they occur regularly (i.e., bi-annually, annually, etc.) and can be operationalized within the fabric of a company’s culture.
3. Re-supply Plan
Determining timely re-supply needs can pose various challenges. There are times when the CTM or investigational medicinal product (IMP) is packaged and labeled once and then circumstances occur that require a campaigned approach to fulfill the needs of the study. In order to sufficiently plan work after the initial campaign, it is imperative to have a tool to predict the needs of the patients so there is ample time to have these supplies available for distribution. The initial and re-supply plans are created from current inventory quantities, the distribution plan, demand inventory, lead times through the major units of operation, and the anticipated “use-by” or expiry of the CTM/IMP. While there are many software tools available for this task, Excel has the basic functionality to generate and update the plan.
A well-engineered re-supply plan aligned with lean principles in waste management will help any organization produce the right amount of CTM/IMP at the right time for the right cost. A well-thought-out re-supply plan is vital. Without it, there is a high risk of delaying or interrupting a trial. And if too much CTM/IMP is produced or shipped at the wrong intervals, wasted materials and money could result.
4. Distribution Schedule
Once study drug is released and available for distribution, it is important to determine the amount and frequency of trial material to be distributed to the site. Some studies are designed to be single dispensation trials, i.e., 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. However, there are other studies where the medication is provided by multiple shipments. Whether a randomization trial supply management (RTSM) system or a basic Excel file is used, the methodology of distribution needs to be clearly defined.
A distribution plan considers paradigms associated with the conditions from depot to site and also includes factors of quality and cost. Some distribution schedules, particularly for blinding purposes, could have the ability to unblind a site but maintain high efficiency in distribution; the inverse is equally true. It may be feasible to “seed” the site with an initial quantity of kits, then send a follow-up shipment or series of shipments containing a predetermined or prepackaged quantity of kits as a re-supply; this approach relies on a prediction algorithm, which is used to order kits for return visits. The number of kits required for returning subjects can be predicted because subjects' visit schedules are determined by the subjects' initial or previous visits as determined by the approved protocol. The approach taken needs to be logical and palatable for the sponsor and the site as well as mindful of the study design.
5. Risk Mitigation Register
There are risks to supplying a clinical trial. Where can potential risks be identified from the protocol? What risks can be collected outside of the protocol and should be considered when determining potential risks? Here again, a company template can aid in the development of a risk matrix. For example, a template that is organized to evaluate clinical supply risk into three phases of the supply for a study can prove helpful. These three phases may include preproduction, production, and post-production activities. Each of these phases poses a unique set of risks with some degree of severity to fulfill the needs of the study. A risk management and mitigation methodology enables stakeholders to identify issues early on, which in turn allows for the design of effective mitigation strategies before the risks occur.
In the preproduction phase, some risks include the activities in project planning, contracts and agreements, and capacity of a clinical packaging organization, among other things. With a matrix approach, each of these can be ranked and measured to assess the degree of risk to supply. One of the more frequent risks during preproduction could be simply the availability of a material or component to make or package the clinical materials; both raw materials and packaging components could take weeks or months to obtain. For international studies, preproduction considerations associated with documentation, including the need for import/export permits, regulatory submissions, and labeling requirements, may pose risks.
During the production phase, any number of risks could present themselves, including deviations, batch losses, and equipment failure. It is important to remain vigilant during the production of the supplies to ensure that all stakeholders remain alert and focused. And should something surface that could impede the post-production operations, a nimble and alert team is often better prepared to resolve issues than one that is fragmented and not engaged.
Upon the distribution of the supplies, post-production risks may influence the ability to supply the study. As noted above, a prospective risk matrix is an indispensable tool that could not only help mitigate situations but equally maintain momentum of supply reaching the subjects as needed for the study.
In summary, it is critical to have tools and techniques to manage CTM/IMP and guarantee that clinical supply is available when needed. Sponsors with well-defined systems in place and solid teams of employees to support the effort can ensure successful clinical trials.
About The Author:
Christopher Ohms is a San Francisco Bay Area native and serves as director of supply chain at Rigel Pharmaceuticals. Prior to joining Rigel, Ohms held positions at Gilead Sciences, Patheon, Stanford School of Medicine, Pain Therapeutics, and ALZA. His 27-year career in the medical and pharmaceutical settings has been in quality, project management, research, development, commercial operations, manufacturing, packaging and labeling, supply chain, sales and operations planning, and global clinical/commercial contracted relationships and oversight. Ohms has co-authored eight patents and holds a B.S. in biology and an M.A. in English literature.