Clinical trial operations involve a great many components and moving parts. One of the major challenges is that while many parts are interdependent, a trial may develop rather differently than the designers envisioned. Having a mechanism to adjust to changes in enrollment, dealing with sensitive drug trial material, addressing localization issues; all of these and a dozen more can have a dramatic impact on trial expense and timelines.
A thorough understanding of the supply chain for drug product and monitoring trial progress is very important. One of the later steps in delivering drug product to a site for a specific subject or group of subjects is labeling. By committing specific drug product, only "just in time", drug product can be maintained in a condition to be redirected to an alternative site where it is most needed. For example, in a long duration trial, there may be a loss of drug product for one or more subjects weeks or months into a protocol. With a good supply chain, limited drug supply can be prioritized to cover that investment of time rather than enrolling a new subject. Completing the label specifics very late in the delivery chain allows for very careful management of drug supply.
Designing a thorough supply chain is horrendously time consuming. But you can develop this incrementally. Many managers develop this with Excel and with rather coarse unitary steps. All of drug product as manufactured and then inventoried might be a unitary step. Drug supply in your depots might be another unitary step (such as five primary depots worldwide). Then fully labeled, randomized drug supply at each site is a final unitary step. With more experience with your tool and developing through the trial, additional unitary step nodes can be added. For example, material in quarantine ready for shipment, material in transit, material in country in quarantine having cleared customs – you can add any granularity that you find helpful.
The point of a supply chain model is to understand how much material you have and how much you need on hand to be ready at each site for the rate of enrollment you anticipate, and then adjust to the rate in practice, and then to continue to manage supply during the course of each subject’s trial. For each unitary step, you need "enough", which means a threshold level plus some safety stock. It is setting those thresholds and safety stock levels that is critical. Knowing all of the upstream unitary steps and time to move material between steps in order to have enough (at least in the important nodes), is the blessing and the curse of SCM systems and JIT processes. There are many different requirements to consider, for example: critical nodes tend to need larger safety stock, too much safety stock in the supply chain means additional product costs, and changing safety stocks over time are all factors to take into account. It would be ideal to supply the last patient out with material that depletes sequential upstream unitary step nodes so you are left with very little trial material or comparator.
Labels and package inserts need to be in full compliance with local regulations at each site, including having regulatory approval, before you enroll subjects. You may find a universal product insert is satisfactory, even if it tends to be large. Consider however that regulations change with some frequency, particularly worldwide, so you may find a change in the rules or that a ruling in Country Z necessitates an updated package insert. Do you include a supplemental insert? That may not be permitted. Do you prepare a County Z insert and use that only and completely in Country Z? Now you need to manage your inventory for any product going to that country.
Many sponsors print basic information on the label in a useful basic set of languages to assure a chance for thoughtful handling in at least the major trial countries, then supplement that as needed with additional localization. The basic label, as well as the localization information can be printed and held in inventory at a suitable storage node. Then a supplemental of final label is applied to the trial drug product container conveniently close to the final usage time and location. Remember all of these processes need to be carefully controlled and auditable.
Some sponsors find it helpful to print key localization information only on an as-needed basis, i.e. a unitary step node. Localization material is printed and stored, then applied to the packaging conveniently late in the supply chain. This needs to be managed for however many flavors of labeling your trial requires. This also requires adding an "apply and validate labeling" unitary step node, and perhaps additional nodes for shipping.
Drug Product Supply Chain
Trials are unique, and the differences can have a huge impact on their design and management. For drug supply, there are several key questions: What is the shelf life of the API alone or finished as drug product? What are the requirements of shipping, and storage? Where will you use the drug material, and how and when do you plan to push it out to trial sites in 20 or 500 locations in tens or hundreds of countries?
You may be lucky enough to have years of shelf life, but shorter is very common. Next, what might the drug product be sensitive to? Heat, moisture, light are some of the parameters that impact drug product. Many drug products must be shipped with a rigorous cold chain. What happens if a batch is stuck in a plane or in a quarantine area in customs in a hot country, to the point that material is no longer qualified for use in the trial? Even a brief temperature excursion can make a batch unsuitable. What if the material is safely in a depot, but is compromised by a power failure, or freak of nature? Then there is simple theft or mismanagement. Lost material needs to be replaced to protect your investment in subjects in any trial, and most particularly for a long duration trial with dosing for later time periods.
Any drug product that must be delivered to the subject must be available when and as needed. These questions pertain equally to comparators. Test articles and comparators are rarely inexpensive, so you need to have a plan that includes sourcing sufficient drug product with a capacity to manufacture or secure additional material, even significantly beyond your original trial design, if developments make that additional supply necessary.
Much sure care is taken to plan for drug product distribution. Where are your trial sites? What logical distribution chain do you want, using many nodes perhaps closer to the trial sites, or fewer nodes at more central locations and supplying a greater number of sites.
A very common challenge is randomization. Do you keep a depot of active test article in bulk form and count out tablets for a single subject only when randomized, or do you keep bottles of NN tablets (for a trial protocol) to supply a subject when needed? Do you keep dozens, or hundreds, of multiple-dose tablet cards or bottles at your depot, or do you manage these at the trial site? Where in the process do you apply the final codes and details needed for compliance with the protocol and regulations?
One solution used by many is a large label booklet with the product insert spelled out in as many languages as you need for a trial. This can make for a very bulky product insert. If you use only a local product insert, then you need to have enough printed to support the trial. What if you plan for 100 subjects in southern India and 100 in northern India with a different product insert (local language), but enrollment or weather shifts this dramatically and you find yourself short of one flavor?
A careful supply chain design can help considerably. Most large CROs will tell you they can handle a problem of any magnitude but ask any Clin Ops person and you will find the CROs often overpromise, or are unable to manage the complexity and changes that actually develop in practice.
Managing trial and trial supply is a challenge at any scale. With thoughtful planning and staffing, your company can minimize outlays and time. Your company’s success may depend on it.