Drug supply planning is an established part of clinical trial management, but shortages create a different type of operational challenge because the product that becomes unavailable may not be the investigational product at all. This is particularly relevant in oncology, where an investigational therapy may be administered in combination with an approved treatment, but it can also occur in studies that depend on active comparators, background therapies, rescue medications or other commercially sourced products required by the protocol. A sponsor may have sufficient investigational product available at every participating site and still find itself unable to deliver the treatment regimen as planned.
When that happens, the issue quickly extends beyond supply management. Decisions about continued enrollment, treatment interruption, allocation of remaining stock, alternative sourcing and potential protocol changes can involve clinical operations, medical monitoring, regulatory affairs, quality, pharmacy and supply functions simultaneously. Sites need guidance quickly, while sponsors may be making decisions with incomplete information about the duration or geographic extent of the shortage.
For trial leadership, the challenge is therefore not simply how to respond once a product is unavailable, but how early the study can recognize that an emerging supply constraint is beginning to change the risk profile for patients and the trial.
A shortage begins before the study runs out of drug
One of the most important distinctions in managing a shortage is the difference between having product available today and having sufficient treatment coverage for the patients the study has already committed to treating.
Consider an oncology combination study in which the investigational product remains readily available but the approved backbone therapy enters a national shortage. The study has approximately eight weeks of commercial supply remaining, while additional supply is anticipated within six weeks. On paper, the situation may appear manageable. The calculation changes, however, when patients are already receiving treatment, others have been randomized but have not yet received their first dose, and additional candidates are progressing through screening.
Every new randomization creates future demand during a period in which the timing of resupply remains uncertain. If a six-week disruption becomes eight or ten weeks because of manufacturing, quality or allocation issues, today’s decision to continue enrollment may ultimately affect the ability to maintain treatment for patients already participating in the trial.
The National Cancer Institute’s Cancer Therapy Evaluation Program (CTEP) addresses this issue specifically for shortages of commercial agents used in clinical trials. Its guidance recommends that sites determine whether adequate supply exists to cover the anticipated shortage before evaluating new patients for participation and that new patients should not be consented when adequate supply cannot be confirmed.¹
The broader operational principle is important: during a shortage, supply adequacy should be evaluated against future treatment commitments, not simply current inventory. Waiting until a site cannot fill its next treatment order leaves considerably fewer options for protecting existing patients, redistributing supply or evaluating alternatives.
Move from inventory visibility to treatment visibility
Most studies already monitor investigational product inventory, shipment status, resupply and expiry. During a shortage, however, aggregate inventory can provide a misleading picture of risk.
A site holding 20 units may appear well supplied until those units are considered alongside eight actively treated patients with upcoming doses. Another site may hold only six units but have one patient receiving treatment. The relevant question is therefore not simply how much product remains, but how much treatment that inventory can support and for how long.
A useful shortage assessment connects available supply with patient demand: patients currently receiving treatment and their upcoming doses, patients randomized but not yet treated, participants in screening, usable stock at individual sites and depots, product in transit, expiration dates and restrictions on moving supply between locations.
This can reveal problems that global inventory totals obscure. A study may have sufficient product overall but face an imminent treatment gap in one country because supply cannot be transferred quickly across borders. Conversely, inventory sitting at a low-enrolling site may be approaching expiry while another site faces an immediate shortage.
Identifying those imbalances early creates options. Finding them the day before a patient’s scheduled treatment creates an emergency.
Enrollment becomes part of the treatment-continuity decision
Enrollment targets remain important during study conduct, particularly when recruitment has been difficult. During a shortage, however, continued enrollment cannot be separated from the study’s ability to support the treatment newly enrolled patients are expected to receive.
This becomes particularly relevant in studies where treatment duration is variable. An oncology participant who is benefiting from therapy may remain on treatment considerably longer than forecast, meaning that calculations based on average treatment duration can underestimate future demand.
The question for a sponsor is therefore not simply whether enough product exists to initiate another patient. It is whether there is reasonable confidence that the patient’s protocol-defined treatment can be supported without compromising participants already receiving therapy.
Depending on the circumstances, screening may continue while randomization is temporarily controlled, enrollment may be paused in countries with constrained supply, new site activation may be delayed, or additional randomizations may require centralized review until supply stabilizes. These decisions should occur while options remain available rather than after inventory becomes critical.
A shortage tests study governance as much as supply management
The situation becomes more complicated when sites begin identifying their own solutions. A hospital pharmacy may locate commercial inventory from another supplier, one site may have excess stock that another urgently needs, or an investigator may ask whether treatment can be delayed or a different presentation used.
Some of these solutions may be appropriate, but availability alone does not make an alternative acceptable within a clinical trial. Alternative sourcing or presentations can raise questions about product quality, traceability, labeling, accountability, storage and, in blinded studies, maintenance of the blind. Changes to treatment may also have protocol, regulatory or ethics implications depending on the circumstances and jurisdiction.²
The effectiveness of the response therefore depends on whether the study can rapidly bring the relevant perspectives together. Medical teams need to assess what is clinically acceptable; supply and quality teams need to determine what can be sourced and used; regulatory teams need to assess the implications of a proposed change; and clinical operations needs to translate those decisions into guidance that sites can implement.
CTEP similarly recommends a coordinated management plan for participants already enrolled in an affected study rather than allowing individual sites to independently modify treatment in response to a shortage.¹ The objective is not to replace investigator judgment, but to ensure that an investigator facing a treatment decision has timely access to the information and sponsor guidance needed to make that decision appropriately.
When this happens in a real study: a Confidence experience
Confidence encountered this challenge during an infectious disease study when a shortage affected aztreonam, a protocol-specified rescue therapy for patients who did not respond adequately to study treatment. Although the shortage did not involve the investigational product itself, it had immediate implications for enrollment and patient management because the study could no longer assume that rescue therapy would remain available throughout a newly enrolled patient’s treatment period.
The response therefore extended beyond locating additional supply. Sites were asked to adjust screening and enrollment decisions based on the available supply window and the likelihood that individual patients might require rescue therapy. A defined cut-off date was established after which aztreonam could no longer be initiated or continued, and investigators were instructed to contact the clinical monitor when questions arose regarding patient management or potential alternative treatment options.
At the same time, the study team explored local sourcing where feasible and applied closer patient-level risk assessment when evaluating participants who might be more likely to require rescue treatment. The team also considered whether a protocol amendment could become necessary if the shortage continued, allowing that option to be evaluated before the study reached a point where fewer alternatives remained. Ultimately, an amendment was not required because the study had already achieved its key objectives.
What made the situation particularly instructive was that the supply constraint involved neither the investigational product nor the primary study treatment. Yet the availability of aztreonam still influenced who could safely enter the study, how patients were managed and what operational decisions the study team needed to make. That distinction points to a broader consideration for trial planning.
Trial resilience has to extend beyond the sponsor’s own product
Sponsors understandably have greater visibility into the manufacturing strategy and projected supply of their own therapy than they do for commercially available products used elsewhere in a treatment regimen. Yet the experience above demonstrates how a dependency outside the sponsor’s direct supply chain can become critical to trial conduct when that product is necessary for protocol-defined treatment or patient management.
For combination studies, active-comparator trials and protocols dependent on specific background, supportive or rescue therapies, planning should therefore identify external dependencies for which there is no straightforward substitute. Teams can consider in advance whether alternative presentations or sources exist, whether local commercial sourcing could be feasible, whether inventory can practically be redistributed, what substitutions the protocol permits, and what changes could trigger regulatory or ethics review.
The most difficult decisions should not be designed during the crisis
The hardest shortage may be one in which there genuinely is not enough drug to meet anticipated demand.
The American Society of Clinical Oncology (ASCO) has examined the ethical considerations surrounding oncology drug shortages, including allocation within clinical research. Its guidance makes clear that research participation does not automatically establish priority access to a scarce therapy and that allocation decisions may need to consider the role of the drug in standard-of-care treatment, availability of appropriate substitutes and the clinical circumstances.³
For trial leadership, this means that the process for difficult decisions should be established before scarcity becomes severe. Patients already receiving treatment, participants randomized but awaiting their first dose, candidates undergoing screening and potential future participants do not necessarily present the same clinical or ethical considerations.
There may not be a universal allocation rule, but there can be clarity around who assesses the clinical implications, who reviews supply and alternatives, who has decision authority, how individual cases are escalated and how those decisions are documented. This reduces the risk that critical choices are shaped primarily by which site calls first or where limited inventory happens to be located.
The shortage does not end when supply returns
Once supply stabilizes, the immediate pressure may disappear, but the impact on the study may remain. Patients may have experienced delayed or missed doses, treatment interruptions, alternative sourcing or other changes in protocol conduct, while enrollment patterns may have changed during the disruption.
Affected patients and treatment cycles should therefore remain identifiable, together with the duration and nature of any interruption, alternative product or source used, associated protocol deviations and relevant safety information. Maintaining this information contemporaneously is considerably more reliable than reconstructing the event months later during data cleaning or database lock.
FDA guidance on protocol deviations emphasizes consistent identification, classification, documentation and reporting, particularly where deviations may affect participant safety or the reliability and interpretability of trial data.⁴ Understanding the footprint a shortage leaves in the study is therefore part of managing the event, not simply an administrative exercise after supply returns.
Resilience is measured before the drug reaches zero
Not every shortage can be prevented, particularly when a trial depends on commercially available products outside the sponsor’s control. What can be influenced is how early the study recognizes that constrained supply is beginning to affect treatment commitments and how effectively the organization responds.
At Confidence, we view this as part of trial resilience rather than simply drug supply management. It requires visibility that connects available supply with patient-level demand, an understanding of how continued enrollment changes future treatment commitments, and governance that can bring medical, regulatory, quality, supply and operational perspectives together while meaningful options remain.
The strongest response may be one that never reaches the point at which a site reports that it cannot treat tomorrow’s patient. By then, the range of available choices has already narrowed. A more meaningful measure of preparedness is whether the study identified the risk early enough to protect treatment continuity while there was still time to act.
References
- National Cancer Institute, Cancer Therapy Evaluation Program (CTEP). Managing Drug Shortages During Clinical Trials. Guidance regarding commercial agents in shortage used in NCI-sponsored clinical trials.
- International Council for Harmonisation (ICH). ICH E6(R3): Guideline for Good Clinical Practice. Principles and provisions relating to participant protection, investigational product management, protocol compliance, quality management and risk-based trial conduct.
- American Society of Clinical Oncology (ASCO). Ethical Guidance for the Practical Management of Oncology Drug Shortages. Journal of Clinical Oncology.
- U.S. Food and Drug Administration. Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices. Draft Guidance for Industry, December 2024.