Drug Shortages In Clinical Trials: A Policy Blueprint

By Joy Acha, BPharm, MPH, MBA, research program coordinator, Johns Hopkins Bloomberg School of Public Health

Clinical trial drug shortages are not rare edge cases. They are a recurring, costly, and largely silent crisis embedded in the architecture of modern drug development. Yet compared to commercial pharmaceutical shortages that have attracted congressional scrutiny, regulatory mandates, and sustained media coverage, shortages within the investigational drug supply chain remain poorly tracked, inconsistently reported, and nearly invisible in policy discussions.

That invisibility carries a real cost. When the supply of an investigational drug fails mid-trial, patients may be forced off a therapy that represents their best available treatment option. Sponsors face protocol amendments, enrollment disruptions, and data integrity risks. In the worst cases, trials close entirely, erasing years of scientific investment and delaying access to treatments patients urgently need.

The clinical supply community has the expertise and motivation to solve this problem. What it has lacked is a coherent policy framework to coordinate action across sponsors, contract manufacturers, regulators, and logistics providers. This article proposes practical steps that organizations can begin taking now, alongside longer-term structural reforms the industry should advocate for together.

Understanding Why Clinical Supply Fails

Clinical drug shortages rarely emerge without warning. They are produced by a predictable set of structural vulnerabilities that, left unaddressed, will continue generating disruptions at scale.

Geographical clustering in active pharmaceutical ingredient (API) manufacturing sits at the top of the list. A significant share of APIs used in clinical trials originates from a small number of facilities, often clustered in a narrow geographic corridor. A single quality failure, regulatory action, or natural disaster at one of these facilities can simultaneously affect multiple trials across multiple sponsors — a systemic risk that has no direct commercial equivalent.

Regulatory complexity compounds the problem, though its weight varies across the trial life cycle. Early-phase trials (Phase 1 and 2) are often conducted within a single country, where regulatory requirements are relatively contained and supply chains are simpler to manage. But as trials advance to Phase 3 and expand across countries to meet enrollment target, that simplicity disappears, with each country having distinct requirements governing investigational drug imports, labeling, and qualified person (QP) release. Sponsors managing multi-country trials navigate these requirements without a unified international framework, creating friction that slows supply and amplifies the impact of any upstream disruption.

Demand unpredictability creates a third layer of risk and, unlike manufacturing or regulatory complexity, it lives inside the trial itself. Every clinical trial launches with an enrollment forecast: how many patients per site, per month, across the life of the study. That forecast drives supply decisions at every level, from batch sizing at the CMO to resupply thresholds in the IRT system. The problem is that enrollment never follows the plan. Sites that were projected to enroll steadily go quiet; others that were expected to contribute modestly suddenly accelerate. Both scenarios create supply crises. Slow enrollment ages drug toward expiry and generates costly waste, while unexpectedly fast enrollment depletes site stock faster than resupply cycles can keep pace. IRT systems, for all their sophistication, can only optimize against the assumptions they were given.

Finally, comparator drug sourcing introduces a layer of supply risk whose severity depends heavily on one critical factor: who owns the comparator. When a sponsor runs a trial against their own approved product, they retain manufacturing visibility and supply priority, and the comparator is simply another SKU in a supply chain they already manage. But this is not always the case, and for many sponsors it is rarely the case. Smaller biotechs and academic investigators who make up a significant share of clinical trial activity seldom have an approved commercial product of their own to draw on.

Why This Demands More Than Operational Fixes

The pharmaceutical industry has built robust policy infrastructure around commercial drug shortages, mandatory reporting, regulatory oversight, and escalation pathways that activate when supply fails. Investigational drug supply operates in a different world entirely: one where disruptions go unreported, consequences go unmeasured, and the policy response is, in most cases, nonexistent.

1. Patient Safety: When investigational drug supply fails at the site level, patients are the first to absorb the impact. A stockout that forces a patient off an investigational therapy mid-trial is not merely an operational inconvenience, it is a potential clinical harm, a protocol deviation, and in some therapeutic areas, the loss of a patient's only viable treatment option. For patients enrolled in oncology or rare disease trials who have exhausted approved therapies, a supply-driven interruption can be irreversible. Current policy frameworks contain no mechanism to track these events, no requirement to report them, and no systematic review of how often they occur. That gap is not a minor administrative oversight; it is a failure of the regulatory infrastructure that is supposed to protect research participants.

2. Trial Integrity: Supply disruptions do not stay contained at the logistics level; they propagate into the scientific record. Stockouts trigger dose modifications, unplanned enrollment pauses, and protocol amendments that introduce variability into data sets that regulators and statisticians will later scrutinize. In blinded trials, emergency resupply workarounds can create unblinding risks if procedural controls are not airtight. Supply-related protocol amendments consume months of regulatory time and can, in competitive therapeutic areas, hand a development advantage to a rival program that maintained supply continuity. Policy that ignores supply chain integrity is, in effect, tolerating preventable threats to the validity of clinical evidence.

3. Financial and Public Health Costs: The financial consequences of clinical supply disruptions are large enough to constitute a public health concern in their own right. Research from the Tufts Center for the Study of Drug Development estimates the direct cost of a single delayed day in Phase 3 development at approximately $55,716 in 2023, meaning a one-month supply disruption carries a direct cost exposure exceeding $1.5 million, before accounting for wasted drug, emergency logistics, or delayed market entry. For a blockbuster candidate, delayed approval translates into lost prescription revenue estimated at approximately $500,000 per day. These costs ultimately flow through to drug pricing, development investment decisions, and the pace at which new therapies reach patients. A policy environment that tolerates avoidable supply disruptions is not just a neutral bystander; it is an active contributor to the inefficiency of the drug development system it is meant to oversee.

4. The Data Gap: The most structurally damaging consequence of the current policy vacuum is the absence of reliable data. Commercial pharmaceutical shortages are subject to mandatory FDA reporting under the Food and Drug Administration Safety and Innovation Act (FDASIA) and tracked in publicly accessible databases, giving regulators, manufacturers, and health systems the visibility needed to anticipate and respond to supply stress. Investigational drug supply disruptions carry no equivalent requirement. There is no centralized registry, no mandatory disclosure framework, and no systematic mechanism for regulators to identify vulnerability patterns before they escalate into patient-level events. Industry surveys suggest that up to 80% of clinical trials experience some form of delay, with supply chain factors contributing meaningfully, but without mandatory reporting, that figure remains an estimate rather than a measurable, actionable data point. Effective policy requires evidence. Building the evidence base for clinical supply policy begins with closing this reporting gap.

The Policy Landscape

1. Food and Drug Administration Safety and Innovation Act: The FDASIA marked the first serious federal attempt to build a systematic shortage prevention infrastructure. Since FDASIA's enactment in 2012, manufacturers have been required to notify the FDA of certain changes in the production of certain finished drugs and biological products, notifications intended to help the agency prevent and mitigate shortages. The results at the commercial level have been meaningful: the number of new drug shortages has shown an overall trending decrease since the notification requirement was amended in 2012, with 49 new shortages in 2022 and 55 in 2023, compared to a record high of 251 new shortages in 2011. For the investigational drug supply chain, however, FDASIA offers nothing. Its reporting requirements apply exclusively to approved commercial products. A sponsor whose investigational drug manufacturing line goes down has no obligation under FDASIA to notify the FDA, and the agency's Drug Shortage Program has no mandate to intervene. The framework that reduced commercial shortages by roughly 80% over a decade has no equivalent application to the drugs being tested in clinical trials today.

2. The CARES Act (2020): The Coronavirus Aid, Relief, and Economic Security Act (CARES) built on FDASIA's foundation by expanding the shortage notification requirement and introducing new supply chain resilience obligations. Specifically, the CARES Act amended the FD&C Act to require manufacturers of drugs critical to public health and manufacturers of the active pharmaceutical ingredients used in such drugs to develop, maintain, and implement redundancy risk management plans that identify and evaluate risks to supply for each manufacturing establishment. This was a meaningful step forward for the commercial supply chain. For investigational drugs, it changed nothing. The redundancy risk management requirement applies to drugs deemed "critical to public health" a designation oriented entirely toward approved, marketed products. Clinical-stage sponsors and their CMOs manufacturing investigational medicinal products fall outside this requirement entirely. The CARES Act expanded the perimeter of commercial shortage protection without moving that perimeter one inch closer to the investigational supply chain.

3. FDA's Drug Shortage Program: The FDA's Drug Shortage Staff represents genuine institutional expertise and operational capacity. Industry can notify the FDA Drug Shortage Staff of new discontinuances, GMP issues, increases in product demand, recalls, supply interruptions, or other events through the CDER Direct NextGen Portal a mechanism intended only for drug manufacturers and applicants of approved products. The program's track record at the commercial level demonstrates what proactive shortage management can achieve: the number of shortages the FDA prevented increased from 179 in 2020 to 224 in 2023, continuing a trend that began in 2014 when FDA reported 101 prevented shortages. But the Drug Shortage Staff's mandate covers approved commercial products only. There is no equivalent portal, no equivalent notification mechanism, and no equivalent prevention infrastructure for investigational drug supply disruptions. The institutional capability exists, but the mandate to apply it to clinical trial supply does not.

4. The Government Accountability Office's Own Verdict: Perhaps the most telling indicator of the current policy framework's limitations is the federal government's own assessment of it. The GAO found that the Department of Health and Human Services (HHS) did not have a coordinating structure across the department to oversee its responses and strategies for drug shortages, a multifaceted issue that requires a collaborative governmental approach, according to FDA, Congress, and others. The GAO made two formal recommendations: that HHS implement a formal coordination mechanism and ensure it reflects leading practices for cross-agency collaboration. "The GAO's April 2025 audit delivered a verdict that should concern anyone invested in clinical supply policy: not only had its earlier coordination recommendation gone unimplemented, but the limited coordination infrastructure that did exist was being dismantled. The Drug Shortage Coordinator position created by the Biden administration in 2023 was eliminated in May 2025 when its funding expired, and HHS formally declined to concur with the GAO's recommendation to replace it with a permanent mechanism — stating that the current administration had not indicated how it would direct supply chain coordination going forward.¹ As of early 2026, the federal government has no formal cross-agency structure for managing commercial drug shortages. The investigational drug supply chain, which has never had equivalent infrastructure, is even further from the coordinated policy response the scale of this problem demands."

A Blueprint For Action

The path forward on clinical trial drug shortages is not uncharted. Across the U.S., Europe, and Canada, regulators have spent the better part of a decade building shortage management infrastructure for commercial medicines that, despite its limitations, offers a working model the clinical supply community can learn from, adapt, and in some cases directly extend to the investigational drug context. The question is no longer whether action is possible. It is whether the industry will advocate for it with sufficient urgency, and whether sponsors will begin building resilience into their own operations while that advocacy takes hold.

The following recommendations operate at two levels: what individual sponsors can implement now within their existing operational authority, and what the industry must collectively pursue through regulatory engagement and policy reform.

1. Build Supply Risk Assessment Into Trial Design, Not Crisis Response

Sponsors should conduct a formal clinical supply risk assessment (CSRA) at the outset of every trial, treating it as a nonnegotiable planning deliverable rather than a reactive tool deployed after disruption has already occurred. The CSRA should document manufacturing dependencies, identify single-source vulnerabilities across both the investigational product and any comparator drugs, establish buffer stock targets calibrated to realistic enrollment scenarios, and define a tiered escalation protocol for shortage events at each phase of the supply chain.

The principle here is not new; it is standard practice in financial risk management and in commercial pharmaceutical manufacturing. Its systematic application to the investigational supply chain remains inconsistent. Sponsors that institutionalize supply risk assessment as a trial design requirement, not an operational afterthought, will be better positioned to prevent disruptions, respond faster when they occur, and demonstrate supply chain due diligence to regulators reviewing their IND or clinical trial authorization (CTA).

2. Mandate Backup Supplier Qualification

Sponsors negotiating clinical manufacturing agreements should require dual-source supplier qualification as a standard contract term wherever it is technically feasible. A CMO that is unwilling to support backup supplier development should be evaluated as a supply risk, not simply as a cost-competitive option. Where single-source arrangements are unavoidable due to the novelty of the manufacturing process or the specialized nature of the compound, sponsors should negotiate contractual protections including advance notice obligations, technology transfer rights, and priority resupply provisions.

Here, the EU offers a concrete model worth following. The EMA's Executive Steering Group on Shortages recommended in April 2024 that manufacturers increase EU manufacturing capacity, diversify suppliers in the supply chain, and stockpile safety stocks as part of a coordinated approach to securing supply of critical medicines. These are commercial market recommendations, but their logic applies directly to the investigational supply chain. Sponsors should not wait for regulators to mandate diversification; they should build it into their procurement strategy now.

3. Establish Mandatory Supply Risk Disclosure at IND/CTA Filing

Regulatory agencies should require sponsors to submit a clinical supply risk assessment as part of IND applications and CTAs. This single policy change would do more to shift the industry's supply risk culture than any amount of voluntary guidance because it would make supply risk planning a prerequisite for trial authorization, not a best practice that organizations can deprioritize under budget pressure.

Canada has already moved in this direction for its commercial drug framework. Health Canada's proposed 2025 regulatory amendments would require manufacturers to develop and maintain, for drugs on a Critical and Vulnerable Drug List, an assessment of shortage risks and an outline of measures to prevent and mitigate them for the entire period the manufacturer sells the drug. Extending an equivalent requirement to investigational drugs at the IND/CTA stage would represent a proportionate and overdue regulatory step.

4. Harmonize Clinical Supply Standards Internationally

The absence of a unified international framework for investigational drug supply management is not a minor regulatory gap; it is a structural inefficiency that imposes unnecessary cost and risk on every multi-country trial. The International Council for Harmonization (ICH) should develop a dedicated guideline on clinical supply chain resilience, analogous to ICH Q10 on pharmaceutical quality systems, establishing international baseline standards for supply risk management, shortage notification, and emergency response coordination.

The EU has already recognized the need for this kind of structured international collaboration. The EU's 2025 pharmaceutical legislation reform establishes stronger obligations for companies to ensure continuous supply of medicines, an obligation to notify shortages and withdrawals in advance, and monitoring of expected and actual shortages by both EMA and national competent authorities. The reform also establishes an EU list of critical medicines, a supply chain vulnerability framework that, adapted for the investigational context, could serve as a template for an ICH-level clinical supply resilience standard. The EMA's shortage task force, which operated from 2016 to 2024, led to the establishment of the EU Single Points of Contact for Shortages network and delivered policy measures including shortage prevention plans and shortage mitigation plans, all of which represent transferable models for a harmonized international clinical supply framework.

The views expressed are my own and not those of Johns Hopkins University.

About The Author:

Joy Acha is a pharmacist and health policy researcher working at the intersection of pharmaceutical supply chains, access, and public policy. She currently works as a Research Program Coordinator at the Johns Hopkins Bloomberg School of Public Health. Her work focuses on strengthening supply chain resilience, improving drug affordability, and translating data into actionable policy insights. She holds a Master of Public Health and Master of Business Administration from Johns Hopkins University. She has co-authored publications on oncology drug shortages, pharmaceutical tariffs, and diabetes care affordability, contributing to evidence that shapes policy solutions and strengthens health system resilience in the U.S. and globally.