In 2023, drug shortages were substantial, leaving oncology patients without treatment despite the myriad of drugs being approved by the FDA annually. This has been the highest rate of drug shortage since 2014, with no single cause at fault.1 However, for the past decade, the United States has been experiencing these shortages, leading to detrimental impacts on health care.2
Overview of Drug Shortages
Recently, product quality issues have been identified as the primary cause of drug shortages. The lack of transparency on the part of the pharmaceutical industry raises unresolved questions for health systems and pharmacies. Institutions have responded by improving communication and amplifying the need for multidisciplinary collaboration to maintain a successful and expected quality of patient care.2
Impact on Fludarabine
One of the current chemotherapeutic drugs experiencing a shortage, fludarabine, has been identified by shortage trackers since December 2021 with no complete resolution to date.3 Fludarabine monophosphate is a purine analogue that is commonly used for conditioning during allogeneic hematopoietic cell transplantation (HCT), lymphodepletion for chimeric antigen receptor (CAR) T-cell therapy, and relapsed/refractory acute myeloid leukemia (R/R AML). Despite its use in a variety of malignancies, there is a notable absence of ongoing studies evaluating and providing therapeutic alternatives.3
Significance of Fludarabine
A necessary step in having a successful adoptive immune cell transfer is host immune depletion.3 Allogeneic HCT heavily relies on host immune depletion to reduce the risk of allograft rejection. With the addition of fludarabine in total body irradiation (TBI), allograft rejection decreases. Common conditioning regimens for allogeneic HCT requiring fludarabine include fludarabine, cyclophosphamide, and TBI; fludarabine and TBI; and FCE (fludarabine, cytarabine, etoposide). For autologous HCT, a fludarabine/melphalan (flu/mel) combination is used.3-5 With the addition of fludarabine to these regimens, lymphodepletion treatment yields a greater persistence of CD4+ and CD8+ T cells.6
Additionally, fludarabine combinations used for R/R AML include FLAG (fludarabine, cytarabine, granulocyte colony-stimulating factor), FLAG-Ida (FLAG and idarubicin), and FLAG-Ida-Ven (FLAG-Ida and venetoclax).4 The potential clinical implications of omitting or substituting fludarabine in lymphodepletion before CAR T-cell therapy are uncertain but hold the potential for profound impact on a treatment designed for curative purposes. The heightened demand for fludarabine persists in the realm of allogeneic transplantation. Conventional and reduced-intensity myeloablative regimens that feature fludarabine, such as flu/mel, busulfan/ fludarabine, and various conditioning approaches, remain among the most widely employed conditioning strategies in the United States.
Current Challenges and Proposed Solutions
The year 2023 has witnessed a distressing record of scarcity, affecting 11 chemotherapy agents and a prostate-specific membrane antigen targeted therapy, highlighting the profound impact on cancer treatment. This emphasizes the unprecedented nature of these shortages, signaling a critical challenge in maintaining the expected level of patient care in oncological practice. The surge in drug shortages is not an isolated event but part of a broader trend affecting various therapeutic areas. Among the most vulnerable are sterile injectable generic products, particularly those with a cost below $9 per dose, which are identified as being at the highest risk.2 Many older chemotherapy agents essential to cancer care fall within this category, posing a significant challenge. These shortages stem from a convergence of factors, notably product quality issues with major suppliers. The situation underscores a concerning lack of transparency within the pharmaceutical industry regarding the exact causes and contributing factors to these shortages.
According to the American Society of Health-System Pharmacists, 56% of the drug shortages in 2022 had unknown causes, emphasizing the complexity of the issue.1 In addition, supply/demand imbalances, manufacturing issues, business decisions, and regulatory/ raw material problems collectively contribute to the challenging landscape of drug shortages. The profound impact of these shortages on public health is evident, as health care providers all over grapple with uncertainties in drug availability.1 In the past, the oncology field has faced similar challenges with drug shortages, prompting clinicians to pivot to alternative therapies when feasible. In addition, the Hematology/Oncology Pharmacy Association conducted a survey, revealing a 34% increase in oncology drug shortages in 2019 compared with 2018. This underscores the problem severity, as the data show it affects 68% of institutions surveyed.7
Response to Shortages
In the context of a critical shortage of fludarabine, a retrospective study was conducted that focuses on the impact of this shortage on the treatment landscape for diseases such as AML. The retrospective analysis led by Tinajero et al delves into the descriptive analysis of 2 regimens: FLAG-Ida-Ven and CLIA-Ven (cladribine, cytarabine, idarubicin, venetoclax) for R/R AML during the fludarabine shortage. The response rates for both regimens were 46% and 57%, respectively, with measurable residual disease negative remissions achieved by 86% and 75%. However, the CLIA-Ven group demonstrated potentially higher toxicity, with a higher incidence of grade 3 or 4 nonhematologic adverse events. Although the study was retrospective and limited by sample size, it was the first to describe intensive Ven-based regimens in the R/R setting with different purine analogues. This study emphasizes the need for larger studies to confirm these findings due to the small number of patients in this retrospective analysis.7
Shortages, particularly in oncology drugs, can lead to disturbances in the scheduling of chemotherapy treatments, changes in the administered dose or regimen, and even missed doses due to the unavailability of alternative agents.7 As experts in medications, pharmacists bring a wealth of knowledge in applied therapeutics, insights into medication workflows, and a keen awareness of the impact of shortages.8 Some institutions have implemented local-level strategies to address shortages, such as adopting pharmacy dose banding and rounding doses down to reserve vials. If a dose reduction exceeding 5% becomes necessary, these adjustments are being implemented to optimize vial allocation.
The administration of fludarabine based on adjusted body weight rather than actual body weight is also being utilized, along with a shift in billing methodology from single-dose vials to a system based on dose delivery. This method enables the distribution of split vials among patients, and clinical teams are encouraged to coordinate schedules for patients requiring fludarabine on the same days to minimize drug wastage. Lastly, the stability of fludarabine, as determined by high-performance liquid chromatography, persists for 14 to 21 days at 2 to 8 °C, which implies the possibility of preserving the reconstituted products for short-term use by patients.3
Pharmacist’s Role and Conclusion
Although past shortages have presented acceptable alternatives, the current challenge is distinct in that there is no sufficiently studied alternative regimen available to replace the established standard of care: the fludarabine/cyclophosphamide regimen for CAR T-cell therapy. Pharmacists can play a key role by urging the American Society for Transplantation and Cellular Therapy to endorse treatment centers that include rationing plans for fludarabine. This aims to maximize patient benefits and uphold the integrity of clinical trials. Simultaneously, they can advocate with suppliers and regulatory agencies to prevent future drug shortages and contribute by formulating algorithms to manage the currently restricted supplies. This involvement aims to provide an institutional approach to patient care that is clear and consistent.3
About the Authors
Jose Tinajero, PharmD, BCOP, is a clinical pharmacist specialist at the City of Hope National Medical Center in Los Angeles, California, and his areas of specialization include cellular therapies, hematologic malignancies, and hematopoietic stem cell transplantation.
Amir Ali, PharmD, BCOP, is a clinical pharmacist specialist at the University of Southern California (USC) Norris Comprehensive Cancer Center and an adjunct assistant professor of pharmacy practice at USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
Tammy Harutunyan is a class of 2025 PharmD candidate at the University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
Teny Khachadourian is a class of 2025 PharmD candidate at the University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
Michaela Maher is a class of 2025 PharmD candidate at the University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
Pharmacists are pivotal in ensuring that innovative solutions are implemented to sustain clinical trials and clinical care during drug shortages. The impact of these shortages extends beyond drug availability, affecting the ability to maintain a consistent and effective patient response. The current surge in oncology drug shortages demands urgent attention and innovative solutions. This not only jeopardizes the accessibility of essential medications but also poses challenges to traditional approaches to patient care. There are political and organizational strategies that exist; however, there is limited published information on clinical substitutions. Pharmacists have the potential to take a leading role in these areas and engage in clinical research to offer solutions for alternative interventions. Pharmacists can also advocate for a comprehensive approach that engages drug manufacturers, the FDA, and health care providers, underscoring the urgency for collaborative efforts to address the underlying causes and implications of drug shortages in oncological practice.2
Regulatory bodies now acknowledge the use of single-arm trials with external historical controls, especially in oncology, to evaluate promising treatments for specialized areas including leukemias and lymphomas. However, when new treatment indications rely on time-related events like treatment failures, this design may introduce biases in comparisons with external controls. Randomized controlled trials have traditionally been the gold standard for regulatory approval, but they are resource intensive. Real-world data (RWD) have gained interest as a supplement to randomized experiments, with the 21st Century Cures Act sparking discussions in the United States. One potential application of RWD is creating external untreated comparator cohorts for single-arm trials. This is particularly valuable when new therapies show substantial early benefits, making it ethically challenging to withhold treatment, or when the patient pool is too small for sufficient outcomes in an internal untreated group. However, integrating trial data with nonexperimental data introduces confounding concerns, requiring careful consideration of confounder measurement in both cohorts. Investigators must address differential confounder misclassification to avoid increasing bias in estimates when controlling for potential confounders.9
References
Tucker N. Oncology drug shortages persist, calling for solutions. Targeted Oncology. April 4, 2023. Accessed March 5, 2023. https://www.targetedonc.com/view/oncology-drug-shortages-persist-calling-for-solutions
Maziarz RT, Diaz A, Miklos DB, Shah NN. Perspective: an international fludarabine shortage: supply chain issues impacting transplantation and immune effector cell therapy delivery. Transplant Cell Ther. 2022;28(11):723-726. doi:10.1016/j.jtct.2022.08.002
Visani G, Tosi P, Zinzani PL, et al. FLAG (fludarabine + high-dose cytarabine + G-CSF): an effective and tolerable protocol for the treatment of ‘poor risk’ acute myeloid leukemias. Leukemia. 1994;8(11):1842-1846.
van Besien K, Kunavakkam R, Rondon G, et al. Fludarabine-melphalan conditioning for AML and MDS: alemtuzumab reduces acute and chronic GVHD without affecting long-term outcomes. Biol Blood Marrow Transplant. 2009;15(5):610-617. doi:10.1016/j.bbmt.2009.01.021
Ramos CA, Rouce R, Robertson CS, et al. In vivo fate and activity of second- versus third-generation CD19-specific CAR-T cells in B cell non-Hodgkin’s lymphomas. Mol Ther. 2018;26(12):2727-2737. doi:10.1016/j.ymthe.2018.09.009
Jackson GH. Use of fludarabine in the treatment of acute myeloid leukemia. Hematol J. 2004;5(suppl 1):S62-S67. doi:10.1038/sj.thj.6200392
Tinajero J, Ngo D, Lee B, et al. AML-408 comparing intensive purine analogues regimens with cladribine and fludarabine: CLIA-Venetoclax vs FLAG-Ida-Venetoclax for relapsed and refractory acute myeloid leukemia during a fludarabine shortage. Clin Lymphoma Myeloma Leuk. 2023;23(suppl 1):S298-S299. doi:10.1016/S2152-2650(23)01056-X
Ammar MA, Tran LJ, McGill B, et al. Pharmacists leadership in a medication shortage response: illustrative examples from a health system response to the COVID-19 crisis. J Am Coll Clin Pharm. 2021;4(9):1134-1143. doi:10.1002/jac5.1443
