In hematology/oncology, drug shortages typically affect older, less expensive drugs, but when no alternatives are available, clinicians may struggle to provide the best care.
It’s been more than a year since the U.S. was hit with a prolonged shortage of the critical chemotherapy agent vincristine, but pediatric hematologist/oncologist Lauren Pommert, MD, clearly remembers its aftermath. She and her partners at Children’s Wisconsin would review a list of all their leukemia and lymphoma patients to coordinate who would receive their therapy on time and who would not.
“Basically, every week we would go over the list to see who was coming into clinic and decide who would get vincristine based on their diagnosis, where they were in therapy, and their overall risk stratification,” said Dr. Pommert, who is now a pediatric oncologist at Cincinnati Children’s Hospital and an assistant professor in the department of pediatrics at the University of Cincinnati.
The vincristine shortage was a perfect storm of manufacturing issues: at the beginning of 2019, two companies were making vincristine – the brand manufacturer Pfizer and the generic producer Teva Pharmaceuticals. Then, in the middle of 2019, Teva exited the market and stopped production of the drug. Though Teva said its share of the market was just 3%, Pfizer ran into manufacturing problems around the same time, putting the drug into shortage. The crisis resolved in 2020 after Teva reentered the market and Pfizer was able to successfully ramp up production.
The shortage of vincristine, an older and inexpensive chemotherapy agent, was felt acutely in the pediatric setting. It is part of nearly every childhood cancer therapy regimen and there is no alternative therapy that can be substituted for it.
That type of critical shortage leaves hematologists and oncologists with few options. Dr. Pommert said that she and her colleagues prioritized patients in critical phases of therapy and those with high-risk disease. They reduced, delayed, or completely omitted vincristine doses for low-risk patients or those in the maintenance phase of therapy. They also adjusted doses so that none of the vials of the medication opened went to waste. “We were forced to ration the medications that we had,” she said.
The impact of this type of rationing on patient outcomes is largely unknown. “We know the outcomes data if patients receive all of their intended chemotherapy doses, and we also know that patients who receive less than their intended doses have a higher risk of relapse,” Dr. Pommert said. “For vincristine, we don’t know the result of a couple of missed doses. How many missed doses is too many? What number would cause an increased risk of relapse? We don’t know the answers.”
The vincristine crisis is just one example of the intermittent drug shortages across oncology and hematology therapies and supportive medications that occur at any given time, prompting clinicians and pharmacists to search for supplies, make substitutions, and identify evidence-based alternatives. “It is unacceptable that, in such a resource-rich country, we are forced to alter well-studied treatment plans and are endangering our ability to maintain or improve cure rates for pediatric cancers,” Dr. Pommert stressed.
ASH Clinical News spoke with Dr. Pommert and other clinicians and pharmacists about the challenges of navigating drug shortages and strengthening the supply chain.
A Constant State of Shortage
The American Society of Hematology (ASH) has been active on the issue of drug shortages for over 10 years, informing the U.S. Food and Drug Administration (FDA) that ongoing shortages of critical hematology therapies have negatively affected treatment decisions, caused rationing of care, increased costs, and created emotional distress for patients and families.1
Tabitha Alvarado, the oncology infusion compliance coordinator at the University of Kentucky, handles inventory in oncology and deals with shortages and procurement. She estimated that she spends about one-third of her time dealing with shortage-related issues. When learning about drug shortages, her first point of contact is usually the drug wholesaler, followed by the FDA and associations like the American Society of Health-System Pharmacists (ASHP).
The FDA maintains a list of current drug shortages on its website, which includes the formulations and doses in shortage, the availability and estimated shortage duration, and the reason for the shortage. An additional list of vaccine and biologics shortages is available through the FDA’s Center for Biologics Evaluation and Research. ASH also hosts its own list of reported shortages affecting hematology, along with information about recently resolved shortages and discontinued drugs.
Unfortunately, it can take up to a week for news of a shortage to make it onto these lists, Ms. Alvarado said. When it does, the information provided can be vague, leaving those in the drug supply chain with limited information about how long they will struggle to obtain medications.
Why Do Shortages Happen?
Most drug shortages are a result of manufacturing issues, experts said, whether it’s a problem with obtaining raw materials, an issue of contamination at a manufacturing facility, or a producer leaving the market. In some cases, like with the current shortage of intravenous tocilizumab (Actemra), demand for a drug outpaces the available supply.
Genentech announced that as of August 16, 2021, the company would stock out of Actemra IV 200 mg and 400 mg. By mid-August, Actemra IV 80 mg was in short supply and expected to go out of stock soon. The company said it expected replenishments of stock by the end of August, but anticipated intermittent stockouts in the coming months, depending on the impact of the COVID-19 pandemic.
Another recent demand-related shortage has been seen with tocilizumab, an immunosuppressive drug that is used for rheumatoid arthritis and is part of the management of cytokine release syndrome for patients undergoing antibody-based or chimeric antigen receptor (CAR) T-cell immunotherapy. The spike in demand comes as tocilizumab is increasingly being used to treat severely ill patients hospitalized with COVID-19.
Scott Soefje, PharmD, director of pharmacy cancer care services at Mayo Clinic in Rochester, Minnesota, said his institution is having trouble obtaining tocilizumab. “The volume and use of that drug has skyrocketed over the last month or so because of the [COVID-19] surge. We’re scrambling to make sure that we have enough,” he said. “We won’t even start a patient on CAR T-cell therapy until we know we have the drug on hand.”
In most cases, oncology-related shortages occur with generic medications. For those typically older and less expensive drugs, profit margins are slim and fewer manufacturers are likely to produce them, making the supply chain even more vulnerable. The fact that many drugs and their raw materials are manufactured outside of the U.S. can also create supply chain problems, simply because of transportation issues.
“Some of our most important drugs, our curative drugs, are generics,” said Leslie T. Busby, MD, a medical oncologist and hematologist at Rocky Mountain Cancer Centers and chairman of the US Oncology Network’s pharmacy and therapeutics committee. “One of the questions we have to ask is: Should some of these critical drugs be repatriated? What would that look like? What would it take so that they can still meet their costs?”
Even when drug supplies are stocked, problems can arise. For example, severe winter storms in Texas delayed shipments of drugs to cancer centers around the country early in the year.
Shortages in hematology/oncology drugs saw a spike about 10 years ago but have been less frequent in recent years, according to experts who spoke with ASH Clinical News. However, an FDA spokesperson said that the agency is continuing to see shortages of older sterile injectable drugs, including those used for hematology-related therapies. Examples from recent years include etoposide, bleomycin, and vincristine.
“Manufacturing of sterile injectables is a complex process. When a problem or delay occurs at one manufacturer, even if other manufacturers are making the drug, the limited manufacturing capacity at the other manufacturers can still lead to a shortage,” the FDA spokesperson explained. “In addition, these older drugs are often less profitable than newer therapies and companies may lack incentives to continue to make them.”
In 2019, the FDA published a paper outlining three root causes for drug shortages: a lack of incentives for manufacturers to produce drugs that are less profitable; a market that fails to recognize and reward manufacturers who engage in continuous quality improvement and early detection of supply chain issues; and logistic and regulatory challenges that make it difficult to recover from a disruption.2
The Drug Supply Chain Gang
Health systems devote much time to managing the drug supply chain, with a goal of mitigating any potential drug shortages, identifying early warning signs of shortage, and maintaining adequate supplies of critical medications.
“We try to be as forward-thinking as we can,” Dr. Busby said.
As chairman of the pharmacy and therapeutics (P&T) committee for the US Oncology Network, Dr. Busby works with the supply chain and inventory management teams to let them know which drugs need to be on hand because they are essential curative treatments without alternatives. Shortages occur most often in the background of clinical care. Even though a drug may be in short supply for a limited time, health systems are able to rely on existing stock, find it from other wholesalers, or even acquire it from another institution.
The P&T committee, which includes physicians and pharmacists from across the network, usually gets involved when a drug shortage is prolonged. At that point, they need to consider the clinical picture – discussing potential alternatives and how to direct curative therapies to the most appropriate patients.
For example, when the chemotherapy agent etoposide was in shortage, the P&T committee shared information about alternatives that could achieve outcomes and asked clinicians to save etoposide for curative regimens.
The Mayo Clinic team also spends time and resources to proactively manage drug shortages. “One of the problems with drug shortages is that we often don’t know there’s a drug shortage until we place an order and the wholesaler notifies us that they’re going to back-order or short the drug,” Dr. Soefje said.
At the start of the COVID-19 pandemic, the Mayo Clinic cancer pharmacy team met with the drug supply chain group to discuss what critical cancer medications could potentially be disrupted, likely because a drug or key ingredient was manufactured overseas, Dr. Soefje explained. In some cases, they increased their supply of those drugs for several months to guard against a potential shortage. They backed off the practice this spring, but they are revisiting the idea now in light of the surge in cases involving the Delta variant.
A Scarcity of Evidence
As clinicians are increasingly asked to consider alternatives to established regimens, they are turning to the medical literature to aid their decision-making. Sarah K. Tasian, MD, chief of the Hematologic Malignancies Program at the Children’s Hospital of Philadelphia, said an evidence-based approach has helped her institution cope with shortages without jeopardizing patient outcomes.
Dr. Tasian, who is also an associate professor of pediatrics at University of Pennsylvania’s Perelman School of Medicine, said that, over the past five years, her institution has dealt with intermittent shortages of L-asparaginase and Erwinia L-asparaginase – key components of pediatric acute lymphocytic leukemia treatment. While in the past they were quick to switch children to these drugs if they became allergic to treatment with PEG-asparaginase, the lack of availability has forced them to consider other approaches.
“For us, it’s difficult because some of the children will only get four to eight courses of these medications,” Dr. Tasian explained. “Just because we have the medications right now doesn’t necessarily mean that the children are going to get everything that they need to complete their gold-standard curative treatment regimens.”
Now, her hospital documents the severity of any reaction and uses real-time laboratory testing to check patients’ serum asparaginase activity levels before deciding whether to make a switch. “For children who had a rash or some symptoms of hypersensitivity, but whose labs showed that they had effective asparagine depletion, we would try to push on and maximize their PEG-asparaginase dosing,” she said.
They also changed their proactive practice by premedicating all patients with allergy medications and slowing infusion to two hours instead of one.
“These were some of the rescue strategies in the past for patients who had allergic reactions, but we put them in proactively and empirically to try to reduce the risk of patients developing allergic or anaphylactic symptoms,” Dr. Tasian said. “That was actually something good that came out of the shortage. It forced us to think critically about our practices and also coincided nicely with real-time clinical serum asparaginase activity monitoring.”
Clinicians at Massachusetts General Hospital (MGH) also had success reexamining their use of heparin when that drug went into critical shortage in 2019. The shortage was triggered by an outbreak of African swine fever in pigs in China, dramatically reducing the pig population and restricting a key ingredient in heparin production.3
MGH responded by activating its Hospital Incident Command System, a program designed to respond to a variety of drug shortages and other emergencies. That activation triggered a multidisciplinary task force to create detailed clinical algorithms that allowed them to reduce the use of heparin by 80% in less than two months.
The algorithms employed a tiered approach: Heparin was recommended for life-saving cases, and alternatives were used when appropriate. “We never denied someone heparin,” said Rachel P. Rosovsky, MD, a hematologist at MGH and an assistant professor of medicine at Harvard Medical School, who served on the task force. In the cases where the algorithm called for an alternative, MGH disseminated robust data supporting the efficacy and safety of low molecular weight heparin for venous thromboembolism (VTE) prophylaxis. The team also shared literature to support the use of fondaparinux, apixaban, rivaroxaban, dabigatran, and betrixaban for VTE prophylaxis in certain patient populations. The task force stratified its recommendations based on the strength of the evidence and what agents were available on the hospital formulary.
In this experience, the key to safely reducing heparin use was inclusion and education, Dr. Rosovsky explained. The task force included representatives from across specialties and updates were communicated regularly on an internal website. “Everybody knew what we were doing at all times.”
MGH also rolled out extensive education around the heparin alternatives, providing lectures to every department in the hospital and integrating information into the hospital’s electronic medical record system. Dr. Rosovsky and a member of the pharmacy team responded around the clock to calls with questions about the therapeutic changes. Through that education, many physicians were more comfortable moving away from heparin. “We saw this as a real opportunity to change practices,” Dr. Rosovsky said.
The FDA’s Role
The FDA plays a key role in alerting clinicians to shortages, working with drug manufacturers to prevent them in the first place, and also working with the manufacturers to address the issues in a timely manner. Drug manufacturers are required to notify the FDA at least six months in advance of a product discontinuation or an anticipated manufacturing interruption. When that type of notice is not possible, manufacturers must notify the agency as soon as they become aware of an issue. The FDA recently issued guidance to industry requesting that manufacturers also provide notification of increased demand.4
The agency works directly with companies to address manufacturing and quality problems, ranging from incorrect labeling to sterility issues, and can exercise regulatory discretion to address shortages that pose a public health risk. The agency estimated that, through its work to mitigate shortages, it prevented 199 new shortages in 2020.5
When a shortage occurs, the FDA communicates with other companies who are producing the drug to ramp up their production, by expediting approval of new production lines or new raw material sources. The agency can also help bolster supply by extending the expiration date, when the evidence supports it, to enable companies to ship out drugs that are close to expiration or already expired.
When U.S. manufacturers are unable to resolve a shortage quickly or the shortage drug is in critical demand, the FDA may look for a firm that is able to redirect product into the U.S. market. The agency has a list of criteria to evaluate overseas products to ensure efficacy and safety, including the drug formulation and the quality of the manufacturing site.6
Working Toward Solutions
In its 2019 report on drug shortages, the FDA recommended a few enduring strategies for tackling drug shortages, including developing a rating system to incentivize drug manufacturers to invest in quality management practices in their facilities. The agency also proposed promoting private sector contracts that have built in risk-adjusted financial incentives to encourage manufacturers to stay in the market.
ASH has also played a critical role in keeping hematologists informed of drug shortages, working with both the FDA and manufacturers to obtain early notice of drugs in short supply, the reasons behind those shortages, and estimates of when the products will be available.
In addition, ASH has worked with members of Congress to vet legislative proposals aimed at the root causes of drug shortages and continues to monitor legislation focused on drug shortage issues.
In 2019, during the last session of Congress, Sens. Patty Murray (D-WA) and Lamar Alexander (R-TN) introduced “The Mitigating Emergency Drug Shortages (MEDS) Act” (S. 2723), which would have increased manufacturer requirements for shortage reporting. It also called on the Department of Health and Human Services to provide guidance on market-based incentives that would encourage the manufacture of drugs in shortage, as well as the domestic manufacturing of finished drugs and key ingredients for drugs in shortage. The bill was referred to committee but did not advance in the Senate.7 A more recent proposal, introduced in the U.S. House of Representatives in June 2021, calls for providing incentives to maintain, expand, and relocate manufacturing of active pharmaceutical ingredients and other items in the U.S. The “MADE in America Act” (H.R. 3927) was introduced by Rep. Earl L. “Buddy” Carter (R-GA).8
The Congressional response to the COVID-19 pandemic also included measures to prevent and address potential drug shortages. In March 2020, as part of the Coronavirus Aid, Relief, and Economic Security (CARES) Act, Congress required the FDA to prioritize the review of applications for generic drugs in shortage and expedite inspections and review for abbreviated new drug applications and supplements. The law also mandates more detailed manufacturer reporting about a shortage’s precipitating events, its likely duration, and its expected impact. Manufacturers are also required to develop risk management and redundancy plans for their supply chains and perform risk assessments to identify factors that could negatively impact manufacturing of drugs.9
As Congress considers additional legislative fixes to the drug shortage issue, advocacy from hematologists through efforts such as the ASH Grassroots Network will continue to play a crucial role. Drs. Pommert and Tasian added, though, that advocacy from parents and families will also be critical to moving bills forward.
“I would like to leverage the power of parents in these discussions,” Dr. Tasian said. “A lot of physicians and families are not aware of these drug shortages until they hit close to home. Once we learn that a life-saving chemotherapy drug is unavailable for their child because of shortages, it feels completely egregious. The voices of impassioned parents are honestly so much more effective than what we can do as pediatric oncologists. We need their partnership.” —Mary Ellen Schneider
- American Society of Hematology. Letter to the FDA: Identifying the Root Causes of Drug Shortages and Finding Enduring Solutions; Public Meeting; Request for Comments. January 11, 2019.
- U.S. Food and Drug Administration. Drug Shortages: Root Causes and Potential Solutions. March 11, 2020. Accessed September 1, 2021. https://www.fda.gov/drugs/drug-shortages/report-drug-shortages-root-causes-and-potential-solutions.
- Rosovsky R, Barra ME, Roberts RJ, et al. When pigs fly: a multidisciplinary approach to navigating a critical heparin shortage. Oncologist. 2020;25(4):334-347.
- U.S. Food and Drug Administration. Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act: Guidance for Industry. March 2020. https://www.fda.gov/media/136486/download.
- U.S. Food and Drug Administration. Report to Congress: Drug Shortages for Calendar Year 2020. Accessed September 1, 2021. https://www.fda.gov/media/150409/
- U.S. Food and Drug Administration. Frequently Asked Questions about Drug Shortages. November 13, 2020. Accessed September 1, 2021. https://www.fda.gov/drugs/drug-shortages/frequently-asked-questions-about-drug-shortages.
- Congress.gov. S.2723 – Mitigating Emergency Drug Shortages Act, 116th Congress (2019-2020). October 29, 2019. Accessed September 1, 2021. https://www.congress.gov/bill/116th-congress/senate-bill/2723/text.
- Congress.gov. H.R.3927 – MADE in America Act, 117th Congress (2021-2022). June 16, 2021. Accessed September 1, 2021. https://www.congress.gov/bill/117th-congress/house-bill/3927/text.
- American Society of Health-System Pharmacists. Issue Brief: CARES Act Provisions on Shortages and Readiness. March 20, 2020. Accessed September 1, 2021. https://www.ashp.org/covid-19/issue-brief-cares-shortages.