No Simple Solutions: Oncology Drug Shortage Persists

Critical drugs used to treat cancer are in short supply in the United States and around the globe. The shortage touches all aspects of hematologic oncology, from common chemotherapy regimens to transplantation, cellular therapy, and clinical trials. While the reasons behind the shortage are complex, one thing is painfully clear.

“It is not exactly a black and white situation, but it is definitely affecting patient care,” said Marcos de Lima, MD, Director of the Blood and Bone Marrow Transplant and Cellular Therapy Program at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

As the oncology drug shortage presses on, many are grappling with its impact and trying to find solutions for patients. However, without a clear-cut solution or end in sight, the situation can feel precarious at times.

“A key issue is uncertainty,” Erin R. Fox, PharmD, MHA, BCPS, FASHP, Associate Chief Pharmacy Officer of Shared Services at the University of Utah Health and Adjunct Professor at the University of Utah College of Pharmacy, said in a statement to Blood Cancers Today. “Allocations mean that providers can only access products in small amounts week to week. This helps ensure fair access, but because the amounts are uncertain, clinicians don’t know if there will be enough product available in three to four weeks for a patient’s next treatment.”

The list of drug shortages from the US Food and Drug Administration (FDA) included multiple oncology drugs, including numerous agents used to treat blood cancers, as of August 2023.¹ Of particular concern for many are the shortages of carboplatin and cisplatin, which are used as single agents and in combinations to treat a variety of cancers.

“In addition to treatment, they’re also used within clinical trials, so in terms of both clinical care and research in the oncology space, this shortage of cisplatin and carboplatin has a dramatic impact,” said Alyssa Schatz, MSW, Senior Director of Policy and Advocacy at the National Comprehensive Cancer Network (NCCN).

Beyond these two well-known chemotherapy agents, several other key drugs used to treat blood cancers are also on the FDA list of shortages. These include injectable azacitidine, methotrexate injections and tablets, injectable cladribine, injectable cytarabine, injectable dacarbazine, and injectable fludarabine phosphate.¹

For example, the shortage of fludarabine phosphate, which is often used with busulfan or melphalan in conditioning regimens for patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), represents an additional challenge in the transplant process.² Even drugs associated with chemotherapy, such as palifermin, are in shortage.¹

“[Palifermin] helps prevent a complication of high-dose chemotherapy called mucositis and inflammation of the mouth and esophagus,” Dr. de Lima said. “It has simply disappeared. Supposedly, we should see it again toward the end of this year. I’m still waiting. This is one you cannot find.”

How Does the Oncology Drug Shortage Impact Patients, Clinical Trials?

With multiple drugs in shortage, the effect can be felt throughout the entire field of oncology.

“The ongoing shortages of common generic chemotherapy agents such as cisplatin, carboplatin, and methotrexate are challenging for health systems and providers,” Dr. Fox said.

In terms of hematologic oncology, Dr. de Lima pointed to the impact on transplant and cellular therapies, which often require the use of regimens based upon drugs that are currently in short supply.

“Basically, folks are having to resort to drugs that are less studied or were deemed inferior back in the late 90s and early 2000s,” he said. “There are cousins of fludarabine that were not used simply because they were deemed inferior way back when. People are having to improvise a little bit to compensate.”

The shortage of fludarabine, which is used in reduced intensity conditioning regimens for HSCT, has a major impact on certain patients.

“The fastest growing segment in transplant today is people above 60 and 65 years of age, and fludarabine is a backbone of this preparation,” he said.

In terms of fludarabine, Dr. de Lima said his institution was “lucky” because it “had a large supply” of the drug. However, the shortage still came with an impact.

“We had to limit its use for a while by prioritizing transplants, but at other institutions I know people have been struggling a lot,” he said.

Another group of patients who are particularly impacted are those preparing to receive chimeric antigen receptor (CAR) T-cells because a lymphodepletion regimen involving fludarabine is used “almost universally” in this setting, Dr. de Lima said.

“The regimens without fludarabine are considered not so good,” he said. “I know that several places had to improvise as well for CAR-T cells. There are alternatives, but … some of them are not listed, some insurances may look at them and say, ‘What are you doing? This is not a priority approval.’”

The NCCN Drugs and Biologics Compendium—a reference containing over 500 entries for drugs across the oncology space—is a resource that can help providers identify alternatives to drugs that are currently in short supply.³ It can help clinicians navigate potential options by providing “authoritative, scientifically derived information designed to support decision-making about the appropriate use of drugs and biologics in patients with cancer,” according to information from the NCCN.³

Dr. de Lima and Schatz both pointed to the NCCN Guidelines, which the NCCN Drugs and Biologics Compendium is based upon, as a resource to help negotiate with insurers. However, they both emphasized that there still can be challenges in terms of insurance approval for alternatives.

“The good news is that there are safe alternatives in many cases in times of a drug shortage,” Schatz said. “But one thing that we are concerned about at NCCN is that a lack of guidance and clarification from payers may cause harmful delays in care when those alternatives aren’t covered quickly.”

While it can be difficult to find a suitable alternative that is covered by insurance for patients who are treated in a more routine setting, clinical trials face additional challenges. The protocols for many clinical trials have strict requirements about the exact drugs and sequencing used in the trial. For example, a clinical trial might prescribe fludarabine, cyclophosphamide, and CAR-T cells as a specific treatment sequence.

In certain settings, institutions might prioritize the clinical trial, “because with clinical trials, you don’t have an option,” Dr. de Lima said. However, “other places had to either slow down or shut down those studies for a while because they didn’t have the drug available,” he added.

The delay or halt of clinical trials impacts not only individual patients, but the overall advancement of hematologic oncology research and treatment.

“I think [the shortage] affected potentially both trials in cell therapy and bone marrow transplants that were very prescriptive and didn’t have alternatives written down on the actual protocol,” Dr. de Lima said.

Can the ‘Heart of the Issue’ Be Addressed?

Market considerations and the economics surrounding generic drugs play a key role in the shortage. Schatz said she believes “the heart of this issue is a market problem.” Although it may seem paradoxical, she explained that “low drug prices are actually a key driver of this shortage” because companies that manufacture generic versions of brand-name drugs operate on a “razor-thin margin,” which “means any interruption or delay in manufacturing could create a ripple effect throughout the market.”

The economics of the situation creates a challenge that is difficult for any single entity to address.

“That razor-thin operating margin demands that these generics plants operate near capacity, and it also reduces the number of manufacturers in the market that are making generics,” Schatz said. “So then when a crisis occurs and a manufacturer is closed, the system doesn’t have the capacity to ramp up and address that with additional supply.”

The FDA can do certain things to prevent and resolve drug shortages, such as expedite reviews of new production lines or material sources to increase production, extend product expiration dates if it is safe to do so, and import medicines if they meet safety and effectiveness criteria, according to its website.⁴

However, the FDA cannot require a pharmaceutical company to make a drug, “even if it is a medically necessary drug,” officials said.⁴ Additionally, the FDA cannot require a company to make more of a drug or change how much and to whom the drug is distributed.

The FDA does require companies to notify it about “manufacturing interruptions or product discontinuances and create a risk management plan for their product supply chain” and emphasized that “early notification from drug companies of any issue that could lead to a potential disruption in supply is critical to preventing or lessening the impact of drug shortages.”⁴

Schatz shared her insights on the current FDA response to the situation.

“The FDA has been importing drugs during the shortage,” Schatz said. “Appropriately, they have also been implementing enhanced quality and safety measures to ensure that those drugs that are being imported in are safe.”

However, she emphasized that importing drugs is a “short-term response” to the issue, noting that “there are many other stakeholders that are also coming together collaboratively to begin working on long-term solutions, because drug shortages are not a new development.”

The big-picture, long-term solutions will need to be multipronged efforts involving numerous entities.

“The good news is both the White House and Congress are looking at this issue,” Schatz said. “Our convening stakeholders are seeking public comment and working on this with an appropriate sense of urgency. There are multiple proposals looking to tackle this right now. [Centers for Medicare and Medicaid Services] has also put forth their own proposal around reimbursement for a buffer stock of medicines. There are some market-based reforms in Congress. There are a variety of proposals and people coming together to try to address it, both in the short term and in the long term.”

Beyond action at a federal level, multiple medical societies—such as the American Society of Hematology, the American Society of Clinical Oncology, and the American Society of Transplantation and Cellular Therapy—are “taking a role” to negotiate on behalf of clinicians and patients, Dr. de Lima said.

As patients, clinicians, health care systems, and medical societies await larger solutions, the effects of the shortage continue to be felt throughout the country. However, multiple entities are working together to maintain and manage supplies. For example, the City of Hope has worked with a team to address the situation.

“Through our active participation with the Alliance of Dedicated Cancer Centers pharmacy leadership group, we have been engaged with the FDA regarding this matter to procure these important medicines for our patients during this very challenging time,” City of Hope officials said in a statement to Blood Cancers Today. “We are managing our current supply at hand through a dedicated team of integrated staff across our national cancer care system and have been able to provide the very best care possible for our patients.”

However, not every patient receives care at a comprehensive cancer center in the United States, and the impact of the shortage extends far beyond national borders.

“Outside of the US, our colleagues in developing countries are not seeing any of these drugs because the little bit that remains is coming to us and possibly to Europe,” Dr. de Lima said. “In places where the power, the money, and the volumes are not so high, they ran out of these drugs months ago. It’s much worse than here.”

The situation also extends far beyond the present moment, as drug shortages have occurred in the past. For example, an FDA report showed a peak of 251 new drug shortages during 2011, compared with 49 new shortages in 2022.⁵ The FDA listed 181 current or resolved drug shortages on its website as of August 2023.¹

“Although the number of new drug shortages has declined since 2011 as a result of work by many groups, including [the] FDA, shortages continue to pose a real challenge to public health, particularly when the shortage has involved a critical drug to treat cancer, to provide parenteral nutrition, or to address other serious medical conditions, such as a shortage of antibiotics,” FDA officials wrote in the report.⁵ “In the past year, [the] FDA has seen manufacturers in the United States and abroad continue to experience quality issues as well as struggle with capacity constraints.”

The FDA report emphasized the importance of continuing to develop and implement solutions that focus on preventing future shortages. Specifically, it outlined needs that “require ongoing work to be fully addressed,” which include the need to “gain better insight into the supply chain” and the need to “increase the resilience of the supply chain.”⁵

Others outside of the FDA have echoed these needs. For example, Dr. de Lima noted one “potential solution” to the supply chain issue is to look at cheaper manufacturing of generic medications outside the United States. However, he said there are several caveats and challenges with this, such as intellectual property considerations, and more.

“The question as always is quality assurance and the legalities of this, that’s where the FDA comes in,” he said.

Schatz spoke about addressing the situation from multiple angles.

“We potentially need some market interventions to address preventing shortages as well as predicting when shortages are more likely to occur so that we can prepare for that response,” she said.

In terms of gaining insights into the supply chain, Schatz emphasized the importance of developing informatics infrastructure to “help us understand when a shortage occurs, what supply we have and how we can allocate that in a way that is going to mitigate harm as much as possible.”

That effort will require many entities to combine their resources and information.

“We have data in a variety of places, and we need all different stakeholders to come together so that we can have a more centralized system to understand risk, opportunities to prepare and intervene, and also opportunities to mitigate harm when a shortage does occur,” she said.

While the situation and solutions at hand are both complex and may require broad, high-level efforts from many stakeholders, individuals can still make a difference. Dr. de Lima and Schatz both emphasized the importance of making patient and clinician voices heard amid the drug shortage.

“I think that the first step is to make sure that people listen to us,” Dr. de Lima said.

Schatz urged people affected by the shortage to call their elected officials about the situation.

“Patients need to know that their voice really matters,” she said. “I’ve been doing policy and advocacy work for my entire career, and I can tell you that when someone who is personally impacted shares their story, it helps to change minds and create a sense of urgency.”

Overall, the combined efforts of individuals, health care systems, manufacturers, government, and other institutions will be critical to addressing this shortage, as well as preventing future shortages.

“These [shortages] have happened before, and if we don’t implement long-term sustainable solutions, they will happen again,” Schatz said. “But they’re not inevitable and we can come together to address these issues.”

References

1. Current and resolved drug shortages and discontinuations reported to FDA. US Food and Drug Administration. Accessed August 23, 2023. https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm.
2. Jain T, Alahdab F, Firwana B, Sonbol MB, Almader-Douglas D, Palmer J. Choosing a reduced-intensity conditioning regimen for allogeneic stem cell transplantation, fludarabine/busulfan versus fludarabine melphalan: A systematic review and meta-analysis. Biol Blood Marrow Transplant. 2019;25(4):728-733. doi:10.1016/j.bbmt.2018.11.016
3. The NCCN Drugs & Biologics Compendium®. National Comprehensive Cancer Network. Accessed August 23, 2023. https://www.nccn.org/compendia-templates/compendia/drugs-and-biologics-compendia
4. Drug shortages infographic. US Food and Drug Administration. Published December 7, 2022. Accessed August 24, 2023. https://www.fda.gov/drugs/drug-shortages/drug-shortages-infographic
5. 10th Annual Report to Congress on Drug Shortages for Calendar Year 2022. US Food and Drug Administration. Accessed August 24, 2023. https://www.fda.gov/media/169302/download?attachment