Generic cancer drugs are still in short supply

Abstract

Generic carboplatin and cisplatin are inexpensive and indispensable. The platinum-based, injectable chemotherapeutic drugs have factored prominently in curative regimens and combination therapies that have significantly extended patients’ lives. By rights, they should be the poster children of cost-effective cancer care. Instead, they have become the focal points of a painful drug shortage in the United States that has dragged on since February 2023.

“This is the most critical chemotherapy shortage I’ve ever seen, and this is, certainly, a public health emergency,” says Angeles Alvarez Secord, MD, MHSc, director of gynecologic oncology clinical trials at Duke Cancer Institute in Durham, North Carolina. “It breaks my heart that you have cancer patients—or any patient for that matter—going through this.”

Drug shortages are a long-standing headache for hospitals, but the breadth and duration of the ongoing shortage in what another expert calls “bread-and-butter” oncology drugs have created an unusually acute crisis. The shortage has also renewed calls for government action that multiple providers and professional societies say is long overdue.

“It’s really mind blowing that we are here in 2023 dealing with pretty significant impacts on patients,” says Kirollos Hanna, PharmD, director of pharmacy at Minnesota Oncology and an assistant professor of pharmacy at the Mayo Clinic College of Medicine in Rochester, Minnesota. With cisplatin and carboplatin, he says, “We were at a point where we said, ‘No metastatic disease utilization.’ We said, ‘Find something else, even if the data are subpar.’ That’s all we had to work with, because we needed to be sure we were curing our bladder and testicular cancer patients.”

Stephen Colvill, MBA, assistant research director of the Duke–Margolis Center for Health Policy at Duke University, says that the severe impact of the cancer drug shortage has increased the visibility of what has been a “pretty consistent” problem. Among the root causes, he cites a lack of investment in modernized equipment, facilities, quality infrastructure, redundancy, and risk mitigation plans for generic drugs both within and beyond the United States.

In late 2022, a major production facility in Ahmedabad, India, owned by Intas Pharmaceuticals, failed a surprise Food and Drug Administration (FDA) inspection for a range of egregious safety and quality infractions. When the plant shut down, it knocked out an estimated half of all cisplatin and methotrexate production for the US market. Because the sterile, injectable form of cisplatin is complicated to make, other production facilities could not easily pick up the slack. Then, as demand spiked for alternatives, the ripple effect contributed to shortages of carboplatin as well.

By May 2023, 93% of academic cancer centers reported a shortage of carboplatin, while roughly 70% were short of cisplatin, according to a National Comprehensive Cancer Network (NCCN) survey.¹ Two thirds of the centers reported that methotrexate, used to treat a variety of cancers and autoimmune conditions, was in short supply too. A follow-up NCCN survey in October 2023 found that 72% of cancer centers were still short on carboplatin and that 59% lacked enough cisplatin.² The methotrexate shortage had not eased at all, whereas other drugs, such as 5-fluorouracil, fludarabine, and hydrocortisone, were showing signs of increased scarcity.

The fallout has been particularly severe for smaller and underresourced medical institutions, and this raises troubling equity and access questions. “We’re not talking about people living a couple of months longer; we’re talking about people surviving cancer,” says Lori Wirth, MD, an associate professor of medicine at Harvard Medical School and the medical director of the Head and Neck Oncology Program at Massachusetts General Hospital in Boston, Massachusetts. “If there isn’t equal access to these lifesaving therapies, it’s a major problem.”

Larger hospital networks have been better able to move drugs from one place to another when needed. Even so, several have had to develop rationing plans for the most affected medications. If faced with a severe shortage, “we would prioritize access to those drugs for patients who are receiving treatment with curative intent,” says Dr Wirth. That means patients being treated for palliative reasons could potentially have to do without. “It was incredibly wrenching, really distressing, and mind boggling,” she says of the hospital system’s rationing exercise. “These are drugs that are the oncology equivalents of penicillin or azithromycin.”

Dr Secord, who is also president of the Society of Gynecologic Oncology, recalls that society members in at least 40 states were reporting a cisplatin or carboplatin shortage at one point. The society has offered guidance and mitigation strategies to worried providers and patients. “We are still utilizing those mitigation strategies here at Duke to try to help us, because we still have a shortage. It hasn’t gone away,” she says.

Several experts have pointed out that shortages almost exclusively affect generic drugs. “We rarely see shortages with branded products,” Dr Hanna says. One contributing factor is the relatively small profit margin for generic drug manufacturing. Consequently, those drugs are not a priority for major manufacturers and are made instead by a limited number of facilities that, like the one in Ahmedabad, are often abroad, and they can have an outsized impact on availability if they go offline.

Other experts cite an imbalance toward production models that emphasize efficiency and cost savings but are less adept at handling the unavoidable risks and unknowns of drug manufacturing. “Perhaps we’ve shifted too much toward the low-cost, lack of redundancy side of things and for lifesaving, essential drugs, that’s probably not the best way to do it,” Colvill says.

In June 2023, the FDA announced a temporary easing of restrictions to allow cisplatin imports from China, but the move was widely seen as a short-term solution. Andrew G. Shuman, MD, associate professor and chief of the Clinical Ethics Service at the University of Michigan Medical School in Ann Arbor, cautions that the United States is already highly reliant on foreign-sourced drugs and drug ingredients. That long-term concern is reflected by Senate bills seeking to mitigate what some policymakers have deemed a national security threat. “This is truly an issue of national security in addition to our public health risk for our nation,” Dr Shuman says.

Other legislative and policy proposals are seeking to reimagine and reinforce the health care supply chain and avoid overreliance on any one facility. Currently, the FDA cannot order any manufacturer to increase production short of a government-declared state of emergency, as happened during the coronavirus disease 2019 pandemic. The government could, however, offer incentives to the manufacturers of important generic drugs. “We incentivize practices when they can reduce total cost of care. Why not incentivize a manufacturing plant for ensuring a steady supply stream of critical medications?” Dr Hanna says.

Beyond tax incentives, proposals have included federal grants and loans and public–private partnerships for expanding the drug manufacturing infrastructure. “We do this for gas, oil, and water, which are critical substances that all Americans rely and depend upon,” Dr Shuman says. “I would argue that cancer drugs fit into that mold as well.”

At Duke, the recently launched Drug Supply Chain Resilience and Advanced Manufacturing Consortium is working to identify both short-term and long-term steps that the government and private sector could take toward a more reliable drug supply chain. Proposed legislation, for example, would allow the FDA to establish a certification process that identifies high-quality drugs and manufacturing processes.

Other pending legislation would require drug manufacturers to alert the FDA of anticipated shortages and divulge who makes the active pharmaceutical ingredients in their products. “If there had been better communication when the first shortages of cisplatin and carboplatin were anticipated, we could have rolled out mitigation strategies then and been proactive,” Dr Secord says. Instead, many providers remained in the dark.

At the state level, Dr Hanna says, legislation could remove some roadblocks to cooperatively transferring drugs from one health system to another during severe shortages. “We have hospitals within the state of Minnesota that could not get any cisplatin,” he says. Because they could not easily get it from other health systems either, they faced the prospect of abruptly ending patients’ therapy or transferring them to a different institution.

The good news, according to Dr Shuman, is that multiple reports have detailed root causes and potential solutions for the chronic drug shortages. The catch is that many of those solutions require legislative action. “There are many proposed laws now that absolutely will move the needle in the right direction,” he says. “But until and unless those get traction and have the bipartisan support necessary to get through, we will be reliving this nightmare indefinitely.”

In the absence of Congressional action and extensive coordination throughout the health care system, Dr Secord says, the problem will only get worse. “There are going to be empty seats at our holiday tables this year because of the chemotherapy shortages,” she says.