Chemotherapy Shortages Mitigated by Transparency and Economic Incentives

As the current chemotherapy drug shortage involving cisplatin and carboplatin that began in February 2023 has reached its peak, efforts have turned to identifying strategies to mitigate the effect of potential shortages in the future. Many underlying factors contribute to drug shortages but the biggest contributor remains economic in nature.

Overall, there are 3 root causes of drug shortages according to the report, “Drug Shortages: Root Causes and Potential Solutions,” from the FDA.¹ These include a lack of incentives to manufacturers to develop less profitable drugs; there is a lack of reward for manufacturers who use mature production and quality systems to improve supply chain issues; and logistical and regulatory requirements that contribute to the difficulty in recovery when a disruption occurs.¹

In particular, the shortages for cisplatin and carboplatin resulted when an FDA inspection of a manufacturing plant in India led to the plant being shuttered and production coming to a halt. Although 5 manufacturers supply the world with the ingredients for these agents, the creation of the chemotherapy occurs in this 1 plant, thus creating a bottleneck.

“The immediate cause was the shutdown of this plant in India, but the bigger picture points to a disastrous infrastructure for the manufacture of generic sterile injectables,” Julie Gralow, MD, FACP, FASCO, chief medical officer at the Society of Clinical Oncology (ASCO), said in an interview with Targeted Therapies in Oncology. “There’s a need for greater transparency in the manufacturing process, so that 1 plant doesn’t supply the whole market,” Gralow continued.

Gralow acknowledged that hand-in-hand with the manufacturing are the economics of the situation. “The original manufacturer of the drug that has been making a profit stops producing because the profits dry up and the patent expires,” Gralow explained. “When a drug goes off patent, the companies that manufacture generics come in to bid, and they undercut prices, so it’s a race to the bottom,” Gralow continued.

When it was recognized that a shortage was imminent, the FDA allowed for temporary importation, and issued temporary licenses. “But there are costs associated with the application process, and it takes time and effort on the company’s part to complete those applications. Manufacturers weren’t quick to jump right in,” Gralow said.

NCCN Survey

A survey conducted by the National Comprehensive Cancer Network (NCCN) showed that 93% of cancer centers reported a shortage of carboplatin and 70% reported shortages of cisplatin.² Findings were published June 7, 2023 and involved 27 NCCN member institutions across the US.

According to the survey, despite the high rates of shortage, 100% of the centers said they were still able to treat patients who needed cisplatin without any delays or claim denials. For patients who required carboplatin, however, only 64% of centers could meet regimen requirements. Further, only 20% reported being able to continue this prescription for some but not all patients. Regarding prior authorizations (PAs), 16% of centers report treatment delays as a result of re-obtaining PAs for modified treatment plans, but none have met with denials.

Highlights from the survey provided insights about how the cancer centers were meeting the challenge of the carboplatin and cisplatin shortage (FIGURE).²

Gralow offered her thoughts on the report. “I thought 2 questions were particularly interesting. One was, ‘Is your site experiencing a shortage of cisplatin and carboplatin?’ Nearly every site responded ‘Yes.’ The other question was, ‘Has the shortage impacted the ability of your patients to get access at the intended dose and interval for cisplatin?’ And all the centers responded that the shortage had not impacted their ability to get access,” Gralow said.

Mitigation and guidance efforts were likely helpful as well, Gralow noted. Substituting alternate medications for carboplatin and cisplatin were suggested and efforts that focused on modifying approved doses were initiated by the cancer centers. “If the approved dose ranged from an area under the curve of 4 to 6 for carboplatin because clinical studies had looked at both, cancer centers administered the lower dose,” Gralow said. “Similarly, if the guidelines suggested a dosing interval every 3 or 4 weeks, centers opted for the 4 week interval,” Gralow continued. The interval dose spacing allowed the centers some wiggle room with their supplies of drug.

The NCCN survey featured large, comprehensive cancer centers, which might have more buying power to purchase the agents rather than the smaller cancer centers, Gralow added.

ASCO has started collecting anecdotal stories from members about their experience with the chemotherapy shortage. Physicians who are located in smaller cancer centers have had some challenges obtaining enough of the agents because of lesser buying power. Gralow shared that when some of the smaller sites requested to buy a portion of the larger cancer center’s stockpile, the larger centers instead suggested that they send patients to the larger center for treatment or clinical trial enrollment. It should be noted that in many cases, there was not the option of selling or transferring to another center because the drug had been purchased under the 340B discounted pricing eligible to centers particating in Medicaid programs. “So the point is that there is drug available,” Gralow said.

Legislative Response

In 2017, The American Society of Health- System Pharmacists convened a roundtable meeting of health care professional organizations, including the American Society of Anesthesiologists, American Society of Clinical Oncology, American Medical Association, American Hospital Association, the FDA, and the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, to review and identify ongoing drug supply chain barriers associated with shortages that were present back then.³

“Recommendations based on what came out of that meeting were issued that covered legislation, regulatory, but mostly market and economic solutions,” Gralow said. “If you go back to that report, we’re still saying that we recommend all of those things again.”

Gralow said that she had recently testified in The Subcommittee on Health of the Committee on Energy and Commerce at the US House of Representatives during the “Legislative Solutions to Bolster Preparedness for All Hazards and Public Health Security Threats” hearing in June 2023. The purpose of the testimony was to reauthorize the Pandemic and All-Hazard Preparedness Act (PAHPA), the Strategic National Stockpile (SNS), and further define the role of the SNS to mitigate oncology-drug shortages.

During her testimony Gralow said, “Factors such as manufacturing disruptions, quality control issues, regulatory challenges, supply chain vulnerabilities, and market dynamics contribute to the persistent shortage of critical cancer medications. While some shortages may be temporary, others persist for prolonged periods, leaving patients at risk and health care providers struggling to deliver optimal care.”

The following recommendations were made to guide policymakers to address these challenges:

• Incentivize advanced manufacturing technology and develop new continuous manufacturing technology for critical drugs and active pharmaceutical ingredients (APIs) in both foreign and domestic facilities.
• Improve the function and composition of the SNS.
• Improve multinational cooperation and collaboration on supply chain resilience, including support for intergovernmental, regulatory, and public-private partnerships.
• Incentivize manufacturers to improve quality and resilience by providing publicly available quality management ratings, reducing contamination, and identifying key starting materials, active pharmaceutical ingredients, and finished dosage forms of essential medicines.
• Replicate tasks for critical drug manufacturing transparency and oversight for medical devices and ancillary supplies.

“If that kind of transparency existed, we would have understood the severity of the shortage back in November or December 2022,” Gralow said. “Although there are regulatory and legislative solutions, the long-term fix has to do with the [drug manufacturing] market and economics. And the fact is, we are going to have to pay more for these drugs,” she said.

Clinical Trial Implications

Regarding the impact of the drug shortage on clinical trial research, Gralow said the National Cancer Institute has identified at least 100 ongoing clinical trials that have been impacted by the shortage.

“What I’m hearing from clinical trial sites that are having trouble obtaining cisplatin and carboplatin is that the manufacturers are supplying it, so it’s unclear if there is a real issue with trials,” Gralow said. “If the trial is a registration trial, it’s my understanding that in cases, the sites are getting the drug. But that might not be the case for smaller trial sites,” Gralow continued.

She also noted that it’s possible that eligibility has dropped for some trials at some sites. These sites might not shut down a trial, but they’ve slowed in recruiting. The sites don’t want to close out the trial and they are hoping that the drug becomes available in time,” Gralow said.

Other feedback from the cooperative group trials, for example, suggest that a lot of trials have the potential to be disrupted but they’re not seeing major decreases in enrollment, which is good news according to Gralow.

At the moment, the oncology community has weathered this round of drug shortages. But efforts such as improving transparency and economic incentives to encourage more generic drug manufacturers to remain in the market might be the longterm solutions.

REFERENCES:

1. FDA. Drug shortages: Root causes and potential solutions. A report by the drug shortages task force 2019. 2019. https://bit.ly/46nozN5. Accessed September 21, 2023.

2. NCCN Releases Statement Addressing Ongoing Chemotherapy Shortages; Shares Survey Results Finding More than 90% of Cancer Centers are Impacted. National Comprehensive Cancer Network. News release. Issued June 7, 2023. Accessed September 21, 2023. https://bit.ly/3ZpKpgm

3. Drug shortages roundtable: Minimizing the impact on patient care. Am J Health Syst Pharm. 2018;75(11):816-820. doi:10.2146/ajhp180048