Cancer Drug Shortages Persist, Increasing Calls for Action

As health care providers across the United States grapple with ongoing shortages of cancer drugs, experts are sounding the alarm about drugs that are becoming harder to obtain.^1,2

On September 12, the Biden administration announced that the cisplatin supply had been restored to almost 100% of pre-shortage levels, and supplies of carboplatin and methotrexate were increasing.³

However, all 3 drugs were still in short supply at many cancer centers last month, according to a National Comprehensive Cancer Network (NCCN) survey.⁴ Meanwhile, shortages of vinblastine and dacarbazine have become a concern.^1-5

“[V]inblastine, dacarbazine, and methotrexate are essential for treating lymphomas and other blood cancers that are common among kids and young adults,” Julie Gralow, MD, chief medical officer and executive vice president of the American Society of Clinical Oncology (ASCO) in Alexandria, Virginia, said in an interview.

The shortages mean these patients may not be treated with the best therapy, added Lia Gore, MD, head of pediatric hematology/oncology/bone marrow transplant at Children’s Hospital Colorado in Aurora.

“We know that our pediatric regimens are based on years of experience and adherence to the protocols, including timing and dosing of each drug in a regimen,” Dr Gore said. “If the drugs are not given in the appropriate doses, in sequence, or in combination with the other elements — or not given at all — it basically compromises or potentially compromises the chance of a good outcome or cure.”

“For patients and families dealing with an already devastating diagnosis and life situation, this only adds undue burden to them and their lives,” Dr Gore added. “Especially hard is when a family says, ‘We live in a highly developed country. What do you mean you can’t get a drug that has been around for 40 years and we know is safe and effective?’”

Cancer Drug Shortages by the Numbers

NCCN previously surveyed 27 member institutions about cancer drug shortages in May of this year.⁶ Carboplatin was in short supply at 93% of cancer centers surveyed, and cisplatin was in short supply at 70% of centers.

The cisplatin shortage did not impact treatment at the centers surveyed, but only 64% of centers said they were able to give carboplatin to all patients who needed it.

ASCO also surveyed its members on the cisplatin and carboplatin shortages and received responses from 47 practices reporting data from November 7, 2022, through September 11, 2023.¹

Respondents said the shortages forced them to lower doses of carboplatin and cisplatin, switch chemotherapy drugs, change the sequence of treatment, prioritize treatment for patients with early-stage cancer, and discontinue treatment that was being given with life-prolonging intent for patients with metastatic disease. 

“Cancer care professionals are having to make wrenching treatment decisions based on a shortage of generic drugs that have been around for decades and should be readily available,” Dr Gralow said.

“A drug that is delayed by a week usually can be accommodated within treatment plans without any problem,” Dr Gore noted. “A drug that is not available for months or years is compromising to everyone who needs it and could spell the difference between cure and not.”

In the latest NCCN survey of 29 cancer centers conducted last month, 86% of centers reported a shortage of at least 1 cancer drug.⁴ Centers reported shortages of carboplatin (72%), methotrexate (66%), cisplatin (59%), 5-fluoroucil (55%), fludarabine (45%), hydrocortisone (41%), dacarbazine (28%), liposomal doxorubicin (24%), and vinblastine (21%), among others.  

Most centers said treatment was not greatly impacted by the shortages, but some centers reported relying on allotted shipments of drugs from manufacturers to have enough to treat patients.

In addition, 5% of 21 responding centers said they were not able to treat all patients who needed carboplatin at the intended dose and schedule, and 12% of 17 responding centers said the same about cisplatin.

Furthermore, 71% of 17 responding centers said they had not received any indication from manufacturers of when cisplatin would be readily available, and 62% of 21 responding centers reported the same about carboplatin.

Current Status of Key Cancer Drugs

According to the US Food and Drug Administration’s (FDA) drug shortage database, additional lots of cisplatin are expected to be available this month, and lots of carboplatin are expected this month and next.⁵

Supplies of vinblastine and dacarbazine were released in September. Additional lots of dacarbazine are expected to be available in November. Supplies of methotrexate were released last month, and additional lots are expected this month.

“While over the past month, it appears to be somewhat easier to obtain methotrexate than the months prior, it remains challenging to obtain sufficient supply of this without significant efforts,” Brittany Lee, MD, a pediatric oncologist at Seattle Children’s Hospital in Washington, said in an interview.

“For instance, when an order of a particular amount is requested, a smaller, sometimes insufficient quantity is supplied. Sufficient supplies have required emergency supply requests and significant time and efforts of pharmacists,” said Dr Lee, who is leading the response to drug shortages at her institution.

Dr Lee noted that some institutions have had to hire employees who are dedicated to working on drug procurement full-time, while others have staff members who are spending time during and outside of normal clinic hours on this problem.

Causes of Cancer Drug Shortages

The shortages of cisplatin and carboplatin happened after an investigation by the FDA revealed quality control issues at a factory in India that produced a large amount of chemotherapy drugs for the US.⁷ However, these shortages are not unique.

According to the IQVIA Institute for Human Data Science, the number of drug shortages across medical specialties has more than doubled in recent years, increasing from 168 molecules in shortage in 2011 to 359 in June 2023.¹

Three of the most reliable factors contributing to drug shortages are manufacturing complexity, low drug prices, and concentration of production by a small number of manufacturers, according to US Pharmacopeia (USP).¹ USP made these conclusions based on data from the Medicine Supply Map (MSM), a predictive data model that uses machine learning and advanced analytics to identify, characterize, and quantify factors linked to supply chain disruptions of drug products.⁸

Manufacturing complexity, low drug prices, and concentration of production are interrelated issues, Vimala Raghavendran, vice president of informatics product development at USP in Rockville, Maryland, said during a meeting hosted by USP, the American Cancer Society (ACS), and ACS Cancer Action Network (CAN) last week.¹

Raghavendran explained that manufacturing complexity drives up the cost of manufacturing drugs. These costs and low drug prices mean that manufacturers have difficulty turning a profit. This leads to production concentration “because it is more expensive to make a medicine in multiple places than it is to make it in one place,” Raghavendran said.

Data from the MSM showed that, for 14 of 20 essential cancer drugs, over 40% of production is concentrated in 1 facility.^1,8,9 In 2022, 5 facilities manufactured over 50% of essential oncology injectables in the US.¹

The financial challenges manufacturers face is a key cause of cancer drug shortages, according to Ted Okon, executive director of Community Oncology Alliance in Washington, DC.¹⁰ Okon outlined this problem when testifying before the House Committee on Energy and Commerce Subcommittee on Health in June.

Okon cited Medicare’s Part B drug reimbursement system, which caps drug pricing, as part of the issue. He said mandatory 340B drug pricing discounts and Medicare rebates, as well as the Inflation Reduction Act drug price inflation caps, drive down drug prices and lead manufacturers to cut costs in any way they can.

Other factors that can cause or exacerbate drug shortages include natural disasters, staffing issues related to the COVID-19 pandemic, and shutdowns or strikes by couriers or airlines, Dr Gore said.^11,12

How to End Drug Shortages in Oncology and Beyond

Dr Gore called for “a multifactorial, multi-layered solution” to the drug shortages because “the reasons for drug shortages are multifactorial and multi-layered.”

Dr Gralow identified several potential solutions. “First, we need a clear national response plan for when critical drugs are in short supply,” she said. “Drug shortages have been a problem for more than a decade. Yet our country has no protocol for what to do when they happen.”

In the short-term, Dr Gralow said, we need a comprehensive list of critical cancer drugs, and the list should be used to create a national reserve of these drugs. She also highlighted the need for a clear communications channel to inform cancer centers when a shortage is expected. The FDA should also identify and pre-qualify alternative manufacturers, she said.

“We have some mandatory reporting from manufacturers in terms of when there is going to be a disruption in supply, which has been very helpful,” Jacqueline Corrigan-Curay, JD, MD, principal deputy center director of the FDA’s Center for Drug Evaluation and Research in Silver Spring, Maryland, said during the USP/ACS/ACS CAN meeting.¹ “We don’t have reporting in terms of when there is an excess in demand that’s leading to a shortage.”

Raghavendran said USP recommends building early warning capabilities using predictive analytics to identify vulnerable drugs and prioritize shortage prevention, as well as establishing a vulnerable medicines list that accounts for supply chain weaknesses.¹

Data-driven solutions are key to preventing shortages, Anthony Sardella, chair of the API Innovation Center in St Louis, Missouri, said during the USP/ACS/ACS CAN meeting.¹ He highlighted 2 data points that can be used to derive solutions.

“The first one, from an economic standpoint, is data around the potential of advanced manufacturing technologies, like continuous flow, to reduce the cost of production to make the economics of production more favorable,” he said.

The second is “inventorying the excess or available existing US-based manufacturing that could be repurposed or deployed, in partnership, to produce some of these important, high-profile medicines,” Sardella said.

In the long-term, Dr Gralow said, legislation that addresses systemic issues is important for preventing drug shortages.

“Congress must address the broad market and regulatory forces that create generic drug shortages,” Dr Gralow said. “Legislation should incentivize manufacturers to improve quality and transparency, require makers of essential drugs to share where they are sourcing their drug ingredients (active pharmaceutical ingredients) with the FDA, and reduce reliance on other countries for critical drug ingredients.”

At the House subcommittee meeting, Okon recommended that Congress pass legislation removing price caps, discounts, rebates, and regulation.¹¹

Dr Gore said another possibility is having the government manufacture some essential drugs.

She added that cooperation across disciplines is needed to prevent drug shortages. Academics, professional providers, pharmaceutical companies, government, and advocates are just some of the parties who should be involved in the conversation.

Disclosures: Dr Gralow, Dr Gore, Dr Lee, and Okon have no relevant disclosures. Disclosures were not provided for speakers at the USP/ACS/ACS CAN meeting.

References

1. Mitigating cancer drug shortages. US Pharmacopeia via Youtube. Recorded September 26, 2023. Accessed October 5, 2023.

2. Lovelace Jr, B. Pediatric cancer drugs in shortage as drug supply crisis drags on. NBC News. Published September 25, 2023. Accessed October 5, 2023.

3. Clancy E. Cisplatin shortage nearly resolved; Supplies of carboplatin, methotrexate increasing. Published September 21, 2023. Accessed October 5, 2023.

4. NCCN best practices committee drug shortage follow-up survey results. National Comprehensive Cancer Network. Published October 5, 2023. Accessed October 5, 2023.

5. FDA drug shortages. US Food and Drug Administration. Accessed October 5, 2023.

6. Smith J. Chemotherapy shortage affecting more than 90% of NCCN cancer centers surveyed. Cancer Therapy Advisor. Published June 7, 2023. Accessed October 5, 2023.

7. Allen A. Drugmakers are abandoning cheap generics, and now US cancer patients can’t get meds. KFF Health News via Cancer Therapy Advisor. Published July 4, 2023. Accessed October 5, 2023.

8. Supply chain insights – Medicine Supply Map. United States Pharmacopeia. Accessed October 5, 2023.

9. Fundytus A, Sengar M, Lombe D, et al. Access to cancer medicines deemed essential by oncologists in 82 countries: An international, cross-sectional survey. Lancet Oncol. 2021;22(10):1367-1377. doi:10.1016/S1470-2045(21)00463-0

10. Tallent A. As cancer drug shortages increase, patients’ lives are at stake. Cancer Therapy Advisor. Published June 23, 2023. Accessed October 5, 2023.

11. Pfizer restarts production plant in North Carolina following tornado damage in July. HealthDay via Cancer Therapy Advisor. Published September 26, 2023. Accessed October 5, 2023.

12. Forster V. COVID-19 is still causing drug shortages that impact cancer care. Cancer Therapy Advisor. Published August 19, 2022. Accessed October 5, 2023.

This article originally appeared on Cancer Therapy Advisor