Generic Drug Shortage Is Creating Treatment Barriers Across Cancer Space

"For there to be a true resolution, there needs to be something that comes down from legislation that is national, that governs all...[This requires] working with the FDA and the government to invest and fund some type of manufacturers and plants," according to Kirollos Hanna, PharmD.

In February 2023, the FDA announced that a shortage of carboplatin and cisplatin, both of which are treatments that are often used in combination with other therapies for curative intent in patients with cancer.¹ Notably, these shortages have had a negative impact across every disease state, including in the gynecologic and genitourinary cancer spaces.

To help alleviate the burden placed on cancer treatment centers, hospitals, academic institutions, and more, the FDA approved the use of drugs from China that have not been approved in the United States.² The temporary importation of the cisplatin injection at 50 mg/50 mL in the interim will help provide treatment options for patients during the shortage.

In light of these developments, CancerNetwork^® spoke with Dana M. Chase, MD, and Kirollos Hanna, PharmD, about how these shortages have impacted treatment options and the ability to care for patients in the gynecologic and genitourinary cancer spaces, respectively. Additionally, they reviewed how their institutions have adapted, and how they hope to see this mitigated in the future.

The Impact of Drug Shortages

The FDA has attributed the drug shortages to several different factors including manufacturing quality issues, production delays, and discontinuation of drugs.³ Currently, the most recent shortage is due to of disruption to the manufacturing line which was impacted by the COVID-19 pandemic, according to the FDA.

In lieu of the shortage, the National Comprehensive Cancer Network conducted a study in which 27 member institutions were included.⁴ Of those institutions, 93% described experiencing a shortage of carboplatin and 70% had a shortage of cisplatin. Additional data included 100% of the centers being able to continue treating patients with cisplatin therapy. Conversely, only 64% of centers reported that they were able to keep patients on carboplatin-based regimen. Treatment delays were observed in 16% of institutions that were attributed to re-obtain a prior authorization for a modified treatment plan. It is worth noting that none of the delays were due to prior authorization rejections.

Qilu Pharmaceuticals, the manufacturer helping the United States to import the necessary therapeutics from China, highlighted the necessary changes to be able to distribute cisplatin in the United States. This included updating the label to include the drug type and regimen, drug interactions, and color of the product.² However, the imported cisplatin therapies will not include a barcode that would be registered in United States facilities, a unique serial number, lot number, or expiration date.

“It’s exciting to see the FDA thinking of unique strategies to bring in some drug supply to alleviate some of the [shortages] we’re seeing here in the United States. It also makes you think, ‘Why have we not been doing this over time to try to improve supply chains [issues] in any type of drug shortages?’” Hanna, director of pharmacy at Minnesota Oncology and assistant professor of pharmacy at the Mayo Clinic College of Medicine and Science, said in an interview with CancerNetwork^®.

Large oncology organizations, like the American Society of Clinical Oncology (ASCO) drafted a set of recommendations outlining strategies for re-prioritizing non-essential use of agents in limited supply, increasing the amount of time between cycles, and minimizing waste by optimizing vial size, utilizing dose rounding, and having multi-use vials.⁵ To make sure these plans were executed, the organization highlighted the need to create a multidisciplinary committee that can help monitor the shortages, implement policies, and provide equal use of the drugs in the shortage.

Drug Shortages in the Gynecologic Cancer Space

The Society of Gynecologic Oncology (SGO) drafted guidelines to strategize and best conserve the use of carboplatin and cisplatin, reserving the supply for patients who will have “the most significant benefit.”⁶ Some key highlights from the guidelines include minimizing the ordering of non-essential platinum therapy, increasing time between treatment cycles, considering the potential use of other therapies, and rounding down doses.

At the University of California Los Angeles (UCLA) Health, the gynecologic oncology department has implemented a strategy that centers around prescribing lower doses. Chase, an associate professor of UCLA obstetrics and gynecology in the Division of Gynecologic Oncology, reviewed how his institution is trying to utilize carboplatin without compromising on efficacy while also cutting back on the usage.

“Instead of using the typical dose, which is a dose of an AUC [area under the curve] of 6, we have decided we would use an AUC of 5, especially in our patients with endometrial cancer; the dose usually used in clinical trials at an AUC of 5,” Chase explained.

SGO has also produced guidelines on the recommended treatments for patients with gynecologic cancers, which were published in April in response to the shortage. The guidelines highlight in several areas that, if possible, patients should be placed on clinical trials to help preserve platinum drugs. For cervical cancer, cisplatin and carboplatin are the current first-line standard of care and should be reserved for curative intent. In reference to vulvar or vaginal cancers, cisplatin should be prioritized in regimens indicated for curative intent. This includes the neoadjuvant, adjuvant, and when prolonged clinical benefit may be observed.

Clinicians should consider using carboplatin at an AUC of 2 intravenously (IV) every week or oral fluorouracil and IV mitomycin. SGO has noted that fluorouracil monotherapy is not an appropriate agent to treat cervical cancer. Gemcitabine at 300 mg/m² via a weekly IV and paclitaxel at 30 to 40 mg/m² IV weekly may also be appropriate regimens to consider.

The cost of alternative treatments is another point that was highlighted by the SGO guidelines. A 2014 study published in Value in Health compared costs between platinum-containing regimens and non-platinum regimens in ovarian cancer.⁷ The study’s investigators identified that for those with early- or late-stage ovarian cancer, it was more cost-effective to be treated with platinum-based therapy vs non-platinum–based therapy.

Although Hanna primarily manages genitourinary cancers, he discussed how the cost of drug shortages has impacted cancer treatment overall.

“We’ve been dealing with shortages for years now,” he explained. “What I find interesting is if you look at pembrolizumab [Keytruda], nivolumab [Opdivo], or daratumumab [Darzalex]—all of these branded therapeutics—these [are] monoclonal antibodies where so much money is invested from these larger pharmaceutical companies. We will never find a shortage of these drugs. We have never seen a shortage of these drugs. Why is it that these critical therapeutics that in many areas are tied to curative intent regimens?”

As carboplatin and cisplatin are deemed generic drugs, Chase said clinicians do sometimes take the agents for granted. She theorized that these generic, inexpensive drugs, may not be turning out as high of a profit as the treatments Hanna reviewed, which could cause distributors to produce less, or stop production altogether.

Drug Shortages Still Rampant in Bladder Cancer

In the bladder cancer space, the shortage of carboplatin and cisplatin is nothing new, according to Hanna.

“When you’re talking about bladder cancer, specifically in terms of GU [genitourinary] cancers, treatments like cisplatin and carboplatin play a critical role at different stages for these patients,” he said.

However, for years, GU oncologists have had to substitute or conserve these curative intent therapies for those whose need is more critical. At Hanna’s institution, when these treatments are in very short supply, they do conserve the platinum-based drugs for patients with bladder cancer because of the curative intent.

One of the larger issues, Hanna stated, is identifying would-be therapeutic alternatives. However, ASCO has outlined a series of alternative systemic therapies in the neoadjuvant, adjuvant, first-line, or second-line settings in the genitourinary space.

In the phase 1/2 EV-103 trial (NCT03288545), enfortumab vedotin-ejfv (Padcev) monotherapy or with pembrolizumab was evaluated in patients with metastatic urothelial cancer.8 While the population was comprised of patients who were platinum-ineligible, these early data still showed positive outcomes, indicating that the treatment could be an alternative treatment option in the metastatic setting.

Regarding treatment strategies at the Mayo Clinic College of Medicine and Science, Hanna’s institution has adapted to the recent shortages well. When news of the shortage broke, the institution’s leaders made the decision to keep carboplatin dosage use at minimum levels, to ensure the drug wouldn’t run out as quickly.

“We then started to implement strategies to help utilize a little bit less of the drug where it didn’t clinically impact our patients,” Hanna said. “This was for both carboplatin and cisplatin. [We use] strategies like dose rounding; if we can dose round down to a vial size or a billing unit, we do that. We informed providers if there’s a clinically appropriate situation where instead of giving a patient a 21-day cycle of carboplatin to go to a 28-day cycle.”

Similar to the gynecologic cancer space, Hanna also dose reduces patients from an AUC of 6 to an AUC of 5. Clinical pharmacists also began working more closely with providers to determine optimal treatment alternatives to help conserve the therapies.

How Can Drug Shortages be Tackled in the Future?

Moving forward, both Hanna and Chase elaborated as to how they believe these drug shortages may be mitigated. Hanna indicated that it comes down to the production line and working with manufacturers.

“For there to be a true resolution, there needs to be something that comes down from legislation that is national, that governs all,” he said. “[This requires] working with the FDA and the government to invest and fund some type of manufacturers and plants.”

Chase’s take-home message for avoiding future drug shortages includes a need to, as cancer doctors or oncologists, “better understand the process of generating these drugs that are generic and don’t yield a big profit.”

On the FDA website’s, it cites a need and desire to help in addressing the drug shortages and identify solutions to increase production if manufacturers are willing to do so. Additionally, the FDA is willing to work with other manufacturers to expedite production but cannot require an increase of production.

While the drug shortage is affecting various cancer types, it has caused providers to think outside of the box as to how they can best help their patients. Both Chase and Hanna continue to work alongside their institutions to come up with safe and effective innovations and solutions to provide the best care and outcomes for their patients. However, both of them are in agreement that significant change, both legislative and logistical, is needed to prevent future shortages from happening.

References

1. FDA. FDA drug shortages. Accessed Jun 28, 2023. https://bit.ly/44rjKBn
2. Temporary importation of cisplatin injection with non-U.S. labeling to address drug shortage. News release. Qilu Pharmaceutical. May 24, 2023. Accessed June 28, 2023. https://bit.ly/431J7Zh
3. FDA. Frequently asked questions about drug shortages. Accessed June 28, 2023. https://bit.ly/3Xt01yO
4. NCCN releases statement addressing ongoing chemotherapy shortages; shares survey results finding more than 90% of cancer centers are impacted. News release. National Comprehensive Cancer Network. June 7, 2023. Accessed June 28, 2023. https://bit.ly/43TWV9v
5. American Society of Clinical Oncology. Clinical Guidance. Accessed June 28, 2023. https://bit.ly/3pzph9Y
6. SGO statement: carboplatin and cisplatin shortages. News release. Society of Gynecologic Oncology. April 21, 2023. Accessed June 28, 2023. https://bit.ly/44hVguN
7. Lairson DR, Parikh RC, Cormier JN, Du XL. Cost-utility analysis of platinum-based chemotherapy versus taxane and other regimens for ovarian cancer. Value Health. 2014;17(1):34-42. doi:10.1016/j.jval.2013.11.007
8. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 Cohort K: antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Presented at the 2022 European Society of Medical Oncology Congress; September 9-13, 2022; Paris, France. Abstract LBA73.