Oncology Drug Shortages Persist, Calling for Solutions

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In oncology, a generous number of drugs and multi-drug regimens are available, and FDA approvals tend to occur monthly. Still, a countless number of patients are not receiving the treatment they need due to ongoing drug shortages.

“Drug shortages are impacting every therapeutic area of practice at this time. In 2023, shortages are reaching record numbers, and unfortunately, our oncology medications are not immune,” Jeffrey Pilz, PharmD, MPA, MS, BCPS, assistant director of pharmacy, Medicantion Safety and Drug Policy, The Ohio State University Wexner Medical Center, told Targeted Oncology™ (TO).

Drug shortages are occurring at the highest rate since 2014.¹ In the oncology space, 11 chemotherapy agents and a prostate-specific membrane antigen (PSMA) targeted therapy are short on supply.²

Jeffrey Pilz, PharmD, MPA, MS, BCPS

“Several factors are converging to cause the increase in recent shortages, although no single cause is at fault commonly across all products currently designated in national shortage. Drug shortages are not new, [and have had] major impacts on healthcare for the [United States] for the last decade. Sterile injectable generic products, especially those costing less than $9 USD per dose, are at highest risk of shortages. Unfortunately, many of the older chemotherapy agents used in cancer care fall into this category. [Several] product quality issues with major suppliers have exacerbated shortages most recently. However, the pharmaceutical industry lacks transparency into drug shortages so often the exact cause and contributing factors remain unknown to end users, including health systems and pharmacies,” said Pilz.

According to the American Society of Health-System Pharmacists, 56% of the drug shortages in 2022 had unknown causes, while 19% are related to supply/demand, and 18%, 5%, and 2%, respectively, are related to manufacturing issues, business decisions, and regulatory/raw materials problems.¹

The oncology field has experienced multiple drug shortages in the past, during which oncologists pivoted to the use of alternative therapies when possible.

Learning from the Past

The Hematology/Oncology Pharmacy Association recently conducted a survey to assess the impact of drug shortages on its members. The survey was distributed between December 2019 and July 2020. It revealed that 1 or more drug shortages were reported by the majority of respondents. This highlights the severity of drug shortages in the healthcare system, which can have a detrimental effect on patient care.³

The survey showed that 1 or more drug shortages were reported by 68% of institutions. The survey also showed a 34% increase in oncology drug shortages in 2019 compared with 2018.³

At the time, several shortages were ongoing, including nab-paclitaxel, vincristine, vinblastine, intravenous immunoglobulin, leucovorin, and Bacillus Calmette-Guerin (BCG). These shortages have resolved, but there is much to be learn from them.

Nab-paclitaxel

Roby Thomas, MD, a medical oncologist, and hematologist at UPMC Hillman Cancer Center, explained the impact of the nab-paclitaxel shortage in an interview with TO.

Roby Thomas, MD

“We've had multiple issues with drug shortages over the last couple of years, primarily because of supply chain issues. In the fields that I focus on, gastrointestinal and genitourinary oncology, we had a shortage of nab-paclitaxel for quite some time, and that was in the United States. What made it so challenging is we use that drug often in pancreatic cancers. At UPMC Hillman Cancer Center, we have a high volume of pancreatic cancers, and it's 1 of our standard-of-care therapies,” explained Thomas.

With indications in pancreatic cancer, breast cancer, non–small cell lung cancer, and ongoing studies in gastric cancer, breast cancer with brain metastases, and gastric cancer, there is vast need for nab-paclitaxel in the United States.

The FDA-approved doses of nab-paclitaxel range from 80 mg to 260 mg. During the shortage, more than 1,200 studies included nab-paclitaxel, according to PubMed.

“What made it uniquely challenging for us was that we have many different phase 1 and phase 2 clinical trials in which nab-paclitaxel would be part of a standard-of-care regimen. People might be randomized to get gemcitabine and nab-paclitaxel with or without another study drug or placebo, for example, but we couldn't recruit people because we just didn't have the study medication. It did not just have a direct effect in terms of less nab-paclitaxel availability, but also in terms of accrual and clinical trials. It was a challenging time for pancreatic cancer in general,” said Thomas.

Instead of using nab-paclitaxel, oncologists had the option of using an effective chemotherapy regimen as upfront treatment. However, there were concerns about the implementation of the alternative treatment approach in some patients.

“During the nab-paclitaxel shortage we could use FOLFIRINOX in the first-line setting for patients, according to phase 3 data. At the time, we would say, well, we don't have any other options. We'll just reduce our FOLFIRINOX for patients and hope they tolerate it better,” said Thomas.

For most patients, reducing the dose was successful, but for elderly patients with pancreatic cancer in the first-line setting, treatment with FOLFIRINOX was less tolerable. In addition, disease progression can always occur.

“In that specific case, we were fortunate, but certainly we had patients that progressed through that. And then again, we're stuck with the question of what do we do? We have to go back into the toolbox, but the toolbox is relatively limited when it comes to pancreatic cancers. That makes it very challenging,” said Thomas.

There is limited information about patient outcomes during and following the nab-paclitaxel shortage. Thomas said that a real-world study is needed to provide insight on the how the lack of nab-paclitaxel affected survival, hospital re-admission, and mortality in patients with cancer.

Thomas explained that historic chemotherapy shortages like the nab-paclitaxel problem made an impact on the field. This kind of drug, according to Thomas, is the “bread and butter” of treatment for various cancers.

During periods of shortage, less-ubiquitous therapies BCG also had a large impact on cancer.

BCG

BCG for the treatment of adult patients with high-risk BCG unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors was in shortage from 2019 to 2020. According to the American Urology Association, the shortage was caused by a high global demand for the product.⁴

Globally, guidelines state that use of mitomycin C and gemcitabine in the post-operative setting can improve relapse-free survival in patients with low-risk NMIBC. But for induction and maintenance therapy, BCG is recommended for patients with intermediate or high-risk disease. Still, in the case of a BCG shortage, mitomycin C and gemcitabine may be an alternative.⁵

Considering the length of the BCG shortage, oncologists began looking into other treatment alternatives. Using only 1/3 of the normal dosage of BCG was on the potential avenue to follow during the shortage, according to institutional review board-approved review of data from patients with NMIBC treated between 2000 and 2022. The study investigated time to recurrence, time to progression, and cancer-specific survival among patients treated with only 1/3 of the recommended dose of BCG.⁶

Data came from 563 patients with NMIBC. Of those patients, 150 (26.6%) were given the 1/3 dose of BCG, and 413 (73.4%) received the full dose of BCG. In the population of patients treated with the 1/3 dose vs the full dose, time to recurrence was not adversely affected (P = .449). Results also showed that time to progression was not impacted by using 1/3 of the BCG dose vs the full dose (P = .716). Cancer-specific survival as also determined to be similar in the 1/3-dose population and the full-dose population.

“There is a potential to learn a lot of valuable lessons from drug shortages. Sometimes the lessons are positive, such as leveraging a shortage to improve processes at an institution or improve efficiencies in the way patient care is conducted. One of the metrics by which the FDA assesses drug shortages is the impact on public health, and the shortages greatly impacting public health often have long-standing repercussions. In 2017, major shortages of IV fluids and infusion bags led to creative use of IV push administration of several medications, especially beta-lactam antibiotics and some supportive care medications. Current shortages of fludarabine and methotrexate have resulted in improved communication between different teams and highlight the need for multidisciplinary collaboration for institutions to be successful in maintaining the expected level of patient care,” said Pilz

The Current Impact

The current picture of how drug shortages are impacting oncologists and their patients is not completely clear. Considering the length of shortages, studies have begun to look at chemotherapies like dacarbazine and fludarabine, but there has been no research around the other 9 drugs that are in short supply.

Chemotherapy

Dacarbazine is indicated for the treatment of metastatic melanoma as well as the second-line treatment of Hodgkin lymphoma. It is an important drug in the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen for the treatment of classical Hodgkin lymphoma.

The shortage of dacarbazine has been ongoing for more than a year, warranting alternative options. One study suggested the use of newer regimens like bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), based on its efficacy and safety in a HD12 trial (NCT00265031).⁷

The study investigated the use of 8 cycles of an escalated dose of BEACOPP followed by radiotherapy compared with 4 + 4 dosing. A total of 1,670 were included and were assessed for 5-year freedom from treatment failure (FFTF), overall survival (OS), and toxicity. The results showed a 5-year FFTF of 86.4% in the escalated BEACOPP arm compared with 84.8 in the 4 + 4 arm, showing a difference of -1.7 (95% CI, -5.2%-1.9%).⁸

Regarding safety, toxicity-related deaths were seen in 19 patients in the escalated BEACOPP vs 27 patients in the 4 + 4 arm.⁸

Another potential alternative is procarbazine⁹, which in a regimen also consisting of cyclophosphamide, vincristine, prednisone (C-MOPP), was shown to have good efficacy to ABVD. In the 67 Japanese patients treated with the 2 regimens, the response rate was 92.5% with complete response (CRs) shown in 83.6%.¹⁰ Grade 4 leukocytopenia occurred in 28.4% of patients. There were also cases of alanine aminotransferase elevation in 4.5%, nausea/vomiting in 11.9%, and central nervous system toxicity in 1.5% of patients. No deaths in the study were related to treatment.

Hagop Kantarjian, MD

“In the case of leukemia, there was a similar drug shortage that started about 3 months ago. This is a drug called fludarabine that has been in chronic lymphocytic leukemia [CLL] and sometimes part of the standard allogeneic transplant,” Hagop M. Kantarjian, MD, professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, told TO, in an interview. “What has happened is because of the expansion of the chimeric antigen receptor [CAR] T cells, and because of the preoperative regimens using fludarabine with melphalan, everybody started using the fludarabine in access amounts. This worsened the shortage that was caused by supply chain issues.”

Fludarabine is a staple in CLL treatment, particularly as part of multi-drug regimens and during transplant. To date, there have been no studies looking into alternative therapies to offer potential solutions for the fludarabine shortage.

One perspective from Maziarz et al¹¹ around the shortage of fludarabine placed a spotlight on gaps in the system. Institutions must now discover ways to maintain clinical trials and clinical care during drug shortages.

PSMA Targeted Therapy

Unlike many of the therapies on the FDA’s drug shortage list, Lu 177 vipivotide tetraxetan (Pluvicto) is short on supply due to quality issues at the manufacturing site.¹²

Lu 177 vipivotide tetraxetan was granted FDA approval in March of 2022 for the treatment of patients with metastatic castration-resistant prostate cancer in the post androgen receptor pathway inhibition, post-taxane-based chemotherapy setting.¹³

In the phase 3 VISON study (NCT03511664), treatment with Lu 177 vipivotide tetraxetan achieved a median OS of 15.3 months, which exceeded that of standard-of-are in the study (HR, 0.61; 95% CI, 0.52-0.74; P < .0001). The radiographic PFS shown with Lu 177 vipivotide tetraxetan in the study was 8.7 months vs 3.4 months with SOC (HR, 0.40; 99.2% CI, 0.29-0.57; P < .001). In addition, the drug was tolerable with the most frequent adverse events being fatigue (43.1%), dry mouth (38.8%), and nausea (35.3%).¹⁴

“In prostate cancer, it's one of those things where we have the VISION study demonstrating the utility of [Lu 177 vipivotide tetraxetan] in a highly refractory setting. There were high response rates, which is very promising for patients who have had multiple lines of therapy, including chemotherapy. This national shortage is another example of having some throughput, and it was getting exciting, patients were getting this life-changing medication at our institutions. But now, this has all come to a screeching halt. We have patients on months long waiting lists when this may be all the time they have, and so it's been really disheartening to have to deal with these things,” explained Thomas.

Lu 177 vipivotide tetraxetan was the first approved tumor-targeted radionuclide therapy, and therefore, no alternative treatments exist.

Overall, the issue with drug shortages is not the ability to treat but the inability to ensure response. Many of the alternatives being used in clinics across America have not been studied, according to Kantarjian and therefore, there is no way to know how patients will respond.

“Anytime you have a protocol of a combination of drugs and one of them is missing, that means that we may not be able to deliver the same results in terms of response and survival, as would have been with that regimen. Of course, when this happens, we scrambled to get an alternative plug into the regimen. But this becomes more of an approach that is not approved and an approach that is not guaranteed,” said Kantarjian.

Solutions

Battling drug shortages in oncology can be difficult because for some patients, access to the correct drug or lack thereof could be a life-or-death situation. However, drug shortages will still occur, and the solutions must relate to both limiting shortages and managing cancer during periods of shortage.

“How do we solve the problem of cancer drug shortages,” Kantarjian began. “I'm more interested in cancer drugs because patients with cancer can do or die by whether they have a drug available or not. The first issue is to have a source of manufacturing that's reliable, and make sure that the path from the manufacturing source to the drug company to the patient is stable,” he added.

Drug shortages usually start with the developers or manufacturers. Kantarjian stated that the FDA must keep a list of generic drugs and require manufacturers in the United States to have the full supply of the drugs needed to treat all patients with the disease it is intended for.

“For example, the FDA must mandate that any company that's producing these drugs, the manufacturer, or the drug company that takes it from the manufacturer, they have to have a 3 to 6 months warning signal about the possibility of a shortage. In such cases, the FDA will have to have an emergency plan to get approved, generic drugs which exist, either inside or outside the United States, to provide an alternative for the other drug,” said Kantarijian. “These are simple solutions that people talk about, and having a multifaceted approach where the drug manufacturers, the FDA, and the health care providers work together will be important for the future.”

In terms of managing disease, allocation is actively used across hospital and practices across the country and worldwide. For example, hospital sometime create waitlists during periods of drug shortage, and these waitlists can queue patients based on their age, disease stage, and other factors that are indicative of their ability to survive without treatment.¹⁵

Finally, the American health care system can be restructured to focus more on treating disease like cancer than making a profit from people who are struggling with those diseases.

“If we can alter the classical for-profit drug supply system, then we can have parallel source of dots that stabilize the market forces to reasonable levels as they should be, rather than to access profiteering levels, as they have sometimes become,” said Kantarjian.

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_{13. 1 Novartis PluvictoTM approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. News release. Novartis. March 23, 2022. Accessed March 23, 2022. https://bit.ly/3iw9bab}

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