‘Complete Disruption’ of Supply of Essential Pediatric Chemo

Once again, there is a looming shortage of an essential anti-cancer medicine.
Vincristine, which has been used for more than half a century and serves as a backbone of treatment regimens for most childhood cancers, is rapidly disappearing from the shelves of hospital pharmacies.
This isn’t the first time that vincristine has been in short supply, but the situation now is more dire than during previous shortages.
“We have experienced shortages before but never a complete disruption like now, where there is no supply coming into the country,” said Peter C. Adamson, MD, chair, Children’s Oncology Group, Philadelphia, Pennsylvania. “We’ve been worried before, but the supply has never been disrupted like it is now.”
Both Pfizer and Teva manufactured vincristine for the US marketplace, but this past July, Teva announced that it was permanently halting production. According to the US Food and Drug Administration (FDA), “Teva made a business decision to discontinue the product.”
Without Teva, Pfizer became the only source of vincristine for patients being treated in the US. But production has been on shaky ground, as the company has run into some snags while ramping up its inventory to fill the gap left by Teva’s withdrawal from the market.
“It seems that this shortage resulted from manufacturing problems experienced by Pfizer, since they are now the sole supplier,” Michael Link MD, of Stanford University School of Medicine and Lucile Packard Children’s Hospital in California, told Medscape Medical News.
According to the New York Times , the FDA says that they are working closely with Pfizer and “exploring all options” to ensure that vincristine is available to patients who need it.

“The vincristine shortage is a game-changer as it is the single most widely used chemotherapeutic in childhood cancer,” said Yoram Unguru, MD, a pediatric hematologist/oncologist at The Herman and Walter Samuelson Children’s Hospital at Sinai and Johns Hopkins Berman Institute of Bioethics in Baltimore, Maryland. “Nearly every child with cancer in the US will receive multiple doses of vincristine over the course of their treatment.  For some children with cancer, vincristine comprises one half of all chemotherapy administered.”
What makes this shortage more critical than previous ones is that there is no other company to pick up the slack. “We are now faced with a tragic situation,” Unguru told Medscape Medical News. “When Teva stepped down from making vincristine, the tea leaves were present for all to read.”
“It doesn’t take a medical economist to appreciate that with only a single company manufacturing vincristine, a shortage was highly probable, if not inevitable,” he continued. “Instead of uproar and meaningful steps to bolster vincristine supply, instead we got silence.”

However, the current situation appears more related to Pfizer’s manufacturing woes than to Teva. Adamson explained that Teva only had a relatively small share of the market for vincristine, so when the FDA reached out to Pfizer, they didn’t think it would be a challenge to close the gap left by Teva. “But inevitably they ran into a manufacturing problem, and now Teva isn’t available to help fill that gap,” he said.
Jessica Smith, a spokesperson for Pfizer, told Medscape Medical News that “due to a competitor’s outage, we are expediting additional shipments of this critical product over the next few weeks to support three to four times our typical production output. Pfizer is committed to providing this important medicine to patients.”
According to the FDA’s latest report, Pfizer plans on having vincristine available by late October, with an estimated full recovery by December or January, depending on the vial size.
Adamson is hopeful that vincristine will become available in the designated time frame, which will mitigate any significant disruption in care. “But if we had to wait until December or January, then I think it will impact treatment and outcomes,” he said.

Endless Shortages

Drug shortages, unfortunately, have become the “new normal” in US healthcare. While a wide range of drugs used to treat a variety of ailments have been in short supply —on and off and off and on — during the past decade, there has been a chronic stream of shortages of chemotherapeutic agents essential to the treatment of childhood cancers. Most of the drugs used in these regimens are older, generic injectables, and shortages tend to affect them disproportionately. They are more difficult to manufacture but command low prices, a combination which is less than enticing for pharmaceutical companies to embrace.
Almost a decade ago, in 2010, the American Society of Health-System Pharmacists reported that the current shortages were the worst that have ever been experienced in hospital pharmacies, and the shortage of intravenous agents was approaching a national crisis.
Vincristine was one of the drugs gone missing, along with carboplatin, cisplatin, doxorubicin, etoposide, leucovorin, and nitrogen mustard.

At that time, Link, the Stanford oncologist, told Medscape Medical News that “in some of these cases, there are no equivalents, there are no work-arounds.”
In 2012, vincristine was one of two dozen anti-cancer agents that were reported to be in short supply, and again, virtually all of them were older generics. Early last year, vincristine, along with etoposide, once again became scarce.
“The primary difference between the prior vincristine shortage in February 2018 and the current shortage is that now there is now only a single supplier,” said Unguru. “There is no alternative or substitute for vincristine.
Adamson agrees, noting that vincristine is widely used across childhood cancers and a shortage has the potential to cause enormous problems. “The majority of childhood cancers require it and the majority of children with cancer need it,” he said. “It is mind boggling that this is happening in the US, and that doctors may have to make judgment calls or ration it.”

2003 Medicare Payment Reform Part of Problem

As the frequency of cancer drug shortages continued to increase and persist, many studies and experts have weighed in on the causes and possible solutions. But in an open letter written this week to the oncology community, Adamson points out that while “the issues that lead to shortages are complex and involve aging manufacturing facilities overseas and a consolidation of suppliers,” he also feels it fair to point out that Europe is impacted to a far lesser extent compared to the US, and that economic factors play a role in many of the shortages.
The shortages primarily involve generic sterile injectables, he said, and while perhaps not the primary cause, at least some of the issues can be traced to the 2003 Medicare payment reform. This legislation capped the amount of money that could be charged for intravenous drugs at 6% over the “average sales price,” to be adjusted every 6 months. The average sales price this year for a vial of vincristine was about $5, and thus, “the economics of supplying drugs like vincristine are challenging.”
Adamson also notes that a significantly higher amount is spent on generics in Europe, and a lower amount on newer drugs, which is the opposite situation of that in the US. “The bottom line,” he stressed, “is that long-term solutions to this problem involve US Medicare regulations, economic, and other policies.”

Call for Action

Long-term solutions are needed to ensure an uninterrupted drug supply, but it is a multifaceted process. Unguru emphasizes that greater government involvement is essential, as well as offering manufacturers incentives and subsidies to guarantee adequate and affordable access to these lifesaving drugs.

Essential medicines should be viewed in the same manner as public utilities, and reasonable reimbursement needs to be provided for sterile generic injectables. “We need to recognize that shortages are primarily the result of economic considerations and business decisions,” he said, and, accordingly, partner with and leverage the innovative business model of groups like Civica Rx as long as these outfits commit to produce a range of essential and critical infrastructure drugs, including chemotherapeutics.
Civica Rx is a not-for-profit generic drug company that was created in 2018, with a “mission to ensure that essential generic medications are accessible and affordable.” Their plan is either to directly manufacture generic drugs or subcontract manufacturing to reputable contract manufacturing organizations, and the first two drugs on their list are the antibiotics vancomycin and daptomycin.
Unguru also pointed out that beyond the immediate negative effects of shortages, such as the effect on lives and inferior care, there is an “equally concerning, albeit often overlooked downstream effects of shortages —namely, quality.”

“Specifically, there exists a clear link between drug shortages and drug quality — the US healthcare system imports close to 90% of the raw ingredients we rely upon for the drugs we use,” he said. “Many of these ingredients come from countries like China and India and from plants and manufacturing sites that have censured for poor quality and outright data manipulation.”
In an attempt to mitigate the shortages, the FDA has actually imported ingredients for chemotherapy drugs from foreign plants already censured for poor quality. “The end result, inferior and poor quality drugs, were administered to children and adults with cancer who were unaware of this,” Unguru explained.
Adamson issued a “call to action” in his letter, emphasizing that the focus needs to be on solutions for children with cancer right now, along with efforts for longer-term, economic policy solutions. “In the upcoming days and weeks, I am hopeful we can arrive at focused action items for advocacy solutions that have the goal of guaranteeing cancer drug supplies for children in the United States,” he writes.

Some proposals that merit consideration include establishing and maintaining a national stockpile of key cancer drugs used for the treatment of children with cancer and US government purchasing contracts that provide a guaranteed buyer and may help stabilize a fragile market.
But a stopgap measure is needed right now for cancer patients currently undergoing treatment. “There were children who were supposed to receive vincristine this week but who didn’t get it, and some centers have a week’s supply and they are doing the best they can,” said Adamson. “It may be a small number impacted right now but any number is outrageous.”
He emphasized that immediate relief is needed. “We need a strategy that we can implement in the next month, and we also need real solutions.”
https://www.medscape.com/viewarticle/920039#vp_1