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Drugs essential to the treatment of childhood cancers are continually in short supply in the United States, and these continuing drug shortages are jeopardizing the high success rates that have been achieved in recent decades, say experts.

Survival rates for children living in high economic countries have reached 85% at 5 years, they point out.

This impressive statistic is largely the result of integrating research with clinical care, and at the core are multiagent combination chemotherapy and supportive care agents. Most of these drugs are injectables, which make up the “backbone of many proven and life-saving pediatric oncology regimens,” they write.

However, many of the drugs are in short supply.

For example, from July 2016 to September 2016, bleomycin, etoposide phosphate, and erwinia asparaginase were in short supply, and these agents are included as part of curative regimens for a variety of childhood cancers, including leukemias, brain tumors, lymphomas, bone tumors, neuroblastoma, retinoblastoma, and germ-cell tumors.

In addition, in early 2018, along with vincristine, etoposide once again became scarce and these two drugs are part of curative regimens for children with nearly every form of childhood cancer.

Outlining the issue in a position paper published online March 4 in JAMA Pediatrics, the authors also suggest potential solutions.

One of these is to create an Essential Medicines List (EML) in the United States.

“Essential medicines lists are used in other countries, but one has yet to be established for the United States,” says co-author Stacey Berg MD, professor of pediatric hematology and oncology at Baylor and Texas Children’s Hospital.

“These medicines should be considered critical infrastructure in healthcare, and this approach has implications beyond pediatric oncology; children with other serious diseases should have access to evidence-based medicines that are deemed essential to preserve life and function,” she argues.

“All children, including those undergoing treatment for cancer, have a fundamental right to healthcare, and these drug shortages compromise that right,” she said in a statement from Baylor College of Medicine.

In their paper, the authors point out that the World Health Organization (WHO) already has a model EML that was first compiled in 1977.

The Universal Declaration of Human Rights and the subsequent International Covenant on Economic, Social, and Cultural Rights (CESCR) state that all people have the right to enjoy the “highest attainable standard of physical and mental health,” which includes access to health resources to reach that standard.

However, in the United States there is a different attitude, the authors suggest.

“We recognize in the paper, the crux of drug shortages relates to the US view on healthcare as a privilege, not a basic human right,” commented lead author Yorum Unguru, MD, assistant professor in the School of Medicine, Johns Hopkins University, Baltimore.

“And that is what we say in our paper, that the ‘US position on universal health care is at the core of US health care disparities and is associated directly with health care access,’ which includes drug shortages and affordability, including drug pricing,” Unguru told Medscape Medical News.

Unguru and colleagues note that very costly cancer drugs are never in short supply; the shortages overwhelmingly affect those that cost a few dollars a dose.

“The primary driver for pediatric oncology drug shortages — chemotherapy and supportive care agents alike — is indeed economic, although this is true for all drugs. The majority of pediatric oncology shortages involve older generic drugs that are off patent that are made by very few companies,” he told Medscape Medical News.

Thus, the premise for an EML is that “proven and lifesaving medications” should take priority over expensive and less proven medications. Considerations of both cost and effectiveness have long been applied toward creating critical drug lists in countries with more limited resources.

Unlike other countries, the United States does not have an EML or a national medicines list, the authors emphasize. The closest approximation is the Medicaid preferred drug list (PDL), which is administered by individual states that in turn establish the PDLs. The authors point out that there is a lack of standardization or transparency in the lists’ creation. They also find it “troubling” that “a drug’s clinical effectiveness may not inform inclusion in state PDLs,” unlike how a drug is considered for inclusion in the EML.

The authors propose a pediatric oncology–specific EML for the United States that includes chemotherapy and supportive care agents.

In their paper, they include a sample list of drugs as a starting point. This list includes drugs proposed by the WHO as well as drugs selected based on review of US treatment protocols for childhood cancers. Of note, all of the drugs on the list were rigorously tested and proven safe and effective, which are prerequisites for inclusion in the WHO EML.

Call to Arms

While an EML is an essential component in preventing drug shortages, the group of authors acknowledge that it cannot guarantee an uninterrupted supply by itself.

Other innovative ideas are needed, they write. Recommendations and solutions have been proposed by a large number of professional organizations, governmental agencies, patient advocacy groups, and individuals, but progress to date has been limited.

The authors propose more input from the public, and that patients and families affected by drug shortages must be proactively engaged. To increase awareness and stimulate public pressure, cancer centers should publicly post current data about the shortages.

Another proposal is to offer some type of incentive to pharmaceutical companies, such as subsidies to maintain drugs in the EML in adequate supply. Shortages are frequently linked to poor manufacturing and quality control, so improving factory and manufacturing lines could also keep the supply intact.

Given the over-consolidated marketplace, he pointed out, some drugs like erwinia asparaginase, are made by a single company (Jazz Pharmaceuticals). Because of the economics, the vast majority of these injectables (~70%) are manufactured by two or three companies. “If these companies make a business decision to shut down production or if a manufacturing or quality control issue similarly shuts down production, the result is an almost immediate shortage,” he explained. “Also, because most companies only keep enough drug on the shelf for immediate use with no backup, shortages are almost guaranteed.”

Unguru added that many of these old sterile injectables are reimbursed based upon a formula with the average sales price plus 6%. “This often means dollars per dose, while the opposite is true for many brand-name drugs that are reimbursed at exorbitant cost,” he said. “There are a lot of ways to prevent this, which have been suggested by our group and others.”

“The most likely incentive to have an effect is financial, be it money, guarantees on speedy approval, exclusivity on production, or reciprocal purchase of a company’s drug,” Unguru said.

In July 2018, the US Food and Drug Administration (FDA) announced the formation of a Drug Shortage Taskforce. Scott Gottlieb, MD, then FDA commissioner, suggested several potential solutions, including expanding the authority of the FDA and other federal agencies to ensure that patients in need have access to medications, improving manufacturers’ capacity, and creating and maintaining a list of essential medicines to prevent interruptions in supply.

Unguru noted that on November 27, 2018, there was a public meeting that included perspectives of clinicians, academics, and the Pharmaceutical Research and Manufacturers of America. “The FDA is currently in the process of finalizing their recommendations, which they will report to Congress,” he said. “What will come of this is unclear; however, at the meeting, there was discussion of an EML, which is a start in the right direction.”

However, barring a change in law, the FDA can do relatively little, Unguru emphasized. “What is clear is that the government must grant FDA or another body the power to prevent these types of shortages from continually happening,” he said. “Without policy change, there is no chance a meaningful difference will occur.”

Partnerships and Conversations

Approached by Medscape Medical News for an independent comment, Debra L. Friedman, MD, the E. Bronson Ingram chair in pediatric oncology at Vanderbilt University School of Medicine, Nashville, explained that while the idea of an essential medicine approach is appealing, she doesn’t know how feasible it is. “Also, as the investigators state, this would be a slippery slope as other pediatric subspecialists as well as medical oncologists and subspecialists would argue that medications they use for life-threatening conditions with curative intent treatment should be included,” she said.

“We have experienced drug shortages repeatedly over the past 5 years and it does not appear to be getting better,” Friedman commented. “I think that a more in-depth analysis of why these shortages occur and how we can partner with the pharmaceutical industry to better estimate supply and demand, even for the agents for which there is little profit to the companies, is important.”

Another potential solution to consider, she noted, is the possibility of manufacturing lower-dose vials to avoid waste or to create mechanisms by which hospital pharmacies can safely create multiple doses from single-dose vials.

“Honest conversations also need to occur with parents, and they should appropriately lobby the governmental agencies as well as pharmaceutical companies of the importance of not sacrificing supplies of chemotherapeutic agents for children, when cure rates are so high,” Freidman added.

In addition, she suggested that “partnership between pediatric oncology centers and perhaps even some oversight by NCI’s Children’s Oncology Group in managing same during shortages may help.”

What is often the case is that one hospital may have the drugs in supply, but administrative and financial barriers prevent transfer from one facility to another. “As there are not that many larger centers treating childhood cancer in the country, and they are generally hospitals/academic medical centers as opposed to private practice, this could be an avenue of opportunity,” she said.

Unguru has disclosed no relevant financial relations. Berg reports grants from Children’s Oncology Group during the conduct of the study, and co-author Lisa Marie Johnson reports receiving grants from Children’s Oncology Group and serving as the chair of the Children’s Oncology Group Subcommittee on Bioethics.

JAMA Pediatr. Published online March 4, 2019. Abstract

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