Perspective
The Shortage of Essential Chemotherapy Drugs in the United States
Mandy L. Gatesman, Pharm.D., and Thomas J. Smith, M.D.
N Engl J Med 2011; 365:1653-1655
November 3, 2011
Comments open through November 9, 2011
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For the first time in the United States, some essential chemotherapy drugs are in short supply. Most are generic drugs that have been used for years in childhood leukemia and curable cancers — vincristine, methotrexate, leucovorin, cytarabine, doxorubicin, bleomycin, and paclitaxel. 1 The shortages have caused serious concerns about safety, cost, and availability of lifesaving treatments. In a survey from the Institute for Safe Medication Practices, 25% of clinicians indicated that an error had occurred at their site because of drug shortages. Many of these errors were attributed to inexperience with alternative products — for instance, incorrect administration of levoleucovorin (Fusilev) when used as a substitute for leucovorin or use of a 1000-mg vial of cytarabine instead of the usual 500-mg one, resulting in an overdose. Most cancer centers quadruple-check drugs for accuracy, and we're unaware of any documented death of a patient with cancer such as the nine deaths in Alabama attributable to the use of locally compounded liquid nutrition because the sterile product was not available. However, it is only a matter of time.
These shortages have increased the already escalating costs of cancer care. Brand-name substitutes for generic drugs can add substantial cost. For instance, Abraxane, a protein-bound version of paclitaxel, costs 19 times as much as equally effective generic paclitaxel (see table
Average Wholesale Prices (AWPs) of Selected Oncology Drugs in Short Supply and Their Potential Alternatives. ). Since 2010, health care labor costs in the United States have increased by about $216 million because of the increased time and work required to manage drug shortages. 2 A gray market for essential drugs — an unofficial alternative market of drugs obtained by vendors outside the usual distribution networks — has grown rapidly, with unregulated vendors charging markups of up to 3000% for cancer drugs.
The main cause of drug shortages is economic. If manufacturers don't make enough profit, they won't make generic drugs. There have been some manufacturing problems, but manufacturers are not required to report any reasons or timetable for discontinuing a product. Contamination and shortages of raw materials probably account for less than 10% of the shortages. In addition, if a brand-name drug with a higher profit margin is available, a manufacturer may stop producing its generic. For instance, leucovorin has been available from several manufacturers since 1952. In 2008, levoleucovorin, the active l-isomer of leucovorin, was approved by the Food and Drug Administration. It was reportedly no more effective than leucovorin and 58 times as expensive, but its use grew rapidly. Eight months later, a widespread shortage of leucovorin was reported.
The second economic cause of shortages is that oncologists have less incentive to administer generics than brand-name drugs. Unlike other drugs, chemotherapeutics are bought and sold in the doctor's office — a practice that originated 40 years ago, when only oncologists would handle such toxic substances and the drugs were relatively cheap. A business model evolved in which oncologists bought low and sold high to support their practice and maximize financial margins. Oncologists buy drugs from wholesalers, mark them up, and sell them to patients (or insurers) in the office. Since medical oncology is a cognitive specialty lacking associated procedures, without drug sales, oncologists' salaries would be lower than geriatricians'. In recent decades, oncology-drug prices have skyrocketed, and today more than half the revenue of an oncology office may come from chemotherapy sales, which boost oncologists' salaries and support expanding hospital cancer centers.
Before 2003, Medicare reimbursed 95% of the average wholesale price — an unregulated price set by manufacturers — whereas oncologists paid 66 to 88% of that price and thus received $1.6 billion annually in overpayments. 3 To blunt unsustainable cost increases, the Medicare Modernization Act mandated that the Centers for Medicare and Medicaid Services (CMS) set reimbursement at the average sales price plus a 6% markup to cover practice costs. This policy has reduced not only drug payments but also demand for generics. In some cases, the reimbursement is less than the cost of administration. For instance, the price of a vial of carboplatin has fallen from $125 to $3.50, making the 6% payment trivial. So some oncologists switched to higher-margin brand-name drugs. 4 Why use paclitaxel (and receive 6% of $312) when you can use Abraxane (for 6% of $5,824)?
Now practices are struggling to treat their patients because of the unavailability of drugs. Short-term solutions include gray-market purchases, which more than half of surveyed hospitals say they've made, but that option introduces safety and quality-control issues. Pharmacists are intensively managing inventories and alerting prescribers to developing shortages and potential alternatives. Some centers now have a red–yellow–green system for quickly recognizing developing shortages and determining which patients get priority (usually those with curable cancers) when supply is limited.
Long-term, non–market-based solutions have been elusive. Proposed legislation would require manufacturers to give 3 to 6 months' notice before discontinuing a drug in order to allow others to pick up production. However, it is likely that gray-market vendors would buy the remaining inventory of such drugs and charge huge markups. Creating a national stockpile is impractical: Do we stockpile the drugs and then waste whatever is not used or stockpile the ingredients and make new batches as needed? A national health care plan with a single formulary and a central pharmacy stockpile is possible for Medicare or Veterans Affairs but unrealistic given oncologists' dependence on drug income and difficulties with timely, safe distribution.
Market solutions take one of two approaches: let the market work and accept short-term uncertainties or regulate the market more tightly. For instance, the CMS could reimburse at the average sales price plus 30%, but that wouldn't help if the drug price has fallen from $125 to $3.50 per vial. The government could set a floor for average sales prices to encourage the production of generic drugs, but that would increase the total cost of cancer drugs unless brand-name prices were reduced. Europe has fewer shortages for that reason: prices are set higher for generics so that companies will make them, but prices of brand-name drugs are often much lower than U.S. prices.
More far-reaching reforms of oncology practices and reimbursement are necessary if there is no national intervention or federal market regulation. One solution is adopting clinical pathways for which practices are paid disease-management fees that are not based on chemotherapy sales. For instance, one large oncology group has developed care pathways specifying preferred drug combinations and sequences — for example, allowing only a few first-line, mostly generic regimens for patients with non–small-cell lung cancer, as compared with the 16 possible drugs and many more combinations included in National Comprehensive Cancer Network pathways. This approach has been shown to result in equal or better survival, less use of chemotherapy near the end of life, and 35% lower costs than usual care. 5 Another solution is to pay physicians salaries, as Kaiser Permanente, Veterans Affairs, and most academic centers do, but that would reduce oncologists' earnings at a time when a 40% workforce shortage is predicted, so the effect must be monitored.
To ensure a predictable supply of generic cancer drugs, manufacturers need reasonable markets and profits, and oncologists need incentives to use generics. Standardized clinical pathways with drug choices based only on effectiveness will enable the prediction of drug needs, practices for effective management of inventory, and planning by manufacturers for adequate production. Such pathways, disease-management fees, and physician salaries would dramatically change oncologic practice, but since drug costs will increase by 4 to 6% this year alone, they are necessary. The current system not only is unsustainable but also puts oncologists in potential ethical conflict with patients, since it hides revenue information that might influence drug choices and thus affects costs and patients' copayments.
The only good news is that the drug shortages may catalyze a shift from a mostly market-based system to one that rewards the provision of high-quality cancer care at an affordable cost.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article (10.1056/NEJMp1109772) was published on October 31, 2011, and updated on November 2, 2011, at NEJM.org.
Source Information
From the Virginia Commonwealth University Health System, Richmond (M.L.G.); and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore (T.J.S.).
The ractopamine dispute is front page news in Taiwan. The country's newly sworn in cabinet will discuss the contentious dispute at its first meeting later this week and President Ma has already publicly discussed the issue, according to local media reports.
"We have always maintained the same position as U.S. officials -- that Taiwanese have concerns about U.S. beef imports and the use of ractopamine," said Ma, at a recent press conference.
The opposition party has been especially outspoken against lifting the ban on ractopamine.
"No meat products, whether beef, lamb, pork or chicken, should be allowed into Taiwan if it contains leanness enhancers," said one lawmaker, according to
Focus Taiwan.
Taiwan, which is the sixth largest export market for beef and pork, began testing U.S. beef for ractopamine in January 2011 and within days found trace levels of the drug. U.S. food safety officials said the levels found ranged from 2.4 to 4.07 parts per billion (ppb), which falls below both the U.S. Food and Drug Administration standard, of 30 ppb, and the proposed international standard of 10 ppb, but Taiwanese officials pulled the meat from the shelves of grocery stores, including Costco, citing consumer concerns.
In early June, Taiwan rejected nearly 100 tons of frozen U.S. beef after it tested positive for ractopamine at 1.5 ppb. Ten days later, Burger King Taiwan temporarily suspended sales of products containing bacon after the Taiwan Department of Health found U.S.-imported pork products to contain ractopamine and seized the pork before hitting grocery store shelves. Public health officials said they found 3 ppb in fully cooked bacon products. Burger King declined to comment on the matter.
The issue has strained the U.S.-Taiwan trade relationship. Taiwan's policy on ractopamine is often cited as a primary reason the two countries have tabled bilateral Trade and Investment Framework Agreement talks. U.S. officials maintain that Taiwan's policy is not science-based.
With renewed pressure from Washington to lift the ban, consumers and farmers are threatening protest, according to Focus Taiwan.
Ractopamine, a drug made by Elanco, a division of Eli Lilly, was first approved by the FDA for pork production 1999, it has since been approved in 25 other countries. The drug has sparked long-running trade conflicts beyond the U.S.-Taiwan hangup.
A recent
msnbc.com report, produced by the Food and Environment Reporting Network, described the deadlock between China, the European Union and the United States at the Codex Alimentarius Commission, which sets global food safety standards.
"The EU and China, which together produce and consume about 70 percent of the world's pork, have blocked the repeated efforts of U.S. trade officials to get a residue limit European scientists sharply questioned the science backing the drug's safety, and Chinese officials were concerned about higher residues in organ meats, which are consumed in China."
High level controversy at Codex is rare. Though the commission adopts dozens of standards each year by consensus, Codex has been stalled on a residue standard for ractopamine since 2008.
"U.S. trade officials say China wants to limit competition from U.S. companies, and the EU does not want to risk a public outcry by importing meat raised with growth-promoting drugs, which are illegal there," added the report.
"Setting a Codex standard for ractopamine would strengthen Washington's ability to challenge other countries' meat import bans at the World Trade Organization."
While ractopamine use remains controversial abroad, there is little awareness in the United States, even though there have been issues with the drug.
"Although few Americans outside of the livestock industry have ever heard of ractopamine, the feed additive is controversial. Fed to an estimated 60 to 80 percent of pigs in the United States, it has sickened or killed more of them than any other livestock drug on the market, an investigation of Food and Drug Administration records shows."
The full
Food and Environment Reporting Network story, which was also been
picked up by Taiwan media, can be found
here.
When
Hiroaki Matsunami, PhD, associate professor at Duke University, set out to study a chemical in male mouse urine called MTMT that attracts female mice, he didn't think he would stumble into a new field of study.
But the research has led scientists at Duke University Medical Center and the
University of Albany to the discovery that it's the copper in our bodies that makes mammals recoil from sulfurous chemical smells.
Working with Eric Block, PhD, the Carla Rizzo Delray Distinguished Professor of Chemistry at the University of Albany, the team looked at reasons why mammals, including people, can detect even trace amounts of sulfur-containing substances, like MTMT.
"While we were doing our experiments, on even very dilute specimens of MTMT, our neighbors on the lab hallway complained," Matsunami said with a laugh. He is an associate professor in the
Duke Department of Molecular Genetics and Microbiology and the
Department of Neurobiology.
The Duke laboratory ran a high-throughput test of several hundred mammalian odor receptors, and found that one receptor that bound copper ions resulted in superior detection of even trace amounts of sulfur.
Underarm odors from bacteria, skunk spray, volcanic gases and odorized natural gas (for leak detection) are examples of sulfurous substances.
The work was published in the
Proceedings of the National Academy of Sciences online the week of Feb. 6.
"We learned that copper was the metal that allowed for detection of all the sulfur-containing compounds we tested, and it was Eric Block's idea that metal ions must be involved," Matsunami said. "Further, I see no reason why the mouse receptor activity would be different from human receptors, because we have the same kind of olfactory receptors."
Block and colleagues created several dozen sulfur-containing compounds for testing.
The odor impact of the sulfur-containing molecule MTMT can be attenuated by manipulating the copper concentration in the nasal mucus. The team did experiments using a chemical that binds to copper in the mouse nose, so that copper wasn't available to the receptors, and the mice didn't detect the MTMT, Matsunami said.
"This study establishes for the first time the key role of a metal, namely copper, in the activity of an olfactory receptor," Eric Block said. "What's also exciting is that, because olfactory receptors are transmembrane G protein-coupled receptors (GPCRs) of the same type as receptors for drugs, our discovery suggests a possibility that some drug-receptor responses may also be enhanced in the presence of copper or other metal ions."
Other authors include Siji Thomas and Shaozhong Zhang, of the University of Albany Department of Chemistry; Timothy Connelly, Qiuyi Chi and Minghong Ma of the Department of Neurobiology, University of Pennsylvania School of Medicine; and Xufang Duan, Zhen Li, Lifang Wu, Guo-Qiang Chen and Hanyi Zhuang, all of the Ruijin Hospital in China. The senior authors on the paper were Dr. Matsunami and Dr. Zhuang, formerly of Duke, who is also with the Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai.
This research is supported by National Natural Science Foundation of China Grants, Shanghai Pujiang Program Grant, the Program for Innovative Research Team of Shanghai Municipal Education Commission grant from the Chen Guang Project funded by Shanghai Municipal Education Commission and Shanghai Education Development Foundation, and a grant from the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, from the Leading Academic Discipline Project of Shanghai Municipal Education Commission. The U.S. National Institutes of Health (NIH), National Basic Research Program of China, U.S. National Science Foundation, and NIH/National Institute on Deafness and Other Communication Disorders also funded the work.
This article is dedicated to the memory of Dr. Lawrence C. Katz of Duke, who worked on related studies and with Eric Block found the first evidence of neurons that respond to social odors.
Drugmakers realise they need to demonstrate the value of their new treatments to payers, but many are concerned about their ability to do so.
That is one of the key findings from a new report from the Economist Intelligence Unit, sponsored by Quintiles. The analysis, called 'The Value Challenge', is based on findings of a survey of 399 senior executives from the life sciences industry, and it states that the situation is "further complicated by a shift in the balance of power among industry stakeholders, each of which may require different evidence to be convinced of a product’s value".
The EIU report argues that the value challenge is "not just a temporary symptom of current economic conditions, but a long-term issue that is a leading concern for a majority of drug companies worldwide". Moreover, although deteriorating financial circumstances are prompting some payers —particularly governments —to focus more closely on reducing pharmaceutical spending, "the demand for proof of value has been evolving for decades".
However, many stakeholders, especially biopharma companies, "lack confidence in the industry’s ability to respond to the value challenge", the report claims. Only about one-half of survey respondents say that the pharmaceutical sector is adjusting well to increasing demands for proof of value.
All respondents are harsher about biopharmaceutical companies’ ability to demonstrate value and, among payers and regulators, only 25% are confident about the broader claims of value made by these firms. However, 68% of life sciences respondents saw the growing demand to provide value has had an important impact on their business models; 85% have made at least one change to their model for this reason, 82% to their R&D strategy, and 78% to their commercial plans.
The EIU survey also notes that biopharmaceutical companies see their market power decreasing, but others still regard them as dominant players. The report quotes Ed Pezalla, national medical director for pharmaceutical policy and strategy at US insurance major Aetna, as saying that “the industry is still making decisions about what drugs come to market and what they can charge. It is just beginning to pay attention to payer sensitivity.”
"Food Fraud is a much broader set of crimes than just counterfeiting or adulteration," says John Spink, the associate director of Michigan State University's Anti-Counterfeiting and Product Protection Program. "The term Economically Motivated Adulteration has been used by [the U.S. Food and Drug Administration], and although there has been a lot of activity using this term in the food industry, it actually involves all FDA regulated products."
Spink and Douglas Moyer, both faculty at Michigan State University, published a paper in the Journal of Food Science in November specifically aimed at defining the public health risks of food fraud, hoping to provide a base reference for the issue and help shift the current focus on intervention to one of prevention.
"The food-related public health risks are often more risky than traditional food safety threats because the contaminants are unconventional," write Spink and Moyer. "Current intervention systems are not designed to look for a near infinite number of potential contaminants."
As it stands now, food fraud crackdowns often focus on the economic impact of cheating the system, not public health, and are reactive, not preventative.
In late November, European Union's Europol teamed up with Interpol to conduct a week-long, multi-country food fraud operation. Agents seized hundreds of tons of fake and substandard food and drink--including champagne, cheese, olive, oil, and tea--from Bulgaria, Denmark, France, Hungary, Italy, The Netherlands, Romania, Spain, Turkey and the United Kingdom.
Known as "Operation Opson," the effort, which took six-months to plan, ultimately turned up a lot of fraudulent food.
The team seized 13,000 bottles of substandard olive oil, 30 tons of fake tomato sauce, around 77,000 kg of counterfeit cheese, more than 12,000 bottles of substandard wine worth 300,000 EUR (or nearly $400,000), five tons of substandard fish and seafood, and nearly 30,000 counterfeit candy bars. Authorities also said the sale of fake or substandard caviar on the internet was under investigation.
Interestingly, when Interpol-Europol announced the results, they specifically cited public health as a key reason to crack down on fraudulent food practices.
"Consumers buying these goods, either knowingly or unknowingly, are putting their health at risk as the counterfeit food and drink are not subject to any manufacturing quality controls and are transported or stored without proper regard to hygiene standards," authorities said about the operation.
Interpol-Europo said Operation Opson, which means "food" in ancient Greek, had three critical goals:
- Raise awareness of the dangers posed by counterfeit and substandard foods;
- Establish partnerships with the private sector to provide a cohesive response to this type of crime;
- Protect consumers by seizing and destroying substandard foods and identifying the criminals behind these networks.
"One of the main goals of this operation was to protect the public from potentially dangerous fake and substandard food and drinks, which is a threat that most people are not even aware of," said Simone Di Meo, Criminal Intelligence Officer with Interpol's Intellectual Property Rights programme and coordinator for Operation Opson.
Explicitly linking fraudulent or substandard food to public health risk is something Spink and his team at Michigan State University would like to see happen here in the United States more often.
"I find it amazing, and refreshing, that Interpol-Europol have focused this Operation Opson on a underappreciated product risk. Most times, consumers and even lawmakers, consider product counterfeiting to be a technical problem with economic losses. While they may understand the risks of pharmaceutical drug counterfeiting, they are often unaware of the food risks," said Spink. "Any and every type of food fraud has a public health vulnerability - we may not have experienced an actual public health incident, but the bad guys are not following good manufacturing practices."
Photo courtesy of Europol.
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