With little notice until recently, a shortage of medicine is starting to impair treatment at America’s hospitals. Common, cheap and necessary drugs needed to fight bacteria or cancer, to ease pain or to nourish premature infants are running out.

Many of these meds are injectables, which must be made under sterile conditions. All are generics, which sell for pennies compared to the buck-buster drugs that feed the bottom lines at the big-name drug companies.

Most shortages are unnanounced until a wholesaler’s shipment arrives lacking an ordered drug. “It’s unbelievable,” says Sara Shull, manager of the drug policy program at the University of Wisconsin Hospitals and Clinics in Madison. “Today I was trying figure out alternatives to papaverin,” an old drug used to prevent spasm in the many surgeries that involve grafting a blood vessel. “We have identified some alternatives, and I am now I working with the surgeon to figure out how to dose them, how to apply them. Is it bathed on? Sprayed on? He’s busy, we’re all busy, and sorting this all out takes a lot of time. The continual need to find replacements gives me a headache.”

Shortage-induced substitution played a role in Alabama, where nine hospital patients were killed by intravenous nutrients this summer, says Allen Vaida, executive vice president of the Institute for Safe Medication Practices, a non-profit that targets medicine hazards. “Because of a shortage, this compounding pharmacy was making a product from raw material, and it got a bacterial contamination.” (The maker of the nutrient solution, Meds IV pharmacy in Birmingham, Ala., is apparently out of business.)

Medications on this rack will restock a robot that fills individual patient envelopes that will be sent tomorrow to nurses’ stations in the hospital. Actually, the robot restocks itself in its 24/7 delivery of thousands of prescription drugs.

Photo: The Why Files

ENLARGE

Source: U.S. House of Representatives

Shortages are growing, especially for injectable medicines.

Running long on shortages

Pharmacists have always had to find substitute medicines, as patients keep coming through the door, but Vaida cites Food and Drug Administration numbers to argue that shortages are now at “crisis” proportions. “The FDA shows 70 shortages in 2006, 129 in 2007 and last year, there were 211. So far this year, we are already above 200 shortages, and the year isn’t done. Shortages have been around forever, but they have never reached this number.”

Some drugs can be substituted, says Vaida, but “especially with chemotherapy and nutritional products, it’s not like are three alternatives for some medications, as there are with blood-pressure drugs. Some chemotherapies are specific for certain cancers, and if they are not available, you may have no alternative or [you] may have to use a third-line alternative.”

The pharmaceutical situation has never been more complicated, with more than 45,000 prescription drug products on the market, from about 1,400 manufacturers. Although we could not easily find numbers, drug shortages are also rising in the United Kingdom, where the supply situation is complicated by the restriction on exports within the European Union.

Shortages have many possible causes, but because manufacturers tend to be closed-mouthed, it’s not clear which problems are most momentous or easiest to solve:

How short is short?

A drug is considered “short” if a specific dosage and formulation is unavailable, and in some cases, a similar item can be substituted. But Shull says that’s still a problem in a big hospital. If a product that is normally purchased in a pre-loaded syringe is only available in a vial, University of Wisconsin Hospitals and Clinics can no longer send a “unit of dose” to the nurse, and “that’s what the nurses are expecting,” Shull says.

Changing procedures complicate care and raise costs, Shull adds. “All our people are working in a complex system, with lives on the line. These shortages can be a recipe for increased errors.” Her hospital must dedicate one staffer to securing supplies of the common blood-thinner heparin, she says. Searching for alternate sources is less rewarding than studying the efficacy of various medication treatments, she adds. “It’s not what I was taught in pharmacy school, but when your back is up against the wall, you have no other options.”

Beyond impairing patient care, shortages have also become a major burden in medical research. Tests of new medicines, often set up to run at several hospitals nationwide, must give standardized meds to the treatment and control groups, and chaos can result when the drugs become unavailable. “These shortages are now affecting clinical trial options for patients with cancer,” Robert DiPaola, director of the Cancer Institute of New Jersey, told the House Energy and Commerce Subcommittee on Health on Sept. 23. “Due to the uncertainty of being able to obtain many of these drugs, enrollment of patients on clinical trials has been delayed or stopped in several of our trials.”

Howard Koh, assistant secretary of health and human services, reinforced that message to the committee: “Many of the cancer drugs in short supply … are mainstays of the anti-cancer arsenal, and were largely developed through federally funded research begun 20, 30, even 40 years ago. They are still essential to treatment and research,” he said. The National Cancer Institute is currently sponsoring 349 clinical trials that require these drugs, Koh added. “Taken together, these studies represent thousands of patients, as well as a significant federal investment in clinical trials research.”

At the same hearing, Mike Alkire, chief operating officer of Premier healthcare alliance, told Congress how widespread the shortages have become. In a recent Premier survey, 53 percent of hospital pharmacists said they had faced at least six shortages “that had the potential to cause a medication safety issue or an error in patient care.” And 34 percent of respondents said at least six shortages had “resulted in a delay or cancellation of a patient-care intervention.”

Premier estimates that the 2,500-plus non-profit U.S. hospitals in its membership pay an extra $66 million per year due to these shortages — which translates to $415 million at all U.S. hospitals.

Market going gray?

When the usual sources run dry, hospital pharmacists often get emails, faxes and phone calls from the “gray market,” sources outside the usual supply chain. In the summer of 2011, the Institute for Safe Medication Practices surveyed 549 hospitals and found that:

Alkire, of the Premier alliance, told Congress that the gray market is “appalling,” with an average markup of 650 percent. Forty-five percent of the offers were marked up at least 1,000 percent above normal price, and drugs for leukemia and non-Hodgkin’s lymphoma were marked up 4,000 percent. “We saw similar markups for medicines for sedation during surgeries; to dilate veins and prevent brain or heart spasms; and to prevent damage during a heart attack,” Alkire said.

For these reasons, University Hospital at UW-Madison does not buy gray, says Shull, although it does buy from a wholesaler that seems to have supplies of drugs when nobody else does.

The gray market arouses suspicion: How do some firms know about shortages before anybody else? How do they obtain drugs when normal sources are short?

“There is speculation going on,” says Vaida. “Some secondary wholesalers may try to buy up some available drugs and sell them for higher prices. Often times, they are looking for people who need the product, and try to obtain it from whatever sources. Some are playing it almost like Wall Street, anticipating what may go on shortage — if two manufacturers have just consolidated, and there’s a generic product that is only going to be made by one of them.”

Cures for missing meds

Many measures have been proposed to ease the medication shortage:

Photo: Armin Kübelbeck

Generic, injectable drugs comprise the majority of shortages.

The FDA seems to be getting the message. In testimony to the subcommittee on Sept. 23, Koh claimed that the agency had already headed off 99 looming shortages in 2011, compared to 38 for all of 2010. But Koh added that today’s shortages “include standard therapies for the treatment of lung, breast, ovarian, testicular and colorectal cancers, as well as several types of lymphomas and leukemias.”

Sometimes, Koh said, common-sense, proven measures can sidestep shortages. “… the FDA was able to mitigate a shortage by allowing the use of a filter to safely remove foreign particles contained within vials of injectable drugs, averting the obvious risk to patients of having metal shavings or other particulate matter injected into their veins.”

A pessimist, of course, could say the higher number of averted shortages simply reflects the greater number of shortages overall.

At any rate, organizations concerned with shortages say they are in a vise. “From our members’ perspective, it’s become [a] crisis,” says Hill. “We are seeing shortages nationwide. We have been tracking this for about 10 years, but in the last few years, we’ve seen a spike in the numbers.”

Given the problem’s multiple and sometimes obscure, roots, Hill sees “no single solution, and that’s the troublesome part. Unfortunately we will be dealing with this for a while. But there are some things we can do. We’d like to establish a mandatory early-warning system, so a manufacturer that has a problem has to notify the FDA. The FDA says it has avoided 99 shortages in the past year when it had that information. When there are multiple sources, the FDA can reach out to other manufacturers and urge them to ramp up production.”

David J. Tenenbaum

Can a gene that causes dwarfism also confer major health benefits? Perhaps, according to a new study showing that a group of extremely short people in Ecuador get no diabetes, even though they are unusually obese.

The 22-year study of people living in villages on the slopes of the Andes mountains also found just one case of cancer in the 99 patients it tracked, many fewer than among non-dwarf relatives.

The absence of two of the worst diseases of aging was strong evidence that the mutation that causes what’s called “Laron syndrome” has an upside, says Valter Longo, a gerontologist at the University of Southern California, and the senior author on the new study. “If you talk to anybody in the field, there is no way you can have a population with increased obesity and no diabetes. What was particularly strange was having zero deaths from cancer with 22 years of direct monitoring.”

Unfortunately, the subjects did not outlive the comparison group of relatives, due to large numbers of accidents and other alcohol-related problems.

The Laron’s patients are descendants of “Conversos,” Jews who were forcibly converted to Catholicism in Spain after 1492, and who emigrated to Latin America to escape continued persecution. Laron’s syndrome is also found in Israel and several other Middle-eastern countries.

The root of Laron’s syndrome, AKA growth hormone receptor deficiency, is a genetic mutation that disables the growth-hormone receptor, says Arlan Rosenbloom, a professor emeritus of pediatric endocrinology at the University of Florida who has long studied the Ecuadorian group but was not involved with the current report. “Growth hormone binds to its receptor on cell surfaces to stimulate production of insulin like growth factor-I (IGF-I) which is the real ‘growth hormone,’” Rosenbloom says. “Failure of the growth-hormone receptor cuts growth after birth by 50 percent. The Ecuadorians with this condition, 99 living individuals, comprise upwards of one-third of all individuals in the world with growth-hormone receptor deficiency.”

Image: Mikael Häggström

Growth hormone, secreted by the pituitary gland, travels to the liver, where it stimulates the formation of insulin-like growth factor 1, which stimulates bone growth.

The genetic angle

The new comparison of genetic differences between Laron patients and their non-dwarf relatives emerged from what Rosenbloom calls “spectacular epidemiological observations” by first author Jaime Guevara-Aguirre, an Ecuadorian endocrinologist who treats the Laron’s patients.

Working with Rafael de Cabo, a collaborator at the National Institute on Aging, Priya Balasubramanian from Longo’s research group exposed human epithelial cells, where most human cancers originate, to blood serum from control and Laron subjects. Serum is the cell-free portion of blood. “We wanted to know how this would affect the expression of dozens of genes,” says Longo, who studies cellular changes in aging.

The springboard of modern aging research is caloric restriction, because a diet with roughly 65 percent of normal calories is the only life-extension technique that works in a vast range of organisms. Although a similar group of protective genes activate under caloric restriction in yeast, fruitflies and mice, “We did not expect that a lot of the genes we study in yeast would come out as the most affected” in patients with a broken growth-hormone receptor, Longo says. “Serum from the Laron patients caused changes that we and others have shown to be highly protective in simple systems [like yeast]. We hoped for this but never really expected that many of the same genes would be coming up.”

At the molecular level, a key mechanism of aging is “oxidative stress,” damage to proteins and DNA caused by reactive molecules and fragments containing oxygen. When the researchers exposed human cells to the oxidant hydrogen peroxide, far fewer DNA breaks appeared in cells bathed in serum from the Laron patients, suggesting that they were protected against cancer.

The study found a second critical difference: When the DNA was damaged, cells in Laron serum were much more likely to commit suicide through apoptosis. Because apoptosis is a major obstacle to cancer, this suggested that cells in a Laron patient that had started on the path toward cancer would be more likely to kill themselves before going rogue.

Combined, the two phenomenon seem to explain why during the 22-year study only one of the Laron’s patients being tracked had a cancer, which was successfully treated. About 17 percent of their normal-height relatives had cancer during the same period.

Growing more confident

The study illuminates the role of insulin-like growth factor-1 (IGF-1), a growth hormone that, while required during development, may cause problems later on. “Large population studies show that people with the highest levels of IGF-I are at increased risk for certain types of cancer,” says Rosenbloom.

Longo notes that the effects of IGF-1 may depend on whether it is formed in an individual organ or distributed in blood. “Our hypothesis is that we do not need a ton of circulating IGF-1,” Longo says. Laron patients have between 0 and 10 percent of the normal level of IGF-1, “but they are fine, several made it into their 80s.”

The Ecuadorian study was more evidence that IGF-1 formation requires a functioning growth-hormone system. A drug that blocks the growth-hormone receptor has been approved for treating acromegaly, or gigantism, which is caused by excessive production of growth hormone.

You don’t have to be a hypochondriac to wonder if such a drug could prevent cancer and diabetes in adults, but the new study shows correlation, not proof, and Longo advocates a more modest first step in clinical trials. Return to caloric restriction for a moment: Studies in mice show that fasting reduces IGF-1 and protects healthy cells — but not tumor cells — from damage during chemotherapy, and some cancer patients have begun fasting to reduce collateral damage during chemo. “I think that soon enough, we will start with a clinical trial of this growth-hormone receptor antagonist to protect cancer patients against chemotherapy toxicity,” Longo says.

The new study is further proof, that, up and down the line from yeast to mice to people, similar “conserved” biochemical mechanisms influence aging, cancer and diabetes, Longo says. “The conservation hypothesis is something I am very convinced of, but I did not expect what we saw. Maybe we would see major reductions in cancer and insulin resistance [a marker of diabetes], but to see not one case of diabetes, not one cancer death, and to see the genetic matches with the simple systems that we study, that was as good as we could hope for.”

The evolution of a cancer

Genetically, cancer is a mess. Tumor cells don’t do the work of a healthy cell, but they are awfully good at making sloppy copies of themselves. Removed from the normal restraints and error-checking that keep healthy cells honest, cancer cells can change over time as they evolve to fight the immune system and cancer drugs.

 

Chart: NIH

The new study in Nature tracks the evolution of a breast cancer, a diagnosis that becomes more common with age.

Until now, getting a picture of these genetic changes has been an insurmountable task. Just “reading” the normal DNA in one person cost billions and took about a decade. But now, techniques for hyperspeed DNA sequencing are starting to produce libraries of genetic data, raising the hope of unraveling the varying genetics of cancer.

Nature is now reporting the most thorough study of evolution in a single patient’s breast cancer. “This week, for the first time, we have looked in detail at the evolution of a cancer genome over time,” says Samuel Aparicio, a professor at the BC [British Columbia] Cancer Research Center and the paper’s senior author. The study compared the cancer’s genes before and after it had spread, nine years later.

One disease, or many?

The ability to look in detail at cancer genes raises the prospect of eventually understanding the cause of the many diseases we call cancer. Cancer is a curious beast, and its genetics can get more bizarre with time. In the Aparicio study, the tumor cells nine years after diagnosis showed 32 significant mutations, only five of which were common in the original tumor.

Understanding these early and late mutations could shed light on the origin and spread of cancer.

 

From original graphic by DOE

Understanding the genetics of cancer could help in prevention and in treatment.

High-speed sequencing could eventually help doctors select treatments based on the genetics of the cells in the tumor, and Aparicio says his team has already begun tracking patient’s genes. “We will be able to build up our idea of what mutations might be conferring resistance or sensitivity to drugs. Eventually, we can ask, ‘did this or that genome respond better to this drug?’”

Making treatment decisions could be complicated, however, as even the original tumor showed genetic weirdness that is not found in healthy tissue. This genetic diversity is important, Aparicio says. “When one considers developing a therapeutic strategy, we tend to regard the cancer genome as a single entity. Cancer biologists have known this for decades, but we just have not had the means to see it.”

Moral of the story: Weapons against a “single” cancer are actually confronting multiple foes, which have — or may evolve — multiple genetic tricks for evading cancer-killing medicines and the immune system.

 

From graphic by NIH

Sequencing DNA relies upon matching pairs of components that have specific preferences for partners. If you know the sequence on one strand, you can predict the sequence of the other.

Consequential sequencing system

Scientists have wanted to understand the changing genetics of cancer for decades, but this study was only possible due to phenomenal advances in sequencing speed that are meanwhile causing the cost to drop, some say, faster than the price of computers.

Ultra-speed “synthesis DNA sequencing” relies on DNA’s ladder-shaped, double-stranded structure. The molecule is built of pairs of components called “bases” that are picky about partners: The base nicknamed “A” will only link to “T”. Likewise, “G” is specific to “C.”

Any time you see a C, you know it’s got to be linked to a G. So knowing the sequence on one strand tells you the sequence on its complementary strand.

Technicians start synthesis sequencing by splitting the DNA ladder lengthwise and anchoring millions of short strands to a sample plate. The sequencing machine then introduces new bases and watches as they complete the anchored strands. Because each base will only link to its complementary pair member, the process of attachment shows the structure of the DNA fragments that were originally attached to the plate.

Synthesis sequencing is just catching on, and the current study looked at one tumor, from one patient. To understand which mutations are most dangerous, “one really has to … look at multiple cancers,” Aparicio says.

However, one mutation that already seems portentous is HAUS3, which causes defects in proteins that organize the chromosomes as they undergo the delicate process of uncoiling, duplicating, and recoiling during cell division, Aparicio says. “We know from other studies that if we deplete those proteins, cell division becomes error-prone, which leads to instability in the genome, so conceivably mutations in those genes might have been involved in the early stages of cancer.”

 

Graphic: National Cancer Institute

The secondary cancer, called a metastasis, is more likely to cause death than the primary tumor.

A first look

As an early look into the tangled genomics of cancer, the study is a good first step, says Michael Gould, an oncologist at the University of Wisconsin-Madison School of Medicine and Public Health. “In this data from one patient, the original tumor had a lot fewer meaningful mutations than previous reports on breast cancer cell lines. If this holds up for other solid tumors, and I believe it will, there will not be a huge catalog of mutations in any individual [primary] tumor, and that’s good.”

However, Gould adds that compared to a previous study of the blood cancer leukemia, the British Columbia study also found more genetic change over time. “In leukemia, the primary and metastatic tumors had the same spectrum of mutations, and people concluded there was not necessarily genetic evolution going on, that maybe when the cancer first comes up, you either have a metastatic mutation or you don’t. In this [breast cancer] study, and maybe it’s generalizable to other solid tumors, there is some evolution going on between the primary and metastatic tumor.”

As Aparicio says, the treatment goal of this type of genomic analysis is already beginning, as researchers try to correlate different genetics with treatment outcomes. But learning about gene damage in the primary tumor may also identify the original cause of the cancer. Whether that cause resides in the environment or the patient, such insights should become the basis for better cancer prevention.

David J. Tenenbaum