Cover Story

Drug shortages threaten patient health and safety

For many cancer drugs, there are no available or effective substitutions.

Drug shortages in the United States, which reached record highs in 2010, continue to vex physicians, patients and manufacturers. Although the shortages have affected all medical specialties, they have been felt most acutely in oncology, emergency medicine, anesthesia and cardiology, significantly affecting patient care.

In 2010, there were 178 shortages of medically necessary drugs vs. 157 in 2009, according to Jouhayna Saliba, PharmD, senior regulatory program manager of the Center for Drug Evaluation and Research Drug Shortage Program for the FDA. “We are continuing to see a large number of shortages in 2011, unfortunately. However, we don’t know yet if this year will be worse than 2010,” Saliba told HemOnc Today.

The American Society of Health-System Pharmacists (ASHP), which tracks all medications in shortage, not just those that are medically necessary, lists 197 drugs in shortage.

According to Saliba, the FDA is especially concerned about the 132 sterile injectable drugs that are on the shortage list. “Older sterile injectables are especially vulnerable to shortage due to the small number of firms currently making these drugs, the limited capacity at the firms and the complexity of the manufacturing process,” she said. “When one firm has a problem or discontinues [a drug], it’s difficult for the remaining firms to meet the shortfall.”

ASCO president Michael Link, MD
ASCO president Michael Link, MD, speaks to Congressional staffers at a July 13 briefing on drug shortages on Capitol Hill.

Photo courtesy of American Society of Clinical Oncology.

Critical problem

This issue has reached a critical point, according to Joseph Hill, the director of federal legislative affairs for ASHP. “We’re almost approaching it as a crisis situation with our members,” he said. “We’ve seen them occurring nationwide, primarily oncology drugs but also some of the nutritional drugs, some pain medications, some anesthetics. It’s a critical problem.”

The medications involved are not seldomly-used drugs. “Some of these drugs have become the mainstay of curative therapies for certain cancers,” Michael Link, MD, president of ASCO, told HemOnc Today. “When one thinks of the curable cancers now, one thinks in terms of lymphomas and leukemias, many of the childhood tumors and testicular cancer — the mainstay drugs in the treatment of these cancers have been in short supply.”

Doxorubicin (Adriamycin, Pharmacia and Upjohn), an important drug in the treatment of lymphoma and sarcomas, is on the list. Cisplatin, which revolutionized the treatment of testicular cancer, is in short supply, according to Link. Daunorubicin and cytarabine, both essential for adult and childhood leukemia treatment, are in shortage. Supplies of leucovorin and methotrexate are also low. “These are drugs that are well-known,” he said. “They’ve been around for a long time and are a part of the fabric of cancer treatment.”

Etoposide, vincristine and, most recently, paclitaxel are other chemotherapeutic agents on the shortage list.

Not just cancer drugs

This issue cuts across all medical specialties, according to Link, a pediatric oncologist at the Lucile Packard Children’s Hospital at Stanford University. “This is not just a shortage of cancer-specific drugs or anticancer drugs,” he said. “This is a shortage of antibiotics and anesthetic drugs as well.”

Many are “cornerstone drugs in other disease settings, such as intravenous furosemide,” Robert J. Mayer, MD, Stephen B. Kay Family Professor of Medicine at Harvard Medical School, told HemOnc Today. Mayer is also faculty vice president for academic affairs at the Dana-Farber Cancer Institute.

Other medications listed include azithromycin, norepinephrine, ketorolac, fentanyl and epinephrine, ciprofloxacin and gentamicin.

The length of the shortages varies and depends on the cause, according to Saliba. “If it’s a big quality defect involved, it may take several months to resolve,” she said. For less severe issues, the shortage could be resolved in as little as a few days.

Multifactorial causes

The causes for the drug shortages are multifactorial. One of the biggest problems has been manufacturing issues, which can range from simple to complex.

“It could be something minor, such as a labeling change or the wrong label on the wrong box,” Saliba said. “That is something that could be fixed quickly. But the more severe issues are sterility issues, where we’re seeing particulates in vials and contaminations.”

Hospira and another manufacturer alerted physicians to a crystallization problem in certain lots of cytarabine injection in February. An investigation revealed that the crystals were particles of active ingredient, according to the company’s “Dear Health Care Professional” letter. Most likely, dried cytarabine on the filling needles entered the vials during manufacturing and acted as a seed for crystal formation. The company resolved the problem and resumed manufacturing in March, according to Dan Rosenberg, Hospira spokesman.

Raw material shortages have been the cause in a few cases. “We’re seeing that if there’s a sole source supplier for the active pharmaceutical ingredient (API), and there’s a problem with the supply of that API or the quality of that API is compromised, all of these can lead to manufacturers having to shut down manufacturing lines and product not being available,” Hill said.

Robert J. Mayer, MD
Robert J. Mayer

In 2010, Hospira was short on cytarabine’s API, which comes from an outside supplier, causing the product to be off the market for a time, Rosenberg said.

“Hospira experienced a supply shortage in 2010 and early 2011, but is now back on the market and is prioritizing the drug’s manufacture ahead of other products to meet critical patient needs while other manufacturers continue to experience difficulties,” Rosenberg told HemOnc Today.

Manufacturer discontinuation has been a major cause of the shortages. In many cases, the manufacturer made a business decision to stop producing a particular compound because the medication was off patent and no longer returning a large profit.

“In view of all those explanations, somewhat of a deeper underlying explanation may be simply that it’s not profitable to produce generic drugs,” said Richard L. Schilsky, MD, professor of medicine and chief of the section of hematology/oncology at the University of Chicago. “And all of the drugs that have been in short supply have been generics.

“When there is a manufacturing problem … or when there are raw materials in short supply, there aren’t many incentives to rush to correct the problem because the profit margin on these drugs is so small,” Schilsky said. “That’s a deeper, underlying problem that must be addressed.”

How shortages affect patients

There are several side effects of the drug shortage, the most important being the effect on patient care. Physicians have been forced to use substitutes or find workarounds. For antibiotics or anesthetics, that is feasible because “there are still alternative therapies to cure infections or put patients to sleep,” Link said. “But in the anticancer field, for many of these drugs — depending on the tumor, of course — there is no good substitution.” Drugs such as doxorubicin and cytarabine, however, are the therapeutic mainstays for adult and pediatric leukemias. “If these drugs are unavailable, there’s simply no way to treat the leukemia.”

Sometimes, the substitute or workaround may not be as effective. “For example, substituting carboplatin for cisplatin in the treatment of testicular cancer, will work for the majority of patients, but the overall cure rate will be lower,” Link said.

“One of our concerns is that if there is a product where a substitute is available, there are times when that drug substitute is a much older drug product,” Hill said. “You may have new or younger clinicians who aren’t familiar with the product because they’ve never used it before. There is concern that using some of these older products could jeopardize patient care.”

Patient care has been affected, according to the Institute for Safe Medication Practices (ISMP). From July 2010 to September 2010, ISMP surveyed more than 1,800 health care practitioners who indicated that the drug shortages have significantly increased the potential for errors and patient harm, according to a press release.

The potential for harm

About one in three survey respondents said their facility had an error related to a drug shortage that could have harmed a patient. Roughly one in four respondents indicated that there were errors that reached patients; one in five reported adverse patient outcomes, according to the release. Voluntary reporting methods make tracking errors and adverse events challenging, so many respondents suggested that the frequency of errors and adverse events related to the drug shortages is actually much higher.

These substitution errors resulted in deaths, according to Michael R. Cohen, RPh, MS, ScD, ISMP president. “We have had errors with people who weren’t familiar with a new drug and confusing the dose,” he said. In response to the morphine shortage, physicians substituted hydromorphone, which is six or seven times more potent than morphine. The hydromorphone was administered at the intended dose for morphine, resulting in two deaths.

There have been dosing problems when physicians used substitute anesthetics, he said. “We’ve had reports of patients waking up during surgery,” Cohen said.

Michael R. Cohen, RPh, MS, ScD, ISMP president
Michael R. Cohen

ISMP members reported errors with chemotherapeutic agents, too. There was a dosing error when a pharmacist used the 500 mg mixing protocol on a 1,000 mg vial of cytarabine. Switching out capecitabine (Xeloda, Hoffmann-La Roche) for leucovorin has produced serious gastrointestinal toxicity for many patients.

In some cases, the patient received less medication than anticipated. One prescriber converted a patient from IV etoposide to oral dosing but was not aware that the oral dose needed to be double the IV dose. In another case, pre-diluted methotrexate was not available, according to the survey results. The vial of dry powder was reconstituted improperly, and the patient received less than the prescribed dose as a result.

Care delayed for some patients

For some patients, the shortages have affected the timing of treatment. Link told HemOnc Today of a patient with acute leukemia whose treatment was delayed because the drugs needed for therapy were not available. The physicians and hospital tried to locate a sufficient medication supply. “Delays in cancer therapy are never a good idea,” Link said. “We can’t quantitate how those delays will affect outcome, but we know that, in general, it’s not a good idea to delay therapy. In most cases, this will have an overall negative effect on outcome.”

Addressing the shortages consumes many resources. “It’s a costly problem,” Cohen said. “We’ve actually had multiple hospitals that have told us they have half of an FTE (full-time equivalent) or even a full FTE invested in the drug shortage to take care of these situations.”

The costs increase when it becomes necessary to operate in the gray market. “[There have been] massive increases in availability of gray market sources, which charge 10-fold more and greater for the drugs you were able to purchase before at usual price,” Cohen said.

But gray market purchases can be questionable, according to Cohen. The origin, potency and storage of the drugs cannot always be ascertained.

“Before, when we got the drug directly from the manufacturer or through a wholesaler, there was no question that these were handled properly,” he said. “Now, we have evidence that some of these drugs that are being ordered have gone through five and six turns before they actually got to the pharmacy.”

Influence on clinical trials

Some institutions have turned to stockpiling drugs. “I’ve been told that large academic centers, knowing that this may occur, have stocked up their pharmacies, whereas private doctors’ offices or private groups or even smaller hospitals are not able to do that,” Mayer said.

“We heard one horror story that a local hospital had a large supply of a drug and was selling it to other hospitals and practices at a mark-up,” Link said.

Clinical trials have also been affected, Link said. “If a patient is on a clinical trial that involves one of the drugs that are in short supply, or when a new drug is added to a standard combination, if one of the drugs in the standard combination is not available, well, of course, that affects the ability to continue to treat a patient who is on a clinical trial.”

Also, it can affect trial result interpretation. If a standard drug in a trial becomes unavailable and is replaced with a less effective compound, “it might make the new regimen look better than it really is because, in fact, some patients were getting a suboptimal control arm,” Schilsky said. “That’s a concern for the interpretation of clinical trials going forward.”

Solutions

Solving this problem of why shortages occur will first depend on clearly identifying the causes, according to Link. Although the FDA is responsible for ensuring that medications are safe and effective, it is not tasked with guaranteeing an adequate drug supply. “I suspect that [solving this] is going to depend on increasing the authority of the FDA to track the supply of medically necessary drugs and to find out in advance whether there’s going to be a shortage. Time and prior notification would at least give the agency the leverage and time necessary to do something in advance of a shortage,” he said.

Early notification has already demonstrated its effectiveness, Saliba said. “Last year, we can say that 38 drugs were prevented from going into shortage because of early notification.”

Quicker approvals may improve the shortages. “We’re looking at expedited approvals for some of these products, especially if they are pre-approved or pre-1938 drugs,” Hill said. “We’re looking at ways that the FDA could speed up that process and make it easier for these manufacturers to get into the market.”

One potential solution is offering incentives to manufacturers. A big incentive would be to allow manufacturers to make more money, according to Schilsky. “The economic solutions are fairly clear,” he said. “The political solutions to achieve those economic solutions are more complicated.”

Another option would be to offer manufacturers some incentive, such as a tax break, to ensure that the drug stays in adequate supply, Schilsky said.

Richard L. Schilsky, MD
Richard L. Schilsky

For controlled drugs, manufacturers are only required to keep certain amounts of API on hand, as determined by the DEA, according to Hill. “What happens if you have a manufacturer that has a problem? The other manufacturers can’t ramp up production because they’re only able to have so much API at their plant,” he said. “If there’s a way to sort of temporarily lift that in the case of a drug that’s going into shortage, that’s another avenue.”

Government guarantees

Another incentive could be to have the government guarantee sufficient revenue by paying manufacturers up front, Schilsky said. Based on readily available data — standard dose, average patient body size, average number of courses needed to get a patient into remission — it would be possible to estimate the number of grams of cytarabine that need to be produced to ensure an adequate supply.

“So, one possible solution is that the government, maybe through an agency like the National Cancer Institute, says to generic manufacturers: ‘Go ahead and make the drug in this amount. We’ll pay you upfront, so you have no risk, and then we know that the drug is going to be available,’” Schilsky said.

In a few cases, drug importation may be the solution. Recently, the FDA helped ease the shortage of levoleucovorin (Fusilev, Spectrum Pharmaceuticals) by giving the manufacturer temporary permission to import levoleucovorin 100 mg powder for injection for US distribution.

The company experienced a brief shortage when the manufacturing facility required work, according to Paul Arndt, senior manager of investor relations at Spectrum Pharmaceuticals. “We now have ample supplies of Fusilev to meet current and future demand,” he said.

Teva Pharmaceuticals was in a similar situation after putting a voluntary hold on injectable drug manufacturing at its US plants in April 2010, Denise Bradley, senior director of corporate communications for Teva Pharmaceuticals, told HemOnc Today. “Leucovorin is made in our Irvine facility, so the production hold on that facility is the cause of our shortage there,” she said. “We have been working with FDA to import Teva’s UK-approved version of leucovorin in order to get this product to patients.”

Importation is a last resort, however, according to Saliba. “Whenever US domestic supplies are not able to meet patient needs, in terms of absolutely critically needed drugs, we look for outside sources and firms who are willing and able to import these drugs to help with the US drug shortage,” she said, adding that the agency evaluates the imported product carefully, ensuring that it is safe, effective and produced in a facility that meets FDA standards.

Government action

The Preserving Access to Lifesaving Medication Act addresses the issue of early notification. US Sens. Amy Klobuchar, D-Minn., and Robert Casey, D-Pa., introduced the legislation in February, which if passed would compel prescription drug manufacturers to provide early notification to the FDA of any event that could lead to a drug shortage.

Fast Facts

“There is an unprecedented shortage of critical medications used to treat a wide range of illnesses — from cancer to cystic fibrosis to cardiac arrest — that is causing significant risks to patient safety,” Klobuchar said. “I have heard from hospitals and pharmacists across Minnesota who are having difficulties acquiring vital medication needed to fill prescriptions, and I have heard from patients who are facing alarming disruptions in their treatments.

“Physicians, pharmacists and patients are currently among the last to know when an essential drug will no longer be available. That’s not right,” she said. “This common-sense solution will help set up an early warning system so pharmacists and physicians can prepare in advance and ensure that patients continue to receive the best care possible. As we move forward, it is important that we have better coordination between the pharmaceutical industry, the FDA and health care providers so patients don’t lose access to the medications they depend on.”

“This [bill] is an important first step,” Link said. “The most important thing is that it sheds a lot of light on the problem, which is ongoing. … The bill, by itself, will be insufficient to solve this problem.”

Link said he hopes that the increased media attention and advocacy will yield a resolution soon. Because of recent therapeutic advances, pediatric oncologists are able to provide a cure to almost 80% of children with cancer, he added.

“But all of those curative therapies are based on these drugs, many of which are in short supply. If these drugs continue to be in short supply, the oncology community will continue to struggle in giving the best treatments to patients,” he said. – by Colleen Owens

For more information:

Disclosure: Drs. Link, Mayer, Saliba and Schilsky, as well as Mr. Cohen and Mr. Hill, reported no relevant financial disclosures.

POINT/COUNTER

Has the shortage of oncology drugs reached the point where rationing is necessary?

POINT

Over the past several months, we have certainly encountered the problem of drug shortages for several of our standard chemotherapy agents. It is clearly an international problem, and presents treating clinicians with only a few options at a time of considerable tension and concern, as patients face the administration of therapy for their leukemia or cancer.

The choices the doctors can make are few. We can decide to use a different agent of equal effectiveness and toxicity, we can delay treatment, or we can use the drug in short supply at a lower dose. Using a different agent may be equally effective treatment or not.

At Massachusetts General Hospital, we try to use the best regimen with the best scientific basis. So far, we have been fortunate in that, with a very large population of patients and extensive pharmacy use on a daily basis, we have considerable flexibility to make choices. Usually, we can apply a substitute drug with similar effectiveness and acceptable toxicity or delay the start of treatment for one patient who can wait while another patient, who urgently needs treatment, is started immediately.

We have a team of individuals at our hospital who track the shortages and help plan our steps forward to ensure that drugs are available, certainly for those that need treatment urgently and for the Children’s Oncology Group. The situation has resulted in a lot of extra work for many of us, and one has to wonder what the solution might be. We already spend large amounts of money on the new drugs, but many of these are saving lives that would otherwise be lost. The older drugs that are now generic and low cost are no longer a priority of pharmaceutical companies.

Some solutions that immediately come to mind would be government regulations mandating manufacture of critical drugs, price controls that would raise the price of generics (and/or lower the price of new expensive drugs), or encouragement of manufacture of drugs outside the country where costs might be less and the meager profits more enticing. The nation currently faces major economic challenges, and what we will pay for Medicare, specifically, and health insurance, generally, is a large portion of that debate. Access to health care, and now to specific drugs, is a part of this bigger economic problem.

Philip C. Amrein, MD, is an assistant professor of the department of medicine at the Harvard Medical School. He reported no relevant financial disclosures.

COUNTER

As a leukemia/lymphoma doctor, I am constantly involved in the drama and shock my patients experience when they learn they have been diagnosed with acute leukemia. Their lives are changed forever, and the patients and their families must fight a tough battle balancing cancer-induced and chemotherapy-related toxicities to achieve a complete remission and then to consolidate the response with high-dose chemotherapy.

It is a physician’s nightmare to have to decide how to assign a drug among four cancer patients who need it if there is only enough to treat two of them. Our group and many other medical oncology groups faced this situation about 3 months ago. Our pharmacy was spending days on the phone trying to borrow or to buy the needed quantity of the drug. I contacted a few oncology centers, including my former colleagues in Canada, only to receive the same answer: “Sorry, but we do not have enough for our patients, either.” It was only then that I realized the scale of the problem; it is yet to be determined how many patients have been affected by the cytarabine crisis. We ended up going to the gray market and paying thousands of dollars for the otherwise inexpensive drug. Yet, that was a small price to pay to know that all of our patients have received adequate treatment.

With the 46th anniversary of Medicare approaching, the program is under threat due to the enormous expenses of modern medical care. It feels counter intuitive that it is always (or nearly always) the older and cheaper generic drugs that are in short supply. The only logical explanation for the persistent shortage of the cheap compounds is that it is simply not profitable for the manufacturers to produce them. In view of the growing economic debt and the emerging bankruptcy of the medical system, I feel it is critical to support the production of the cheap but effective and clinically important drugs, such as cytarabine, bleomycin, anthracyclines, paclitaxel and many others. One way to deal with the crisis is to implement incentives and/or privileges that will benefit the companies that are willing to continue to produce the old, cheap but effective and clinically important medications rather than turning away from their production and focusing only on the more profitable, patented compounds. In addition, it seems reasonable to explore the option of importing the critically needed medications from reputable manufacturers from other countries.

Elena Gitelson, MD, PhD, is an assistant professor at the Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation at the Thomas Jefferson University of Philadelphia. She reported no relevant financial disclosures.

Drug shortages in the United States, which reached record highs in 2010, continue to vex physicians, patients and manufacturers. Although the shortages have affected all medical specialties, they have been felt most acutely in oncology, emergency medicine, anesthesia and cardiology, significantly affecting patient care.

In 2010, there were 178 shortages of medically necessary drugs vs. 157 in 2009, according to Jouhayna Saliba, PharmD, senior regulatory program manager of the Center for Drug Evaluation and Research Drug Shortage Program for the FDA. “We are continuing to see a large number of shortages in 2011, unfortunately. However, we don’t know yet if this year will be worse than 2010,” Saliba told HemOnc Today.

The American Society of Health-System Pharmacists (ASHP), which tracks all medications in shortage, not just those that are medically necessary, lists 197 drugs in shortage.

According to Saliba, the FDA is especially concerned about the 132 sterile injectable drugs that are on the shortage list. “Older sterile injectables are especially vulnerable to shortage due to the small number of firms currently making these drugs, the limited capacity at the firms and the complexity of the manufacturing process,” she said. “When one firm has a problem or discontinues [a drug], it’s difficult for the remaining firms to meet the shortfall.”

ASCO president Michael Link, MD
ASCO president Michael Link, MD, speaks to Congressional staffers at a July 13 briefing on drug shortages on Capitol Hill.

Photo courtesy of American Society of Clinical Oncology.

Critical problem

This issue has reached a critical point, according to Joseph Hill, the director of federal legislative affairs for ASHP. “We’re almost approaching it as a crisis situation with our members,” he said. “We’ve seen them occurring nationwide, primarily oncology drugs but also some of the nutritional drugs, some pain medications, some anesthetics. It’s a critical problem.”

The medications involved are not seldomly-used drugs. “Some of these drugs have become the mainstay of curative therapies for certain cancers,” Michael Link, MD, president of ASCO, told HemOnc Today. “When one thinks of the curable cancers now, one thinks in terms of lymphomas and leukemias, many of the childhood tumors and testicular cancer — the mainstay drugs in the treatment of these cancers have been in short supply.”

Doxorubicin (Adriamycin, Pharmacia and Upjohn), an important drug in the treatment of lymphoma and sarcomas, is on the list. Cisplatin, which revolutionized the treatment of testicular cancer, is in short supply, according to Link. Daunorubicin and cytarabine, both essential for adult and childhood leukemia treatment, are in shortage. Supplies of leucovorin and methotrexate are also low. “These are drugs that are well-known,” he said. “They’ve been around for a long time and are a part of the fabric of cancer treatment.”

Etoposide, vincristine and, most recently, paclitaxel are other chemotherapeutic agents on the shortage list.

Not just cancer drugs

This issue cuts across all medical specialties, according to Link, a pediatric oncologist at the Lucile Packard Children’s Hospital at Stanford University. “This is not just a shortage of cancer-specific drugs or anticancer drugs,” he said. “This is a shortage of antibiotics and anesthetic drugs as well.”

Many are “cornerstone drugs in other disease settings, such as intravenous furosemide,” Robert J. Mayer, MD, Stephen B. Kay Family Professor of Medicine at Harvard Medical School, told HemOnc Today. Mayer is also faculty vice president for academic affairs at the Dana-Farber Cancer Institute.

Other medications listed include azithromycin, norepinephrine, ketorolac, fentanyl and epinephrine, ciprofloxacin and gentamicin.

The length of the shortages varies and depends on the cause, according to Saliba. “If it’s a big quality defect involved, it may take several months to resolve,” she said. For less severe issues, the shortage could be resolved in as little as a few days.

Multifactorial causes

The causes for the drug shortages are multifactorial. One of the biggest problems has been manufacturing issues, which can range from simple to complex.

“It could be something minor, such as a labeling change or the wrong label on the wrong box,” Saliba said. “That is something that could be fixed quickly. But the more severe issues are sterility issues, where we’re seeing particulates in vials and contaminations.”

Hospira and another manufacturer alerted physicians to a crystallization problem in certain lots of cytarabine injection in February. An investigation revealed that the crystals were particles of active ingredient, according to the company’s “Dear Health Care Professional” letter. Most likely, dried cytarabine on the filling needles entered the vials during manufacturing and acted as a seed for crystal formation. The company resolved the problem and resumed manufacturing in March, according to Dan Rosenberg, Hospira spokesman.

Raw material shortages have been the cause in a few cases. “We’re seeing that if there’s a sole source supplier for the active pharmaceutical ingredient (API), and there’s a problem with the supply of that API or the quality of that API is compromised, all of these can lead to manufacturers having to shut down manufacturing lines and product not being available,” Hill said.

Robert J. Mayer, MD
Robert J. Mayer

In 2010, Hospira was short on cytarabine’s API, which comes from an outside supplier, causing the product to be off the market for a time, Rosenberg said.

“Hospira experienced a supply shortage in 2010 and early 2011, but is now back on the market and is prioritizing the drug’s manufacture ahead of other products to meet critical patient needs while other manufacturers continue to experience difficulties,” Rosenberg told HemOnc Today.

Manufacturer discontinuation has been a major cause of the shortages. In many cases, the manufacturer made a business decision to stop producing a particular compound because the medication was off patent and no longer returning a large profit.

“In view of all those explanations, somewhat of a deeper underlying explanation may be simply that it’s not profitable to produce generic drugs,” said Richard L. Schilsky, MD, professor of medicine and chief of the section of hematology/oncology at the University of Chicago. “And all of the drugs that have been in short supply have been generics.

“When there is a manufacturing problem … or when there are raw materials in short supply, there aren’t many incentives to rush to correct the problem because the profit margin on these drugs is so small,” Schilsky said. “That’s a deeper, underlying problem that must be addressed.”

How shortages affect patients

There are several side effects of the drug shortage, the most important being the effect on patient care. Physicians have been forced to use substitutes or find workarounds. For antibiotics or anesthetics, that is feasible because “there are still alternative therapies to cure infections or put patients to sleep,” Link said. “But in the anticancer field, for many of these drugs — depending on the tumor, of course — there is no good substitution.” Drugs such as doxorubicin and cytarabine, however, are the therapeutic mainstays for adult and pediatric leukemias. “If these drugs are unavailable, there’s simply no way to treat the leukemia.”

Sometimes, the substitute or workaround may not be as effective. “For example, substituting carboplatin for cisplatin in the treatment of testicular cancer, will work for the majority of patients, but the overall cure rate will be lower,” Link said.

“One of our concerns is that if there is a product where a substitute is available, there are times when that drug substitute is a much older drug product,” Hill said. “You may have new or younger clinicians who aren’t familiar with the product because they’ve never used it before. There is concern that using some of these older products could jeopardize patient care.”

Patient care has been affected, according to the Institute for Safe Medication Practices (ISMP). From July 2010 to September 2010, ISMP surveyed more than 1,800 health care practitioners who indicated that the drug shortages have significantly increased the potential for errors and patient harm, according to a press release.

The potential for harm

About one in three survey respondents said their facility had an error related to a drug shortage that could have harmed a patient. Roughly one in four respondents indicated that there were errors that reached patients; one in five reported adverse patient outcomes, according to the release. Voluntary reporting methods make tracking errors and adverse events challenging, so many respondents suggested that the frequency of errors and adverse events related to the drug shortages is actually much higher.

These substitution errors resulted in deaths, according to Michael R. Cohen, RPh, MS, ScD, ISMP president. “We have had errors with people who weren’t familiar with a new drug and confusing the dose,” he said. In response to the morphine shortage, physicians substituted hydromorphone, which is six or seven times more potent than morphine. The hydromorphone was administered at the intended dose for morphine, resulting in two deaths.

There have been dosing problems when physicians used substitute anesthetics, he said. “We’ve had reports of patients waking up during surgery,” Cohen said.

Michael R. Cohen, RPh, MS, ScD, ISMP president
Michael R. Cohen

ISMP members reported errors with chemotherapeutic agents, too. There was a dosing error when a pharmacist used the 500 mg mixing protocol on a 1,000 mg vial of cytarabine. Switching out capecitabine (Xeloda, Hoffmann-La Roche) for leucovorin has produced serious gastrointestinal toxicity for many patients.

In some cases, the patient received less medication than anticipated. One prescriber converted a patient from IV etoposide to oral dosing but was not aware that the oral dose needed to be double the IV dose. In another case, pre-diluted methotrexate was not available, according to the survey results. The vial of dry powder was reconstituted improperly, and the patient received less than the prescribed dose as a result.

Care delayed for some patients

For some patients, the shortages have affected the timing of treatment. Link told HemOnc Today of a patient with acute leukemia whose treatment was delayed because the drugs needed for therapy were not available. The physicians and hospital tried to locate a sufficient medication supply. “Delays in cancer therapy are never a good idea,” Link said. “We can’t quantitate how those delays will affect outcome, but we know that, in general, it’s not a good idea to delay therapy. In most cases, this will have an overall negative effect on outcome.”

Addressing the shortages consumes many resources. “It’s a costly problem,” Cohen said. “We’ve actually had multiple hospitals that have told us they have half of an FTE (full-time equivalent) or even a full FTE invested in the drug shortage to take care of these situations.”

The costs increase when it becomes necessary to operate in the gray market. “[There have been] massive increases in availability of gray market sources, which charge 10-fold more and greater for the drugs you were able to purchase before at usual price,” Cohen said.

But gray market purchases can be questionable, according to Cohen. The origin, potency and storage of the drugs cannot always be ascertained.

“Before, when we got the drug directly from the manufacturer or through a wholesaler, there was no question that these were handled properly,” he said. “Now, we have evidence that some of these drugs that are being ordered have gone through five and six turns before they actually got to the pharmacy.”

Influence on clinical trials

Some institutions have turned to stockpiling drugs. “I’ve been told that large academic centers, knowing that this may occur, have stocked up their pharmacies, whereas private doctors’ offices or private groups or even smaller hospitals are not able to do that,” Mayer said.

“We heard one horror story that a local hospital had a large supply of a drug and was selling it to other hospitals and practices at a mark-up,” Link said.

Clinical trials have also been affected, Link said. “If a patient is on a clinical trial that involves one of the drugs that are in short supply, or when a new drug is added to a standard combination, if one of the drugs in the standard combination is not available, well, of course, that affects the ability to continue to treat a patient who is on a clinical trial.”

Also, it can affect trial result interpretation. If a standard drug in a trial becomes unavailable and is replaced with a less effective compound, “it might make the new regimen look better than it really is because, in fact, some patients were getting a suboptimal control arm,” Schilsky said. “That’s a concern for the interpretation of clinical trials going forward.”

Solutions

Solving this problem of why shortages occur will first depend on clearly identifying the causes, according to Link. Although the FDA is responsible for ensuring that medications are safe and effective, it is not tasked with guaranteeing an adequate drug supply. “I suspect that [solving this] is going to depend on increasing the authority of the FDA to track the supply of medically necessary drugs and to find out in advance whether there’s going to be a shortage. Time and prior notification would at least give the agency the leverage and time necessary to do something in advance of a shortage,” he said.

Early notification has already demonstrated its effectiveness, Saliba said. “Last year, we can say that 38 drugs were prevented from going into shortage because of early notification.”

Quicker approvals may improve the shortages. “We’re looking at expedited approvals for some of these products, especially if they are pre-approved or pre-1938 drugs,” Hill said. “We’re looking at ways that the FDA could speed up that process and make it easier for these manufacturers to get into the market.”

One potential solution is offering incentives to manufacturers. A big incentive would be to allow manufacturers to make more money, according to Schilsky. “The economic solutions are fairly clear,” he said. “The political solutions to achieve those economic solutions are more complicated.”

Another option would be to offer manufacturers some incentive, such as a tax break, to ensure that the drug stays in adequate supply, Schilsky said.

Richard L. Schilsky, MD
Richard L. Schilsky

For controlled drugs, manufacturers are only required to keep certain amounts of API on hand, as determined by the DEA, according to Hill. “What happens if you have a manufacturer that has a problem? The other manufacturers can’t ramp up production because they’re only able to have so much API at their plant,” he said. “If there’s a way to sort of temporarily lift that in the case of a drug that’s going into shortage, that’s another avenue.”

Government guarantees

Another incentive could be to have the government guarantee sufficient revenue by paying manufacturers up front, Schilsky said. Based on readily available data — standard dose, average patient body size, average number of courses needed to get a patient into remission — it would be possible to estimate the number of grams of cytarabine that need to be produced to ensure an adequate supply.

“So, one possible solution is that the government, maybe through an agency like the National Cancer Institute, says to generic manufacturers: ‘Go ahead and make the drug in this amount. We’ll pay you upfront, so you have no risk, and then we know that the drug is going to be available,’” Schilsky said.

In a few cases, drug importation may be the solution. Recently, the FDA helped ease the shortage of levoleucovorin (Fusilev, Spectrum Pharmaceuticals) by giving the manufacturer temporary permission to import levoleucovorin 100 mg powder for injection for US distribution.

The company experienced a brief shortage when the manufacturing facility required work, according to Paul Arndt, senior manager of investor relations at Spectrum Pharmaceuticals. “We now have ample supplies of Fusilev to meet current and future demand,” he said.

Teva Pharmaceuticals was in a similar situation after putting a voluntary hold on injectable drug manufacturing at its US plants in April 2010, Denise Bradley, senior director of corporate communications for Teva Pharmaceuticals, told HemOnc Today. “Leucovorin is made in our Irvine facility, so the production hold on that facility is the cause of our shortage there,” she said. “We have been working with FDA to import Teva’s UK-approved version of leucovorin in order to get this product to patients.”

Importation is a last resort, however, according to Saliba. “Whenever US domestic supplies are not able to meet patient needs, in terms of absolutely critically needed drugs, we look for outside sources and firms who are willing and able to import these drugs to help with the US drug shortage,” she said, adding that the agency evaluates the imported product carefully, ensuring that it is safe, effective and produced in a facility that meets FDA standards.

Government action

The Preserving Access to Lifesaving Medication Act addresses the issue of early notification. US Sens. Amy Klobuchar, D-Minn., and Robert Casey, D-Pa., introduced the legislation in February, which if passed would compel prescription drug manufacturers to provide early notification to the FDA of any event that could lead to a drug shortage.

Fast Facts

“There is an unprecedented shortage of critical medications used to treat a wide range of illnesses — from cancer to cystic fibrosis to cardiac arrest — that is causing significant risks to patient safety,” Klobuchar said. “I have heard from hospitals and pharmacists across Minnesota who are having difficulties acquiring vital medication needed to fill prescriptions, and I have heard from patients who are facing alarming disruptions in their treatments.

“Physicians, pharmacists and patients are currently among the last to know when an essential drug will no longer be available. That’s not right,” she said. “This common-sense solution will help set up an early warning system so pharmacists and physicians can prepare in advance and ensure that patients continue to receive the best care possible. As we move forward, it is important that we have better coordination between the pharmaceutical industry, the FDA and health care providers so patients don’t lose access to the medications they depend on.”

“This [bill] is an important first step,” Link said. “The most important thing is that it sheds a lot of light on the problem, which is ongoing. … The bill, by itself, will be insufficient to solve this problem.”

Link said he hopes that the increased media attention and advocacy will yield a resolution soon. Because of recent therapeutic advances, pediatric oncologists are able to provide a cure to almost 80% of children with cancer, he added.

“But all of those curative therapies are based on these drugs, many of which are in short supply. If these drugs continue to be in short supply, the oncology community will continue to struggle in giving the best treatments to patients,” he said. – by Colleen Owens

For more information:

Disclosure: Drs. Link, Mayer, Saliba and Schilsky, as well as Mr. Cohen and Mr. Hill, reported no relevant financial disclosures.

POINT/COUNTER

Has the shortage of oncology drugs reached the point where rationing is necessary?

POINT

Over the past several months, we have certainly encountered the problem of drug shortages for several of our standard chemotherapy agents. It is clearly an international problem, and presents treating clinicians with only a few options at a time of considerable tension and concern, as patients face the administration of therapy for their leukemia or cancer.

The choices the doctors can make are few. We can decide to use a different agent of equal effectiveness and toxicity, we can delay treatment, or we can use the drug in short supply at a lower dose. Using a different agent may be equally effective treatment or not.

At Massachusetts General Hospital, we try to use the best regimen with the best scientific basis. So far, we have been fortunate in that, with a very large population of patients and extensive pharmacy use on a daily basis, we have considerable flexibility to make choices. Usually, we can apply a substitute drug with similar effectiveness and acceptable toxicity or delay the start of treatment for one patient who can wait while another patient, who urgently needs treatment, is started immediately.

We have a team of individuals at our hospital who track the shortages and help plan our steps forward to ensure that drugs are available, certainly for those that need treatment urgently and for the Children’s Oncology Group. The situation has resulted in a lot of extra work for many of us, and one has to wonder what the solution might be. We already spend large amounts of money on the new drugs, but many of these are saving lives that would otherwise be lost. The older drugs that are now generic and low cost are no longer a priority of pharmaceutical companies.

Some solutions that immediately come to mind would be government regulations mandating manufacture of critical drugs, price controls that would raise the price of generics (and/or lower the price of new expensive drugs), or encouragement of manufacture of drugs outside the country where costs might be less and the meager profits more enticing. The nation currently faces major economic challenges, and what we will pay for Medicare, specifically, and health insurance, generally, is a large portion of that debate. Access to health care, and now to specific drugs, is a part of this bigger economic problem.

Philip C. Amrein, MD, is an assistant professor of the department of medicine at the Harvard Medical School. He reported no relevant financial disclosures.

COUNTER

As a leukemia/lymphoma doctor, I am constantly involved in the drama and shock my patients experience when they learn they have been diagnosed with acute leukemia. Their lives are changed forever, and the patients and their families must fight a tough battle balancing cancer-induced and chemotherapy-related toxicities to achieve a complete remission and then to consolidate the response with high-dose chemotherapy.

It is a physician’s nightmare to have to decide how to assign a drug among four cancer patients who need it if there is only enough to treat two of them. Our group and many other medical oncology groups faced this situation about 3 months ago. Our pharmacy was spending days on the phone trying to borrow or to buy the needed quantity of the drug. I contacted a few oncology centers, including my former colleagues in Canada, only to receive the same answer: “Sorry, but we do not have enough for our patients, either.” It was only then that I realized the scale of the problem; it is yet to be determined how many patients have been affected by the cytarabine crisis. We ended up going to the gray market and paying thousands of dollars for the otherwise inexpensive drug. Yet, that was a small price to pay to know that all of our patients have received adequate treatment.

With the 46th anniversary of Medicare approaching, the program is under threat due to the enormous expenses of modern medical care. It feels counter intuitive that it is always (or nearly always) the older and cheaper generic drugs that are in short supply. The only logical explanation for the persistent shortage of the cheap compounds is that it is simply not profitable for the manufacturers to produce them. In view of the growing economic debt and the emerging bankruptcy of the medical system, I feel it is critical to support the production of the cheap but effective and clinically important drugs, such as cytarabine, bleomycin, anthracyclines, paclitaxel and many others. One way to deal with the crisis is to implement incentives and/or privileges that will benefit the companies that are willing to continue to produce the old, cheap but effective and clinically important medications rather than turning away from their production and focusing only on the more profitable, patented compounds. In addition, it seems reasonable to explore the option of importing the critically needed medications from reputable manufacturers from other countries.

Elena Gitelson, MD, PhD, is an assistant professor at the Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation at the Thomas Jefferson University of Philadelphia. She reported no relevant financial disclosures.