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 dont 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], its difficult for the remaining
firms to meet the shortfall.
ASCO president Michael Link, MD, speaks to
Congressional staffers at a July 13 briefing on drug shortages on Capitol
Photo courtesy of American Society of
This issue has reached a critical point, according to Joseph Hill, the
director of federal legislative affairs for ASHP. Were almost
approaching it as a crisis situation with our members, he said.
Weve seen them occurring nationwide, primarily oncology drugs but
also some of the nutritional drugs, some pain medications, some anesthetics.
Its 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
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. Theyve 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.
This issue cuts across all medical specialties, according to Link, a
pediatric oncologist at the Lucile Packard Childrens 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 its 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.
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
were 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 companys 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,
Raw material shortages have been the cause in a few cases.
Were seeing that if theres a sole source supplier for the
active pharmaceutical ingredient (API), and theres 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.
In 2010, Hospira was short on cytarabines API, which comes from an
outside supplier, causing the product to be off the market for a time,
Hospira experienced a supply shortage in 2010 and early 2011, but
is now back on the market and is prioritizing the drugs manufacture ahead
of other products to meet critical patient needs while other manufacturers
continue to experience difficulties, Rosenberg told HemOnc
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 its 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 arent many incentives to rush to correct
the problem because the profit margin on these drugs is so small,
Schilsky said. Thats a deeper, underlying problem that must be
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, theres simply no way to treat the
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 arent familiar with the product because theyve 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.
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
werent 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. Weve had reports of patients waking up during
surgery, Cohen said.
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
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.
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
cant quantitate how those delays will affect outcome, but we know that,
in general, its 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. Its a
costly problem, Cohen said. Weve 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
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.
Some institutions have turned to stockpiling drugs. Ive 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.
Thats a concern for the interpretation of clinical trials going
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 theres 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,
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. Were looking at
expedited approvals for some of these products, especially if they are
pre-approved or pre-1938 drugs, Hill said. Were 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
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
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
cant ramp up production because theyre only able to have so much
API at their plant, he said. If theres a way to sort of
temporarily lift that in the case of a drug thats going into shortage,
thats another avenue.
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. Well 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 Tevas 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.
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.
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. Thats 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
dont 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
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,
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.
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 Childrens 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
Philip C. Amrein, MD, is an assistant professor of the
department of medicine at the Harvard Medical School. He reported no relevant
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 physicians 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
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.