Supply Problems Endanger Patients
Public Health Feature – October 2011
Tex Med. 2011;107(10):23-29.
By Crystal Conde
Associate Editor
You need look no farther than neonatal intensive care units in Houston to see the effects of a nationwide shortage of drugs that affects the quality of care and patient safety. Physicians at Texas Children's Hospital and Ben Taub General Hospital say it's difficult to give the babies the nutrition they desperately need because of a shortage of calcium gluconate, an injectable that provides needed minerals.
"Right now, we don't have drugs that allow us to make IV nutrition optimal. Because of the shortage, babies, particularly the smaller, more vulnerable ones, are at increased risk of fractures," said Michael Speer, MD, a faculty member in the Neonatology Section of Baylor College of Medicine and Texas Medical Association president-elect.
Besides calcium gluconate, neostigmine, propofol, epinephrine, furosemide, and a host of sterile injectables, as well as antibiotics and other medications, are among the drugs on an expansive list of shortages tracked by the U.S. Food and Drug Administration (FDA). A record 246 drugs were in short supply as of June, according to FDA. That figure has many Texas physicians worried about potential risks to patient safety and quality of care.
Brad Butler, MD, a Longview anesthesiologist and chair of the TMA Committee on Professional Liability, says that while alternative medications often can replace preferred drugs during a shortage, the change in protocol it necessitates isn't ideal.
"Some of the alternative drugs aren't as effective and can have worse side effects for the patients," he said. "You can also increase the risk of adverse outcomes or errors when you have to switch to a substitute."
Indeed, last year's shortage of 211 drugs caused some patients to develop complications and even die from receiving a less effective alternative medication or the wrong dosage of the substitute drug or from having to go without the drug altogether.
According to the Drug Information Service of the University of Utah, recent shortages are up drastically from 74 drugs in 2005. (See "Drug Shortage Resources.")
A national Institute for Safe Medication Practices (ISMP) survey conducted from July through September 2010 reveals health professionals encountered many difficulties from drug shortages. The most common problems included:
- A lack of information about the duration of the shortage;
- No advance warning and suggested alternatives;
- No information about the cause of the shortage;
- Substantial resources expended to develop a plan of action to respond to the shortage;
- Difficulty obtaining a suitable alternative drug; and
- A significant financial impact on hospitals.
Thirty-five percent of respondents to the 2010 ISMP survey indicated that a drug shortage caused their facilities to make errors that could have harmed patients in the past year. About 25 percent reported errors that reached patients, and one in five reported adverse patient outcomes.
Among the more than 1,000 errors and adverse patient outcomes described in the survey are:
- Two patients died from being administered intravenous hydromorphone prescribed at the intended dose for morphine.
- A patient with a pseudomonas infection sensitive only to the antibiotic amikacin died when the drug could not be provided.
- A paralyzed, ventilated patient was not sedated because propofol was not available and an alternative drug was never prescribed.
- A patient with renal failure received the neuromuscular blocking agent pancuronium, causing excessive and prolonged paralysis and tachycardia.
- Substituting the chemotherapy drug Xeloda (capecitabine) for leucovorin caused serious gastrointestinal toxicity in many patients.
Dr. Butler says he learns of drug shortages from pharmacies and hospitals every month. He describes drug shortage notification as somewhat inadequate and sometimes delayed.
Dr. Speer wants FDA to expand its authority related to drug shortages.
"It would be helpful if FDA could give physicians, pharmacists, and health care facilities advanced warning of impending drug shortages. Another option would be for FDA to establish joint agreements with reputable manufacturers in other countries, allowing the United States to import drugs in short supply. Many foreign governments have rules and regulations governing the manufacture of pharmaceuticals. FDA could vet them to ensure they're enforced," he said.
Health organizations are examining the causes of the shortage and collaborating with stakeholders to develop recommendations to prevent shortages and to improve communication about impending drug discontinuations and limited supplies.
The TMA House of Delegates adopted a recommendation on drug shortages and physician communication made by the TMA Committee on Infectious Diseases at TexMed 2011.
The committee said "better tracking of drug shortages and more effective communication are certainly warranted to make health care professionals aware of shortages and allow them to plan accordingly."
The report's recommendation directs the association to "work with the American Medical Association and appropriate federal agencies to increase federal monitoring of potential drug shortages and enhance communications with physicians regarding drug shortages and alternative treatments."
The AMA Council on Science and Public Health will present a report on national drug shortages to the AMA House of Delegates at its interim meeting next month. Resolution 504, introduced by the Florida delegation to AMA at the 2011 Annual Meeting, asks the association to evaluate the problem of drug shortages and report on the role of government regulation, plaintiff lawsuits, pharmaceutical company decisions, and any other relevant factors contributing to the drug shortage. The resolution also asks AMA to make recommendations to prevent national drug shortages.
Other groups have weighed in on the drug shortage plaguing the United States. The American Society of Anesthesiologists (ASA) held a Drug Shortages Summit last year to address the problem. (See "ASA Drug Shortages Summit Recommendations.")
TMA Foundation President Russell Kridel, MD, a member of the AMA Council on Science and Public Health, says that while physicians individually can't do a lot to reverse the country's worsening drug shortage problem, organized medicine can play a role in affecting positive change.
"It's incumbent on the FDA and the government to see that physicians and patients are vulnerable to shortages and the decisions of pharmaceutical companies. Physicians need to have some advance warning that shortages are coming to give us enough time to look at alternative medications," he said.
FDA's Role
Dr. Speer says drug shortages frustrate physicians because "the best medication for the patient's condition is no longer available." He adds that physicians have no choice but to make drug substitutions that may not be in the patient's best interest.
It's critical that TMA and AMA examine the drug shortage problem "because it affects patient safety and welfare," he says, noting that the public has little, if any, knowledge of the problem.
Dr. Speer sees patients at Texas Children's Hospital and within the Harris County Hospital District (HCHD). The district, like many health systems and outpatient facilities in Texas, has grappled with drug shortages for some time.
During the summer, HCHD notified staff members that more than 75 drugs on its formulary were in short supply or on back order. The report listed antibiotics, injectables, topical solutions, and one vaccine, and featured alternate medications and estimated resupply dates.
"Part of the problem lies in increasing consolidation of the drug industry," Dr. Speer said. "There are many fewer companies in existence competing with one another. There is often only one company producing a given generic medication. If that one company ceases production, for whatever reason, there is no drug."
Additional factors influencing drug supply include scarcity of raw materials, manufacturing problems, and unexpected demand. Business decisions within the pharmaceutical industry could also be at play, such as cutting back on producing low-cost generic drugs in favor of more profitable brand-name drugs.
Dr. Speer says some manufacturers may dial down or discontinue producing some of the older generic drugs for financial reasons.
According to FDA, as more versions of a drug become available, the price of a drug can decrease. If the costs associated with making a drug begin to outweigh sales profit, companies may wish to discontinue making the drug in favor of newer, more profitable products. Couple this with a reduction in the number of companies making an older drug or a delay in manufacturing, and you have a recipe for shortages.
In the wake of a shortage, FDA works with manufacturers to address low-risk (wrong expiration date on package) and high-risk (particulate in product or sterility issues) quality and safety problems. FDA may use its regulatory discretion to address shortages to mitigate any significant risk to patients.
FDA can encourage remaining firms to ramp up supply. When a company needs a new manufacturing site or new raw material supplier, FDA can expedite the review of these changes. For products in shortage or at risk for shortage, FDA can expedite the review of new manufacturers interested in producing the product.
In rare cases, the agency can temporarily import drugs from other countries or unapproved sources. FDA did this with the anesthetic propofol, for example. The propofol shortages began in fall 2009 when two U.S.-based manufacturers halted distribution and recalled several lots of propofol products due to quality problems. This action left only one company to supply propofol to the entire United States.
FDA used its regulatory enforcement discretion to temporarily allow the importation of fresenius propoven 1%, an unapproved drug, into the United States. FDA deemed the propofol product, approved in other countries, comparable to the product used in the United States.
While FDA can exercise some regulatory discretion in extreme circumstances, the agency can't force a manufacturer to produce a product or impose a penalty on a manufacturer for not notifying FDA of a discontinuation.
By law, manufacturers don't have to report plans to discontinue producing a product unless they are the sole manufacturers of a drug that is life-supporting, life-sustaining, or intended for use in the prevention of a debilitating disease or condition.
Shortages Increase Costs
Increasing drug shortages affect patient care and increase costs to the nation's health system, according to a 2010 study by the American Society of Health-System Pharmacists (ASHP) in partnership with the University of Michigan Health System. The American Journal of Health-System Pharmacy published the study, "Impact of Drug Shortages on U.S. Health Systems" in July.
The study's authors surveyed 353 hospital pharmacy directors across the country to quantify the personnel resources required to manage the drug shortages, define the extent to which recent shortages affected health systems, and determine if there are adequate resources to manage the shortages.
The study found labor costs associated with managing shortages translate to an estimated annual impact of $216 million nationally. On top of that, three specific drug shortages – dextrose syringes, epinephrine injection, and succinylcholine injection – affected more than 80 percent of health systems. Seventy percent of respondents described the resources available to manage drug shortages as "less than good."
American Hospital Association (AHA) survey data complement ASHP's findings. AHA revealed that nearly all 820 hospital respondents reported at least one drug shortage in the six months leading up to the study, and nearly half reported 21 or more shortages during that period. The ASHP survey had similar findings; 47 percent of large hospitals experienced 30 or more shortages.
Health care organizations, including AHA, want Congress to establish an early warning system of drug shortages and mandate that manufacturers report drug interruptions or discontinuations to FDA.
U.S. Sens. Amy Klobuchar (D-Minn.) and Bob Casey (D-Penn.) introduced legislation to that effect in February. The Preserving Access to Life-Saving Medications Act requires prescription drug manufacturers to give early notification to FDA of any incident that would likely result in a drug shortage. Incidents may include changes to raw material supplies, adjustments to manufacturer production capabilities, and certain business decisions such as mergers, withdrawals, or changes in output. The bill also directs FDA to provide up-to-date public notification of any shortage and the actions the agency would take to address it.
"Physicians, pharmacists, and patients are currently among the last to know when an essential drug will no longer be available; that's not right," said Senator Klobuchar in a press release. "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."
The bill is pending in the Senate Committee on Health, Education, Labor, and Pensions.
Shortages' Impact on Anesthesiology
Dr. Butler says the drug shortage greatly affects anesthesiology, among other specialties. In April, the American Society of Anesthesiologists (ASA) surveyed its members on drug shortages.
Ninety percent of the 1,373 respondents reported a current shortage of at least one anesthesia drug. Ninety-eight percent reported a shortage of at least one anesthesia drug in the past year. The drugs most frequently in short supply were propofol (89 percent), succinylcholine (80 percent), and thiopental (60 percent).
Dr. Butler says many of the scarce drugs specific to his specialty are sterile injectables, which also were part of the nationwide shortage last year, according to FDA. The agency reports the 2010 drug shortage involved a greater percentage of sterile injectables – 77 percent – than in past years. Critical drugs involved include succinylcholine, naloxone, furosemide, and emergency syringes.
Reasons for the 2010 sterile injectable shortage FDA cited include product quality problems, manufacturing discontinuations, delays and capacity issues, lack of raw materials, loss of manufacturing sites, component shortages, and increase in demand because of another drug shortage.
ASA survey respondents reported about half of patients experienced a less-than-optimal outcome as a result of the drug shortage, such as postoperative nausea and vomiting, and about half of patients experienced longer operating room or recovery times.
Dr. Butler says drug shortages impact clinical practice, too. ASA survey respondents reported drug shortages forced them to use alternative drugs, change procedures in some way, and postpone or cancel cases.
Hospitals have responded to the shortages in various ways, he says.
"Some hospitals try to stockpile some critical use or high-volume medications, but there can be restrictions placed on order allocation by suppliers. Frequently, pharmacies have been restricting the use of certain medications in short supply or removing them from availability and only releasing them if requested by physicians for a critical need."
Cancer drugs are part of the shortage, as well. Cytarabine is in shortage and is the only known drug to effectively treat acute myelogenous leukemia (AML), a fast-progressing cancer that typically takes a patient's life within three months if not treated quickly and properly. In the United States, 10,000 cases of AML are diagnosed annually.
The cytarabine shortage concerns Hagop Kantarjian, MD, chair of the Department of Leukemia at M.D. Anderson Cancer Center. A patient's AML survival rate is typically 40 percent to 50 percent with the drug. Without cytarabine, however, the survival rate is zero, and no substitute drug exists for it.
M.D. Anderson's leukemia department is the largest in the world and has a sufficient supply of the drug for now. Dr. Kantarjian says cytarabine, an inexpensive generic drug, is in short supply only in the United States, not in other countries. In fact, he says he receives phone calls every day from oncologists all over the United States who ask about the cytarabine shortage.
"As leukemia physicians, we have a moral obligation to continue to bring this issue to national attention until this problem is solved in the United States. I simply do not understand the deafening silence behind this major problem that may be killing U.S. citizens on a daily basis," he says.
Dr. Kantarjian says that in response to the cancer drug shortages, oncologists across the nation are concocting combinations of regimens for curative diseases like lymphoma and Hodgkin's disease outside the clinical trial process.
"We need an investigation as to why these drug shortages started happening recently, why the number of shortages is increasing, and why no one's paying attention to this. I notice these shortages are only in generic drugs, not the expensive drugs under patent," he said.
Crystal Conde can be reached by telephone at (800) 880-1300, ext. 1385, or (512) 370-1385; by fax at (512) 370-1629; or by email.
SIDEBAR
Drug Shortage Resources
U.S. Food and Drug Administration
The FDA Drug Safety and Availability website communicates information on new drug warnings and other safety information, drug label changes, and shortages of medically necessary drug products to consumers and health professionals. Register to receive FDA e-mail drug shortages alerts online. Report drug shortages to FDA by email.
The FDA Center for Drug Evaluation and Research (CDER) has a Drug Shortage Program to address and respond to actual or potential shortages of medically necessary drugs. Manufacturers may report a shortage, upon which the CDER investigates the problem. Once CDER has verified the shortage, the agency tries to resolve it, although it's still up to manufacturers to notify FDA.
American Society of Health-System Pharmacists
The Drug Shortages Resource Center provides information on current shortages, resolved shortages, and drugs no longer available. The site also features guidance on managing drug shortages, including purchasing drug products in short supply and sample drug shortages policy.
"ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems," [PDF] published in the Aug. 1, 2009, issue of the American Journal of Health-System Pharmacy, desribes the factors contributing to or exacerbating shortages and features a three-phase approach to contingency planning for management of drug product shortages and includes strategies for prevention.
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SIDEBAR
ASA Drug Shortages Summit Recommendations
Stakeholders, including representatives from health professional organizations, pharmaceutical manufacturers, government agencies, and suppliers, attended the 2010 American Society of Anesthesiologists Drug Shortages Summit. They discussed the scope and causes of drug shortages and developed recommendations to address issues associated with drug shortages.
The summit's recommendations include:
- Explore expanding Food and Drug Administration (FDA) authority to require manufacturer notification of market withdrawals;
- Define and implement evidence-based and other criteria for identifying critical drug therapies that are vulnerable to drug shortages;
- Explore providing incentives to manufacturers that produce critical drug products or upgrade manufacturing plants to meet or exceed good manufacturing practices in exchange for guarantee of continued production of these therapies;
- Establish an expedited approval pathway for those unapproved drugs (pre-1938 therapies) deemed critical therapies;
- Increase collaboration with industry, the Drug Enforcement Administration, and FDA to establish a process that would more readily modify active pharmaceutical ingredients quotas in response to drug shortages of controlled substances; and
- Establish improved processes to extend product stability for products in short supply.
Read the full Drug Shortages Summit report and recommendations online.
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