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Record-high drug shortages threaten patient health and safety
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Drug shortages in the United States, which reached record highs in 2010, continue to vex physicians, patients and manufacturers. Although affecting all medical specialties, the effects of drug shortages have been felt most acutely in oncology, emergency medicine, anesthesia and cardiology, significantly affecting patient care.
The number of drug shortages annually has tripled from 61 in 2005 to 178 in 2010, according to an Oct. 31 FDA report, titled “A Review of FDA’s Approach to Medical Product Shortages.”
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Source:
Cardiology Today |
Rhonda Cooper-DeHoff, PharmD, MS, of
the University of Florida, Gainesville, discussed the impact of drug shortages
in cardiology.“We have continued to see a large number of shortages in 2011, unfortunately,” Jouhayna Saliba, PharmD, senior regulatory program manager of the Center for Drug Evaluation and Research Drug Shortage Program for the FDA, said in an interview. “However, we don’t know yet if this year will be worse than 2010.”
In response to the growing attention surrounding drug shortages in the United States, President Barack Obama signed an executive order on Oct. 31 urging the FDA to use broader reporting of manufacturing discontinuances that could lead to shortages of life-saving and life-supporting drugs. The president also called for expedited regulatory review of new drug suppliers, manufacturing sites and manufacturing changes and for more communication with the US Department of Justice about possible price gauging.
“Many different factors contribute to drug shortages, and solving this critical public health problem will require a multifaceted approach,” the president’s executive order said.
According to the FDA, early identification has helped prevent 137 drug shortages since the beginning of 2010. Despite that, drug shortages have increased in frequency and severity in recent years and are adversely affecting patient care.
Critical problem
The issue of drug shortages has reached a critical point, according to Joseph Hill, director of federal legislative affairs for the American Society of Health-System Pharmacists. “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.”
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The medications involved are not seldom-used drugs. “Some of these drugs have become the mainstay of curative therapies for certain cancers,” Michael Link, MD, pediatric oncologist at the Lucile Packard Children’s Hospital at Stanford University, said in an interview. “[However,] this is not just a shortage of cancer-specific drugs or anticancer drugs. This is a shortage of antibiotics and anesthetic drugs as well.”
Many are “cornerstone drugs in other disease settings, such as intravenous furosemide,” said Robert J. Mayer, MD, Stephen B. Kay Family Professor of Medicine at Harvard Medical School.
Some cardiology drugs affected by the shortages include amiodarone, digoxin, diltiazem, furosemide, heparin sodium, nitroglycerin, reteplase (Retavase, Centocor), ticlopidine (Ticlid, Roche Palo) and torsemide. Other medications listed include azithromycin, norepinephrine, ketorolac, fentanyl and epinephrine, ciprofloxacin, dopamine, lidocaine and gentamicin.
According to Rhonda Cooper-DeHoff, PharmD, MS, associate professor in the department of pharmacotherapy and translational research in the College of Pharmacy at the University of Florida, Gainesville, most drugs in short supply are injectable solutions. Saliba said the FDA is especially concerned about more than 130 sterile injectable drugs that are on the shortage list, noting that “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. … When one firm has a problem or discontinues [a drug], it’s difficult for the remaining firms to meet the shortfall.”
“The majority of the impact is in the acute setting of a hospital, as opposed to tablet medications filled at retail pharmacies,” said Cooper-DeHoff, who is also a member of the Cardiology Today Editorial Board. “If you have a patient with a diagnosis that requires an injectable product in short supply, then you might have to prescribe an alternative medication that may not be as efficacious as the preferred agent.”
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.
According to Kimberly Parks, DO, transplant cardiologist at Massachusetts General Hospital, cardiologists have not been affected by shortages to the same extent as oncologists. But there is the potential for the problem to become an issue.
“A lot of life-saving CV drugs are intravenous and have the potential to become contaminated during production,” Parks told Cardiology Today. “We could definitely be subjected to the same shortages that the are being seen with oncology drugs.”
Parks noted a national shortage of furosemide, a commonly used drug for patients with HF, which led her institution to only allow the drug to be given in small doses. “There are some patients that require high doses of furosemide, but we had to use an alternative drug, bumetanide,” Parks said. “This works well in some instances, but in some patients, it is associated with more side effects than furosemide. These agents are not a one-size-fits-all type of solution.”
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FDA.gov |
Multifactorial causes
One of the biggest problems with recent drug shortages 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, a chemotherapy agent, 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.
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,” he said in an interview.
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.
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“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 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.”
Another issue, according to Cooper-DeHoff, is that there are fewer manufacturers of injectable medications than there are of oral medications. Few manufacturers compound injectable agents due to the complexity of the process and the increased regulatory requirements.
“If you lose one manufacturer, that could affect 50% of the supply of a particular drug,” Cooper-DeHoff said.
How shortages affect patients
There are several adverse 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.
Sometimes, however, the substitute or workaround may not be as effective. In other circumstances, the drug substitutes that are available for use are outdated.
“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.”
Potential for harm
Limited epidemiological data exist on drug shortages. Three hundred eleven pharmacy experts representing 228 hospitals and other health care sites responded to a survey by the group purchasing organization Premier Healthcare Alliance that covered the second half of 2010. Eighty-nine percent of respondents reported drug shortages that may have caused a safety issue or medical error, and 80% reported a shortage that had resulted in the delay or cancellation of a patient care intervention.
Although media and other widespread reports of adverse effects associated with shortages are common, satisfactory systematic studies of the effect of shortages on patient care are lacking. An informal Internet survey of more than 1,800 health care practitioners conducted by the Institute for Safe Medication Practices (ISMP) from July to September 2010 provided examples of drug shortages and their effect on patient care. Thirty-five percent of respondents indicated they experienced a “near miss” as a result of a drug being in shortage in the previous year, with about one in four reporting a medication error and one in five reporting an adverse event. Adverse consequences were reportedly related to less effective alternative medications, delays in surgical procedures, delays in clinical trials and lack of familiarity with alternative drugs. 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.
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These substitution errors resulted in deaths, according to Michael R. Cohen, RPh, MS, ScD, ISMP president. 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.
According to Parks, besides furosemide, the drug levophed was in shortage at her institution.
“Many patients who developed cardiogenic shock were not able to get levophed, a life-saving drug for this condition,” Parks told Cardiology Today. “There are alternative agents, but in some cases, they are somewhat inferior to levophed. We did not experience any deaths related to this shortage, but there certainly was that potential.”
Influence on clinical trials
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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.”
If a trial includes an injectable product in short supply, there could quickly become a shortage, according to Cooper-DeHoff. If this occurs, the trial may have to be stopped, or there may have to be a substitution, which could confound the results of the trial.
Solutions
Solving this problem of why shortages occur will 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.
Parks said one of the major problems is that alternative drug manufacturers and hospitals are not notified early enough about the shortages.
“Hospitals find out about the shortages when the packages don’t arrive when planned,” Parks said. “Early warnings that there is a shortage of a particular medication would certainly boost the ability to provide alternative agents.”
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.”
Government action
For its report released on Oct. 31, the FDA conducted a review of medical product shortage activities in four product centers in the agency and talked to external stakeholders in the drug arena to understand different perspectives on the current problem. Based on these conversations, a review of published and unpublished information on drug shortages and analyses of existing or newly created databases, the report concluded that the problem of medical product shortages is complex and stems from economic, legal, regulatory, policy and clinical decisions that are deeply interconnected. “While the FDA has taken on the task of working with manufacturers to help prevent and mitigate these shortages, many of the root causes and potential solutions to the shortage problem lie beyond its purview.”
The report includes a number of actions and recommendations while acknowledging that there is no single, simple solution to resolve the medical product shortage problem. Immediate actions include:
- Writing a letter to drug manufacturers reminding them of current legal obligations to notify the FDA in advance of the discontinuation of certain drugs and to voluntarily notify the FDA of other potential disruptions to drug supply as soon as they become aware of them.
- Developing guidance and regulations that clarify and enhance the information on potential drug shortages that is submitted by industry.
- Provide additional staffing resources for FDA’s efforts to prevent and mitigate shortages.
- Support legislation that requires early notification by manufacturers for drug shortages and provides new authority to FDA to enforce these requirements.
- Implement and maintain a database that can analyze the characteristics of drug shortage.
The FDA also identified several longer-term actions, including identification of factors that contribute to success or failure in preventing drug shortages; identifying quality issues in manufacturing processes that contribute to severe drug shortages; and encouraging product manufacturers to develop and maintain a plan for backup manufacturing and sources of API and other essential product components. – by Colleen Owens, Emily Shafer and Katie Kalvaitis
For more information:
- American Society of Health-System Pharmacists. Drug shortages: current drugs. Available at: www.ashp.org/drugshortages/current. Accessed July 6, 2011.
- FDA. Current drug shortages. Available at: www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm. Accessed July 6, 2011.
- Cherici C. Navigating drug shortages in American healthcare. Available at: www.premierinc.com/about/news/11-mar/drug-shortage-white-paper-3-28-11.pdf. Accessed Sept. 28, 2011.
- ISMP. Drug shortages: National survey reveals high level of frustration, low level of safety. ISMP medication safety alert. Available at: www.ismp.org/newsletters/acutecare/articles/20100923.asp. Accessed Sept. 28, 2011.
Disclosure: Drs. Cooper-DeHoff, Link, Mayer, Parks, Saliba and Schilsky, as well as Mr. Cohen and Mr. Hill, reported no relevant financial disclosures.