May 1, 2013
Volume 77, Number 5
Drug Shortages: Where Are We and Where Are We Going?
Heather C. Nixon, M.D. Committee on Patient Safety and Education
Feyce M. Peralta, M.D. Committee on Patient Safety and Education
The blame game is on … from Capitol Hill to the Wall Street Journal to the halls of your local operating room, everyone is buzzing about who is responsible for the epidemic of drug shortages. According to the University of Utah Drug Information Service, the number of active drug shortages by the end of 2012 was 299.1 At the last ASA annual meeting in Washington, D.C., special sessions addressed the New England Compounding Center crisis, and anesthesia providers openly vented their frustrations. Unfortunately, no one party can completely shoulder the blame. The creation, manufacturing, distribution and regulation of pharmaceuticals is a complex process. Any step in this process may result in shortages.2
The process starts with the availability and quality assurance of raw materials. Next, drug manufacturing can be plagued with quality issues, including contamination of equipment or products, defective products, equipment malfunctions, packaging or labeling irregularities or compliance problems. If medications are to be compounded, outside compounding facilities may have their own quality problems as evidenced by the recent fungal contamination of methylprednisolone by the New England Compounding Center.3,4 Once produced, even everyday factors such as weather conditions may affect distribution. Likewise, governmental oversight may halt production if quality concerns warrant investigation. In a recent congressional meeting, the U.S. House of Representatives Committee on Oversight and Government Reform accused the FDA of contributing to the drug shortages by suspending production at four major suppliers during 2011.5 These closures followed reports by the FDA of serious violations, including multiple contaminations and safety concerns.6 The pharmaceutical industry is also subject to financial constraints, and companies may choose to discontinue products if profits are low or equipment upgrades for aging infrastructure are not financially sound investments to continue generic drug production.7 In 2011, nine percent of sterile injectable shortages were due to manufacturer discontinuation.7 This can be particularly problematic if production redundancy does not exist from other companies. Occasionally, drugs in shortage may be secondary consequences of other drug shortages. For example, propofol shortages may increase demand for alternative induction agents such as etomidate or ketamine.
Overall, quality problems seem to be the most common source of drug shortages. According to a report by the U.S. Department of Health and Human Services (HHS), more than 54 percent of the injectable shortages have been caused by quality problems.1 As one can see, although the majority of shortages are due to quality, drug shortages are a complex problem with no real resolution in sight.8
So What Is Being Done?
Drug shortages are not a new problem. The FDA established the Drug Shortage Program (DSP) in 1999 in response to fears that the electronic crash expected for Y2K would create more shortages.8 In following years, as greater numbers and more prolonged shortages developed, this program expanded. The DSP has tracked data on drug shortages and become more involved in working to solve issues of scarcity. Its ability to quell shortages was limited, however, as the FDA was generally not notified about shortages until end-users reported inadequate supplies. Therefore, in July 2012, the U.S. Food and Drug Administration Safety and Innovation Act (FDASIA; http://www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf) was passed. FDASIA requires drug manufacturers to alert the FDA six months in advance of any identified upcoming shortage. This advanced notice may theoretically allow the FDA to aid in the process of ensuring continued supply. Although this legislation promotes early intervention for potential shortages, there are currently no real penalties for noncompliance by pharmaceutical manu-facturers. If shortages are not reported in a timely manner by manufacturers, the FDA is only empowered to issue public letters of noncompliance, which may have little effect on future reporting. Furthermore, compounding pharmacies are not governed by the same legislation or quality measures as drug manufacturers.9 Instead, drug compounders are regulated at the state level and guided by U.S. Pharmacopoeia (USP) Convention and specifically Chapter <797> guidelines. If production problems arise at the compounding level, little notice may be given.
So What Is the Current Impact of Drug Shortages?
Drug shortages do not only cause patient and provider frustration, they may lead to poor patient care and possible patient harm. In a 2012 survey of ASA members, 97.6 percent of providers reported at least one drug shortage in the previous year. In addition, high percentages of less optimal outcomes, longer operating room times or recovery were also noted. Most concerning were the six deaths were reported to be due to drug shortages (See ASA website for full results of the survey;
http://www.asahq.org/for-members/advocacy/federal-legislative-and-regulatory-activities/drug-shortages.aspx#Drug Shortages Survey). These results are not surprising. Drug shortages are not only inconvenient, but they can lead to medication errors. Frequent changes in medication suppliers can cause confusion; changing labels may increase “look-alike” errors and changing concentrations may lead to dosing errors. Providers may not realize that replacement suppliers use preservatives that may be harmful if used inappropriately. Drugs with worse side-effect profiles or narrow therapeutic windows may be chosen if other preferred medications are not available.
Anesthesia providers may be particularly hard hit by shortages, as many anesthetic drugs are sterile injectables. The production of sterile injectables requires specialized equipment and more complex procedures, and therefore may be more susceptible to quality problems. In order to cope with shortages of these drugs, some providers are resorting to measures that contradict the U.S. Centers for Disease Control and Prevention (CDC) guidelines regarding single-dose medications. Currently, the CDC guidelines suggest that medications that are labeled as “single-use” or “single-dose” should only be accessed by one syringe and one needle and then used on one patient, despite the fact that many of these medications are packaged with more total drug than would be necessary for one patient. The CDC launched the “one and only” campaign in 2007 to promote this practice. Since that time, at least 19 outbreaks of bloodborne pathogens and bacterial infections were traced to inappropriate use of single-dose vials for multiple patients. The CDC contends that most single-dose vials do not contain antimicrobial preservatives and that repeated punctures may increase the risk of infectious contamination, even with clean needles or
syringes (full statement; http://www.cdc.gov/injectionsafety/PDF/CDC-SDV-Position05022012.pdf). The CDC further advises that if single-dose or single-use vials need to be conserved, repackaging for multiple patients can be performed, but only if repackaging is performed by a qualified individual according to standards set forth by the United States Pharmacopeia, specifically General Chapter <797>. These are the same standards to which pharmaceutical compounding companies should adhere. Unfortunately, the majority of surgeries in the United States take place in the outpatient setting, where pharmacist services may not be available to appropriately divide the medications under Chapter <797> guidelines. This leaves many providers to face the choice of cancelling cases, administering suboptimal medications or dividing medications against CDC guidelines. The question arises: why can’t pharmaceutical companies package medications for “single-dose” into more appropriate doses for single use? This might help conserve drugs and limit the temptation to use single-dose medications for multiple patients.
What Can Providers Do to Improve Patient Safety?
Set systems in place to recognize and deal with shortages:10
Design a customized approach with multi-disciplinary involvement that takes into consideration the limitations of the institution.
Designate drug shortage managers within each department or management structure. This person would be responsible for tracking use and ensuring continuous supplies of critical medications. If shortages were to arise, this individual would meet with front-line providers to identify areas of high use and possibly work with providers to identify safe and judicious criteria for use or limitations on use. Likewise, front-line providers should be consulted prior to medication changes.
Create alert systems that notify frontline providers. Each institution will have to identify the method that works best for their system. E-mail alerts, EMR alerts or white boards in clinical care sites, or at the drug distribution sites, are examples of notification systems. Try to target end-users who will be affected so as to avoid alert/notification fatigue. If anesthesia providers are alerted to every drug on shortage (including chemotherapy agents), alert fatigue may develop.
Educate providers (especially trainees) of the potential for medication errors due to shortages (look-alike errors, dosage changes, addition of preservatives).
Create a reporting system through which all providers should be encouraged to report any changes due to shortages that may increase the potential for patient harm or error.
For more information concerning ASA’s efforts to end drug shortages, please go to: http://www.asahq.org/for-members/advocacy/federal-legislative-and-regulatory-activities/drug-shortages.aspx
Heather C. Nixon, M.D. is
Assistant Professor of Anesthesiology,
University of Illinois Hospital and Health Sciences System, Chicago.
Feyce M. Peralta, M.D. is Assistant Professor at Northwestern University Feinberg School of Medicine, Chicago.
1. Kuehn BM. Despite curbing new drug shortages, shortfall of drugs a persistent problem. JAMA. 2013;309(6):532-533.
2. De Oliveira GS Jr, Theilken LS, McCarthy RJ. Shortage of perioperative drugs: implications for anesthesia practice and patient safety. Anesth Analg. 2011;113(6):1429-1435.
3. Kainer MA, Reagan DR, Nguyen DB, et al.; Tennessee Fungal Meningitis Investigation Team. Fungal infections associated with contaminated methylprednisolone in Tennessee. N Engl J Med. 2012;367(23):2194-2203.
4. Centers for Disease Control and Prevention. Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy - United States, 2012. MMWR Morb Mortal Wkly Rep. 2012;61(41): 839-842.
5. U.S. House of Representatives Committee on Oversight and Government Reform. FDA’s contribution to the drug shortage crisis: staff report. 112th Congress. Committee on Oversight and Government Reform website. http://oversight.house.gov/wp-content/uploads/2012/06/6-15-2012-Report-FDAs-Contribution-to-the-Drug-Shortage-Crisis.pdf. Published June 15, 2012. Accessed March 13, 2013.
6. Fox ER, Tyler LS. Call to action: finding solutions for the drug shortage crisis in the United States. Clin Pharmacol Ther. 2013;93(2):145-147.
7. Woodcock J. Reliable drug quality: an unresolved problem. PDA J Pharm Sci Technol. 2012;66(3):270-272.
8. Kweder SL, Dill S. Drug shortages: the cycle of quantity and quality. Clin Pharmacol Ther. 2013;93(3):245-251.
9. Pergolizzi JV Jr, Labhsetwar S, Lequang JA. Compounding pharmacies: who is in charge? Pain Pract. 2013;13(3):253-257.
10. Mhyre J, Nixon H. Drug shortage crisis: patient safety concerns for obstetric anesthesiologists. SOAP Newsl. 2012;summer:14.