Introduction and Background
In this section:
- Frequency of Drug Shortages
- Growing Attention to Drug Shortages
- Impact of Drug Shortages
- Characteristics of Drug Shortages
- Legal Framework for FDA Medical Product Shortage Efforts
The Food and Drug Administration (FDA or the Agency) is responsible for protecting the public health by assuring that human drugs, biological products (including vaccines), veterinary drugs, and medical devices intended for human use are safe and effective. Drug shortages have been defined by FDA as "a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the patient level." 1
While many of the root causes of medical product shortages lie outside the purview of FDA (the accompanying issue brief by the Assistant Secretary for Planning and Evaluation (ASPE) entitled "Economic Analysis of the Causes of Drug Shortages" provides additional analysis of the root causes of drug shortages), the Agency has taken on the task of working with manufacturers to prevent and mitigate such shortages. This report examines efforts being undertaken by FDA and other stakeholders in response to medical product shortages in four of the seven Centers within FDA: the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), and the Center for Veterinary Medicine (CVM). It also examines data related to all medical product shortages and issues certain recommendations that, in a number of instances, can be applied to all product categories. However, many other recommendations apply to products regulated by CDER alone. In this report, the term "drug shortages" refers to shortages specifically pertaining to human drugs. 2 "Medical product shortages" refers to all shortages, including human drugs, biologics, medical devices, and veterinary drugs.
Only limited epidemiological data exist for drug shortages. Three hundred and eleven pharmacy experts representing 228 hospitals and other health-care sites responded to a survey by the group purchasing organization (GPO) Premier Healthcare Alliance that covered the second half of 2010 (response rate not calculable). Eighty-nine percent of respondents reported drug shortages that may have caused a safety issue or medical error and 80% reported that a shortage had resulted in the delay or cancellation of a patient care intervention. 3
In April 2011, the American Society of Anesthesiologists (ASA) conducted an online survey of 1373 anesthesiologists (response rate not calculable) in which over 90% of respondents reported currently experiencing a shortage of one or more anesthetics and 98% reported ever experiencing an anesthetic shortage. Ninety-one percent of respondents reported switching to an alternative anesthetic and about 10% reported postponing or cancelling a procedure. 4
A recent survey of community hospitals by the American Hospital Association (AHA) generated 820 responses (response rate: 16.4%). 5 In the previous six months, 99.5% of respondents indicated they had experienced at least one drug shortage, with 44% reporting more than 20 shortages. 6 Similar findings were reported in a survey of Canadian pharmacists, indicating that the drug shortage problem is not confined to the United States. 7 Indeed, staff in CDER’s Drug Shortage Program (DSP) report that some countries in Europe and Canada are experiencing similar shortages to the United States. Canada and the United States often depend upon the same manufacturers.
Based on data generated by CDER, the number of drug shortages has been rising steadily over the last five years. While there were only 61 shortages reported by CDER in 2005, in 2010 there were 178; data for 2011 are unavailable (See Figure 1). Some of this increase is likely due to FDA’s efforts to encourage notifications, particularly in the later years. The American Society of Health-System Pharmacists (ASHP) typically reports larger numbers of shortages (for an explanation, see "FDA Communication" under the Review and Discussion of Key Issues section below), but their data confirm an increase in shortages of approximately the same magnitude starting at the same time. 8
The rising number of drug shortages has generated increased attention from health-care providers, patients, legislators, and journalists. In recognition of the expanding problem, ASHP, ASA, the American Society of Clinical Oncology (ASCO), and the Institute for Safe Medication Practices (ISMP) convened a meeting of key stakeholders to discuss the problem and potential solutions in November 2010. More recently, CDER held an open, solutions-oriented meeting with manufacturers, providers, and the public on September 26, 2011.
Congress has also become concerned about drug shortages, after hearing growing concerns from patients and providers who have been unable to obtain critical drugs. On September 23, 2011, the Health Subcommittee of the House of Representatives Energy and Commerce Committee held a hearing entitled "Examining the Increase in Drug Shortages." Legislation has been introduced by Senator Amy Klobuchar (D-MN) and cosponsors and Representative Diana DeGette (D-CO) and cosponsors. (For more detail, see "Reporting of Supply Disruptions" in the Review and Discussion of Key Issues section below). In addition, the Government Accountability Office (GAO) is conducting an examination of FDA’s response to drug shortages at the request of Senators Bob Casey (D-PA), Tom Harkin (D-IA), and Richard Blumenthal (D-CT), who are members of the Senate Committee on Health, Education, Labor, and Pensions. This report is expected in the fall of 2011.
The number of published medical journal articles on drug shortages and the growing number of news reports also reflect the rising awareness of drug shortages. A search of PubMed on July 19, 2011, using the search terms "drug shortage(s)" and "medication shortage(s)," revealed a clear increase in the number of articles over time, mostly in the form of commentaries. 9 In 2011, there have already been 17 such articles, up from one to two per year from 2006 to 2008. Three of the more prominent articles on drug shortages are an article describing ASHP guidelines for managing drug shortages 10 and two articles by DSP, one describing FDA’s general approach to drug shortages 11 and another focused on the recent propofol shortage. 12 News articles on drug shortages in prominent newspapers are appearing with great frequency as well. 13, 14, 15, 16, 17
As the frequency of drug shortages has risen, there have been shortages of many commonly used drugs, including succinylcholine, naloxone, furosemide, epinephrine, and norepinephrine. Other drugs that have been in shortage, such as the cancer drug cytarabine, are important not only because they treat a critical disease, but also because they lack an effective alternative. In the past year, public attention to the drug shortage problem has shifted rapidly among an array of drug categories. During that period, anesthetics, "crash cart" drugs, intravenous nutritional supplements, and, most recently, cancer drugs have all at times been the focus of media articles.
While most drugs do not experience shortages, the impact of drug shortages on patients can be significant and even life-threatening. Certain drugs that have recently been in shortage, such as "crash cart" drugs, can literally be life-saving in the acute setting, while others, such as outpatient chemotherapy drugs, must be administered within days or weeks in order to provide maximum benefit. In one instance, a shortage of generic propofol led clinicians to substitute etomidate, resulting in eight patient reports of suspected phlebitis in a single hospital system. 18 Awareness of these potential clinical consequences increases the urgency of the Agency to take additional steps to aid in the prevention and resolution of shortages.
However, while media and anecdotal reports of the adverse effects of shortages abound, there are no satisfactory systematic studies of the impact of shortages on patient care. An informal Internet survey of health-care practitioners (n = "more than 1800"; response rate not calculable) conducted by the ISMP between July and September 2010 provided examples of drug shortages and their impact 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. 19 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. The impact upon National Institutes of Health clinical trials has been underlined specifically. 20 In the AHA study cited above, 82% of respondents reported delays in treatment, 69% said a patient had received a less effective drug, and 35% reported that a patient had experienced an adverse outcome. Seventy-eight percent reported rationing or restricting drugs and 92% said they had experienced increased drug costs as a result of shortages. 21 These reports are difficult to evaluate in view of the studies’ limitations.
Some studies have also estimated the costs of drug shortages to the health-care system. ASHP recently surveyed 1322 of its U.S. member pharmacy directors, of whom 353 responded (response rate: 27%). Pharmacists and pharmacy technicians reported spending on average nine and eight hours each week, respectively, dealing with medication shortages, a work load that translated into estimated labor costs of $216 million per year. 22 The Premier survey reported above tallied $78 million in drug shortage-related costs to its members in 2010. 23 Four months of a shortage of selegiline was estimated to cost $75,000 because an innovator product had to be substituted for a generic in shortage. 24
According to information from FDA’s medical product Centers, the great majority of the medical product shortages reported to FDA pertains to prescription drug products intended for human use. Most of the drug shortages involve generic, sterile injectables; in 2010, these accounted for 74% of all reported drug shortages. As Figure 1 demonstrates, in recent years sterile injectables have accounted for a rising number and percentage of drug shortages managed by CDER’s DSP. The impact of sterile injectables appears disproportionate. According to sales data from the pharmaceutical market analysis company IMS Health analyzed for this report by the Office of Surveillance and Epidemiology (OSE) in CDER, such products accounted for only 29% of generic drug product volume in terms of packages/bottles/vials of products sold in 2010. Among the approximately 80 manufacturers making generic injectables, about 40 experienced a shortage in 2010.
Compared to oral drugs, sterile injectables are more complex and require more specialized processes and equipment to manufacture, leading to a higher likelihood of manufacturing problems. Perhaps as a result, there are relatively few companies that produce sterile injectable drugs and thus a still smaller number that will manufacture any particular injectable. Because of considerably more complex manufacturing processes, shortages of sterile injectables typically last months; those of oral drugs are generally resolved more rapidly. Economic issues are discussed in greater detail below in the portion of the Review and Discussion of Key Issues section entitled "Market Conditions" and the accompanying ASPE Issue Brief provides economic analysis of this issue, particularly for the sterile injectable market.
Information previously collected by DSP 25 was entered into a new database covering the period January 1, 2010 to August 26, 2011. After excluding shortages prevented by DSP, 127 unique shortages reported to FDA were available for analysis, including several drugs that were in shortage more than once. Sixty-five of these shortages started in 2010 and 62 started in 2011. This represents 37% of the shortages identified by DSP in 2010 (data from DSP for 2011 were unavailable). According to DSP, the shortages available for analysis tended to be larger, of longer duration, and of greater public health impact than shortages not analyzed, a factor that must be taken into account if extrapolating from the data presented below to the larger universe of drug shortages.
Of the 127 shortages studied, 50% were generic or unapproved 26 drugs, 43% were innovator drugs, and 7% had both categories in shortage. Unapproved drugs are generally older drugs marketed without required FDA approval; these represented fourteen of the 127 shortages (11%). Injectable medications accounted for 102 (80%) of drugs in shortage (92% of generic or unapproved drug shortages vs. 70% of innovator drugs 27 ), followed by oral tablets/capsules (10%). Dermal preparations, inhalation products, and oral liquids each accounted for less than 2% of shortages (see Figure 2).
Of 171 companies mentioned in the 127 drug shortages (some shortages involved more than one manufacturer), three companies accounted for 40% of mentions: one company was involved in 27 shortages, another in 23 shortages, and a third in 19 shortages.
Shortages occurred among a large number of drug classes, with oncology drugs accounting for 28% of shortages (see Figure 3), followed by antibacterial drugs (13%). One hundred and eighteen shortages (93%) involved so-called "medically necessary" drugs (see discussion of this term under "Legal Framework" below) and 52 (41%) were both medically necessary and sole-source drugs.
Quality problems at the drug manufacturing facility resulting in disruptions in supply were the leading cause of drug shortages (see Figure 4), accounting for 43% of all shortages, followed by other delays in manufacturing or shipping (15%) and a shortage of the Active Pharmaceutical Ingredient (API; 10%). In general, inspection findings that have been followed by shortages have been serious in nature: glass shards, metal filings, and fungal or other contamination in injectable products that must be sterile and pure to be safe for patients. Importantly, even though the majority of APIs are now produced abroad and imported into the United States, the manufacturing problems with shortages are, for the most part, being detected in domestic facilities in which the final product is assembled. In 8% of cases, the manufacturer made a business decision to discontinue production; in other cases, manufacturers responded to a serious problem at the manufacturing facility by discontinuing production. Innovator and generic or unapproved drugs had similar breakdowns by cause, except generic or unapproved drugs had relatively more shortages due to delays in manufacturing and shipping (23% vs. 6%). The main differences between injectable and non-injectable drugs were that injectables were more likely to have had a quality issue (45% vs. 32%) and less likely to have had an API shortage (8% vs. 20%).
CDER’s options for mitigating a drug shortage include notifying and encouraging manufacturers of the same or similar products to increase their production, finding another manufacturer to begin production of the product, using regulatory discretion with regard to selective release of product when accompanied by appropriate warnings or remedies (e.g., filters for products contaminated with particulates), expedited review of an Abbreviated New Drug Application (ANDA), expedited review of new manufacturing lines or raw material sources to help firms increase production, and regulatory discretion with regard to controlled importation of equivalent products approved abroad but not in the United States. Overall, FDA’s most common primary responses to drug shortage problems were to ask other companies to increase production (31%), exercise flexibility through regulatory discretion (28%), and expedite regulatory reviews (26%; see Figure 5). Regulatory discretion with regard to the controlled importation of similar products approved abroad but not in the United States was the primary response in 5% of cases.
The most common primary FDA response to a generic or unapproved drug shortage was asking another firm to increase production (43%), while for shortages of innovator drugs it was expediting regulatory reviews (37%), followed by exercising flexibility and discretion (35%). For injectable drugs, the leading primary FDA responses were asking other firms to step up production (33%) and exercising regulatory discretion (30%), while for non-injectables it was expediting regulatory review (40%). For shortages that began and ended during the study period (n = 64), the median shortage duration was 62.5 days (mean 105 days; median for innovator drugs: 57 days; median for generic/unapproved drugs: 71.5 days 28). In an alternative analysis, shortages that had not been resolved during the study period were also included. Fifty-five percent of such shortages lasted over 120 days (innovator 47% vs. generic or unapproved 64%). 29
The Federal Food, Drug, and Cosmetic Act (FD&C Act) does not grant the Agency legal authority to require companies to continue manufacturing medications that are in shortage. However, manufacturers of certain drugs are required to provide advance notification to FDA of a discontinuance in manufacture under section 506C of the FD&C Act 30 and in the implementing section of the Code of Federal Regulations. 31 Specifically, the statute provides that sole-source manufacturers of certain drugs that are life-supporting, life-sustaining, or intended for use in the prevention of a debilitating disease or condition notify the agency at least six months prior to the date of discontinuation of the manufacture of such drugs. FD&C Act section 506C(b) provides certain criteria for the reduction in the notification period under certain circumstances. The advance notification provision in section 506C of the FD&C Act does not include explicit enforcement authority. However, FDA continues to explore new approaches to help prevent and mitigate shortages under existing statutory authorities.
This notification requirement applies to products approved under a New Drug Application (NDA) or ANDA, which encompasses most drugs regulated by CDER and a very small proportion of CBER-regulated products (e.g., anticoagulants that are part of blood collection bags and Hetastarch products). The bulk of CBER-regulated products (e.g., allergenics, blood and blood products, gene therapies, cellular products, and vaccines) and those therapeutic biologics regulated by CDER (e.g., monoclonal antibodies and therapeutic proteins), all devices, and all veterinary medications have no such reporting requirement related to shortages.
CDER’s Manual of Policies and Procedures (MAPP) uses the term "medically necessary" for "Any drug product used to treat or prevent a serious disease or medical condition for which there is no other adequately available drug product that is judged by medical staff to be an appropriate substitute. Off-label uses and Investigational New Drug products can be considered medically necessary. Patient inconvenience alone is an insufficient reason to classify a drug product as medically necessary." 32 A given drug may be considered medically necessary at one point in time, but not at another, depending on prevailing evidence and/or clinical practice guidelines. CDER uses this definition exclusively to prioritize drug shortages.
Other Centers have also implemented programs to identify and aid in the prevention and mitigation of product shortages. CVM prioritizes shortages of drugs that are needed to treat or prevent serious diseases or conditions, or that are required to assure the availability of safe food products of animal origin for which CVM staff have determined there is no available source of that product or adequate alternative drug product. 33 While animal drug manufacturers are not required to report impending shortages, they are required to submit annual reports for each medicine marketed detailing how much product was sold or distributed. 34 This information can be used by CVM to see whether a drug has had decreased market volume over the past year, possibly signifying a shortage. However, these data are not likely to be detailed or timely enough to identify or manage a shortage. CDRH has additional complexities because generics do not exist in the device field and similar devices may not be interchangeable. CBER also engages in activities intended to aid in the identification, prevention, and mitigation of product shortages such as encouraging manufacturers to increase production, expediting inspections of manufacturing facilities, and expediting application reviews. If a biological product that is in shortage is used to treat, cure, mitigate, prevent, or diagnose a serious disease or medical condition for which there is no adequate alternative product, the shortage is posted on the CBER Biologic Product Shortages web site.
1. Center for Drug Evaluation and Research, Food and Drug Administration. Manual of Policies and Procedures (MAPP), 6003.1. Available at: http://www.fda.gov/downloads/AboutFDA/CentersOffices/
CDER/ManualofPoliciesProcedures/ucm079936.pdf (accessed September 28, 2011).
2. In addition to small molecule drugs, CDER regulates certain larger molecule products, including certain biological products. For more information, see http://www.fda.gov/Drugs/
TherapeuticBiologicApplications/ucm113522.htm (accessed September 28, 2010).
3. Cherici C, Frazier J, Feldman M, et al., Premier Healthcare Alliance. Navigating Drug Shortages in American Healthcare. March 2011. Available at: http://www.premierinc.com/about/news/11-mar/drug-shortage-white-paper-3-28-11.pdf (accessed September 28, 2011).
4. American Society of Anesthesiologists. Survey Reveals 90 Percent of Anesthesiologists Experiencing Drug Shortage of Anesthetics. Press release, May 9, 2011. Available at: http://www.asahq.org/For-the-Public-and-Media/Press-Room/ASA-News/Survey-Reveals-90-Percent-of-Anesthesiologists-Experiencing-Drug-Shortages-of-Anesthetics.aspx (accessed September 28, 2011).
5. The survey report states that it was sent to all U.S. community hospitals. According to the American Hospital Association, there are 5008 such hospitals. See: http://www.aha.org/aha/resource-center/Statistics-and-Studies/fast-facts.html (accessed September 28, 2011).
6. American Hospital Association. AHA Survey on Drug Shortages. Available at: http://www.aha.org/aha/content/2011/pdf/drugshortagesurvey.pdf. Updated July 12, 2011 (accessed September 28, 2011).
7. Eggertson L. Continuing drug shortages affect North American patients. Canadian Medical Association Journal 2010;182:E811-2.
8. Fox E. Update on the status of drug shortages, causes, and significant trends. Presented at CDER Drug Shortage Workshop, Silver Spring, MD, September 26, 2011.
9. Articles on vaccines and foreign drug shortages were excluded.
10. Fox ER, Birt A, James KB, Kokko H, Salverson S, Soflin DL. ASHP guidelines on managing drug product shortages in hospitals and health systems. American Journal of Health-System Pharmacy 2009;66:1399-406.
11. Jensen V, Kimzey LM, Goldberger MJ. FDA’s role in responding to drug shortages. American Journal of Health-System Pharmacy 2002;59:1432-5.
12. Jensen V, Rappaport BA. The reality of drug shortages – the case of the injectable agent propofol. New England Journal of Medicine 2010;363:806-7.
13. Stein R. Shortages of key drugs endanger patients. Washington Post, May 1, 2011. Available at: http://www.washingtonpost.com/national/shortages-of-key-drugs-endanger-patients/2011/04/26/AF1aJJVF_story.html (accessed September 28, 2011).
14. Corben J. Drug shortages distress hospitals. Wall Street Journal, February 1, 2011. Available at: http://online.wsj.com/article/SB10001424052748704680604576110613604195324.html (accessed September 28, 2011).
15. Emanuel EJ. Shortchanging cancer patients. New York Times, August 6, 2011. Available at: http://www.nytimes.com/2011/08/07/opinion/sunday/ezekiel-emanuel-cancer-patients.html (accessed September 28, 2011).
16. Harris G. U.S. scrambling to ease shortage of vital medicine. New York Times, August 18, 2011. Available at: http://www.nytimes.com/2011/08/20/health/policy/20drug.html?pagewanted=all (accessed September 28, 2011).
17. Szabo L. Drug shortages set to reach record levels. USA Today, August 15, 2011. Available at: http://yourlife.usatoday.com/health/story/2011/08/Drug-shortages-set-to-reach-record-levels/49984446/1 (accessed September 28, 2011).
18. Kosarek L, Hart SR, Schultz L, DiGiovanni N. Increase in venous complications associated with etomidate use during a propofol shortage: an example of clinically important adverse effects related to drug substitution. Ochsner Journal 2011;11:143-6.
19. Institute for Safe Medication Practices. Drug Shortages: National Survey Reveals High Level of Frustration, Low Level of Safety. ISMP Medication Safety Alert. Sept 23, 2010. Available at: http://www.ismp.org/newsletters/acutecare/articles/20100923.asp (accessed September 28, 2011).
20. Koh H. Testimony before the U.S. House of Representatives Energy & Commerce Committee, Subcommittee on Health, September 23, 2011. Available at: http://www.hhs.gov/ash/news/testimony_koh_drugshortages_20110923.pdf (accessed October 10, 2011).
21. American Hospital Association. AHA Survey on Drug Shortages. Available at: http://www.aha.org/aha/content/2011/pdf/drugshortagesurvey.pdf. Updated July 12, 2011 (accessed September 28, 2011).
22. Kaakeh R, Sweet B, Reilly C. Impact of drug shortages on U.S. health systems. American Journal of Health-System Pharmacy 2011;68:e13-e21.
23. Cherici C, Frazier J, Feldman M, et al., Premier Healthcare Alliance. Navigating Drug Shortages in American Healthcare. March 2011. Available at: http://www.premierinc.com/about/news/11-mar/drug-shortage-white-paper-3-28-11.pdf (accessed September 28, 2011).
24. Dorsey ER, Thompson JP, Dayoub EJ, George B, Saubermann LA, Holloway RG. Selegiline shortage: causes and costs of a generic drug shortage. Neurology 2009;21;73:213-7.
25. This information only contains a subset of ongoing shortages, but also includes some shortages DSP is working to prevent.
26. There are several thousand prescription drugs currently being marketed in the United States that have never been approved by FDA. Some of these drugs were on the market prior to the 1962 amendments to the FD&C Act, which required manufacturers to provide evidence of a new drug’s effectiveness before it could be approved for marketing to the public.
27. Nine shortages that included both generic/unapproved and innovator drugs were excluded from this analysis.
28. Five shortages that included both generic/unapproved and innovator drugs were excluded from this analysis.
29. The overall analysis included 98 drugs. For the subanalysis by innovator status, six shortages that included both generic/unapproved and innovator drugs were excluded. To be included in this analysis, shortages had to begin at least 120 days before the database closed.
30. 21 U.S.C. 356c.
31. 21 C.F.R 314.81(b)(3)(iii).
32. Center for Drug Evaluation and Research, Food and Drug Administration. Manual of Policies and Procedures (MAPP), 6003.1. Available at: http://www.fda.gov/downloads/AboutFDA/CentersOffices
/CDER/ManualofPoliciesProcedures/ucm079936.pdf (accessed September 28, 2011).
33. Center for Veterinary Medicine, Food and Drug Administration. Program Policy and Procedures Manual 1240.4170.
34. 21 C.F.R 514.80; 21 U.S.C 360b(1)(3).