- Email: [email protected]
The challenge of drug shortages for emergency medicine
THE PRACTICE OF EMERGENCY MEDICINE/EDITORIAL
Linda S. Tyler, PharmD Erin R. Fox, PharmD E. Martin Caravati, MD, MPH
The Challenge of Drug Shortages for Emergency Medicine
From the Drug Information Service (Tyler, Fox) and the Division of Emergency Medicine (Caravati), University of Utah Health Sciences Center, Salt Lake City, UT.
[Ann Emerg Med. 2002;40:598-602.]
Copyright © 2002 by the American College of Emergency Physicians. 0196-0644/2002/$35.00 + 0 47/1/129127 doi:10.1067/mem.2002.129127
5 9 8
Health care providers in the United States have been facing unprecedented drug shortages. One of the first was a nationwide shortage of the diphtheria-tetanus-pertussis (DTP) vaccine in 1984 to 1985.1 Two of the 3 manufacturers stopped distribution of the product. Lots from the sole remaining supplier did not meet the manufacturing standards. There were few shortages for the next decade, but they have dramatically increased during the past few years. Hospitals and emergency departments have been especially impacted because many of them involve parenteral drugs. During the past year, EDs have had shortages of commonly used drugs (Table) such as naloxone, tetanus toxoid, prochlorperazine, fentanyl, and succinylcholine. The reasons for these shortages varied, but the end result is the same. Drug shortages are affecting patient care across the nation. This article will discuss some of the reasons for the recent increase in drug shortages and strategies for dealing with them. The process of how medications are ordered in the pharmacy, delivered, and ultimately arrive in the ED may be unfamiliar to most practitioners. The pharmacy experiences back orders daily, reflecting fluctuations in supply and demand between the manufacturers, wholesalers, and hospitals. The industry average back order was 7% in 2000 (Ronald J. Streck, Healthcare Distribution Management Association Survey Research Program, unpublished data, January 2002), but was as high as 23% in December 2001 (Ronald J. Streck, Healthcare
ANNALS OF EMERGENCY MEDICINE
40:6
DECEMBER 2002
DRUG SHORTAGES FOR EMERGENCY MEDICINE Tyler, Fox & Caravati
Distribution Management Association ad hoc survey, unpublished data, January 2002). Pharmacies are skilled at dealing with most of these temporary supply issues. Until recently, it was rare to have a shortage of a drug that would impact patient care. This article will focus only on those shortages that impact patient care or require the pharmacy to find alternative ways to provide the medication (ie, different packaging sizes), not on those reflected on these purchasing fluctuations. SCOPE OF THE PROBLEM
At the University of Utah Health Sciences Center (UUHSC), we have been tracking drug shortages for many years and developing strategies for managing these situations. In 2001, we began providing these management strategies nationally. Some shortages can be handled within the pharmacy by addressing supply problems that affect the way we access medications, but do not affect patients or how prescribers will order the drug. We notify our physicians when they must use alternative medications, when a supply issue affects the
way they order a medication, or when it will directly impact patients. In 1996, UUHSC had 3 shortages that reached the patient level, and in 1997, we had 8. In 1998, 1999, and 2000, we had 10, 16, and 18 drug shortages, respectively, all affecting patient care. In 2001, our hospital had 83 shortages; 61 of these affected patients and required physician notification. Nationally, we have tracked 157 shortages from January 2001 through June 2002. Of these, we consider 97 (62%) still active and unresolved. Not all shortages will affect all facilities. However, these supply problems are unlikely to be resolved soon. The recent increases in shortages, with many lasting more than a year (Table), make drug shortages a trend that is likely to continue. R E A S O N S F O R S H O R TA G E S
No single reason explains this phenomenon.2 Supply problems may occur because of manufacturing problems, business decisions, inventory practices, natural disasters, war, or regulatory problems. In our experience, the most common reason given by companies for
Table.
Selected drug shortages affecting EDs, 2001 to 2002. Drug
Reason
Naloxone
Major manufacturer discontinued production
Diphenhydramine injection
Major manufacturer discontinued production
Prochlorperazine injection
Raw material shortage
Tetanus-diphtheria vaccine
Major manufacturer discontinued production
Succinylcholine
Raw material shortage
Etomidate
Raw material shortage
Antivenin (crotalidae) Polyvalent Manufacturing difficulties and Crotalidae Polyvalent Immune Fab (ovine) (CroFab)
DECEMBER 2002
40:6
ANNALS OF EMERGENCY MEDICINE
Duration
Comments
January 2001 to July 2002 Alternative agent, nalmefene, is more difficult to use as a result of different dosing. Preservative-free product remains unavailable. May 2001 to present Benztropine, another agent useful for managing acute dystonic reactions, has been on shortage since October 2001 and is still unavailable. March 2001 to present Other antiemetics, including promethazine injection and metoclopramide injection, have also been in short supply during this shortage. July 2000 to June 2002 Tetanus toxoid and pediatric diphtheria-tetanusacellular pertussis vaccines are also affected. January to July 2001 During this shortage, rapacuronium, a likely alternative, was withdrawn from the market because of safety concerns. October 2001 to present Methohexital, a likely alternative agent, is also on shortage. January 2001 to present Both products have had availability problems since 2001.
5 9 9
DRUG SHORTAGES FOR EMERGENCY MEDICINE Tyler, Fox & Caravati
a shortage is “manufacturing difficulties.” These are important because they are likely to be lengthy in duration as manufacturers fix mechanical problems or attempt to obtain new raw materials. Most manufacturers are extremely reluctant to discuss a shortage or back order situation because it could dramatically impact their business. Manufacturers must consider financial, public relations, legal, and regulatory issues. Sometimes, the reasons behind a shortage do not become public for many months. With the Merck vaccine shortages, the company would not give out information about the shortage. Several months later, a newspaper report3 described the US Food and Drug Administration (FDA) regulatory issues the company was addressing. Companies may discontinue a product or change production on the basis of a business decision or reports of adverse drug events. Rapacuronium was discontinued because of reports of severe bronchospasm, including 5 deaths.4 This occurred at the same time that succinylcholine was in short supply. In addition, one company’s decision to discontinue a product creates an increased demand for the other manufacturers or for the alternative products also causing a shortage. Many years ago, shortages at the manufacturer level may not have been perceived by individual institutions. More product was in the pipeline from the manufacturer to the wholesaler to the institution. Now, the supply chain has extremely tight, “just-in-time” inventories, with most hospitals stocking less product than in the past and, thus, with less capacity to accommodate back orders. The unprecedented shortages of the past several years may be caused, in part, by industry consolidation, with fewer companies producing raw materials and manufacturing drugs. Although the true rate of industry consolidation is not known, many large companies have merged recently to form a single entity. Examples include Aventis,5 which was formed in 1999 by consolidating Hoescht and Rhone-Poulenc. GlaxoSmithKline6 was formed in 2000 and was once 3 separate companies: Glaxo, SmithKline, and Burroughs-Wellcome. As much as 80% of raw ingredients for pharmaceuticals come from foreign sources. Although many manufacturers may be listed for a drug, there may be only one
6 0 0
source of the raw materials.7 A good example of problems with raw materials is the dexamethasone injection shortage. The raw material used to produce dexamethasone injection was derived from an animal source. Because of concerns about “mad cow disease,” manufacturers of dexamethasone decided to switch to a plant source. Initially, this switch took time, both to obtain the new source and for the FDA to approve the new source.8 Wars and natural disasters affect drug supplies. The hurricane in 1997 damaged many manufacturing plants in the Caribbean, causing gentamicin and piperacillin/ tazobactam shortages. During Desert Storm, the Department of Defense had first priority for morphine, typhoid vaccine, antimalarial drugs, and albumin. Many hospitals experienced some backorders on albumin, and parenteral typhoid vaccine was not available. Sometimes a single company is the only manufacturer of the drug, and when they have difficulties, no drug is available. Examples include the measles-mumpsrubella (MMR) vaccine and protamine injection. A single manufacturer in the United States produces both of these essential agents. This is also a potential reason the United States is affected by shortages more than other countries. For example, the MMR vaccine is available from only one manufacturer in the United States, whereas in Europe there are several manufacturers of this vaccine.9 ROLE OF THE FDA
FDA regulatory actions can contribute to shortages. When the FDA finds regulatory violations, it can take several actions, including warning letters, injunctions, seizure of product, and consent decrees. A consent decree is more serious than a warning letter or citation. A company enters into a consent decree with the FDA only after the government has decided to take legal action against a company. A consent decree is an agreement between the company and the FDA, in which the company promises to fix any problems, but does not have to admit fault, and the FDA ceases further legal actions if the problems are addressed. This usually occurs when a company has received many warnings,
ANNALS OF EMERGENCY MEDICINE
40:6
DECEMBER 2002
DRUG SHORTAGES FOR EMERGENCY MEDICINE Tyler, Fox & Caravati
but has not corrected the problems. Often, manufacturing is interrupted while the company addresses these quality issues. The FDA is issuing consent decrees more frequently than several years ago because warning letters are not always effective.10 Product recalls, whether initiated by the manufacturer or the FDA, can also cause shortages. The FDA’s role in managing shortages is predominantly in working with those that are deemed “medically necessary.”7 The FDA evaluates the drug on the basis of the labeling and how the drug is used in practice. The FDA strives to balance the public safety issues with the clinical need for the drug, trying to avoid a shortage. They can exercise enforcement discretion, including protocol for limited distribution, expedited reviews of marketing data for new suppliers, or assess preclinical and clinical data for alternative suppliers. Medical necessity is determined by the FDA and not by industry. However, the FDA cannot require a company to make a drug if the company decides to stop making the drug. In these instances, the FDA would try to work with other manufacturers to produce the drug. The FDA has a Web site (http://www.fda.gov/cder/ drug/shortages) for “drug” shortages. This Web site reflects the information the manufacturers have provided to the FDA on drugs, but not biologics (such as vaccines). Information on biologic shortages is in the biologics section of the FDA Web page (http://www.fda. gov/cber), but there is not a specific site for shortage information. Shortages can also be reported through this Web site. M A N A G I N G D R U G S H O R TA G E S
Companies are under no obligation to notify anyone of a shortage. Practitioners usually do not receive advanced notice. If the sole manufacturer of a lifesaving drug were to permanently discontinue the product, the company is required by law to give the FDA 6 months’ notice,7 but there are no consequences for not providing this notice. Calls to a single customer service department may generate a different response to the same question about a shortage. Often, companies can only address the labeled uses of the drug and not the
DECEMBER 2002
40:6
ANNALS OF EMERGENCY MEDICINE
clinical issues of practitioners. Some companies may even refuse to answer questions about shortages, stating that this is “proprietary” information. When the pharmacy first discovers a drug supply problem, the Drug Information Service staff tries to ascertain the nature of the problem and how long it will last. Based on our experience, communication within the companies can be challenging, resulting in difficulties in obtaining and providing useful and timely shortage information. The American Society of Health-System Pharmacists has created a Web site, http://www.ashp.org/shortage, for providing this essential information. The information is developed for practitioners and emphasizes the clinical management of patients and alternatives available. Like disaster management, good planning, communication, and guidelines help to minimize any adverse impact these shortages may have on patient care and prevent frustration in an already stressful environment. Developing a process for dealing with shortages facilitates managing these situations. Emergency physicians should liaison with the pharmacy to get information on potential shortages as soon as possible. Emergency physicians should be represented on Pharmacy and Therapeutic (P&T) committees and provide input into strategies for managing shortages. When a shortage is likely to impact the ED, physicians should determine appropriate alternatives, reassess indications, and develop departmental guidelines so all patients are treated equally. Hospitals should not “stockpile” the drug. This makes it difficult to get the drug to the patients who may need it the most. If a shortage impacts how you care for your patients, document this in the patient’s chart. Physicians may also want to keep a file of these patients or telephone hospital risk management when shortages impact patient care. Keep staff and patients informed when patient care delays or compromised care occurs. At UUHSC, practitioners are notified and involved in the decisionmaking process as soon as the pharmacy knows of a potential shortage situation that will impact patient care. For many drugs, it is just a matter of notifying the practitioners that the drug is unavailable and outlining potential available alternatives. When tetanus toxoid became difficult to get, the P&T Committee
6 0 1
DRUG SHORTAGES FOR EMERGENCY MEDICINE Tyler, Fox & Caravati
quickly evaluated it and set criteria to preserve the supply we had for patients who had tetanus-prone injuries. It was another 6 months before the Centers for Disease Control and Prevention established similar guidelines. At a national level, make sure your professional organizations are aware of this problem and are actively lobbying for action. You may also let your congressional representatives know how this issue is affecting patient care at your hospital. All hospitals should develop an administrative process for identifying shortages, assessing the clinical impact, and communicating this information within the organization. P&T committees should be involved in developing institution-specific strategies for managing shortages, especially when a drug needs to be used according to limited criteria. Attempting to compound product or purchase it from compounding pharmacies as a temporizing measure can be hazardous. Last year, there were several deaths caused by use of a compounded, contaminated betamethasone product, used epidurally.11 Compounding sterile products using raw source materials cannot guarantee a safe product that is free of dangerous contaminants. These are usually not tested for pyrogens and contamination. Finding solutions to this issue will be difficult. It will involve analyzing the complex relationships between producers of raw materials, manufacturers, the FDA, wholesalers, those financing health care, health care practitioners, and patients. This issue is already beginning to attract the interest of those involved in the process, as well as government and professional organizations. It could take many years to fully address the causes of drug shortages. In summary, it is not your imagination: drug shortages impact how we care for patients, and the magnitude of the problem is increasing. The recent increase of shortages is not caused by a single factor. Manufacturing problems are increasing and are more likely to cause supply interruptions because many necessary products are produced by a single company. Likewise, the recent advent of tighter inventory supplies also means that supply problems are more likely to result in a shortage. The key
6 0 2
reasons behind the current increases in shortages are mainly a decrease in the total number of companies producing a drug (consolidation) and an increase in manufacturing problems and raw material shortages, which can also encompass regulatory problems. These problems are unlikely to resolve in the future, because the pharmaceutical industry continues to consolidate and manufacturing problems or raw material shortages are impossible to predict. Communication within your organization and with your patients is critical to manage these situations and minimize the impact on your practice. The Drug Information Service at University of Utah Hospitals and Clinics develops and provides information on drug shortages to the American Society of Health-System Pharmacists under a grant from Novation. This information is available to practitioners at http://www.ashp.org/shortage. Reprints not available from the authors. Address for correspondence: Linda S. Tyler, PharmD, Department of Pharmacy Services A-050, University of Utah Hospitals and Clinics, 50 North Medical Drive, Salt Lake City, UT 84132; E-mail [email protected].
REFERENCES 1. Diphtheria-tetanus-pertussis vaccine shortage—United States. JAMA. 1985;253:2223. 2. American Society of Health-System Pharmacists Council on Administrative Affairs. ASHP guidelines on managing drug product shortages. Am J Health-Syst Pharm. 2001; 58:1445-1450. 3. Merck vaccine plant in West Point, PA, cited for list of flaws. Knight Ridder/Tribune Business News. January 9, 2002:B3. 4. MedWatch, US Food and Drug Administration Web site. Raplon voluntary recall. Available at: http://www.fda.gov/medwatch/safety/2001/raplon_DDL.htm. Accessed July 26, 2002. 5. Aventis Web site. Available at: http://www.aventis.com/main/0,1003,EN-XX-2721944429—,00.html. Accessed July 26, 2002. 6. GlaxoSmithKline Web site. Available at: http://www.gsk.com/about/background.htm. Accessed July 26, 2002. 7. Jensen V, Kinzey LM, Goldberger MJ. FDA’s role in responding to drug shortages. Am J Health-Syst Pharm. 2002;59:1423-1425. 8. Fox ER, Tyler LS. Dexamethasone shortage [American Society of Health-System Pharmacists Web site]. Available at: http://www.ashp.org/shortage/dexamethasone.html. Accessed July 26, 2002. 9. Hutchinson TA, Shahan DR, eds. Drugdex System [database online]. Greenwood, CO: Micromedex; edition expires September 20, 2002. 10. FDA systems-based inspection approach to be expanded by early 2002. Pink Sheet. November 19, 2001;28. 11. Meningitis deaths linked to drug shortages [American Society of Health-System Pharmacists Web site]. Available at: http://www.ashp.org/public/news/breaking/ ShowArticle.cfm?id=2425. Accessed July 31, 2002.
ANNALS OF EMERGENCY MEDICINE
40:6
DECEMBER 2002
Linda S. Tyler, PharmD Erin R. Fox, PharmD E. Martin Caravati, MD, MPH
The Challenge of Drug Shortages for Emergency Medicine
From the Drug Information Service (Tyler, Fox) and the Division of Emergency Medicine (Caravati), University of Utah Health Sciences Center, Salt Lake City, UT.
[Ann Emerg Med. 2002;40:598-602.]
Copyright © 2002 by the American College of Emergency Physicians. 0196-0644/2002/$35.00 + 0 47/1/129127 doi:10.1067/mem.2002.129127
5 9 8
Health care providers in the United States have been facing unprecedented drug shortages. One of the first was a nationwide shortage of the diphtheria-tetanus-pertussis (DTP) vaccine in 1984 to 1985.1 Two of the 3 manufacturers stopped distribution of the product. Lots from the sole remaining supplier did not meet the manufacturing standards. There were few shortages for the next decade, but they have dramatically increased during the past few years. Hospitals and emergency departments have been especially impacted because many of them involve parenteral drugs. During the past year, EDs have had shortages of commonly used drugs (Table) such as naloxone, tetanus toxoid, prochlorperazine, fentanyl, and succinylcholine. The reasons for these shortages varied, but the end result is the same. Drug shortages are affecting patient care across the nation. This article will discuss some of the reasons for the recent increase in drug shortages and strategies for dealing with them. The process of how medications are ordered in the pharmacy, delivered, and ultimately arrive in the ED may be unfamiliar to most practitioners. The pharmacy experiences back orders daily, reflecting fluctuations in supply and demand between the manufacturers, wholesalers, and hospitals. The industry average back order was 7% in 2000 (Ronald J. Streck, Healthcare Distribution Management Association Survey Research Program, unpublished data, January 2002), but was as high as 23% in December 2001 (Ronald J. Streck, Healthcare
ANNALS OF EMERGENCY MEDICINE
40:6
DECEMBER 2002
DRUG SHORTAGES FOR EMERGENCY MEDICINE Tyler, Fox & Caravati
Distribution Management Association ad hoc survey, unpublished data, January 2002). Pharmacies are skilled at dealing with most of these temporary supply issues. Until recently, it was rare to have a shortage of a drug that would impact patient care. This article will focus only on those shortages that impact patient care or require the pharmacy to find alternative ways to provide the medication (ie, different packaging sizes), not on those reflected on these purchasing fluctuations. SCOPE OF THE PROBLEM
At the University of Utah Health Sciences Center (UUHSC), we have been tracking drug shortages for many years and developing strategies for managing these situations. In 2001, we began providing these management strategies nationally. Some shortages can be handled within the pharmacy by addressing supply problems that affect the way we access medications, but do not affect patients or how prescribers will order the drug. We notify our physicians when they must use alternative medications, when a supply issue affects the
way they order a medication, or when it will directly impact patients. In 1996, UUHSC had 3 shortages that reached the patient level, and in 1997, we had 8. In 1998, 1999, and 2000, we had 10, 16, and 18 drug shortages, respectively, all affecting patient care. In 2001, our hospital had 83 shortages; 61 of these affected patients and required physician notification. Nationally, we have tracked 157 shortages from January 2001 through June 2002. Of these, we consider 97 (62%) still active and unresolved. Not all shortages will affect all facilities. However, these supply problems are unlikely to be resolved soon. The recent increases in shortages, with many lasting more than a year (Table), make drug shortages a trend that is likely to continue. R E A S O N S F O R S H O R TA G E S
No single reason explains this phenomenon.2 Supply problems may occur because of manufacturing problems, business decisions, inventory practices, natural disasters, war, or regulatory problems. In our experience, the most common reason given by companies for
Table.
Selected drug shortages affecting EDs, 2001 to 2002. Drug
Reason
Naloxone
Major manufacturer discontinued production
Diphenhydramine injection
Major manufacturer discontinued production
Prochlorperazine injection
Raw material shortage
Tetanus-diphtheria vaccine
Major manufacturer discontinued production
Succinylcholine
Raw material shortage
Etomidate
Raw material shortage
Antivenin (crotalidae) Polyvalent Manufacturing difficulties and Crotalidae Polyvalent Immune Fab (ovine) (CroFab)
DECEMBER 2002
40:6
ANNALS OF EMERGENCY MEDICINE
Duration
Comments
January 2001 to July 2002 Alternative agent, nalmefene, is more difficult to use as a result of different dosing. Preservative-free product remains unavailable. May 2001 to present Benztropine, another agent useful for managing acute dystonic reactions, has been on shortage since October 2001 and is still unavailable. March 2001 to present Other antiemetics, including promethazine injection and metoclopramide injection, have also been in short supply during this shortage. July 2000 to June 2002 Tetanus toxoid and pediatric diphtheria-tetanusacellular pertussis vaccines are also affected. January to July 2001 During this shortage, rapacuronium, a likely alternative, was withdrawn from the market because of safety concerns. October 2001 to present Methohexital, a likely alternative agent, is also on shortage. January 2001 to present Both products have had availability problems since 2001.
5 9 9
DRUG SHORTAGES FOR EMERGENCY MEDICINE Tyler, Fox & Caravati
a shortage is “manufacturing difficulties.” These are important because they are likely to be lengthy in duration as manufacturers fix mechanical problems or attempt to obtain new raw materials. Most manufacturers are extremely reluctant to discuss a shortage or back order situation because it could dramatically impact their business. Manufacturers must consider financial, public relations, legal, and regulatory issues. Sometimes, the reasons behind a shortage do not become public for many months. With the Merck vaccine shortages, the company would not give out information about the shortage. Several months later, a newspaper report3 described the US Food and Drug Administration (FDA) regulatory issues the company was addressing. Companies may discontinue a product or change production on the basis of a business decision or reports of adverse drug events. Rapacuronium was discontinued because of reports of severe bronchospasm, including 5 deaths.4 This occurred at the same time that succinylcholine was in short supply. In addition, one company’s decision to discontinue a product creates an increased demand for the other manufacturers or for the alternative products also causing a shortage. Many years ago, shortages at the manufacturer level may not have been perceived by individual institutions. More product was in the pipeline from the manufacturer to the wholesaler to the institution. Now, the supply chain has extremely tight, “just-in-time” inventories, with most hospitals stocking less product than in the past and, thus, with less capacity to accommodate back orders. The unprecedented shortages of the past several years may be caused, in part, by industry consolidation, with fewer companies producing raw materials and manufacturing drugs. Although the true rate of industry consolidation is not known, many large companies have merged recently to form a single entity. Examples include Aventis,5 which was formed in 1999 by consolidating Hoescht and Rhone-Poulenc. GlaxoSmithKline6 was formed in 2000 and was once 3 separate companies: Glaxo, SmithKline, and Burroughs-Wellcome. As much as 80% of raw ingredients for pharmaceuticals come from foreign sources. Although many manufacturers may be listed for a drug, there may be only one
6 0 0
source of the raw materials.7 A good example of problems with raw materials is the dexamethasone injection shortage. The raw material used to produce dexamethasone injection was derived from an animal source. Because of concerns about “mad cow disease,” manufacturers of dexamethasone decided to switch to a plant source. Initially, this switch took time, both to obtain the new source and for the FDA to approve the new source.8 Wars and natural disasters affect drug supplies. The hurricane in 1997 damaged many manufacturing plants in the Caribbean, causing gentamicin and piperacillin/ tazobactam shortages. During Desert Storm, the Department of Defense had first priority for morphine, typhoid vaccine, antimalarial drugs, and albumin. Many hospitals experienced some backorders on albumin, and parenteral typhoid vaccine was not available. Sometimes a single company is the only manufacturer of the drug, and when they have difficulties, no drug is available. Examples include the measles-mumpsrubella (MMR) vaccine and protamine injection. A single manufacturer in the United States produces both of these essential agents. This is also a potential reason the United States is affected by shortages more than other countries. For example, the MMR vaccine is available from only one manufacturer in the United States, whereas in Europe there are several manufacturers of this vaccine.9 ROLE OF THE FDA
FDA regulatory actions can contribute to shortages. When the FDA finds regulatory violations, it can take several actions, including warning letters, injunctions, seizure of product, and consent decrees. A consent decree is more serious than a warning letter or citation. A company enters into a consent decree with the FDA only after the government has decided to take legal action against a company. A consent decree is an agreement between the company and the FDA, in which the company promises to fix any problems, but does not have to admit fault, and the FDA ceases further legal actions if the problems are addressed. This usually occurs when a company has received many warnings,
ANNALS OF EMERGENCY MEDICINE
40:6
DECEMBER 2002
DRUG SHORTAGES FOR EMERGENCY MEDICINE Tyler, Fox & Caravati
but has not corrected the problems. Often, manufacturing is interrupted while the company addresses these quality issues. The FDA is issuing consent decrees more frequently than several years ago because warning letters are not always effective.10 Product recalls, whether initiated by the manufacturer or the FDA, can also cause shortages. The FDA’s role in managing shortages is predominantly in working with those that are deemed “medically necessary.”7 The FDA evaluates the drug on the basis of the labeling and how the drug is used in practice. The FDA strives to balance the public safety issues with the clinical need for the drug, trying to avoid a shortage. They can exercise enforcement discretion, including protocol for limited distribution, expedited reviews of marketing data for new suppliers, or assess preclinical and clinical data for alternative suppliers. Medical necessity is determined by the FDA and not by industry. However, the FDA cannot require a company to make a drug if the company decides to stop making the drug. In these instances, the FDA would try to work with other manufacturers to produce the drug. The FDA has a Web site (http://www.fda.gov/cder/ drug/shortages) for “drug” shortages. This Web site reflects the information the manufacturers have provided to the FDA on drugs, but not biologics (such as vaccines). Information on biologic shortages is in the biologics section of the FDA Web page (http://www.fda. gov/cber), but there is not a specific site for shortage information. Shortages can also be reported through this Web site. M A N A G I N G D R U G S H O R TA G E S
Companies are under no obligation to notify anyone of a shortage. Practitioners usually do not receive advanced notice. If the sole manufacturer of a lifesaving drug were to permanently discontinue the product, the company is required by law to give the FDA 6 months’ notice,7 but there are no consequences for not providing this notice. Calls to a single customer service department may generate a different response to the same question about a shortage. Often, companies can only address the labeled uses of the drug and not the
DECEMBER 2002
40:6
ANNALS OF EMERGENCY MEDICINE
clinical issues of practitioners. Some companies may even refuse to answer questions about shortages, stating that this is “proprietary” information. When the pharmacy first discovers a drug supply problem, the Drug Information Service staff tries to ascertain the nature of the problem and how long it will last. Based on our experience, communication within the companies can be challenging, resulting in difficulties in obtaining and providing useful and timely shortage information. The American Society of Health-System Pharmacists has created a Web site, http://www.ashp.org/shortage, for providing this essential information. The information is developed for practitioners and emphasizes the clinical management of patients and alternatives available. Like disaster management, good planning, communication, and guidelines help to minimize any adverse impact these shortages may have on patient care and prevent frustration in an already stressful environment. Developing a process for dealing with shortages facilitates managing these situations. Emergency physicians should liaison with the pharmacy to get information on potential shortages as soon as possible. Emergency physicians should be represented on Pharmacy and Therapeutic (P&T) committees and provide input into strategies for managing shortages. When a shortage is likely to impact the ED, physicians should determine appropriate alternatives, reassess indications, and develop departmental guidelines so all patients are treated equally. Hospitals should not “stockpile” the drug. This makes it difficult to get the drug to the patients who may need it the most. If a shortage impacts how you care for your patients, document this in the patient’s chart. Physicians may also want to keep a file of these patients or telephone hospital risk management when shortages impact patient care. Keep staff and patients informed when patient care delays or compromised care occurs. At UUHSC, practitioners are notified and involved in the decisionmaking process as soon as the pharmacy knows of a potential shortage situation that will impact patient care. For many drugs, it is just a matter of notifying the practitioners that the drug is unavailable and outlining potential available alternatives. When tetanus toxoid became difficult to get, the P&T Committee
6 0 1
DRUG SHORTAGES FOR EMERGENCY MEDICINE Tyler, Fox & Caravati
quickly evaluated it and set criteria to preserve the supply we had for patients who had tetanus-prone injuries. It was another 6 months before the Centers for Disease Control and Prevention established similar guidelines. At a national level, make sure your professional organizations are aware of this problem and are actively lobbying for action. You may also let your congressional representatives know how this issue is affecting patient care at your hospital. All hospitals should develop an administrative process for identifying shortages, assessing the clinical impact, and communicating this information within the organization. P&T committees should be involved in developing institution-specific strategies for managing shortages, especially when a drug needs to be used according to limited criteria. Attempting to compound product or purchase it from compounding pharmacies as a temporizing measure can be hazardous. Last year, there were several deaths caused by use of a compounded, contaminated betamethasone product, used epidurally.11 Compounding sterile products using raw source materials cannot guarantee a safe product that is free of dangerous contaminants. These are usually not tested for pyrogens and contamination. Finding solutions to this issue will be difficult. It will involve analyzing the complex relationships between producers of raw materials, manufacturers, the FDA, wholesalers, those financing health care, health care practitioners, and patients. This issue is already beginning to attract the interest of those involved in the process, as well as government and professional organizations. It could take many years to fully address the causes of drug shortages. In summary, it is not your imagination: drug shortages impact how we care for patients, and the magnitude of the problem is increasing. The recent increase of shortages is not caused by a single factor. Manufacturing problems are increasing and are more likely to cause supply interruptions because many necessary products are produced by a single company. Likewise, the recent advent of tighter inventory supplies also means that supply problems are more likely to result in a shortage. The key
6 0 2
reasons behind the current increases in shortages are mainly a decrease in the total number of companies producing a drug (consolidation) and an increase in manufacturing problems and raw material shortages, which can also encompass regulatory problems. These problems are unlikely to resolve in the future, because the pharmaceutical industry continues to consolidate and manufacturing problems or raw material shortages are impossible to predict. Communication within your organization and with your patients is critical to manage these situations and minimize the impact on your practice. The Drug Information Service at University of Utah Hospitals and Clinics develops and provides information on drug shortages to the American Society of Health-System Pharmacists under a grant from Novation. This information is available to practitioners at http://www.ashp.org/shortage. Reprints not available from the authors. Address for correspondence: Linda S. Tyler, PharmD, Department of Pharmacy Services A-050, University of Utah Hospitals and Clinics, 50 North Medical Drive, Salt Lake City, UT 84132; E-mail [email protected].
REFERENCES 1. Diphtheria-tetanus-pertussis vaccine shortage—United States. JAMA. 1985;253:2223. 2. American Society of Health-System Pharmacists Council on Administrative Affairs. ASHP guidelines on managing drug product shortages. Am J Health-Syst Pharm. 2001; 58:1445-1450. 3. Merck vaccine plant in West Point, PA, cited for list of flaws. Knight Ridder/Tribune Business News. January 9, 2002:B3. 4. MedWatch, US Food and Drug Administration Web site. Raplon voluntary recall. Available at: http://www.fda.gov/medwatch/safety/2001/raplon_DDL.htm. Accessed July 26, 2002. 5. Aventis Web site. Available at: http://www.aventis.com/main/0,1003,EN-XX-2721944429—,00.html. Accessed July 26, 2002. 6. GlaxoSmithKline Web site. Available at: http://www.gsk.com/about/background.htm. Accessed July 26, 2002. 7. Jensen V, Kinzey LM, Goldberger MJ. FDA’s role in responding to drug shortages. Am J Health-Syst Pharm. 2002;59:1423-1425. 8. Fox ER, Tyler LS. Dexamethasone shortage [American Society of Health-System Pharmacists Web site]. Available at: http://www.ashp.org/shortage/dexamethasone.html. Accessed July 26, 2002. 9. Hutchinson TA, Shahan DR, eds. Drugdex System [database online]. Greenwood, CO: Micromedex; edition expires September 20, 2002. 10. FDA systems-based inspection approach to be expanded by early 2002. Pink Sheet. November 19, 2001;28. 11. Meningitis deaths linked to drug shortages [American Society of Health-System Pharmacists Web site]. Available at: http://www.ashp.org/public/news/breaking/ ShowArticle.cfm?id=2425. Accessed July 31, 2002.
ANNALS OF EMERGENCY MEDICINE
40:6
DECEMBER 2002