The shortage of medications and other biomedical products has significantly affected patient care over the last 2 decades.1 Medication shortage can pose only minor disruption in health care when the medication has limited indications and there are suitable therapeutic alternatives available, but it may have a significant impact on public health for medications such as vaccines or when there are no therapeutic alternatives. We are currently facing a national shortage of several medications used perioperatively. Table 1 lists medication shortages posted on the American Society of Health-System Pharmacists (ASHP) website during the year 2010 that can directly affect the practice of anesthesiologists. The aim of this review is to elucidate the current anesthesia drug shortages and the implications that they have on patient care and safety during surgery and recovery. Because the effects of drug shortages on patient care and safety were never tested in controlled studies, we gathered information about facts that are known based on lower levels of evidence such as practices guidelines, case reports, and case series.
The shortage of biomedical products is not a new phenomenon. Vaccines have frequently been in short supply, and records of vaccine shortages date as far back as 1957 during the Influenza Pandemic.3 Although medication shortages were relatively infrequent 15 to 20 years ago, only 3 medications were in short supply in 1996; shortages surged after the year 2000, with 119 medications on the short supply list.4 The number of shortages have remained at this level since 2000, with 140 medications in short supply as of December 2010.2 In addition to the greater number of medication shortages, the duration of unavailability has lasted longer in recent years.5 The median duration of shortage by different classes of anesthesia medications that were listed on the ASHP website during 2010 is presented in Figure 1. More alarming is the fact that alternative hypnotic drugs (propofol, thiopental, and etomidate) and muscle relaxants (succinylcholine, rocuronium, vecuronium, and atracurium) were concurrently on the shortage list for more than a year.
Medication shortages are defined by the majority of health care organizations as the lack of available supply that results in a change in the way the medication is prepared by the pharmacy, or as the need to change patient management, requiring prescribers to select a therapeutic alternative.4 Anesthesiologists are acutely aware of drug shortages because they frequently prepare many of the medications they administer. Although the practice of preparing our own medications might change in the future to improve sterility and prevent drug error, it is still probably the most common practice in the United States and around the world. Other specialties may not be immediately affected by medication shortages, because hospital pharmacies can initially deal with a shortage by preparing a medication using a different concentration that is not immediately affected by the shortage.
Shortages of medications have been reported for all routes of drug administration; however, sterile injectable medications are the greatest number of all shortages.6 The proportion of shortages of injectable medications compared with noninjectable medications has increased from 23% in 2005 to 60% in 2010 (Fig. 2). The manufacturing complexity of sterile, injectable drugs makes them vulnerable to decreased supply because a limited number of companies have the manufacturing capability to prepare these products, especially when alternative generic medication is available and the financial incentive has been reduced. In addition, production schedules for medications frequently follow “just-in-time” practices, such that when one supplier faces a production shortfall, the others often cannot compensate for the deficit. As anesthesiologists, most of the medications we use daily are administered IV, and it is the main reason our practice can be affected profoundly by these shortages.
It is often difficult to identify a single cause responsible for a medication shortage because multiple steps along the production pathway may be responsible. Raw material shortages can be particularly problematic because most of the products come from sources outside the United States, thus limiting the efficacy of manufacturing control practices that can assure the production of raw materials is enough to meet the demand.7 For example, Hospira (Lake Forest, IL) reported the lack of raw materials as the cause of the shortage of ephedrine.2 Manufacturing issues such as equipment maintenance, loss of capable workers, and compliance factors may also interrupt manufacturing and be responsible for medication shortages. The shortage of thiopental and some formulations of fentanyl, vecuronium, and rocuronium has been reported to be the result of manufacturing-related issues.2
Voluntary recalls, another important factor that can initiate an abrupt decrease in medication supply, is especially costly if a single provider has a large share of the market. Recalls are usually performed when there is a suspicion about a safety issue regarding the formulation. The presence of particulate matter and labeling errors are common reasons for recall of sterile injectable drugs. Other causes of drug recall are presented in Table 2. The shortages of propofol, pancuronium, and ketorolac were all initiated by a manufacturer recall.
Economic and strategic business factors can lead to manufacturing discontinuation of a drug by a pharmaceutical company, resulting in a medication shortage. Business decisions are often based on the size of the profit generated by a drug, and include factors such as patent expiration, availability of similar competitor products, future clinical demand, and the company position regarding the market share of the respective drug. When drug manufacturing is discontinued suddenly by a company, it may take several months for another manufacturer to fill this gap in production (or manufacturing). Manufacturer discontinuation is listed as a reason for the shortage of propofol, naloxone, ondansetron, metoclopramide, and phenylephrine.2
Increases in medication demand can also create a medication shortage even when manufacturing and supply factors are not affected. An increase in demand might be created by a change of clinical practice, or it might be artificially generated by a decrease in the supply of a drug alternative. The increased demand for opioids has generated shortages within the last year of several opioids, including morphine and hydromorphone (Table 1). The higher demand is attributed to a recent emphasis in clinical practice, supported by the development of guidelines, to achieve optimal acute and chronic pain control.8–10 The hypnotics etomidate and ketamine were also on the shortage list because of increased demand, which was created by the decreased supply of propofol and thiopental. Hospira recalled propofol in mid-October 2009, which initiated the propofol shortage. The shortage was aggravated by the fact that TEVA Pharmaceuticals USA (North Wales, PA) discontinued production of propofol in May 2010. The shortage of ketamine began in July 2010, and ketamine manufacturers cited the increased demand as the sole reason for the shortage. The shortage of etomidate began in November 2010 with manufacturers also stating the increased demand as the only reason for the shortage.a
Current business practices on inventory management can also aggravate medication shortages. “Short” inventories are the common practice not only at pharmaceutical companies but also at hospital pharmacies.11 Manufacturers and distributors average a 30-day supply, whereas pharmacies only average a 15-day inventory. Short inventory reduces losses associated with expiration on the validation period for the medication, and it also reduces costs associated with storage. Although this practice makes financial sense for companies, a minor decrease in production caused by factors previously discussed can critically decrease the supply of a drug. This decrease may otherwise be avoided if larger inventories were available.
The consequences of a drug shortage on patient care can be devastating.12 This is especially true if a drug alternative is not available. Short supplies of medications have been affecting pediatric patients with cancer for >10 years. These patients may experience treatment delays, less-effective therapeutic options, or therapies with a higher incidence of side effects. Patients undergoing elective procedures can have their procedures canceled, or they can be performed with less than optimal therapeutic alternatives. Emergency procedures may need to be relocated to a different hospital, producing delays in treatment. Drug shortages can therefore increase risks to patients, and can also have a negative economic impact on institutions.
The shortage of propofol can have an enormous impact on patient care because of the widespread use of this medication.6 In the operating room, in addition to its use as an anesthetic induction drug and as a component of many total IV anesthetic techniques, propofol is used frequently as an adjunct to general anesthesia. When added to a sedation regimen, propofol improved patient satisfaction and decreased postprocedural nausea and vomiting.13 Outpatient surgery is nearly 70% of all procedures in the United States,14 and propofol is used most frequently because of its favorable effect of reducing postoperative nausea and vomiting.15 Beyond the use in the operating room, propofol is the most frequently used sedative in intensive care units in the United States.16 Propofol has a better profile for sedation than alternative medications in several clinical settings.17–20 It causes fewer adverse effects compared with alternative drugs such as methohexital (also not available).21 Although it is conceivable that the current shortage of propofol can affect patient care and safety, data confirming this are still lacking.
Medication shortages may result in an environment that predisposes to an increase in the likelihood of medication errors, thus impairing patient safety. Medication substitutes with higher concentration or potency than the ones routinely used can lead to an overdose when health care providers administering those medications are not informed about the drug concentration changes. Data collected through medication error reporting programs from January 2003 through August 2004 revealed 832 cases of medication errors, which identified medication shortages as the cause of the error.22 The number of medication errors by type is shown in Table 3. A specific case example includes a case of fentanyl overdose, followed by respiratory arrest, caused by a shortage of 2-mL (50 μg/mL) formulation of the drug. The nurse responsible for the patient retrieved two 5-mL ampoules (total of 10 mL, or 500 μg) of fentanyl from a drug dispensing machine. The entire 10-mL dose (representing a 5-fold increase over the prescribed dose) was administered to the patient. A root-cause analysis revealed that the total contents of the vial (i.e., total μg/total mL) were not clearly stated on the fentanyl label, and the purchase of the larger 5-mL ampoule size (total dose 250 μg) instead of the standard 2 mL (total dose 100 μg) created confusion for the nurse. Another patient had a respiratory arrest requiring subsequent intensive care unit admission because sufentanil was used in substitution for fentanyl during a fentanyl shortage. Recently, a nurse anesthetist was responsible for an overdose of ketamine in an endoscopy suite. The patient was supposed to receive 2 mL of ketamine 10 mg/mL (20 mg total), but because of a shortage of this formulation, the patient received 2 mL of a 50 mg/mL concentration (100 mg total dose).23
Sterile injectable drugs are particularly vulnerable to errors when health care providers do not adhere to labeling guidelines that recommend avoidance of multiple entries into a single-use vial. This can result in contamination of the vials, and it can transmit infectious diseases such as hepatitis and human immunodeficiency virus. In an endoscopy suite in Nevada, 50-mL vials of propofol were used for multiple patients, contradicting the label guideline, and resulting in the transmission of hepatitis C to some patients, whereas another 40,000 patients were exposed to human immunodeficiency virus, hepatitis B, and hepatitis C.24 The shortage of the most frequently used 20-mL vials of propofol may require providers to use larger 50-mL vials, creating a more favorable environment for events such as the one in Nevada to occur. Anesthesia providers should be specifically educated to avoid such practices.
During periods of decreased supply of a medication, hospital pharmacies implement policies to use the drug in the most efficient way to avoid wasteful usage.11 The impact of these policies may result in limited availability of a drug, or change in the location where a medication is available. These circumstances are particularly dangerous for drugs used in emergency events, where delay in administration might translate into an adverse outcome to a patient.
Naloxone, also present on the shortage list,2 is critical in managing adverse respiratory events during the perioperative period,25 during procedures outside the operating room,26 and in obstetric patients.27 Practice guidelines on patient sedation28 and the use of neuraxial opioids29 require that opioid antagonists such as naloxone be readily available to patients in case of respiratory depression. The standard concentration of naloxone is 0.4 mg/mL; however, an additional alternative concentration that has not been affected by drug shortage is 1 mg/mL. This change in concentration could also lead to an overdose, with life-threatening side effects such as cardiac arrhythmias and pulmonary edema30 if health care providers are not well informed about current available formulations.
The shortage of succinylcholine2 can affect patient care, because this medication is used for emergency airway management and there are no alternative nondepolarizing muscle relaxants with similar onset and duration properties (since rapacuronium was taken off the market).31 Succinylcholine is the neuromuscular blocking drug most frequently used by emergency room physicians when dealing with airway management issues.32 Lack of availability of succinylcholine can result in the use of nondepolarizing drugs that may lead to inferior intubation conditions33 and a longer duration of paralysis, representing a potential increased risk to patients with unanticipated difficult airways who are also difficult to mask ventilate.34 More worrisome is the fact that rocuronium, the nondepolarizing drug most frequently used as an alternative to succinylcholine, is also on the shortage list.
Recently, neostigmine was cited in the shortage list.b A practice survey in the United States and Europe revealed that routine reversal of muscle relaxants is practiced by a minority of clinicians.35 Data suggest that this practice can lead to residual neuromuscular paralysis after surgery.36 The unavailability of neostigmine may therefore further decrease the frequency of muscle relaxant antagonism at the end of surgical procedures, exposing more patients to risk. Edrophonium, an alternative to neostigmine, is also currently on the shortage list because of an increased demand created by the neostigmine shortage.b In cases in which anesthesia providers need to use edrophonium as a substitute to neostigmine, it is important to note the different pharmacokinetic properties of edrophonium, such as earlier onset of action.37 Edrophonium is also a less reliable and effective reversal drug than neostigmine when antagonism of neuromuscular block is attempted at deeper levels of block.38
Medication shortages can create a very stressful period of time for pharmacists and health care institutions. Proactive measures must be taken to identify, resolve, and possibly prevent a medication shortage before patient care and safety are jeopardized. Prescribers often blame the pharmacists for the shortages, but institutions have to prepare themselves with the help of all health care providers to deal effectively with a medication shortage. Because of the pivotal role of pharmacists in dealing with medication shortages, the ASHP has developed a guideline to help institutions deal more effectively with medication shortages (Fig. 3). This guideline involves 3 phases: identification and assessment, preparation, and contingency.39 Assessment is the detailed examination of the shortage, and the impact it will have on the care of patients. Preparation is what can be done to minimize the impact of a shortage on clinical care, such as the identification of alternative therapies. The contingency phase occurs when the drug has no alternative product available, or when the available product comes from a nontraditional source. Risk management, liability issues, and budget issues have to be anticipated during this phase. These guidelines also reinforce the multidisciplinary nature of the teams created to manage shortage situations.
Health care institutions should have their own internal plan to deal with medication shortages.39 This involves the selection of a committee that can help to implement therapeutic alternative medications and prioritize drug use according to the urgency of the medical conditions. These tasks often involve a multidisciplinary team consisting of nurses, pharmacists, physicians, and administrative staff. The committee must assure that the proper dissemination of information to heath care providers about the drug shortage occurs in the organization. Identification of the impact on patient care relative to each drug needs to occur, and frequently involves evaluation of inventories and input from different medical specialties. Because anesthesiologists are frequently affected by drug shortages, it would be advisable for anesthesia departments to have a representative on the hospital committee responsible for managing the respective drug shortage.
The Food and Drug administration (FDA), through the Center for Drug Evaluation and Research (CDER), has a program to address drug shortages. The program was implemented to address drug shortages with specific impact on the general public. The drug shortage program receives information about specific drugs from health care providers, health care organizations, and manufacturers. There is, however, no requirement, enforced by law, to inform the FDA about a potential shortage. Reports of drug shortages can be communicated using the CDER's drug shortage website (www.fda.gov/cder/drugshortages/default.htm). If the shortage is not transient, the CDER communicates with experts in the medical field to determine the impact of the lack of the respective drug on patient care. Depending on the cause of a drug shortage, the FDA can provide substantial assistance. When drug recall is the main cause of the shortage and the decreased supply of the product can significantly affect patients, the FDA reviews these actions in an attempt to avoid shortage of medically necessary products.40 When lack of raw materials is the main cause for medication shortage, manufacturers can obtain the FDA's assistance to obtain the raw materials needed. The FDA has no control over companies that decide to discontinue a drug because of better business practices, even if it generates a public health issue.
In exceptional occasions of a drug shortage, the FDA can allow importation of “unapproved” alternative medications. This has occurred with the current propofol shortage. The FDA allowed the temporary use of an unapproved propofol formulation, Propoven 1% (Fresenius Kabi, Ltd., Cheshire, UK),6 after inspection of its manufacturing facilities and testing to evaluate the safety of the product. However, several concerns have been raised over the years about the quality of medication manufactured overseas.41 Allowing potentially lower-quality products to enter the United States because of more lenient guidelines than the ones normally used by the FDA is another potential safety issue generated by a drug shortage.
It is the authors' opinion that as anesthesiologists we have an obligation to report shortages, especially the ones that cause deviations from the best practices of patient care. Although we might be able to adjust our practice to alternative medications, we should not wait for an adverse event before we engage as part of the solution to this national problem. Drug errors leading to adverse events to patients are reported <5% of the time,42 making it difficult to link drug shortages to patient adverse events.
Because anesthesia-related drug shortages seem to be increasing in number and duration, the shortage can become a public health issue in the near future. Government regulation can be a potential approach to deal with the problem. Noah43 examined this issue and concluded that in addition to requiring an increase in drug inventories, policymakers have to encourage the production of drugs by private manufacturers. More flexible regulations regarding manufacturers' facilities, the creation of mechanisms to protect companies against tort liability, and allowing more profits to generic manufacturers can be effective ways to decrease drug shortages. New legislation has been introduced in the Senate to address drug shortages.c This legislation attempts to implement stricter rules on the obligation of manufacturers to communicate drug production derangements to the FDA, which can formulate strategies to avoid a drug shortage.
In conclusion, several anesthesia medications are currently on a national shortage list, which can affect patient care and safety. Anesthesiologists should be actively involved in the steps necessary to provide a fast resolution and that can minimize adverse effects to patient care. These include (1) prompt notification to the FDA or ASHP of a lack of medication supply (it can speed the resolution of a drug shortage in the majority of cases); (2) active participation on the rapid implementation of available institutional guidelines to deal with drug shortage, such as the one from ASHP; and (3) organizations representing anesthesiology should also seek intense collaborative work with the FDA to prevent future drug shortages that can affect the safety and optimal care of our patients.
Name: Gildasio S. De Oliveira, Jr., MD.
Contribution: Study design, conduct of the study, manuscript preparation.
Name: Luke S. Theilken, MD.
Contribution: Conduct of the study, manuscript preparation.
Name: Robert J. McCarthy, PharmD.
Contribution: Manuscript preparation.
a American Society of Health-System Pharmacists. Drug Shortages Resource Center. Available at: http://www.ashp.org/shortages. Accessed February 11, 2011.
b American Society of Health-System Pharmacists. Drug Shortages Resource Center. Available at: http://www.ashp.org/shortages. Accessed March 24, 2011.
c American Society of Anesthesiologists. Washington Alerts. Available at: www.asahq.org/For-Members/Advocacy/Washington-Alerts. Accessed February 11, 2011.
1. Steinbrook R. Drug shortages and public health. N Engl J Med 2009;361:1525–7
3. Hinman AR, Orenstein WA, Santoli JM, Rodewald LE, Cochi SL. Vaccine shortages: history, impact, and prospects for the future. Annu Rev Public Health 2006;27:235–59
4. Fox ER, Tyler LS. Managing drug shortages: seven years' experience at one health system. Am J Health Syst Pharm 2003;60:245–53
5. Fox ER, Tyler LS. Measuring the impact of drug shortages. Am J Health Syst Pharm 2004;61:2009
6. Jensen V, Rappaport BA. The reality of drug shortages: the case of the injectable agent propofol. N Engl J Med 2010;363:806–7
7. [No authors listed]. Provisional observations on drug product shortages: effects, causes, and potential solutions. Am J Health Syst Pharm 2002;59:2173–82
8. American Society of Anesthesiologists Task Force on Chronic Pain Management; American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology 2010;112:810–33
9. Dulko D, Hertz E, Julien J, Beck S, Mooney K. Implementation of cancer pain guidelines by acute care nurse practitioners using an audit and feedback strategy. J Am Acad Nurse Pract 2010;22:45–55
10. Cormie PJ, Nairn M, Welsh J; Guideline Development Group. Control of pain in adults with cancer: summary of SIGN guidelines. BMJ 2008;337:a2154
11. Fox ER, Tyler LS. Managing drug shortages: seven years' experience at one health system. Am J Health Syst Pharm 2003;60:245–53
12. Traynor K. Shortages frustrate pediatric oncologists. Am J Health Syst Pharm 2006;63:797–8
13. Joo HS, Perks WJ, Kataoka MT, Errett L, Pace K, Honey RJ. A comparison of patient-controlled sedation using either remifentanil or remifentanil-propofol for shock wave lithotripsy. Anesth Analg 2001;93:1227–32
14. Glass PS. Preface: ambulatory and office-based anesthesia. Anesthesiol Clin 2010;28:xv–xviii
15. Le TP, Gan TJ. Update on the management of postoperative nausea and vomiting and postdischarge nausea and vomiting in ambulatory surgery. Anesthesiol Clin 2010;28:225–49
16. Wunsch H, Kahn JM, Kramer AA, Rubenfeld GD. Use of intravenous infusion sedation among mechanically ventilated patients in the United States. Crit Care Med 2009;37:3031–9
17. Pershad J, Wan J, Anghelescu DL. Comparison of propofol with pentobarbital/midazolam/fentanyl sedation for magnetic resonance imaging of the brain in children. Pediatrics 2007;120:e629–36
18. Miner JR, Danahy M, Moch A, Biros M. Randomized clinical trial of etomidate versus propofol for procedural sedation in the emergency department. Ann Emerg Med 2007;49:15–22
19. Leitch JA, Anderson K, Gambhir S, Millar K, Robb ND, McHugh S, Kenny GN. A partially blinded randomised controlled trial of patient-maintained propofol sedation and operator controlled midazolam sedation in third molar extractions. Anaesthesia 2004;59:853–60
20. Vargo JJ, Zuccaro G Jr, Dumot JA, Shermock KM, Morrow JB, Conwell DL, Trolli PA, Maurer WG. Gastroenterologist-administered propofol versus meperidine and midazolam for advanced upper endoscopy: a prospective, randomized trial. Gastroenterology 2002;123:8–16
21. Lee JS, Gonzalez ML, Chuang SK, Perrott DH. Comparison of methohexital and propofol use in ambulatory procedures in oral and maxillofacial surgery. J Oral Maxillofac Surg 2008;66:1996–2003
24. Centers for Disease Control and Prevention (CDC). Acute hepatitis C virus infections attributed to unsafe injection practices at an endoscopy clinic: Nevada, 2007. MMWR Morb Mortal Wkly Rep 2008;57:513–7
25. Eckstrand JA, Habib AS, Williamson A, Horvath MM, Gattis KG, Cozart H, Ferranti J. Computerized surveillance of opioid-related adverse drug events in perioperative care: a cross-sectional study. Patient Saf Surg 2009;3:18
26. Andrus CH, Dean PA, Ponsky JL. Evaluation of safe, effective intravenous sedation for utilization in endoscopic procedures. Surg Endosc 1990;4:179–83
27. de Morais BS, Silva YP, Cruvinel MG, de Castro CH, Hermeto MV. Accidental subarachnoid administration of 4 mg of morphine: case report. Rev Bras Anestesiol 2008;58:160
28. American Society of Anesthesiologists Task Force on Neuraxial Opioids. Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration. Anesthesiology 2009;110:218–30
29. American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96:1004–17
30. van Dorp EL, Yassen A, Dahan A. Naloxone treatment in opioid addiction: the risks and benefits. Expert Opin Drug Saf 2007;6:125–32
31. Jooste E, Klafter F, Hirshman CA, Emala CW. A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism. Anesthesiology 2003;98:906–11
32. Strayer RJ. Rocuronium vs. succinylcholine revisited. J Emerg Med 2010;39:345–6
33. Perry JJ, Lee JS, Sillberg VA, Wells GA. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev 2008;2:CD002788
34. Mallon WK, Keim SM, Shoenberger JM, Walls RM. Rocuronium vs. succinylcholine in the emergency department: a critical appraisal. J Emerg Med 2009;37:183–8
35. Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ. A survey of current management of neuromuscular block in the United States and Europe. Anesth Analg 2010;111:110–9
36. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003;98:1042–8
37. Devcic A, Munshi CA, Gandhi SK, Kampine JP. Antagonism of mivacurium neuromuscular block: neostigmine versus edrophonium. Anesth Analg 1995;81:1005–9
38. Kopman AF. The current status of edrophonium: have we come “full circle”? Can J Anaesth 1991;38:145–50
39. ASHP Expert Panel on Drug Product Shortages, Fox ER, Birt A, James KB, Kokko H, Salverson S, Soflin DL. ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems. Am J Health Syst Pharm 2009;66:1399–406
40. Jensen V, Kimzey LM, Goldberger MJ. FDA's role in responding to drug shortages. Am J Health Syst Pharm 2002;59:1423–5
41. Okie S. Multinational medicines: ensuring drug quality in an era of global manufacturing. N Engl J Med 2009;361:737–40
42. Cullen DJ, Bates DW, Small SD, Cooper JB, Nemeskal AR, Leape LL. The incident reporting system does not detect adverse drug events: a problem for quality improvement. Jt Comm J Qual Improv 1995;21:541–8
43. Noah L. Triage in the nation's medicine cabinet: the puzzling scarcity of vaccines and other drugs. S C Law Rev 2002;54:371–403