Erin R. Fox

ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems

Drug product shortages can adversely affect drug therapy, compromise or delay medical procedures, and result in medication errors.[1][1],[2][2] Health care professionals are increasingly concerned about the clinical effect that shortages have on patients and the tremendous resources required to

Drug Shortages: A Complex Health Care Crisis

National tracking of drug shortages began in 2001. However, a significant increase in the number of shortages began in late 2009, with numbers reaching what many have termed crisis level. The typical drug in short supply is a generic product administered by injection. Common classes of drugs affected by shortages include anesthesia medications, antibiotics, pain medications, nutrition and electrolyte products, and chemotherapy agents. The economic and clinical effects of drug shortages are significant. The financial effect of drug shortages is estimated to be hundreds of millions of dollars annually for health systems across the United States. Clinically, patients have been harmed by the lack of drugs or inferior alternatives, resulting in more than 15 documented deaths. Drug shortages occur for a variety of reasons. Generic injectable drugs are particularly susceptible to drug shortages because there are few manufacturers of these products and all manufacturers are running at full capacity. In addition, some manufacturers have had production problems, resulting in poor quality product. Although many suppliers are working to upgrade facilities and add additional manufacturing lines, these activities take time. A number of stakeholder organizations have been involved in meetings to further determine the causes and effects of drug shortages. A new law was enacted in July 2012 that granted the Food and Drug Administration additional tools to address the drug shortage crisis. The future of drug shortages is unknown, but there are hopeful indications that quality improvements and additional capacity may decrease the number of drug shortages in the years to come.

Antibacterial Drug Shortages From 2001 to 2013: Implications for Clinical Practice

BACKGROUND Previous studies have described drug shortages; however, there has been no comprehensive evaluation focusing on US antibacterial shortages. METHODS Drug shortage data from the University of Utah Drug Information Service database were analyzed, with a focus on antibacterial agents from 2001 to 2013. We used descriptive statistics to describe trends in drug shortages, analyze drug classes commonly affected, and investigate whether drugs experienced multiple periods of shortages. RESULTS One hundred forty-eight antibacterial drugs were on shortage over the 13-year study period, with 26 drugs still active on shortage as of December 2013. The median number of new shortages per year was 10 (interquartile range [IQR], 7). The number of drugs on shortage increased at a rate of 0.35 additional drugs every month (95% confidence interval, .22-.49) from July 2007 to December 2013 (P < .001). The median shortage duration was 188 days (IQR, 366.5). Twenty-two percent of drugs experienced multiple shortage periods. CONCLUSIONS There were a substantial number of drug shortages from 2001 to 2013, with a dramatic rise in shortages since 2007. Shortages of agents used to treat multidrug-resistant infections are of concern due to continued transmission and limited treatment options.

Recent trends in drug shortages: an update from the 2003 report

In 2003, we reported our seven-years experience managing drug shortages.[1][1] This report explores the recent trends we have identified while managing drug shortages at our own health system and while providing shortage content for Novation and the ASHP Drug Shortage Resource Center, with emphasis

High Generic Drug Prices and Market Competition: A Retrospective Cohort Study

Use of generic drugs as a percentage of total dispensed prescriptions has increased in recent years, from 57% in 2004 to 86% in 2013 (1). The U.S. Government Accountability Office estimates that this increased use has saved the U.S. health care system

Longitudinal Trends in U.S. Drug Shortages for Medications Used in Emergency Departments (2001-2014).

1 trillion over the past decade, with

Potential Association between Drug Shortages and High-Cost Medications

157 billion in savings from 2010 alone (2). Patients also realize these savings in the form of lower copayments, leading to increased medication adherence and improved health outcomes (35). In recent years, rising prices have been reported for several generic medications (6). One review found that the price of digoxin increased by 637% in a single year (7). Concern over rising generic drug prices has garnered much attention from policymakers, physicians, and patients (8, 9). Many factors have been linked to these price increases, including shortages in the manufacturing supply chain (leading to reduced production) (10) and a reduction in the number of manufacturers of a drug (resulting in insufficient competition). In the most problematic cases, companies like Turing and Valeant have purchased older drugs, such as pyrimethamine (Daraprim [Turing]) and isoproterenol (Isuprel [Valeant]), that are produced by a single manufacturer and have raised prices by thousands of percent. Although increases in generic drug prices are thought to be the result of insufficient competition, no study has examined the relationship between price increases and market competition levels. Understanding how prices relate to market changes may help identify drugs at risk for price changes so that interventions may occur before patient care is affected. Therefore, we sought to examine the association between market competition levels and changes in generic drug prices for a large cohort of generic drugs in the United States. Methods The study was approved by the Institutional Review Board at the University of Florida. Study Cohort and Data Sources We used MarketScan Commercial Claims and Encounters data from January 2008 to June 2013. MarketScan, an employer- and health-plansourced drug database, collects information on approximately 30 million patients annually from 130 commercial health plans. The outpatient pharmacy files contain patient-level data for pharmacy services, including price information on patient copayments and third-party payments for each dispensed prescription. In addition, they provide information on drug fill dates, quantity of drug supplied, and National Drug Code (NDC) numbers. The NDC numbers were used to link the outpatient pharmacy data files to Red Book (11), a drug information database of more than 200000 prescription and over-the-counter health care items. Red Book provides information on active ingredients, dosage forms, drug strength, manufacturer name, and whether the dispensed NDC was a generic or brand-name medication. We considered distinct combinations of active ingredients, dosage forms, and drug strength as individual study drugs. For example, diazepam 2-mg tablets, 5-mg tablets, and rectal gel were considered as individual study drugs. Only drugs classified by Red Book as either single-source or multisource generic for the entire study period were included in the study. Outcome We summed the patient out-of-pocket costs (copayments, coinsurance, and deductibles) and the amount paid by the third-party payer to estimate the overall price of a dispensed prescription. We combined these costs to account for any cost shifting from third-party payers to patients over time. To ensure valid comparisons, this overall price was standardized by the metric quantity of the drug dispensed. Depending on the dosage form, this metric quantity might be the number of tablets, grams of ointment, or milliliters of solution dispensed. The 5.5 years of data were divided into 11 periods of 6 months each, and the first 6-month period (first half of 2008) was designated as the baseline period. Average prices were calculated for each drug in the 11 periods. Prices calculated during the baseline period were adjusted as a covariate, and prices estimated in the 10 subsequent study periods were modeled as the dependent variable. In other words, the outcome of the study was the change in drug price from its baseline value (measured in the first half of 2008). Independent Variables We used the HerfindahlHirschman Index (HHI) to estimate market competition levels for each drug. The HHI is the U.S. Department of Justices preferred method of quantifying market competition (12) and is calculated by summing the squares of the market shares of individual firms (generic manufacturers) (13). Index values range from approaching 0 (a large number of small generic drug manufacturers) to 10000 (a monopoly, or 1 generic drug manufacturer). Because the HHI is calculated by squaring the market share of individual generic drug manufacturers, it gives disproportionately higher weights to a larger market share. For example, a generic drug that is produced by 4 manufacturers with market shares of 10%, 20%, 30%, and 40% has an HHI value of 102+202+302+402, or 3000; higher HHI values indicate a less competitive market. We estimated the market share of a manufacturer by dividing the number of prescriptions attributable to that manufacturer by the number of prescriptions dispensed for a given study drug in that period. The HHI has some important thresholds. An HHI value of 2500 represents quadropoly-like competition levels, at which a generic drug is produced by 4 manufacturers with equal market shares (that is, 252+252+252+252). Similarly, an HHI value of 5000 represents a duopoly-like competition level, at which a generic drug is produced by 2 manufacturers with equal market shares (that is, 502+502). An HHI value of 8000, indicating a near-monopolylike competition level, is achieved when 1 manufacturer controls nearly 90% of the generic drug market (that is, 902). As previously stated, an HHI value of 10000 represents a monopoly, in which a single manufacturer produces the generic drug. The primary association of interest was between competition levels (HHI) and changes in drug prices. Prices may increase faster for drugs with low baseline competition levels (time-stable component of HHI) or for those that become less competitive over time (time-varying component of HHI). The index value measured during the baseline period was designated as the baseline HHI value. Change in HHI from its baseline value was estimated by calculating the difference between the HHI in the previous study period and its baseline value. We used lagged values of HHI to ensure that a change in HHI preceded a change in price. Although we modeled HHI as a continuous variable (see the Statistical Analysis section), for descriptive purposes, by using HHI thresholds of duopoly (HHI value, 5000) and near-monopoly (HHI value, 8000), we categorized drugs into highbaseline competition (HHI value, <5000), mediumbaseline competition (HHI value, 5000 to <8000), and lowbaseline competition (HHI value, 8000) groups. Covariates We controlled for baseline market size, because it could be associated with both HHI and drug prices. The baseline market size, defined as the percentage of the total generic drug market held by a drug, was calculated by dividing the number of fills for each drug (for example, diazepam 2-mg tablets) by the number of fills for the entire cohort of generic drugs in the baseline period. Using tertiles of market size, we grouped the study drugs into small, medium, and large markets. We also adjusted for dosage forms by creating dummy variables to classify the drugs into 7 categories: tablets; extended-release tablets; capsules; extended-release capsules; cream, lotion, or gel; solution; and miscellaneous. We used the University of Utah Drug Information Services (UUDIS) database to collect information on drug shortage status (14). The UUDIS database, considered one of the most reliable and comprehensive sources on drug shortages in the United States (15), contains information on active ingredients, dosage forms, drug strengths, and shortage start and end dates. We linked the study drugs to the UUDIS database and modeled the number of months that a drug was in shortage as a lagged, time-varying, cumulative, continuous variable. Statistical Analysis Within the data were 3 sources of correlation nested within one another. Prices measured repeatedly for the same drug constituted the first level of data. The second and third levels were related to manufacturing efficiencies and cross-price elasticity of demand. Although not always the case, owing to overlap in manufacturing processes, drugs with the same active ingredients and dosage forms may be easier to produce. For example, manufacturers that produce diazepam 2-mg tablets may also produce diazepam 5-mg tablets, and their prices may be correlated. Therefore, we modeled the combinations of active ingredients and dosage forms (for example, diazepam tablets) as the second hierarchical level. Cross-price elasticity of demand means that prices for substitutable generic drugs may be similar to one another. Prices for a generic statin may be more like those for another generic statin than those for a generic antibiotic. We used American Hospital Formulary Service Drug Information and classified all active ingredients into drug classes, as a surrogate for this effect, and accordingly modeled drug classes (for example, statins) as the third hierarchical level. Because drug prices were highly skewed and nonnormal, we log transformed them and used a linear mixed-effects model (see section 1.5 of the Supplement for complete model specifications). We modeled time as a categorical factor to avoid assumptions of linear trends. Parametric specifications of time also were considered (section 1.4 of the Supplement). We computed SEs using the KenwardRoger degrees-of-freedom approximation (16). To account for the correlation within the data, we fit an unstru

Drug shortages: Implications for medical toxicology

OBJECTIVES This was a study of longitudinal trends in U.S. drug shortages within the scope of emergency medicine (EM) practice from 2001 to 2014. METHODS Drug shortage data from the University of Utah Drug Information Service were analyzed from January 2001 to March 2014. Two board-certified emergency physicians classified drug shortages based on whether they were within the scope of EM practice, whether they are used for lifesaving interventions or high-acuity conditions, and whether a substitute for the drug exists for its routine use in emergency care. Trends in the length of shortages for drugs used in EM practice were described using standard descriptive statistics and regression analyses. RESULTS Of the 1,798 drug shortages over the approximately 13-year period (159 months), 610 shortages (33.9%) were classified as within the scope of EM practice. Of those, 321 (52.6%) were for drugs used as lifesaving interventions or for high-acuity conditions, and of those, 32 (10.0%) were for drugs with no available substitute. The prevalence of EM drug shortages fell from 2002 to 2007; however, between January 2008 and March 2014, the number of EM drug shortages sharply increased by 435% from 23 to 123. From January 2008 to March 2014 shortages in drugs used as a direct lifesaving intervention or for high-acuity conditions increased 393% from 14 to 69, and shortages for drugs with no available substitute grew 125% from four to nine. Almost half (46.6%) of all EM drug shortages were caused by unknown reasons (the manufacturer did not cite a specific reason when contacted). Infectious disease drugs were the most common EM drugs on shortage, with 148 drug shortages totaling 2,213 months during the study period. CONCLUSIONS Drug shortages impacting emergency care have grown dramatically since 2008. The majority of shortages are for drugs used for lifesaving interventions or high-acuity conditions. For some, no substitute is available.

The prevalence of pharmaceutical shortages in the United States

Shortages and sudden price increases of certain drugs may both occur emergently, with little to no warning, and they can have a dramatic impact on patient care. Little data are available linking drug shortages and price increases. Many of the same characteristics that may make medications susceptible to shortages can also place them at risk for sudden price increases. These characteristics include unapproved drugs, off‐patent sole‐source medications, and infrequently used medications. We reviewed drug shortage data from the University of Utah Drug Information Service to demonstrate how frequently these characteristics occurred and resulted in higher drug prices. Clinicians can use drug shortage management principles to mitigate the impact of sudden price increases for patients and health care organizations.

Generics Substitution, Bioequivalence Standards, and International Oversight: Complex Issues Facing the FDA.

Abstract Context. Drug shortages have significantly increased over the past decade. There are limited data describing how shortages impact medical toxicology of drugs. Objective. To characterize drug shortages affecting the management of poisoned patients. Materials and Methods. Drug shortage data from January 2001 to December 2013 were obtained from the University of Utah Drug Information Service. Shortage data for agents used to treat poisonings were analyzed. Information on drug type, formulation, reason for shortage, shortage duration, marketing, and whether the drug was available from a single source was collected. The availability of a substitute therapy and whether substitutes were in shortage during the study period were also investigated. Results. Of 1,751 shortages, 141 (8.1%) impacted drugs used to treat poisoned patients, and as of December 2013, 21 (14.9%) remained unresolved. New toxicology shortages increased steadily from the mid-2000s, reaching a high of 26 in 2011. Median shortage duration was 164 days (interquartile range: 76–434). Generic drugs were involved in 85.1% of shortages and 41.1% were single-source products. Parenteral formulations were often involved in shortages (89.4%). The most common medications in shortage were sedative/hypnotics (15.6%). An alternative agent was available for 121 (85.8%) drugs; however, 88 (72.7%) alternatives were also affected by shortages at some point during the study period. When present, the most common reasons reported were manufacturing delays (22.0%) and supply/demand issues (17.0%). Shortage reason was not reported for 48.2% of drugs. Discussion. Toxicology drug shortages are becoming increasingly prevalent, which can result in both suboptimal treatment and medication errors from using less familiar alternatives. Conclusion. Drug shortages affected a substantial number of critical agents used in the management of poisoned patients. Shortages were often of long duration and for drugs without alternatives. Providers caring for poisoned patients should be aware of current shortages and implement mitigation strategies to safeguard patient care.