	Background

		FDA’s Oversight of Drugs

FDA’s approval is required before brand-name drugs and generic drugs  can be marketed for sale in the United States. DSS also analyzes market  research data from IMS Health to compare current supply of the drug with  historical demand. Meanwhile, since  2012, the number of ongoing shortages (shortages that began in prior  years) has remained high with over 250 ongoing shortages each year  from 2012 through 2015. Although the timing of FDA’s approvals of submissions does not  establish a causal link, it could indicate that prioritizing reviews may be a  useful strategy in addressing some drug shortages. FDA Prioritized Review of Both Drug Applications and Supplements to Address Shortages and the Majority Were for Generic Sterile Injectable Drugs

From January 2010 through July 2014, FDA prioritized its review of 383  submissions—applications and supplements to change approved drug  applications—to address drug shortages. Number of Warning Letters FDA Issued to Sterile Injectable Drug Establishments Increased, Including Letters to Establishments Linked to Widespread Shortages

		Number of Warning Letters FDA Issued to Sterile Injectable Drug Manufacturers Increased, but the Percentage of Inspections Resulting in Letters Was Relatively Small

The number of warning letters FDA issued annually to sterile injectable  drug manufacturing establishments found to be out of compliance with  manufacturing standards generally increased from fiscal year 2007  through fiscal year 2013. Seven Sterile Injectable Drug Establishments Linked to Widespread Shortages Received Warning Letters and All Had Previous Indications of Difficulty Meeting Manufacturing Standards

From fiscal year 2010 through fiscal year 2012, seven sterile injectable  drug manufacturing establishments that received warning letters for  noncompliance with manufacturing standards slowed or shut down  production. Shortages of Sterile Injectable Anti- infective and Cardiovascular Drugs Were Strongly Associated with Certain Factors

Shortages of sterile injectable anti-infective and cardiovascular drugs  during 2012, 2013, and 2014 were strongly associated with certain factors  we examined. We estimated a regression model to examine the  relationship between drug shortages and four factors: (1) a decrease in  the number of suppliers, (2) sales of a generic version, (3) the failure of  an establishment making the drug to comply with manufacturing  standards resulting in a warning letter, and (4) price decline. The strong association between shortages and both (1) a decrease in the  number of suppliers and (2) the failure of an establishment making the  drug to comply with manufacturing standards resulting in a warning letter  suggests that shortages may be triggered by supply disruptions. Relatively low profit margins may cause suppliers to exit the  market for less profitable drugs in favor of more profitable ones or may  make it unprofitable to increase supply, which could make the market  vulnerable to shortages. Agency and Third- Party Comments and Our Evaluation

We provided a draft of this report for comment to the Department of  Health and Human Services (HHS). Appendix I: Comparison of Drug Shortage Data Collected by the Food and Drug Administration and the University of Utah Drug Information Service

Throughout our work we have received questions from members of  Congress about the similarities and differences between the drug  shortage data collected by the Food and Drug Administration (FDA) and  the University of Utah Drug Information Service (UUDIS). Many of the shortages that FDA identified during this time  period were also identified by UUDIS during this same time period. Both anti-infective and cardiovascular drugs  continue to be subject to multiple and prolonged shortages. FDA classifies  establishment inspections as official action indicated when serious  deficiencies are found that warrant regulatory action. Drug Shortages: Public Health Threat Continues, Despite Efforts to Help  Ensure Product Availability.
Why GAO Did This Study

Drug shortages are a serious public health concern. GAO previously found that many shortages were of sterile injectable drugs and could generally be traced to supply disruptions caused by manufacturers slowing or halting production to address quality issues.
Congress included a provision in statute for GAO to review several aspects of drug shortages. This report examines (1) trends in drug shortages, (2) FDA's efforts to prioritize reviews of drug submissions to address shortages, (3) trends in FDA warning letters issued to sterile injectable manufacturing establishments for noncompliance with manufacturing standards, and (4) the relationship between certain factors and shortages of sterile injectable drugs. GAO analyzed—using various methods including regression analyses—drug shortage data from the University of Utah Drug Information Service from 2010 through 2015; drug sales data from IMS Health from 2010 through 2014 for sterile injectable anti-infective and cardiovascular drugs (which have been subject to multiple and prolonged shortages); and FDA data, including data on warning letters related to inspections conducted from October 2006 through September 2013 and data on prioritized reviews from January 2010 through July 2014, which were generally the latest available data at the time GAO began its analysis. GAO also interviewed FDA officials and reviewed agency documents, including documents related to the issuance of warning letters to seven establishments FDA and others said were linked to widespread shortages.

What GAO Found

When available supplies of prescription drugs are insufficient, patient care may be adversely affected. The number of new shortages has generally decreased since 2011, while the number of ongoing shortages remained high.
To help address shortages, the Food and Drug Administration (FDA) prioritized the review of—more quickly reviewed—383 drug applications and supplements during the time period GAO examined. Most were for generic sterile injectable drugs. FDA's approval of some of these submissions occurred before the shortage was resolved. Although the timing of FDA's approval does not establish a causal link, it could indicate that FDA's action helped address some shortages.
GAO found that, as part of FDA's oversight of drug safety and quality, it generally issued an increasing number of warning letters to sterile injectable drug establishments during the time period GAO reviewed for noncompliance with manufacturing standards outlined in federal regulations. However, the percentage of inspections resulting in warning letters remained relatively small as the number of inspections also increased. Moreover, seven establishments that were linked to widespread shortages and received warning letters all had previous indications of difficulty complying with manufacturing standards.
Shortages of sterile injectable anti-infective and cardiovascular drugs in 2012, 2013, and 2014 were strongly associated with certain factors GAO examined. Two factors—a decline in the number of suppliers and failure of at least one establishment making a drug to comply with manufacturing standards resulting in a warning letter—suggest that shortages may be triggered by supply disruptions. A third factor—drugs with sales of a generic version—suggests that due to relatively low profit margins for generic drugs, manufacturers are less likely to increase production, making the market vulnerable to shortages. The Department of Health and Human Services (HHS) reviewed a draft of this report and reiterated its commitment to addressing drug shortages. GAO incorporated HHS's technical comments as appropriate.