Drug Shortages: Certain Factors Are Strongly Associated with This Persistent Public Health Challenge
Released: 2016-07-07T00:00:00

Letter

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. To obtain FDA’s approval to market a brand-name drug, sponsors must submit a new drug application (NDA) containing data on the safety and effectiveness of the drug as determined through clinical trials and other research. To obtain FDA’s approval to market a generic drug, sponsors must submit an abbreviated new drug application (ANDA). The ANDA must contain data showing, among other things, that the generic drug is bioequivalent to, or performs in the same manner as, a drug approved through the NDA process. If a sponsor wants to change any part of its original NDA or ANDA after its approval—such as changes to manufacturing location or process, the type or source of active ingredients, or the labeling—it must generally submit an application supplement to notify FDA of the change. If the change has a substantial potential to adversely affect factors such as the identity, strength, quality, purity, or potency of the drug, the sponsor must obtain FDA approval. As part of the application and application supplement review process, FDA may conduct an inspection of the establishment where the drug will be manufactured to verify the accuracy and authenticity of the data contained in the application, to determine that the establishment is following commitments made in the application, and to verify that the establishment is prepared to make the drug named in the application or supplement.

After approving brand-name and generic drugs for marketing in the United States, FDA’s oversight responsibilities continue, as it is charged with monitoring their safety, effectiveness, quality, and promotion. FDA periodically inspects drug manufacturing establishments, including those manufacturing brand-name, generic, and over-the-counter drugs to assess their ongoing compliance with current good manufacturing practice regulations. In addition to these surveillance inspections, FDA may also conduct for-cause inspections when the agency receives information indicating problems in the manufacture of marketed drugs, among other reasons. FDA may conduct an inspection that includes multiple components (e.g., both preapproval and surveillance) during a single visit to an establishment. Based on the agency’s findings during an inspection, FDA classifies the inspection as either (1) no action indicated, when insignificant or no deficiencies were identified; (2) voluntary action indicated, when deficiencies were identified and must be corrected, but the agency is not prepared to take regulatory action; or (3) official action indicated, when serious deficiencies were found that warrant regulatory action.

Specifically, if FDA identifies a violation of law or regulations during an inspection and therefore finds the establishment to be out of compliance with manufacturing standards, the agency may issue a warning letter. FDA issues warning letters when the agency has identified violations that may lead to enforcement action if not promptly and adequately corrected. Recommendations to issue a warning letter are either made by staff in FDA’s district offices or by staff in FDA’s Center for Drug Evaluation and Research. Multiple levels of the Center’s staff review all warning letter recommendations. It is FDA policy to consider many factors in determining whether to issue a warning letter. For example, the agency is to consider the compliance history of the establishment, the nature of the violation (e.g., whether the establishment was aware of the violation, but failed to correct it), and the risk associated with the product and the impact of the violation on such risk. FDA is also to consider corrective actions taken or promised by the establishment since the inspection, and it may decide not to issue a letter if an establishment’s corrective actions are adequate and the violations that would have supported the letter have been corrected. To determine whether actions planned or taken by an establishment to correct violations are adequate FDA may, among other activities, review documentation describing proposed or completed corrective actions or hold meetings with representatives of the establishment to discuss these actions. FDA is also required by law to consider whether issuing the warning letter could reasonably cause or exacerbate a shortage of a life-saving drug. If it determines a shortage could occur or an existing shortage could worsen, the agency must evaluate the risks associated with the impact of such a shortage upon patients and the risks associated with the violation before taking action, unless there is an imminent risk of serious health consequences or death from not taking action. Once issued, warning letters are publicly posted on FDA’s website.

FDA Oversight of Drug Shortages

FDA’s Drug Shortage Staff (DSS) coordinates the agency’s response to drug shortages. FDA is notified of actual and potential drug shortages by manufacturers, health professionals, and the public. Once DSS becomes aware of a potential or actual shortage, DSS attempts to determine whether the total supply of the drug and any pharmaceutical equivalents is inadequate to meet demand. To verify that a shortage is in effect or a potential shortage is pending, DSS contacts all manufacturers of the drug to collect up-to-date information on the inventory and demand for the drug and manufacturing schedules. DSS also analyzes market research data from IMS Health to compare current supply of the drug with historical demand.

DSS coordinates as needed with several other FDA offices including the Office of Generic Drugs and the Office of Compliance to address drug shortages. Once DSS verifies a shortage or potential shortage of a drug, it may seek assistance from these offices to address that shortage, including the following: identifying the extent of the shortage and determining whether other manufacturers are willing and able to increase production of the shortage drug; prioritizing reviews of drug applications, supplements, and inspections for manufacturers attempting to restore, increase, or begin production of the shortage drug; and applying regulatory discretion, such as refraining from taking enforcement action to stop the distribution of a drug that is in shortage despite a labeling or quality issue.

For example, DSS provides the Office of Generic Drugs with drug shortage information so that the office can identify ANDAs or ANDA supplements it can prioritize its review of to address a shortage.

While there are a number of steps FDA can take to address a shortage, FDA cannot require manufacturers to start producing or continue to produce a drug. It also cannot require manufacturers to maintain or introduce manufacturing redundancies in their establishments to provide them with increased flexibility to respond to shortages. Finally, FDA cannot control the prices of marketed drugs.

Characteristics of the Sterile Injectable Drug Industry

In our February 2014 report, we identified unique characteristics of the sterile injectable drug industry that may make these drugs susceptible to shortages. These characteristics include limited inventory, need for regulatory approval, production complexity, and constrained manufacturing capacity.

Limited inventory. The widespread use of “just-in-time” inventory practices can increase the vulnerability of the supply chain to shortages. For example, according to one manufacturer representative, manufacturers typically have about 2 to 3 months of inventory on hand, wholesale distributors usually have about 1 month, and providers only have a few weeks of inventory. Consequently, when a manufacturer stops production, a shortage can result quickly.

Regulatory approval. New manufacturers may not be able to quickly enter the market to produce a drug in shortage because FDA’s approval of an ANDA—which can take more than a year—is required. Further, even existing manufacturers of the drug need FDA approval of changes to manufacturing conditions or processes that have a substantial potential to adversely affect factors such as the identity, strength, quality, purity, or potency of the drug before the drug manufactured under the new conditions or processes can be marketed. For example, FDA approval of an application supplement may be required for changes in location of a manufacturing site or the source of the raw materials or components for manufacturing a drug.

Production complexity. Costly, specialized equipment is required to manufacture prescription drugs and production processes are complex, particularly for sterile injectables. Maintaining sterility throughout the production process is challenging, yet it is particularly important for these drugs as serious injury can occur if contaminated drugs are injected into patients. Some generic sterile injectable drugs need to be manufactured on lines or in facilities dedicated solely to those drugs, thus creating challenges for new manufacturers to enter the market. We previously found that sterile injectable anti-infective and oncology drugs require lines, and sometimes whole facilities, that are limited to the production of such drugs. For example, some anti- infective drugs, such as penicillin, can trigger serious allergic reactions at very low levels and as a result, may be limited to specific manufacturing lines.

Constrained manufacturing capacity. The generic sterile injectable drug industry is highly concentrated and this limited manufacturing capacity has been challenged in recent years as the industry has expanded the number of generic products it manufactures. The pressures to produce a large number of drugs on only a few manufacturing lines leaves the manufacturers that do participate in the generic sterile injectable market with little flexibility when one manufacturer ceases production of a particular drug. For example, manufacturer representatives told us that manufacturing establishments schedule the production of each drug in their product line for specific time periods, often months in advance. An establishment that produces a particular drug may not be able to produce additional quantities in response to a shortage until the next time the particular product is scheduled for production—which could be months after a shortage begins. If a manufacturing establishment has available production capacity, the manufacturer also faces risks when deciding to ramp up production to address a shortage. In particular, one manufacturer representative said that manufacturers do not know how long their competitors will be out of the market. If the manufacturer that left the market quickly restarts production of the drug, the manufacturer that made the investment to ramp up production to address the shortage may face a financial liability if it is unable to sell the additional product it manufactured.

Another capacity-related issue is that the company whose name is on the drug label, which we term the supplier, may or may not be the same as the company that actually manufactures the drug. Rather than produce the drug themselves, some suppliers enter into a relationship with a contract manufacturer to produce the drug on their behalf. Therefore, the number of suppliers of a particular drug may not be the same as the number of manufacturers of that drug. The number of suppliers could also be different than the number of manufacturers if the name on the drug’s label is that of a repackager, a distributor, or the parent company of the manufacturer.

New Drug Shortages Have Decreased Since 2011, but Many Shortages Persist for Multiple Years

New drug shortages continue to be reported, although the number of new shortages each year has generally decreased since 2011. New shortages peaked in 2011 with 257 reported, while 136 new shortages were reported in 2015, a decrease of 47 percent from 2011. 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. (See fig. 1.) As a result, the majority of drug shortages each year since 2012 have been ongoing shortages rather than newly reported shortages. For example, in 2015, 68 percent of the shortages (291 out of 427) were ongoing shortages that began in a prior year.

Since 2013, the majority of the ongoing shortages in a given year were first reported at least 2 years earlier. (See fig. 2.) For example, in 2015, 171 of the 291 ongoing shortages (59 percent) were first reported during 2013 or an earlier year, while the remaining 120 ongoing shortages were first reported during 2014.

The duration of all shortages reported from January 2010 through December 2015 varied, ranging from 1 day to almost 6 years.Of these shortages, 65 percent lasted 1 year or less, while 12 percent lasted more than 3 years. The average duration of all shortages reported during this time period was 418 days. The fact that some shortages have lasted 3 or more years suggests that manufacturers and FDA have had difficulty addressing the issues behind these persistent shortages. For example, FDA stated that some drugs have been in shortage for multiple years because manufacturers have been unable to address the issues that led to the shortage or have chosen not to continue producing the drugs.

The experiences of providers dealing with shortages every day generally supports the trend seen in the UUDIS data that shortages persist. In following up with representatives from the 10 national associations representing health care providers (including hospitals, physicians, and pharmacists) that we contacted for our 2014 report, we learned that shortages continue to affect providers’ ability to safely and effectively care for patients. Reflecting on their experiences with shortages in the last 2 years, representatives of 6 of the 10 associations reported that shortages had remained constant or increased, 2 reported a decrease, and 2 others did not identify a trend in recent shortages, but noted that they were still a concern.

FDA Prioritized Reviews of 383 Submissions to Respond to Drug Shortages

FDA prioritized its review of 383 drug applications and supplements to address shortages from January 2010 through July 2014, 240 of which were for generic sterile injectable drugs. Our analysis of a subset of those submissions indicates that some were approved before the shortage was resolved. 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. These submissions represent 3 percent of all submissions that FDA received during this time period. Almost all of the submissions that FDA prioritized during this time period were ANDAs or ANDA supplements for generic drugs; the remaining few were NDA supplements for brand-name drugs. (See fig. 3.)

Further, the majority of the submissions for which FDA prioritized its reviews to address drug shortages were for generic sterile injectable drugs. Specifically, 63 percent (240) of the 383 submissions granted a prioritized review were for generic sterile injectable drugs, and an additional 4 percent (17) were for brand-name sterile injectable drugs. Twenty-four percent (92) of the prioritized submissions were for drugs in capsule or tablet form, while the remaining 9 percent (34) were for drugs in other dosage forms, such as ointments or patches.

Overall, FDA had completed at least one review cycle for approximately 80 percent of the 383 prioritized submissions as of October 30, 2014. FDA’s review of a submission may span several review cycles before the agency makes a decision regarding its approval, and once the review of a submission is prioritized any subsequent reviews of it are also prioritized. An additional review cycle may occur if, for example, to ensure the safety and efficacy of the product, FDA asks a sponsor to supply additional data, analyses, or other information to address concerns identified in its review. According to FDA it has historically taken, on average, about four review cycles to approve an ANDA. As of October 30, 2014, 43 percent (164) of the 383 prioritized submissions had been approved and FDA had completed at least one review for another 37 percent (140). The majority of submissions for which FDA had not completed a review cycle as of October 2014, were received in 2013 and 2014. See table 1 for the status of the 383 prioritized submissions FDA received from January 2010 through July 2014.

For the submissions in our review that FDA approved as of October 30, 2014, the time from when they were prioritized to approval varied by submission type. These review times ranged from 3 days to more than 3 years for ANDA supplements and from 3 days to 6 months for NDA supplements. For ANDAs, review times ranged from 40 days to more than 3 years. See table 2 for the median time to approval for submissions that FDA received and prioritized its review of from January 2010 through July 2014.

If FDA does not approve a submission after the first review, it will provide sponsors with complete response letters seeking additional information that addresses deficiencies that FDA identified, making the time to approval longer. For 47 of the 71 approved ANDAs, FDA issued at least one complete response letter and therefore these ANDAs had more than one review cycle, with a range of two to five cycles. The remaining 24 approved ANDAs were approved at the end of the first review cycle in which they were prioritized. Of the 70 approved ANDA supplements, 52 were approved at the end of the first review cycle in which their review was prioritized, with the number of review cycles ranging from one to three. Of the 12 approved NDA supplements, 11 were approved at the end of the first review cycle that FDA prioritized.

Lastly, FDA prioritized its review of submissions to address drug shortages for many different sponsors and sometimes for more than one submission per drug during this time period.

The 383 prioritized submissions came from 107 different sponsors.

The number of prioritized submissions for any given sponsor ranged from 1 to 24. The majority of these sponsors (69 percent) had 1 to 2 submissions prioritized, and 9 percent of the sponsors had more than 10 submissions prioritized.

The 383 prioritized submissions were associated with 160 drugs. The number of submissions for each drug ranged from 1 to 16. Multiple submissions for a single drug were typically from multiple sponsors seeking approval to market the drug. Seventy percent of these drugs were associated with 1 to 2 prioritized submissions, while 6 percent were associated with 7 or more prioritized submissions.

Analysis of a Subset of Drug Submissions Suggests that Prioritization Can Be Helpful In Preventing or Resolving Some Drug Shortages

Our analysis of a subset of the 383 submissions, consisting of 153 submissions that were associated with 38 drugs, suggests that FDA’s prioritization of submissions may be helpful in addressing some drug shortages. To examine this strategy, we reviewed the following:

Relationship between submissions and shortage prevention or resolution. When we examined the subset of prioritized submissions that were associated with 38 drugs, we found that 15 of the drugs were associated with at least one prioritized submission that was approved before the shortage was resolved or a potential shortage was prevented. The timing of FDA’s approvals of these submissions suggests that this strategy may have contributed to addressing shortages of these 15 drugs, although it does not establish a causal link. Specifically, the approved submissions for these 15 drugs may have helped resolve 12 shortages, prevent 2 shortages, and mitigate 1 shortage. These approved submissions were for drugs in several therapeutic classes (including anti-infective, oncology, and central nervous system drugs) and used to treat a variety of conditions (including bacterial infections, breast cancer, and attention deficit hyperactivity disorder). Conversely, another 13 of the 38 drugs did not have any prioritized submissions approved prior to the shortage resolution or prevention date, so submissions for those drugs could not have contributed to addressing a shortage. However, for 9 of these 13 drugs at least one prioritized submission was approved after the shortage was resolved or prevented, which FDA determined may have helped to reduce supply vulnerabilities and prevent future shortages. In addition, submissions for 2 of the 38 drugs were not approved as of October 2014 and the shortages the submissions were prioritized to address remained active. Finally, the submissions for 8 of the 38 drugs were not associated with a specific shortage at the time of prioritization, although the majority of these drugs had previously been in shortage or were otherwise vulnerable to shortage. (See table 3.)

Time to approval for approved submissions. The median time to approval from the date prioritized differed for the 26 submissions that may have contributed to the prevention or resolution of a shortage, compared to the 24 submissions approved after the associated shortage was prevented or resolved. This difference was more pronounced for ANDAs than for supplements. Specifically, the median time to approval for ANDAs that may have helped to prevent or resolve a shortage was almost 4 months faster than it was for ANDAs that were not approved until after the prevention or resolution of the associated shortage.

For the 26 submissions that may have contributed to the prevention or resolution of a shortage, the median time to approval was 494 days for ANDAs and 87 days for supplements.

For the 24 submissions that were not approved until after the associated shortage was prevented or resolved, the median time to approval was 613 days for ANDAs and 80 days for supplements.

Given that the median time to approval for prioritized ANDAs is over a year, prioritizing reviews of ANDAs to address drug shortages is generally not a strategy for addressing shortages in the short term. However, this strategy may be useful to address drug shortages that have persisted across multiple years or recurred multiple times in a few years. This may also be a helpful approach if FDA is notified as early as possible about potential shortages. FDA’s drug shortages strategic plan states that early notification of potential supply disruptions is critical because it puts the agency in a better position to use all of its available strategies to address drug shortages, including prioritizing its reviews of ANDAs from sponsors who want to enter the market for a drug that is vulnerable to shortage or already in shortage. The success of this strategy, however, also depends on whether sponsors are willing or able to submit ANDAs for drugs that are vulnerable to shortage or already in shortage, which is beyond FDA’s control.

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. The number of letters issued ranged from 1 letter resulting from an inspection conducted in fiscal year 2007, to 11 letters resulting from fiscal year 2010 inspections and another 11 letters resulting from fiscal year 2011 inspections. In addition, FDA issued a growing number of such letters to non-injectable drug establishments, ranging from 16 letters resulting from fiscal year 2007 inspections to 45 letters resulting from fiscal year 2010 inspections and another 45 letters resulting from fiscal year 2011 inspections.

Although the number of warning letters issued increased, the percentage of inspections that resulted in warning letters in a given year remained relatively small. One percent of FDA’s fiscal year 2007 inspections of sterile injectable drug establishments resulted in the issuance of warning letters, compared with 5 percent of such inspections in fiscal years 2010 and 2011. (See fig. 4.) The percentage of inspections of non-injectable drug establishments that resulted in warning letters was similar, ranging from 1 percent of fiscal year 2007 inspections to 4 percent of fiscal year 2013 inspections.

As the number of warning letters issued to sterile injectable drug establishments for noncompliance with manufacturing standards generally increased from fiscal year 2007 through fiscal year 2013, so did shortages of these drugs. (See table 4.) Both the number of warning letters and the number of shortages were particularly high in fiscal years 2010 and 2011. While a corresponding rise in warning letters and shortages in certain years could reflect an increase in FDA inspection rigor, as was suggested by some sources in the literature review conducted for our prior report, it could also indicate growing manufacturing problems. Such problems could lead to shortages as establishments recalled defective products or shut down or slowed production to correct manufacturing problems. What is not known is whether establishments experiencing such manufacturing problems would have shut down or slowed production in the absence of an FDA warning letter.

FDA officials disputed the notion that the agency’s issuance of warning letters to establishments found to be out of compliance with manufacturing standards caused shortages. First, FDA officials noted that some shortages are unrelated to manufacturing problems and therefore could not have been caused by FDA’s issuance of warning letters for manufacturing violations. This notion is consistent with our prior analysis of FDA shortage data, which found that from January 2011 through June 2013, 30 percent of shortages were reportedly caused by issues unrelated to manufacturing, such as increased demand or unavailability of raw materials or components. Second, although the agency does have other enforcement powers to stop distribution of a product, FDA officials stated that warning letters issued for noncompliance with manufacturing standards do not order a stop in production or distribution. Finally, FDA officials stated that it is important to put warning letter data in perspective by considering the reason that FDA conducted the inspections that resulted in warning letters. According to FDA officials, if the inspections that resulted in warning letters were inspections with a for-cause component and thus were conducted to investigate potential manufacturing problems, then any underlying manufacturing problems that led to the warning letter could also have caused shortages. For example, officials told us that during this time frame, inspections of sterile injectable drug manufacturers were often conducted because of reports of problems with particulates, such as a number of voluntary recalls conducted in response to glass fragments in sterile injectable drugs in 2010 and 2011.

Our analysis of 7 years of FDA data on inspection type does not reveal a clear trend in terms of the relationship between shortages, warning letters, and one indication of potential manufacturing problems—the frequency of inspections with a for-cause component. Our analysis shows that between fiscal years 2007 and 2013 the percentage of inspections with a for-cause component was consistently higher for sterile injectable drug manufacturing establishments than it was for non- injectable establishments. (See fig. 5.) FDA officials told us that they evaluate the health hazards of all reports of potential manufacturing problems that they receive. However, because of the potentially serious health consequences of using a sterile product that has been contaminated, the agency may be more likely to conduct a for-cause inspection in response to reports of potential manufacturing problems at a sterile injectable drug establishment than at one that manufactures non- injectable drugs. Across this time period, the percentage of sterile injectable drug establishment inspections with a for-cause component varied. After declining from its fiscal year 2007 peak, the percentage of sterile injectable drug establishment inspections with a for-cause component grew to 17 percent of fiscal year 2011 inspections. Fiscal year 2011 was also both the peak in new sterile injectable drug shortages and warning letters issued to sterile injectable drug establishments. While the number of warning letters issued to sterile injectable drug establishments was equally high a year earlier in fiscal year 2010 and new shortages were at their second highest, the percentage of inspections with a for- cause component was at its lowest—10 percent. Thus, comparing the trend in inspections with a for-cause component to the trends in shortages and in warning letters provides support for FDA officials’ contention that there were underlying manufacturing problems that could have led to shortages and warning letters in some years, but not others.

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. FDA and others said these slowdowns and shutdowns led to widespread shortages. For example, the fiscal year 2012 voluntary shutdown of one of the seven establishments reportedly led to the actual or potential shortage of more than 100 drugs. Another of the seven establishments manufactured more than 300 different drugs, so its production slowdown also led to multiple shortages.

FDA issued warning letters to all seven establishments after finding that the establishments were not in compliance with manufacturing standards during inspections conducted from fiscal year 2007 through fiscal year 2011. Although FDA did not require the establishments to shut down or slow production, the agency noted in a letter to a member of Congress about this issue that when products manufactured under problematic conditions pose a safety threat to patients—such as glass shards or metal shavings in vials of injectable drugs or fungal contamination— manufacturers generally must stop production to resolve the problem. Such problems were experienced by six of the seven establishments linked to widespread shortages when particulates were discovered in their sterile injectable products. For example, a drug at one establishment was found to contain microscopic particles that were “stringy, amorphous, and globular” and sterile injectable drugs at two other establishments contained stainless steel particles. The presence of metal particles in sterile injectable drugs can cause serious injury to patients when injected. Following the receipt of reports of serious injury and illness, a drug manufactured at the seventh establishment was discovered to contain endotoxin, a component of certain bacteria, which may cause severe fever and death if present in a drug.

FDA documents and data indicate that all seven of these establishments had difficulty meeting manufacturing standards prior to FDA’s issuance of a warning letter, which, at least for these establishments, runs counter to the claim that the increase in warning letters was an indication that the agency began to apply manufacturing standards more rigorously. For example, FDA staff previously recommended issuing warning letters to two of the establishments, but after further internal review, FDA issued an untitled letter to one establishment and did not issue a warning letter to the other. (See fig. 6.) For two other establishments, the inspections preceding the inspection that resulted in the warning letter often included a for-cause component. For example, one of the two establishments was inspected six times between fiscal year 2007 and the inspection that resulted in the warning letter and each inspection was conducted in response to manufacturer reports of potential manufacturing problems submitted to FDA, complaints from consumers or health care providers, or both.

Our analysis of FDA documents also shows that, for four establishments, the same manufacturing violations that led FDA to issue a warning letter had also been observed during previous FDA inspections. In the case of one of the four establishments, FDA documents show that the agency had expressed concerns about one violation 5 years prior to the inspection that resulted in the warning letter.

For nearly all of the seven establishments linked to widespread shortages, there were continued indications of difficulty meeting manufacturing standards following their receipt of a warning letter. In addition to issuing one establishment a warning letter, FDA subsequently sought and obtained an injunction against this establishment to prevent it from manufacturing and distributing most drugs until FDA determined that the establishment was compliant with the Food, Drug, and Cosmetic Act. An agency press release about the injunction noted that inspections of the establishment found several product quality problems, including facility cleaning issues and poor equipment maintenance practices resulting in equipment shedding particles into some sterile injectable products. Despite investments to address these issues, this establishment decided to cease manufacturing all drugs and was permanently closed in 2013. Subsequent inspections of four other establishments resulted in the classification of official action indicated, signifying that FDA continued to identify serious deficiencies that warranted regulatory action. With these continued indications of potential manufacturing problems at multiple sterile injectable establishments manufacturing such medically necessary drugs as those used to treat cancer, administer anesthesia, and prevent blood clots, shortages of multiple sterile injectable drugs persist. FDA officials told us that these seven establishments all made improvements and in many cases are now helping to prevent and resolve some shortages. However, as of April 2016, five of these seven establishments continue to cause shortages, according to FDA officials.

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. We found all factors but price decline to be strongly associated with shortages of the drugs in our study. For each factor, table 5 displays the estimated percentage point increase in the probability of a shortage when the factor is present for all drugs relative to the mean probability of a shortage predicted for all drugs in our study by our model. These estimates show that the presence of a single factor increases the probability of a drug shortage by as much as 16.8 percentage points from what the model otherwise predicts for all drugs in our study.

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. Characteristics of the sterile injectable drug industry may make these drugs susceptible to shortage when the number of suppliers decreases. For example, a supplier may decide to permanently discontinue an unprofitable product or the unavailability of raw materials may lead to production delays. Further, failure to comply with manufacturing standards resulting in a warning letter could also trigger a supply disruption if a manufacturer chooses to temporarily shut down production in a particular establishment to correct the conditions that led to a warning letter. In this industry, there is limited inventory in the supply chain, manufacturing capacity is constrained because production is scheduled months in advance, new manufacturers must receive regulatory approval before entering the market, and the production process is complex. After a supply disruption for any reason, if other manufacturers are not able to increase supply in a timely manner, a shortage may ensue.

For the drugs in our study, the association between noncompliance with manufacturing standards resulting in a warning letter and shortages is largely driven by the structure of the generic injectable manufacturing industry. The warning letters received by three large manufacturing establishments for failure to comply with manufacturing standards appear to be driving our finding that failures to comply with manufacturing standards resulting in warning letters were strongly associated with certain sterile injectable drug shortages. In this industry, establishments produce multiple drugs and so one establishment’s failure to comply with manufacturing standards that results in receipt of a warning letter could affect many drugs. For example, 69 percent of the 118 drugs in our study were manufactured by at least one of nine establishments. Thus, if one of these nine establishments failed to comply with manufacturing standards, many drugs in our study could be affected. For example, in 2012 one establishment that failed to comply with manufacturing standards and received a warning letter manufactured 22 drugs in our study. (See table 6.)

While the strong association between failure to comply with manufacturing standards resulting in the receipt of a warning letter and shortages could support the contention that FDA regulatory activity triggered some shortages, it could also support the contention that there were growing manufacturing problems and possibly related quality concerns that both precipitated the warning letters and led to shortages. The findings of one study indicate that supply disruptions that led to recent shortages of generic sterile injectable drugs were often linked to quality problems. According to this study, quality problems stem from various sources, including insufficient maintenance, outdated or inadequate design of sterile manufacturing processes, and poor oversight that does not test for or respond adequately to indicators of potential quality problems.

Additionally, our finding that sales of a generic version were associated with shortages suggests that relatively low profit margins may also trigger shortages for sterile injectable drugs. Specifically, compared with drugs for which there were only brand-name sales and thus only one supplier, drugs sold generically may have multiple suppliers and relatively lower profit margins. The 88 drugs in our study sold generically were available from an average of four suppliers during 2013, and 10 drugs had eight or more suppliers. Researchers have found that prices, and consequently profit margins, decline for generic drugs as the number of suppliers increase. 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.

Lastly, though we did not find a price decline in the previous year to be significantly associated with shortages of the anti-infective and cardiovascular drugs in our study from 2012 through 2014, other evidence indicates that price may influence the amount of drugs produced. Research indicates that price influences a supplier’s profit margins, which may affect a supplier’s decision to stay in the market or invest in the manufacturing establishments. Further, research on shortages in another therapeutic class examined price trends and found that the average price of oncology drugs decreased every year leading up to a shortage, whereas the average price stayed the same or increased for oncology drugs that were not in shortage. (See app. II for more information about our data sources and methodology for our regression model, and app. II, III, and IV for more information about the relationship between certain factors and whether a drug was in shortage.)

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). We also provided excerpts of this report for comment to UUDIS. We received written comments from HHS, which are reproduced in appendix V. We also received technical comments from HHS and UUDIS, which we incorporated as appropriate.

In its comments, HHS reiterated its commitment to the prevention of new drug shortages and the mitigation and resolution of those shortages that do occur. HHS concurred with our finding that there are still critical shortages affecting the public health. However, in contrast to our finding based on UUDIS data that ongoing shortages remain high, HHS presented FDA drug shortage data indicating that ongoing shortages have decreased. HHS attributed this difference to FDA and UUDIS defining drug shortages differently, which we describe in detail in appendix I of our report. It is important to note that HHS presents FDA’s drug shortage data from 2010 through 2015 to describe the decrease in drug shortages, but we have previously identified reliability concerns with these data, which we describe in appendix I. Because of these concerns, we have not used FDA’s drug shortage data in our current and previous work, and we instead relied on UUDIS drug shortage data, which we continue to believe are the most comprehensive and reliable information available for the time periods we reviewed. Also, despite the declining trend in both new and ongoing shortages suggested by the FDA drug shortage data, our communications with health care provider organizations suggest that shortages are still a significant concern. Representatives from 8 of the 12 organizations representing health care providers told us that, in their experience, shortages have remained constant or increased.

HHS stated it is not surprising that we identified an association between warning letters and drug shortages, given that the most common cause of drug shortages is manufacturing deficiencies, and that warning letters, by definition, are issued in response to such deficiencies. HHS cautions that this association should not be interpreted as suggesting that warning letters themselves cause shortages. We agree with this note of caution. HHS also noted that our regression analysis may overestimate the direct impact of issuing warning letters because we did not include other measures of manufacturing quality in our model. We considered a number of additional variables in developing our model, some of which are described in appendix II. However, given the size of our study population (118 drugs), we limited the number of variables in our regression analysis. Our model includes key variables grounded in economic theory and findings from our previous work on drug shortages.

We are sending copies of this report to the appropriate congressional committees, the Secretary of HHS, and other interested parties. In addition, the report is available at no charge on the GAO website at http://www.gao.gov.

If you or your staff have any questions about this report, please contact me at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made key contributions to this report are listed in appendix VI.

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). This appendix provides a summary of each data source and the results of a comparison of data from both sources.

Background

FDA and UUDIS, on behalf of the American Society of Health-System Pharmacists (ASHP), both track and maintain data on drug shortages that occur in the United States. Both organizations make drug shortage information publically available through their respective websites. FDA and UUDIS also maintain drug shortage data that are separate and more comprehensive than the information available on the respective websites. For example, FDA does not post shortages on its website if a shortage is expected to be resolved quickly. Meanwhile, UUDIS only posts information on ASHP’s website for a subset of shortages that it deems to be critical.

We have previously conducted analyses of UUDIS drug shortage data to determine trends in the number of drug shortages from January 2001 through June 2013. UUDIS began tracking data on drug shortages in 2001 to inform ASHP’s members, such as hospital pharmacists, and other health care providers about the status of new, ongoing, and resolved shortages. These data are generally regarded as the most comprehensive and reliable source of drug shortage information for the time periods we have reviewed. We used UUDIS data because while conducting work for our 2011 report, we found that FDA did not have a database on drug shortages. While FDA collected some information, it did not lend itself to analysis—it was not easily retrievable, routinely recorded, or sufficiently reliable. Because FDA was unable to provide us with the information necessary to analyze trends in drug shortages, we obtained these data from UUDIS. FDA has since taken steps to track drug shortage data in a systematic manner; it started tracking drug shortages in 2011 in response to our report, and its efforts have evolved over the last several years. However, the data it has compiled since our 2011 report was issued do not include information on shortages prior to 2010.

Description of FDA and UUDIS Drug Shortage Data

FDA and UUDIS have different definitions of what constitutes a drug shortage. Consequently, they do not always determine the same drugs are in shortage and they do not generally report the same number of shortages overall. Specifically, the Food and Drug Administration Safety and Innovation Act, which FDA implements, defines a drug shortage as a period of time when the demand or projected demand for a drug within the United States exceeds the supply of the drug. In determining whether a shortage exists, FDA focuses on the overall market for a specific drug, meaning that even if a particular manufacturer does not have product available, it is not a shortage if the other manufacturers of that product can meet the projected demand for the whole market. For example, if Manufacturer A has no product available, and Manufacturer B is able to manufacture enough product to satisfy the entire market demand, FDA would not consider this situation a drug shortage, even if Manufacturer B’s product is a different strength and package size as long as it views the different sizes and strengths as clinically interchangeable. In contrast, UUDIS defines a shortage as a supply issue that affects how pharmacies prepare and dispense a product or that influences patient care when prescribers must choose an alternative therapy because of supply issues.

According to a UUDIS official, the organization therefore focuses on the supply of drugs by national drug code, which is a code that uniquely identifies specific drug products for a given manufacturer. Focusing on the supply of drugs by national drug code means that if one manufacturer does not have enough supply of all strengths and package sizes to meet demand for a period of time it will be considered a shortage. For example, if Manufacturer A has no product available and Manufacturer B has product available—whether it is the same strength and package size or not—UUDIS would consider this to constitute a drug shortage. A UUDIS official said that focusing on supply of a drug by national drug code is important for pharmacists and clinicians because it is the level at which products are ordered and used. Further, the UUDIS official said that substituting one package size for another may create a safety issue. For more information about FDA’s and UUDIS’s processes for determining whether a drug shortage exists, see table 7.

Methodology

To compare FDA’s and UUDIS’s drug shortage data, we reviewed documentation from both FDA and UUDIS. We also analyzed data from both sources related to drug shortages from January 2013 through March 2013. Given our previous finding that shortages last about 9 months to a year on average, we selected this time frame for our comparison to allow for sufficient time for shortages that began during this time frame to have been resolved by the time we started our analysis in July 2014. Data from this time period were also available from both FDA and UUDIS when we started our analysis. Although we considered analyzing data for a more recent time period, FDA did not have reliable drug shortage data readily available from January 2014 through July 2014 when we began our analysis.

We considered an FDA shortage and a UUDIS shortage to be a match if they shared the same active ingredient and route of administration (e.g., hydroxyzine injection) and had some overlapping time period that both were considered to be in shortage. For example, if FDA identified a shortage of a specific drug that began in January 2013 and lasted through December 2013, we considered the UUDIS shortage of the same drug to be a match if it occurred at any point from January 2013 through December 2013. We confirmed the results of our comparison with FDA and UUDIS. For shortages that did not match, we asked both organizations for reasons why one source identified a shortage while the other did not. The purpose of this comparison is to generally illustrate the differences between the two sets of data. The findings of our comparison are not generalizable to drug shortage data from other time periods.

Comparison of FDA and UUDIS Drug Shortage Data from January 2013 through March 2013

Number of Drug Shortages Identified by FDA and UUDIS

Our analysis shows that FDA and UUDIS identified a different number of shortages that began from January 2013 through March 2013—17 and 39 respectively. Many of the shortages that FDA identified during this time period were also identified by UUDIS during this same time period. Specifically, 8 of the 17 shortages that FDA identified as beginning within this time frame matched to a UUDIS shortage that was also identified during the same period. Another 5 of the 17 shortages identified by FDA matched to a UUDIS shortage that was identified as beginning either before January 2013 or after March 2013. The remaining 4 shortages were not identified by UUDIS during any time period.

While many of the shortages identified by FDA during this time period were also identified by UUDIS, our analysis showed the opposite was true for shortages identified by UUDIS. Specifically, most of the 39 shortages UUDIS identified during this timeframe—28 of 39—were not identified as shortages by FDA. Another 3 of the 39 shortages matched to an FDA shortage that was identified as beginning either before January 2013 or after March 2013. (See fig. 7.)

For the 8 shortages that both FDA and UUDIS identified from January 2013 through March 2013, we found that in 5 out of 8 instances FDA identified shortages earlier than UUDIS. Also, UUDIS and FDA both had instances of first considering a shortage resolved (in 3 and 5 instances, respectively). (See table 8.) In the 5 instances in which FDA identified a shortage first, the agency identified the shortage between 6 and 50 days prior to UUDIS. In the 1 instance in which UUDIS identified a shortage first, the organization identified the shortage 13 days prior to FDA. When FDA considered a shortage resolved prior to UUDIS (in 5 out of 8 instances), this determination was made between 23 and 359 days prior to UUDIS. When UUDIS considered a shortage resolved prior to FDA (in 3 out of 8 instances), it reached this conclusion between 67 and 199 days prior to FDA.

FDA provided various reasons for why it did not consider 28 of the 39 drug shortages UUDIS identified from January 2013 through March 2013 to be shortages. According to FDA officials, the most common reason is that the agency determined that other manufacturers had the same package size and strength of the drug available. (See table 9.) For example, UUDIS identified a shortage of methylprednisolone sodium succinate injection, a drug used to treat endocrine disorders and allergic reactions, among other things, on January 15, 2013, and considered the shortage resolved on October 23, 2013. UUDIS considered methylprednisolone sodium succinate injection to be a shortage at this time because Manufacturer A discontinued production due to raw material issues, and Manufacturer B had the drug on intermittent back order. Though UUDIS acknowledged that Manufacturer C had this drug available, as did Manufacturer B at times, it posted extensive clinical alternatives on ASHP’s website for those providers that were unable to obtain the available drug. FDA did not consider methylprednisolone sodium succinate injection to be in shortage at this time because the agency determined that manufacturers other than Manufacturer A had the same strength and package size of the drug available to meet demand.

Overall, the 28 UUDIS shortages that FDA did not consider to be shortages lasted from 6 days to over 2 years, according to UUDIS’s data. In the case of the 5 UUDIS shortages that FDA stated were short- term supply disruptions rather than shortages, the duration ranged from about a month to over 2 years—one shortage was still active as of December 2015. FDA officials described a short-term supply disruption as a situation where manufacturers report a disruption, but that inventory in the supply chain remains available and FDA has not received any reports of shortage from the public. FDA officials said that these types of disruptions commonly involve delays in importing drugs manufactured at foreign establishments or other short-term delays involving transport. FDA also said that it prevented 3 of the 28 shortages that UUDIS identified. According to UUDIS data, those 3 shortages lasted from about 8 months to over 2 years. Lastly, though FDA did not determine that these 28 situations met its criteria to be a drug shortage, UUDIS deemed 13 of these shortages critical, a designation made because alternative medications were unavailable, the shortages affected multiple manufacturers, or the shortages were widely reported.

There were also 4 shortages that FDA identified from January 2013 through March 2013 that UUDIS did not determine to be in shortage. UUDIS did not consider these drugs to be in shortage because it (1) was never notified that these drugs were in short supply or (2) heard from suppliers that they had full stock. According to FDA data, these four shortages lasted between 2 months to more than 2 years.

Appendix II: Scope and Methodology – Relationship between Certain Factors and Sterile Injectable Drug Shortages

To examine the relationship between certain factors and sterile injectable drug shortages, we used economic theory and findings from our previous work on drug shortages to identify factors that may be associated with shortages. We included these factors in a multivariate regression model to determine which factors are associated with shortages.

Study Population and Data Sources

Our study population included all sterile injectable anti-infective and cardiovascular drugs that were marketed and sold from 2010 through 2014—a total of 118 drugs. We defined a drug to be all products with the same active ingredient and route of administration (e.g., epinephrine injection). We limited the analysis to sterile injectable drugs because we previously found that approximately 65 percent of all critical shortages from January 2009 through June 2013 were for sterile injectable drugs. We selected anti-infective and cardiovascular drugs because in our prior reports we found that approximately one-fourth of all critical drug shortages reported from January 2009 through June 2013 were for drugs in these therapeutic classes. Both anti-infective and cardiovascular drugs continue to be subject to multiple and prolonged shortages. Also, prior studies have focused on other classes, such as oncology.

To identify the drugs in our study population, we used National Sales PerspectivesTM data from IMS Health, a company that collects and analyzes health care data. We selected all drugs that were in the anti- infective and cardiovascular Anatomical Therapeutic Classes as listed in the 2014 guidelines from the European Pharmaceutical Market Research Association. For each drug, we also used these data to develop annual measures of suppliers, dollar sales, volume sales, and sales for generic and brand-name products. In addition, for each drug we calculated a proxy for average annual transaction price by dividing total dollar sales of the drug by total volume sales.

We used data from the University of Utah Drug Information Service (UUDIS) to determine whether a drug was in shortage during 2012, 2013, and 2014 and when each shortage was first reported to UUDIS. UUDIS defines a shortage as a supply issue that affects how pharmacies prepare and dispense a product or that influences patient care when prescribers must choose an alternative therapy because of supply issues. For example, UUDIS would consider acyclovir injection to be in shortage if the 20 mL package size was available, but the 10 mL package size was not because health care providers would need to draw out 10 mL doses from a 20 mL vial, which may create a safety issue. In our analysis, drugs classified as being in shortage were in shortage at any time during a given calendar year, and includes shortages that started in a prior year and remained ongoing.

We used drug registration and listing data from the Food and Drug Administration (FDA) to identify the establishments that were listed as manufacturing the drugs in our study population. Using FDA’s warning letter data, we then determined whether each drug was manufactured by at least one establishment that failed to comply with manufacturing standards and received a warning letter from FDA at any time in the 2 years before each of the years we examined in our regression analysis. If FDA identifies a violation of law or regulations during an inspection, the agency may then take various regulatory actions, such as issuing a warning letter. FDA issues warning letters when it identifies violations that may lead to enforcement action if not promptly and adequately corrected.

Regression Model and Panel Data File

We developed an econometric model to examine the association between shortages of sterile injectable anti-infective and cardiovascular drugs and certain factors. Our model uses 3 years of shortage history for each drug in our study to examine the relationship between whether a drug was in shortage during 2012, 2013, or 2014 (dependent variable), and certain factors (the explanatory variables) described below.

To estimate the model we created a panel data file that has three observations, corresponding to 2012, 2013, and 2014, for each of the 118 drugs in our study. Each of the 354 observations contains data on whether the drug was in shortage that year plus data on certain factors pertaining to the preceding 1 or 2 years.

Dependent Variable: Whether a Drug Was in Shortage

Our dependent variable is a binary variable indicating whether a drug was in shortage during 2012, 2013, or 2014 in a repeated measures model. We selected this time period because, according to UUDIS data, the number of shortages was the highest during 2014, and the number of shortages was also high during 2012 and 2013.

Explanatory Variables

We developed four categories of factors that may be associated with shortages: drug characteristics, market structure, compliance with manufacturing standards, and price and volume of sales. Our inclusion of an explanatory variable to measure compliance with manufacturing standards is unique to this study. Our regression model controlled for one factor from each category. We hypothesized that each of the following factors would be positively associated with a shortage in the following year:

Generic sales (drug characteristic). Because drugs sold generically are more likely to have lower profit margins when compared to their brand-name counterparts, we hypothesized that suppliers of such drugs are less likely to increase production in response to a shortage. Drugs sold generically include drugs that had any sales of a generic product, regardless of the presence of any brand product sales. We classified branded generic products as generic products.

A decline in the number of suppliers (market structure). Such a decline may disrupt the supply of a drug if other suppliers do not increase their production. The number of suppliers for each drug during a year is the number of suppliers that had sales of the drug at any point during that year.

Failure to comply with manufacturing standards resulting in a warning letter (compliance with manufacturing standards). Manufacturers may choose to temporarily shut down production to correct the conditions that led to the violations of current good manufacturing practice regulations cited in a warning letter. They may also shut down permanently if the costs of correcting the problematic conditions outweigh the potential benefits of producing drugs at that establishment. A drug was associated with a warning letter if at least one establishment manufacturing the drug received a warning letter for failure to comply with manufacturing standards.

Price decline (price and volume of sales). Shortages may occur if prices decline because suppliers will not have a financial incentive to increase production of the drug in shortage. For each drug, we calculated a proxy for the average annual price as the ratio of its total dollar sales to its total volume sales. We adjusted all prices to 2014 dollars using the Consumer Price Index for all urban consumers.

Model Specification

We used our 3-year panel data file to estimate a repeated measures logistic regression model in which the dependent variable was a binary variable indicating whether there was a new or ongoing drug shortage in the given year (2012, 2013, or 2014). The model included the following binary explanatory variables for whether: there were sales of the drug in its generic or branded generic form during the previous year, the number of suppliers of the drug was greater 2 years before the given year compared with 1 year before it, the proxied average price of the drug was greater 2 years before the given year compared with 1 year before it, and an establishment that manufactured the drug failed to comply with manufacturing standards and received a warning letter from the FDA in either of the preceding 2 years.

We used the coefficient estimates from the repeated measures logistic regression model to calculate for each explanatory variable the estimated percentage point increase in the probability of a shortage when the explanatory variable is present for all drugs relative to the mean probability of a shortage predicted for all drugs in our study by our model. We did this in three steps. First, for each explanatory variable, we estimated the probability of a shortage in the presence of that variable by setting the value of the variable to one, leaving the values of the other explanatory variables unchanged, and then calculated the probability. Second, we used the coefficient estimates from the regression model and the data for every drug in our study to calculate the mean probability of shortage predicted for all the drugs in our study, which was 0.607. Third, to compute the estimated percentage point increase in probability of a shortage for each explanatory variable, we computed the difference between the probability of a shortage for each explanatory variable (step 1) and the mean probability of a shortage predicted for all drugs in our study (step 2).Table 10 presents the coefficients (log odds ratios) and odds ratios we estimated from our repeated measures logistic regression model.

For each explanatory variable, the estimated probability of a shortage if that variable is present for every drug in our study is presented in table 11.

Additional Factors

To inform our selection of the explanatory variables to include in the regression model, we computed descriptive statistics for a broad range of factors in the following categories: drug characteristics, market structure, compliance with FDA manufacturing standards, and price and volume of sales. Specifically, we compared frequencies, medians, and trends over time for these factors for drugs in shortage and those not in shortage during 2014. Some of the additional factors that we analyzed were:

Years since brand-name or generic drug approval (drug characteristic). The years since brand-name drug approval is based on the date of the oldest approved new drug application associated with a particular drug. The years since generic drug approval is based on the oldest approved abbreviated new drug application associated with a particular drug. Both of these measures truncate at 32 years because FDA’s data source for approval history—Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)— does not provide approval dates before 1982.

Number of establishments that manufacture the drug (market structure). We used FDA drug registration and listing data from 2009 and 2014 to identify the number of establishments that were listed as manufacturing the drugs in our study. As many establishments manufacture more than one drug, we also created a measure that identifies the relationship between the establishments and all of the drugs in our analysis.

Receipt of an official action indicated inspection classification (compliance with manufacturing standards). FDA classifies establishment inspections as official action indicated when serious deficiencies are found that warrant regulatory action. When an inspection is so classified, FDA may take various regulatory actions, including issuing a warning letter, which we include in our regression model.

Limitations

Our analysis has some limitations. First, our findings are limited to data for sterile injectable anti-infective and cardiovascular drugs that were marketed and sold from 2010 through 2014 and shortages in these two therapeutic classes from 2012 through 2014. Our findings are not generalizable to drugs in other routes of administration, other therapeutic classes, or shortages during other time periods. Second, missing manufacturing location data may have caused us to underestimate or overestimate the relationship between shortages and noncompliance with manufacturing standards resulting in a warning letter. For the drugs in our study that were missing manufacturing location data, we could not always identify whether the drugs were manufactured by at least one establishment that received a warning letter. Therefore, we may have misclassified some drugs that were manufactured by establishments that received a warning letter as drugs manufactured by establishments that did not receive a warning letter. Whether we may have overestimated or underestimated the relationship depends on whether the potentially misclassified drugs were in shortage. If these potentially misclassified drugs were in shortage, our model may underestimate the relationship between shortages and receipt of a warning letter. If these potentially misclassified drugs were not in shortage, our model may overestimate the relationship between shortages and receipt of a warning letter. The extent to which we may have underestimated or overestimated this relationship is unclear. For 57 of the 118 drugs in our study, we found partial manufacturing location data, and for 3 drugs we found no manufacturing location data. We were not able to identify these data for drugs if the IMS data did not include a national drug code for a particular product or if the manufacturer was not listed in FDA’s drug registration and listing data. Finally, our proxy for average transaction price for the drugs in our study applies to all strengths and package sizes of the drug, because we defined a drug to include all products with the same active ingredient and route of administration, regardless of strength or package size. We used this definition of a drug because it is the definition that UUDIS uses to record drug shortages. In the market, average transaction prices for each drug vary by strength and package size.

Data Reliability and Audit Standards

We took several steps to ensure that the data used to produce this analysis were sufficiently reliable. Specifically, we assessed the reliability of the IMS Health National Sales PerspectivesTM data by interviewing officials at IMS Health. We also reviewed relevant documentation and examined the data for obvious errors, such as missing values and values outside of expected ranges. We assessed the reliability of the UUDIS and FDA data by interviewing officials, reviewing relevant documentation, and examining the data for obvious errors. We determined that these data were sufficiently reliable for the purposes of this analysis.

Appendix III: Comparison of Selected Factors for Sterile Injectable Anti-infective and Cardiovascular Drugs by Shortage Status, 2012 - 2014

This appendix compares certain factors for sterile injectable anti-infective and cardiovascular drugs in shortage during 2012, 2013, and 2014 to those same factors for drugs not in shortage during those years. Drugs classified as being in shortage during a year were in shortage anytime during that year, and include shortages that started in a prior year and remained ongoing. In general, we found differences between drugs that were in shortage during this time period and drugs that were not in shortage (see table 12). For example, our analysis showed that for 19 to 23 percent of these drugs in shortage between 2012 and 2014, the number of suppliers decreased during the 2-year period before the shortage compared with 6 percent or less of drugs that were not in shortage. A decline in the number of suppliers indicates that a supplier that had sales for a particular drug in one year had no sales for that drug in the next.

Appendix IV: Comparison of Selected Factors for Sterile Injectable Anti-infective and Cardiovascular Drugs by Shortage Status in 2014

This appendix compares certain factors for sterile injectable anti-infective and cardiovascular drugs in shortage in 2014 to those same factors for drugs not in shortage that year. Drugs classified as being in shortage were in shortage anytime during 2014, and include shortages that started in a prior year and remained ongoing. In general, we found differences between drugs that were in shortage and not in shortage in 2014 for certain factors, such as for sales of generic versions of the drug (see table 13).

Appendix V: Comments from the Department of Health and Human Services

Appendix VI: GAO Contact and Staff Acknowledgments

GAO Contact

Staff Acknowledgments

In addition to the contact named above, Geri Redican-Bigott, Assistant Director; Katherine L. Amoroso; Zhi Boon; Sandra George; Alison Goetsch; Cathleen Hamann; Rebecca Hendrickson; Richard Lipinski; Yesook Merrill; Vikki Porter; Oliver Richard; Daniel Ries; Merrile Sing; Alison Smith; and Eric Wedum made key contributions to this report.

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