Risk Management and Drug Shortages: Controlled SubstancesBy
A recent report by the US General Accounting Office (GAO) was critical over the lack of coordination between the US Food and Drug Administration (FDA) and the US Drug Enforcement Agency (DEA) for contributing to shortages of controlled substances, primarily generics. The FDA and the DEA, however, offer differing views.
Quality and related manufacturing issues were behind much of the attention given to the problem of drug shortages, which peaked in 2011, and which have since declined. But for one area, controlled substances, a lack of regulatory coordination between the US Food and Drug Administration (FDA) and the US Drug Enforcement Agency (DEA) was cited as a contributing factor to drug shortages, according to report issued by the US General Accounting Office (GAO) in February 2015. The FDA testified before Congress in May 2015 to address these concerns, an issue that impacts both drug product and bulk substance manufacturers of controlled substances.
Controlled substances and drug shortages: the numbers
Drug shortages for controlled substances have to be considered in the overall context of all drug shortages. The number of new drug shortages in the United States rose steadily between 2005, when the FDA began tracking 60 new shortages, and the all-time high in 2011, when 251 new shortages were reported. After a series of interventions, including an Executive Order on reducing prescription drug shortages issued by the President Barack Obama in 2011, enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, FDA outreach to a variety of stakeholders, including work with the pharmaceutical industry, the number of new drug shortages declined significantly in 2012 to 117, fell even further to 44 in 2013, and remained steady in 2014, with 44 new shortages occurring. However, there continues to be new shortages occurring in 2015, as well as older shortages that have persisted. In information as of May 2015, the FDA is tracking and working to resolve over 70 shortages that began in 2014 and prior years, which is a decrease from the 97 ongoing shortages tracked at the end of 2013.
In looking at controlled substances, of the 168 shortages of drugs containing controlled substances that were reported from January 2001 through June 2013, nearly 70% began between 2008 and 2013, according to the GAO report. The number of new shortages reported each year peaked in 2009–with 28 that year–and has somewhat declined since then although the number still remains significantly above pre-2008 levels. The recent increase in these shortages mimics the pattern found for shortages of all drugs, which showed a sharp increase since 2007 and subsequent declines after peaking in 2011. The 168 shortages of drugs containing controlled substances represent a small percentage of the total 1,575 drug shortages reported from January 2001 through June 2013. The vast majority of shortages of drugs containing controlled substances–96%–lasted longer than one month and some of these shortages spanned multiple years. The average duration was nearly one year; however, some were much longer. For instance, a single shortage of lorazepam injection, a medication used to treat anxiety, lasted slightly more than five years, according to the GAO analysis.
Drugs, substances, and certain chemicals used to make drugs are classified by the DEA into five distinct categories or schedules depending upon the drug’s acceptable medical use and the drug’s abuse or dependency potential. The abuse rate is a determinate factor in the scheduling of the drug. Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychological and/or physical dependence. As the drug schedule changes, Schedule II, Schedule III, Schedule IV, and Schedule V, so does the abuse potential. Schedule V drugs represents the least potential for abuse. Drugs containing Schedule II substances accounted for more than half of the shortages of drugs containing controlled substances that were reported from January 2001 through June 2013. Fifty-seven percent of shortages involved Schedule II substances while the remaining schedules–schedules III, IV, and V–comprised 15%, 26%, and 2% of shortages, respectively, according to the GAO report. Shortages of drugs containing Schedule II, III, and IV substances ranged on average from 356 days to 359 days. However, shortages of schedule V drugs were shorter, lasting an average of 228 days.
Although though the number of shortages reported has declined in recent years, the number of active shortages of drugs containing controlled substances remains high, according to the GAO analysis. The active shortage total for each year includes both new shortages reported that year and shortages that started in a prior year that were still ongoing. Of the 87 shortages of drugs containing controlled substances identified as critical from January 2001 through June 2013, half involved pain relievers (analgesics).These shortages were identified as critical because alternative medicines were not available, the shortages affected multiple manufacturers, or multiple reports of shortages from different provider institutions were reported. There were also shortages of anti-anxiety medications, sedative hypnotic drugs, and stimulants. All of these types of drugs belong to the broader class of drugs that affect the central nervous system and are used to treat seizures, manage anxiety, and to provide sedation and pain reduction, among other things.
Most critical shortages of drugs containing controlled substances–68 of 87 (78%)–involved a generic drug. This 78% includes 38 critical shortages of drugs available only in generic form and 30 shortages of drugs available in both brand-name and generic forms. Another 19 critical shortages were of drugs available only in brand-name form (22%). The GAO analysis also showed that 40 critical shortages (46%) involved generic pain relievers. These 40 critical shortages include 19 shortages of analgesics only available in generic form (22%) and 21 shortages of analgesics available in brand-name and generic form (24%).
Most critical shortages of drugs containing controlled substances–79 shortages (91%) involved drugs that were manufactured by four or fewer companies and 39 of those shortages involved drugs manufactured by only one company. The remaining 8 shortages involved drugs that were manufactured by five or more companies (9%). Finally,injectable drugs were in short supply slightly more often than orally administered drugs during this time period, with 44 critical shortages of injectable drugs (51%) and 35 critical shortages of orally administered drugs (40%). The remaining shortages involved drugs with other routes of administration, such as those administered topically.
Each year the US DEA’s Office of Diversion Control establishes three types of quotas for Schedule II substances: Aggregate production quotas (APQs), bulk manufacturing quotas, and procurement quotas. APQa are established for each basic class of Schedule I and II substances (i.e, such as amphetamines) that can be manufactured in the United States in a given year to provide for the estimated medical, scientific, research, and industrial needs of the United States, lawful export requirements, and the establishment and maintenance of reserve stocks. APQs limit the amount of bulk materials that may be manufactured or synthesized in the United States, and subsequently available for use in the manufacture of drug products containing Schedule I and II controlled substances.
Bulk manufacturing quotas limit the amount of a basic class of Schedule I or II controlled substance that an individual bulk manufacturer can manufacture through the extraction or synthesis of plant material or other controlled substances. Each bulk manufacturer must apply to the DEA to obtain the bulk manufacturing quota for a specific substance class, and the bulk manufacturing quotas granted to manufacturers in sum cannot exceed the APQs established by the DEA. Beginning with 2013, APQs, the DEA established an additional 25% reserve in APQs in the event of natural disaster or other unforeseen event that could result in substantial disruption.
Procurement quotas limit the amount of a basic class of Schedule I or II controlled substance that an individual manufacturer can procure from a manufacturer of bulk raw materials in order to manufacture into dosage forms of a drug or into other substances. The sum of procurement quotas determines the amount of bulk material that needs to be produced.
The Food and Drug Administration Safety and Innovation Act (FDASIA), enacted in July 2012, contains several provisions related to drug shortages that require coordination between the FDA and the DEA. When the FDA is notified of a supply disruption of a drug that is life-supporting, life-sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, and that contains a controlled substance subject to quotas, FDASIA requires that the FDA request, if FDA determines that it is necessary, that the DEA increase quotas applicable to that controlled substance. FDA’s Drug Shortage Staff (DSS) tracks drug shortages until their resolution, and posts information on its website about current and resolved shortages.The FDA also obtains information from the American Society of Health-System Pharmacists, which becomes aware of drug shortages through voluntary reporting from hospitals, pharmacists, and other healthcare providers. The FDA responds to shortages by taking actions within its authority to address the underlying causes and to enhance product availability. For example, the FDA may offer feedback on a manufacturers’ proposed approach to responding to quality concerns.
Similarly, when FDA has determined that a Schedule II drug is in shortage in the United States, manufacturers may also make such requests by submitting quota applications, and FDASIA requires that the DEA respond to these requests from manufacturers within 30 days. Regardless of whether the request came from FDA or manufacturers, if the DEA determines that issuing additional quota is not necessary to address a shortage, it must provide a written response.
The GAO study findings
The GAO report, released in February 2015, found that DEA has not effectively administered the quota process that limits the amount of controlled substances available for use in the United States. Each year, manufacturers apply to DEA for quota needed to make their drugs. The GAO report, however, reported that the DEA has not responded to them within the time frames required by its regulations for any year from 2001 through 2014. According to the GAO report, DEA officials attributed this lack of compliance to inadequate staffing, and manufacturers who reported quota-related shortages cited late quota decisions as causing or exacerbating shortages of their drugs.
The GAO report said that DEA’s weak internal controls jeopardize the agency’s ability to effectively manage the quota process. For instance, agency officials said that DEA does not conduct quality checks to ensure the accuracy of the data in its Year-End Reporting and Quota Management System (YERS/QMS). GAO estimates that 44% of YERS/QMS records in 2011 and 10% 2012 had errors. DEA officials said that 2011 was the first year manufacturers applied for quota electronically, and they expected data from 2012 and beyond to be more accurate.
The GAO report said that the DEA also lacks critical management information because it does not have performance measures related to setting quotas, nor does it monitor data to assess its performance. The study also found that the DEA does not have reasonable assurance that the quotas it sets are in accordance with its requirements and cannot ensure continuity of its operations, as it does not have protocols, policies, training materials, or other documentation to manage the quota process.
The GAO was also critical of the lack of coordination between the FDA and the DEA with with respect to controlled substances. The report concluded that despite statutory provisions requiring the DEA and the FDA to coordinate certain efforts to address shortages of drugs containing controlled substances, the agencies have not established a sufficiently collaborative relationship. The GAO report cited as an example that the DEA and the FDA disagree about what constitutes a shortage. In its report, the GAO said that the DEA officials also said that with respect to controlled substances, the FDA’s posting of drug-shortages information on its website encourages manufacturers to falsely report shortages to obtain additional quota. However, the GAO report said that the FDA reports that it takes steps to investigate and confirm the shortages on its website. Given such barriers to coordination, the GAO report said that the DEA and FDA cannot effectively act to prevent or alleviate shortages. The GOA study said that although the DEA and the FDA have a memorandum of understanding (MOU) in place, it has not been revised since the 1970s, and they have been working for more than two years to update it. The GAO study said that officials from both agencies said an updated MOU could facilitate information sharing and help prevent and mitigate future shortages of drugs containing controlled substances.
Congress addresses issue
In May 2015, Captain Valerie Jensen, Associate Director of the Drug Shortages Staff (DSS) in the FDA’s Center for Drug Evaluation and Research (CDER), testified before the US Senate Caucus on International Narcotics Control, to address this issue of drug shortages for controlled substances. She noted that the FDA’s drug-shortage process and the factors that may contribute to drug shortages are the same for both controlled substances and non-controlled substance. This can include quality problems with the manufacturer, such as a sterility failure or production line breakdown, or specific drugs experiencing quality failures, such as contamination with glass, metal, or other foreign particles. She said that the last time a manufacturer reported a shortage that was related to a DEA-established quota was in 2011, and since that time, all shortages of controlled substances have been reported to be caused by other factors, including quality failures, manufacturing delays, discontinuations, and raw material problems, and were not related to the DEA or the established quota, according to the FDA. In September 2014, CDER revised its Manual of Policies and Procedures (MaPP) to clarify FDA’s process of addressing shortages of controlled substances. According to the revised MaPP, when FDA’s DSS determines that a potential or actual shortage involves a request for an adjustment in applicable quotas made by an active pharmaceutical ingredient (API) or final dosage manufacturer of a Schedule II product, the FDA takes various steps to identify and notify the DEA. Since FDASIA was enacted, the FDA asserts that there have not been any shortages of controlled substances reported to be due to quota allocations.To help streamline and improve communications, the FDA and the DEA have developed a MOU that sets forth steps and procedures for more consistent and efficient exchange and tracking of information between the two agencies.
In her testimony, Jensen said that the FDA is working to mitigate the factors that lead to shortages of all kinds. In October 2013, the FDA released a Strategic Plan, called for in FDASIA, both to improve the FDA’s response to potential, imminent, or existing shortages and to advance longer-term approaches for addressing the underlying causes of shortages to prevent supply disruptions from occurring in the first place, which the agency is now implementing. Among other things, the plan suggests that FDA improve data and response tracking. In line with this suggestion and with the GAO’s suggestion in a February 2014 report on drug shortages, the FDA created a dedicated data system that focuses solely on collecting data related to shortagesâ€”a system that integrates data from the other general data systems and is designed to improve tracking efficiency. This new drug data system enables the FDA to more efficiently track and assess issues relating to drug shortages, including enhancing the tracking of time from notification of shortage to resolution. The plan also suggests that the FDA enhance public communications about drug shortages. To address this suggestion,the FDA updated its online Drug Shortage Database on the FDA website to improve functionality and allow users to sort by different therapeutic categories. Also, Jensen said that the FDA recently launched a drug shortages mobile app to improve access to information, by allowing users to search or browse for drug information and report suspected drug shortages or supply issues to FDA.
In concluding her testimony, Jensen said: “It is extremely important that FDA and DEA have good coordination and communication when there is an impending shortage of a controlled substance, whether or not it is reported to be related to quota. FDA has processes in place to govern how we communicate about potential shortages with DEA, informed by FDASIA mandates and our own Strategic Plan for Preventing and Mitigating Drug Shortages. FDA and DEA worked closely together to finalize our MOU to further streamline our communications, and we look forward to continued collaboration with DEA to further our shared mission of serving the American public.”
Marcia Crosse, Director, Health Care, at the GAO also testified before the Senate Caucus on International Narcotics Control to provide a further update and expound on its February 2015 report. Crosse asserted that the GAO found significant weaknesses involving the DEA’s management of the quota process for controlled substances. She cited that that DEA had not responded to manufacturers’ annual quota applications for bulk manufacturing and procurement quotas by its regulatory deadline of July 1 for any year from 2001 through 2014. From the GAO’s analysis of a random probability sample of YERS/QMS source documents, the GAO estimated that DEA took an average of 182 days in 2011 and 178 in 2012 beyond July 1 to establish annual bulk manufacturing and procurement quotas. The report also said that the DEA has not proposed APQs on or before May 1, as required by its regulations, for any year from 2001 through 2014.
In her statement, Crosse said that manufacturers have expressed concerns about the DEA’s timeliness in establishing quotas and have asserted that the amount of time it takes DEA to respond to their annual and supplemental quota applications has caused or exacerbated shortages of some drugs containing schedule II substances. Ten manufacturers reported to the FDA that quota related issues caused seven of the 40 shortages of drugs containing Schedule II substances from January 2010 through June 2013. In its May 2015 report, the GAO said that DEA officials do not agree that quotas can cause such shortages because the agency authorizes quotas at the basic class level of a substance, such as amphetamine or morphine. DEA cannot authorize quota for specific drug products containing those substances, as this is precluded by the Controlled Substance Act. Because of concerns with the reliability of DEA’s data, among other things, the GAO said it could not confirm whether DEA’s lack of timeliness in establishing quotas has caused or exacerbated shortages.
Going forward: GAO recommendations
The GAO issued four recommendations to the DEA to ensure it is best positioned to administer the quota process. Specifically, the GAO recommended that DEA (1) strengthen its internal controls of YERS/QMS, (2) establish performance measures related to quotas, (3) monitor and analyze YERS/QMS data, and (4) develop internal policies for processing quota applications and setting aggregate, annual, and supplemental quotas. “In commenting on a draft of our report,” said Crosse in her statement, “DEA did not explicitly agree or disagree with these four recommendations. In some instances, DEA indicated that it had already taken steps consistent with them or said that it is supportive of strengthening its management of the quota process.”
In her May 2015 statement, Crosse said that the GAO recommended that the DEA expeditiously establish formal policies and procedures to facilitate coordination with the FDA as directed by FDASIA, including a specific time frame in which it will be expected to respond to the FDA’s requests to expedite shortage-related quota applications. The GAO also made two additional recommendations to both the DEA and the FDA to strengthen their abilities to respond to shortages of drugs containing controlled substances. The GAO recommended that the two agencies promptly update the MOU, and that has now been accomplished. The GAO also recommended that in the MOU or in a separate agreement, the agencies specifically outline what information they will share and the time frames for sharing such information in response to a potential or existing drug shortage. The MOU did not include these details, according to the GAO.
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