The Scoop on Drug Shortages

A new feature on the pharma landscape is the shortfall in the supply of many medicines essential to the treatment of major health disorders, including cancer, heart disease, and stroke. The problem has festered largely undetected for years, but is gaining fresh momentum as a consequence of medical need, globalization, changes to manufacturing practice, and the exit of some companies from certain low margin segments of the business. Price controls have even been cited by some analysts as a driver behind the interruption of many maintenance therapies needed to help patients keep their conditions under control. To help readers separate truth from fiction, Pharm Exec asked the Tufts Center for the Study of Drug Development (TCSDD) to summarize new survey research—partly commissioned by a grant from Amgen—that documents the scope of the threat and identifies the structural roots of the shortages. In a larger sense, the study underscores how effective management of the drug supply chain is emerging as something much more than an engineering feat: instead it's a societal obligation, one that the industry is going to be measured on in return for that all-important license to operate. This is particularly evident for the generics side of the business, which accounts for the majority of drug shortages tallied to date. —William Looney, Editor-in-Chief

Drug shortages are a global challenge, not only for treatments in oncology but also anti-infectives and drugs that treat the central nervous system and cardiovascular diseases. Of particular note is the shortage of sterile injectable drugs used to treat cancer-related illnesses, anesthetics for surgery, emergency medical interventions, and electrolytes for intravenous feeding. The numbers behind the story are significant: drug shortages in the United States alone tripled in the brief five-year period between 2005 and 2010.

Although the latest reports by the Food and Drug Administration (FDA) have indicated fewer drug shortages in 2012 compared to 2011, there is nevertheless a tremendous residual effect on stakeholders in the supply chain and, more importantly, on patients. The FDA and other government and regulatory agencies worldwide are focusing on resolving drug shortages. Our research seeks to analyze the characteristics of drug shortages and their impact, with the ultimate aim of assisting regulators and other stakeholders to resolve the problem.

Study protocol

Tufts CSDD developed a two-part methodology that entailed building a database of current drug shortages and conducting interviews with experienced hospital pharmacists to gather firsthand knowledge of how drug shortages are managed and the challenges that they pose. Tufts CSDD staff gathered publicly available data on 240 drug shortages occurring between 2001 and February 2012, from lists maintained by the American Society of Health-System Pharmacists (ASHP) and the FDA. Data on therapeutic area, drug classification, molecule type, disease state, and the overall duration of the shortage for each drug was collected and analyzed. Tufts CSDD research staff coded the root cause of each drug shortage and summarized these causes by major grouping. Drug shortages that were resolved during this study were also included and reviewed for insights. We examined primary and secondary sources of research on this topic to provide context and clarification into the data collection process. Lastly, we assessed the economic cost and effects of drug shortages through interviews with hospital pharmacists.

Drug shortage characteristics

During the observation period (2001 through February 2012), the vast majority (94 percent) of drugs were small molecule chemical entities and 6 percent were large molecule biologics (e.g., proteins, polyclonal antibodies). Most drug shortages (80 percent) involved generic equivalents, only 20 percent involved branded drugs.

More than three out of four (77 percent) drug shortages in our sample were sterile injectables and 20 percent were administered orally. Of the branded drug shortages, 81 percent were sterile injectables. The number of branded large molecule therapies are projected to increase rapidly through 2016—10 of the top 20 drugs. And the number of generic biologics (i.e., biosimilars) entering the market is also expected to rise sharply during the next three to five years. Given that all large molecules are administered in a sterile injectable format, the incidence of drug shortages is expected to rise sharply and the challenge to manage these shortages will likely intensify.

Drug shortages have occurred in a wide variety of therapeutic areas, though there are several that are disproportionately large. One out of five drug shortages (18 percent) involve anti-infective treatments; 17 percent of shortages involve drugs targeting diseases of the central nervous system and pain. Drug shortages targeting cardiovascular illnesses and cancer-related illnesses represent 12 percent and 11 percent of all shortages, respectively.

The supply chain is delicately balanced where a disruption of a single manufacturer can have a huge negative impact on the delivery of drugs to pharmacies throughout the United States. This balance is in large part a function of the highly concentrated nature of manufacturers capable of providing sterile injectibles. Teva, Hospira, and Bedford Laboratories produced 71 percent of sterile injectables involved in supply shortages between 2001 and February of 2012. The voluntary suspension of Ben Venue Laboratories in the fall of 2011 due to Good Manufacturing Practice (GMP) violations, for example, resulted in a major shortage of Doxil and placed enormous pressure on the other manufacturers to fill the void. Ben Venue is the manufacturing arm of Bedford Laboratories, a subsidiary of Boehringer-Ingelheim.

The average product shortage duration was approximately 19 months. Four out of every 10 drug shortages is associated with manufacturing problems. The second most common reason, accounting for 27 percent of all shortages, is high demand coming from a variety of sources including consumers, as well as competitors looking to secure comparator drugs for clinical testing. A little more than one out of 10 drug shortages (13 percent) is due to drug discontinuation and withdrawal from the market. The leading cause of manufacturing delays was voluntary suspension of suppliers for requalification of equipment. Inspection citations and raw materials shortages were infrequent reasons for drug shortages and they tended to occur outside the United States.

Reported primary and secondary reasons for drugs shortages, by drug classification.

Economics plays a critical role in drug shortages. Unanticipated changes in supply and demand of a generic drug are often at the core of a drug shortage. Low-cost generics are not profitable for manufacturers and in some cases sales decline over time. In response, a manufacturer may divert capacity to more profitable areas, perpetuating a cycle of shortages. This often leads to a "gray market" where price gouging by third party sellers occurs.

A number of challenges prevent the FDA from acting directly against drug manufacturers. First, the FDA relies on voluntary information provided by manufacturers since they are not legally required to supply reasons for drug shortages. The FDA is also limited in its ability to inspect manufacturers overseas. The agency has recently increased its staffing to meet industry demands and is currently working with manufacturers to find alternatives. Recently, for example, the FDA approved the importation of Lipodox from Sun Pharma (a company based in India) to solve the shortage of Doxil, an oncology drug. The FDA issued a draft guidance in October 2011 mandating that drug manufacturers report shortages. This guidance was passed by Congress in the summer of 2012.

From the pharmacist frontline

In interviews with Tufts CSDD researchers, hospital pharmacists report that drug shortages have a major impact on costs, personnel time, and patients.

The costs associated with additional hospital pharmacy staffing are significant. A major published study on drug shortages found that the labor cost alone to manage drug shortages is an estimated $216 million annually in the United States. The costs associated with pharmacists, pharmacy technicians, and nurses in a 400-bed hospital (or greater) are in the range of $25,077 to $118,800 per year. One UK-based interviewee remarked that "we have to divert staff time to chasing outstanding orders and we spend a lot of time working out alternative treatments." Some recent UK data collected by a government survey found that 43 percent of pharmacists spend two to five hours per week sourcing out-of-stock medication. In addition, some hospitals need to increase the medication that they hold in stock as a strategy for dealing with the unreliability of certain drug supply chains. This extra inventory adds to hospital pharmacy expenses and dollars must be re-allocated to cover these costs.

Information technology systems—in particular, large databases containing inventory data and tracking capabilities—within the pharmacy play a key role in managing and resolving shortages. One hospital pharmacist warned, however, that there is an inverse relationship between system sophistication and the ease with which shortages are managed. "We've found that the more sophisticated your pharmacy drug distribution system is, the harder it is to manage shortages." Pharmacists spend a lot of unplanned time developing alternative treatment plans. One interviewee mentioned that "every patient must receive optimal treatment. We spend time working out alternative treatments; all guidelines have to have an alternative."

The lack of published data available on patient outcomes poses difficulties when assessing the impact of an alternative drug due to a shortage. One hospital pharmacist remarked that "when switching to another product, we may use a different concentration of a drug and we're concerned that there may be an adverse outcome or an error that may have occurred."

Key Survey Statistics

Efforts by independent groups to collect evidence on patient outcomes have been ongoing. For instance, the Institute for Safe Medication Practices (ISMP) is an independent, non-profit organization that is focused on patient outcomes and involved with industry stakeholders in the healthcare arena. The organization is concerned with improving patient safety and has reported on adverse patient outcomes brought about by drug shortages.

Recent efforts to curb shortages

Many countries are now developing solutions to address drug shortages across Europe including Germany, Belgium, and France. A number of government and legislative actions, including an Executive Order from President Obama on October 31, 2011, are also ongoing. Recently three top manufacturers indicated that they would be expanding their capacity for manufacturing generic sterile injectables. Policymakers like the FDA; other regulatory agencies worldwide, including the European Medicines Agency and national authorities in Germany, Belgium, and France; and manufacturers have all been directed to derive new solutions and policies to prevent drug shortages or to more effectively manage them.

One hospital pharmacist noted that achieving sustainable solutions to drug shortages would only occur by involving physicians and patients in the process and by building awareness among various constituents within hospital settings. Another interviewee warned that "we need to change our policy and involve doctors and patients in this discussion—as well as start advocacy groups." In many cases, physicians and patients may not be fully aware of shortages or their magnitude.

Key industry associations, including the EAHP (European Association of Hospital Pharmacists), the ASHP (American Society of Health-System Pharmacists), are involved in efforts to raise awareness and to reduce the incidence of drug shortages. In addition, patient advocacy groups are now bringing much needed visibility to the issue of drug shortages and are attempting to empower patients via access to information on websites, special webinars, or through social media. Some patient advocacy groups, such as Fightcolorectalcancer.org, make information about drug shortages available to patients and provide this information online. It provides detailed information about the shortage status of the heavily used drugs leucovorin and 5 FU (fluorouracil) on its website and also identifies alternative treatments and other critical "what to do" guidance for patients.

In our view, cooperation among all stakeholders will be needed to not only reduce the incidence of shortages, but to alleviate their unquestionably harmful effects on the patient population. Resolution of this problem will depend on government and industry leadership under a worldwide effort focused especially on anticipatory actions at the front line—by physicians, hospital staff, and patients.

Mary Jo Lamberti, PhD, is a Senior Project Manager at Tufts CSDD. She can be reached at Mary_jo.lamberti@tufts.edu. Ken Getz, MBA, is a Senior Research Fellow and Director of Sponsored Research Programs at Tufts CSDD. He can be reached at Kenneth.getz@tufts.edu.