Medication shortage du jour: Root-cause analysis

Compared with 2006, the number of medication shortages experienced in 2010 has tripled, compromising patient safety and outcomes, increasing drug costs and forcing health care providers to use agents with which they are unfamiliar or less than suitable therapeutic alternatives.

The drug shortage list on the American Society of Health-System Pharmacists website — one of the most comprehensive sources for medication shortage information — contains 222 unique drug shortage bulletins as of May. Nearly one-quarter of the medications in short supply are commonly used by cardiologists, electrophysiologists and interventionalists. Some examples include: amiodarone; digoxin; diltiazem; dopamine; furosemide; heparin sodium; lidocaine; nitroglycerin; propofol (Diprivan, AstraZeneca); reteplase (Retavase, Centocor); ticlopidine (Ticlid, Roche Palo); and torsemide. The etiology of these shortages is multifactorial. The most common causes include manufacturing delays, production shortages, business decisions and regulatory issues.

Manufacturing delays

J. Erin Allender

Many manufacturers are currently unable to acquire the raw materials necessary to compound medications. In 2002, approximately 20% of raw materials were produced in the United States. Natural disasters and political or social upheavals can limit importation. When raw materials reach an American manufacturer, antiquated equipment or equipment malfunction can also limit production. Because most manufacturers operate at maximum capacity and use one production line for multiple products, any interruption can affect the production of several agents. A shortage will result, especially if there is no alternative manufacturer.

Injectable products seem to be the most vulnerable to these issues, comprising 66% of the current drug shortages. Relatively few manufacturers compound injectables due to the complexity of the process and the increased regulatory requirements. In addition, long manufacturing lead times mean that increases in output from current production lines or the addition of new lines may not acutely affect supply. When two of the four manufacturers licensed to produce IV diltiazem stopped making the product, the remaining companies were unable to keep up with demand. Because approval of new production lines or sites can take months, a shortage ensued.

Production strategies

Unlike the products of many other industries, pharmaceuticals have a relatively short expiration date. Thus, most manufacturers follow a “just-in-time” production strategy: They limit storage costs and increase turnover by decreasing the supply/demand margin. If production declines or halts, the small inventory may be hoarded by pharmaceutical distributors, repackaging companies and pharmacies. Manufacturers may attempt to prevent hoarding by releasing equal allotments to buyers, but these shipments are insufficient for some and too generous for others, relative to demand. Likewise, new guidelines, FDA-approved indications or shortages of similar products may acutely increase demand. With many manufacturers already operating at maximum capacity and the necessary delays to production start-up, a shortage may be unavoidable.

Business decisions

When generic formulations of a branded product come to market, the cost of production and pricing wars diminish profit. Companies may decrease or discontinue production in favor of increasing production of a more profitable product. Companies may also reallocate funds from manufacturing to drug research and development or marketing of other more profitable branded medications. Mergers may further limit the number of manufacturers that compound a particular agent. Thus, when one manufacturer encounters delays or must recall its product, there may not be another company capable of supplying the drug. The current amiodarone and furosemide shortages occurred because manufacturers discontinued production to focus on other products. Of the three remaining furosemide manufacturers, one was forced to recall its product, increasing the severity of the shortage.

Regulatory issues

Manufacturers are required to notify the FDA when they are experiencing quality issues. In addition, the agency may identify quality issues that make drug recalls necessary. One large maker of injectables such as atropine, dopamine and phenylephrine recently recalled almost all of its products due to particulate contamination. Once the issues have been resolved, the FDA may lack the personnel required to re-inspect the facility in a timely manner, lengthening the shortage. In lieu of fixing the quality issue and awaiting re-inspection, some manufacturers simply discontinue the product. Companies are currently required to give the FDA a 6-month notice before ceasing production of a “medically necessary” drug if there is no alternate, FDA-approved source. Unfortunately, the agency lacks the authority to penalize manufacturers that are noncompliant, and it cannot force a manufacturer to continue to produce a product; however, the FDA can and will expedite approval of new manufacturing sites or permit legal drug importation to secure supplies of medically necessary agents. For example, the FDA granted approval to import the unapproved European drug Fresenius Propoven 1% (Fresenius Kabi AG) to manage the recent propofol shortage.

Possible end in sight

The burden of drug shortages and the associated negative effect on patient care has garnered the attention of legislators. In February, US Sen. Amy Klobuchar, D-Minn., proposed the “Preserving Access to Life-Saving Medications Act.” Instead of focusing solely on “medically necessary” drugs, the bill proposes requirements for manufacturers of any FDA-approved product. In short, manufacturers would be required to notify the FDA of any scenario that may cause a drug shortage, defined as “a period of time when the total supply of all versions of a drug available at the user level will not meet the current demand for the drug at the user level.” A 6-month notice would be required for planned product discontinuation, interruptions in production, diminution of production or company mergers. For unplanned events that may affect output (eg, raw materials shortage), manufacturers would be required to alert the FDA as soon as possible. Perhaps most importantly, the bill gives the FDA authority to fine noncompliant manufacturers.

The bill also requires the FDA to proactively identify medications vulnerable to shortages. The number of manufacturers, the sources of raw material or active ingredients, supply chain characteristics, production complexity and the availability of therapeutic alternatives are criteria that may be used to identify vulnerable drugs. If the drug is deemed medically necessary, the FDA would have to collaborate with the manufacturer to ensure continuity of production and develop processes for addressing drug shortages.

Conclusions

Drug shortages have compromised patient care and safety and have burdened our health care system. Root cause analyses identified manufacturing delays, production shortages, business decisions and loopholes in our pharmaceutical industry regulations as common causes. New bills have been proposed to prevent or mitigate supply issues, but their incorporation into law may require more lobbying, and their ultimate effect is unknown. Until then, a shortage is an opportunity for health care providers to collaborate to conserve drugs in short supply and brainstorm safe, effective alternatives.

J. Erin Allender, PharmD, BCPS, is a cardiology critical care clinical specialist at WakeMed Health and Hospitals in Raleigh, N.C.

Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor, department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board. For suggestions of future topics for this column, please contact Dr. Cooper-DeHoff, dehoff@cop.ufl.edu.

For more information:

• American Society of Health-System Pharmacists. Drug shortages. Available at: www.ashp.org/DrugShortages/Current. Accessed May 9, 2011.
• American Society of Health-System Pharmacists. Drug distribution and control: Procurement–Guidelines. Available at: www.ashp.org/DocLibrary/BestPractices/ProcureGdlShortages. Accessed May 19, 2011.
• Open Congress. Preserving Access to Life-Saving Medications Act. Available at: www.opencongress.org/bill/112-s296/text. Accessed May 15, 2011.

Disclosures: Drs. Allender and Cooper-DeHoff report no relevant financial disclosures.