Managing prescription drug shortages has become quite complex and requires a multidisciplinary team of creative healthcare professionals to keep up with the changing supply chain. Shortages include, but are not limited to, generic sterile injectables, anti-cancer drugs, anesthetics, pain medications, and nutritionals, creating an estimated annual impact on U.S. hospitals of $216 million from purchase of therapeutic substitutions.
Pharmacists are frequently asked, “Why does this happen?” There are multiple contributing factors in the supply chain that affect drug shortages.
• Raw Material Shortages. Nearly 80% of pharmaceutical grade raw materials are sourced outside of the USA. Drug availability is impacted when political instability interrupts U.S. trade in foreign countries, animal diseases contaminate tissue from which raw materials are harvested, or environmental issues affect plant growth from which raw materials are sourced. Remember the heparin recall a few years ago due to adulteration with oversulfated chondroitin in China?
• Quality Issues. Nearly 42% of sterile injectable drug shortages in 2010 were caused by product quality issues (e.g., particulates, microbial contamination, stability changes). Recently, Bedford Labs recalled injectable medroxyprogestrone due to silicone particles found in the product. A few years ago, Benvenue announced it was closing a plant that produced injectable methotrexate and Doxil, two chemotherapeutic agents, due to quality control issues. Only three other companies in the USA manufacture either methotrexate or Doxil, causing a supply issue for children with leukemia, as well as women with ovarian cancer, respectively.
• Manufacturing Difficulties or Production Decisions. Business decisions regarding branded drugs are made every day based on availability of generic drugs, the product’s market size, patent expirations, drug approval status, and anticipated clinical demand for the product. Manufacturers are not required to report product discontinuations to the FDA unless they are the sole source of a life supporting medication or a medication used to prevent a debilitating disease. Mature brand enthusiasm decays over time and there is a diminishing financial return to the manufacturer followed by a decision to sunset the brand. J&J stopped manufacturing branded IV Levaquin when it went generic.
• Change in Product Formulation. In 2006 there was a transition from albuterol and other metered dose inhalers with chlorofluorocarbons to metered dose inhalers containing hydrofluoroalkanes. Line extensions and formulation changes can evolve for marketing reasons or safety reasons or both.
• Regulatory Issues. FDA enforces standards like current Good Manufacturing Practice (cGMP). Yet, the FDA will help manufacturers out of cGMP compliance return to compliance when a significant corrective action involves a medically necessary product. FDA does not have the authority to require a manufacturer to produce any drug, even if the drug is a medical necessity. Bedford Labs’ oncology line was shut down by the FDA within the past year (i.e., carboplatin, cisplatin, leukovorin, Taxol). Bedford was told by the Feds that Bedford can not ship out any oncology product on hold in their warehouse until further FDA notice.
• Industry Consolidation and Company Mergers. Mergers frequently involve closing a manufacturing facility and result in a narrowed drug product portfolio for the post merger corporation. Baxter recently sold their entire generic injectable line to Westward resulting in a shortage of lidocaine, fentanyl, ketorolac, and midazolam. There are fewer generic drug manufacturers today than in the past even though there is a long line of applicants for new generic drug manufacturing processes at the FDA.
• Restricted Drug Distribution and Allocation. A drug manufacturer can place restrictions on limited drug supplies by requiring its drug is sourced through a specialty distributor. Clozapine and Tikosyn can only be supplied to a pharmacy registered in the manufacturers’ programs. Other prescription drugs are only supplied specific to each patient at the time the physician prescribes them.
• Just in Time Inventory (JIT). JIT is a strategy to minimize costs at various points along the supply chain. Some drug shortages may be wholesaler dependent, as drug shortages can occur when contracts with suppliers are delayed. Drug wholesalers oftentimes charge the drug manufacturers for stocking their drugs, and the drug manufacturers restrict the wholesalers from overstocking.
Wholesaler purchase differs from direct manufacturer purchase, or purchasing from med/surg suppliers.
• Changes in Product Demand and Shifts in Clinical Practice. When a new indication for a marketed drug is FDA approved, when new hospital programs start, or when a drug representative promotes new products and unanticipated demand increases for those products, it may be more difficult for the hospital or physician office based practice to keep up with supply. Direct-to-consumer advertising on television and in print ads also contributes to fluctuating product demand.
• Gray Market. The number of licensed non-traditional distributors who buy direct from the drug manufacturers to stockpile scarce drugs and resell at much higher prices are increasing as drug shortages go on. Purchasing from the gray market does not ensure drug pedigree, especially if sourced outside of the USA. Drug pedigree is a law in Florida and other states where most of the gray market wholesalers are located, but not law in Ohio. Gray market Epogen was available several years ago.
• Natural Disasters. About seven months ago a fire at a Hospira manufacturing plant in New York reduced inventory for emergency syringes (e.g., dextrose, sodium bicarbonate, epinephrine). This forced the manufacturer to decrease production of another medication in another facility to continue making the drug for a life threatening indication.
Managing Drug Shortages.
Participants of the Drug Shortage Summit on November 5, 2010, including the American Society of Health Systems Pharmacists, the Institute for Safe Medication Practices, the American Society of Anesthesiologists, and the American Society of Clinical Oncology, agreed that:
• expand FDA authority to require manufacturers to notify FDA of supply interruptions/product discontinuations;
• allow FDA to require manufacturers to develop continuity of supply plans;
• require development of expedited approval pathways for pre-1938 drugs.
• encourage confidential notification to FDA when there is a single source active pharmaceutical ingredient.
• explore incentives that encourage manufacturers to enter the market or stay in the market to minimize potential for shortages.
• collaborate with the DEA to alter quotas for controlled substances in short supply.
Senator Amy Klobuchar’s Bill 296 (H.R. 2245) requires drug manufacturers to notify the FDA at least six months in advance when experiencing a planned interruption in the production of a drug potentially resulting in a shortage situation or as soon as possible if an unexpected interruption or adjustment in supply transpires. The bill supports development of contingency plans for drugs vulnerable to shortage.
On October 31, 2011, President Obama issued an executive order directing the FDA to expand its reporting of prescription drugs and speed up regulatory reviews to respond to shortages.
Healthcare professionals around the country are actively working together in multidisciplinary teams to come up with alternate therapeutic options for these drug shortages which are not going away any time soon.
For more information, please visit the ASHP drug shortages web resource center @ www.ashp.org/drugshortages.