Executive Summary: A Review of FDA’s Approach to Medical Product Shortages
Despite the fact that the U.S. Food and Drug Administration (FDA) has successfully prevented 137 shortages since the beginning of 2010, drug shortages have been increasing in frequency and severity in recent years and adversely affecting patient care. Some recent shortages have involved drugs for life-threatening conditions and, in some cases, the product in shortage has been the only product for the patient’s condition. While most drugs do not experience shortages, this is a significant public health problem, one that deserves the concerted attention of government and industry.
To that end, FDA conducted a review of medical product shortage activities in four product Centers in FDA and talked to external stakeholders in the drug arena to understand their perspectives on the current problem.1 Based on these conversations, a review of published and unpublished information on drug shortages, and analyses of existing or newly created databases, this report concludes that the problem of medical product shortages is complex and stems from economic, legal, regulatory, policy, and clinical decisions that are deeply interconnected. Many parties along the entire supply chain, including essential raw ingredient suppliers, Active Pharmaceutical Ingredient manufacturers, final drug product manufacturers, wholesalers, group purchasing organizations, clinicians, and, ultimately, patients are affected. While FDA has taken on the task of working with manufacturers to help prevent and mitigate these shortages, many of the root causes and potential solutions to the shortage problem lie beyond its purview. The Agency is also limited in its current authorities as it formulates a response to the problem.
In addition, the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Planning and Evaluation conducted an analysis of underlying economic factors that lead to periods of prescription drug shortages, particularly market factors that have contributed to shortages of sterile injectable oncology drugs. The report finds that growth in demand has occurred while the capacity of manufacturing facilities has remained stable, leading to a very high rate of capacity utilization. This analysis can be found at http://aspe.hhs.gov/sp/reports/2011/DrugShortages/ib.shtml.
Key Facts about Drug Shortages
- The number of drug shortages annually has tripled from 61 in 2005 to 178 in 2010.
- Of the 127 studied2 drug shortages in 2010-11, sterile injectables accounted for the majority (80%). The major therapeutic classes of drugs in shortage included oncology drugs (28%), antibiotics (13%), and electrolyte/nutrition drugs (11%).
- The leading primary reasons for the shortages reported to FDA were problems at the manufacturing facility (43%), delays in manufacturing or shipping (15%), and active pharmaceutical ingredient shortages (10%).
- Manufacturing quality problems that have resulted in shortages can be serious, including findings of glass shards, metal filings, and fungal or other contamination in products meant for injection into patients.
FDA Actions to Prevent Drug Shortages
FDA helped to prevent 38 drug shortages in 2010 and 99 to date in 2011, an increase DSP staff attribute, at least in part, to improved notification by manufacturers.3 The most common FDA actions to prevent a drug shortage were:
- Expediting review of new manufacturing sites, new suppliers, and specification changes (71%),
- Exercising regulatory flexibility and discretion (20%),
- Asking other firms to increase production (7%).
FDA Actions in Response to Drug Shortages
In the shortages studied, the Agency’s three most common actions were:
- Asking other firms to increase production (31%),
- Working with manufacturers to identify means to mitigate the dangers of products with quality issues (28%; e.g., work with a firm to include a filter with a product containing particulates), and
- Expediting review of regulatory submissions (26%).
FDA also exercised regulatory discretion regarding controlled importation of similar products approved abroad but not approved in the United States in 5% of cases.
Unique Manufacturing and Market Features of Sterile Injectables
- Manufacturing such products is complex and can more easily lead to problems that affect safety.
- Dedicated manufacturing lines are often required.
- The top three generic injectable manufacturers hold 71% of the market by volume.
- Most sterile injectables have one manufacturer that produces at least 90% of the drug (innovator and generic combined).
- “Just in time” manufacturing and inventorying practices leave little margin for error.
Together, these factors make shortages of sterile injectables more likely to occur and harder to prevent or mitigate.
Actions and Recommendations
There is no single or simple solution that can resolve the medical product shortage problem. Efforts to address the problem will need to be multifaceted, sustained over the long-term, and will require the engagement of all parties involved in the manufacture and distribution of medical products. Nonetheless, this report has identified a number of respects in which FDA’s internal processes might be improved, so that FDA is maximizing its contribution to the prevention and mitigation of shortages.
- Write a letter to drug manufacturers reminding them of their current legal obligations to notify FDA in advance of the discontinuation of certain drugs and urging them to voluntarily notify FDA of other potential disruptions to the supply of drugs that are not currently required, as soon as they become aware of them
- Develop guidance and regulations that clarify and enhance the information on potential drug shortages that is submitted by industry
- Provide additional staffing resources for FDA’s efforts to prevent and mitigate shortages
- Support legislation that requires early notification by manufacturers for drug shortages and provides new authority to FDA to enforce these requirements
- Implement and maintain a database that can analyze the characteristics of drug shortages
- Identify factors that contribute to success or failure in preventing drug shortages and continue exploring new approaches to preventing drug shortages under existing authorities
- Identify the quality issues in manufacturing practices that have contributed to severe drug shortages and develop approaches to address them
- Encourage product manufacturers to develop and maintain a plan for back up manufacturing and sources of Active Pharmaceutical Ingredients and other essential product components
- Explore development of a sentinel reporting network (e.g., major healthcare systems, wholesalers, physician specialty societies) to facilitate early warning of drug shortages
- Encourage wholesalers to develop and publicize their procedures for distributing medical products in shortage
- Continue to maximize public disclosure of information regarding medical product shortages in FDA’s possession, within the bounds of what must remain confidential
- Continue improving communication between FDA’s field investigators and the Center for Drug Evaluation and Research’s Office of Compliance and Drug Shortage Program staff
- Improve the Drug Shortage Program’s web site as a communications tool for health-care providers and other members of the public
- Explore the feasibility of developing a model based on available data on drug shortages, manufacturer characteristics, and market factors with the goal of assessing the probability of future shortages
1. In this report, the term “drug shortages” refers to shortages specifically pertaining to human drugs. “Medical product shortages” refers to all shortages, including human drugs, biologics, medical devices, and veterinary drugs.
2. This represents a subset of drug shortages that occurred during 2010 and 2011. These shortages tended to be larger, of longer duration, and of greater public health impact than shortages not studied (see “Characteristics of Drug Shortages” in the text).
3. Cox E. Drug shortages: FDA’s strategies and role. Presented at CDER Drug Shortage Workshop, Silver Spring, MD, September 26, 2011.