Drug Shortages Summit Summary Report
The Drug Shortages Summit was co-convened by the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists (ASA), the American Society of Clinical Oncology (ASCO), and the Institute for Safe Medication Practices (ISMP) on November 5, 2010 in Bethesda, Maryland. The goals of the summit were to:
- Discuss the scope and causes of drug shortages;
- Shed light on the harm to patients that is occurring due to drug shortages;
- Discuss the potential need for changes in public policy and stakeholder practices to prevent patient harm from shortages; and
- Develop an assertive action plan that reflects the recommendations and intent of stakeholders to work together to stop patient harm and disruptions in patient care caused by drug shortages.
Summit participants included representatives from health professional organizations, pharmaceutical manufacturers, and supply chain entities. Representatives of the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention also attended portions of the meeting as observers. A complete list of attendees is found in Appendix A.
This summary report reflects discussion at the Drug Shortages Summit, including recommended actions that will be further evaluated based on feasibility, impact, and resources required for implementation. Avoidance of unintended consequences (e.g., hoarding) will also be considered in this evaluation. Next steps will focus on establishing workgroups to explore, prioritize, and develop detailed action plans to achieve summit recommendations that are selected for implementation based on these criteria. Additional information will be available from the co-conveners and at www.ashp.org/drugshortages as these plans are developed
Introductory comments by Henri R. Manasse, Jr., Ph.D., Sc.D., Executive Vice President and Chief Executive Officer, ASHP; Mark A. Warner, M.D., President, ASA; and Michael P. Link, M.D., President-elect, ASCO illustrated the negative effect of drug shortages on patient care, including delayed care, inferior clinical outcomes, and patient injury or death. Participants were encouraged to collaborate to address what was described as a public health crisis. Presentations by Erin R. Fox, Pharm.D., Manager, Drug Information Service, University of Utah Hospitals & Clinics; Burgunda (Gundy) V. Sweet, Pharm.D., Director, Drug Information and Medication Use Policy, University of Michigan Health System; and Michael R. Cohen, R.Ph., M.S., Sc.D., President, ISMP described causes and current trends for drug shortages (Appendix B), resource utilization for managing drug shortages (Appendix C), and safety concerns associated with drug shortages (Appendix D), respectively. FDA staff, including CAPT Valerie Jensen, R.Ph., Associate Director, CDER Drug Shortage Program and CDR Jouhayna Saliba, Pharm.D., Senior Program Manager, Center for Drug Evaluation and Research (CDER) Drug Shortage Program, provided an overview (Appendix E) of Agency activities in this area, described current regulatory authority related to drug shortages, and responded to participant questions. Additional information on causes, impact, and proposed solutions for drug shortages is contained in the background documents provided to participants prior to the summit (Appendices F through H).
Outcomes of the Drug Shortages Summit included development of initial recommendations and participant agreement to continue collaborating to address issues associated with drug shortages. Broad areas of work will include exploring strategies to:
- Improve communication among stakeholders in the pharmaceutical supply chain and health care providers, and
- Remove barriers faced by the FDA and drug manufacturers to minimize the impact of drug shortages.
Regulatory and Legislative Factors
Summary of Causes: Regulatory barriers and ambiguities, including the lack of FDA authority to require some actions, were considered significant contributors to drug shortages. Examples include the absence of a requirement for manufacturers to notify FDA of anticipated market withdrawal and no statutory authority for enforcing notification requirements for medically necessary drugs. Several drug shortages (e.g., concentrated morphine sulfate solution, levothyroxine injection) have been precipitated by actual or anticipated action by the FDA as part of the Unapproved Drugs Initiative, which is designed to increase enforcement against drugs that lack FDA approval to be marketed in the United States. (These drugs are commonly called pre-1938 drugs, referring to their availability prior to passage of the Food, Drug, and Cosmetic Act of that year.) Product manufacturers noted that the cost and complexity of completing a New Drug Application (NDA) for those unapproved drugs is a disincentive for entering or maintaining a market presence. Other regulatory barriers include the time for FDA review of Abbreviated New Drug Applications (ANDA) and supplemental applications, which are required for changes to FDA-approved drug products (e.g., change in source for active pharmaceutical ingredients (API), change in manufacturer). Manufacturers described this approval process as lengthy and unpredictable, which limits their ability to develop reliable production schedules. Participants noted that some FDA activities are based on internal policies, not regulation. While this was perceived as allowing for flexibility and discretion, it may also result in unpredictable or delayed responses. Manufacturers believed that a perceived backlog of applications awaiting approval may be related to insufficient FDA resources. Another contributing cause to drug shortages may be the availability of improved assays and other technologies that have resulted in issuance of new product specifications (e.g., revised United States Pharmacopeia [USP] standards for assessing heparin potency). In addition, when one manufacturer submits revised standards that are accepted by USP, other companies are required to meet the new specifications. Shortages may be caused when companies are delayed in complying with these new requirements. For controlled substances, pre-established Drug Enforcement Agency (DEA) quotas can delay or prohibit manufacturers from obtaining API to increase production of these products when another manufacturer experiences a shortage or production issue. Other potential causes that were discussed, but considered less or not causative of drug shortages included evolving regulatory requirements for packaging (e.g., barcodes), Risk Evaluation and Mitigation Strategies, and inconsistencies in international drug approval processes that prevent use of foreign products when shortages occur.
- Explore expanding FDA authority to require manufacturer notification of market withdrawals (e.g., notification required 9 to 12 months prior to planned market exit).
- Evaluate the current definition of medically necessary, including the established criteria and responsible party for making this determination, to assess the need for increased FDA statutory authority in this area.
- Define and implement evidence-based and other criteria for identifying critical drug therapies that are vulnerable to drug shortages. Criteria might include factors such as availability of therapeutic alternatives, supply chain characteristics, and other elements that determine products’ vulnerability for shortages.
- Explore providing incentives (e.g., tax credits) to manufacturers that produce critical drug products or upgrade manufacturing plants to meet or exceed Good Manufacturing Practices (GMP) in exchange for guarantee of continued production of these therapies.
confidential notification of FDA when there is a single API or manufacturing source. Notification would also apply to informing FDA of an interruption in the supply of raw materials, API, or manufacturing processes. (This recommendation also listed under Raw Materials Sourcing and Manufacturing Factors as a voluntary action).
- Explore reauthorization of PDUFA as a mechanism to establish a modified/reduced user fee program for generic drugs, which would provide FDA additional resources to support prioritization and expedited review of supplemental applications and ANDA. Intent of user fee program would be to provide more timely approval of applications and incentivize manufacturers to enter market based on increased ability to plan production schedules.
- Establish an expedited approval pathway for unapproved drugs (i.e., pre-1938 therapies) to facilitate approval of products that are deemed critical therapies. In addition, reduce or eliminate the current NDA user fee that is required for these products. Incentives could also be considered.
- Assess the need to establish or enhance use of existing processes to expedite approval of ANDA, supplemental applications (e.g., alternate source API), and new or altered production lines for drugs in short supply. In addition, advocate for additional FDA resources to minimize wait time for approval of these applications.
- Evaluate processes for new product specifications (e.g., USP standards), including appropriateness of timeline for implementation. (Note: Invite USP to participate in these discussions).
- Increase collaboration with industry, DEA, and FDA to establish a process that would more readily modify API quotas in response to drug shortages of controlled substances.
- Establish improved processes to extend product stability for products in short supply.
manufacturing redundancies (e.g., multiple manufacturing sites for a sole product or multiple API sources, when available) as part of the FDA approval process. (This recommendation also listed under Raw Materials Sourcing and Manufacturing Factors as a voluntary action).
Other proposed solutions discussed briefly by summit participants included harmonizing international drug approval processes in order to minimize barriers to importation (when desirable) and clarifying the definition of public health emergency to determine if this mechanism could facilitate allocation and other activities that avoid or minimize the effect of drug shortages.
Raw Materials Sourcing and Manufacturing Factors
Summary of Causes: Manufacturing-related causes that contribute to drug shortages are multifactorial. Inability to fully comply with GMP, which results in production stoppages or recalls, was considered a major cause. It was noted that FDA has increased inspections of injectable drug manufacturing processes based on the higher likelihood of harm should these processes be inconsistent with GMP. Manufacturers have also voluntarily increased their quality standards, which on occasion, has resulted in companies being temporarily unable to meet their own standards. Participants recognized that there is limited understanding of the complexity and inter-relatedness of drug production activities. For example, increased product demand in response to another drug product shortage may result in a secondary shortage. Manufacturers generally run production lines at full capacity and may be unable to quickly accommodate increased market demand or FDA requests to produce additional quantities of these alternative therapies. Unpredictable timelines for FDA approval of supplemental applications and ANDA for new-to-market generics also contribute to uncertainty in production planning processes. In addition, there are limited sources of API. Some API are sole source products, which increases a product’s vulnerability to drug shortages. Summit participants were encouraged to consider market realities when identifying issues and recommending solutions for drug shortages. For example, information on API suppliers is often kept confidential for competitive reasons. Other causes that were discussed, but considered less or not causative of drug shortages included natural disasters and changes in product formulation.
confidential notification of FDA when there is a single API or manufacturing source. Notification would also apply to informing FDA of an interruption in the supply of raw materials, API, or manufacturing processes. (This recommendation also listed under Regulatory/Legislative Factors as a proposed required action.)
manufacturing redundancies (e.g., multiple manufacturing sites for a sole product or multiple API sources, when available). (This recommendation also listed under Regulatory/Legislative Factors as a proposed required action.)
- Establish or improve mechanisms to communicate anticipated or actual manufacturing and inventory problems (e.g., standardize terminology for causes of shortages, eliminate causes being described as “reason unknown ” or “not provided”). Some information may require privileged communication between FDA and manufacturers to avoid unintended consequences (e.g., hoarding, releasing business information that supports fair business competition). Other mechanisms should focus on improving communication and transparency among supply chain entities and health care providers. Ensuring that information on the reason for and anticipated duration of the shortage reaches frontline clinicians was considered key.
- Maintain/improve adherence to GMP to avoid quality issues and recalls.
Business and Market Factors
Summary of Causes: Several market factors were noted as contributing to drug shortages, including consolidation of firms that leads to fewer manufacturers for a given product, reassignment or reallocation of production lines, lack of transparency or communication about actual or possible product shortages, and lack of business incentives to enter a specific product market. Some participants believed that insufficient profit margins and product liability concerns are factors that lead to market withdrawals. However, manufacturers stated that these factors do not contribute to the decision to discontinue a product, which was described as being multifactorial (e.g., complexity of manufacturing newer drugs can necessitate shifting of manufacturing resources away from other products.) Other causes that were discussed, but considered less or not causative of drug shortages were unpredictable fluctuations in product demand (i.e., changes in clinical practice) and patent challenges.
- Improve communication to, among, and from product manufacturers and FDA, including detailed information on reason and anticipated duration of shortage. Also enhance communication to supply chain entities and health care providers (e.g., Dear Provider letters).
- Decrease barriers/disincentives to market entry (See recommendations under Regulatory/Legislative Factors).
Summary of Causes: Inventory practices by health care facilities (e.g., just-in-time inventory) and supply chain entities (e.g., sole source and bundled purchasing) were identified as a significant factor that contributes to the impact of drug shortages on patient care. This practice results in no inventory cushion to address short-term shortages. In addition, regional and local differences in product availability were described as resulting from contractual agreements with wholesalers and group purchasing organizations (GPOs). Current systems for product allocation are intended to address this, but are often imperfect based on a lack of reliable information on resumed product availability. Another system limitation is the inability of GPOs to determine competitive pricing that would facilitate establishing multiple contracts for a specific product. Drug procurement is especially challenging for ambulatory infusion centers and small and rural facilities, which generally lack the business relationships that facilitate product availability for larger facilities or health systems. Hoarding was described as a significant concern related to drug shortages.
- Enhance communication among manufacturers, health professional associations, and FDA to facilitate improved independent product distribution.
- Evaluate alternative distribution models for products in short supply, such as establishing a central “clearinghouse” to facilitate fair and equitable distribution of these products.
Another proposed solution discussed briefly by summit participants was creation of a national “stockpile” for critical therapies. Direct manufacturer distribution of products in short supply was discussed, but not preferred, because of limitations in the current model that result in inequitable product distribution. For all recommendations, participants were especially cautious of avoiding unintended consequences (e.g., hoarding) related to distribution practices.