FDA Activities Working With Manufacturers to Help Prevent and Mitigate Medical Product Shortages
In this section:
- Center for Drug Evaluation and Research
- Center for Biologics Evaluation and Research
- Center for Devices and Radiological Health
- Center for Veterinary Medicine
- A Comparison of Medical Product Shortage Activities Across FDA Centers
As each medical product Center at FDA addresses shortage problems, each brings its own perspectives, needs, and authorities to bear. Currently, medical product shortages are heavily concentrated in drugs, with CDER’s DSP managing 30 to 40 drug shortages at any given time, while the other Centers experience only a handful of other medical product shortages each year. The information gathered for this report was generated through meetings with medical product shortage staff in CDER, CBER, CDRH, and CVM. Additional meetings involved CDER’s Office of Compliance and FDA’s Office of Regulatory Affairs (ORA). The authors also met with external stakeholders who have been affected by drug shortages. These external stakeholders included manufacturers’ associations (innovator and generic), manufacturers of intravenous generics, wholesalers, GPOs, professional associations (medical and pharmacy), non-governmental organizations, and academics. The meetings occurred between January and June 2011.
Of the FDA Centers, CDER has been most significantly affected by medical product shortages. CDER’s DSP estimates that, at any point in time, it is working on 30-40 ongoing shortages. As mentioned, the reported number of shortages has increased significantly over the past decade from 61 in 2005 to 178 in 2010 (see Figure 1). CDER tracks shortages in both prescription and over-the-counter (OTC) medications, but, because they may be less likely to be “medically necessary,” most shortages tracked by FDA involve prescription products.
CDER’s DSP receives notification of shortages from manufacturers, ASHP, health-care providers, wholesalers, GPOs, and the public. As noted, manufacturers are only required to report to FDA the expected discontinuation of certain sole-source drugs. DSP staff state that more often than not manufacturers fail to provide notification of actual or potential shortages. Again, the advance notification provision in section 506C of the FD&C Act does not include explicit enforcement authority.
Although CDER evaluates all drug shortage reports it receives, higher priority is afforded those it considers medically necessary. Accordingly, upon receiving notification of an actual or potential drug shortage, DSP staff confirm the shortage with the manufacturer and request a determination of medical necessity from CDER’s clinical division. In some circumstances, it seeks input on the medical necessity determination from outside stakeholders such as specialty societies. It also obtains data from IMS Health, a company that tracks pharmaceutical sales from manufacturers to retail and non-retail channels of distribution in the United States, to establish the rate of consumption or “burn rate” for the product and thus when supplies will run out. The IMS Health, IMS National Sales PerspectivesTM database provides each firm’s market share in terms of dollars and units sold.
The medical necessity determination also informs the balance struck by DSP between the potential risks associated with a particular quality defect and any benefit to patients of exercising regulatory discretion with regard to continuing drug availability. As part of the drug shortage process outlined in CDER’s MAPP, 1 DSP staff seek an explanation for the shortage from the manufacturer, and inform the public of the existence of the shortage via communications with ASHP and other professional organizations, and via its own web site. 2
As noted previously, once a shortage has been confirmed, CDER has a number of means at its disposal to mitigate the problem. These include notifying and encouraging manufacturers of the same or similar products to increase their production, finding another manufacturer to begin production of the product, using regulatory discretion with regard to selective release of product when accompanied by appropriate warnings or remedies (e.g., filters for products contaminated with particulates), expedited review of an ANDA, expedited review of new manufacturing lines or raw material sources to help firms increase production, and regulatory discretion with regard to controlled importation of similar products approved abroad but not in the United States, as long as the shortage persists. Although reinspection of manufacturing facilities is typically not necessary to restart production, in those cases where reinspection is needed, the agency will expedite it. DSP coordinates efforts across CDER to resolve shortages, including staff in the Office of Generic Drugs, the Office of New Drug Quality Assessment, Office of Compliance, and the relevant clinical divisions. However, FDA has no capacity or authority to manufacture medications nor any authority to force manufacturers to do so.
Nonetheless, data provided by DSP suggest that 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 action to prevent a drug shortage (see Figure 6) was expediting review of new manufacturing sites, new suppliers, and specification changes, followed by exercising regulatory flexibility and discretion (the benefit of the drug was judged to outweigh the risk of the quality or manufacturing issue).
DSP has recently added a fifth full-time employee; the DSP staffing level had remained essentially stable at four full-time equivalents over the previous six years. Many other offices within CDER also provide staff on a part-time basis to address drug shortages (see Appendix 1). For example, CDER’s Office of Compliance has a dedicated Recalls and Shortages Branch that helps manage shortages for the Office. When it becomes aware of a recall or impending recall, this branch will work with DSP to determine if the drug involved is a medically necessary drug and if the recall will result in or have an impact upon a shortage. If so, CDER’s Office of Manufacturing and Product Quality (OMPQ) works with the firm to determine the extent and risk of the product problem and works to prevent and mitigate a shortage.
CBER regulates allergenics, blood and blood products, certain devices specific to biological products, gene therapies, human tissues and cellular products, vaccines, and xenotransplantation products. CBER has been less significantly affected by medical product shortages than CDER. The number of shortages of products regulated by CBER has been fairly stable over the last several years, with sterile injectables, particularly vaccines, accounting for most.
Biologics are often complex and time-consuming for companies to develop. There are about 150 licensed biologic products in the United States, compared to thousands of approved drugs. Shortages of biological products can be difficult to foresee because most manufacturers engage in “just in time” production and, as a result, many products that appear to be at risk for shortage never progress to an actual shortage. However, CBER product shortages can also take on national significance (e.g., influenza vaccine shortages).
Manufacturing problems are the most common cause of biological product shortages. These may be brought to the Agency’s attention by the manufacturer itself or may be revealed during an inspection by FDA. Other causes of biological product shortages include corporate decisions to discontinue the product, distribution or production changes/disruptions, lack of availability of component materials, changes in release procedures, demand increases driven by new product indications or promotional campaigns, and catastrophic events/natural disasters.
Biological product shortages are closely monitored by staff within the Immediate Office of the Director of CBER’s Office of Compliance and Biologics Quality (OCBQ). Actual or potential shortages may be reported to CBER by medical professionals, consumers/patients, manufacturers, other government offices, patient advocacy groups, media sources, and others. Reports may come to CBER through the CBER shortage email account and its shortage telephone number. The relative infrequency of biologics shortages has allowed CBER to manage the problem with a single employee. CBER has in place a Standard Operating Policy and Procedure (SOPP) 8506 titled Management of Biological Product Shortages. OCBQ is currently in the process of drafting SOPPs for use within its own office.
When a biological product shortage or discontinuation is reported (and CBER reports that manufacturers tend to do so promptly), CBER attempts to verify that an actual shortage or discontinuation exists through communications with manufacturers, other FDA offices, and external entities such as ASHP, as well as through market research data when available. All relevant files and databases are searched for information on the product in shortage and potential alternatives. This information is then shared widely within FDA and with other Department of Health and Human Services (DHHS) Agencies such as the Centers for Disease Control and Prevention. If the biological product is used to treat, cure, mitigate, prevent, or diagnose a serious or life-threatening condition and there is no other available source or alternative therapy, the shortage is posted on the CBER Biologic Product Shortages web site. 4
Similar to CDER, CBER can draw from an array of policy options when addressing a shortage problem. These include encouraging manufacturers of the product to increase their production, encouraging other manufacturers of similar prescription drugs to increase production, expediting inspections of manufacturing facilities to begin or restart production, and expediting review of Biologics License Applications (BLAs), NDAs or ANDAs. In many instances, vaccine shortages can be ameliorated by delaying vaccination, building on the community levels of immunity that have developed in the population over time as a result of vaccination.
CDRH measures and monitors medical product shortages differently from other FDA Centers. While therapeutically equivalent drugs are pharmacologically equivalent and bioequivalent and therefore substitutable, devices cleared as “substantially equivalent” under CDRH’s 510(k) provisions are generally not identical and may not be substitutable; even different models of the same device from a single manufacturer may not be interchangeable. Accessories and consumables, such as ventilator tubing and infusion sets, to particular devices are often brand- and version-specific, and shortages of either may result in a shortage of the device itself. Even if devices are theoretically substitutable, provider practices and preferences can contribute to shortages because physicians are often trained by manufacturers to use certain devices and may be unfamiliar with alternative devices.
CDRH identified a variety of causes of device shortages, including reliance on sole-source and/or foreign manufacturers, increasingly complex devices where a supply bottleneck of a single small component can jeopardize entire production lines, a shortage of a drug needed for the device to function, and the fragmentation of the device industry so that non-standardized and brand-specific technologies are produced. Device shortages may also occur if the firm conducts a recall or CDRH takes action against a firm due to manufacturing problems. In addition, the industry operates in a “just in time” production mode, so that production keeps pace with demand.
CDRH has formal procedures to determine if a shortage exists, in addition to procedures on how to address shortages. However, device manufacturers are not required to submit to FDA information regarding their manufacturing capacity and the number of products put into distribution, which hinders FDA’s ability to respond to the shortage. Even in cases where manufacturers voluntarily submit information to the Agency, FDA may not be authorized by manufacturers to disseminate that information, limiting public knowledge about the circumstances surrounding a shortage. Assessing the magnitude or impact of device shortages is difficult because the industry lacks databases to monitor the market share of specific devices, brands, and models. 5
Device manufacturers are not required to notify FDA of actual or potential shortages. CDRH acknowledges that it rarely receives notices of shortages from manufacturers themselves, more frequently learning of shortages through reports by user facilities or the media.
Device shortages are collaboratively managed by the staff of the Office of the CDRH Center Director and CDRH’s Office of Compliance. While CDRH does not have a position dedicated solely to handling device shortages, the Center’s point of contact for shortages is located in the Office of the Center Director. The shortage staff work closely with the Office of Compliance in performing risk and shortage assessments prior to taking any action that might reduce product availability. When addressing a shortage, Center staff typically request that manufacturers of similar devices increase production, but, due to the complexities of device production, there is typically a lag of up to six months before additional devices are available. CDRH takes into account whether a shortage would result from a regulatory action and will typically allow a product to remain in distribution if the overall benefits outweigh the risks.
CDRH has developed a database listing devices susceptible to shortages in disaster and emergency settings. However, maintaining a database of timely manufacturing data is dependent upon voluntary cooperation from manufacturers, and is often limited because of the confidential and proprietary nature of such information. The information, therefore, cannot be released to the public and is used only for CDRH internal planning and response purposes. As part of its shortage evaluation process, CDRH also conducts investigations of affected manufacturers following recalls or natural catastrophic events to gather information to assess the potential for device shortages.
CVM has generally experienced few veterinary drug shortages. Although CVM has received more reports of shortages of late, it is unclear whether this is a result of an actual increase in shortages, greater public awareness leading to increased reporting of shortages, or reduced public awareness of alternative products. The small numbers of past shortages make aiding in the prediction or prevention of potential shortages difficult.
Veterinary drug product manufacturers are not required to notify CVM of product shortages. However, such manufacturers are required to submit annual reports that include certain information about the distribution of each animal drug product, including the quantity of the drug distributed during the reporting period. 6 CVM receives notification of product shortages from manufacturers, the press, consumer groups, veterinarians, producer associations, the animal health industry, and through FDA surveillance and enforcement activities. CVM staff indicated that they would prefer more frequent reporting by manufacturers.
CVM takes action only in the event of a shortage of a veterinary drug that is needed to treat or prevent a serious disease or condition or that is required to assure the availability of safe human food products of animal origin. In addition, as in CDER and CBER, staff determine whether there is any other available source of that product or an adequate alternative. 7 When CVM is notified of a potential veterinary medicine shortage, the information is directed to the CVM shortage coordinator who is responsible for confirming that an actual shortage exists and establishing whether the drug meets these criteria. Internally, CVM maintains a list of drugs in shortage that meet these criteria, but does not post shortages on its web site.
CVM acts to resolve product shortages by encouraging other manufacturers of the same product or alternative products to increase their production, utilizing regulatory discretion with regard to the marketing of products that are not compliant with Good Manufacturing Practices (GMPs), and exercising enforcement discretion with regard to the importation of alternative products. The Center has found that many manufacturers who experience shortages are becoming less likely to return to production because products compounded from bulk APIs have addressed the need and manufacturers are likely to have difficulty regaining market share.
CVM’s drug shortage program is located in its Office of Surveillance and Compliance (OSC). CVM staff believe that the Center currently has adequate resources to address and manage veterinary drug shortages. The Center is currently in the process of formalizing its protocol for monitoring and addressing shortages.
Information gathered during meetings with CDER, CBER, CDRH, and CVM is summarized in Appendix 2, which reveals a number of respects in which the Centers’ medical product shortage activities are similar and others where they are different. This is not to imply that all Centers need to develop identical programs. Rather, Appendix 2 is intended to serve as a starting point for the sharing of best practices between the Centers, with the clear understanding that different Centers face varying challenges in addressing shortages that could require dissimilar approaches and solutions, particularly given the Centers’ varying medical product shortage experiences and statutory authorities.
Only CDER has employees working full-time on the shortage issue. Established plans and protocols for addressing drug and medical product shortages have been or are in the process of being developed for all Centers. CBER reports that manufacturers regularly report shortages, while other Centers report less reliable notification. Injectable drugs are most commonly affected in CDER, CBER, and CVM. Although all Centers reported exercising regulatory discretion in attempting to resolve shortages, only CDER, CDRH, and CVM have used enforcement discretion with regard to importation to alleviate shortages, after carefully weighing the overall benefits and risks.
1. Center for Drug Evaluation and Research, Food and Drug Administration. Manual of Policies and Procedures (MAPP), 6003.1. Available at: http://www.fda.gov/downloads/AboutFDA/CentersOffices/
CDER/ManualofPoliciesProcedures/ucm079936.pdf (accessed September 28, 2011).
2. FDA. Drug Shortages. Available at http://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (accessed September 28, 2011).
3. Cox E. Drug shortages: FDA’s strategies and role. Presented at CDER Drug Shortage Workshop, Silver Spring, MD, September 26, 2011.
4. FDA. Biologic Product Shortages. Available at http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (accessed September 28, 2011).
5. The IMS Hospital Supply Index only captures data from hospitals, not from other sectors of the health-care system in which devices are also used.
6. 21 C.F.R 514.80; 21 U.S.C 360b(1)(3).
7. Center for Veterinary Medicine, Food and Drug Administration. Program Policy and Procedures Manual 1240.4170.