FDA conducts a variety of activities pursuant to its mission to protect the public health. To carry out these functions, FDA is organized into product centers—which regulate products including human and veterinary drugs, vaccines and other biological products, medical devices, most food, and tobacco—a research center, which provides scientific technology, training, and technical expertise, and offices that carry out various functions of the agency. FDA’s response to the contaminated heparin crisis involved a number of FDA centers and offices. FDA’s activities related to its mission and relevant to the heparin crisis include the following: Overseeing drug and device firms. FDA conducts oversight activities such as inspections and investigations of foreign and domestic manufacturing firms, including their suppliers, to determine compliance with good manufacturing practices (GMP), or sampling of imported products. FDA also takes regulatory actions against firms, when appropriate, by issuing warning letters, detaining imports, or recommending seizure of products. Collaborating with USP. FDA collaborates with USP to help ensure the safety and quality of drug products. Under the Federal Food, Drug, and Cosmetic Act, prescription and over-the-counter drugs sold in the United States generally must comply with quality standards published in the USP- National Formulary. USP sets standards for drug quality, purity, and strength, as well as the tests or methods used to assess quality, purity, and strength. Products that do not meet USP standards using the specified methods are considered adulterated by law. Collaborating with foreign regulatory agencies. FDA has confidentiality commitments to facilitate information sharing with regulatory agencies in 19 countries, including Australia, Canada, France, Germany, and Japan. FDA does not have a confidentiality commitment with China; however, FDA negotiated two memorandums of agreement with China in 2007 aimed at improving the safety of Chinese drug products and medical devices, and food exported to the United States. In recent years, FDA has opened offices abroad, including in India, Europe, Latin America, and China. FDA opened its office in China in November 2008, with posts in Beijing, Shanghai, and Guangzhou. An FDA official said the primary mission of these offices is to help gather more information on the safety and quality of products that are being exported to the United States so that FDA can make better-informed decisions about which products to permit to enter the United States. Monitoring adverse events. FDA monitors drug and device safety through its postmarketing surveillance program. FDA’s Adverse Event Reporting System (AERS) is a database that supports the agency’s postmarketing safety surveillance program for all approved drug and therapeutic biologic products. FDA uses AERS to record adverse event reports and to monitor for new adverse events and medication errors associated with drug products marketed in the United States. FDA uses its Manufacturer and User Facility Device Experience (MAUDE) database to record and monitor reports of adverse events related to medical devices. Communicating with the public. FDA communicates information to the public through a variety of means, including press releases, media briefings, public health advisories, and news interviews. FDA also disseminates information on the agency’s Web site, including regulatory information, scientific research, and educational materials. Responding to emergencies. To respond to emergencies or crises, FDA uses a plan to assist the agency in organizing a coordinated response to events involving FDA-regulated products as well as other identified public health emergencies. At the time of the heparin crisis, FDA had its ERP in place, which was issued in February 2005. Working with external entities. When necessary, FDA enters into working relationships with external entities, such as scientists from universities or drug firms, to assist the agency with matters such as the review of research and product applications. For example, scientists serving on advisory committees review and make recommendations on drug applications, and scientists from universities provide expertise in specific scientific disciplines and enhance the science base of the agency through FDA’s Science Advisor Program. FDA has guidance in place for working with external entities in certain situations, including a guide called The Leveraging Handbook. This handbook references statutes and regulations that apply to the behavior of individual FDA employees. It also contains guidance applicable to FDA as an agency to prevent public perception concerns and demonstrate that the agency is worthy of public trust in carrying out its activities. In addition, other laws, regulations, and policies may apply to FDA’s work with external entities, depending on the nature of the arrangements. FDA, like other federal agencies, generally may not accept voluntary services, which may give rise to claims for payment for which funds are not available. However, with a written agreement that services are provided with no expectation of payment, FDA may accept uncompensated services from external entities. Heparin is a medically necessary drug that acts as an anticoagulant; that is, it prevents the formation of blood clots in the veins, arteries, and lungs (see app. I for technical information on heparin and research related to contaminated heparin). The heparin supply chain starts with a raw source material, primarily derived from the intestines of pigs, that is processed into crude heparin. China is the primary source of crude heparin for U.S. manufacturers because of its abundant pig supply. Thousands of small pig farms in Chinese villages extract and process pig intestines in small workshops called casing facilities. Consolidators collect different batches of heparin, typically called heparin lots, from various workshops and combine them into single heparin lots. The consolidators sell the crude heparin lots to manufacturers, who further refine the crude heparin into heparin API, the active ingredient used in heparin drug products and devices. More than half of the finished heparin products in the United States and globally are made from Chinese-sourced materials. There are seven pharmaceutical companies that manufacture and distribute heparin products in the United States. At the time of the crisis, Baxter and APP Pharmaceuticals (APP) were the two largest manufacturers of heparin in the United States, with each company accounting for about half of the total U.S. heparin supply. Both companies received the majority of their crude heparin from Chinese sources. Several FDA centers and offices were involved in the response to the contaminated heparin crisis. Some of these centers and offices and their relevant functions are described below (see app. II for a complete list of FDA centers, offices, and divisions that were involved in the heparin crisis): Office of the Commissioner—leads FDA and implements FDA’s mission. Office of Crisis Management (OCM)—develops crisis management policies, leads and coordinates the agency’s development and updating of emergency preparedness and response plans, including FDA’s ERP, and coordinates the agency’s emergency response. Office of International Programs—works with agencies and governments to advance public health worldwide. Office of Regulatory Affairs (ORA)—leads inspections of regulated domestic and imported products and domestic and foreign manufacturing facilities, and develops enforcement policies. Center for Drug Evaluation and Research (CDER)—regulates over- the-counter and prescription drugs, including biological therapeutics and generic drugs sold in the United States. Center for Devices and Radiological Health (CDRH)—regulates medical and radiological devices sold in the United States. FDA took several actions during the first half of 2008 to protect the public health in response to the heparin crisis. During that time and afterwards, FDA increased oversight of heparin firms, but sometimes faced limitations in oversight and collaborating with others. FDA also worked with heparin manufacturers to recall contaminated heparin products while ensuring an adequate supply for U.S. consumers. In addition, FDA collaborated with its international regulatory partners to exchange information. Because of limitations related to conducting inspections and investigations of heparin firms in China, FDA could not determine the original source of the heparin contamination. To respond to the heparin crisis, FDA took action related to its responsibility to protect the public health by ensuring the safety and security of the nation’s drug and medical device supplies by taking various actions from January through May 2008. On January 7, 2008, after FDA learned about the severe allergic reactions taking place, the agency initiated an investigation at the dialysis facility where the first observed allergic reactions took place and shared information with CDC. At the same time, FDA contacted a medical device manufacturer since it was initially thought the allergic reactions were in response to a medical device. After FDA learned that the problem possibly was associated with Baxter heparin, on January 9, 2008, the agency began investigations and inspections of heparin drug and device firms. FDA received notification of the first recall of nine lots of Baxter heparin products, which took place on January 17, 2008, and began work with this drug firm to learn more about the problem with its heparin. By January 23, FDA learned that Baxter received its heparin API from Scientific Protein Laboratories’ (SPL) establishments in Wisconsin and China. In early February 2008, the agency worked to postpone an expanded recall of Baxter’s heparin products so it could consult with APP to ensure that APP could supply the U.S. heparin market and mitigate a potential heparin shortage. The second recall, which included all lots of Baxter’s single and multidose vial heparin products, took place on February 29, 2008. FDA also facilitated recalls of heparin-containing medical devices with heparin device firms. As the crisis progressed, FDA took additional actions in February and March 2008. By late February, FDA could distinguish contaminated heparin from uncontaminated heparin using preliminary testing methods and continued working to develop these methods. During that month, FDA also formed an internal task force to coordinate the agency’s response to the heparin crisis and reached out to external scientists to assist the agency in identifying the unknown contaminant and to develop tests to detect this contaminant. On March 5, 2008, FDA identified the type of contaminant in suspect heparin lots and by March 6, it shared newly developed testing methods that could differentiate contaminated heparin from uncontaminated heparin. Some other countries also found contamination in their heparin supplies.