Food and Drug Administration: Response to Heparin Contamination Helped Protect Public Health; Controls That Were Needed for Working With External Entities Were Recently Added
Published: 2010-10-29T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: In early 2008, the Food and Drug Administration (FDA) responded to a crisis involving the contamination of heparin, a medication used to prevent and treat blood clots, when the agency received multiple reports of adverse events involving severe allergic reactions. The crisis took place from January 2008 through May 2008, during which time FDA took several actions in its response to the crisis. GAO was asked to review FDA's management of the heparin crisis. This report examines (1) how FDA prevented additional contaminated heparin from reaching U.S. consumers, (2) how FDA coordinated its response to the contaminated heparin crisis, and (3) FDA's monitoring and analysis of adverse events associated with heparin. To conduct this review, GAO reviewed relevant FDA documents, regulations, and guidance; analyzed FDA data; and interviewed FDA officials and other experts involved in the crisis and knowledgeable about drug quality standards.
section_title: What GAO Found
paragraphs: In its response to the heparin crisis, FDA took several actions related to its responsibility to protect the public health by ensuring the safety and security of the nation's drug and medical device supplies. FDA increased its activities related to oversight of heparin firms by conducting inspections and investigations and monitoring heparin imports, and worked with drug and device manufacturers to recall contaminated products while ensuring that an adequate supply of uncontaminated heparin was available. With the help of external entities, FDA identified the unknown contaminant and developed tests to screen all heparin products. Additionally, the agency reached out to its international regulatory partners during the crisis. However, FDA faced some limitations in its efforts to inspect heparin firms in China and collaborate internationally, and the agency was unable to determine the original source of contamination. FDA coordinated internal and external resources to respond to the contaminated heparin crisis, but did not address risks related to working with certain external entities with ties to heparin firms. The agency has issued standards of ethics regarding collaboration with external entities and governmentwide standards apply to the acceptance of services provided free of charge. Despite these existing standards, FDA did not have processes in place to ensure that it considered or applied them when it accepted assistance from external entities with ties to heparin firms on a voluntary basis during the heparin crisis. Not adequately addressing these risks could have affected the public's confidence in FDA's response efforts and in its other activities related to the regulation of heparin products and also left FDA open to claims for payment for services that these external entities provided to FDA. FDA monitored trends in the number of reports of adverse events associated with heparin drug products and heparin-containing medical devices that it received before, during, and after the crisis. FDA also conducted analyses of adverse events, including deaths, associated with heparin drug products and heparin-containing medical devices. However, FDA was unable to determine if any of the adverse events or deaths were linked to contaminated heparin because of data limitations and confounding factors regarding the individual patients, such as the natural course of the underlying disease or condition. In the draft report we provided to the Department of Health and Human Services for comment, we recommended that FDA develop adequate controls to help avoid exposure to risks when working with external entities in future situations similar to the heparin crisis. In response, FDA issued guidance on October 15, 2010, for FDA staff to follow when working with external scientific and other experts in emergency situations when the services are provided on a gratuitous basis. FDA also stressed the unprecedented nature of the heparin crisis and noted various actions it took in response to the crisis.

section_title: Letter
paragraphs: In 2008, the Food and Drug Administration (FDA) responded to a crisis  involving the contamination of heparin, a medication that is used to  prevent and treat blood clots. Beginning in early January of that year,  FDA and the Centers for Disease Control and Prevention (CDC) received  multiple reports of adverse events involving severe allergic reactions in  dialysis patients. While the cause of these events was initially unknown,  about 2 days after CDC received the reports of adverse events, CDC  determined that these reactions were possibly associated with heparin  manufactured by Baxter Healthcare Corporation (Baxter) and notified  FDA of the association. CDC and FDA confirmed that Baxter heparin was  involved about 3 weeks later, after both agencies gathered more  information about the reactions. By late January, FDA determined that the  active pharmaceutical ingredient (API) used to manufacture the  contaminated Baxter heparin came from a facility in China.
Heparin is a medically necessary drug that is used by millions of patients  in the United States each year. It is commonly used before certain types  of surgery, including coronary artery bypass graft surgery; in kidney  patients before they undergo dialysis; and to prevent or treat other serious  conditions, such as deep vein thrombosis and pulmonary emboli. Heparin  is also used in medical devices—for example, some blood oxygenators and  catheters contain or are coated with heparin, and some diagnostic testing  products such as capillary tubes are manufactured using heparin.
In January and February 2008, FDA worked to facilitate recalls of  contaminated heparin and heparin-containing devices once the agency  determined that a recall would not create a heparin shortage. In early  February, FDA engaged external scientists to assist the agency in  identifying the unknown contaminant and in developing tests to detect this  contaminant. In late February, FDA formed an internal task force to  manage its response to the crisis and engaged additional external  scientists when more heparin expertise was needed to identify the specific  contaminant in heparin. The tests to detect whether or not heparin  contained a contaminant were made public in early March, and FDA  identified the specific contaminant in mid-March. In April 2008, FDA held  an international conference with regulators and other stakeholders  throughout the world to discuss the heparin problem, its solution, and how  to prevent similar future crises. Throughout the crisis, FDA held media  briefings and monitored heparin-associated adverse events. FDA  determined the crisis was over by the end of May 2008, and its internal  task force discontinued regular meetings.
FDA officials believe that the contamination of heparin was an instance of  economically motivated adulteration. Several instances of adulterated  products have occurred in the past, including infant formula, pet food, and  toothpaste, and FDA has stated that future instances of adulteration  remain a public health threat. Therefore, it is likely that the agency will  have to respond to similar large-scale public health crises involving FDA- regulated products in the future.
Responding to public health crises is a part of FDA’s mission to protect the  public health, which includes ensuring the safety and efficacy of the  nation’s drug and medical device supplies. As part of its efforts to ensure  the safety and efficacy of drugs and medical devices, FDA conducts  oversight activities, collaborates with external entities, and communicates  information to the public. FDA has recognized that to preserve the public  trust, its actions should adhere to certain principles of integrity, and it has  developed guidance to help ensure that the agency does not compromise  the integrity or the appearance of integrity of its programs or the officials  who manage them. In addition, FDA is to carry out its responsibilities in a  manner consistent with other applicable laws and guidance, including  those related to the use of public funds.
You asked us to review FDA’s management of the contaminated heparin  crisis. In this report, we examine (1) how FDA prevented additional  contaminated heparin from reaching U.S. consumers, (2) how FDA  coordinated its response to the contaminated heparin crisis, and (3) FDA’s  monitoring and analysis of adverse events associated with heparin.
To examine how FDA prevented additional contaminated heparin from  reaching U.S. consumers, we reviewed actions FDA took during the crisis  period, which FDA defined as January 2008 through May 2008. We also  interviewed FDA officials and drug manufacturers and reviewed FDA  documents including inspection reports, investigation memorandums,  warning and untitled letters, testing records, meeting minutes, records of  correspondence, conference documents, media briefing transcripts, public  communications, database reports, and internally produced summaries  (such as a timeline of events related to the crisis). Additionally, we  reviewed laws, regulations, and guidance relevant to FDA’s authorities  regarding inspections and investigations, imports, enforcement, recalls,  and drug shortages. In addition, we examined documents related to FDA’s  international cooperation with foreign regulatory agencies. We conducted  analyses of FDA data on heparin-related inspections and investigations,  testing of imported heparin, and heparin product recalls. We also reviewed  other relevant documents, such as congressional testimonies and our  previous reports. In addition, we used our interviews and document  reviews to learn about any FDA efforts and initiatives that might help  avoid similar crises in the future.
To examine how FDA coordinated its response to the contaminated  heparin crisis, we interviewed FDA and CDC officials, drug manufacturers,  consumer advocacy groups, and academic researchers involved in or  knowledgeable about the contaminated heparin crisis, as well as officials  from the United States Pharmacopeia (USP), the entity that sets drug  quality standards in the United States. We examined FDA’s ability to work  with external entities and related guidance to learn how FDA works with  external entities that have a formal relationship with FDA, as well as  federal statutes and administrative materials on the acceptance of  uncompensated services. We also reviewed relevant FDA documents,  including meeting minutes, records of correspondence, conference  documents, and internally produced summaries. Additionally, we reviewed  FDA’s Emergency Response Plan (ERP) to examine the agency’s  framework for responding to emergencies, and reviewed FDA’s draft  guidance for responding to future emergencies.
To examine FDA’s monitoring and analysis of adverse events associated  with heparin, including deaths, we interviewed FDA officials and reviewed  relevant documents, including two FDA analyses of adverse event reports  associated with heparin drug products, and we also reviewed an FDA  analysis of adverse events associated with heparin-containing medical  devices. To assess trends in heparin-associated adverse events that  occurred before, during, and after the crisis, we also reviewed FDA data  on heparin-associated adverse event reports—from January 2007 through  September 2009 for reports associated with heparin drug products, and  from January 2005 through September 2009 for reports associated with  heparin-containing medical devices. In addition, to understand the  limitations of the data FDA analyzed, we reviewed the 94 death reports  associated with heparin drug products that FDA included in its analyses of  heparin adverse event reports.
To assess the reliability of the FDA data we used under each objective, we  took several steps that included determining how FDA entered  information into its databases, reviewing FDA’s validation processes for its  databases, discussing any limitations, and corroborating data with  information from other sources where possible. We determined that all of  the data we reviewed were sufficiently reliable for the purposes of this  report. We conducted this performance audit from June 2009 through  September 2010 in accordance with generally accepted government  auditing standards. Those standards require that we plan and perform the  audit to obtain sufficient, appropriate evidence to provide a reasonable  basis for our findings and conclusions based on our audit objectives. We  believe that the evidence obtained provides a reasonable basis for our  findings and conclusions based on our audit objectives.
subsections: section_title: Background
paragraphs: 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.
subsections: section_title: Heparin and the Contaminated Heparin Crisis
paragraphs: 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.
section_title: FDA Took Multiple Steps to Protect U.S. Consumers from Additional Contaminated Heparin, but Faced Limitations in Oversight and Collaboration
paragraphs: 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.
subsections: section_title: FDA Took Action through the First Half of 2008 to Protect the Public Health in Response to the Heparin Crisis
paragraphs: 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. Later that month, on March 17,  FDA identified oversulfated chondroitin sulfate (OSCS) as a contaminant  in the heparin associated with adverse events in the United States.
Additionally, because the majority of finished heparin products in the  United States and globally are made with ingredients from China, FDA  worked to ensure the safety of heparin imports. Throughout the crisis,  FDA also provided information about the crisis to a variety of audiences,  including the press, physicians, and medical facilities. By April 2008, the  agency determined that the number of adverse events involving heparin  had returned to precrisis levels. FDA held an international heparin  conference on April 17, and 18, 2008 to exchange information with its  foreign regulatory counterparts. FDA’s task force continued to meet until  May 27, 2008, when it was determined that the crisis was over. Figure 1  shows the timeline of key events in the heparin crisis.
section_title: FDA Increased Its Oversight of Heparin Firms, but Faced Limitations in Its Actions Regarding Some Firms in China
paragraphs: In response to the heparin crisis, FDA increased its oversight activities of  heparin firms by increasing its inspections, investigations, and monitoring  efforts.
Inspections. During and after the crisis, FDA conducted an increased  number of domestic and foreign heparin-related inspections of drug and  device firms compared with the number of inspections prior to the crisis  (see fig. 2). In particular, FDA increased its frequency of inspections of  Chinese firms associated with OSCS contamination in the United States. In  the 20-month period prior to the crisis, FDA did not conduct any  inspections of Chinese heparin firms. In contrast, 11 Chinese firms  constituted 14 of the 21 heparin-related foreign inspections conducted by  FDA during and after the crisis. Of the Chinese firms that FDA inspected,  only 2 had been inspected prior to the contaminated heparin crisis.
FDA officials said that there were and continue to be significant legal and  practical challenges to conducting inspections of crude heparin  manufacturers and the casing facilities that supply them, such as the  limits on FDA’s ability to require foreign establishments to allow the  agency to inspect their facilities, the large number of and incompleteness  of FDA’s information on the casing facilities, and the expenses associated  with conducting foreign inspections. For these reasons, according to FDA  officials, FDA focused on firms’ responsibilities to ensure that they could  trace their crude heparin back to qualified suppliers that produce an  uncontaminated product. Furthermore, according to officials, during inspections FDA inspectors requested that firms conduct their own  investigations of any heparin products for which they received complaints  or that did not meet specifications.
Investigations. In addition to inspections, FDA conducted investigations at U.S. health care facilities and device firms, domestic drug firms, and a foreign drug firm. FDA data show that the agency conducted at least 37  domestic and 1 foreign investigations related to heparin between January  2008 and June 2009, with individual investigations sometimes consistin FDA visits to multiple facilities, such as a drug firm and a health care  provider. The reasons for these investigations included, for example,  obtaining heparin samples, collecting information on firms’ crude and  heparin API suppliers, following up on patient adverse event reports and  the status of product recalls, and witnessing the destruction of  contaminated heparin.
Monitoring imports. Beginning in February 2008, FDA began monitoring  ning  heparin products offered for import by physically examining and detai products to help ensure that additional contaminated heparin did not  reach U.S. consumers. The agency initially issued an import bulletin in late February 2008 instructing FDA staff to assess the admissibility of hep products offered for import, and then replaced it with a plan in mi d- March 2008 to physically sample and test these products for OSC S  contamination. This testing plan, which provided more detailed  instructions than the import bulletin, required that FDA test all imported  heparin API, and other imported heparin products, on a case-by-case ba for contamination upon arrival at the U.S. border unless U.S. firms had  already committed to testing their imported heparin products using FDA’s  sis,  newly developed testing methods. According to FDA data, by the end of  June 2010, FDA had collected 141 heparin samples. Three of these samples  were contaminated with OSCS, including 1 detected after the crisis period  ended in May 2008.
During and after the crisis, FDA also added a total of seven heparin-related  establishments associated with OSCS contamination to an existing import  alert for drug manufacturers found to be in violation of GMPs, which  enabled the agency to detain heparin imports from these establishments  without physically examining them. FDA officials said that these heparin  establishments appeared to stop shipping heparin to the United States  after being added to this import alert.
In some instances, FDA took further action as a result of its inspections  and import testing. Between April 2008 and April 2009, the agency issued  three warning letters and two untitled letters related to the heparin crisis  to drug firms. The agency also added the seven heparin establishments to  the import alert described previously as a direct result of various factors,  including deficiencies observed during inspections, detection of  contaminated heparin during import testing, and FDA’s determination that  establishments were not adequately safeguarding their heparin supply  chains. Additionally, FDA initiated a seizure of heparin products from one  firm after the agency determined that the firm’s efforts to voluntarily recall  contaminated heparin products identified during an inspection were  inadequate.
However, FDA officials believed that they had limited authority to take  action when they encountered refusals, either by the firm or by the  Chinese government, to permit a full inspection of some Chinese firms. In  two instances, Chinese crude heparin consolidators refused to provide  FDA full access during limited inspections—in particular, one consolidator  refused to let FDA inspectors walk through its laboratory and refused FDA  access to its records. FDA classified both limited inspections as “no  action indicated” (NAI) and did not attempt to reinspect the facilities,  document any objectionable conditions, or place the firms on import  alert. FDA officials provided us with various reasons why FDA classified  these limited inspections as NAI and did not pursue these firms further  despite encountering refusals. FDA officials told us that the agency  focused its efforts on the API manufacturers that these firms supplied.
Officials also told us that at least one of these firms was not shipping  crude heparin directly to the United States; however, FDA’s import data  show that both firms shipped crude heparin directly to the United States in  2006, which, according to retrospective testing conducted in 2008 by SPL,  Baxter’s API manufacturer, is when OSCS contamination of SPL’s heparin  supply was first detected. Additionally, officials told us that no GMP  violations were observed during these limited inspections, but  acknowledged in congressional testimony that inspectors were not able to  observe the laboratory of one of the firms. Overall, FDA officials told us  that in both instances the agency did not have sufficient evidence to put  the two consolidators on import alert and that, with some exceptions, a  firm’s refusal to allow for a complete inspection is not itself one of the  bases for product detention at the U.S. border.
Additionally, FDA learned that China’s State Food and Drug  Administration had sealed some firms’ heparin and had instructed the  firms not to open these seals. This prevented at least one firm from  conclusively determining which of its crude suppliers were associated  with OSCS contamination, which FDA learned of during a preapproval  inspection of this particular firm. According to FDA officials, FDA was  concerned that this firm was unable to complete its investigation of  suppliers and requested a reinspection of the firm. From the reinspection,  which took place approximately 1 year later, the agency determined that  the firm had implemented testing methods to detect OSCS contamination,  communicated its expectations and requirements to its suppliers, and  increased the frequency of its supplier audits. FDA also learned during the  reinspection that the firm had completed its testing, which resulted in the  permanent disqualification of two of its suppliers.
FDA officials said that they are continuing to take steps to improve the  quality of drugs manufactured outside of the United States. In addition to  creating and staffing FDA posts overseas, FDA officials told us that the  agency has established a cadre of FDA’s U.S.-based investigators to  conduct foreign drug inspections throughout the world as needed. FDA is  also increasing the size of its cadre of the highest-certified drug inspectors  to assist with foreign inspections, and increasing the number of translators  it brings on foreign inspections, especially to China. FDA officials told us  that the agency continues to emphasize the responsibility of industry to  ensure the safety and security of its supply chain, including placing  emphasis on supply chain traceability during foreign drug inspections. In  addition, according to officials, FDA also continues to revise its inspection  and surveillance programs to focus on higher-risk facilities and products.  For example, officials told us that in fiscal year 2010 the agency developed  and used a risk-based model and other information to focus its annual  surveillance sampling program—a long-standing FDA program to sample  drug components offered for import, which changes focus annually—on  APIs potentially susceptible to economically motivated adulteration.
section_title: FDA Worked with Heparin Manufacturers on Recalls of Contaminated Heparin Products while Ensuring an Adequate Heparin Supply for U.S. Consumers
paragraphs: Beginning in January 2008 when the first recalls of contaminated products  occurred, FDA worked with manufacturers to ensure an adequate supply  of uncontaminated heparin for the U.S. market. Weeks after Baxter  initiated a recall of specific heparin lots associated with adverse reactions  in patients, the company told FDA it wanted to recall almost all of its  heparin products because the number of adverse reactions associated with  its heparin continued to increase. FDA officials said they recognized that a  large-scale recall could pose risks to U.S. patients if the remaining supply  was not adequate to meet facilities’ and providers’ needs for heparin.  Consequently, FDA engaged in discussions with APP, the other main U.S.  heparin manufacturer, to determine the amount of heparin it had available  and to determine if and when it could increase its heparin production to  supply almost the entire U.S. market. FDA and APP officials told us that  APP’s ability to increase production was initially limited and that FDA and  APP worked together to increase APP’s production capacity; for example,  in July 2008, APP obtained permission from FDA to apply for an additional  manufacturing facility—which FDA approved in October 2008—using a  process that, according to APP officials, decreased FDA’s approval time by  months and allowed APP to begin releasing heparin manufactured at the  alternate site and subsequently list it as an approved facility with the  agency.
During this time, FDA worked with Baxter to manage the risks of the  contaminated heparin that remained on the U.S. market and postpone the  expanded recall of almost all Baxter heparin products until the agency was  sure that APP could increase its heparin production to meet the needs of  U.S. patients, thus avoiding a shortage of a medically necessary drug.  According to FDA officials, FDA and Baxter worked together to develop a  risk management plan, and FDA issued a public health advisory to inform  the public of serious adverse events and recommend measures—such as  using the lowest necessary dose, administering the heparin as slowly as  acceptable, and monitoring patients closely for adverse events—to help  minimize these risks in instances where Baxter heparin was the only  product available.
FDA continued monitoring for the possibility of a heparin shortage even  after APP told FDA it could increase production. FDA continued to be  concerned about the adequacy of the U.S. heparin supply in the summer of  2008 due to a shortage of raw materials in China and issues APP faced  with its supply chain. The agency also continued to work with  manufacturers on product recalls. Overall, FDA worked with 15 other drug  and device firms to recall at least 11 drug products and 72 medical device  products as a result of the heparin crisis.
section_title: FDA Collaborated with Its International Regulatory Partners to Exchange Information and Help Prevent Future Crises, but Could Not Determine the Original Source of OSCS Contamination
paragraphs: FDA reached out to its international regulatory partners during the crisis  to exchange information about contaminated heparin, but was ultimately  unable to identify the original source of contamination. In early February  2008, prior to FDA’s public announcement about the adverse events seen  in the United States, FDA told its partners—which included regulatory  agencies in 17 countries, the European Commission, and the European  pharmaceutical regulatory agency—about these adverse events and asked  them to share information on any similar events related to heparin. By  March 2008, FDA was aware of at least 10 countries, including the United  States, that had found OSCS contamination in their heparin supply.  However, only 1 other country, Germany, also observed an increase in  heparin-associated adverse events. Through its communications with  other countries, FDA learned that some Chinese manufacturers associated  with contamination in these countries also supplied heparin to the U.S.  market. Notably, one of these manufacturers was the primary supplier for  APP, the U.S. firm that supplied almost the entire U.S. heparin market  after Baxter recalled its products. In this instance, FDA responded to this  information by conducting an investigation of the manufacturer and as a  result concluded that the heparin distributed by APP in the United States  was not contaminated.
FDA also collaborated with the Chinese government during the crisis,  though FDA was ultimately unable to determine the original source of  contamination. According to FDA officials, FDA’s preliminary  investigation concluded that contamination did not take place in the  United States. As a result, FDA requested jurisdiction from the Chinese  government in order to conduct a criminal investigation in China to  determine the source of contamination. However, Chinese officials would  not grant this request and denied that contamination took place in China.  Through retrospective testing of retained heparin samples conducted by  firms in 2008, FDA learned that OSCS-contaminated crude heparin had  been introduced into the global heparin supply as early as May 2006. FDA  investigators believe that OSCS was increasingly added to heparin by  Chinese establishments that manufacture crude heparin so that the  establishments could cut costs.
Although unable to collaborate with the Chinese government in a formal  criminal investigation, FDA has continued to collaborate with its  international partners to avoid similar crises in the future. For example,  FDA organized an international conference in April 2008 during which  regulators and academics from 10 additional countries around the world,  including China, along with the standard-setting entities for  pharmaceuticals in the United States and Europe, shared information on  their experiences with contaminated heparin during the crisis and  discussed potential steps to prevent future contamination incidents. The  agency also participates in the API Pilot Program with the regulatory  bodies of Europe and Australia. According to FDA officials, drug  regulatory agencies in this program—which began after the heparin  crisis—share and obtain information about API inspections they conduct  around the world to better leverage their inspection resources. Officials  said that FDA’s establishment of overseas offices will also help facilitate  collaboration between FDA and foreign regulatory agencies.
section_title: FDA Coordinated Resources to Respond to the Heparin Crisis, but Did Not Adequately Address Risks Related to Working with Certain External Entities
paragraphs: FDA coordinated internal and external resources to respond to the  contaminated heparin crisis, but did not adequately address risks related  to working with certain external entities with ties to heparin firms. Not  adequately addressing these risks could have affected the public’s  confidence in FDA’s response efforts and in its other activities related to  the regulation of heparin products and also left FDA open to claims for  payment for services that these external entities provided to FDA on a  voluntary basis.
subsections: section_title: FDA Coordinated Internal Resources to Respond to the Heparin Crisis and Plan for Future Crises
paragraphs: In responding to the heparin crisis, FDA coordinated response efforts in  accordance with its ERP and developed a new Emergency Operations  Plan (EOP) to guide its response to future crises. According to FDA  officials, OCM initially coordinated the agency’s response efforts, which  included many of FDA’s offices and centers. FDA officials said the total  number of centers, offices, and divisions within the agency that were  involved in responding to the contaminated heparin crisis was over 40 (see  app. II for a complete list of FDA centers, offices, and divisions that were  involved in the heparin crisis). On February 8, 2008, CDC reported that the  problem was with the heparin drug product and not with medical devices  as was originally thought. Once this link was made, FDA officials  determined that CDER would be best equipped to lead scientific efforts to  identify the contaminant.
According to FDA officials, there was no formal transition of leadership  from OCM to CDER, but once the situation was discovered to be largely a  drug issue, CDER increased its involvement and took over the role of lead  coordinator from OCM. Once CDER assumed this responsibility, FDA no  longer had an agency-level entity responsible for coordinating response  efforts, and CDER coordinated the multiple centers and offices within the  agency that continued to be involved in the crisis. CDER officials created a  task force to coordinate the agency’s response efforts across multiple  centers, offices, and divisions. CDER’s Heparin Task Force was initially  composed of mostly CDER officials but expanded to involve some other  FDA offices. The task force initially met daily and then weekly from  February 25, 2008, through May 27, 2008. An FDA official said that  information from the task force’s meetings was dispersed to relevant staff  throughout FDA through CDER’s e-mail distribution list, which included  over 200 FDA officials. OCM continued to be involved with CDER’s task  force by participating in task force meetings, but it did not have a role in  the ongoing coordination of the agency’s efforts to respond to the heparin  crisis.
After the crisis, FDA conducted some lessons-learned meetings to focus  on difficulties that occurred during the agency’s response. Documentation  from these meetings shows that agency officials believed that FDA staff  showed remarkable dedication during the crisis and that the agency was  successful in removing contaminated products from and preventing the  introduction of further contaminated product into the market place.  However, these documents also show that there were some areas in which  the agency’s response could have been improved. Specifically, these  documents indicate that the lack of details in the ERP and the absence of  coordination at the agency level for the duration of the crisis may have led  to some process delays and difficulty with internal and external  communication. For example, CDER officials stated in a lessons-learned  document that the agency’s response to future crises could benefit from  guidance that clearly delineates who should lead the agency’s efforts  during a crisis. According to this document, CDER officials said that it was  not clear who, OCM or CDER, should lead the agency’s efforts, since the  ERP was not specific about who should coordinate the agency’s response  during a crisis. Additionally, when leadership transitioned to CDER, center  officials had to spend time determining leadership roles within the center.  In another lessons-learned document, CDRH officials said that external  communication was sometimes complicated by CDER being the lead  office. Specifically, issues related to heparin-containing medical devices  were not always included in CDER-led task force discussions and were  consequently often not addressed in CDER’s communications with the  public, other countries, or industry.
FDA officials told us that the agency has been working since October 2008  on the development of the new EOP, which is intended to address some of  the difficulties encountered during previous crises, including lack of  specific details on agency coordination. According to FDA officials, the  new EOP was finalized in September 2010 and replaces the agency’s  existing ERP. FDA officials also told us that the new EOP is based on  guidance from the National Response Framework and will incorporate  principles of emergency operation—including the National Incident  Management System and the Incident Command Structure—that are  designed to help agencies better coordinate efforts in the event of an  emergency. According to these officials, the EOP will be more detailed in  terms of coordination within the agency and clearer about roles and  responsibilities of centers and offices in any emergency, large or small,  that the agency may face. For example, the new EOP is to contain a  section devoted to coordination at the agency level within FDA’s  headquarters. This section will offer guidance and a specific coordination  structure that agency officials can use during an incident to help ensure  that response resources and capabilities from multiple centers and offices  within the agency are well organized. The EOP is to also include two new  coordinator positions—the Agency Incident Coordinator (AIC) and the  Agency Executive Group (AEG)—to facilitate agency-level coordination of  an incident. According to this official, the role of the AIC will be to manage  an incident at the agency level and to serve as a communication bridge  between the Commissioner’s Office and staff in the agency’s centers and  offices responding to an emergency. The AEG will be a group of senior- level executives at FDA who will provide strategic policy direction and  guidance for major emergency response activities. The AEG is expected to  approve important policy decisions in consultation with the AIC and the  Commissioner of FDA.
section_title: FDA Coordinated External Resources to Respond to the Crisis, but Did Not Adequately Address the Risks of Working with Certain External Entities
paragraphs: FDA worked with several external scientists during the heparin crisis, but  did not address certain risks that engaging two of these scientists, and  additional external entities engaged by one of these scientists, posed to the  agency. In February 2008, FDA officials contacted five external scientists,  including one who was employed by the agency as a special consultant, for  assistance with the heparin crisis, and FDA worked with these scientists  for varying time periods. Agency officials told us that they sought the  advice of these external scientists because the agency lacked the  necessary instrumentation and expertise to identify and develop new  testing methods to detect the specific contaminant. According to FDA  officials, these external scientists were engaged to provide the agency with  technical and factual scientific advice related to the identity of the  unknown contaminant and tests to identify this contaminant, and all policy  judgments and decisions related to this advice were made by CDER  officials. FDA communicated with external scientists frequently during the  height of the crisis period and told us that some of these scientists were  brought together for at least two in-person meetings to share and discuss  their individual findings.
All five scientists worked directly with FDA, but they did not all have the  same working arrangements with the agency. One of the scientists was a  participant in FDA’s Science Advisor Program and was considered an FDA  employee. Two of the scientists were employees of a university with  which FDA contracted for testing of heparin samples; the university was  selected in part because of its close proximity to FDA’s Division of  Pharmaceutical Analysis and the availability of advanced instrumentation  and staff expertise necessary for testing. The two remaining scientists that  FDA contacted in late February were not employees of FDA or FDA  contractors. The agency characterized these scientists as volunteers and  told us that they had been informally identified by CDER staff as experts  in heparin analysis. FDA officials said that these two scientists provided  services on an uncompensated basis in response to the oral requests of  CDER staff. With FDA’s knowledge, one of these two scientists obtained  assistance in his work for FDA from external entities, including a drug  development firm and an Italian research institute, also on an  uncompensated basis.
The two scientists characterized by FDA as volunteers had professional  and financial ties to heparin firms. Both served as paid consultants to two  of the primary firms associated with contaminated heparin. In addition,  one of the scientists was a cofounder and member of the board of  directors, as well as an equity interest holder, in a third firm, which, at the  time of the crisis, had a pending application for a heparin product before  FDA. The agency allowed this scientist to obtain assistance in conducting  analytical work to identify the contaminant in heparin from this firm  despite its pending application for a heparin product. This drug  manufacturer dedicated approximately 30 staff members from its  analytical and biology groups for periods ranging from a few weeks to   3 months to assist in the effort to identify the contaminant in heparin.
FDA’s internal guidance, The Leveraging Handbook, addresses risks that  may be presented in collaborative arrangements with external entities. The  handbook cautions FDA employees to weigh certain legal and ethical  considerations when entering into partnerships and references rules  applicable to the behavior of individual employees, but also identifies  other principles, which it characterizes as “institutional ethics.” These  prudential considerations are designed to prevent public perception  concerns and to demonstrate that the agency has established procedures  designed to display that it is worthy of public trust. Among other things,  the guidance cautions staff to consider the ethical implications of  accepting gifts for the agency from external entities, stating that the  agency should be judicious in accepting gifts to avoid the appearance that  its programs or operations may be compromised. Specifically, staff are to  balance the importance of a potential gift to the agency against the  potential appearance problems that may be caused by acceptance of the  gift. Steps to be considered in the balancing test include determining if  accepting the gift would reflect unfavorably on the agency’s ability to carry  out its responsibilities in a fair and objective manner and whether the  acceptance of a gift would compromise the integrity of, or the appearance  of the integrity of, a program or official. Staff are also asked to determine  the value to the agency of accepting the gift and the extent to which it will  enable the agency to accomplish its mission. Further, The Leveraging  Handbook instructs staff to consider the nature and sensitivity of matters  pending before the agency that would affect the interests of the gift donor  and to weigh the agency’s interest in accepting the gift against any actual  or apparent conflict of interest. Finally, the guidance provides for  consideration of whether the gift would be from a prohibited source if the  gift were made to an individual employee and calls for gifts from  prohibited sources to be subject to higher scrutiny.
FDA officials were aware of the scientists’ ties to heparin manufacturers,  but did not take adequate steps to consider whether these relationships  exposed the agency to the risks described in its guidance or to address  these risks before engaging them. FDA officials told us that they believed  that there was insufficient time to address these ties in the midst of the  heparin crisis and that the CDER staff who identified these scientists were  confident that they could independently assess the input from these  scientists through robust, detailed, and transparent discussions; they said  that this would address any appearance problems related to the scientists’  input. FDA officials also emphasized that the agency made all policy  judgments and said that they disclosed the work of these scientists to the  public through peer-reviewed journal articles in late April, after the  specific contaminant in heparin was identified. However, FDA officials  told us that they did not take steps before accepting voluntary services of  these scientists to assess whether their ties to firms associated with  contaminated heparin would compromise the integrity of FDA’s activities,  or the appearance of integrity, so as to undermine the public perception of  FDA’s management of the heparin crisis. Nor is there evidence that they  considered whether the agency’s acceptance of voluntary services from a  scientist with an interest in a firm with an application pending before FDA,  along with employees of that firm, would compromise, or appear to  compromise, the agency’s activities, including its activities related to the  approval of heparin products. Moreover, FDA did not fully disclose the  existence or extent of these scientists’ interests while they were providing  assistance or afterwards. CDER staff did not consult with the Office of  Chief Counsel or agency ethics officials about their working arrangements  with these two scientists or seek advice as to whether the arrangements  were consistent with the agency’s ethics standards.
FDA’s acceptance of voluntary services in connection with the heparin  crisis also exposed the agency to the risk of claims for payment for the  services provided. Federal agencies are generally prohibited from  accepting voluntary services because of the risk of claims associated with  them. The statutory provision barring the acceptance of these services is  best understood in the context of the preceding statutory provision, which  prohibits agencies from incurring obligations in excess of their  appropriations or before such appropriations are made. The fundamental  purpose of the voluntary services prohibition is to preserve the integrity of  the appropriations process by preventing agencies from effectively  incurring obligations in excess of or in advance of appropriations by  accepting voluntary services with the expectation that Congress will  recognize a “moral obligation” to pay for the services rendered.
Consistent with this underlying purpose, voluntary services have been  defined as those that are not rendered under a prior contract or advance  agreement that they will be gratuitous and are, therefore, likely to form the  basis of future claims against the government. However, the acceptance  of services that are offered as gratuitous—that is, with no expectation of  payment—with a record made of that fact, does not violate the voluntary  services prohibition. Such services do not give rise to any obligation or  financial liability and therefore do not expose an agency to the risk of  claims for payment.
FDA officials told us that the agency was authorized to accept voluntary  services during the heparin crisis under an emergency exception and  therefore was not required to obtain a written agreement that the services  were offered with no expectation of payment. The statute provides an  exception for emergencies involving the safety of human life or the  protection of property, which the statute defines as circumstances  involving an imminent threat to the safety of human life or the protection  of property. FDA officials explained that the sharp increase in reports of  severe allergic reactions to heparin in late January 2008 signaled a public  health emergency requiring the agency to quickly identify and assemble  the scientific expertise of those who could help identify the source of the  crisis in order to protect patients and ensure the safety of a medically  necessary drug. By late February 2008, FDA had developed a screening  method to distinguish contaminated heparin from uncontaminated  heparin, but had not identified the precise contaminant or developed  specific methods of testing for this specific contaminant, and obtained the  voluntary services of additional scientists for this purpose.
While the existence of an emergency would provide a legal basis for  agencies to accept voluntary services, it would not protect them from  subsequent claims for payment. To the contrary, the acceptance of  services under the emergency exception would give rise to obligations— that is, financial liabilities—for which claims for payment could be made.  As noted above, however, agencies accepting services in an emergency or  otherwise may guard against claims for compensation by establishing that  the services are gratuitous and, as such, do not give rise to any obligation  or financial liability on the part of the government. This is accomplished  by obtaining a written agreement from those providing services that they  will receive no compensation and waive any future claims against the  government for their services.
FDA did not take steps to establish that the services provided by two of  the external scientists, as well as the services obtained by one of those  scientists from two other entities, imposed no obligation or financial  liability and, in this respect, exposed the agency to the risk that claims for  compensation would be made for which funds were not available.  Regardless of whether the circumstances that existed when FDA  contacted these scientists constituted an emergency, they did not preclude  the agency from addressing this risk. To the extent that time was of the  essence, a letter from those providing services to the agency would have  been sufficient; there is no detailed or prescribed form for the provision of  gratuitous services. In addition, the provision of services was not  unexpected—the agency requested and discussed the services provided by  the selected scientists as part of the ongoing process of resolving the  heparin crisis. By late February 2008, the agency had overseen a recall of  heparin products and determined how to distinguish contaminated  heparin from uncontaminated heparin using a preliminary screening  method. FDA requested the services of the two scientists to help it identify  the specific contaminant and develop appropriate testing methodologies  for its detection, and these scientists provided analyses and opinions to  FDA over a period of several weeks. FDA officials told us that determining  the precise identity of the contaminant and developing appropriate testing  methodologies were necessary to resolve the crisis and that the services  provided and arranged for by the two scientists were critical for doing so.  However, those facts do not explain why FDA did not take appropriate  steps to protect the agency from the financial exposure arising from  services that it had both requested and accepted.
Voluntary services may be accepted where otherwise authorized by law,  and FDA also cited the agency’s authority to accept gifts as the basis for its  acceptance of voluntary services without a written agreement in  connection with the heparin crisis. A gift is generally understood to be a  gratuitous conveyance without any consideration, the essential elements  of which are acceptance, delivery, and the intent to make a gift. By  definition, a gift does not give rise to any obligation or liability and poses  no risk of subsequent claims for compensation. We do not address the  scope of the provision cited by FDA, but note that it does not expressly  authorize gifts of services and contemplates that gifts be made by means  of some instrument. As discussed above, however, there is no evidence to  establish that the external scientists intended to provide their services on  a gratuitous basis—that is, to donate their services and the services of  others to the agency—that would protect the agency from such claims.
section_title: FDA Monitored and Analyzed Adverse Events Associated with Heparin, but It Was Unable to Link Them to Contaminated Heparin
paragraphs: FDA increased its monitoring of adverse events, including deaths,  associated with heparin and conducted analyses. FDA was unable to link  any of the adverse events to contaminated heparin because it was unable  to establish a causal relationship due to data limitations and confounding  factors involving the individual patients.
subsections: section_title: FDA Increased Its Monitoring of Adverse Event Reports Associated with Heparin by Working with Manufacturers and Dedicating Staff Resources
paragraphs: FDA increased its monitoring of adverse event reports by working with  heparin drug and device manufacturers to expedite submission of these  reports to FDA. According to FDA officials, FDA contacted Baxter in  February 2008 to request early submission of its adverse event reports  associated with heparin and requested reports from two other heparin  manufacturers, APP and Hospira, later in March 2008. FDA officials said  that these reports would otherwise have been due later in the year. A few  weeks later, in April 2008, FDA sent a letter to almost 100 manufacturers  and distributors of medical devices that contained or were coated with  heparin. In this letter, FDA required these firms to submit all reports of  heparin-related adverse events within 5 work days of the firm becoming  aware of these events, in accordance with federal regulations. This  requirement remained in effect for 120 days of the date of the letter from  FDA.
FDA also monitored trends in the number of reports of adverse events  associated with heparin drug products and heparin-containing medical  devices that FDA received before, during, and after the crisis. FDA  dedicated staff to manage the increased number of heparin-specific  reports that the agency received during the crisis and to conduct searches  of its AERS and MAUDE databases to retrieve additional related reports  that had already been submitted to FDA prior to the crisis. FDA officials  said that retrieving and entering information from AERS and MAUDE  reports was extremely time and resource intensive in that information had  to be entered manually into spreadsheets and duplicate reports had to be  removed before the data could be analyzed. FDA officials said that there  was a certain baseline number of adverse event reports associated with  heparin in 2007 prior to the heparin crisis and that the number of reports  of adverse events associated with both heparin drug products and heparin- containing medical devices that FDA received decreased after the heparin  crisis, returning to levels typically seen prior to the crisis. For example,  FDA received reports of 176 adverse events associated with heparin drug  products that took place in February 2008, compared with 13 events that  took place in February 2007 and 7 events that took place in February 2009.  Figure 3 shows a breakdown of AERS reports of adverse events that  resulted in death and reports that did not have a fatal outcome  (nondeaths) from January 2007 through June 2009.
Regarding trends in adverse events in heparin-containing medical devices,  during the crisis in March 2008, FDA conducted a search of the MAUDE  database back to January 2005 through December 31, 2007. This search  included all medical device products known to contain heparin using a  search of terms in the report texts consistent with symptoms or signs with  what was known about the contaminant, such as acute respiratory failure  and nausea, and FDA identified 23 reports for that 3-year period. Using   the same search term criteria, FDA identified 91 MAUDE reports   from January 1, 2008, through August 31, 2008, and 16 reports from  September 1, 2008, through September 1, 2009, indicating that the number  of reports associated with heparin-containing medical devices had  decreased since the crisis.
section_title: FDA Analyzed Adverse Events Associated with Heparin and Heparin- Containing Medical Devices, but Was Unable to Link Them with Contaminated Heparin Due to Data Limitations and Confounding Factors Involving Patients
paragraphs: FDA conducted analyses of adverse events, including deaths, associated  with heparin drug products and heparin-containing medical devices. To  analyze adverse events associated with heparin drugs, FDA reviewed a  total of 701 AERS reports associated with heparin that the agency received  from January 1, 2008, through March 31, 2008. Of the 701 reports, 675  were identified by searching AERS for allergic-type adverse events  associated with heparin, such as a drop in blood pressure or acute  respiratory failure, for both death and nondeath events. In its analysis of  allergic-type adverse events associated with heparin, after excluding 101  allergic-type cases from this analysis, FDA included a total of 526  nondeath AERS reports and 48 death reports. FDA reported descriptive  characteristics about this group of reports—for example, the average age  of the patients; the manufacturer of the heparin drug product administered  to the patients; if known, and the clinical setting where the heparin was  administered. FDA also analyzed a total of 94 AERS reports of deaths  associated with heparin, which included 68 allergic-type adverse events  and an additional 26 death reports that were not identified as allergic-type  adverse events. FDA conducted further analyses of these reports using  specific assessment criteria to determine whether they were caused by  heparin, and concluded that three of the deaths were “probable or likely”  linked with heparin. However, FDA did not know whether or not the  heparin these patients received was contaminated because the lot  numbers of the heparin that these patients received were not reported in  the AERS reports.
To analyze adverse events associated with heparin-containing medical  devices, FDA reviewed a total of 143 MAUDE reports that the agency  received from January 1, 2008, through August 31, 2008. FDA reviewed all  of the MAUDE reports that FDA received associated with heparin- containing medical devices with an event date occurring during that time  period. Of the 143 reports, 128 were nondeath adverse events associated  with heparin-containing medical devices, and the remaining 15 MAUDE  reports had a death outcome. Three of these deaths were associated with  medical devices known to contain contaminated heparin. FDA determined  that these MAUDE reports of deaths were unlikely to have been caused by  exposure to contaminated heparin, based on similar assessment criteria  that FDA used with its analysis of the AERS death reports. (See app. III for  FDA’s death assessment criteria, and details of its AERS and MAUDE  analyses.)
FDA’s analyses of adverse events associated with both heparin and  heparin-containing medical devices were constrained by data limitations.  For example, FDA officials told us that the agency does not necessarily  receive a report for every adverse event that occurs. For drug-related  adverse event reports submitted to AERS, manufacturers are required to  submit adverse event reports to FDA, but health providers and consumers  are not required to do so but may submit such reports on a voluntary  basis. For device-related adverse event reports submitted to MAUDE,  importers, manufacturers, and user facilities (such as hospitals and  nursing homes) are required to report certain device-related adverse  events to FDA; others, including health professionals and consumers, may  submit such reports on a voluntary basis. In addition, many submitted  reports do not include sufficient information to allow FDA to determine if  a given report was associated with a contaminated product. FDA officials  told us that they followed up on some of the reports of deaths included in  the agency’s AERS and MAUDE analyses by contacting the facility or  individual that had submitted the report in an attempt to obtain additional  information. Further, in our review of the 94 AERS death reports that FDA  had analyzed, we found that only 13 reports included information on  heparin lot numbers and 28 of the 46 voluntary reports did not list the  heparin manufacturer. Consequently, it was not possible for FDA to  determine the heparin contamination status in the majority of these  deaths.
Further, even with complete information, it was difficult for FDA to link  patient deaths to contaminated heparin because it was unable to establish  a causal relationship due to the confounding factors of individual patients.  For example, the FDA official who conducted FDA’s analyses on adverse  events associated with heparin-containing medical devices told us that it  was hard to separate problems caused by the heparin contained within the  medical device from symptoms or events related to the natural course of  the underlying disease or condition, concurrently administered  medications, or concurrent procedures. In addition, according to FDA  officials, many of the patients that died were very sick and had  complicated conditions that could themselves have caused the reported  events, making it difficult to conclusively link their deaths to contaminated  heparin.
section_title: Conclusions
paragraphs: FDA took various actions in response to the contaminated heparin crisis  to help protect the public health. To help minimize the impact on U.S.  consumers of heparin, the agency increased its oversight activities and  monitoring of adverse events, worked with heparin manufacturers, and  collaborated with its international partners. The agency increased its  activities related to oversight of heparin firms by increasing the number of  inspections and investigations and monitoring heparin imports, and  worked with drug and device manufacturers to recall contaminated  products while ensuring that an adequate supply of heparin was available.  With the help of external entities, FDA identified the unknown  contaminant and developed tests to screen heparin products. Agency  officials also reached out to international regulatory partners during the  crisis to exchange information about contaminated heparin and to help  prevent future crises. Within a few months of the agency’s increased  efforts and cooperation with other entities, adverse events returned to  precrisis levels.
While FDA took steps to protect the U.S. public from contaminated  heparin, it did not take steps to consider and address risks associated with  the way in which it engaged two external scientists and additional external  entities engaged by one of these scientists. Although FDA has issued  standards on collaboration with external entities in other contexts and  governmentwide standards govern the acceptance of services free of  charge, FDA did not take steps to ensure that these standards were  considered and applied in connection with the heparin crisis. We believe  that these standards can be applied in all situations in which the agency  collaborates with external entities, including those situations in which  time pressures exist. In accepting voluntary services from individuals with  ties to heparin firms, including one that was affiliated with a company with  a heparin drug product application before FDA for approval, agency  officials ran the risk of undermining public confidence in the integrity of  FDA’s operations and of subjecting the agency to future claims for  payment.
FDA is charged with protecting the health of the public from problems  related to products that it regulates, and the agency works with external  entities when necessary to ensure that it meets this goal. Because  adulteration of FDA-regulated products could likely happen again, it is  critical that the agency have clear and useful controls in place that it can  apply in circumstances similar to those presented by the heparin crisis to  help ensure that officials take appropriate steps to consider and address  risks posed when engaging external entities.
section_title: Agency Comments and Our Evaluation
paragraphs: The Department of Health and Human Services (HHS) received a draft of  this report and provided comments, which are reprinted in appendix IV.  HHS also provided technical comments, which we incorporated as  appropriate. In its comments, HHS described the challenges FDA faced  when it first learned of severe allergic reactions suffered by dialysis  patients during treatment. HHS described how FDA worked to protect the  public from contaminated heparin while still ensuring that patients had  access to a medically necessary drug. HHS said that FDA needed to  identify and enlist the help of leading heparin experts to identify the  contaminant in heparin. We agree that FDA faced numerous challenges in  responding to the heparin crisis, including the need to obtain expert  assistance. However, we also note the potential risks FDA faced in  working with external scientists on a voluntary basis in the absence of  appropriate controls—the risks of undermining public confidence in its  efforts and of future claims for payment. Therefore, in our draft report, we  recommended that FDA develop adequate controls to help avoid exposure  to these risks when working with external entities in future situations  similar to the heparin crisis. Specifically, we recommended that FDA  develop a process for considering risks, including consulting with  appropriate offices within the agency; develop a process for documenting  the steps taken to address risks; and disseminate guidance on these  processes for its employees. FDA addressed the draft recommendation by  issuing guidance on October 15, 2010, for FDA staff to follow when  working with external scientific and other experts in emergency situations  when the services are provided on a gratuitous basis. The guidance  includes a policy that is responsive to our recommendation, providing  broadly for due consideration of risks that may be presented in  collaborative arrangements with external entities, including conflicts of  interest, as well as for documentation of decisions about addressing such  risks. The guidance also includes specific procedures for the provision of  gratuitous services, screening for conflicts of interest, and public  disclosure.
In its comments, HHS also noted that FDA has learned from the heparin  crisis to improve its processes for responding to emergencies. Specifically,  FDA finalized its new Emergency Operations Plan to respond to future  crises. HHS described various actions FDA took to protect the public  health during the crisis and steps the agency has taken to safeguard the  nation’s heparin supply, including an increased number of inspections of  heparin manufacturing and testing facilities related to the U.S. heparin  supply. We had previously described these actions in the report. HHS also  mentioned legislation currently under consideration by Congress that it  believes will, if enacted, provide FDA with helpful tools to further secure  the nation’s drug supply chain, and ensure that the agency can hold  industry accountable for the security and integrity of its supply chains and  the quality control systems it uses to produce drugs for the American  people.
As agreed with your office, unless you publicly announce the contents of  this report earlier, we plan no further distribution until 30 days from the  report date. At that time, we will send copies of this report to the  Commissioner of FDA and appropriate congressional committees. The  report is also available at no charge on the GAO Web site at  http://www.gao.gov.
If you or your staff have any questions about this report, please contact me  at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of  Congressional Relations and Public Affairs may be found on the last page  of this report. GAO staff who made major contributions to this report are  listed in appendix V.
section_title: Appendix I: Technical Information about Contaminated Heparin
paragraphs: This appendix provides a brief review of the scientific research related to  heparin contamination, focusing on peer-reviewed research articles  published in January 2008 through January 2010.
subsections: section_title: What is heparin?
paragraphs: Heparin is an anticoagulant drug; that is, it prevents the formation of blood  clots in the veins, arteries, and lungs. It is used before certain types of  surgery, including coronary artery bypass graft surgery; in kidney patients  before they undergo dialysis; and to prevent or treat other serious  conditions, such as deep vein thrombosis and pulmonary emboli. Heparin  is also used in medical devices—for example, blood oxygenators or  catheters contain or are coated with heparin, and some diagnostic testing  products, such as some capillary tubes, are manufactured using heparin.
Heparin is a natural product derived from animal tissue. Specifically, most  heparin used in the United States is derived from the intestines of pigs. Pig  intestines are processed into crude heparin, which is further refined into  heparin active pharmaceutical ingredient (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.
The chemical makeup of heparin is complex. Because heparin is a drug  derived from animal tissue, it is not a single chemical, but a mixture of  many similar chemical chains of different sizes.
Two types of heparin are used in clinical practice: unfractionated heparin  (UFH) and low molecular weight heparin (LMWH). The two forms of  heparin differ in their molecular size and the route of administration: UFH  is comprised of larger molecules than LMWH and is usually administered  intravenously, while LMWH is usually administered subcutaneously (that  is, injected under the skin). UFH is used often in the United States,  whereas in Europe the predominant heparin is LMWH. Researchers and  officials we interviewed said that the number of adverse events related to  contaminated heparin may have varied by country because of these  differences in the type of heparin administered and methods of  administration, as well as because of differences in countries’ adverse  event reporting systems. In particular, one researcher explained that in the  United States, physicians tend to administer a bolus dose of heparin,  which is a faster method of administration but places patients at greater  risk for a fatal drop in blood pressure.
section_title: What was the contaminant in contaminated heparin?
paragraphs: Food and Drug Administration (FDA) officials and their collaborators  agreed that oversulfated chondroitin sulfate (OSCS) was a contaminant in  the heparin that caused adverse events during the heparin crisis. FDA  researchers and their collaborators showed that batches of heparin that  had been associated with adverse events contained a contaminant. They  identified that substance as OSCS. Chemically, OSCS is similar to heparin,  but OSCS is probably not a naturally occurring chemical. The researchers  confirmed their identification by matching the contaminant to synthetic  OSCS created by chemical modification of chondroitin sulfate, an  inexpensive natural product used for the self-treatment of arthritis.
Other research articles have provided additional evidence that OSCS was  present in contaminated heparin. For example, Clark et al. performed  analysis on some contaminated heparin batches and concluded that the  properties of the contaminant were consistent with those of OSCS. Viskov  et al. showed that the chemical properties of OSCS isolated from a batch  of contaminated heparin were similar to those of synthetic OSCS. Finally,  Zhang et al. examined samples of heparin from as far back as 1941 and  identified the presence of OSCS in a sample from the U.S. market that was  produced in 2008.
LMWH heparin was also affected by OSCS contamination. Zhang et al.  evaluated the sensitivity of OSCS to five different processes similar to  ones used in preparing LMWH, and found that these processes varied in  the extent to which they affected OSCS.
The source of the OSCS contamination is still unknown, and researchers  have proposed various hypotheses about the source of the OSCS  contamination. For example, Fareed et al. suggested that the  contamination of heparin with OSCS was not accidental, but was based on  a rational design and prior knowledge of the chemical’s molecular and  anticoagulant profiles. Pan et al. conducted an analysis that detected  additional under- and oversulfated contaminants in contaminated heparin  and proposed that the OSCS present in the contaminated heparin batches  could have come from an oversulfated form of a byproduct of the heparin  production process, rather than derived from animal cartilage. Another  study considered this hypothesis but concluded, based on analysis of  oversulfated byproducts provided by Baxter (a major heparin  manufacturer), that production byproducts were likely not the source of  the OSCS found in contaminated heparin.
section_title: How is the contaminant related to the adverse events?
paragraphs: CDC researchers found a link between adverse events and contaminated  heparin. These researchers collected data related to the period  November 2007 through January 2008 from 21 dialysis facilities that  reported adverse events and 23 facilities that reported no adverse events.  With these data, the researchers conducted a case-control study to test  whether facility-level risk factors—such as the size of the facility, the type  of heparin used at the facility, and the type of dialysis equipment used at  the facility—were related to adverse events. They found a significant  association between the number of adverse events reported by facilities  and their use of Baxter heparin. They reported that the type of adverse  reactions experienced by patients who received contaminated heparin  varied, but often included low blood pressure and nausea. The researche could not estimate the percentage of patients who experienced adverse  reactions after receiving contaminated heparin because the total number  of patients in the United States who received heparin during this period is  unknown.
In other articles, researchers have proposed possible biological  mechanisms by which OSCS could have caused the observed adverse  events. Researchers have also suggested that exposure to OSCS cou have effects beyond the acute allergic reactions reported during the  heparin crisis. For example, one article showed that patients who received  dialysis at a university in the United States in 2008 had more of a specif type of antiheparin antibody in their blood than patients who received  dialysis in 2006 and 2007, indicating that OSCS may cause an immun response not seen with uncontaminated heparin. Similarly, other  researchers have presented data showing that the incidence of hep induced thrombocytopenia, a type of immune reaction to hepari n,  increased in Germany during the contaminated heparin crisis.
section_title: How is the detected?
paragraphs: The standard for heparin testing now includes two tests for OSCS. In  October 2009, the United States Pharmacopoeia heparin monograph— testing standard applied to all heparin reaching the U.S. market—was  revised to specify that nuclear magnetic resonance spectroscopy and  the  chromatography be used both to positively identify heparin and to ensure  the absence of OSCS in a sample.
During and after the contaminated heparin crisis, researchers investigated  other methods to detect contaminated heparin. For example, FDA  researchers have studied a screening method that is capable of detecting  oversulfated contaminants like OSCS and could be used to test heparin- coated devices as well as heparin drug products. In addition, researchers  have proposed that it might be possible to screen or check heparin using a  blood test. Other researchers have investigated the use of more advanced  approaches capable of detecting OSCS and other potential contaminants.
section_title: Appendix II: FDA Organizational Chart
subsections: section_title: FDA Centers and Offices Involved in the Heparin Crisis
paragraphs: Diviion of Phrmceticl Anly  (St. Loab)
section_title: Appendix III: FDA’s Analyses of Adverse Events Associated with Heparin and Heparin- Containing Medical Devices
paragraphs: FDA reviewed its Adverse Event Reporting System (AERS) for adverse  event reports associated with heparin drug products that the agency  received from January 1, 2008, through March 31, 2008. FDA conducted  two AERS analyses, including an analysis of allergic-type adverse events,  including deaths, associated with heparin drug products, and an analysis  of reports of deaths associated with heparin drug products that included  allergic-type adverse events and reports that were not identified as  allergic-type adverse events.
To identify reports for its AERS analysis of allergic-type adverse events,  including deaths, associated with heparin drug products, FDA used an  expanded case definition from the Centers for Disease Control and  Prevention’s (CDC) investigation of allergic-type events in hemodialysis  patients. The CDC working case definition included confirmed and  probable cases. A confirmed case, per the CDC case definition, was  defined as an episode of anaphylactic or anaphylactoid reaction (severe  hypersensitivity reactions) with angioedema (swelling) or urticaria  (hives). A probable case was defined as an episode that included at least  two of the following signs and symptoms: (1) generalized or localized  sensations of warmth; (2) numbness or tingling of the extremities;   (3) difficulty swallowing; (4) shortness of breath, wheezing, or chest  tightness; (5) low blood pressure/tachycardia; or (6) nausea or vomiting.
Each report in FDA’s AERS analyses of allergic-type adverse events also  included at least one Medical Dictionary for Regulatory Activities  (MedDRA) preferred term (PT) found under the Standardized MedDRA  Query Plus (SMQ+) “anaphylactic reaction” as well as additional non-SMQ  preferred terms of interest. MedDRA is clinically validated international  medical terminology used by regulatory authorities (see table 1 for a list of  FDA’s search term criteria).
In addition, AERS cases meeting at least one of the following seven  criteria were excluded from further analysis of allergic-types adverse  events associated with heparin drug products:  1.  cases judged to have a clearly identifiable alternative clinical  explanation for the events,  2.  cases in which the event reportedly occurred prior to the year 2007,  3.  cases that could not be clinically interpreted,  4.  cases of heparin-induced thrombocytopenia with or without  5.  cases where it was uncertain if the patient was treated with heparin,  6.  cases from literature reports that described unrelated issues, and  7.  cases reported in error and retracted by the reporter.
In its analysis of AERS reports of deaths associated with heparin drug  products, FDA included reports of both allergic-type adverse events as  well as reports that were not identified as allergic-type adverse events  since these cases had a fatal outcome. Table 2 shows the specific  assessment criteria that FDA used in its analyses of AERS reports of  deaths associated with heparin drug products to determine whether or not  there was an association between the event of death and heparin. FDA did  not apply these criteria to its analysis of allergic-types adverse events  associated with heparin drug products. See figure 4 for details of FDA’s  AERS analyses.
In its Manufacturer and User Facility Device Experience (MAUDE)  analysis of adverse events, including deaths, associated with heparin- containing medical devices, FDA included all MAUDE reports that it  received with an event date from January 1, 2008, through August 31, 2008.  However, if a MAUDE report did not specifically have an event date listed,  but was received by FDA during the specified time period, it was  conservatively assumed to have occurred during that time frame and  included in its MAUDE analysis. For each MAUDE report of death, FDA  considered the patient’s underlying condition, including the severity of the  patient’s condition, medications the patient was taking, and concomitant  procedures or surgeries being undertaken to determine if there was a  plausible explanation for the death. The presence of symptoms using the  SMQ+ search terms as noted in table 1 were also taken into account as  well as the timing of the event relative to the use of the heparin-containing  medical device. In this analysis, FDA used assessment criteria similar to  those in table 2 to classify the deaths associated with heparin-containing  medical devices that were known to contain contaminated heparin as  unlikely. FDA used a time criterion of 3 hours for the occurrence of the  event for its MAUDE analysis compared with 1 hour for the AERS analyses  because, according to an FDA official, adverse reactions to a heparin- containing medical device could potentially take longer to occur than  when a patient receives a heparin drug product intravenously (see   fig. 5 for details of FDA’s MAUDE analysis).
section_title: Appendix IV: Comments from the Department of Health and Human Services
section_title: Appendix V: GAO Contact and Staff Acknowledgments
subsections: section_title: Acknowledgments
paragraphs: In addition to the contact named above, key contributors to this report  were Tom Conahan, Assistant Director; Susannah Bloch; Helen  Desaulniers; Linda Galib; Julian Klazkin; Lisa A. Lusk; and Samantha  Poppe.