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Report to the Ranking Member, Committee on Energy and Commerce, House
of Representatives:
United States Government Accountability Office:
GAO:
October 2010:
Food and Drug Administration:
Response to Heparin Contamination Helped Protect Public Health;
Controls That Were Needed for Working With External Entities Were
Recently Added:
GAO-11-95:
GAO Highlights:
Highlights of GAO-11-95, a report to the Ranking Member, Committee on
Energy and Commerce, House of Representatives.
Why GAO Did This Study:
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.
What GAO Found:
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.
View [hyperlink, http://www.gao.gov/products/GAO-11-95] or key
components. For more information, contact Marcia Crosse at (202) 512-
7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Background:
FDA Took Multiple Steps to Protect U.S. Consumers from Additional
Contaminated Heparin, but Faced Limitations in Oversight and
Collaboration:
FDA Coordinated Resources to Respond to the Heparin Crisis, but Did
Not Adequately Address Risks Related to Working with Certain External
Entities:
FDA Monitored and Analyzed Adverse Events Associated with Heparin, but
It Was Unable to Link Them to Contaminated Heparin:
Conclusions:
Agency Comments and Our Evaluation:
Appendix I: Technical Information about Contaminated Heparin:
Appendix II: FDA Organizational Chart:
Appendix III: FDA's Analyses of Adverse Events Associated with Heparin
and Heparin-Containing Medical Devices:
Appendix IV: Comments from the Department of Health and Human Services:
Appendix V: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: FDA's Standardized MedDRA Query Plus Search Term Criteria:
Table 2: FDA's AERS Death Analysis Assessment Criteria:
Figures:
Figure 1: Timeline of Key Events in the Heparin Crisis:
Figure 2: Average Monthly Domestic and Foreign Heparin-Related
Inspections Conducted by FDA before, during, and after the
Contaminated Heparin Crisis:
Figure 3: Reports of Adverse Events in Patients Who Were Administered
Heparin Drug Products, January 2007-June 2009:
Figure 4: FDA Analysis of AERS Reports Associated with Heparin Drug
Products:
Figure 5: FDA Analysis of MAUDE Reports Associated with Heparin-
Containing Medical Devices:
Abbreviations:
AEG: Agency Executive Group:
AERS: Adverse Event Reporting System:
AIC: Agency Incident Coordinator:
API: active pharmaceutical ingredient:
APP: APP Pharmaceuticals:
CDC: Centers for Disease Control and Prevention:
CDER: Center for Drug Evaluation and Research:
CDRH: Center for Devices and Radiological Health:
EOP: Emergency Operations Plan:
ERP: Emergency Response Plan:
FDA: Food and Drug Administration:
GMP: good manufacturing practice:
HHS: U.S. Department of Health and Human Services:
LMWH: low molecular weight heparin:
MAUDE: Manufacturer and User Facility Device Experience:
MOA: memorandum of agreement:
MPS: China's Ministry of Public Security:
NAI: no action indicated:
OAI: official action indicated:
OCM: Office of Crisis Management:
ORA: Office of Regulatory Affairs:
OSCS: over-sulfated chondroitin sulfate:
PT: preferred term:
SFDA: State Food and Drug Administration of the People's Republic of
China:
SMQ: Standardized MedDRA Query:
SMQ+: Standardized MedDRA Query Plus:
UFH: unfractionated heparin:
USP: United States Pharmacopeia:
VAI: voluntary action indicated:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
October 29, 2010:
The Honorable Joe Barton:
Ranking Member:
Committee on Energy and Commerce:
House of Representatives:
Dear Mr. Barton:
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.[Footnote 1] 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.[Footnote 2]
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.[Footnote 3]
Heparin is a medically necessary drug that is used by millions of
patients in the United States each year.[Footnote 4] 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.[Footnote 5] 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.
[Footnote 6] 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.
Background:
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:
FDA's activities related to its mission and relevant to the heparin
crisis include the following:
* Overseeing drug and device firms.[Footnote 7] 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.[Footnote 8]
* Collaborating with USP.[Footnote 9] 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.[Footnote 10] 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.[Footnote 11] 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.[Footnote 12] 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.[Footnote 13]
* 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.[Footnote
14] This handbook references statutes and regulations that apply to
the behavior of individual FDA employees. It also contains guidance
applicable to FDA as an agency to prevent public perception concerns
and demonstrate that the agency is worthy of public trust in carrying
out its activities. In addition, other laws, regulations, and policies
may apply to FDA's work with external entities, depending on the
nature of the arrangements. FDA, like other federal agencies,
generally may not accept voluntary services, which may give rise to
claims for payment for which funds are not available. However, with a
written agreement that services are provided with no expectation of
payment, FDA may accept uncompensated services from external entities.
Heparin and the Contaminated Heparin Crisis:
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 appendix 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 appendix II for a
complete list of FDA centers, offices, and divisions that were
involved in the heparin crisis):
* Office of the Commissioner--leads FDA and implements FDA's mission.
* Office of Crisis Management (OCM)--develops crisis management
policies, leads and coordinates the agency's development and updating
of emergency preparedness and response plans, including FDA's ERP, and
coordinates the agency's emergency response.
* Office of International Programs--works with agencies and
governments to advance public health worldwide.
* Office of Regulatory Affairs (ORA)--leads inspections of regulated
domestic and imported products and domestic and foreign manufacturing
facilities, and develops enforcement policies.
* Center for Drug Evaluation and Research (CDER)--regulates over-the-
counter and prescription drugs, including biological therapeutics and
generic drugs sold in the United States.
* Center for Devices and Radiological Health (CDRH)--regulates medical
and radiological devices sold in the United States.
FDA Took Multiple Steps to Protect U.S. Consumers from Additional
Contaminated Heparin, but Faced Limitations in Oversight and
Collaboration:
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.
FDA Took Action through the First Half of 2008 to Protect the Public
Health in Response to the Heparin Crisis:
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.
Figure 1: Timeline of Key Events in the Heparin Crisis:
[Refer to PDF for image: timeline]
January 4, 2008:
FDA received first notification of adverse events in dialysis patients.
January 7, 2008:
CDC received first notification of adverse events in dialysis patients.
January 9, 2008:
CDC notified FDA of a possible association between Baxter heparin and
adverse events.
January 17, 2008:
Baxter recalled 9 lots of heparin that it produced and were implicated
in adverse events.
February 8, 2008:
FDA worked with Baxter to postpone an expanded recall to mitigate a
potential heparin shortage.
February 22, 2008:
FDA formed its Heparin Task Force.
February 29, 2008:
Baxter expanded its recall once FDA determined that a recall would not
create a heparin shortage.
March 5, 2008:
FDA identified the type of contaminant in suspect lots of heparin.
March 6, 2008:
FDA posted to its Web site laboratory screening methods to detect
whether heparin was contaminated.
March 17, 2008:
FDA identified the specific contaminant.
April 17-18, 2008:
FDA held an International Heparin Conference to exchange information
with its foreign regulatory counterparts.
May 27, 2008:
Heparin Task Force discontinued regular meetings.
Key entities in the heparin crisis:
Food and Drug Administration;
Centers for Disease Control and Prevention;
Baxter Healthcare Corporation.
Source: GAO analysis of FDA information.
[End of figure]
FDA Increased Its Oversight of Heparin Firms, but Faced Limitations in
Its Actions Regarding Some Firms in China:
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 figure 2).[Footnote 15] 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.[Footnote 16] Of the Chinese firms that FDA inspected, only 2
had been inspected prior to the contaminated heparin crisis.[Footnote
17]
Figure 2: Average Monthly Domestic and Foreign Heparin-Related
Inspections Conducted by FDA before, during, and after the
Contaminated Heparin Crisis:
[Refer to PDF for image: stacked vertical bar graph]
Heparin-related inspections per month, on average:
20 months before the crisis (May 2006-Dec. 2007):
Domestic inspections: 0.65;
Foreign inspections: 0.25 (None of FDA’s foreign heparin-related
inspections in this time period took place at Chinese establishments).
5 months during the crisis (Jan.-May 2008):
Domestic inspections: 3.2;
Foreign inspections: 1.2 (Two-thirds of FDA’s foreign heparin-related
inspections in this time period took place at Chinese establishments).
20 months after the crisis (June 2008-Jan. 2010):
Domestic inspections: 1.6;
Foreign inspections: 0.75 (Two-thirds of FDA’s foreign heparin-related
inspections in this time period took place at Chinese establishments).
Source: GAO analysis of FDA data.
Notes: The inspections in this figure include preapproval inspections,
GMP inspections, and inspections that include both preapproval and GMP
components. FDA may conduct preapproval inspections of domestic and
foreign establishments before approving a new drug or device to be
marketed in the United States. The agency conducts GMP inspections to
ensure that manufacturers of drugs and devices already marketed in the
United States are meeting specifications and producing safe and
effective products, in accordance with FDA GMP regulations. See 21
C.F.R. pts. 210, 211, 820 (2010).
Inspections are classified as occurring before, during, or after the
crisis based on the month in which they were initiated by FDA.
[End of figure]
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,
[Footnote 18] 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
these 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 consisting of 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
heparin products offered for import by physically examining and
detaining 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 heparin products offered for import,[Footnote 19] and
then replaced it with a plan in mid-March 2008 to physically sample
and test these products for OSCS 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 basis, 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 newly developed
testing methods.[Footnote 20] 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.[Footnote 21]
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.[Footnote 22] 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.[Footnote 23] 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.[Footnote 24]
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.[Footnote 25] 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.[Footnote
26] 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.
[Footnote 27] 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.
FDA Worked with Heparin Manufacturers on Recalls of Contaminated
Heparin Products while Ensuring an Adequate Heparin Supply for U.S.
Consumers:
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.[Footnote 28] 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.[Footnote 29] 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.
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:
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.[Footnote 30] 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.[Footnote 31] 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.[Footnote 32] 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.
FDA Coordinated Resources to Respond to the Heparin Crisis, but Did
Not Adequately Address Risks Related to Working with Certain External
Entities:
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.
FDA Coordinated Internal Resources to Respond to the Heparin Crisis
and Plan for Future Crises:
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 appendix 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.
[Footnote 33] 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.[Footnote 34] 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.[Footnote 35] 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.
FDA Coordinated External Resources to Respond to the Crisis, but Did
Not Adequately Address the Risks of Working with Certain External
Entities:
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.
[Footnote 36] 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.[Footnote 37] 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.[Footnote 38] 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."[Footnote 39] 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.[Footnote 40] 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.[Footnote 41]
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.[Footnote 42] 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.[Footnote 43] 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.[Footnote 44] 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.[Footnote 45] 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.[Footnote 46] 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.
[Footnote 47] 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.[Footnote 48] 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.[Footnote 49] 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.[Footnote 50] 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.[Footnote 51]
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.[Footnote 52] 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.[Footnote 53]
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.[Footnote 54] 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.[Footnote 55] 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.[Footnote 56] 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.
FDA Monitored and Analyzed Adverse Events Associated with Heparin, but
It Was Unable to Link Them to Contaminated Heparin:
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.
FDA Increased Its Monitoring of Adverse Event Reports Associated with
Heparin by Working with Manufacturers and Dedicating Staff Resources:
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.[Footnote 57] 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[Footnote 58] had to be removed before the data could
be analyzed.[Footnote 59] 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.[Footnote 60] 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.
Figure 3: Reports of Adverse Events in Patients Who Were Administered
Heparin Drug Products, January 2007-June 2009:
[Refer to PDF for image: vertical bar graph]
Date: January 2007;
Death reports: 12;
Nondeath reports: 65.
Date: February 2007;
Death reports: 9;
Nondeath reports: 4.
Date: March 2007;
Death reports: 8;
Nondeath reports: 5.
Date: April 2007;
Death reports: 8;
Nondeath reports: 9.
Date: May 2007;
Death reports: 11;
Nondeath reports: 7.
Date: June 2007;
Death reports: 7;
Nondeath reports: 13.
Date: July 2007;
Death reports: 16;
Nondeath reports: 10.
Date: August 2007;
Death reports: 16;
Nondeath reports: 15.
Date: September 2007;
Death reports: 9;
Nondeath reports: 19.
Date: October 2007;
Death reports: 15;
Nondeath reports: 29.
Date: November 2007;
Death reports: 23;
Nondeath reports: 45.
Date: December 2007;
Death reports: 42;
Nondeath reports: 140.
Date: January 2008;
Death reports: 50;
Nondeath reports: 353.
Date: February 2008;
Death reports: 54;
Nondeath reports: 122.
Date: March 2008;
Death reports: 28;
Nondeath reports: 84.
Date: April 2008;
Death reports: 11;
Nondeath reports: 48.
Date: May 2008;
Death reports: 3;
Nondeath reports: 20.
Date: June 008;
Death reports: 1;
Nondeath reports: 6.
Date: July 2008;
Death reports: 10;
Nondeath reports: 11.
Date: August 2008;
Death reports: 1;
Nondeath reports: 12.
Date: September 2008;
Death reports: 0;
Nondeath reports: 4.
Date: October 2008;
Death reports: 3;
Nondeath reports: 9.
Date: November 2008;
Death reports: 2;
Nondeath reports: 10.
Date: December 2008;
Death reports: 2;
Nondeath reports: 12.
Date: January 2009;
Death reports: 3;
Nondeath reports: 2.
Date: February 2009;
Death reports: 2;
Nondeath reports: 5.
Date: March 2009;
Death reports: 0;
Nondeath reports: 2.
Date: April 2009;
Death reports: 1;
Nondeath reports: 5.
Date: May 2009;
Death reports: 3;
Nondeath reports: 3.
Date: June 2009;
Death reports: 5;
Nondeath reports: 2.
Source: FDA.
Notes: The death and nondeath reports in the figure are from AERS
reports, which were submitted to FDA by consumers, health care
professionals, and product manufacturers. According to FDA, the
numbers of reports are crude counts; duplicate reports have not been
identified and removed. A formal causality analysis was not performed
on all of these cases.
The numbers of death and nondeath reports in the figure reflect the
date the adverse event occurred. However, when only the year of an
event is known, AERS assigns a default event date of January 1 of that
year. Reports that provide no information at all related to when the
event occurred are not assigned any event date and the AERS event date
field is left blank. According to FDA, for January 2007, 57 of the 65
nondeath reports and 2 of the 12 death reports defaulted to January 1,
2007, and for January 2008,106 of the 353 nondeath reports and none of
the death reports defaulted to January 1, 2008. No reports in 2009
defaulted to January 1, 2009.
[End of figure]
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.
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:
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.[Footnote 61] 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.[Footnote 62] 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.[Footnote 63] 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.[Footnote 64] 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 appendix 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.[Footnote 65] 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.[Footnote 66]
Conclusions:
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.
Agency Comments and Our Evaluation:
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.[Footnote 67] 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
[hyperlink, 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.
Sincerely yours,
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Technical Information about Contaminated Heparin:
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.
What is heparin?
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.
What was the contaminant in contaminated heparin?
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.
[Footnote 68] 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.[Footnote 69] Viskov et al. showed that the chemical properties
of OSCS isolated from a batch of contaminated heparin were similar to
those of synthetic OSCS.[Footnote 70] 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.[Footnote 71]
LMWH heparin was also affected by OSCS contamination.[Footnote 72]
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.[Footnote
73]
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.[Footnote 74] 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.[Footnote 75] 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.[Footnote 76]
How is the contaminant related to the adverse events?
CDC researchers found a link between adverse events and contaminated
heparin.[Footnote 77] 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 researchers 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.[Footnote 78] Researchers have also suggested that exposure to
OSCS could 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 specific type of antiheparin antibody in their
blood than patients who received dialysis in 2006 and 2007, indicating
that OSCS may cause an immune response not seen with uncontaminated
heparin.[Footnote 79] Similarly, other researchers have presented data
showing that the incidence of heparin-induced thrombocytopenia, a type
of immune reaction to heparin, increased in Germany during the
contaminated heparin crisis.[Footnote 80]
How is the contaminant detected?
The standard for heparin testing now includes two tests for OSCS. In
October 2009, the United States Pharmacopoeia heparin monograph--the
testing standard applied to all heparin reaching the U.S. market--was
revised to specify that nuclear magnetic resonance
spectroscopy[Footnote 81] and chromatography[Footnote 82] 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.
[Footnote 83] In addition, researchers have proposed that it might be
possible to screen or check heparin using a blood test.[Footnote 84]
Other researchers have investigated the use of more advanced
approaches capable of detecting OSCS and other potential
contaminants.[Footnote 85]
[End of section]
Appendix II: FDA Organizational Chart:
FDA Centers and Offices Involved in the Heparin Crisis:
Office of the Commissioner:
* Office of the Chief Counsel;
* Office of Legislation;
* Office of External Affairs;
* Office of Public Affairs;
* Office of International Programs;
* Office of the Counselor to the Commissioner[A]:
- Office of Crisis Management;
- Office of Emergency Operations.
Reporting to the Office of the Commissioner:
Center for Drug Evaluation and Research:
Office of the Center Director:
* Office of Compliance:
- Division of Compliance Risk Management and Surveillance;
- Division of Manufacturing and Product Quality;
* Office of Surveillance and Epidemiology:
- Division of Pharmacovigilance II;
* Office of Counter Terrorism and Emergency Coordination;
* Office of Pharmaceutical Science:
- Office of New Drug Quality Assessment;
- Office of Generic Drugs;
- Office of Biotechnology Products;
- Office of Testing and Research[A]: Division of Pharmaceutical
Analysis (St. Louis lab);
* Office of New Drugs:
- Office of Oncology Drug Products[A]: Division of Medical Imaging and
Hematology Products;
- Office of Antimicrobial Products[A]: Drug Shortages Program.
Center for Devices and Radiological Health:
Office of the Center Director:
* Office of Compliance;
* Office of Surveillance and Biometrics:
- Division of Post-Marketing Surveillance;
* Office of Science and Engineering Laboratories.
Office of Regulatory Affairs:
Associate Commissioner for Regulatory Affairs:
* Office of Regional Operations:
- Division of Import Operations and Policy;
- Division of Field Investigations;
* Office of Criminal Investigations;
* Regional Field Office–Central Region:
- Forensic Chemistry Center;
* District Offices:
- Kansas City District Office;
- Denver District Office;
- New Jersey District Office;
- New York District Office;
- Chicago District Office;
- Minneapolis District Office;
- Los Angeles District Office;
- Cincinnati District Office.
Source: GAO analysis of FDA information.
[A] Office was not directly involved in crisis.
[End of figure]
[End of section]
Appendix III: FDA's Analyses of Adverse Events Associated with Heparin
and Heparin-Containing Medical Devices:
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).
Table 1: FDA's Standardized MedDRA Query Plus Search Term Criteria:
Anaphylactic reaction SMQ+ and non-SMQ preferred terms:
Scope/category: SMQ narrow;
Anaphylactic reaction SMQ+ and non-SMQ preferred terms: Preferred
term: Anaphylactic reaction, anaphylactic shock, anaphylactoid
reaction, anaphylactoid shock, circulatory collapse, shock, type I
hypersensitivity.
Scope/category: SMQ Broad Oral/Respiratory PTs;
Anaphylactic reaction SMQ+ and non-SMQ preferred terms: Preferred
term: Acute respiratory failure, asthma, bronchial oedema,
bronchospasm, cardio-respiratory distress, chest discomfort, choking,
choking sensation, cough, dyspnoea, hyperventilation, laryngeal
dyspnoea, laryngeal oedema, laryngospasm, laryngotracheal oedema,
oedema mouth, oropharyngeal spasm, oropharyngeal swelling, respiratory
arrest, respiratory distress, respiratory failure, reversible airways
obstruction, sensation of foreign body, sneezing, stridor, swollen
tongue, throat tightness, tongue oedema, tracheal obstruction,
tracheal oedema, wheezing.
Scope/category: SMQ Broad Skin PTs;
Anaphylactic reaction SMQ+ and non-SMQ preferred terms: Preferred
term: Allergic oedema, angioedema, erythema, eye oedema, eye swelling,
eyelid oedema, face oedema, fixed eruption, flushing, generalised
erythema, lip oedema, lip swelling, oedema, periorbital oedema,
pruritus, pruritus allergic, pruritus generalised, rash, rash
erythematous, rash generalised, rash pruritic, skin swelling,
swelling, swelling face, urticaria, urticaria papular.
Scope/category: SMQ Broad;
Cardiovascular PTs;
Anaphylactic reaction SMQ+ and non-SMQ preferred terms: Preferred
term: Blood pressure decreased, blood pressure diastolic decreased,
blood pressure systolic decreased, cardiac arrest, cardio-respiratory
arrest, cardiovascular insufficiency, diastolic hypotension,
hypotension.
Scope/category: Non-SMQ PTs of interest;
Anaphylactic reaction SMQ+ and non-SMQ preferred terms: Preferred
term: Diarrhoea, drug hypersensitivity, hyperhidrosis,
hypersensitivity, loss of consciousness, nausea, vomiting.
Source: FDA.
[End of table]
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
thrombosis,
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.
Table 2: FDA's AERS Death Analysis Assessment Criteria:
Association: Probable/likely;
Assessment criteria: Adverse event had reasonable time relationship to
heparin administration (minutes to less than or equal to 1 hour), and;
Death unlikely related to disease or other drug products, and; Death
occurred during adverse event or within hours of heparin
administration.
Association: Possible;
Assessment criteria: Adverse event had reasonable time relationship to
heparin administration (minutes to less than or equal to 1 hour), and;
Possible contributory role of disease or other drug products (i.e.,
another possible explanation for the event).
Association: Unlikely;
Assessment criteria: Event had an improbable time relationship greater
than 1 hour) to heparin administration, or; Disease or other drug
products provide plausible explanations (i.e., more likely explanation
for the event than heparin administration).
Association: Unable to assess;
Assessment criteria: Cannot be assessed due to insufficient or
contradictory information.
Source: FDA.
[End of table]
Figure 5: FDA Analysis of AERS Reports Associated with Heparin Drug
Products:
[Refer to PDF for image: illustration]
1,216 total events reported between 1/1/08 and 3/31/08;
701 events reviewed for FDA’s AERS analysis;
FDA removed duplicate data and chose to analyze all death reports and
only the allergic-type adverse nondeath events associated with heparin.
675 cases with allergic-type adverse event symptoms;
26 death cases associated with nonallergic-type symptoms included in
death analysis;
574 allergic-type cases included in adverse events analysis; FDA
reported descriptive characteristics for these 574 cases. FDA also
used the 10 heparin lot numbers most frequently included in these
reports to determine there was no clear association between the level
of concentration of the contaminant and types of adverse events
experienced by patients.
101 allergic-type cases excluded from adverse events analysis;
526 nondeath allergic-type adverse event cases included in adverse
events analysis; FDA did not undertake additional analysis of
causality for these adverse event reports.
48 allergic-type death cases included in both adverse events and death
analyses;
20 allergic-type death cases included in death analysis;
94 total death cases analyzed:
Of the 94 cases, 68 met FDA’s search term criteria:
7 had a known contamination status:
* 4 were associated with contaminated heparin;
- 2 “possible”; 2 “unassessable;” [FDA classification]
* 3 were associated with uncontaminated heparin:
- 3 “unassessable. [FDA classification]
61 had an unknown contamination status:
- ”3 “probable/likely;”
- 4 “possible;”
- 24 “unlikely;”
- 30 “unassessable;” [FDA classification] FDA did not know the
contamination status of the heparin associated with the three deaths
that it categorized as
“probable/likely.”
Of the 94 cases, 26 did not meet FDA’s search term criteria:
5 had a known contamination status:
* 1 was associated with contaminated heparin;
* 4 were associated with uncontaminated heparin.
21 had an unknown contamination status:
* 26 “unlikely” or“unassessable.” [FDA classification]
Source: GAO analysis of FDA data.
[End of figure]
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
figure 5 for details of FDA's MAUDE analysis).
Figure 6: FDA Analysis of MAUDE Reports Associated with Heparin-
Containing Medical Devices:
[Refer to PDF for image: illustration]
143 total events reported between 1/1/08 and 8/31/08;
143 total events included in FDA’s MAUDE analysis; FDA analyzed all
reports of adverse events and deaths associated with heparin-
containing medical devices.
128 adverse events:
47 did not meet FDA’s search term criteria; of these:
26 were associated with uncontaminated heparin, and the rest had an
unknown contamination status.
81 met FDA’s search term criteria; of these:
42 did not meet time of event criteria;
28 were associated with contaminated heparin, 6 were associated with
uncontaminated heparin, and 8 had an unknown contamination status.
39 met FDA’s search term criteria and time of event criteria; FDA did
not undertake additional analysis of causality for these adverse event
reports.
15 deaths:
5 did not meet FDA’s search term criteria; of these:
2 were associated with uncontaminated heparin, and the rest had an
unknown contamination status.
10 met FDA’s search term criteria; of these:
8 did not meet time of event criteria:
- 5 had an unknown contamination status;
- 3 were associated with contaminated heparin; FDA classified these 3
deaths as unlikely to be caused by contaminated heparin.
2 met FDA’s search term criteria and time of event criteria; Both of
these reports were associated with uncontaminated heparin.
Source: GAO analysis of FDA data.
[End of figure]
[End of section]
Appendix IV: Comments from the Department of Health and Human Services:
Department Of Health & Human Services:
Office Of The Secretary:
Assistant Secretary for Legislation:
Washington, DC 20201:
October 15 2010:
Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
441 G Street N.W.
Washington, DC 20548:
Dear Ms. Crosse:
Attached are comments on the U.S. Government Accountability Office's
(GAO) correspondence entitled: "Food And Drug Administration: Response
to Heparin Contamination Helped Protect Public Health but More
Controls are Needed for Working with External Entities" (GAO 11-95).
The Department appreciates the opportunity to review this
correspondence before its publication.
Sincerely,
Signed by:
Jim R. Esquea:
Assistant Secretary for Legislation:
Attachment:
[End of letter]
General Comments Of The Department Of Health And Human Services (HHS)
To The Government Accountability Office's Draft Report Entitled, "Food
And Drug Administration: Response To Heparin Contamination Helped
Protect Public Health But More Controls Are Needed For Working With
External Entities" (GAO-11-95):
The Department appreciates the opportunity to review and comment on
this draft report.
For the Food and Drug Administration (FDA), the heparin story began in
January 2008, when the agency was confronted with an escalating public
health emergency in which clusters of dialysis patients were
experiencing severe allergic reactions during treatment. Although the
initial cause of the reactions was unknown, a common link was the use
of the blood thinner, heparin, a medically necessary drug. The
complicating factor was that the available screening methods were not
able to detect the contaminant or contaminants causing the problems.
Because of this undetectable adulterant, FDA was not able to
distinguish good lots of heparin from bad lots. Agency officials could
not withdraw all heparin from the market to avoid the risk of
contaminated heparin because a complete market withdrawal would have
caused the shortage of a drug that is necessary for the safe, daily
treatment of hundreds of thousands of American patients.
To minimize the risk to patients of both contaminated heparin and a
shortage of heparin, the agency mounted an immediate effort to
identify the contaminant that was causing the adverse reactions.
By the end of February 2008, FDA scientists had developed new
qualitative methods that helped distinguish good from bad heparin
lots. These qualitative screening methods were essential to the
agency's initial efforts to implement a step-wise process for
recalling the lots of heparin most likely to be contaminated. However,
these tests were not sufficient to safeguard the heparin supply and
reduce risks to patients because they were imprecise, likely
classified some good heparin lots as suspect, and were not capable of
identifying and quantifying the contaminant, oversulfated chondroitin
sulfate (OSCS), and establishing OSCS's linkage to the observed
adverse events. Removal of all suspect batches from the U.S. market,
including some good heparin (non-contaminated) lots, could have
created a heparin shortage that would have severely harmed patients.
To avoid this harm, it was critically important to single out the
adulterant that was actually causing the adverse events and to
establish—through a robust method of scientific validation—the
biological link between the suspected culprit, OSCS, and the adverse
events.
To accomplish this task, FDA needed to quickly identify and enlist the
help of the world's leading experts in the field of the molecular
characterization of heparin, a complex polysaccharide.
Two peer reviewed scientific articles (Nature Biotechnology[Footnote
1] and New England Journal of Medicine[Footnote 2]) were published to
describe these validation methods and to communicate the findings to
the global scientific and regulatory communities. The New England
Journal of Medicine article in particular documents the painstaking
process of scientific validation that these experts and FDA scientists
pursued to link definitively OSCS to the adverse reactions. This
process included, among other things, nuclear magnetic resonance
imaging, chemical testing, and animal studies to replicate the
allergic response experienced by the patients who suffered ill effects.
Because of this work, higher standards are now applied to a drug that
continues to be essential for patients every day, in this country and
throughout the world. In addition, the scientific work establishing
the biological link between OSCS and the allergic reactions has given
companies throughout the world the ability to screen for it in their
supplies of crude heparin, the component from which they make the
finished product. Today, this testing of crude heparin supplies is
central to current regulatory efforts to safeguard the global supply
of heparin.
This successful effort to protect public health would not have been
possible without the unique expertise and extraordinary efforts of the
outside scientists with whom FDA engaged.
The heparin story, however, is bigger than a crisis that threatened
the health and lives of people around the world. It is a story of the
increasing globalization of the supply chains of medically necessary
drugs, medical devices, and other products. It is a story of the
increasing opportunities those extended and fractured supply chains
present to those who, for economic gain or to intentionally harm
people, are willing to adulterate foods and drugs. It is a story of
how FDA, working within the constraints it faces in both capacity and
authority, has worked diligently to prevent such assaults on the
public health. It is not the first such story, and it may not be the
last. It is a clarion call to the agency, and anyone with an interest
in promoting the public health, to improve the assays for testing drug
and other products' ingredients, to improve controls on quality in,
and to collect better information about, the supply chains of
products, and to develop tools for anticipating, preventing, and
prosecuting such crimes and acts of terrorism.
Since the heparin contamination crisis, FDA has taken a number of
significant steps to safeguard the U.S. supply of this medically
necessary drug. The agency has increased inspections of heparin
manufacturing and testing facilities related to the U.S. heparin
supply. The U.S. Pharmacopoeia standard now requires all heparin
manufacturers to test for the presence of OSCS. The agency has adopted
a risk-model designed to identify other drugs that may be at increased
risk for economically motivated adulteration. It has improved the
databases that it maintains with information about drug supply chains.
It has enhanced its efforts to work with and build the capacity of
other regulators across the globe.
The Congress also has begun work that affects these efforts. New
legislation currently is under consideration by Congress that would
provide the agency helpful tools to further secure our nation's drug
supply chain and ensure that the agency can hold industry accountable
for the security and integrity of their supply chains and the quality
control systems they use to produce drugs for the American people. In
particular, the bill provides for the following new authorities:
* Drug supply quality and safety — to require foreign and domestic
drug manufacturers to implement quality systems and adopt plans to
identify and mitigate hazards.
* Documentation for imports — to provide FDA with explicit authority
to refuse admission of drugs to the United States if all required
information about the import is not submitted to FDA.
* Subpoena authority — to grant FDA authority to issue subpoenas to
compel production of documents and witnesses related to possible
violations.
* Prohibition against delaying, limiting or refusing inspection — to
grant FDA explicit authority to refuse admission of drugs to the
United States if inspection is delayed, limited or refused.
* Criminal and civil penalties — to modernize penalties for criminal
violations of the Federal Food, Drug, and Cosmetic Act to include
higher maximum prison sentences; and to grant authority to impose
civil money penalties for violations relating to drugs and improper
import entry filings.
* Administrative detention and destruction — to grant FDA the
authority to administratively detain violative drug products, an
authority the agency already has for food and devices; and to
streamline the process for the destruction of drugs offered for import
that are valued at $2,000 or less or that pose a reasonable
probability of causing a significant adverse health effect.
* Extraterritorial jurisdiction — to provide FDA with explicit legal
authority to pursue prosecutions for conduct that occurs outside of
the United States.
FDA has learned from the heparin crisis to improve its processes for
responding to emergencies. For example, the agency has recently
updated its Emergency Operations Plan, and it has also implemented a
policy to address risks in using outside experts who provide services
gratuitously in such emergencies, a policy that is responsive to GAO's
single recommendation in the report. The policy provides that in an
emergency, FDA will consider and obtain, as appropriate, external
scientific experts as the agency responds to, and resolves, the
crisis. It will obtain these resources expeditiously, while giving due
consideration to risks that may be presented in collaborative
arrangements with external entities, including conflicts of interest.
Responsible FDA staff will consult internally with the appropriate FDA
offices as the agency addresses such risks and will document its
decisions about such issues. The agency will also disclose information
about its use of external experts and any relevant conflicts of
interest.
Appendix IV Footnotes:
[1] Nature Biotechnology, Oversulfated Chondroitin Sulfate is a
Contaminant in Heparin Associated with Adverse Clinical Events, April
23, 2008.
[2] The New England Journal of Medicine, Contaminated Heparin
Associated with Adverse Clinical Events and Activation of the Contact
System, June 5, 2008. This article (10.1056/NEJMoa0803200) was
published at www.nejm.org on April 23, 2008.
[End of section]
Appendix V: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Acknowledgments:
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.
[End of section]
Footnotes:
[1] The drug heparin is typically administered to patients
intravenously. However, patients may also receive heparin through the
use of medical devices that contain or are coated with heparin, such
as catheters, vascular stents, and tubing.
[2] Following this preliminary work, CDC conducted an epidemiological
review of 152 adverse events associated with heparin in patients in
dialysis centers from November 19, 2007, through January 31, 2008. D.
B. Blossom, et al., "Outbreak of Adverse Reactions Associated with
Contaminated Heparin," New England Journal of Medicine, vol. 359, no.
25 (2008).
[3] An active pharmaceutical ingredient is any substance or mixture of
substances intended to be used in the manufacture of a drug
(medicinal) product and that, when used in the production of a drug,
becomes an active ingredient of the drug product. Such substances are
intended to furnish pharmacological activity or other direct effect in
the diagnosis, cure, mitigation, treatment, or prevention of disease
or to affect the structure and function of the body.
[4] FDA considers a product to be medically necessary, or a medical
necessity, if it is used to treat or prevent a serious disease or
medical condition, and there is no other available source of that
product or alternative drug or therapy that is judged by medical staff
to be an adequate substitute. According to FDA, patient
"inconvenience" alone is an insufficient basis to classify a product
as a medical necessity.
[5] FDA's working definition of "economically motivated adulteration"
is the fraudulent, intentional substitution or addition of a substance
in a product for the purpose of increasing the apparent value of the
product or reducing the cost of its production, i.e., for economic
gain. 74 Fed. Reg. 15497 (Apr. 6, 2009).
[6] We use the term "external entities" to refer to nongovernmental
organizations and experts who offer expertise to the agency but who
are not permanent employees of the agency. For example research
institutes, drug firms, and individual scientists from universities
could be considered external entities.
[7] We use the term "firm" to refer to entities that are involved in
manufacturing, testing, or shipping of products. Drug and device firms
may be comprised of more than one establishment; that is,
establishments under the same firm may include, for example,
manufacturing facilities and storage warehouses.
[8] An inspection is an examination of a manufacturing facility to
determine compliance with applicable law and FDA regulations, and an
Establishment Inspection Report is written to document it. An
investigation is information gathering conducted with the purpose of
determining and documenting facts concerning a particular issue, such
as a disaster, product tampering, or complaint follow-up. A memorandum
is almost always prepared based on the information gathered in an
investigation. FDA regulations on good manufacturing practices require
manufacturers to meet certain specifications in the manufacturing
process to ensure that their products are safe and have the identity,
strength, quality, and purity that their products purport to have. GMP
requirements apply to finished drug products and active pharmaceutical
ingredients, as well as devices. See 21 U.S.C. § 351(a)(2)(B), 21
C.F.R. pts. 210, 211, 820 (2010).
[9] USP is a nongovernmental, public standards-setting authority for
prescription and over-the-counter drugs that are manufactured or sold
in the United States.
[10] See 21 U.S.C. §§ 321(j), 351(b).
[11] FDA also has commitments with the European Commission and the
World Health Organization. A list of entities with confidentiality
commitments with FDA and links to the commitments can be found at
[hyperlink,
http://www.fda.gov/InternationalPrograms/Agreements/ConfidentialityCommi
tments/default.htm] (accessed July 8, 2010).
[12] A copy of FDA's agreement with China regarding drugs and medical
devices can be found at [hyperlink,
http://www.fda.gov/InternationalPrograms/Agreements/MemorandaofUnderstan
ding/ucm107512.htm] (accessed July 12, 2010).
[13] Generally, if a manufacturer receives drug-or certain device-
related adverse event reports, it must send them to FDA. Health care
professionals and consumers can voluntarily file adverse event reports
with FDA and may also report these events to the products'
manufacturers. User facilities (e.g., hospitals and nursing homes)
must report certain device-related--but not drug-related--adverse
events to FDA as well. 21 C.F.R. §§ 314.80(c), 803.30, 803.50 (2010).
[14] See U.S. Department of Health and Human Services, Food and Drug
Administration, The Leveraging Handbook-An Agency Resource for
Effective Collaborations, Final Guidance, February 2003, Corrected
June 2003 (Rockville, Md., 2003), [hyperlink,
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/WhatWeDo/UCM12
1662.pdf] (accessed July 28, 2010).
[15] These numbers of foreign and domestic heparin-related inspections
represent all heparin-related inspections of which we are aware and
for which we were able to obtain documentation from FDA.
[16] In this analysis we defined the 20-month period before the crisis
as May 2006-December 2007, the 5-month period during the crisis as
January-May 2008, and the 20-month period after the crisis as June
2008-January 2010.
[17] FDA officials told us that prior to the contaminated heparin
crisis, the agency did not usually inspect crude heparin manufacturers
and instead focused on API manufacturing facilities. According to
FDA's heparin-related inspection reports, there were both crude and
API Chinese heparin firms that had never been previously inspected.
However, the classification was not always clear: In one inspection
report, for example, FDA considered a manufacturer of crude heparin to
be an API manufacturer, while in another the inspectors described the
manufactured material as "crude heparin sodium API." FDA officials
told us that their classification of crude heparin and heparin API
depends on various processing steps and the unique circumstances in
which the products are used. Officials also told us that some firms
have challenged the agency in its attempt to regulate crude heparin.
[18] Casing facilities are the workshops where the process of
extracting and processing pig intestines to make crude heparin takes
place.
[19] According to FDA, import bulletins are generally intended for
informational purposes only and might not provide policy or coverage
guidance. For example, FDA's heparin import bulletin, issued February
27, 2008, instructed FDA's district offices to contact headquarters
when imported heparin shipments arrived at the U.S. border, but did
not provide more specific instructions for what to do with the heparin
shipments.
[20] FDA initially had to request this commitment from manufacturers
because the agency's newly developed testing methods were not
validated and incorporated into USP's heparin monograph. FDA worked
with USP to update its heparin monograph with these methods, which
were officially incorporated on June 18, 2008, and during this time
FDA requested monthly testing results from firms that had committed to
testing. Beginning in March 2009, the monthly updates on heparin test
results were no longer required; however, FDA requested that firms
notify the agency of any positive results within 3 days of the
testing. FDA and USP officials told us that they worked together on a
second revision, which included a more precise testing method and was
issued in October 2009. In addition, a USP official told us that both
agencies are currently working together on a third revision of the
heparin monograph that will focus in part on further increasing test
sensitivity and detection of impurities.
[21] FDA collected an OSCS-contaminated sample of crude heparin sodium
in December 2008 from a shipment manufactured and shipped by a Chinese
firm.
[22] FDA added these seven establishments to its existing Import Alert
66-40, "Detention without Physical Examination of Drugs from Firms
Which Have Not Met Drug GMPs," which was issued prior to the
contaminated heparin crisis to detain products from specific drug
establishments that FDA determined through inspections to be in
violation of GMPs. Unlike import bulletins, import alerts provide
guidance for import coverage. FDA is authorized to detain or refuse
products when offered at the U.S. border for import if the products
appear to be adulterated "from the examination of such samples or
otherwise..." 21 U.S.C. § 381(a)(3), (b).
[23] FDA issues warning letters to regulated manufacturers to notify
them of violations of regulatory significance. In contrast, FDA issues
untitled letters to manufacturers to notify them of violations that do
not meet the threshold of regulatory significance for a warning letter.
[24] Seizure is a civil action against specific violative goods. FDA
initiates a seizure by forwarding a seizure action to the U.S.
attorney in whose judicial district the violative goods are located.
The U.S. attorney files a Complaint for Forfeiture with the U.S.
district court, which then issues a motion and warrant directing
seizure of the goods. In this instance, U.S. marshals, accompanied by
FDA investigators, seized adulterated heparin sodium and heparin
lithium in November 2008 that was being held under quarantine at the
firm. According to FDA, the U.S. Marshals found that the inventory of
this quarantined product was consistent with inventories conducted
during previous inspections by FDA in May and September 2008, and the
seized heparin remained in quarantine at the firm until it was removed
and destroyed by a contracted waste management company in March 2009.
[25] According to FDA officials, limited inspections are narrow in
scope and do not include a full assessment of all GMP provisions.
Officials said that most GMP problems are likely to be cited at
downstream manufacturing facilities, such as the production site of
APIs or finished drug products, due to more stringent GMP
expectations, including increased testing, manufacturing, and overall
quality assurance requirements.
[26] FDA classifies inspections as NAI if no objectionable conditions
or practices were found during the inspection (i.e., conditions or
practices that violate current good manufacturing practices), or if
the significance of the documented objectionable conditions found does
not justify further FDA action. Other FDA inspection classifications
include voluntary action indicated (VAI) and official action indicated
(OAI). A classification of VAI means that objectionable conditions
were identified but any corrective actions are left to the
establishment to take voluntarily. A classification of OAI means that
objectionable conditions were found that warrant regulatory action by
FDA.
[27] More recently, FDA conducted a pre-approval inspection of SPL,
which was completed in September 2010, and cited the firm for its
failure to fully investigate a complaint the firm received after the
heparin crisis regarding contaminated heparin. FDA officials told us
that the heparin involved in this case was initially manufactured and
distributed in late 2006 and 2007.
[28] FDA also encouraged another manufacturer at this time to submit
an application for a generic heparin product to further mitigate a
potential shortage, and granted expedited review to this additional
manufacturer's application. FDA officials told us that other generic
drugs granted expedited review, such as drugs for the President's
Emergency Plan for AIDS Relief, typically take about 6 months to
approve. However, despite the expedited designation, the approval
process for this particular application took 18 months, so this
product was not available until well after the crisis period ended.
FDA officials explained that the decision on this approval took longer
than usual to ensure that the agency's approach to approval criteria
for generic heparin products was scientifically appropriate.
[29] According to information compiled by FDA investigators, the
number of pig farmers in China had decreased by 40 percent over the 5
years prior to the crisis because of economic and agricultural trends.
The availability of raw materials for heparin was further limited
after the crisis because many crude manufacturers were found to have
OSCS contamination. Additionally, investigators reported that a major
earthquake--which killed an estimated 3.1 million pigs in Sichuan
Province--and blue ear pig disease contributed to the potential
shortage of materials. FDA continued to monitor the adequacy of the
U.S. heparin supply because of these issues and because APP reduced
its number of qualified API suppliers after it agreed to increase
production to meet the demand of the entire U.S. market.
[30] An FDA official told us that existing agreements with other
countries stated that FDA could notify regulatory agencies in these
countries of the adverse events associated with heparin in the United
States before the agency made this information public. Of the 17
countries with which FDA communicated, the agency had confidentiality
commitments with all except China; however, the official said that the
agency notified China of these adverse events as well because of the
terms of an existing memorandum of agreement.
[31] Experts believe that an increase in heparin-associated adverse
events was seen only in some countries for various reasons, such as
differences in the type of heparin used and the way in which heparin
is administered. For more information, see appendix I.
[32] In December 2007, prior to FDA's knowledge of increased adverse
events associated with heparin, the U.S. Department of Health and
Human Services and China's State Food and Drug Administration (SFDA)
entered into a memorandum of agreement (MOA) in which both countries
agreed to engage in regulatory cooperation regarding improving the
authenticity, quality, safety, and effectiveness of drugs. The MOA,
however, only includes API and not crude material in its definition of
a drug. FDA investigators told us they were denied access to some of
the Chinese workshops that supplied crude heparin manufacturers. FDA
officials also told us that FDA and other U.S. government officials
contacted China's Ministry of Public Security (MPS) in June 2008 to
request consideration of a joint criminal investigation. MPS told the
U.S. officials that FDA would need to first request a referral from
China's SFDA to receive jurisdiction to investigate in China. However,
FDA's request for a referral was declined by SFDA. According to FDA
officials, SFDA told FDA that it did not have jurisdiction over
Chinese exports and did not have any law enforcement capabilities.
Chinese officials told FDA officials that contamination did not happen
in China. FDA officials told us that they are aware of domestic
heparin recalls in China that took place after SFDA ordered that all
Chinese heparin undergo testing to detect OSCS.
[33] See CDC, Morbidity and Mortality Weekly Report, Acute Allergic-
Type Reactions Among Patients Undergoing Hemodialysis-Multiple States,
2007-2008 (Feb. 8, 2008).
[34] The National Response Framework is a guide developed by the U.S.
Department of Homeland Security that details how the first-response
entities across the country conduct all-hazards response--from the
smallest incident to the largest catastrophe. It is built upon
scalable, flexible, and adaptable coordinating structures to align key
roles and responsibilities across the nation, linking all levels of
government, nongovernmental organizations, and the private sector.
[35] The new plan provides guidance for three operational levels of
agency response: routine, increased, and escalated. For example, a
report of a single person's illness, injury, or consumer complaint
with no or very few similar complaints in FDA systems would typically
call for a routine response from the agency with normal staffing and
regular work hours. Whereas an event such as Hurricane Katrina or the
heparin crisis would lead to an escalated response in which additional
support personnel and subject-matter experts might be needed and would
be working 24 hours a day, 7 days a week.
[36] FDA contacted these five scientists at different times throughout
the month. The agency began heparin-related work with three of the
scientists in early February and engaged the other two scientists in
late February. The agency also continued to work with these five
scientists for varying time periods. For example, one scientist told
us that his work with the agency ended in April 2008, two of these
scientists told us that their work with the agency continued through
May 2008, and one scientist told us that his work with the agency
continued until at least September 2008.
[37] This scientist was appointed under section 209(f) of title 42,
United States Code, which provides for the appointment of special
consultants without regard to the civil service laws.
[38] The application, which was pending at the time that this firm
provided uncompensated services in support of FDA's effort to identify
the contaminant, was approved in July 2010. FDA officials stated that
its collaboration with this scientist had no impact on the agency's
decision regarding the application.
[39] In response to our inquiries, FDA identified The Leveraging
Handbook as a source of guidance with respect to consultants and
experts. Although the working arrangements addressed in the handbook
are more formal arrangements than those used with the external
scientists with ties to heparin firms, the ethical principles included
in this guidance would be applicable to the informal arrangements with
these scientists during the heparin crisis.
[40] FDA officials told us that the agency exercised its authority to
accept gifts in accepting the services of these scientists in this
situation.
[41] Prohibited sources include a person or organization that conducts
activities regulated by the agency or seeking official action by the
agency. See 5 C.F.R. § 2635.203(d) (2010).
[42] See T. K. Kishimoto, et al. "Contaminated Heparin Associated with
Adverse Clinical Events and Activation of the Contact System," New
England Journal of Medicine, vol. 358, no. 23 (2008) and M. Guerrini,
et al. "Oversulfated Chondroitin Sulfate Is a Contaminant in Heparin
Associated with Adverse Clinical Events," Nature Biotechnology, vol.
26, no. 6 (2008).
[43] According to FDA, the agency's main concern about engaging these
experts was that their relationship with the pharmaceutical firms
might limit their ability to participate in a free exchange of
information with the agency. The agency reported that CDER officials
took steps to ensure that the manufacturers agreed that their
consultants could engage in free and open discussions with CDER staff.
[44] For example, the published articles after the contaminant was
identified did not fully disclose the assistance provided by the other
entities or that the drug firm had a pending application for a heparin
product before FDA. Further, no public disclosures were made while the
scientists were providing assistance in identifying the specific
contaminant.
[45] 31 U.S.C. § 1342 (2006).
[46] 31 U.S.C. § 1341 (2006).
[47] See Principles of Federal Appropriations Law, vol. 2, 3rd ed.,
[hyperlink, http://www.gao.gov/products/GAO-06-382SP] (Washington,
D.C.: February 2006), at 6-93-6-95.
[48] B-204326, July 26, 1982.
[49] 27 Comp. Dec. 131, 132-133 (1920) (The voluntary services
prohibition was intended to guard against claims for compensation, and
a service offered clearly and distinctly as gratuitous with a proper
record made of that fact does not violate the statute.) More recently,
the Department of Justice explained that the voluntary services
prohibition was intended to eliminate subsequent claims against the
United States for compensation of the "volunteer," rather than to
deprive the government of truly gratuitous services. 6 Op. Off. Legal
Counsel 160, 162 (1982).
[50] Prior to 1990, the statutory provision referred only to
"emergencies involving the safety of human life or the protection of
property." In response to an opinion of the Attorney General regarding
agencies' authority to incur obligations during a temporary lapse in
appropriations, 43 Op. Att'y Gen. 293 (1981), Congress amended the
voluntary services prohibition to limit agency activities and related
obligations to extreme circumstances: "[A]s used in this section the
term 'emergencies involving the safety of human life or the protection
of property' does not include ongoing, regular functions of government
the suspension of which would not imminently threaten the safety of
human life or the protection of property." Pub. L. No. 101-508, §
13213(b), 104 Stat. 1388, 1388-621 (1990); H.R. Conf. Rep. No. 101-
964, at 1170 (1990) (the statutory change was intended to "guard
against what the conferees believe might be an overly broad
interpretation of [the Attorney General's opinion] regarding the
authority for the continuance of Government functions during the
temporary lapse of appropriations, and affirm that the constitutional
power of the purse resides with Congress.").
[51] In describing its use of external entities during the heparin
crisis, FDA did not disclose why these scientists were engaged as
volunteers and others, engaged earlier, were not, or why services of a
voluntary nature were necessary in late February 2008 to protect
heparin users from an imminent threat given the steps that the agency
had already taken, including the development of a preliminary
screening method to distinguish contaminated heparin from
uncontaminated heparin and recalls of contaminated heparin.
[52] Cf. OMB Circular No. A-11, Preparation, Submission, and Execution
of the Budget, § 124.3 (agencies may incur obligations for essential
activities necessary to protect life and property during a lapse in
appropriations); Memorandum for the Director of the Office of
Management and Budget, Government Operations in the Event of a Lapse
in Appropriations, August 16, 1995 (the emergency exception authorizes
agencies to enter into obligations, but does not by itself authorize
paying employees in emergencies); 43 Op. Att'y Gen. 293, 306
("Congress has contemplated expressly ... that emergencies will exist
that will justify incurring obligations for employee compensation in
advance of appropriations ...").
[53] See, e.g., B-302811, July 12, 2004. In that decision, we
addressed a contract under which real estate brokers agreed to provide
services at no cost to the General Services Administration (GSA) with
the understanding that they would be compensated by commissions from
landlords. We noted that the acceptance of services without payment
pursuant to a valid, binding "no-cost contract" did not augment GSA's
appropriation or violate the voluntary services prohibition because
the agency had no financial liability to the brokers and the brokers
would have no expectation of a payment from GSA; if a landlord were to
fail to pay a broker, the broker would have no claim against GSA.
[54] Cf. B-310108, Feb. 6, 2008 (dire circumstances did not preclude
the Forest Service from using expedited reapportionment procedures to
avoid the overobligation of its apportionment for wildland fire
management).
[55] FDA stated that the agency has express authority to accept gifts
of services and cited section 238 of title 42, United States Code.
Section 238 authorizes the Secretary of Health and Human Services to
accept on behalf of the United States "gifts made unconditionally by
will or otherwise for the benefit of the [Public Health] Service or
for the carrying out of any of its functions."
[56] B-274855, Jan. 23, 1997.
[57] See 21 C.F.R. § 803.53(b) (2010).
[58] FDA officials explained that they sometimes received adverse
event reports from consumers or health care professionals as well as
manufacturers regarding the same event.
[59] FDA officials told us that the agency continues work to replace
AERS with the new FDA Adverse Event Reporting System (FAERS). FAERS is
intended to make retrieval and analysis of adverse event and death
data more efficient and will contain software that would make analysis
of safety signals closer to real time.
[60] FDA also posted and updated the number of adverse events, which
resulted in death, associated with heparin drug products, submitted to
AERS from January 1, 2007, through May 31, 2008, on its Web site to
respond to media requests. These numbers showed that reports of deaths
had decreased since contaminated heparin was recalled from the U.S.
market; however, FDA was unable to determine the contamination status
of the heparin associated with most of these reports.
[61] FDA identified the 701 reports, from which duplicate reports had
been removed, based on an expanded case definition from the CDC
investigation of allergic-type events in hemodialysis patients in
January 2008 and specific search term criteria (see appendix III for
CDC's case definition and FDA's search term criteria).
[62] The 101 allergic-type event cases were excluded based on specific
criteria, including events that took place prior to January 1, 2007,
and if the case had a clear alternative clinical explanation for the
adverse event.
[63] Of the 68 allergic-type death cases, 48 were also included in
FDA's analysis of allergic-type adverse events and 20 were part of the
101 allergic-type event cases that were excluded from the analysis of
allergic-type events. FDA officials said that almost all of the death
cases were reviewed regardless of their inclusion status in the
allergic-type adverse events analysis. Seven death cases that occurred
prior to January 1, 2007, and 1 death case that was a duplicate report
were not included in FDA's analysis of AERS death reports.
[64] If a MAUDE report did not specifically have an event date listed,
but was received by FDA between January 1, 2008, and August 31, 2008,
it was conservatively assumed to have occurred during that time frame
and included in the MAUDE analysis.
[65] See generally 21 C.F.R. §§ 314.80, 314.98, 803.1, 803.30, 803.40,
803.50 (2010).
[66] In our analysis of the 94 AERS death reports, we found that of
the 78 reports that listed at least one condition for each patient, 63
of these reports listed multiple conditions.
[67] See FDA Staff Manual Guides, Volume III--General Administration,
External Relations, External Expert Gratuitous Services in an
Emergency, October 2010, [hyperlink,
http://www.fda.gov/AboutFDA/ReportsManualsForms/StaffManualGuides/ucm229
673.htm] (accessed October 19, 2010).
[68] Marco Guerrini et al., "Oversulfated Chondroitin Sulfate is a
Contaminant in Heparin Associated with Adverse Clinical Events,"
Nature Biotechnology vol. 26, no. 6 (June 2008): 669-675.
[69] M. Clark et al., "Molecular Profiling of Heparinase-I Resistant
Glycosaminoglycans in Contaminated Heparins. Comparative Studies with
Uncontaminated Heparin and Porcine Oversulfated Chondroitin Sulfate,"
International Angiology vol. 27, no. 5 (October 2008): 370-376.
[70] Christian Viskov et al., "Isolation and Characterization of
Contaminants in Recalled Unfractionated Heparin and Low-Molecular-
Weight Heparin," Clinical and Applied Thrombosis/Hemostasis, vol. 15,
no. 4 (August 2009): 395-401.
[71] Zhenqing Zhang et al., "Analysis of Pharmaceutical Heparins and
Potential Contaminants Using 1H-NMR and PAGE," Journal of
Pharmaceutical Sciences, vol. 98, no. 11 (November 2009): 4017-4026.
[72] According to German researchers we interviewed, in Germany, one
brand of LMWH was found to be contaminated, and a second brand was
recalled in Europe.
[73] Zhenqing Zhang et al., "Oversulfated Chondroitin Sulfate: Impact
of a Heparin Impurity, Associated with Adverse Clinical Events, on Low-
Molecular-Weight Heparin Preparation," Journal of Medicinal Chemistry,
vol. 51, no. 18 (2008): 5498-5501.
[74] Jawed Fareed et al., "Biological Profile of the
Hyper/Oversulfated Chondroitin Sulfate Contaminant Isolated from
Recalled Heparin," Seminars in Thrombosis and Hemostasis, vol. 34, no.
supplement 1 (2008): 119-127.
[75] Jing Pan et al., "Oversulfated Chondroitin Sulfate Is Not the
Sole Contaminant in Heparin," Nature Biotechnology, vol. 28, no. 3
(March 2010): 203-207.
[76] Marco Guerrini et al., "Orthogonal Analytical Approaches to
Detect Potential Contaminants in Heparin," PNAS, vol. 106, no. 40
(October 6, 2009): 16956-16961.
[77] David B. Blossom et al., "Outbreak of Adverse Reactions
Associated with Contaminated Heparin," New England Journal of
Medicine, vol. 359, no. 25 (December 18, 2008): 2674-2684.
[78] Takashi Kei Kishimoto et al., "Contaminated Heparin Associated
with Adverse Clinical Events and Activation of the Contact System,"
New England Journal of Medicine, vol. 358, no. 23 (June 5, 2008): 2457-
2467 and Boyangzi Li et al., "Oversulfated Chondroitin Sulfate
Interaction with Heparin-Binding Proteins: New Insights into Adverse
Reactions from Contaminated Heparins," Biochemical Pharmacology, vol.
78, no. 3 (August 2009): 292-300.
[79] Cafer Adiguzel et al., "Increased Prevalence of Antiheparin
Platelet Factor 4 Antibodies in Patients May Be Due to Contaminated
Heparin," Clinical and Applied Thrombosis/Hemostasis, vol. 15, no. 2
(April 2009): 145-151.
[80] Andreas Greinacher and Theodore E. Warkentin, "Contaminated
Heparin," New England Journal of Medicine, vol. 359, no. 12 (September
18, 2008): 1291-1292.
[81] Nuclear magnetic resonance (NMR) spectroscopy measures the
behavior of certain atomic nuclei, such as hydrogen nuclei, placed in
a strong magnetic field. The molecular and chemical environment around
the nuclei--that is, the chemical makeup and structure of a sample--
produces characteristics shifts in the sample's NMR spectrum.
[82] Chromatography is an analytical method based on separation of the
components of a mixture by selective adsorption.
[83] Cecilia Tami et al., "Inhibition of Taq Polymerase as a Method
for Screening Heparin for Oversulfated Contaminants," Biomaterials,
vol. 29, no. 36 (2008): 4808-4814.
[84] Susanne Alban and Susanne Lühn, "Prothrombin Time for Detection
of Contaminated Heparins," New England Journal of Medicine, vol. 359,
no. 25 (December 18, 2008): 2732-2734.
[85] A number of research articles have been published in this area.
For example, see Marco Guerrini et al., "The Tainted Heparin Story: An
Update," Thrombosis and Haemostasis, vol. 102, no. 5 (November 2009):
907-911.
[End of section]
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