DOD Animal Research: Controls on Animal Use Are Generally Effective, but
Improvements Are Needed (Letter Report, 07/08/1999,
GAO/NSIAD/HEHS-99-156).

In analyzing 24 Department of Defense (DOD) projects on biological
defense, combat casualty care, and radiation research, GAO found that
DOD's controls over the use of nonhuman primates, cats, dogs, and farm
animals were generally effective but needed some improvements. DOD
employed measures to avoid or minimize unnecessary duplication,
requiring investigators to conduct and document literature searches and
submit project proposals for scientific and animal use reviews. DOD
needs to clarify its requirement that investigators search particular
databases of ongoing research to ensure that searches are consistently
implemented. DOD investigators could have used additional alternatives
to refine experimental procedures in 8 of the 24 projects. Routine pain
relief could have been administered in five studies of burn treatments
without compromising the objectives. Animals could have been euthanized
earlier than the investigators proposed without affecting research
results. However, records did not document the alternatives that were
considered but not adopted. GAO made recommendations to reduce the
likelihood that proposed research unnecessarily duplicates other
research and to improve the consideration of refinement alternatives.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  NSIAD/HEHS-99-156
     TITLE:  DOD Animal Research: Controls on Animal Use Are Generally
	     Effective, but Improvements Are Needed
      DATE:  07/08/1999
   SUBJECT:  Biomedical research
	     Research program management
	     Redundancy
	     Military research and development
	     Data bases
	     Internal controls
	     Experimental animals
IDENTIFIER:  DOD Basic Research Plan
	     DOD Defense Technology Area Plan
	     DOD Joint Warfighting Science and Technology Plan
	     DOD Biomedical Research Database

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    United States General Accounting Office GAO
    Report to the Chairman and Ranking Minority Member, Committee on
    Armed Services, House of Representatives July 1999
    DOD ANIMAL RESEARCH Controls on Animal Use Are Generally
    Effective, but Improvements Are Needed GAO/NSIAD/HEHS-99-156
    United States General Accounting Office
    National Security and Washington, D.C. 20548
    International Affairs Division B-278778.1
    Letter July 8, 1999 The Honorable Floyd Spence Chairman The
    Honorable Ike Skelton Ranking Minority Member Committee on Armed
    Services House of Representatives In 1992 and 1994 the House
    Committee on Armed Services held hearings on concerns that had
    been raised by the public and animal welfare interest groups about
    Department of Defense (DOD) research projects that utilize animals
    and inadequate public disclosure of DOD's activities involving the
    use of animals.  DOD's Inspector General also investigated DOD's
    animal use projects and made several recommendations to improve
    oversight and public accountability.  In response to the
    recommendations, DOD made several changes, including a new and
    publicly available database of animal use projects,1 new practices
    for preparing and reviewing research, and an annual animal use
    report to Congress. However, the public and animal welfare groups
    have continued to raise questions about whether DOD uses animals,
    particularly higher-order animals such as nonhuman primates, cats,
    dogs, and farm animals, appropriately.  In light of these
    concerns, your Committee directed us to examine DOD's management
    and oversight of its animal research programs.2  As agreed with
    your offices, we examined to what extent projects funded or
    performed by DOD utilizing animals (1) were directed toward
    military objectives; (2) unnecessarily duplicated other research;
    and (3) incorporated alternatives that reduced, replaced, or
    refined the use of animals. We reviewed relevant legislation,
    regulations, policies, and procedures and interviewed DOD and
    other federal officials as well as representatives from animal
    research and animal welfare interest groups.  We also reviewed 1
    In an earlier report we discussed strengths and limitations of the
    database.  See DOD Animal Research:  Improvements Needed in
    Quality of Biomedical Research Database (GAO/NSIAD/HEHS-99-24,
    Dec. 14, 1998). 2 House Report 103-499 by the House Armed Services
    Committee in consideration of the National Defense Authorization
    Act for Fiscal Year 1995. Letter           Page 1
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 DOD's
    database of fiscal year 1996 animal use projects, the most current
    and complete information available at the time of our review, and
    collected information from various DOD program offices to
    determine the objectives of each of the projects.  We chose 24 of
    these projects, concentrating on the areas of biological defense,
    combat casualty care, and radiation research, to examine the
    issues of unnecessary duplication and the consideration of
    alternatives.3  We visited the 14 DOD and other research
    facilities where these projects were conducted to review
    applicable processes and records. We also contracted with
    independent experts to assist our evaluation of these projects.
    Our findings on the 24 projects are not generalizable to all DOD
    research that used animals in fiscal year 1996.  See appendix I
    for a detailed discussion of our scope and methodology. Results in
    Brief        DOD's controls over animal use were generally
    effective, but some improvements are needed to further ensure that
    animals are used appropriately.  We were able to link all but one
    of the 805 animal use projects in fiscal year 1996 to a military
    objective or a congressionally directed program.  About half the
    projects were directed toward military research objectives that
    evolved from formal DOD planning processes, while about 35 percent
    supported DOD missions such as medical training and education.
    Another 15 percent did not address a direct military need but were
    part of congressionally directed programs such as breast cancer
    research.  Many of the projects that addressed military objectives
    also had civilian applications such as emergency medicine. We did
    not identify any unnecessary duplication in the 24 research
    projects we reviewed.  DOD employed measures to avoid or minimize
    unnecessary duplication.  These measures included requiring
    investigators to conduct and document literature searches and
    submit project proposals for scientific and animal use reviews.
    Although the inherent limitations of any literature search
    constrain DOD's ability to identify and avoid unnecessary
    duplication, DOD needs to clarify its requirement that
    investigators search particular databases of ongoing research to
    ensure that searches are consistently implemented. 3 Our study
    does not address several other areas where the public and animal
    welfare groups have raised concerns about DOD's use of animals
    such as whether the results of animal tests can be extrapolated to
    humans and whether research on brain injuries should continue to
    be conducted with animals. Letter    Page 2
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 Although DOD
    considered and incorporated alternatives to replace and reduce the
    use of animals in the 24 research projects we reviewed,
    investigators could have used additional alternatives to refine
    experimental procedures in 8 of them.  These refinements could
    have improved the welfare of the animals without compromising the
    projects' objectives.  For example, routine pain relief could have
    been administered in five studies of burn treatments.  In two
    other studies, animals could have been euthanized earlier than the
    investigators proposed without affecting research results.
    However, we were unable to determine the extent to which
    refinement alternatives were considered in the development and
    review of these protocols because records did not document the
    alternatives that were considered and not adopted. We are making
    recommendations to the Secretary of Defense intended to reduce the
    likelihood that proposed research unnecessarily duplicates other
    research and to improve the consideration of refinement
    alternatives. Background    In fiscal year 1996, DOD sponsored 805
    projects using a total of 319,000 animals.4  These projects were
    conducted at various DOD research and training facilities (such as
    the U.S. Army Medical Research Institute for Infectious Diseases)
    as well as at public and private research facilities (such as
    universities and hospitals) funded by DOD.  The animals used
    ranged from fish and amphibians to farm animals and nonhuman
    primates. However, mice and rats accounted for 80 percent of the
    animals used.5 These projects encompassed a very diverse set of
    research, training, and education activities.  For example, in
    several projects, DOD tested different vaccines and treatments on
    various species of monkeys that were exposed to biological warfare
    agents or infectious diseases.  Other projects used sheep, pigs,
    rats, and rabbits to investigate burn treatment therapies.  Some
    projects used rhesus monkeys, dogs, guinea pigs, ferrets, and
    rodents to assess the health effects of ionizing radiation.
    Furthermore, as part of their training in emergency medicine,
    military surgeons and medics performed practice surgeries on pigs,
    goats, and other animals. 4 DOD was unable to provide us with an
    estimate of the total cost of these projects but did provide an
    estimate for its animal use projects for fiscal year 1997,
    amounting to about $100 million. 5 DOD summarized the data in
    Department of Defense Animal Care and Use Programs 1996: Report to
    the Senate Armed Services Committee and the House of
    Representatives National Security Committee. Page 3
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 DOD is
    subject to federal laws and regulations governing how animals are
    used as subjects in research and training projects. These laws and
    regulations establish standards for the care and use of animals in
    research and training, including requirements to minimize the
    potential for unnecessary duplication and promote the use of
    alternatives.6  In addition, DOD has established its own policies
    and guidelines governing animal use. DOD officials and other
    experts generally agree that unnecessary duplication, although not
    formally defined by law or regulation, refers to research that
    repeats existing procedures without contributing to the
    advancement of scientific knowledge or presenting new information.
    Some duplication is usually necessary because research results
    must be reproducible.  Reproduction is achieved when investigators
    replicate prior research to determine whether similar results do
    occur. DOD and other experts view alternatives as methods (such as
    computer simulation and cell culture techniques) that replace or
    reduce the number of laboratory animals required for an
    investigation or refine an existing procedure to minimize an
    animal's pain or distress. Overall responsibility for establishing
    policies on animal use activities within DOD resides with the
    Director of Defense Research and Engineering, while implementation
    of the policies resides with each armed service or Defense agency
    such as the Armed Forces Radiobiology Research Institute.  The
    principal agent for ensuring that regulations and policies are
    implemented at DOD and non-DOD facilities rests with institutional
    animal care and use committees (IACUC).  DOD's policy is that its
    IACUCs have a minimum of five members, including at least one
    doctor of veterinary medicine and at least one member not
    affiliated with the institution in any other way. DOD's process to
    reduce unnecessary duplication and promote alternatives relies
    upon investigators to prepare detailed plans-called protocols-of
    their proposed animal use activities and several levels of review
    of these protocols.  DOD's policy states that protocols must
    contain descriptions of the research or training activity,
    justifications for the use of the animals, descriptions of the
    experimental procedures, steps to be taken to protect the welfare
    of the animals, and the results of literature searches carried out
    to detect unnecessary duplication and availability of
    alternatives.  These items are included in DOD's standard protocol
    format, which was adopted 6 The Animal Welfare Act, 7 U.S.C.
    2131-2158, as amended which is implemented by USDA regulations 9
    C.F.R. Parts 1-4; and the Health Research Extension Act of 1985,
    42 U.S.C. 289d. Page 4
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 for fiscal
    year 1996.  Before investigators can begin using animals, the DOD
    funding agency reviews their protocols for scientific merit, and
    the IACUC reviews them for animal care considerations.  As part of
    their review, IACUCs assess whether available alternatives were
    considered and adopted where appropriate.  In addition, DOD
    requires that a service-level veterinarian review all its projects
    at non-DOD facilities as well as projects at DOD facilities using
    nonhuman primates.  See appendix II for a detailed discussion of
    DOD's process for reviewing animal use projects. DOD Animal Use
    We were able to link all but one of the 805 animal use projects in
    fiscal year Projects Generally     1996 to military objectives or
    congressionally directed programs.  Projects addressing military
    objectives included a variety of research, training, and Addressed
    Military     education activities, while those addressing
    congressionally directed Objectives or          programs were
    primarily outside DOD's military mission in areas such as
    Congressional          breast cancer research.  Many of the animal
    use projects directed at military objectives also addressed
    civilian needs. Directives             We attempted to collect
    information on the objectives of DOD's animal use projects from
    its fiscal year 1996 Biomedical Research Database (BRD), a central
    source of information on the 805 projects conducted that year.
    While it contained information on the location of the research and
    a brief statement of the projects' research objectives and
    methods, the database lacked information on the link between the
    projects and specific military or congressional objectives.7  As a
    result, we had to contact 16 different DOD program offices,
    including the U.S. Army Medical Research and Materiel Command, the
    Office of Naval Research, the Air Force Office of Scientific
    Research, and the Armed Forces Radiobiology Research Institute
    (AFRRI), to obtain information on objectives. The individual
    program offices varied in how they were able to identify
    objectives for the projects.  Officials in some offices were able
    to do so using documentation in existing records.  In other
    offices, however, DOD lacked documentation, but program officials
    used their knowledge of the work to link each project.  We were
    able to link 688 of the 805 projects to military objectives and
    another 116 to congressionally directed programs that did not have
    direct military relevance (see table 1). 7 In December 1998 we
    recommended that DOD more clearly link projects with research
    goals and justifications in the BRD.  See DOD Animal Research
    (GAO/NSIAD/HEHS-99-24, Dec. 14, 1998). Page 5
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 Table 1:
    DOD Animal Use Objectives (fiscal year 1996) Number of Objectives
    projects Objectives developed within a formal research planning
    process to support military objectives Combat casualty care
    87 Infectious diseases
    70 Biological weapons defense
    67 Operational medicine
    57 Toxicity studies and environmental assessments
    43 Medical chemical defense
    30 Sensor development
    16 Assessing effects of naval activities on marine mammals
    14 Medical radiological defense
    4 Subtotal
    388 Objectives that supported other military needs Clinical
    investigations
    146 Training
    82 Toxicity evaluations
    31 Other mission objectives
    41 Subtotal
    300 Objectives that supported congressionally directed programs
    Breast cancer research
    98 Pathology research
    17 Neurotransmitter research
    1 Subtotal
    116 Objectives not linked to military needs or congressionally
    directed programs
    1 Total
    805 Of the 688 projects that we found linked to military
    objectives, 388 addressed specific military research objectives
    identified through DOD's formal research planning processes. These
    388 projects used most of the animals as well as most of the
    nonhuman primates. The projects' objectives evolved from processes
    that DOD and each of the services established to identify
    operational military requirements and develop appropriate research
    to address these requirements.  Each year, DOD's Director of
    Defense Research and Engineering develops formal Page 6
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 programming
    guidance for each of the services to help ensure that their
    research efforts support the current and long-term needs of the
    Department. This guidance is provided primarily in three plans:
    the Basic Research Plan, the Defense Technology Area Plan, and the
    Joint Warfighting Science and Technology Plan, which identify
    objectives and investment strategies for technologies critical to
    DOD's missions.  Each service has its own planning and review
    process to address the objectives identified in the plans and to
    develop other objectives and strategies to meet its own research
    needs. The services collect input from other DOD components that
    are the principal users of the research results and match their
    own needs with existing budget resources and research
    capabilities. The services then develop and publish specific
    annual research plans. Various programs conduct individual
    research projects to support these specified research objectives.
    The projects that were linked to research objectives developed
    within DOD's formal research planning process were designed to
    improve the readiness and capabilities of servicemembers by
    developing information, products, and technologies.  For example,
    the infectious disease projects used nonhuman primates and other
    animals to develop vaccines to protect servicemembers from
    infectious diseases such as malaria, dengue fever, hepatitis, and
    typhus.  The operational medicine objective included projects
    using rats and other animals to develop countermeasures against
    the effects of operational stress (such as sleep deprivation and
    fatigue) on military performance.  The sensor development projects
    used marine mammals and other animals to develop information to
    improve the military's ability to detect underwater and airborne
    objects. The projects that supported other military objectives did
    not focus on meeting DOD's operational research requirements.
    Instead, they supported other mission-related activities such as
    medical education and training. For example, faculty, students,
    and physicians at DOD medical treatment and training centers
    conducted clinical investigations to improve the knowledge and
    skills of medical professionals.  One clinical investigation
    project used hamsters to determine the effect of high-pressure
    oxygen on tumors of the mouth.  The training projects were
    intended to develop the skills of medics, corpsmen, and other
    military medical personnel.  For example, cats and ferrets were
    used in several military hospitals in the training of physicians
    in inserting tracheal tubes into pediatric patients. The toxicity
    testing projects used different animals to evaluate the health
    hazards of various munitions and compounds found on military
    bases. Page 7                               GAO/NSIAD/HEHS-99-156
    DOD Animal Research B-278778.1 The projects conducted as part of
    congressionally directed research programs did not address direct
    military objectives. Most of them were part of the congressionally
    directed Breast Cancer Research Program, administered by the Army.
    These projects investigated a wide range of concerns about breast
    cancer, including molecular biology, detection, diagnosis, and
    treatment.  The pathology projects were conducted at the Armed
    Forces Institute of Pathology as part of a congressionally
    directed research program in which DOD pathologists collaborate
    with civilian pathologists. We were unable to link one project
    with a military need or a congressionally directed program. In
    this project, a private corporation conducted anemia research on
    rabbits in a Navy laboratory overseas. DOD officials agreed with
    our assessment that this project, which has ended, did not address
    a military need or a congressionally directed program. We found
    that some of the projects that addressed military objectives also
    had civilian applications because the medical needs of military
    personnel are often similar to those of the civilian population.
    In particular, projects addressing combat casualty care and
    infectious diseases for military personnel have direct relevance
    to the treatment and care of civilians.  For example, as part of
    its combat casualty care program, the Army used pigs and rabbits
    to develop and test a fibrin bandage containing plasma proteins
    that accelerate blood clotting.  The Army is currently
    collaborating with the American Red Cross to commercialize this
    technology for uses in both the military and civilian sectors.
    Similarly, DOD used nonhuman primates and other animals to develop
    vaccines against hepatitis, malaria, dengue virus, and other
    infectious diseases that affect military and civilian populations.
    DOD Efforts to Avoid             We did not identify any cases of
    unnecessary duplication in our review of Unnecessary
    24 DOD-funded research projects that used animals in fiscal year
    1996. DOD, research facilities, and investigators employed several
    measures to Duplication Generally  minimize the risk of
    duplicating other studies unnecessarily.  Nonetheless, Succeeded
    certain factors such as the limited effectiveness of literature
    searches could affect DOD's ability to systematically identify and
    avoid unnecessary duplication. Page 8
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 No Evidence
    of                     We identified no unnecessary duplication in
    the 24 research projects Unnecessary Duplication in  conducted in
    fiscal year 1996 that we reviewed.  We evaluated each project 24
    Projects                        in several ways.  We reviewed the
    materials used in the original consideration and approval of the
    project and interviewed principal investigators and IACUC members
    to determine how they addressed the likelihood that the project
    would unnecessarily duplicate other studies.  We provided the same
    materials to the U.S. Department of Agriculture's Animal Welfare
    Information Center (AWIC) and had its information specialists
    conduct an independent search of scientific literature relevant to
    each project.8  We then had a nationally recognized subject matter
    expert and two experts in research methodology and animal use
    alternatives separately review the materials and the AWIC
    literature search for each project. Practices Used to Help
    Each of the 14 facilities we visited had practices in place to
    help ensure that Avoid Unnecessary                  investigators'
    research did not unnecessarily duplicate other studies.
    Duplication                        Investigators conducted
    searches of published literature in their fields. The literature
    searches varied in the number and types of databases used.
    However, as recommended by DOD, investigators generally searched
    major databases such as MEDLINE.9 Investigators of the 24 research
    protocols provided written assurance, as required, that they had
    made a good faith effort to ensure that their project would not
    unnecessarily duplicate other research. Investigators we spoke
    with also mentioned other practices they employed to reduce the
    likelihood of unnecessary duplication.  They emphasized that
    attending seminars and conferences in their particular subject
    area, consulting and collaborating with other experts, and
    reviewing relevant professional publications all contributed to
    their ability to stay current in their field.  Investigators
    further noted that the desire to publish results of their findings
    in peer-reviewed journals provided additional incentive for
    avoiding unnecessary duplication because journals seek to publish
    research that could advance science.  All but four of the projects
    we 8 AWIC, an information service of the National Agricultural
    Library, was established to provide technical assistance in
    conducting searches to identify alternatives. 9 MEDLINE is the
    National Library of Medicine's bibliographic database covering the
    fields of medicine, nursing, dentistry, veterinary medicine,
    health care systems, and other sciences.  The MEDLINE file
    contains bibliographic citations and author abstracts from
    approximately 3,900 biomedical journals published in the United
    States and 70 other countries. Page 9
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 reviewed
    resulted in one or more peer-reviewed publications and/or
    conference presentations. The 24 research projects also went
    through several reviews that partly addressed the potential for
    unnecessary duplication.  For example, all but one project went
    through a scientific merit review.  According to DOD guidance,
    such reviews include a consideration of the project's contribution
    to science.  Scientists and department heads located at DOD's
    research facilities conducted scientific merit reviews for 16 of
    the 17 sampled projects at those facilities.  As for the remaining
    project, an agency official told us that a science review was not
    required at the time the project was approved.  The seven projects
    at the non-DOD facilities we visited went through either a peer
    review by non-DOD scientists or a review by a DOD scientist from
    the program funding office. Each project was also reviewed by the
    IACUC at its research facility.  Some of the IACUC chairpersons
    stated they reviewed the investigators' written assurance
    statements and literature search documentation. The IACUCs relied
    on investigators to review abstracts and articles obtained from
    literature searches, and identify unnecessarily duplicative
    research. However, the IACUCs generally did not independently
    replicate the literature searches.   Some of the IACUCs used other
    resources to assist them in their review.  For example, the IACUC
    at one DOD facility required investigators to work with a
    reference librarian to perform literature searches and submit the
    search results for IACUC review.  At two DOD and one non-DOD
    facility, a reference librarian served as an IACUC member to focus
    on the quality and appropriateness of the investigators'
    literature searches. DOD also requires that a service-level
    veterinarian trained or experienced in laboratory animal science
    and medicine perform a review of all projects at non-DOD
    facilities as well as projects involving the use of nonhuman
    primates.  The purpose of these reviews is to ensure that the
    research projects adhere to DOD's policies and requirements.  DOD,
    however, did not always enforce its requirement for these service-
    level veterinarian reviews.   We found that one Defense Advanced
    Research Projects Agency (DARPA) and two AFRRI projects did not
    receive the required service-level veterinary reviews because no
    veterinarian was assigned to them.  For the DARPA project, a
    service-level veterinarian was not assigned to review the protocol
    until approximately 1 year after the project began.  The two AFRRI
    projects were completed without ever receiving such a review. When
    we pointed out this problem to AFRRI officials, they made Page 10
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 arrangements
    to have a service-level veterinarian perform the required reviews
    on all their ongoing projects that use nonhuman primates. Two
    Factors Could Limit the  Although DOD relies on literature
    searches as a key element to reduce the Effectiveness of
    Literature        likelihood that proposed research would
    duplicate other work Searches
    unnecessarily, two factors could limit the searches'
    effectiveness.  First, the services and Defense agencies that
    sponsor research at non-DOD facilities differed in their
    implementation of a key aspect of literature search requirements.
    Second, literature searches are limited in their ability to
    identify potentially duplicative research because not all research
    is published. Since 1995, DOD has required that all investigators
    search the Defense Technical Information Center (DTIC) and the
    Federal Research in Progress (FEDRIP) databases or their
    equivalents.  Searching these databases is important because they
    are the primary sources of information on research in progress in
    the federal government. We previously reported that it is
    important that investigators have access to such information
    because of the time lag between completing research and
    publishing.10 We found, however, that the policy on searching
    these databases of ongoing research or their equivalents is not
    clear.  In particular, service-level veterinarians differed in
    their interpretation of the meaning of equivalent. For example,
    the veterinarian who reviewed DARPA projects told us that he does
    not recognize any other databases in lieu of DTIC and FEDR IP.
    However, the Army's veterinarian considers MEDLINE to be the
    equivalent of FEDRIP.  In contrast, the Navy's veterinarian told
    us that he does not accept MEDLINE as an equivalent to FEDRIP but
    does accept a search of the National Technical Information Service
    database.11 Although DOD officials, principal investigators, and
    experts emphasized the importance of conducting literature
    searches, they also noted that literature searches have inherent
    limitations in identifying unnecessary duplication.  These
    limitations affect all research, whether funded by DOD 10
    Biological Warfare: Better Controls in DOD's Research Could
    Prevent Unneeded Expenditures (GAO/NSIAD-91-68, Dec. 27, 1990). 11
    The National Technical Information Service is the government's
    central source for the sale of scientific, technical, engineering,
    and related business information produced by or for the U.S.
    government. Page 11
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 or by other
    public or private organizations.  For example, studies that show
    no effect are not generally published.  In addition, some research
    involves proprietary information and rarely gets published; other
    research involves classified information and never gets published.
    Because of all the research that is not published, investigators
    may not be able to identify the full extent of research that has
    been conducted in their field. DOD Could Do More to  Although
    DOD's efforts to promote alternatives in animal research have
    Promote the Use of                generally been successful in the
    replacement or reduction of the animals used, we found additional
    refinements that could have been implemented Alternatives
    to reduce animals' pain or distress in 8 of the 24 protocols.  We
    found two additional projects in which investigators and IACUCs
    could have more closely addressed alternatives after investigators
    proposed changes to previously approved protocols.  Identifying
    and implementing alternatives is challenging, but investigators
    did not adequately document the alternatives that were considered
    when they designed their studies. Protocols Addressed
    In the 24 protocols we reviewed, investigators addressed
    replacement and Replacement and Reduction  reduction issues as
    required by explaining why they planned to use animals
    Alternatives                      and the proposed species and
    numbers of animals.  To assess DOD's use of alternatives, we
    reviewed materials used in the original consideration and approval
    of the project and had a nationally recognized subject matter
    expert and two experts in research methodology and animal use
    alternatives separately review the materials for each project.  In
    all 24 protocols, investigators provided explanations of why they
    planned to use animals to meet research objectives.  In 18 of the
    24 protocols, investigators provided detailed discussions of the
    reasons for using animals, including reasons why proposed research
    could not be done using nonanimal models such as cell cultures or
    computer models.  For example, the investigator on a study of a
    new type of skin graft justified the use of animals by explaining
    that cell cultures could not be used to determine the success of
    these grafts in treating burns and that animals were needed to
    assess the immune system's response to the grafts.  Documenting
    the consideration of replacement alternatives became a requirement
    when DOD adopted its standard protocol in fiscal year 1996.  This
    documentation is intended to assist reviewers' ability to
    determine the quality of investigators' consideration of
    replacement alternatives. In two protocols, investigators
    identified and incorporated nonanimal models as ways to reduce,
    though not totally replace, animal use.  For Page 12
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 example, in
    one protocol, the investigator proposed to use cell cultures to
    screen vaccines before they were tested on mice.  This process was
    designed to reduce the number of vaccines used on the mice, thus
    reducing the number of mice required. Investigators' explanations
    for the proposed use of a specific animal species usually focused
    on why the species was most appropriate to meet research
    objectives.  The specificity with which protocols addressed this
    issue varied widely, reflecting differences in facilities'
    protocol forms.  For example, justifications ranged from check
    marks on a standard checklist of reasons why the animals might be
    used to detailed discussions of the advantages of using the
    requested species.  One protocol we reviewed contained a detailed
    discussion of why monkeys and dogs were the best species for the
    proposed experiments and why rodents, as an alternative lower-
    order species, were not as well-suited.  This discussion was
    supported by an extensive bibliography.  In addition, four of the
    six biological warfare defense protocols we reviewed proposed
    using monkeys and provided written justification explaining that a
    monkey's response to biological warfare agents is similar to a
    human's.  Similarly, the use of pigs in several research protocols
    exploring resuscitation treatments was proposed because pigs have
    a cardiovascular system similar to that of humans. The protocols
    we reviewed also showed consideration of the number of animals
    being proposed for use in the research.  We found cases in which
    investigators incorporated methods to reduce the number of
    animals.  In one protocol, the investigator planned to use
    historical data from previous experiments rather than using
    additional animals as a basis for comparison.  In another
    protocol, the investigator designed the study to use one animal
    control group with two experimental groups of animals instead of a
    separate control group for each experimental group.  In a third
    protocol, the investigator planned to use an alternative
    statistical technique that would reduce the number of animals
    needed while still achieving statistically valid results.  In
    addition, since fiscal year 1996, investigators at DOD facilities
    have been required to certify that statisticians have reviewed
    proposed research to help ensure that the lowest number of animals
    as possible is used consistent with research objectives.
    Investigators at non-DOD facilities are required to provide
    similar information in their proposals to DOD. We found one
    project in which the number of animals could have been reduced,
    had the investigator reversed the sequence of proposed animal Page
    13                                GAO/NSIAD/HEHS-99-156  DOD
    Animal Research B-278778.1 procedures.  In this case, the
    investigator planned to first measure the accuracy of an
    ingestible device in detecting the onset of traumatic shock in
    pigs.  He then planned to assess how long the device would remain
    effective in the digestive systems of monkeys, whose digestive
    system is similar to humans'.  The investigator planned to wound
    the pigs but not the monkeys.  The investigator requested and
    received approval to test 400 pigs but not the monkeys.  We
    believe that the monkeys should have been tested first because had
    the device not remained effective in the monkeys' digestive
    systems, experiments on the pigs would not have been necessary.
    However, DOD subsequently terminated funding for this project due
    to budget reductions, and the second component involving the
    monkeys was never conducted.  A service-level veterinarian agreed
    with us that it would have been preferable to have first tested
    the monkeys. Protocols Addressed      All the protocols we
    reviewed described refinements to be used as required Refinements
    but More     to alleviate pain.  However, we found that other
    refinement alternatives Could Have Been Done     were available
    and could have been used in 8 of the 24 protocols.  We were unable
    to determine the extent to which these refinements were considered
    because documentation was generally lacking. All the protocols we
    reviewed described procedures for administering pain relief to
    animals as required and euthanizing them when appropriate.  In
    addition, the investigator of one project on experimental burn
    treatments identified alternative anesthetics and analgesics to be
    used to improve pain relief for animals.  In another case, the
    IACUC required that the investigator reduce animals' pain and
    distress by euthanizing them earlier than the investigator had
    proposed.  In this study of burn treatments, the IACUC required
    the investigator to euthanize rats when their body temperature
    dropped 4 degrees because scientific literature had demonstrated
    that such a temperature drop indicates impending death.  The
    investigator had not proposed euthanizing the rats until later.
    Subsequent to approval of the protocol for this research, the
    IACUC issued a written policy requiring investigators to consider
    this alternative when preparing protocols. In contrast, we found
    that other refinement alternatives were available and could have
    been used in 8 of the 24 protocols.  In five of these, the
    alternative was a refinement in the administration of pain relief
    to animals subjected to burns.  In these protocols, sheep, pigs,
    rats, and mice were to be anesthetized while third-degree burns
    were being administered. However, the investigators did not plan
    to give the animals analgesia routinely after the burns.
    Investigators or attending veterinarians were to Page 14
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 monitor
    animals for behavioral changes usually associated with pain or
    distress such as postural changes, ruffled hair coat, and lack of
    appetite before administering analgesia.  DOD officials stated
    that in general, pain relief was not needed after the burns were
    administered because the burns were limited to a well-defined area
    where the nerve endings had been destroyed by the burns, resulting
    in no pain. Whether analgesia should be administered on a routine
    or as-needed basis in these situations is controversial.  Experts
    and non-DOD officials involved in regulating animal research told
    us that in experiments such as these, animals can experience pain
    around the periphery of the burned area and should be given
    analgesia routinely after burns are administered.  They also
    pointed out that it can be difficult to identify pain in animals
    and that if the results of the research would not be compromised,
    routine administration of analgesia is warranted as a preventive
    measure.  DOD officials acknowledged that there is uncertainty
    over the issue. Given this controversy, we believe that
    investigators and IACUCs should fully consider the appropriateness
    of analgesia administration in similar studies.  Neither the
    investigators' protocols nor the IACUC records, however, contained
    information on whether refinements involving the routine
    administration of analgesia had been considered.  For example, at
    a non-DOD facility where one of these five studies was conducted,
    the IACUC record of consideration consisted only of the protocol
    number, which was listed among over two dozen protocols approved
    at one meeting, and brief notes on additional information
    requested by the IACUC. None of the requested information
    concerned the use of analgesia. Similarly, at another facility we
    visited, the Association for Assessment and Accreditation of
    Laboratory Animal Care International, an independent accreditation
    organization,12 found that the IACUC did not adequately document
    that pain and distress were addressed in the protocol approval
    process.  DOD's standard protocol format, which was implemented in
    fiscal year 1996, does not require investigators to discuss
    refinement alternatives that are considered but not adopted. Other
    refinement alternatives could have been implemented in the sixth
    and seventh projects.  In these projects, mice that had been given
    a toxin could have been euthanized sooner, on the basis of a drop
    in their body temperature, without compromising the research
    results.  The presence of 12 DOD requires that all of its
    facilities apply for AAALAC accreditation. Page 15
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 hypothermia
    (low body temperature) as an objective indicator of impending
    mortality for this type of toxin was published as early as 1992,
    before the development of both protocols.13  Although evidence of
    the effectiveness of this measurement approach was available and
    was employed in one of the other protocols we reviewed, DOD
    officials said that the validity of the evidence had not yet been
    demonstrated on different types of research and species of
    animals.  Researchers at Army laboratories recently conducted two
    studies to investigate the hypothermia-based end-point indicator.
    While one of the studies confirmed a correlation between lowered
    body temperature and mortality, the other was unable to identify a
    similar correlation.  None of the records we reviewed contained
    information on investigators' or IACUCs' consideration of this
    refinement. In the eighth protocol, an alternative vaccine could
    have been used in a study testing the effectiveness of a vaccine
    to protect monkeys from a potential biological warfare agent.  In
    this study, monkeys that had been treated with an experimental
    vaccine against staphylococcal enterotoxin B were exposed to the
    toxin.  The vaccine was prepared from the toxin and, as a result,
    had a greater likelihood of having side effects that could cause
    pain and distress to the monkeys than a vaccine prepared using a
    recombinant technique.  Research had been published as early as 3
    years before this protocol was prepared pointing to the
    availability of recombinant techniques for developing a vaccine
    against this toxin.14 However, the protocol and IACUC records did
    not address this alternative. Identifying Alternatives Is
    Finding alternatives that can be used in research is challenging
    for Challenging                     investigators. These
    challenges affect all research, whether it is funded by DOD or by
    other public or private organizations.  Although DOD requires
    investigators to conduct a literature search to identify
    alternatives to painful procedures, literature searches may not
    capture all the possible alternatives, in part because the
    literature may not specifically identify alternatives.  For
    example, an investigator may have used an innovative type of
    anesthesia on animals but may not have discussed the procedure in
    the published results of the research.  Because alternatives cut
    across 13 Soothill, J.S., Morton, D.B., and Ahmad, A., "The HID50
    (hypothermia-inducing dose 50): an alternative to the LD50 for
    measurement of bacterial virulence," International Journal of
    Experimental Pathology (Feb. 1992), pp. 95-98. 14 Harris, T.O., et
    al., "Lack of complete correlation between emetic and T-cell-
    stimulatory activities of staphylococcal enterotoxins," Infection
    and Immunity (Aug. 1993), pp. 3175-3183. Page 16
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 many fields
    of research, investigators need to search numerous sources,
    including some abroad, to find available information on
    alternatives. The universe of alternatives is broad and changes
    constantly.  An alternative can be as narrow as a better form of
    anesthesia and as broad as cell cultures and computer models which
    do not use animals at all.  At the same time, scientific advances
    can lead to the development of new alternatives.  One example is
    the development of nonanimal procedures for the production of
    monoclonal antibodies.  Previously, these antibodies were produced
    primarily using animals such as mice but they can now be produced
    using cell culture techniques. AWIC and the Center for
    Alternatives to Animal Testing15 are working on projects,
    supported by the Office for Protection from Research Risks (OPRR)
    of the National Institutes of Health, designed to help improve the
    usefulness of literature searches for alternatives by making it
    easier to find alternatives among the numerous online sources.
    OPRR has entered into an agreement with AWIC to develop an
    interactive Internet-based training program on searching for
    alternatives.  The program will be based on AWIC's existing
    training program on literature searching for alternatives. Also,
    OPRR has been working with the Center for Alternatives to Animal
    Testing to explore the development of a comprehensive search
    engine for the numerous electronic sources of information on
    alternatives.  These efforts could assist all researchers,
    including DOD-funded investigators, to more effectively and
    efficiently identify alternatives. In addition, continuing review
    of protocols at some facilities could be more rigorous.  While the
    facilities we visited generally had procedures in place to ensure
    that IACUCs reviewed and approved significant changes to protocols
    after research had begun and conducted periodic reviews of
    investigators' progress in completing their protocols, we found
    instances in which investigators and IACUCs could have more
    closely addressed alternatives.  One protocol at a non-DOD
    facility underwent numerous major changes after it was originally
    approved by the institution's IACUC. The scope of the project was
    expanded to inflict injuries on different parts of pigs' bodies,
    change pain killers used on the pigs, and assess different
    resuscitation treatments on the pigs.  We found no evidence in the
    amended 15 This center, based at Johns Hopkins University in
    Baltimore, Maryland, operates the ALTWEB Internet site, which
    provides links to numerous sources of information on animal use
    alternatives. Page 17
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 protocols or
    IACUC records we obtained that alternative procedures were
    considered. In an experiment at a DOD facility to develop field
    techniques for resuscitating severely injured servicemembers, the
    first 14 of 21 pigs (67 percent) that were tested died
    unexpectedly.  Because it was concerned about the high ratio of
    deaths, the IACUC considered and approved changes intended to
    reduce the risk of death from the surgical procedures. But in a
    later phase of the experiment, 11 of 28 pigs (39 percent) died, in
    part because of the inexperience of a project member who performed
    the surgical procedures.  In a memo explaining these deaths to the
    facility's IACUC, the investigator set the goal of reducing the
    mortality rate in this experiment to not more than 20 percent.
    The investigator put in place provisions (such as additional
    training for surgical staff) intended to correct the problems that
    caused these deaths.  Although we found evidence that the IACUC
    was responsive to the unexpected deaths, which occurred over a
    period of several years, it acted only after a high number of
    deaths had occurred.  However, the IACUC subsequently implemented
    a policy requiring investigators to report any unexpected deaths
    within 48 hours. Conclusions    DOD's controls on animal use were
    generally effective but improvements are needed.  Although we were
    able to link virtually all animal use projects to military
    objectives, DOD lacks centralized information on the military
    justification for each project.  Without such information, neither
    Congress nor the public have an adequate basis for understanding
    and assessing the reasons DOD uses animals in its research.  We
    continue to believe that DOD should implement our previous
    recommendation to improve the information reported on individual
    projects that use animals. DOD implemented several procedures that
    worked well to avoid unnecessary duplication by the 24 projects we
    reviewed.  We did not find unnecessary duplication by any of these
    projects.  However, the process for assessing duplication could be
    improved further.  DOD has not adequately defined what it
    considers appropriate databases for literature searches.  We are
    concerned that as a result, investigators at non-DOD facilities
    may not routinely search databases such as FEDRIP and DTIC that
    provide information on government research in progress.
    Information on ongoing research is important to help investigators
    identify the potential for unnecessary duplication. Page 18
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 DOD was
    generally successful in considering and implementing replacement
    and reduction alternatives in the 24 research projects we
    reviewed.  However, we found additional refinements that could
    have been implemented in one-third of these projects.  We
    recognize the challenges that investigators and IACUC members face
    in identifying alternatives, especially because scientific
    literature does not always discuss alternatives and scientific and
    veterinary practices change rapidly.  Furthermore, uncertainty
    remains over the need to use some alternatives such as the routine
    administration of analgesia in burn studies.  However, we were
    unable to determine the extent to which the refinements we
    identified were considered by investigators and IACUCs because
    protocols and IACUC records did not document the alternatives that
    were considered but not adopted.  DOD has adopted a standard
    protocol requiring investigators to discuss replacement
    alternatives considered but not adopted.  A similar requirement to
    document the refinement alternatives that were considered could
    encourage investigators to focus more on these alternatives and
    provide IACUCs better information on alternatives when they review
    protocols. Recommendations    To further reduce the likelihood of
    proposed research unnecessarily duplicating other research, we
    recommend that the Secretary of Defense clarify DOD's policy
    regarding which databases of research in progress investigators
    must search.  We also recommend that the Secretary further
    facilitate the consideration of refinement alternatives by
    investigators and IACUCs.  Specifically, the DOD standard animal
    use protocol form should be amended to require investigators to
    identify refinement alternatives that were considered but not
    adopted and explain why they were not adopted. Agency Comments
    In written comments on a draft of this report (see app. III), DOD
    concurred with our recommendations.  DOD stated that it will
    clarify the databases that should be searched for research in
    progress and will amend the standard protocol to identify
    refinement alternatives that were considered but not adopted and
    to explain why specific alternatives were not adopted. DOD raised
    a concern about the title of the report, saying it should be
    changed by replacing the word "needed" with "suggested."  DOD
    believed that the term "needed" implies that improvements are
    required or necessary to meet a standard, and noted that our
    report did not present instances in which federal standards were
    not met.  While we found no Page 19
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 evidence
    that DOD failed to meet federal standards, the changes we are
    recommending are necessary to guard against unnecessary
    duplication and to promote the implementation of alternatives in
    DOD's projects that utilize animals.  DOD also included technical
    comments in its response which we incorporated where appropriate.
    We are sending this report to the Honorable William Cohen,
    Secretary of Defense and other interested parties.  We will also
    make copies available to others upon request. If you have any
    questions about this report, please call Kwai-Cheung Chan at (202)
    512-3092 or Stephen P. Backhus at (202) 512-7101.  GAO contacts
    and staff acknowledgements are listed in appendix IV. Kwai-Cheung
    Chan Director, Special Studies and Evaluations National Security
    and International Affairs Division Stephen P. Backhus Director,
    Veterans' Affairs and Military Health Care Issues Health,
    Education, and Human Services Division Page 20
    GAO/NSIAD/HEHS-99-156  DOD Animal Research B-278778.1 Page 21
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Contents Letter
    1 Appendix I
    24 Scope and Methodology Appendix II
    28 DOD's Process for Reviewing Animal Research Proposals Appendix
    III
    31 Comments From the Department of Defense Appendix IV
    33 GAO Contacts and Staff Acknowledgements Related GAO Products
    36 Tables                   Table 1:  DOD Animal Use Objectives
    (fiscal year 1996)                      6 Table I.1:  Research
    Facilities Included in Study                          26 Figure
    Figure II.1:  DOD's Process for Reviewing Animal Research
    Protocols in Fiscal Year 1996
    28 Page 22                             GAO/NSIAD/HEHS-99-156  DOD
    Animal Research Contents Abbreviations AFRRI       Armed Forces
    Radiobiology Research Institute AWIC        Animal Welfare
    Information Center BRD         Biomedical Research Database DARPA
    Defense Advanced Research Projects Agency DOD         Department
    of Defense DTIC        Defense Technical Information Center FEDRIP
    Federal Research in Progress IACUC       Institutional Animal Care
    and Use Committee OPRR        Office for Protection from Research
    Risks Page 23                              GAO/NSIAD/HEHS-99-156
    DOD Animal Research Appendix I Scope and Methodology
    Appendix I Our objectives were to determine to what extent
    projects using animals funded or performed by the Department of
    Defense (DOD) (1) were directed toward military objectives; (2)
    unnecessarily duplicated other research; and (3) incorporated
    alternatives that reduced, replaced, or refined the use of
    animals. To assess the extent to which animal use projects were
    directed toward military objectives, we used the Biomedical
    Research Database (BRD) to identify the universe of projects using
    animals being conducted by DOD. We used the fiscal year 1996 BRD
    because it contained the most current summary information on
    animals used in research, education, training, and testing at the
    time we began our review.1  This database covered 805 animal use
    projects conducted by DOD and the military services. Because the
    BRD does not include information about military objectives for
    each project, we collected this information from the 16 DOD
    program offices that sponsor animal use projects.  We asked
    officials there to identify the specific service-level research
    objectives linked to each project.  We reviewed documentation,
    where available, to confirm their assessments.  For other
    projects, we relied on officials' assessments, which were based on
    their knowledge of the projects that had been conducted. We also
    interviewed DOD officials in 14 offices that have responsibility
    for developing military research objectives and policies for
    clinical investigations and reviewed policies and reports. To
    address our second and third objectives, we reviewed legislation
    and regulations related to the welfare of research animals and
    relevant DOD policy documents and directives.  We reviewed
    published literature on animal use issues and attended conferences
    on this subject.  We interviewed veterinarians and others who
    manage DOD's laboratory animal use programs.  We also met with
    representatives from government agencies, accrediting
    organizations, animal welfare groups, and others, including the:
    Animal Plant and Health Inspection Service, United States
    Department of Agriculture (USDA); Animal Welfare Information
    Center, USDA; 1 The BRD does not include information on DOD's use
    of animals for human or animal consumption, ceremonial activities,
    and recreation or its training, care, and use of military working
    animals. Page 24
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix I Scope and
    Methodology National Institute of Environmental Health Sciences,
    National Institutes of Health (NIH), Department of Health and
    Human Services (DHHS); Office for Protection from Research Risks,
    NIH, DHHS; American College of Laboratory Animal Medicine;
    Association for Assessment and Accreditation of Laboratory Animal
    Care International; Humane Society of the United States; In
    Defense of Animals; Physicians Committee for Responsible Medicine;
    Center for Alternatives to Animal Testing, Johns Hopkins
    University; National Association for Biomedical Research; and
    Institute of Laboratory Animal Research, National Academy of
    Sciences. To review research projects, we selected projects from
    three areas of DOD research: treatment of injuries from biological
    weapons, combat casualty care, and treatment of radiation wounds.
    These three areas included 175 of the 805 fiscal year 1996
    projects.  They are areas of research in which animals are often
    injured or exposed to potentially deadly agents and in which the
    animals often either die of their wounds or are euthanized at the
    conclusion of the study.  These areas also included a large
    proportion of projects that used higher-order animals such as
    nonhuman primates.  We did not review projects in other areas
    where animals are used such as infectious diseases, chemical
    defense, human systems technology, and training and education.
    From the 175 projects in the three areas we selected, we
    judgmentally selected 24 projects to review in depth.  We selected
    projects that used large numbers of animals.  In selecting
    specific projects, we also tried to include a wide range of
    species of animals, a mixture of DOD and non-DOD facilities, and
    several military services and Defense agencies.  Seven of the 24
    projects used nonhuman primates and 12 used pigs, dogs, sheep, or
    rabbits.  The other projects used large numbers of rodents.  The
    projects in our sample included research performed at seven DOD
    laboratories and Page 25
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix I Scope and
    Methodology seven non-DOD facilities.  Twelve of the 24 projects
    were sponsored by the Army; 5 were sponsored by the Navy; and 7
    were sponsored by Defense agencies (the Armed Forces Radiobiology
    Research Institute, the Defense Advanced Research Projects Agency,
    and the Uniformed Services University of the Health Sciences).
    Air Force projects were not included because the BRD did not list
    the Air Force as a sponsor of projects in these areas of research.
    We visited the 14 facilities where the 24 projects were conducted
    (see table I.1). Table I.1:  Research Facilities Included in Study
    Funding agency or department in parentheses Number of Facility
    Location                           projects Department of Defense
    facilities Armed Forces Radiobiology Research          Bethesda,
    Maryland                       3 Institute U.S. Army Institute of
    Surgical Research San Antonio, Texas                          4
    U.S. Army Medical Research Institute of  Frederick, Maryland
    3 Infectious Diseases Naval Medical Center
    San Diego, California                    1 Naval Medical Research
    Institute            Bethesda, Maryland                       2
    Uniformed Services University of the        Bethesda, Maryland
    2 Health Sciences Walter Reed Army Institute of Research
    Washington, District of Columbia              2 Non-DOD facilities
    Childrens Hospital Medical Center           Cincinnati, Ohio
    1 (Defense Advanced Research Projects Agency) Massachusetts
    General Hospital (Army) Boston, Massachusetts
    1 Naval Blood Research Institute, Boston  Boston, Massachusetts
    1 University (Navy) University of Arizona (Army)
    Tucson, Arizona                          1 University of North
    Carolina (Army)         Chapel Hill, North Carolina              1
    University of Tennessee Health              Memphis, Tennessee
    1 Sciences Center (Navy) University of Virginia (Defense
    Charlottesville, Virginia                1 Advanced Research
    Projects Agency) Page 26
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix I Scope and
    Methodology We reviewed documentation for each project to assess
    the protocol development and review processes.  The review
    included acquiring and reviewing each research project's animal
    use protocol; Institutional Animal Care and Use Committee (IACUC)
    records for these protocols; IACUC correspondence; institutional
    policies, procedures, and training materials; and correspondence
    between DOD reviewing officials and the investigator. Among those
    we interviewed at the facilities were past and current IACUC
    chairs, attending veterinarians, and other officials.  We also
    interviewed investigators of 18 of the 24 research projects and
    nonaffiliated IACUC members at 11 of the 14 facilities. We
    contracted with the USDA's Animal Welfare Information Center
    (AWIC) to obtain an independent search of scientific literature
    relevant to each project.  Each project was reviewed by three
    experts.  We contracted with four subject matter experts, who
    reviewed projects in their areas of expertise.  Also, we
    contracted with an expert in laboratory animal medicine and an
    expert in the field of alternatives to review all the projects.
    For each project, the experts reviewed research protocols, related
    documents, and the AWIC literature search.  They provided comments
    that we considered when developing our findings on unnecessary
    duplication and alternatives.  Our findings are not generalizable
    to all DOD research that used animals in fiscal year 1996. We
    performed our work from October 1997 to May 1999 in accordance
    with generally accepted government auditing standards. Page 27
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix II DOD's
    Process for Reviewing Animal Research Proposals
    Appendix II DOD's process to reduce unnecessary duplication and
    promote alternatives to animal use relies on investigators to
    prepare detailed plans of their research-called protocols-and
    several levels of review of these protocols (see fig. II.1).  The
    facilities we visited generally followed similar practices, with
    minor variations. Figure II.1:  DOD's Process for Reviewing Animal
    Research Protocols in Fiscal Year 1996 Protocol Development In
    October 1995, DOD implemented a standardized protocol format for
    use by its facilities and required non-DOD facilities to address
    the information contained in the format.  DOD implemented this
    format in response to recommendations by the Inspector General,
    who found that each research facility differed in the information
    it collected on proposed research.  Of Page 28
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix II DOD's
    Process for Reviewing Animal Research Proposals the 24 studies we
    reviewed, 4 of the 5 that were developed after October 1995 used
    the new protocol format.  The other protocols were developed prior
    to 1995 and used different formats. The standard protocol format
    requires that investigators address several elements, including
    the study background, objectives and hypotheses, military
    relevance, experimental design, animal requirements and
    justifications, research procedures, veterinary care, investigator
    qualifications, and safety issues.  In the protocols,
    investigators are required to provide written assurance that the
    proposed research does not unnecessarily duplicate other studies.
    This requirement stems from animal welfare regulations.  In
    addition, DOD requires that its investigators review specific
    electronic databases to identify whether the proposed research
    could unnecessarily duplicate other studies; document the results
    of their search; and identify the databases searched, key words
    used, and the dates of the search.  Investigators must present
    written justification for the use of animals, to include
    consideration of nonanimal alternatives, the total number and
    species of animals to be used, and alternatives being employed.
    Review and Approval of     DOD requires that each protocol pass
    through several review steps before Animal Use Protocols
    animals are used: a scientific review, a facility-level review by
    an IACUC and, for many protocols, a DOD veterinary review.  A
    scientific merit review is conducted by the DOD funding
    organization to determine whether the research is likely to
    contribute to the advancement of scientific knowledge and military
    objectives.  Generally, scientific merit reviews for DOD
    facilities are conducted by in-house scientists.  Scientific merit
    review for research at non-DOD facilities varies depending on the
    funding agency.  For example, the U.S. Army Medical Research and
    Materiel Command conducts scientific merit reviews for projects
    proposed by investigators at non-DOD facilities by contracting
    with scientists who are not affiliated with the command or the
    facility.  On the other hand, the Office of Naval Research uses
    in-house scientists to conduct scientific reviews of its research
    at non-DOD facilities. Proposals that pass scientific review are
    then reviewed by the research facility's IACUC.  The IACUC review
    is critical to the entire process because IACUC approval is
    required before funding is allocated and animals can be ordered or
    used.  The IACUC conducts a review of the protocol to ensure
    compliance with animal welfare laws and regulations. Although
    minutes of the review meetings are maintained, detailed Page 29
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix II DOD's
    Process for Reviewing Animal Research Proposals documentation of
    issues discussed in the consideration of protocols is not
    required. Under certain circumstances, DOD requires a third level
    of review.  If a proposal calls for using nonhuman primates, DOD
    requires that a service-level veterinarian trained or experienced
    in laboratory animal science and medicine perform a review.  The
    purpose of this review is to ensure that the investigator and the
    institution where the research is to be conducted are in
    compliance with the Department of Health and Human Services'
    guidance on the supply and use of laboratory primates.1  In
    addition, DOD requires that these reviewers examine all projects
    at non-DOD facilities, regardless of the species used, for
    compliance with animal welfare and DOD requirements.  The Army
    requires a similar type of review for protocols at its facilities
    that propose to use dogs or cats. Post-approval Review of     Once
    the research has begun, the IACUC annually reviews each protocol.
    Research                    The purpose of the annual review is to
    determine whether the project should continue.  The annual
    protocol report describes the project's status (e.g., active,
    terminated) and any significant changes made to the protocol
    during the year.  In addition, if investigators wish to amend the
    protocol during implementation of their research, they must obtain
    approval from the IACUC before making changes.  The nature of the
    IACUC's review depends on the significance of the change.  IACUCs
    often delegate approval for minor modifications such as a change
    in the dosage of a drug being administered to the veterinarian
    member of the IACUC.  A major modification such as a change in
    number of animals to be used generally necessitates a formal
    review by the IACUC. 1 National Primate Plan, U.S. Department of
    Health and Human Services, NIH-80-1520 (Oct. 1978). Page 30
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix III Comments
    From the Department of Defense AppendIix II Page 31
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix III Comments
    From the Department of Defense Now on p. 19. Now on p. 19. Page 32
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Appendix IV GAO
    Contacts and Staff Acknowledgements Appendix IV GAO Contacts
    John Oppenheim, (202) 512-3111 Bruce D. Layton, (202) 512-6837
    Acknowledgements    In addition to those named above, Jaqueline
    Arroyo, Dan Engelberg, Cary Russell, and Gregory Whitney made key
    contributions to this report. Page 33
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Page 34
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Page 35
    GAO/NSIAD/HEHS-99-156  DOD Animal Research Related GAO Products
    DOD Animal Research: Improvements Needed in Quality of Biomedical
    Research Database (GAO/NSIAD/HEHS-99-24, Dec. 14, 1998).
    Biological Warfare: Better Controls in DOD's Research Could
    Prevent Unneeded Expenditures (GAO/NSIAD-91-68, Dec. 27, 1990).
    Army Biomedical Research: Concerns About Performance of Brain-
    Wound Research (GAO/HRD-91-30, Dec. 12, 1990). (713013)    Letter
    Page 36                           GAO/NSIAD/HEHS-99-156  DOD
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    DOCUMENT Contents Table 1:  DOD Animal Use Objectives (fiscal year
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    GAO/XXXX ??? Contents Page 41     GAO/XXXX ??? Contents Figure
    II.1:  DOD's Process for Reviewing Animal Research Protocols in
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