Alternatives Search: Demonstrating Compliance

1. Define the Questions

Note all possible keywords and subject headings to include in your literature search,  those which are related to your research, as well as those related to the 3Rs.  “Literature Search for Alternatives” worksheet

2. Select Appropriate Databases

Selecting the appropriate databases is critical; you will need to search in more than one database and to tailor your keywords, subject headings, and search strategies to each specific database.

3. Construct the Search Strategies

After developing keyword lists, you will need to develop search strategies, including how to expand and/or narrow your searches.  Keep a record of databases and search strategies for protocol submission.

4. Evaluate Search Results

Review and evaluate your results as you go along in order to make modifications to your search strategies.

5. Manage and Report Search Results

After conducting your searches, you will need a way to keep track of the information that you have located, document the process, and create a narrative concerning any refinements, reductions, or replacements identified.

Which is similar to the search approaches described in:

Additional Alternatives Research Guides

Highly recommended guides:  

CCAC 3Rs Search Guide  |  EUR ECVAM Search Guide  |  UCCAA  |  AWIC  |

European Commission EURL ECVAM Search Guide
… a fundamental requirement, namely that, for legal, ethical and scientific reasons, any researcher planning to, or using, animals for experimental or other scientific purposes must be well-informed about the state of the art of the proposed field of investigation.  In particular, to satifsy the legal and ethical imperatives that animals shall only be used for research and testing if all possible alternatives are considered but found to be inadequate…

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This guide based on work previously done by:
UNC  |  University of Denver  |  University of Toledo  |

Define

Terms and ideas from proposed study, possible search terms, possible search questions:

Reading through the protocol, make notes of terminology, procedures, drugs, considering what questions need to be asked related to replacement (model choice/necessity), reduction (unnecessary duplication, study design), and refinement (methods/procedures potential pain/distress), and current best practice/SOP/guidelines.

Questions to be searched common to all protocols:

Is the proposed research necessary, what has already been done in this area, what models have been used, what best methods/procedures, and alternative consideration for potential pain and distress

• List every procedures in the protocol that has the potential to cause pain or distress.
• Identify other possible terms for each technique that you have identified; determine if a subject heading for each procedure exists in the database that you are using.
• Search each of these procedures, considering alternative methods to accomplish the same goal.
• Begin by searching broadly for each technique. Next, try combining each technique with some of the keywords and subject headings for pain/distress prevention and control, analgesia/anesthesia, and refinement as listed in keywords and in the search examples.

Formulate the Questions

for example:

What is the effect of [intervention/exposure] on [outcome measures] in [animal species/population] for [disease/health problem]?

How to teach [procedure/technique] to [population]?

Consider the research-related terms
Scientific, common names of any species
Scientific, common names of any diseases, conditions
Generic name, trade names of any drugs, chemicals
Scientific, common terms for tissues, systems, or cell lines
Treatments, procedures

Note keywords and synonyms
It is important to record these keywords at the beginning of your literature search so that you are able to both be consistent across searches and provide the required narrative account of your literature search in your protocol. If you make changes or additions to your list of keywords, include those changes in your records.

Altweb Site for news, information, discussion, and resources from the field of alternatives to animal testing

ANZCCART Australian and New Zealand Council for the Care of Animals in Research and Teaching. Many useful resources including Fact Sheets, Newsletters, and publications.

AWIC Animal Welfare Information Center Site for information for improved animal care and use in research, teaching, and testing

CAAT Center for Alternatives to Animal Testing. Johns Hopkins University Global resources for the development of replacement, reduction and refinement alternatives for research and testing

CCAC 3Rs Mircrosite Canadian Council on Animal Care – Replacement, Reduction and Refinement Alternatives

FRAME Fund for the Replacement of Animals in Medical Experiments (UK)Researching alternatives to animal use in research, testing, and education

Go3R Database acts as a filter applied to a PubMed search, simplifying retrieval of journal articles related to both the research topic and the 3Rs.

IACUC.ORG An information resource for members and staff of institutional animal care and use committees. It is a link archive, organized by menus and submenus, produced by the American Association for Laboratory Animal Science (AALAS).

ILAR Institute for Laboratory Animal Research prepares authoritative reports on subjects of importance to the animal care and use community and serves as a clearinghouse for information about animal resources

JAX Mice Databases Mouse Model Lists, Inbred Strains of Mice and Rats, Mouse Genome Database, and more.

Mouse Biology Program UCDavis, provides links to internet resources and databases for transgenic and targeted mutation research

NC3Rs UK-based National Centre for the Replacement, Refinement & Reduction of Animals in Research, Resources, Microsites, Hubs particularly useful.

NICEATM / ICCVAM NTP Interagency Center for the Evaluation of Alternative Toxicological Methods / Interagency Coordinating Committee on the Validation of Alternative Methods

NORINA Norwegian Inventory of Alternatives. Norwegian Reference Centre for Laboratory Animal Science and Alternatives Database of audiovisuals, computer programs, CD-ROMs, interactive videos, and other alternatives for use in the biological sciences

RePORTER NIH Research Portfolio Online Reporting Tools Expenditures & Results Searchable database of federally funded biomedical research projects

3R Guide Norecopa, in collaboration with the Animal Welfare Information Center has produced a database which provides an overview of guidelines, databases, journals, email lists, regulations and policies which may help researchers to implement the 3Rs when planning research that may involve animals.

3Rs Centre ULS The 3Rs-Centre Utrecht Life Sciences (ULS) stimulates the development, acceptation and implementation of 3Rs methods (replacement, reduction and refinement of animal experiments). Two databases: the Interspecies Database (www.interspeciesinfo.com) and the Humane Endpoints website (www.humane-endpoints.info).

Public Access Databases

AGRICOLA Produced by the National Agricultural Library

ALTBIB Bibliography on Alternatives to the Use of Live Vertebrates in Biomedical Research and Testing, National Library of Medicine

CRIS Current Research Information Service; USDA’s reporting system for ongoing and recently completed research projects conducted or sponsored by USDA research agencies, state agricultural experiment stations, the state land-grant university system, other cooperating state institutions, and participants in USDA-administered grant programs.

ECOTOX Ecotoxicology Database for locating single chemical toxicity data for aquatic life, terrestrial plants and wildlife; maintained by EPA.

DTIC Defense Technical Information Center (DTIC) serves the Department of Defense (DoD) community as the central resource for DoD and government-funded scientific, technical, engineering, and business related information.

PubMed Produced by the National Library of Medicine

TOXNET Produced by the National Library of Medicine. A cluster of databases on toxicology, hazardous chemicals, and related areas

ZFIN Zebrafish Model Organism Database of online information for zebrafish researchers

• Formulate your research question: write out your research thesis as completely as possible. If there are multiple objectives, write a statement for each one
• Break the question down into various concepts; do this for each research question you developed, above

• Identify synonyms: for each concept, list various synonyms

After considering your search questions and identifying keywords and synonyms, you have chosen databases that index the information that may provide the answers to your questions.  Constructing a search strategy is dependent on the question, the terms, and the database.  Databases vary by the type and number of records they contain, their dates of coverage, the formats of literature they consider, and their scope. Databases also vary in how they index and their use of controlled vocabulary, like subject headings or a thesaurus.

Keywords can be combined with subject headings or defined terms, for example, in order to increase the precision of the search. Many databases have help pages explaining their specific features; please contact a librarian with any question at all.

To combine terms, use of Boolean logic: using the connector terms AND, OR, & NOT to structure your search query.

• AND requires that both keywords appear in the same document;

• OR requires that one or the other keyword appears;

• NOT requires that the keword is absent.

Use parentheses ( ) to nest concepts together.

Truncation: search for multiple keywords with the same root by using a truncation symbol such as * or ? at the end of the root (ex: using handl* will find handle, handled, handler, handles, and handling). Check what the truncation symbol is for whichever database you are searching by checking the help pages

Phrase searching: For two or more words that are almost always next to each other, you can force most databases to search for them as a phrase by surrounding them with double quotation marks.  For example, “blood sampling”

Subject heading searching: Subject headings, a system of controlled vocabulary used to classify information into specific categories, provide a very powerful way to locate focused, on-topic results. The articles in PubMed, for example, are classified using Medical Subject Headings, or MeSH.

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Considering Reproducibility, EBM and SR

ILAR Roundtables
ILAR Roundtable on Science and Welfare in Laboratory Animal Use
Institute for Laboratory Animal Research
National Academies of Science, Engineering and Medicine;

Reproducibility Issues in Research with Animals and Animal Models
Transportation of Laboratory Animals
Design, Implementation, Monitoring and Sharing of Performance Standards
Gene Editing to Modify Animal Genomes for Research – Scientific and Ethical Considerations

OHAT Systematic Review
National Toxicology Program (NTP)
Office of Health Assessment and Translation (OHAT)

Systematic reviews of preclinical animal studies
Marlies Leenaars, SYRCLE (Systematic Review Centre for Laboratory animal Experimentation)
Radboud University Medical Center, Nijmegen, The Netherlands
Cochrane Community Archive

NC3Rs
Experimental Design Assistant – EDA
The Experimental Design Assistant (EDA) is an online tool to guide researchers through the design of their experiments, helping to ensure that they use the minimum number of animals consistent with their scientific objectives, methods to reduce subjective bias, and appropriate statistical analysis.
Cressey, D.  Better design for animal studies: Web tool aims to reduce flaws in animal studies. Nature. 2016. 531(7592)128.

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Search Strategy: PubMed MeSH and Searching Examples

When searching PubMed it is helpful to use the Medical Subject Headings (MeSH) to find relevant articles. MeSH headings are assigned to each article within MEDLINE by its staff and are intended to be consistent across articles. This allows them to return more relevant and consistent groups of articles when searched.

Selected MeSH

When evaluating your alternatives searches, there are a number of questions you can ask yourself to evaluate the progress of your literature search.  The answers to the questions will help you determine whether your search is complete or whether you need to continue.

How many citations did I find?
If you have found too few citations, consider searching more databases, broadening your search terms, or searching a larger time span. If you find too many citations, perhaps you can limit or narrow your search terms to be more specific.

Are my keyword terms related to my protocol?
Make sure that the words you use to search are relevant to your research – otherwise you will end up with results that are not useful to you.

Are my keyword terms appropriate for the databases I searched?
Some of the best databases use subject headings that can affect your search. For instance, PubMed uses the MeSH term “neoplasm” instead of “cancer”. Other databases may focus more on common language terms.

How many places did I look?
Because the literature on animal research methods falls into so many different interdisciplinary areas, it is necessary to search more than one database. This is because no one database contains all of the information available on any given topic.

Did I set up my search strategy appropriately?
Databases may return odd results because they are confused by how you formulated your search. It will help to check the search tips or help pages in unfamiliar databases for strategies unique to the database.

Is the database you are searching the best for your research?
You may need to select different or additional ones.

Is your search query too long?
Every word you include narrows your search results because the database will try to find all of them in every record returned. Try shortening your search query.

Do you have multiple words that mean the same thing in your search?
Frequently, an abstract or article will use one synonym but not another, meaning that if you include both in the required search terms, you will cancel out finding the article. Overcome this by using Boolean OR.

Are you using Boolean terms correctly?
If you are using Boolean AND or NOT without using parentheses, you may be telling the database to limit your search more than you would like.

Are you searching an adequate time period?
This sort of literature search should include a broad period of time, with at least five years included.

Did you search in enough sources?
As the literature on animal research methods falls into so many different interdisciplinary areas, it is necessary to search more than one database as no one database contains all of the information available on any given topic.

Are your results useful?
Searchers must consider the quality of results that they find to be sure that they are adequate. Are you finding relevant results? If your results do not seem to match your search question, reconsider the search strategy.

Did you format your search query appropriately for the specific database
Databases may return odd results because they are confused by the search query. Remember to capitalize Boolean search connectors (AND, OR, NOT) if necessary and take advantage of other search features in the particular database. See the Help and Tutorial sections of each database that you search for assistance.

Report your results

According to 9 CFR 2.31 (d)(1)(ii) of the Animal Welfare Act, the principal investigator is required to provide a written narrative to the IACUC stating that alternatives to painful procedures have been explored and the results of that search.

Animal Care Policy #12 of the USDA Animal Care Resource Guide, “Written Narrative for Alternatives to Painful Procedures” states:

When a database search is the primary means of meeting this requirement, the narrative must, as a minimum, include:

1. the names of the databases searched;
2. the date the search was performed;
3. the period covered by the search; and
4. the key words and/or the search strategy used.

Regardless of the alternatives source(s) used, the written narrative should include adequate information for the IACUC to assess that a reasonable and good faith effort was made to determine the availability of alternatives or alternative methods. 

It will help your report to keep a log of the above four points for each search performed. You will be required to report this information anew to the IACUC when submitting a new protocol, amending an existing one, or requesting renewal.

Explanations of why an identified alternative was not used in the experimental procedure (if one is available) must also be included in the appropriate fields in your IACUC applications, as stated above.

In some fields, the development of new procedures in research may not be reported in journal literature, and thus may not be indexed in databases such as PubMed/MEDLINE. In these cases, it is the responsibility of the principal investigator to ensure that a search of appropriate literature sources such as government reports and conference proceedings is performed.

When an expert is consulted, a description of his/her credentials and relevant expertise must be included.

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Manage your results

Keeping track of what databases you have searched, what keywords and questions you used in each database, and the results from each search can be time-consuming.  The University Libraries support the use of Endnote, a citation manager, that can help you to organize your search results.

Using citation managers like EndNote, RefWorks, Mendeley, and Zotero has some major advantages. One is that you can attach notes to each reference, including keywords, subjects, and abstracts; this can help you to document your alternatives search. You can also automatically remove duplicate references that you have retrieved from searching different databases.

The Endnote: Getting Started guide can help you get started using this tool. We also offer numerous workshops on using Endnote throughout the year, or you can schedule a time to meet with a reference librarian to help you take advantage of this resource.

NIH OLAW PHS

OLAW Office Laboratory Animal Welfare, NIH

Alternatives links

The Institutional Animal Care and Use Committee

Documents Relevant to the PHS Policy

Guide for the Care and Use of Laboratory Animals

United States Government Principles for the Utilization and Care of Vertebrate Animals

Animal Welfare Regulations

AVMA Guidelines on Euthanasia

What investigators need to know about the use of animals

“…researchers must try to minimize distress in animals whenever possible: Animals used in research and testing may experience pain from induced diseases, procedures, and toxicity. The Public Health Service (PHS) Policy and Animal Welfare Regulations (AWRs) state that procedures that cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia. However, research and testing studies sometimes involve pain that cannot be relieved with such agents because they would interfere with the scientific objectives of the study. Accordingly, federal regulations require that IACUCs determine that discomfort to animals will be limited to that which is unavoidable for the conduct of scientifically valuable research, and that unrelieved pain and distress will only continue for the duration necessary to accomplish the scientific objectives. The PHS Policy and AWRs further state that animals that would otherwise suffer severe or chronic pain and distress that cannot be relieved should be painlessly killed at the end of the procedure, or if appropriate, during the procedure…”

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AAALAC Links

AAALAC relies on and refers to alternatives expectations, guidance, and policies by the Guide,  Ag Guide,  ETS 123,  NIH OLAW,  USDA,  CCAC.

AAALAC Resources: Information on Alternatives