How to Search for Alternatives

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.

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.

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.

Evaluate Search Results:

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

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.

Similar to the approach described in the EURL ECVAM Guide:

Define specific information need
Identify fundamental components of scientific approach
Choose appropriate information resources
Compile search terms
Search in 3Rs-specific context
Limit search results in broader biomedical databases
Broaden the search as necessary

and as described by SYRCLE (Leenaars, Lab Anim, 2012):

Formulate research question
Identify appropriate databases and sources of studies
Transform research question into search strategy
Collect search results and remove duplicates
Identify potentially relevant papers

as well as Sargeant (Zoonoses and Public Health, 2014):

Additional Alternatives Research Guides:

Highly recommended guides:  

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

This guide based on work previously done by:

UNC  |  University of Denver  |  University of Toledo  |

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…

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.

Assessment of potentially painful procedures

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.

MINCEMEAT / 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.

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 Sytematic 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.

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 progresss 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.

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.

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.

Following are the sections of and quotes from laws, regulations, and policies that behind the requirement to prove consideration of alternatives to potentially painful or stressful procedures.

Why Conduct Literature Searches for Alternatives?
USDA. NAL. Animal Welfare Information Center.
Article reviews the legislation, rationale, and benefits of the alternatives literature search.

“…The literature search provides a good faith effort on the part of the researcher and reflects well for the facility. Alternatives may be found that can lead to adoption of experimental methods that are less painful, use fewer animals, and make better scientific and economic sense…

…If the type of compound is known, the search is easily run. If not, it is important to remember that alternatives means more than simply searching for a replacement technique. The investigator can search for a method which uses fewer animals, where mortality is not the endpoint, or techniques that minimize pain or distress. Even environmental enrichment can be considered an alternative…

…The painful procedure must be examined in the context of the entire study. This information is often buried within the paper. Databases generally keyword search for words or phrases in the title, abstract, or descriptor. The painful procedures are sometimes, but not often, mentioned in those categories. Therefore, a broader view is needed to see if the study’s ultimate objectives can be met with alternative methods…

…Many researchers run literature searches when designing a study. This helps determine if the research is original or “unnecessary duplication” (which must be documented). Such searches can easily be tailored to address alternatives…”

Animal Welfare Act U.S. Code, Title 7 Federal Register 9 CFR USDA APHIS Animal Care Animal Care Policies Animal Care Inspection Guide

BASED ON THE

Animal Welfare Act Animal Welfare Act (2/2010) (PDF) Animal Welfare Regulations (PDF)

The current law revises the original law passed in 1966 by incorporating the amendments passed in 1970, 1976, 1985 – Improved Standards for Laboratory Animals Act, 1990 – Protection of Pets, 2002, 2007 – Animal Fighting Prohibition Enforcement Act, and 2008. Text of Original Law:  Animal Welfare Act of August 24, 1966

Legislative History of the Animal Welfare Act: Table of Contents AWIC Resource Series No. 41 September 2007 (updated June 2014)

CODIFIED IN

US Code, Title 7 The Animal Welfare Act (Title 7, U.S. Code), as written and approved by Congress, emphasizes minimizing pain and distress:

Section 13(a)(3)(B)”that the principal investigator consider alternatives to any procedure likely to produce pain or distress in an experimental animal;”

Federal Register 9CFR Final rules published in the Federal Register regarding changes to the Animal Welfare regulations. Final Rules: Animal Welfare; 9 CFR Parts 1 and 2. Federal Register, Vol. 54, No. 168, August 31, 1989, P. 36112-36163 Final Rule: Animal Welfare; Standards; 9 CFR Part 3. Federal Register, Vol. 55, No. 32, February 15, 1991, P. 6426-6505

It suggests a series of databases that can be searched to document whether or not alternatives are available:

“The principal investigator must provide a written narrative of the sources, such as biological abstracts, MEDLINE, the Current Research Information Service (CRIS), and the Animal Welfare Information Center that is operated by the National Agricultural Library. We believe that in fulfilling this requirement Committee members will discuss these efforts with the principal investigator in reviewing the proposed activity. We also believe that considerations of alternatives will be discussed during Committee meetings where proposed activities are presented for approval, and made part of the meeting minutes…”

“[The] IACUC shall determine that… The principal investigator has considered alternatives to procedures that may cause more than momentary or slight pain or distress to the animals, and has provided a written narrative description of the methods and sources used to determine that alternatives were not available”

FEDERALLY REGULATED BY

USDA

Animal Care Policy Manual USDA. APHIS. Animal Care. October 2015 The policy manual gives policies issued by APHIS/Animal Care that clarify the Animal Welfare Act regulations for the USDA Inspectors.

Policy #11: Painful and Distressful Procedures A painful procedure is defined as “any procedure that would reasonably be expected to cause more than slight or momentary pain or distress in a human being to which that procedure is applied, that is, pain in excess of that caused by injections or other minor procedures”. The Institutional Animal Care and Use Committee (IACUC) is responsible for ensuring that investigators have avoided or minimized discomfort, distress and pain to the animals; appropriately considered alternatives to any procedures that may cause more than slight or momentary pain or distress; and consulted with the attending veterinarian in the planning of the procedures…

Policy #12: Consideration of Alternatives to Painful / Distressful Procedures The Animal Welfare Act (AWA) regulations require principal investigators to consider alternatives to procedures that may cause more than momentary or slight pain or distress to the animals and provide a written narrative of the methods used and sources consulted to determine the availability of alternatives, including refinements, reductions, and replacements.

“…When a database search is the primary means of meeting this requirement, the narrative should include:    1. the name(s) of the databases searched (one database is seldom adequate);    2. the date the search was performed;    3. the time period covered by the search;    4. the search strategy (including scientifically relevant terminology) 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.

…Significant changes are subject to prior review by the IACUC. If those changes include a painful or distressful procedure, a consideration of alternatives or a revision of the prior search may be required

Reduction, replacement, and refinement must be addressed, not just animal replacement…”

https://www.aphis.usda.gov/animal_welfare/downloads/Animal-Care-Inspection-Guide.pdfAnimal Care Inspection Guide USDA. APHIS. Animal Care.  February 2015

“The purpose of the Animal Care Inspection Guide is to provide APHIS Animal Care personnel an aid for inspecting USDA licensed and registered facilities. The Inspection Guide will serve as a useful tool to improve the quality and uniformity of inspections, documentation, and enforcement of the Animal Care Program. The Inspection Guide does not supersede the AWA, the AWA Regulations and Standards, the Inspection Requirements Handbook, standard procedures, or the inspector’s professional judgment.  The Inspection Guide is designed to facilitate the decision-making process. It cannot -nor is it intended to -replace the inspector’s professional judgment.”

AC Inspection Guide search: 18 instances of “alternatives” including:

“5.1.3: Examples of citations: Example 1: Protocol #XXXX involves a surgical procedure for 5 adult cats that will cause more than momentary pain and there is no documentation in the protocol that a search for alternatives was conducted.”

“Appendix 4: Animal Care and Use Review IACUC must make a determination as to whether the procedure could potentially cause more than slight or momentary pain or distress. If so, the investigator must search for alternatives to all the procedures in that study that may cause pain or distress.”

“Appendix 8.6: IACUC Protocol Review Protocol must contain and comply…  pain/distress/discomfort are minimized [2.31(d)(1)(i) &2.31(e)(4)]…  contain a complete description of procedures designed toassure that pain/distress/discomfort are minimized[2.31(e)(4)]…”

“Protocols with procedures that may cause pain or distress must meet the following requirements:

the principal investigator(s) has considered alternatives to the painful/distressful procedure [2.31(d)(1)(ii)]    NOTE: Refinement and reduction as well as replacement should be considered in minimizing pain and distress.

for electronic database searches: a written narrative describing the methods and sources used to determine that alternatives were not available, including, but not limited to: [2.31(d)(1)(ii), Policy #12]    date of the search    databases searched    years covered by the search    search strategy(s) used

for non-electronic searches: a written narrative describing the methods and sources used to determine that alternatives were not available, including, but not limited to:[2.31(d)(1)(ii), Policy #12]    years covered by search    search strategy(s) used    sources consulted, including, if applicable: reliable unpublished research data; expert consultation (list credentials)”

“Food and/or Water Deprivation or Restriction When reviewing protocols involving food and/or water deprivation or restriction, some areas to pay special attention to include, but are not limited to: if the animals are likely to experience distress, the principal investigator has considered alternatives to the distressful procedures an alternatives search, if done, was properly conducted and reviewed for possible alternatives to procedures that may cause more than momentary pain or distress”

“Teaching Protocols When reviewing teaching protocols, some areas to pay special attention to include, but are not limited to:

• the justification for the number of animals to be used was appropriate, such as the number of students per animal and procedures needed to be learned

• a consideration of alternatives for procedures that might cause more than momentary pain or distress was properly conducted and reviewed for possible alternative procedures, such as, the use of: veterinary mannequins, live tissue alternatives, mechanical teaching devices

• there is a complete description of the procedures to be used

• if the teaching procedures cause more than momentary or slight pain or distress, proper methods are used to alleviate the pain/distress”

“Appendix 8.7 Inspection Protocol Review 09/10 9.8.7.5

Specific Types of Protocols Painful/Distressful Procedures When reviewing protocols involving procedures that cause more than momentary or slight pain/distress/discomfort (Protocols in Categories D & E), some areas to pay special attention to include, but are not limited to:

• the principal investigator has considered alternatives to the painful/distressful procedure

• there is a detailed narrative describing the methods and sources used to determine that no alternatives to thepainful/distressful procedure are available

• measures used to alleviate the pain/distress are clearly stated, including:  drugs, dosages, and frequency of administration”

Federal Register 9CFR
Final Rules: Animal Welfare; 9 CFR Parts 1 and 2. Federal Register, Vol. 54, No. 168, August 31, 1989, P. 36112-36163

“…The Committee would be required to obtain written assurances from the principal investigator that alternative procedures were considered and that the experiment was not unnecessarily duplicative (initial proposal Sec. 2.35(b)(3)(iii)-(v))…”

“…Under the final rule, research facilities are allowed flexibility in devising their own internal procedures for principal investigators to follow in preparing their written assurance. As stated above, we believe that the Committee will explore the efforts underlying the assurance with the principal investigator to determine whether a reasonable good faith effort was made by the principal investigator in determining that a proposed experiment is not unnecessarily duplicative…”

“…In response to public concern for laboratory animal care and treatment, the 1985 amendments to the Act imposed restrictions on the use of animals so that pain and distress will be minimized whenever possible, alternatives to painful procedures will be considered and unnecessary duplication of experiments avoided, withholding of pain-relieving drugs will be limited to when scientifically justified, and adequate veterinary care will be provided. ..”

Title 7 US Code. Pub. L. 99–198, title XVII, subtitle F (§§1751–1759), §1751, Dec. 23, 1985, 99 Stat. 1645

“…(3) measures which eliminate or minimize the unnecessary duplication of experiments on animals can result in more productive use of Federal funds…”

AC Policy Manual
“duplic” does not appear in the October 2015 Policy Manuay  (it was in the previous version of Policy 12 but was removed in 2011).

AC Inspection Guide
“duplic” appears twice in the September 2013 Inspection Guide , pages 7-20 and 7-21:

“IACUC Protocol Review
The IACUC must review all protocols and significant changes to approved
protocols. [2.31, Policy #11, Policy #12, and Policy #14] …

…Contain a written assurance from the principal investigator that the
proposed activities do not unnecessarily duplicate previous experiments
[2.31(d)(1)(iii), see ]…”

“duplic” appears:

p.25-26 Protocol Review
“…The animal use protocol is a detailed description of the proposed use of laboratory animals. The following topics should be considered in the preparation of the protocol by the researcher and its review by the IACUC: …

unnecessary duplication of experiments…

…While the responsibility for scientific merit review normally lies outside the IACUC, the committee members should evaluate scientific elements of the protocol as they relate to the welfare and use of the animals. For example, hypothesis testing, sample size, group numbers, and adequacy of controls can relate directly to the prevention of unnecessary animal use or duplication of experiments. For some IACUC questions, input from outside experts may be advisable or necessary. In the absence of evidence of a formal scientific merit review, the IACUC may consider conducting or requesting such a review (Mann and Prentice 2004). IACUC members named in protocols or who have other conflicts must recuse themselves from decisions concerning these protocols….”

Health Research Extension Act of 1985 Principles for the Utilization & Care of Vertebrate Animals Used in Testing, Research, & Training PHS Policy on Humane Care and Use of Laboratory Animals Animal Welfare Assurance Guide for the Care and Use of Laboratory Animals

Health Research Extension Act of 1985

“Sect.495: The proper treatment of animals while being used in such research. Guidelines under this paragraph shall require-   “(A) the appropriate use of tranquilizers, analgesics, anesthetics, paralytics, and euthanasia for animals in such research; and   “(B) appropriate pre-surgical and post-surgical veterinary medical and nursing care for animals in such research.”

and

“(1) assurances satisfactory to the Director of NIH that-   “(B) scientists, animal technicians, and other personnel involved with animal care, treatment, and use by the applicant have available to them instruction or training in the humane practice of animal maintenance and experimentation, and the concept, availability, and use of research or testing methods that limit the use of animals or limit animal distress;”

U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training

“III. The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid results. Methods such as mathematical models, computer simulation, and in vitro biological systems should be considered.

1. Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals.
2. Procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia. Surgical or other painful procedures should not be performed on unanesthetized animals paralyzed by chemical agents.
3. Animals that would otherwise suffer severe or chronic pain or distress that cannot be relieved should be painlessly killed at the end of the procedure or, if appropriate, during the procedure.”

PHS Policy on Humane Care and Use of Laboratory Animal

“Implementation by Institutions

1. Review of PHS-conducted or supported research projects
2. In order to approve proposed research projects or proposed significant changes in ongoing research projects, the IACUC shall conduct a review of those components related to the care and use of animals and determine that the proposed research projects are in accordance with this Policy. In making this determination, the IACUC shall confirm that the research project will be conducted in accordance with the Animal Welfare Act insofar as it applies to the research project, and that the research project is consistent with the Guide unless acceptable justification for a departure is presented.  Further, the IACUC shall determine that the research project conforms with the institution’s Assurance and meets the following requirements:
3. Procedures with animals will avoid or minimize discomfort, distress, and pain to the animals, consistent with sound research design.
4. Procedures that may cause more than momentary or slight pain or distress to the animals will be performed with appropriate sedation, analgesia, or anesthesia, unless the procedure is justified for scientific reasons in writing by the investigator.
5. Animals that would otherwise experience severe or chronic pain or distress that cannot be relieved will be painlessly killed at the end of the procedure or, if appropriate, during the procedure.
6. The living conditions of animals will be appropriate for their species and contribute to their health and comfort. The housing, feeding, and nonmedical care of the animals will be directed by a veterinarian or other scientist trained and experienced in the proper care, handling, and use of the species being maintained or studied.”

“Implementation by PHS

1. Information required in applications-proposals for awards submitted to PHS
2. All Institutions

Applications and proposals (competing and non-competing) for awards submitted to PHS that involve the care and use of animals shall contain the following information:

1. rationale for involving animals, and for the appropriateness of the species and numbers used;
2. a complete description of the proposed use of the animals;
3. a description of procedures designed to assure that discomfort and injury to animals will be limited to that which is unavoidable in the conduct of scientifically valuable research, and that analgesic, anesthetic, and tranquilizing drugs will be used where indicated and appropriate to minimize discomfort and pain to animals;”

Guide for the Care and Use of Laboratory Animals

ILAR National Research Council of the National Academies

8th edition, 2011

APPENDICES | ADDITIONAL SELECTED REFERENCES | USE OF LABORATORY ANIMALS | Alternatives; Ethics and Welfare | pages 162-164

page 3 Applicability and Goals “…Throughout the Guide, scientists and institutions are encouraged to give careful and deliberate thought to the decision to use animals, taking into consideration the contribution that such use will make to new knowledge, ethical concerns, and the availability of alternatives to animal use (NRC 1992). A practical strategy for decision making, the “Three Rs” (Replacement, Reduction, and Refinement) approach, is discussed in more detail below. Institutions should use the recommendations in the Guide as a foundation for the development of a comprehensive animal care and use program and a process for continually improving this program…”

page 6 Engineering, Performance, and Practice Standards “…Engineering standard means a standard or guideline that specifies in detail a method, technology, or technique for achieving a desired outcome; it does not provide for modification in the event that acceptable alternative methods are available or unusual circumstances arise. Engineering standards are prescriptive and provide limited flexibility for implementation. However, an engineering standard can be useful to establish a baseline and is relatively easy to use in evaluating compliance…”

page 8 Must, Should and May “…Must indicates actions that the Committee for the Update of the Guide considers imperative and mandatory duty or requirement for providing humane animal care and use. Should indicates a strong recommendation for achieving a goal; however, the Committee recognizes that individual circumstances might justify an alternative strategy. May indicates a suggestion to be considered.

page12 Regulations, Policies and Principles “…The use of laboratory animals is governed by an interrelated, dynamic system of regulations, policies, guidelines, and procedures. The Guide takes into consideration regulatory requirements relevant to many US-based activities, including the Animal Welfare Regulations (USDA 1985; US Code, 42 USC § 289d) and the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS 2002). The use of the Guide by non-US entities also presumes adherence to all regulations relevant to the humane care and use of laboratory animals applicable in those locations. The Guide also takes into account the U.S. Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (IRAC 1985; see Appendix B) and endorses the following principles:

• consideration of alternatives (in vitro systems, computer simulations, and/or mathematical models) to reduce or replace the use of animals • design and performance of procedures on the basis of relevance to human or animal health, advancement of knowledge, or the good of society • use of appropriate species, quality, and number of animals • avoidance or minimization of discomfort, distress, and pain • use of appropriate sedation, analgesia, and anesthesia • establishment of humane endpoints • provision of adequate veterinary care • provision of appropriate animal transportation and husbandry directed and performed by qualified persons • conduct of experimentation on living animals exclusively by and/or under the close supervision of qualified and experienced personnel…”

page 25 Protocol Review “…The animal use protocol is a detailed description of the proposed use of laboratory animals. The following topics should be considered in the preparationof the protocol by the researcher and its review by the IACUC:

availability or appropriateness of the use of less invasive procedures, other species, isolated organ preparation, cell or tissue culture, or computer simulation (see Appendix A, Alternatives)…”

page 27 Special Considerations for IACUC Review “…Certain animal use protocols include procedures or approaches that require special consideration during the IACUC review process due to their potential for unrelieved pain or distress or other animal welfare concerns. The topics below are some of the most common requiring special IACUC consideration. For these and other areas the IACUC is obliged to weigh the objectives of the study against potential animal welfare concerns. By considering opportunities for refinement, the use of appropriate nonanimal alternatives, and the use of fewer animals, both the institution and the principal investigator (PI) can begin to address their shared obligations for humane animal care and use…”

page 27 Experimental and Humane Endpoints “…The experimental endpoint of a study occurs when the scientific aims and objectives have been reached. The humane endpoint is the point at which pain or distress in an experimental animal is prevented, terminated, or relieved. The use of humane endpoints contributes to refinement by providing an alternative to experimental endpoints that result in unrelieved or severe animal pain and distress, including death. The humane endpoint should be relevant and reliable (Hendriksen and Steen 2000; Olfert and Godson 2000; Sass 2000; Stokes 2002). For many invasive experiments, the experimental and humane endpoints are closely linked (Wallace 2000) and should be carefully considered during IACUC protocol review. While all studies should employ endpoints that are humane, studies that commonly require special consideration include those that involve tumor models, infectious diseases, vaccine challenge, pain modeling, trauma, production of monoclonal antibodies, assessment of toxicologic effects, organ or system failure, and models of cardio-vascular shock…”

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…”

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