Why search for alternatives?
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..."
Why search for alternatives? AWA | USDA
BASED ON THE
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)
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
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..."
Animal 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"
"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
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"
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
Specific Types of Protocols
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"
What about "unnecessary duplication"?
"...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. .."
“...(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 ]..."
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...."
Why search for alternatives? AWA | PHS | NIH
"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."
"(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;"
"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.
IV. 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.
V. 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.
VI. 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."
"Implementation by Institutions
C. Review of PHS-conducted or supported research projects
1. 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:
a. Procedures with animals will avoid or minimize discomfort, distress, and pain to the animals, consistent with sound research design.
b. 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.
c. 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.
d. 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
D. Information required in applications-proposals for awards submitted to PHS
1. 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:
b. rationale for involving animals, and for the appropriateness of the species and numbers used;
c. a complete description of the proposed use of the animals;
d. 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;"
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..."
NIH OLAW PHS Links
"...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..."