Decision Making and the IACUC: Part 1—Protocol Information Discussed at Full-Committee Reviews

IACUC protocols can be reviewed by either the full committee or designated members. Both review methods use the principles of the 3 Rs (reduce, refine, replace) as the overarching paradigm, with federal regulations and policies providing more detailed guidance. The primary goal of this study was to determine the frequency of topics discussed by IACUC during full-committee reviews and whether the topics included those required for consideration by IACUC (for example, pain and distress, number of animals used, availability of alternatives, skill and experience of researchers). We recorded and transcribed 87 protocol discussions undergoing full-committee review at 10 academic institutions. Each transcript was coded to capture the key concepts of the discussion and analyzed for the frequency of the codes mentioned. Pain and distress was the code mentioned most often, followed by the specific procedures performed, the study design, and the completeness of the protocol form. Infrequently mentioned topics were alternatives to animal use or painful or distressful procedures, the importance of the research, and preliminary data. Not all of the topics required to be considered by the IACUC were openly discussed for all protocols, and many of the discussions were limited in their depth.

In the United States, most institutions that perform research with laboratory animals are required to have an IACUC. The primary purpose of the IACUC is to help assure animal welfare through compliance with federal regulations and guidelines concerning the care and use of laboratory animals. Before any regulated animals can be used for research, teaching, or testing, investigators must receive approval of their proposed projects from their institution's IACUC.

Two federal departments oversee IACUC activities: the Department of Agriculture and the Department of Health and Human Services. Health and Human Services, through its Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy), 56 oversees compliance with guidelines developed under the authority of the Health Research Extension Act of 1985. 19 That Act governs the use of all vertebrate animals in research, research training, or testing that is funded by the PHS. In contrast, the USDA, which has its own IACUC regulations developed under the auspices of the Animal Welfare Act (AWA) 1 regulates only some of the warm-blooded species used in biomedical research. Nevertheless, institutions that are required to have an IACUC typically have only one such committee to oversee compliance with both federal departments. The methods and requirements for reviewing proposed research projects are nearly the same for both departments.

The large number of animals used in research raises some ethical issues by itself. In 2014, of approximately $21 billion awarded by the NIH for extramural research grants, nearly half of those dollars involved the use of laboratory animals. 33 The precise number of animals used for biomedical and behavioral research in the United States is unknown due to the exclusion of common laboratory rats and mice from the USDA annual census report on laboratory animal usage, but estimates exceeding 25 million per year are common. Of other regulated mammals, approximately 953,000 were used for research and teaching in 2012. 50

An IACUC reviews proposals from personnel at its home institution (for example, a university) who desire to use animals in their research or teaching. The IACUC then makes a decision to approve the proposed animal use, to require modifications or clarifications so that approval might be granted, or to withhold approval of a proposal for animal use. To help the IACUC during its decision-making process, the committee bases its actions on the aforementioned federal laws, regulations, and guidelines governing animal use and the IACUC. However, studies have revealed that federal laws, regulations, and policies are only a starting point for the decisions IACUC must make. Entering into the decision-making equation are personal opinions regarding the perceived importance of a study, 12,44 beliefs about animal use, 12,18,22,25,35,36 the amount of harm the animals will experience, 23,41 the species involved, 38,44,46,47 and many other factors, including the phylogenetic position of the species proposed for use, the perceived applicability of the results to humans, the presence or absence of prior peer review of the study, whether the reviewer knows the investigator, the likelihood of experimental success, and the gender of the reviewer. 12,20,35,37,38,46,48

If the IACUC is to make a decision during a meeting that the members can endorse, the members must have access to sufficient and factual information about the proposed animal-use protocol. The primary goal of this aspect of our research was to discern the verbal information that IACUC members received (or did not receive) during a full-committee review discussion of an animal-use protocol and whether that information included the topics required for IACUC consideration. These required topics are found in the PHS Policy (IV,C, 1), 56 the Guide for the Care and Use of Laboratory Animals (the Guide, p 12), 26 the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (US Government Principles), 57 and the AWA regulations (AWAR, §2.31,d,1; §2.31,e; §2.32; §2.33). 2 The required topics for IACUC consideration are:

1) The reduction of harm to the animal (for example, considering methods to alleviate pain or distress; the euthanasia method; the study endpoint; providing adequate medical and surgical care to the animals);

Materials and Methods

We included 10 academic biomedical research institutions from among the top 50 of NIH grant- and contract-dollar recipients in this prospective study. We divided the 50 institutions into 5 groups (top 10 NIH funded, second 10, and so forth) and selected 4 institutions from each group that represented diversity in their geographic locations. We then contacted those 20 institutions; 18 of them agreed to participate. To help maintain study site anonymity, only 10 of the 18 were chosen for data acquisition. The choice of which 10 institutions to include was made on the basis of the geographic location of the institution and the compatibility of its IACUC meeting dates with the travel availability of our observer. All sites were visited between April and December 2011. The institutions represented the east (3 sites), west (2 sites), north (1 site), south (2 sites), and central (2 sites) United States. First, each site was provided with an overview of our planned research, including its aims, data collection and analysis methods, and the procedures used to assure the confidentiality of all involved persons and their research. All participants were asked for their written consent to be audiorecorded. We included only research-intensive institutions performing biomedical research in an effort to limit the genre of research as a potential confounding variable when interpreting our data. All of the studies reviewed by the IACUC used common laboratory animals (primarily mice but also rats and NHP).

One author (JC), an experienced interviewer and researcher, collected the data. He used a semistructured interview script to interview the chairperson, attending veterinarian, and primary IACUC staff person (data not included in this report) prior to the meetings. At the full-committee meetings of the IACUC (the data from which are the focus of this paper), he did not participate other than to ensure that the recorder functioned and to track the sequence in which participants spoke, to facilitate transcription.

We evaluated a maximum of 10 protocol discussions from each institution and, because of the importance of pain and distress in IACUC considerations, we included only those protocols categorized by the participating institution as indicating that more than slight or momentary pain or distress was likely. When the institution's IACUC agenda was finalized, its IACUC office provided us with protocol information that contained the pain–distress categorization, the species proposed for use, the title of the study, and whether it was a wholly new submission, resubmission, or amendment. We did not know whether the initial pain–distress categorization was made by the IACUC office, the investigator, or a reviewer. All institutions classified pain for all species by using the USDA pain classification (AWAR §2.36) 2 or a minor modification thereof.

In total, 87 protocol discussions (10 each at sites A, B, G, H, I, and J; 9 at site C; 7 at site D; 6 at site F; and 5 at site E) were evaluated. These involved 51 new applications, 14 amendments, 15 renewals, 6 resubmissions from an earlier review, and 1 teaching protocol. The composition of the 10 committees at the time of our visits included 10 chairpersons, 10 attending veterinarians, 8 community members (3 were not present at the time of the meetings, and one site had 2 community members), and 109 other voting committee members. The last group included scientists with experience in research using animals, members with a primary interest in nonscientific areas, additional veterinarians, and others. In addition, there were 36 nonvoting IACUC staff members and 14 nonvoting veterinarians who attended the meetings. The number (mean ± 1 SD) of IACUC members and nonmembers that attended a meeting was 18.7 ± 5.5 people, with a range of 13 to 31 people.

Except as noted, the comments of all meeting participants are summarized in this report, because any person at the meeting, not only IACUC members, potentially could have influenced the ultimate decisions of an IACUC. Every site had nonvoting attendees at the meetings; however, only at site I did researchers whose studies were being reviewed attend and participate at its meeting. These researchers’ comments were not included in this report because inclusion would bias the results more than would exclusion. One committee member declined to be audiotaped; that person's comments (11 speaking turns) were redacted from the transcripts.

The study was approved by the University of Massachusetts Medical School Institutional Review Board.

Meeting structure.

The present report contains information gathered during full-committee reviews at one IACUC meeting at each of the 10 institutions visited. According to federal mandate, a full-committee review occurs when a quorum of IACUC members meets to discuss and vote on research or teaching protocols and any related IACUC business. Nonmembers can also be present and comment but are nonvoting. Typically, the IACUC chairperson designates 1 or 2 committee members to be the primary reviewers of a proposed research study even when the entire committee has access to the protocol prior to the meeting. These reviewers present a synopsis of the study under consideration, along with their opinions of the strengths and weaknesses of the project. The Chair asks for any additional discussion from the members; when the discussion is complete, the Chair requests a vote on the acceptability of the study. All persons at all of the meetings we observed had access, by means of a printout or screen projection of the protocol, to every protocol under discussion.

Data collection and management.

We made encrypted audiorecordings of the entire IACUC meeting at each study site. Encrypted data were returned to the University of Massachusetts Medical School, unencrypted, transcribed, and the original recordings were deleted. The observer redacted any information that might identify a person, protocol, or study site. The role of the person speaking on the transcription (for example, chairperson, attending veterinarian) was identified through notes taken by the observer who was present for the entire meeting.

Coding.

The coding system for this study was developed for mixed-methods research by the investigators and was based on the general methodologies used in other studies. 5,31,32 We reviewed the transcripts of 2 meetings to decide on the initial codes that would capture the content of the discussions. We then attempted to apply these codes to other meetings and refined them until we were comfortable that we had covered all of the relevant topics. Two researchers then independently coded several transcripts until agreement was reached, and additional rules for coding were developed to facilitate that agreement. Finally, agreement was tested and coding was refined until an acceptable κ level (0.64) was achieved. One coder then completed the coding, with periodic reviews with the other coder. The coding process involved reading each of the 87 protocol discussion transcripts and assigning topic codes (for example, pain and distress) to each speaking turn (that is, everything one speaker said until he or she stopped speaking and another person began speaking). Because more than one topic can be discussed during a single speaking turn, multiple topic codes can be assigned to a speaking turn. Likewise, when the same topic code (such as pain and distress) was mentioned more than once during a single speaking turn, it was considered to be a single ‘mention’ of that topic. For example, during a speaking turn, a person might have said, “In my opinion, this study has the potential for causing significant pain to the pigs,” and, during the same speaking turn, might have said, “I'm concerned about the dose of analgesic being proposed.” We would treat this speaking turn as including one mention of the topic code of ‘species’ (due to the mention of pigs) and only one mention of the topic code of ‘pain and distress,’ even though the speaker commented twice on the topic of pain (significant pain; dose of analgesic) during the speaking turn. This method greatly increases the reliability of the coding, because the units to be coded are predefined. In previous research with a similar data set, analyses of word counts associated with a topic yielded very similar results. 32

Our review of the transcripts revealed that some IACUC used ‘humane endpoints’ and ‘euthanasia’ as synonymous terms. Therefore, for our analyses, we combined all such mentions into a single larger code, animal death. This code also incorporated the use of death as a study endpoint and unanticipated animal deaths. Likewise, we initially believed that we would be able to separate the societal benefit of the research from the scientific importance of the study. However, once we evaluated the data, we recognized that such differentiation was infeasible, and we therefore combined these 2 related topics into a single code, importance of the research.

All coded mentions were entered into a commercial online software program (Dedoose, Hermosa Beach, CA) for ease of data organization, manipulation, and analysis. Additional data analyses were conducted by using the SAS statistical package, version 9.3 (SAS Institute, Cary, NC).

Additional review.

The number of mentions arising from the transcripts of the individual meetings did not provide us with information about a topic's context. For example, we could not discern solely from the number of mentions about pain or distress whether analgesia was discussed at all or whether there was a thorough discussion about the proposed method of pain alleviation. To obtain context information for the data, we reassessed the transcripts of 72 protocol discussions (we excluded the amendment discussions and one highly abbreviated discussion) to determine whether the presenter provided sufficient information or whether a spontaneous cogent discussion occurred on the topics required for IACUC consideration. Because such a determination is subjective and requires broad experience working the IACUC, the determination of the quality of the discussion was the sole decision and opinion of the first author (JS), who has extensive experience with IACUC reviews. The general criterion applied was to accept even minimally useful information as being sufficient information that could lead to further discussion. For example, when the presenter of the protocol informed those present of the specific drug proposed to be used for analgesia, this information was considered to be sufficient to initiate further discussion about analgesia or other aspects of pain and distress, if the members chose to do so. However, when a presenter indicated that an investigator had listed all of the drugs and dosages to be used during the study (not only those used for analgesia) without any additional detail, that information was not considered to be sufficient to initiate further discussion about analgesia or other aspects of pain and distress.

Results

Frequency of topics mentioned during full-committee review of protocols.

As noted in the Introduction, our primary goal was to determine the frequency of discussion topics and whether the topics mandated for IACUC consideration in fact were discussed at the full committee review meeting. Although the specific procedure to be performed was a frequently discussed topic ( Table 1 ), we did not consider that the simple mention of a research procedure (such as an ovariectomy) was a mandated responsibility of the IACUC. However, some of the details of certain procedures (for example, pain alleviation, using an appropriate study endpoint) are mandated for IACUC consideration.

Table 1.

Protocol-relevant codes used and frequency of mentions within each code at 10 institutions

The analysis revealed a total of 5632 ‘mentions’ of protocol-relevant codes, including those mandated and not mandated to be considered by the IACUC. Tables 2 through ​ through5 5 show the total number of mentions of all codes by study site, and Table 1 shows the frequency, mean, median, and range with which each of the codes were mentioned across all 10 sites. The largest number of mentions (816, 14.5%) was the code for pain or distress. The second highest number of mentions (13.7%) was associated with a specific procedure that was proposed to be performed (for example, an ovariectomy, an intravenous injection), and the third most-frequent mention (11.7%) pertained to the design of the study. The fewest mentions were in the codes of preliminary data (0.5%), alternatives to animal use (0.5%), and the importance of the proposed research (0.8%). Some large differences between sites emerged. For example, whereas pain or distress received the most mentions overall, this subject was the seventh most-frequently mentioned topic at site F ( Table 4 ; 5.3% of all coded mentions from that site), falling well behind the same site's leading mentions, which were the procedures to be performed, the technical experience of research personnel, and the study design. Similarly, although the species proposed for use was an infrequently raised topic at most of the meetings, at site D ( Table 3 ), this topic received the largest number of mentions.

Table 2.

Number, percentage, and rank of code mentions by study site, all sites combined and sites A and B

Table 3.

Number, percentage, and rank of code mentions by study site, sites C, D, and E

Table 4.

Number, percentage, and rank of code mentions by study site, sites F, G, and H

Table 5.

Number, percentage, and rank of code mentions by study site, sites I and J

The following results and subsequent discussion are focused on the previously noted mandated topics for IACUC consideration.

Pain or distress.

When we reviewed the number of mentions about pain or distress that were linked to each of the 87 protocols we evaluated, we found that at least one mention was made during the discussion of 75 (86%) of those protocols. The pain or distress likely to be experienced by an animal during the performance of a protocol received the first or second most mentions at 7 of the 10 study sites and overall generated the most mentions (14.5%) of any protocol review category ( Tables 1 and ​ and2). 2 ). However, the mere mentioning of pain or distress did not always translate into a minimally effective discussion of the topics. Of the 72 protocol discussions that were reassessed, 61 clearly involved substantial pain or distress to the animals, but only 40 of those 61 transcripts (66%) included at least a minimally focused discussion about pain or distress. The remaining 21 studies simply did not engender an open discussion of how pain or distress would be addressed during the study.

Animal death.

Animal death was mentioned at least once in 54 of the 87 protocol discussions (62%). The general topic of animal death received 543 mentions (9.6%). Overall, animal death was the fifth most-mentioned category.

Animal health and welfare.

Animal health and welfare (for example, medical care)—excluding the more specific topics of pain and distress, animal death, and basic husbandry—was mentioned at least once in 44 of the 87 protocol discussions (50.6%). It was the sixth most-often mentioned category (5% of all mentions), but this figure was heavily influenced by just 2 protocols (from 2 different sites) that accounted for nearly a third of those mentions.

Importance of the research.

This topic was mentioned at least once in 30 of the 87 protocol discussions (34.5%). The topic included the societal benefit of the research and the importance of the scientific question being asked. For most individual IACUC, this combined topic was at or near the bottom in terms of frequency of mention, and in only one IACUC (site D, Table 3 ) did it elicit more than 4% of the items mentioned.

Alternatives.

Alternatives to painful or distressful procedures, or alternatives to animal use, were mentioned at least once in only 13 of the 87 protocols studied (14.9%). Overall, the topic accounted for only 0.5% of all mentions. In addition, comments about alternatives were at or near the low end of the number of mentions made by each IACUC. In the 72 protocols reassessed for depth of discussion, only 3 were judged to have a focused discussion on the use of alternatives.

Skill and experience of the research team (including training).

Overall, skill and experience was mentioned at least once in 39 of the 87 protocols studied (44.8%). The skill and experience of the research team accounted for 6.4% of all coded comments made by all IACUC. Nevertheless, it was the second most-discussed topic at site F ( Table 4 ), where there were 80 mentions about the experience of a research team on one of the protocols reviewed at that site. Of the 72 protocols reassessed for depth of discussion, only 9 such discussions were found.

Species justification.

A mention of the justification for the species to be used occurred at least once in 55 of the 87 protocol discussions (63.2%). This topic was the most mentioned item at only one site (site D, 20.2% of that site's comments), and that finding resulted from a high percentage of mentions about species justification (mice and NHP) in 2 of the 7 protocols reviewed from that site. In other IACUC, the number of mentions about the justification for using a particular species tended to fall in the middle or toward the low end regarding the frequency of mentions by those IACUC (range, 1 to 53 mentions per site, Table 1 ). Overall, species justification constituted just fewer than 3% of all mentions, and a detailed discussion of the topic occurred for only 3 protocols.

Animal number justification.

There were 47 protocol discussions (54%) where a justification for the number of animals to be used was mentioned at least once. Overall, comments about statistical evaluations and animal numbers constituted only 5.3% of all mentions made, with a range of 0 to 78 mentions per site. Significant discussion about the justification for the proposed number of animals was found in 22 (31%) of the 72 reevaluated transcripts.

Experimental duplication.

None of the 10 IACUC mentioned the possible duplication of experiments; therefore this potential code is not shown in the tables.

Discussion

This study of 10 IACUC determined the frequency of topics discussed during full-committee reviews and whether the topics required for consideration by IACUC were part of those discussions. Pain and distress was the most often-mentioned topic, whereas preliminary data received the fewest mentions. Not all of the topics required to be considered by IACUC were discussed during full-committee review, and many of the discussions of required topics were limited in their depth.

The decisions made by an IACUC have been characterized as a moral judgment pertaining to the use of animals. 12 There is, without doubt, great truth to that statement, even though a reviewer's judgment can reflect influences such as self-interest, protection of the interests of other animal users, 25,45,49,54 a lack of understanding about the ubiquity of pain and distress among sentient animals, 25,48 and many additional factors. The general principles for animal use in research are guided by the well-known 3 Rs of research: 43 to reduce the number of sentient animals used to the minimum needed; refine experimental techniques to reduce pain or distress to animals; and replace the use of sentient animals with insentient species or nonliving systems. Our analysis focuses primarily on items that fall under the umbrella of the 3 Rs and that are required by federal regulation for review consideration.

We limited our study to protocols involving pain or distress; therefore, we expected that this topic would be mentioned often. However, other studies that had no such limitation confirm the high priority given by IACUC to pain and distress. 8,12,13,17,44 In addition, given the responsibility of the IACUC to limit pain and distress whenever possible (AWAR §2.31,d,1; PHS Policy IV,C,1) 2,56 and given the personal familiarity that humans have with pain and distress, it is not surprising that this topic frequently arose at full-committee review discussions. In addition, the determination of appropriate experimental endpoints and the choice of euthanasia methods can affect the pain or distress experienced by an animal, and that topic also received many mentions from the IACUC in the current study ( Table 1 ).

Scientists have a special interest and training for understanding experimental designs and the procedures that are used in biomedical research. Scientists who use animals in their research, which often includes the IACUC chairperson, have heavy representation on many IACUC. 15,45 We therefore anticipated that specific , ‘hands-on’ procedures (such as intracranial injection) would be mentioned frequently. Indeed, a specific procedure was the second most-often mentioned code ( Table 1 ). One of the IACUC's responsibilities is to evaluate the aspects of the study design and specific procedures that might result in pain or other forms of distress to animals. These factors can greatly influence the harm–benefit analysis (described in next paragraph). Our subjective impression was that the large amount of time the IACUC spent discussing specific procedures and the experimental design was focused primarily on enhancing the wellbeing of the animals.

In recent years, IACUC have increasingly been urged to evaluate the importance of a planned animal use project (that is, its scientific, clinical, or educational merit) in relation to any pain or distress that the study might cause to an animal (that is, its ethical cost). This bipartite evaluation often is termed a ‘harm–benefit analysis,’ and it can be useful in helping to decide whether the planned research is justified, whether it can be improved to decrease harms to the animal or increase the benefits, or whether the harms are so great that no benefits could justify their use. 24 Depending on the study, harms can include pain, disease, prolonged restraint, withholding of food or water, and so forth.

In a nationwide survey of IACUC chairpersons in the United States, approximately 55% stated that their committees required their members to provide at least a cursory review of a proposed study's scientific merit, even when there had been external review by a peer group. 30 A study of 3 United States IACUC found that most IACUC members believed scientific merit should be assessed carefully when more than slight pain was anticipated, but there was no direct discussion of the ethical cost to the animals. 13 In Canada, the guidelines of the Canadian Council on Animal Care 4 emphasize consideration of the 3 Rs, and other authors found that aspects of an ethical evaluation (such as those related to the 3 Rs) constituted about 16% of the 4641 comments that they coded from 163 Canadian IACUC protocols. 21 In Europe, the European Directive requires “a harm–benefit analysis of the project, to assess whether the harm to the animals in terms of suffering, pain, and distress is justified by the expected outcome, taking into account ethical considerations, and may ultimately benefit human beings, animals, or the environment.” 9 Although the Guide 26 (p 27) states that for some protocols (for example, those including unalleviated pain) “the IACUC is obliged to weigh the objectives of the study against potential animal welfare concerns,” no definitive statement is found in United States laws or regulations that is analogous to that in the European Directive. This absence is the most likely reason for the lack of any specific harm–benefit analysis by any of the IACUC in our study. Nevertheless, the NIH's Office of Laboratory Animal Welfare has written that “. . . the IACUC is expected to include consideration of the US Government Principles in its review of protocols. Principle 2 calls for an evaluation of the relevance of a procedure to human or animal health, the advancement of knowledge, or the good of society. Other PHS Policy review criteria refer to sound research design, rationale for involving animals, and scientifically valuable research. Presumably a study that could not meet these basic criteria is inherently unnecessary and wasteful and, therefore, not justifiable.” 34

An IACUC, therefore, should provide at least a limited evaluation of the proposed research in terms of a harm–benefit justification and perhaps require in-depth evaluation when a proposed study does not undergo formal external peer review, as might happen with an internally funded study at a university. But do harm–benefit analyses actually happen, or are IACUC discussions focused more on the technical aspects of the proposed research, such as providing the correct dose of an analgesic or the appropriate preparation of an animal for surgery? One investigator 7,8 studied 32 United States IACUC and found that only 9 had comments about a study's potential value to society (that is, scientific merit) on the protocol form. Our present study similarly suggests that a specific harm–benefit consideration is not a significant component of United States IACUC discussions, given that we found that only scientific benefits were mentioned (less than 1% of all mentions made and those mentions came from 30 of the 87 protocols we studied). One suggested reason for not routinely including a harm–benefit analysis was that the scientific experts on IACUC-type committees have de facto power over the committees’ agenda and therefore the discussions focus on technical issues—the forte of scientists—rather than ethical ones. 25 Furthermore, performing a harm–benefit analysis is a complex issue, 25,46 and reaching a consensus can be quite difficult. Consequently, “[a harm–benefit analysis] becomes a nonissue in the committee.” 25

One author 25 believes that the single issue that all members can agree on is how to minimize the suffering of animals. Her view is that IACUC believe they can find solutions to minimize animal distress based on the technical aspects of the study; therefore an IACUC often can readily agree on a humane or other study endpoint without worrying whether the study has sufficient scientific importance to involve the use of live animals. This view is supported by other previous work 54 and our present study, both of which indicate a comparatively low frequency of specific discussions about the scientific merit of a planned study but much more frequent discussion on the study design and performing specific procedures in an effective and humane manner. Another colleague offers that “most of us lack the ability—and the desire—to make sophisticated cost-benefit calculations. Instead of insisting on finding the best possible decision, we will often accept one that seems good enough.” 53 One group backs this opinion by stating that scientists “may define animal welfare in accordance with their particular ethical positions but not in accordance with other widely held and defensible positions.” 11 Still others have commented on the lack of ethical review by U.S. IACUC, 6,16,40,46,52 with one researcher 16 stating that “IACUC have restricted themselves to technical or advisory roles focused on reworking the details of some animal-use protocols, but ultimately approving almost all of them.”

There is no uniform international agreement on how to balance the benefit of the research against the harm to animals. For IACUC to perform a harm–benefit analysis, the first challenge will be to develop or accept a working definition of what is (or is not) scientifically important. The subsequent challenge for IACUC will be to develop a different but related metric, that is, a usable harm–benefit analysis. Several groups 9,39,51 have proposed methods for performing such an analysis.

Another required function of the IACUC is to assure that investigators have considered alternatives to painful or distressful procedures (AWAR §2.31,d,1,ii) 2 and methods that use nonanimal systems or less sentient species 26,55,57 These considerations include alternatives such as in vitro studies, epidemiology, computer simulations, the use of clinical studies, and similar modalities. They also include the use of presumably less-sentient species (for example, insects instead of mammals) when the use of live animals cannot be avoided. Mentions of alternatives were at or near the lowest number of mentions by all IACUC in our study. A similar finding emerged from a study of Swedish animal ethics committees. 14 In other studies, only 19 of 32 United States IACUC commented on replacement (including the investigator's rejection of nonanimal alternatives), 8 and in Canada only 1.8% of more than 4600 comments from IACUC involved the concept of replacement. 21 A study of 3 United States university IACUC reported that 76% of respondents agreed that alternatives should be discussed for every protocol. 13 We do not know whether that actually occurred at those schools.

If a valid alternative does exist, then some colleagues believe that performing the experiment with animals is ethically unacceptable. 51 Although we are in general agreement with that viewpoint, finding a published alternative to live animal use in biomedical research is not easy, 49 unless the alternative has already attained widespread use. Given that most biomedical researchers are generally knowledgeable of the literature in their own field and that little is reported in the available literature (including online databases) about the use of alternatives in biomedical research, it is perhaps not surprising that a search for alternatives received little mention at the IACUC meetings we studied.

Assuming an alternative to live animal use is unavailable, the number of mentions about investigators justifying the animal species to be used is of interest because US Government Principle 3 requires the use of an appropriate species, 57 the Guide 26 endorses US Government Principle 3, and the AWA (§2.31,e,2) requires the investigator to provide the IACUC with a rationale for the species proposed to be used. 2 Overall, mentions of the species to be used (including its moral or scientific importance) constituted only 3.0% of all mentions. According to one report, 50% of the IACUC studied commented at least once on the species to be used. 8

Only 6.4% of all mentions addressed the skill and experience of the research team. This important topic was mentioned at least once in only 44% of full-committee reviews and was discussed in some depth in 9 of the 72 protocol discussions we reassessed. We previously reported that 89% of all IACUC members were of the opinion that animal users at their institution had adequate skills to perform the procedures described in their protocols. 49 Therefore, it is pertinent to ask, How does an IACUC assesses research-relevant skills? And, as a corollary, How important are research-relevant skills? Merely asking this question may seem unusual, given that performing skilled surgery, animal handling, injections, and related research procedures would appear to be an obvious technical requirement. Furthermore, there are federal regulations and policies supporting its importance. Yet, if the importance is high but there is limited discussion of the topic at multiple IACUC full-committee reviews, the answer to the question about the importance of skill and experience becomes less clear.

We turn our attention, then, to the first question: How does an IACUC assess research relevant skills? A veterinary anesthesiologist said to one of the authors (JS), “Show me the incision, and I'll tell you who did the surgery,” indicating the importance of technical skills. Procedure repetition, whether in surgery or more basic skills (such as blood collection), is an important criterion for success in the medical arena, 27-29 and research indicates that poorly performing veterinary and medical students tend to overestimate their own technical abilities. 42 This finding may hold true for animal users as well, but can we expect an IACUC to evaluate the technical abilities of a person during the time it takes to review a protocol, which in one study was reported to range from as little as 4 to as many as 150 min? 45 Many IACUC do try to make such an assessment before and after a protocol is approved by reading the investigator's written description of the skill and experience of the research team, hands-on testing of persons working with animals, observations of ongoing procedures, postapproval monitoring, and other means, but simply stated, there are no generally accepted methods for preemptively assessing the proficiency of the many technicians, graduate students, postdoctoral scholars, and principal investigators who are performing multitudes of different procedures on animals. Consequently, the previously mentioned opinion on harm–benefit decisions 25 may also hold true for skill and experience. That is, it is easier for an IACUC to try to assure humane animal use by focusing more of the discussion on the technical aspects of how a procedure will be performed rather than on the competency of the person performing the procedure.

We found that mentions about the number of animals to be used (reduction) 43 comprised about 5% of all mentions: 54% of the 87 protocol discussions we reviewed mentioned animal numbers at least once. Another study found that 62% of IACUC that reviewed the same 4 protocols made at least one comment on the number of animals to be used. 8 Other authors 45 reported that there was an emphasis on sample size rather than experimental design, and some members felt unqualified to judge the requested numbers of animals when reviewing protocols outside of their own area of expertise. These same members believed that the biomedical researcher was best qualified to select appropriate animal numbers. A different study 10 found that most researchers were more concerned with obtaining quality data than with using fewer animals. In fact, many indicated that they already had reduced animal use as much as possible.

IACUC eventually approve almost all of the protocols presented to them. This is not surprising, given that IACUC infrequently have the full responsibility for evaluating the scientific merit of proposed research and subsequently the committees can focus most of their efforts on providing thorough reviews to assure animal welfare. As part of its deliberations, we believe that the IACUC has the responsibility to evaluate a research proposal by using the principles of the 3 Rs as the overarching paradigm, with existing federal regulations providing additional and more specific guidance. The findings from our current study suggest that all of the topics that are required to be considered by IACUC under federal regulations and guidelines were not discussed for all protocols at full-committee reviews, and when some of these topics were discussed, the number of mentions was quite limited and often did not lead to a cogent, useful discussion. These findings do not imply that all federally required topics for consideration are not being considered by the primary reviewers; they may have been considered and deemed to be adequately addressed in the written protocol and not in need of bringing to the attention of the members at the meeting or, in the case of rereviewed protocols, may have been discussed previously. With full-committee review, having a presentation by 1 or 2 primary protocol reviewers followed by an IACUC discussion of the protocol meets the intent and requirement of existing federal regulations and guidelines, particularly when an investigator's final protocol submission includes responses to previously raised questions from one or more reviewers. Under that circumstance, it can be contended that the IACUC should devote its full-committee review discussion to any remaining concerns of the reviewer or other committee members. However, this view can be debated, given that the primary reviewer may not be conscientious, lacks expertise in key protocol topics, or is selective regarding the information provided to the other IACUC members.

We do not disparage the aforementioned perspective regarding reviewing protocols, nor do we suggest that fewer mentions of a topic equates to inferior consideration of that topic, given that the depth of review can vary with the protocol under consideration. Yet, in light of our current findings, we believe a more valuable full-committee review will occur when each of the topics that are mandated for the IACUC to consider are addressed, even if briefly, during full-committee review discussions. For example, if having 10 mice in each study group is part of a protocol and the primary reviewer is satisfied with n = 10, should the full committee be informed of the investigator's rationale for using n = 10 and why the reviewer concurs that 10 mice per group is appropriate? If providing this additional information leads to additional discussion, then this form of intragroup collaboration can potentially have a significant effect on animal welfare for “even if most people within a group are not especially well-informed or rational, it can still reach a collectively wise decision.” 53

Several colleagues 41,54 have emphasized the need for having sufficient information when reviewing animal studies, writing that “. . . a committee structure or authorization practice that does not request sufficient information on animal suffering and research relevance runs the risk of institutionalizing deficient application scrutiny.” 41 We believe that under the typical working conditions of a full-committee review, wherein every member does not read every protocol on the agenda, a protocol discussion can be optimized when the primary reviewer provides committee members with reasonably comprehensive information about the protocol under consideration.

Acknowledgments

This study was supported by grant 5R21RR031900-02 from the NIH.