Building Momentum: Lessons Learned from the 2003 ILAR International Conference

Hilton Klein

As a past chair of the ILAR International Committee, I thank you for the opportunity to speak on today’s topic, about building momentum and taking the opportunity to highlight lessons learned since the 2003 ILAR International Workshop on Science-Based Guidelines.

As responsible investigators using animals in research, you all realize the importance of the Guide for the Care and Use of Laboratory Animals and what it has done for us in the biomedical research community. It has been a significant document of very high impact since it came out in 1996. I doubt that the people on the committee foresaw that this would be a truly international document, but it has emerged as a global document that is used in many countries. It has been translated into at least 12 languages now and serves as the standard for biomedical research where animals are used in laboratories. So its longevity and its global utility have been very impressive.

I want to try to emphasize how dynamic and flexible a document it has been. If you look at the period from 1996 through 2008, you will see that the Guide has been very diverse in its applications. It has been used not only in many countries but also in many different types of research programs. It has been able to cover the complexities of biomedical research laboratories and the use of numerous animal species. It has served its purposes very, very well and been a very significant, dynamic, and diverse document.

It would be useful to review why we had the first workshop and provide a historical perspective. As the previous speaker mentioned, the need for more science behind our standards has been in progression over time, evolving to the point where we are today. In 2000 and 2001 when I was on the ILAR Council, there were preliminary discussions about whether or not there was a need for revising or changing the Guide in some fashion and whether doing anything was wise. The drafts of the European standards for animal care from the Council of Europe (COE) expert groups were newly released. A major concern was how



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Building Momentum: Lessons Learned from the 2003 ILAR International Conference Hilton Klein As a past chair of the ILAR International Committee, I thank you for the opportunity to speak on today’s topic, about building momentum and taking the opportunity to highlight lessons learned since the 2003 ILAR International Workshop on Science-Based Guidelines. As responsible investigators using animals in research, you all realize the importance of the Guide for the Care and Use of Laboratory Animals and what it has done for us in the biomedical research community. It has been a signifi- cant document of very high impact since it came out in 1996. I doubt that the people on the committee foresaw that this would be a truly international docu- ment, but it has emerged as a global document that is used in many countries. It has been translated into at least 12 languages now and serves as the standard for biomedical research where animals are used in laboratories. So its longevity and its global utility have been very impressive. I want to try to emphasize how dynamic and flexible a document it has been. If you look at the period from 1996 through 2008, you will see that the Guide has been very diverse in its applications. It has been used not only in many countries but also in many different types of research programs. It has been able to cover the complexities of biomedical research laboratories and the use of numerous animal species. It has served its purposes very, very well and been a very significant, dynamic, and diverse document. It would be useful to review why we had the first workshop and provide a historical perspective. As the previous speaker mentioned, the need for more science behind our standards has been in progression over time, evolving to the point where we are today. In 2000 and 2001 when I was on the ILAR Council, there were preliminary discussions about whether or not there was a need for revising or changing the Guide in some fashion and whether doing anything was wise. The drafts of the European standards for animal care from the Council of Europe (COE) expert groups were newly released. A major concern was how 15

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16 Animal Research in a Global Environment: Meeting the Challenges much influence the Council of Europe guidelines, Appendix A of ETS 123, would have on the global research community and how that document would drive the need for revisions to the Guide. The ILAR International Committee concluded that this was an important juncture where new COE guidelines and the need to revise the Guide now presented an opportunity where we should examine some of these issues. At the same time, many pharmaceutical companies, some academics, and certainly government agencies were performing research in international labora- tories and doing animal research on a global scale. I want to emphasize in a positive way that when we were doing studies in different laboratories in differ- ent countries with varying standards, the interpretation and the integrity of those studies came into question. Science appeared to offer the unifying solution. So these two issues—the European activities and what potentially was oc- curring in the United States and certainly in the global community—were driv- ers for examining the need to harmonize some of the standards and guidelines. There was some uncertainty about how to do this. The Council felt that it would be rational to convene a meeting and confer on what seemed to be a common lineage among all parties: science-based standards, which joined animal care and use with the research community. In other words, we were talking about science-based guidelines and a conference to bring together and harmonize di- rections among the different parties. We prepared a conference agenda that would explore and benchmark best practices not only on the regulatory side but also on the scientific side, covering the issues that drove a common understanding and some common guidelines for animal care and use. The conference was convened with a group of people from at least 13 different countries; they were scientific experts, veterinary medical experts, and people from the political administrations. The proceedings of the meeting, The Development of Science-Based Guidelines for Laboratory Animal Care and Use, was the final product published in 2003; it presents many of the scientific and regulatory issues discussed during the conference. The goal of the workshop was to look specifically at the conditions of laboratory animal care and the science behind it, and more importantly to look at the gaps in our understanding based on what appears in the scientific literature and encourage future research to close those gaps, so that we would have a good science-based understanding of what we were doing for the animals while also trying to help the research community conduct its research in a thoughtful and meaningful way. I will address some of the outcomes of the conference. After several days of discussion we were able to come to some concrete conclusions. One was that more scientific studies were needed to foster a better understanding of the best conditions for animals in the laboratory and to make sure that the research was conducted in the best possible manner. There were major gaps in our knowledge and the science behind animal care. We also came to a clear understanding—especially with representation from 13 different coun- tries—that this was not only an American problem but an international problem.

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Building Momentum: Lessons Learned from the 2003 ILAR Conference 17 There was variation in the interpretation, but this was a clear-cut conclusion. [It was also clear] that these gaps covered all species and all laboratories. Another realization that emerged from the meeting was that harmonization and working together were the best ways to share information, resources, and knowledge in order to elevate and unify and achieve cohesion for animal care and use programs on a global basis. It was also evident that harmonization needed to be better defined, because there was a great deal of discussion on what harmonization was and what it meant, and more importantly how to accomplish it. Moreover, based on many of the sidebar discussions, it was obvious that a lot more discussion and benchmarking were needed to define the problem. We had over 120 people at the conference and about 150 different opinions on how to do it. It was clear that we needed to address this with all the interested parties. The next step, to maintain momentum, was to have a focus group and seek the opinions of an international group in a more global setting. [This group met] in Berlin in 2005, as a satellite meeting to the 5th World Congress on Alterna- tives and Animals in the Life Sciences. Our first task was to look at the 2003 recommendations and outcomes and ensure that they were still valid, to seek suggestions for future research initiatives, [to consider] where we might do such research, and to identify potential funding sources to try to close gaps in our scientific knowledge. Last, the group aimed to set priorities for the research top- ics to be studied. One of the outcomes of the Berlin workshop was that we had more har- mony and certainly agreement that more scientific studies were needed and that we needed to make sure they addressed key species (I will return to that in a moment). For example, the topics included cage size and determining how im- portant that is and what, if any, scientific evidence existed that could be used as a driver for determining optimal cage sizes. Environmental enrichment was also identified as a very significant issue requiring more study. Particulars of housing conditions in the laboratory emerged as key points of study—e.g., lighting, tem- perature, humidity, number of air changes, sanitation, and the like. These were the topics identified as very important by the participants in the Berlin confer- ence. The priority topics were pain, enrichment, housing, and experimental pro- cedures. There also was recognition that training people to do the work, the de- sign and construction of facilities, and facilities operations were critical topics. The group also posed the question of how to condition and acclimate the ani- mals to get them “research-ready.” These topics all became the top priorities for the next series of workshops and discussions for the future. In 2006 the ILAR International Committee concluded that there should be another focus group to initiate discussion of the housing of animals in research laboratories and to look at scientific evidence in support of housing require- ments. A decision was made to focus only on the major species that constituted about 90% of the animals used in the laboratories and to examine this informa- tion on an international basis. Thus the decision was to focus on monkeys, dogs, and rodents. At this meeting, held in conjunction with the AALAS meeting in

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18 Animal Research in a Global Environment: Meeting the Challenges Salt Lake City, there was representation from different countries, including emerging-market countries like China and India. Many professional organiza- tions were also represented on an international basis. For nonhuman primates, the first point was that cage sizes vary and are important to consider from the perspective of what is needed for the well-being of the monkeys as well as for optimizing scientific outcomes. Almost everyone in that focus group supported group housing. They also recognized the need for environmental enrichment of these animals in a research setting and outlined evidence to support this need. However, while everyone agreed on the impor- tance of environmental enrichment, it was difficult for the group to reach con- sensus on exactly how that was defined. Even so, they all recognized that it had or could have a significant impact on experiments and could create scientific variability if it wasn’t done correctly. With regard to dogs, the group concluded that cage size guidelines varied greatly and needed focus. Most supported group housing. Environmental en- richment was thoroughly discussed, but there was not consensus about exactly how to do it. There was no clear-cut consensus on the value of exercise for dogs, but there was in-depth discussion and very vigorous and healthy debate. The same could be said for the discussions of rodents. It was clear that ro- dent housing varied greatly. Most favored group housing. It was felt that there was a need for more conclusive data and more scientific evidence, especially for the selection of the best bedding types, and whether or not there were benefits or risks associated with wire flooring. As with dogs and monkeys, the group recog- nized that experimental variations could arise from the wrong type of enrich- ment. Other presentations from the international side involved the following in- dividuals: Gilles Demers reviewed harmonization from the ICLAS perspective, David Anderson presented updates of Council of Europe initiatives and revi- sions, Margaret Rose presented Australian initiatives and how this system worked, and Judy MacArthur Clark gave perspectives on the impact of the Council of Europe and the EU regulations on the international community. Since then, in 2006 and 2007, the private sector has been working on glob- alization issues, evaluating the need for science-based guidelines for animal care and use. CHA (Cambridge Health Associates), a commercial organization in Boston, MA, funded fact-finding trips and the preparation of two detailed re- ports examining future trends in animal research in China and in India. These reports are available from CHA (www.chacorporate.com). Of the two, I believe the second, a very objective and fact-driven report, was an important milestone; it predicted very accurately more studies and research spending in those coun- tries. The data from the emerging-market countries must be as robust and have the same fidelity as what we now enjoy in order to make important decisions on medicines and vaccines from the private sector. In other words, their drug- discovery and drug-development data must have the same level of integrity and be well documented and proven through audit and regulatory agencies, espe- cially since the private sector is highly regulated.

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Building Momentum: Lessons Learned from the 2003 ILAR Conference 19 Movement of research activities to emerging-market countries places a clear emphasis on needs in the following areas:  more training and expertise;  high-quality animal facilities (the need for a well-controlled animal en- vironment became very important as a result of the findings in this report); and  consistent, high-quality animal diets, animal quality, colony health, and fundamentals such as high-quality water for use in animal studies. Some laboratories were described in the report as superb, but there were also laboratories that required improvement in the above areas. It was also clear from the report findings that there is a growing number of laboratories that could meet GLP and AAALAC standards for conducting animal studies. That is cause for optimism. Among other findings were [a projected] expansion in the number of labo- ratories doing animal research in these countries. Trend data indicate this is ac- curate. In several cases pharmaceutical companies are now building animal fa- cilities to conduct research in the countries reviewed in this report. Also underscored was the fact that several academic institutions either had or were developing cooperative agreements to conduct research in countries such as China, Indonesia, and India. Thus this is a very rapidly changing landscape and a trend for the future. The question is, How fast will the move be realized? Turning to other views in the context of global animal research and future trends: The NCRR Strategic Plan emphasizes these issues and the need for in- creased capacity in basic research, translational animal research, and clinical research. There will be an emphasis on minority institutions. The need for in- creased capacity is clearly stated in the NIH NCRR report (available at www.ncrr.nih.gov). It emphasizes also that there is a need for improving comparative medi- cine expertise as part of this infrastructure. It supports the development of more resources to safeguard animal health and welfare, emphasizing the need for bet- ter training of people and staff in these institutions, as well as supporting and sustaining the nonhuman primate centers. All are consistent themes globally. The report did make another important point: “This plan transcends geo- graphic boundaries and research disciplines.” That was very significant in the context of this conference. It demonstrates that the private and the public sectors are well aligned in strategy. The other point of the strategic plan was emphasis on the use of informat- ics and the sharing of information. This appears to be a wonderful opportunity for more training enabled by information and technology transfer. A final critical point is that this strategic plan emphasizes a need to maxi- mize partnerships and to get the most out of research investments by creating partnerships between the public and private sectors. Since so much of the private

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20 Animal Research in a Global Environment: Meeting the Challenges sector is now looking toward internationalizing its animal research, I am hopeful that this partnering will either directly or indirectly benefit from NIH and NCRR spending. We have described the historical perspectives and the drivers for science- based guidelines, the trends, and momentum gained so far. But I hope that, as we go through the conference today, it becomes even clearer that ILAR and the National Academies are uniquely positioned to help enable the development of a global infrastructure for animal-based research that is of the highest scientific quality and in which we use science-based guidelines. Science is the common language and currency that transcends country borders. Using high-quality sci- ence we can work more cooperatively and achieve better global standards of care. We must ensure that ILAR is viewed as a facilitator, in cooperation, cer- tainly, with other international organizations, such as AAALAC, IACLAM, ICLAS, FELASA, ACLAM, and ECLAM. In fact ILAR is well aligned and harmonized with these and other international organizations. Through such part- nering based on science-based guidelines, we can amplify our research budgets and be more effective in the way we spend those monies to get more out of the data from studies using animals. In summary, among the many lessons learned since we started the dia- logue on science-based guidelines—on how to share the best regulatory prac- tices and create the best guidelines and oversee the animal facility and the scien- tific research—is that the biomedical research community can work together very well and that we all seek the common goal of improving animal care and use and welfare in the scientific laboratory. That may have been obvious to a few, but I think it is becoming increasingly obvious to many. The other lessons: There still remains considerable debate on how to ac- complish this. We have close agreement on what we want to accomplish, be- cause of conferences like this one; however, we must illuminate how to more effectively use the existing scientific literature and identify scientific research we should develop and fund for the future to help guide improvements in animal welfare and fill the scientific gaps in our knowledge. Clearly, there is a need to conduct more research on specific areas of ani- mal care and use. There is also some urgency and important critical timing in the issues to be discussed. We are challenged to look forward to a more unified and cohesive harmonized set of animal care and use guidelines globally as a matter of routine. We are not there yet. [But] the opportunities, I think, are now clearer. We are a global economy. As countries like China, Indonesia, India, Korea, and Singapore further develop their biomedical research systems to meet medical needs—at about a 10–15% annual growth rate—the increase in biomedical research will also drive the in- crease in the use of animals in research. We must provide optimal care. Pharma- ceutical companies, academia, and the government are increasing the use of animal resource systems in these countries. The infrastructure across all coun-

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Building Momentum: Lessons Learned from the 2003 ILAR Conference 21 tries should be brought to higher standards as illustrated by the CHA report from 2007. Infrastructure needs, which are essential and in need of better scientific drivers and information behind them, as we know from the Guide, are: sanitation systems, animal health and quality, animal facilities, feed, bedding, water, and, most importantly, training of both technical and scientific/veterinary medical personnel for optimal animal care and use. I urge you over the next several days of the meeting to give thought to so- lutions to these questions and problems. The NCRR Strategic Plan has estab- lished a framework for partnering between the public and private sectors to share resources and information globally. Their plan gets at the how part of the question we raised. There is the question of where and what we should do to improve our scientific knowledge of laboratory animal science and animal wel- fare, and science and medical research, using what we have in the current litera- ture and doing critical literature reviews and applying them to setting scientifi- cally based standards, and seeking ways to fund new research to benefit the animals in the way we conduct science. In closing, I thank the ILAR International Committee for creating this ini- tiative for science-based animal care standards, and Dr. Joanne Zurlo and her staff for making this possible. I also thank the [Workshop Steering] Committee for asking me to speak today.

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