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National Research Council (US) Institute for Laboratory Animal Research. Animal Research in a Global Environment: Meeting the Challenges: Proceedings of the November 2008 International Workshop. Washington (DC): National Academies Press (US); 2011.

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Animal Research in a Global Environment: Meeting the Challenges: Proceedings of the November 2008 International Workshop.

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International Coordination of Nonhuman Primates

Framing the Issues

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We are entering a very exciting era indeed of discovery in nonhuman primate (NHP) research, which I will illustrate with a few points.

The emphasis on translational research during Elias Zerhouni’s tenure as director of NIH has certainly stimulated interest in the pathway connecting basic science to human health, not only in the direction of basic to human but also taking information from human clinical work back to animal models and to the bench. NHP research does not represent a wayside in this highway but rather is often an essential vehicle in the process of transferring information from one end of the spectrum to the other.

A second point worth mentioning is that the genome of several NHP species has now been sequenced, with more to come soon. The -omics associated with this are developing very rapidly. The study of genes, proteins, and biochemical reactions in complex primate organisms is enormously exciting at this time.

Being from the University of Wisconsin in Madison, I am personally very excited about the potential application of embryonic stem cells and induced pluripotent cells to alleviate human disease. [But] before transplant therapies can be applied in humans, a great deal of work must be done in nonhuman primate models.

Much work also needs to be done in the realm of vaccine development for HIV, flu, and other viral diseases. The HIV vaccine summit last spring pointed to the need to step back from clinical trials and redouble efforts using NHP models, which will, of course, increase the demand on our animal resources.

Finally, the development of informatics and information technology systems now can enable better organization, management, and sharing of data and dissemination of new knowledge from these studies. This is contributing to the overall excitement in the field.

This era must be enabled by careful consideration of several issues and overcoming current obstacles. The identification of appropriate species and the supply of these species need careful attention. Identifying sources of animals of specific species, characterizing these animals in terms of genetics and their backgrounds, and ensuring quality control in terms of viral status are all important issues for animal health, human occupational safety, and efficient use of these animals in studies.

Forecasting needs must be done in terms of not only species but also the important characteristics: age and sex. To emphasize the age aspect, in studying diseases of aging and processes of aging in rhesus monkeys, we must keep in mind that it takes 25 to 30 years to grow an aged rhesus monkey. That fact is sometimes lost in discussions of supply-and-demand issues. One cannot make short-term shifts in trajectories in managing the supply of nonhuman primates.

Deliberate action pertaining to identifying needs and careful management of primate resources along these lines constitutes refinement, in itself, and will enable achievement of research goals with fewer animals in the long run. It will also lead to financial economy in this endeavor.

Given the globalization of the effort in primate research, and the practicalities of the work, such as transportation of animals and biological materials, it is increasingly important that we consider local, national, and international policies and politics. The next presentations will address many of these points.

Supply and Use of NHP Around the World

The United States

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My presentation will focus on the use and numbers of nonhuman primates (NHP) in research in the United States. To determine these numbers it was necessary to visit a lot of regulatory agencies—including the CDC, USDA, and NCRR/NIH (for chimpanzee data)—and Indonesia. The bottom line is that it is very difficult to quantify this in any meaningful sort of way. It seems that nobody really has the number of nonhuman primates that are used in research. In addition, different organizations and agencies count these numbers in different ways.

In some instances, it was necessary to go to the animal rights groups or to Wikipedia to find out numbers. After averaging all the numbers, the total is approximately 70,000 to 75,000 nonhuman primates each year, and that includes all types of use, whether they are being bred or held or actually used in research.

The CDC has 27 different registered NHP importers in the United States (information provided with the assistance of Bob Mullan and Gail Galland). In the early days of this field, there were over 100 importers of NHP, suggesting that greater regulation has resulted in fewer animals being imported. It is interesting to note that nearly half of these importers are commercial importers, with the rest scattered among zoos and academic institutions.

CDC has requirements for licensing a facility. All NHP are required to stay in a federally registered quarantine for at least 31 days before they can be transferred to another institution. Most institutions quarantine them for a longer period of time.

One of the confounding regulations was the requirement for records on these primates as they moved from the initial importing institution to other institutions. The importing institution has to document whether the animals are being held for scientific, exhibition, research, or educational use and that wherever they send the animals will likewise register in the same category. The intent is to keep these animals out of the pet trade. The CDC inspects facilities, reviews import plans, monitors arriving shipments, assesses disease control measures, reviews animal health records, and investigates illness reports.

The data on NHP importation from 1994 to 2007 show a continual increase. In 2005 to 2007, the last three years for which data are available, the number rose to over 25,000 or 26,000 primates per year being brought into this country. This suggests a greater use of nonhuman primates in the United States. If the data are broken down further one finds that over 93% of imported NHP are Macaca fascicularis, or cynomolgus; 5% are M. mulatta, or rhesus, probably from China. The rest are scattered among other species.

If one looks at the data by importer, each importer brought in from one to over 10,000 animals, with the number of shipments per importer ranging from one to 70 a year. A significant statistic is the percentage of dead-on-arrivals: zero to 0.2%, which is very low. This is a huge improvement from many years ago when a 10% to 15% mortality rate was considered good. Reportable illnesses are very low now as well.

Looking at the importation data further, 60% of these animals are coming from China, followed by Vietnam and Mauritius. Over 85% of the animals are coming from three countries.

NIH (through NCRR) supports eight national primate research centers, which collectively contain almost 28,000 nonhuman primates, with the majority being rhesus monkeys. It becomes clear that it is the rhesus monkey that is used in research, not M. fascicularis (cynomolgus). Cynomolgus monkeys are used by commercial industries, pharmaceutical industries, or CROs for toxicology, efficacy, safety, and pharmacodynamics.

NCRR is moving toward the development of so-called specific pathogen–free colonies, which consist primarily of rhesus colonies, M. mulatta. Those colonies are primarily SPF-4, meaning they are free of SIV, STLB, SRV, and herpes B. There are other colonies called “superclean” that have even more viruses eliminated, such as cytomegalovirus, foamy virus, and perhaps others. At this point, roughly 5,000 rhesus monkeys in SPF-4 colonies are being produced for research by investigators throughout the country. There are plans in the national primate research centers program to create even more SPF colonies in the years to come.

The major types of research conducted at the primate centers are AIDS and other infectious diseases: these account for over 40% of research activity. Neurobiology research is also prevalent, at almost 20% of activity, and various other areas make up the rest.

Many specialized resources emerge from primate center programs. Perhaps one of the more important ones is the NHP tissue program, from which over 42,000 primate tissue samples, organs, genetic samples, cells, fluids, and more are supplied to investigators throughout the nation and internationally.

USDA annual reports provided information about how many primates were in use in registered facilities throughout the United States. There are roughly 46,000 or so NHP listed in these reports, either in column B (used for breeding) or columns C and D (used in research, in situations where there is no pain, momentary pain, or pain alleviated with analgesia). Interestingly there were no reports of animals in column E (unrelieved pain and/or distress). This is difficult to understand since there are clearly projects going on at various facilities that fall under column E.

In summary, based on these and the previous data, an estimated 70,000 to 75,000 primates are used in research.

Now I will address the use of chimpanzees, and I would like to acknowledge the contribution of Tom Butler for the information I will share with you. The most important thing about chimps is that they share roughly 98.5% of their DNA with humans. Therein lies both the benefit and the curse of the issue of chimps in research, and there are many different thoughts about whether or not they should be used for this purpose.

Using chimps means increased expense due to the need for larger cages, larger facilities, stronger people, and more educated people. Six centers in the United States maintain chimpanzees: the Southwest Foundation for Biomedical Research (San Antonio, TX), Michale Keeling Center for Comparative Medicine (Bastrop, TX), New Iberia Research Center (Louisiana), Yerkes Primate Center (Atlanta, GA), Primate Foundation of Arizona (Mesa), and Alamogordo Primate Facility (New Mexico). All but the last two conduct research on chimpanzees.

The population of chimpanzees is continually declining.1 From the latter part of 2006 to the first part of 2007, there was a decline of nearly 100 animals or almost 10% of the chimp population. The population has been declining primarily for health-related reasons. Another consideration is that about half of the animals are owned or subsidized in part by the federal government, which traditionally does not make these chimps available for research by private industry.

A key factor is animal age. The desirable age for chimps in many research projects is roughly up to 21 years of age, which is about the time health problems begin developing, particularly cardiovascular problems. As of 2008, only about half of the US chimp population was below the age of 21, further accentuating the declining usable numbers of chimps for research. Given the current rate of decline, the number of chimps for research will be close to zero by the year 2030. While age can exclude chimpanzees from use in research, other factors to consider in choosing animals include behavioral characteristics, health status, experimental history, and current research.

So there are very few chimps available for research in the United States. Yet there are those who insist that the chimpanzee is the only animal that can be used specifically for pharmacodynamics in a way that the human is used, to test monoclonal antibodies. Many of these monoclonal antibodies cannot be tested in other warm-blooded mammals or in other NHP species because they are eliminated very rapidly. The chimp is the only animal that processes these monoclonals in a way that they can be tested.

Vaccine development is another huge concern in considering research on chimpanzees. The chimpanzee was integral to development of the hepatitis B vaccine and is used to make improvements in it. In addition, it is the only known animal model for hepatitis C and is being used in attempts to develop a hepatitis C vaccine. However, it should be noted that in the early days of AIDS researchers thought chimps would be extremely valuable, but that was not the case.

In terms of emerging infectious diseases, many scientists feel strongly that the chimpanzee should not be allowed to disappear from the US research scene. Some argue that it would be foolhardy to let the chimp population disappear and then need the animals again for future critical research.

In 1997 the National Research Council published a report that set the stage for the future of chimps with regard to breeding (Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use). The breeding ban for chimps in federally funded facilities continues today. The report also recommended that euthanasia not be allowed for population control. Along with this, there was a suggestion that a national chimpanzee sanctuary facility be created; Chimp Haven, in Shreveport, Louisiana, took in its first animals in 2005 and now houses about 110 chimps in retirement. Although the NRC report recommended that there be 1,000 chimps available to meet current research needs, there would need to be 60 births per year. With the federal ban on breeding, there are only about 15 births per year at privately held facilities. Because the population of chimps is aging, it seems certain that the numbers will continually decline. In addition, most chimps have been used for experiments, so there will be virtually no naïve animals for future studies.

In the last part of my presentation, I would like to highlight Indonesia, a typical exporting country for NHP. Most people in the United States are unaware of Indonesia, yet it is the fourth-most populous country in the world, made up of 13,000-plus islands, and home to numerous species of nonhuman primates, including vast numbers of Macaca fascicularis. Much of the following information was obtained from the Indonesian quarantine group, which is responsible for export.

Between 2004 and 2007, there was a rapid increase in the numbers of nonhuman primates exported. Most have been going to China, which is rapidly becoming the giant in terms of NHP use as well as NHP export to the United States and other countries. In China, and to a lesser extent in Indonesia, primate centers and research centers are being built. These countries will no longer want to supply NHP to the US and other countries as they will want to develop research enterprises in their own countries. Many people from those countries have been educated in the United States and Europe and are beginning to feel ready to do research back home.

For example, the Bogor Primate Research Center in Indonesia has the capacity for many major types of research procedures, including those that involve ABSL-3 facilities. Many cutting-edge research projects are ongoing in conjunction with laboratories in that country. The center has virology labs that are as large and as well equipped as those in the United States. This is happening because the Indonesian government and others have invested money and training and now they are prepared to undertake research projects on their own. These types of activities are occurring in many other countries of origin of NHP. These countries are very capable and they are looking to increase these activities.

I will conclude by explaining why there is an increase in NHP exportation. Breeding colonies are developing everywhere in Indonesia because new laws prohibit the exportation of feral animals. Countries of origin such as Indonesia, China, India, and others will be requesting outsourcing of research from the United States.

In summary, obtaining accurate numbers of NHP used in research is difficult at best, but the trend is increasing, not decreasing. The need for research using chimpanzees remains controversial, but they will continue to be used at least in the short term.

I would like to thank Bob Mullan and Gail Galland from CDC, John Harding from NCRR and NIH, Tom Butler for giving me the chimp data, Joko Pamungkas and others from the Bogor Primate Center and the quarantine division of the Indonesian governments, and Pam Ferguson and Patti Rosendahl from Paris NHP.

China as a Resource for NHP

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In this presentation I will highlight how big the Chinese nonhuman primate (NHP) production capability is, the quality of the animals, animal welfare considerations, and how the animals are exported worldwide.

China has been a leading and major supplier country for NHP, not only to the United States but to Europe, Japan, and now to Korea. The numbers of NHP used by various countries in 2002 and estimated for 2007 are 52,000 and 59,000, respectively, by the US1; 4,000 and 5,000 by France2; 3,000 and 4,000 by the UK3; 2,000 and 3,000 by Germany4; 2,000 and 3,000 by Canada5; and 3,000 and 5,000 by Japan.6,7 China has also been exporting NHP to the Netherlands and Spain and, particularly in recent years, has been exporting macaques to Canada.

If one looks at the total number of the macaques imported into the US in 2006–2007, the number was higher in 2006.8 In 2007, 27,000 macaques were imported, of which cynomolgus constituted 93% and rhesus only about 5%. Based on the data from Asia that Dr. Morton presented, almost 25,000 NHP were imported from Asia, representing 93% of the total NHP imports worldwide to the United States for research use.

Specifically looking at China over the past two years, in 2006 the US imported about 11,000 cynomolgus monkeys and about 1,400 rhesus, and in 2007 about 15,000 cynomolgus and 1,350 rhesus.9 As a clarification, cynomolgus monkeys are not native to China. They have come into China from various countries in Asia. Of the cynomolgus monkeys imported in the US from Asia in 2007, 68% are from China compared to 13% from Mauritius. Imports from Cambodia, Indonesia, and the Philippines are rising.

In the past two to three years, Chinese breeders have imported a large number of cynomolgus monkeys from Cambodia. The Chinese government exerts tight control and either restricts or approves the process. For example, in order to import 2,000 or so of the animals by charter from Cambodia to China, it is necessary to acquire an import permit, which usually takes about six months. During this process, the government, both local and central, sends representatives to a region or supply farm for inspection. They check on the number and quality of the animals and whether they are wild-caught or purpose- bred animals.

In the past three years, China has increased the number of breeders. All the primate breeding facilities must obtain a license for production of the nonhuman primates through the Bureau of Wildlife Protection and Conservation in the central government. They must also be approved by a similar office in the provincial government. The government does not allow breeders to sell their animals for up to six years from the start of the facility. Many want to know how many NHP facilities there are in China. There are 32 “qualified” facilities in China, meaning that the facilities are monitored for the number of animals and their quality. Of these facilities, in 2008 23 of them were able to sell/export cynomolgus monkeys and 16 of them rhesus. Some of the facilities engage in cynomolgus monkey breeding only, some of them have both cynomolgus and rhesus, and some of them breed only rhesus monkeys.

Among the 32 NHP facilities half of them are large, meaning they have over 10,000 animals. Some of them are medium-sized or small, with 5,000 to 9,000 animals.

The number of the facilities has been increasing because there is a perceived increasing demand for macaques and particularly for cynomolgus monkeys.

China has a commercial quota system. Toward the end of each year, the Bureau of Wildlife Conservation and Protection as well as the provincial government and an ad hoc committee visit each facility and count the animals in terms of how many young, the ages of the animals, and the total number of breeders. Based on this information, they assign each facility the number of animals allowed to be commercialized (i.e., exported or used domestically in research).

From 2006 to 2008, the quota for cynomolgus production and sale increased. The quota for rhesus increased only slightly and most of the large facilities are not involved in the breeding of rhesus monkeys now.

It should also be noted that most of the breeding facilities for cynomolgus monkeys are in the southern part of China, and facilities for rhesus monkeys are mostly in the central or western part of China.

The number of breeding females in the 32 facilities was obtained from each facility as well as from government data. In 2008 there were about 62,000 breeding cynomolgus monkeys and 8,600 breeding rhesus monkeys.

About 18,000 to 19,000 macaques are exported from China each year and the mortality rate is very low, on the order of 0.06% in 2007. Transportation of NHP has not presented any problems in China. Several airlines—Air China, China Eastern, China Southern, and Hainan Airline—are willing to transport the animals from China worldwide—to the United States, Europe, Japan, and Canada. Since many of the animals come from the south of China, they are shipped from Guangzhou Airport. Animals are also shipped from Shanghai and Beijing. The major receiving airport in the US is Los Angeles, with the second being New York (JFK and Newark). Chicago and Seattle airports also receive animals. Thus, transport of nonhuman primates to worldwide places from China is not a problem.

In looking at the practices related to supply and quality of NHP in China, it usually takes about 2–3 months to obtain the commercial quota as discussed earlier. There is also a quarantine program that is very similar to that in the US for animals to be exported. The quarantine process lasts from 1½ to 2 months, during which the animals must receive three TB tests at two-week intervals and are also tested for various viral, bacterial, and parasitic diseases. China has very good diagnostic methods in terms of simian immunodeficiency virus (SIV) and B virus. However, since the US has the Virus Reference Laboratory (VRL), the viral status of animals imported into the US will be confirmed by the VRL. The animals receive vaccinations for measles and hepatitis A prior to export. Finally, each animal receives a certificate of health by the Provincial Administration of Quality Supervision, Inspection, and Quarantine (AQSIQ). Since 2007, the vast majority—about 90%—of animals are virus free. They also can be vaccinated upon request.

One issue I would like to address is the concern that China is not concerned about animal welfare. In fact, China has five regulations related to welfare of laboratory animals.10 Violation of certain of these regulations carries a penalty.11

New World Primates in Research

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By way of definition, New World monkeys and neotropical primates are the same thing and comprise primates that are indigenous to the Americas. There are four main genera of New World monkeys that are used in research: squirrel monkeys (Saimiri spp.), owl monkeys (Aotus spp.), marmosets (Callithrix jacchus), and tamarins (Saguinus mystax).

New World monkeys are used in virtually all the same ways as the Old World monkeys in biomedical research. They are used for discovery research and for preclinical research. It is essential to draw a distinction between the two [types of research], because the vast majority of primates that are imported are used for preclinical studies, safety, and efficacy studies.

Discovery research focuses on discovering something new, something previously unknown, and is typically investigator-driven research funded by the NIH. Preclinical research focuses on verifying what was learned in discovery research under the highly controlled GLP conditions that are required by the FDA or equivalent regulatory bodies in Europe. Both types of research contribute to the translational science that we talk about in the United States—from bench to bedside.

Genomic comparisons are often used as a rationale for why primates are important for certain kinds of research into human disease. New World monkeys and Old World monkeys share approximately 92% and 94%, respectively, of DNA with humans. Chimpanzees, of course, are even closer, sharing over 98%.

Among the squirrel monkeys (genus Saimiri), three species or subspecies are used in research, primarily in the United States. Saimiri sciureus sciureus is the common squirrel monkey and the one most frequently imported to the United States; S. boliviensis boliviensis, the Bolivian squirrel monkey, and S. boliviensis peruviensis, the Peruvian squirrel monkey, are also used for research. Three species of owl monkeys are used in research: Aotus nancymaae, A. vociferans, and A. azarae. Marmosets (Callithrix jacchus) are used in Europe more than in the United States, but there are several colonies around the country: one at the Wisconsin National Primate Research Center, one at the Southwest National Primate Research Center, and a small colony at the New England Primate Research Center. Tamarins are used probably the least of the four genera, and Saguinus mystax is the most commonly used one in the United States.

Bolivian squirrel monkeys are no longer available through importation due to bans in the country of origin—Bolivia no longer exports squirrel monkeys, so we are not likely to get more of these. Bolivian squirrel monkeys have been very useful in malaria research because they are susceptible to falciparum malaria and Plasmodium vivax. They have also been used in prion disease work, the transmissible spongiform encephalopathies. Squirrel monkeys are susceptible to every prion disease with which they have been infected, including wasting disease of deer, which is a growing problem in the United States. If one looks at lesions from brains with sporadic and variant Creutzfeldt-Jakob disease (CJD), there is a little difference in the lesion. In sporadic CJD there is a generalized spongiform change. In the variant form of the disease, which is thought to have come from eating contaminated beef from animals that had bovine spongiform encephalopathy, the lesion creates a rosette around accumulations of abnormal prion protein. Squirrel monkeys develop these lesions and they look virtually identical to those seen in humans.

Owl monkeys have been used for malaria research, pathogenesis, and vaccine development work with malaria. In our colony we have seen a high prevalence of cardiomyopathies and the sequelae to chronic hypertension. These animals exhibit aortic aneurisms and hypertrophic cardiomyopathy. In the end stages of the disease they develop chronic heart failure, and instead of the heart pumping it just appears to vibrate—the contractility of the heart is virtually gone. This is, as far as we know, the only spontaneous or naturally occurring chronic severe hypertension model in a primate species.

Marmosets have been used for a number of studies of obesity, metabolic syndrome, aging, and reproductive biology. They are valued in reproductive biology because about 80% of these animals produce dizygotic twins, which share the same placenta, so there is a very high prevalence of chimerism.

Tamarins were very important in the development of hepatitis A vaccine. They are susceptible to GB virus B, which is closely related to hepatitis C virus.

In the United States there are three sources of New World monkeys. One is through importation. Second is through an agreement between the Pan American Health Organization (PAHO) and NIH through the Peruvian Primatology Project to provide small numbers of New World monkeys to NIH and through NIH to others that need them for research; not very many animals are imported that way, but it is a source. Then finally, animals can be obtained from the Center for Neotropical Primate Research and Resources at the University of Texas M.D. Anderson Cancer Center, and specifically at the Michale Keeling Center for Comparative Medicine. The Center for Neotropical Primate Research and Resources is supported through two grants from NCRR, one for squirrel monkeys and one for owl monkeys.

To obtain specific information about importation of these species, I went to the CITES1 database and looked up importation data over a 5-year period, from 2002 to 2006. Of all the species, squirrel monkeys are the most commonly imported around the world. Between 2002 and 2006 over 4,000 monkeys were exported to North America and almost 3,000 to other regions of the world.

Looking at the number of squirrel monkeys imported into the United States by year from 1997 to 2006, the highest number was in 2002 (>500); in most years it averaged between 200 and 300 a year. These numbers do not take into account animals procured from domestic colonies, and do include research colonies at institutions around the country.

Owl monkeys imported to the United States have come from two countries, Argentina (Aotus azarae) and Peru (A. vociferans and A. nancymaae). Virtually all of these animals have been used for malaria research.

Animals supplied through the Center for Neotropical Primate Research and Resources have been primarily squirrel monkeys. The owl monkey resource, for which funding began in 2004, has begun to grow, but as with all breeding resources of primates, it takes years to develop them.

To determine the types of research done in various species of NHP, I queried the CRISP database.2 Macaques are by far the most frequently used NHP, with over 650 grants/contracts in 2008 citing their use. About 40 grants this year cite the use of the squirrel monkeys, 15 cite owl monkeys, and 6 cite marmosets. One must be careful in interpreting these numbers because they only reflect NIH extramural research and do not take into account NHP used by the Department of Defense, which used many, as well as the Food and Drug Administration and the Centers for Disease Control and Prevention.

The intramural research program of NIH also uses primates, and they use more macaques than any other genus of primates. However, the NIH Office of Animal Care and Use provided information that imports through PAHO from 2002 to 2006 totaled 230 owl monkeys and 68 squirrel monkeys.

To try to bring it into perspective, New World monkeys are valuable for several key diseases. The owl monkey is an emerging model for cardiovascular disease and chronic hypertension. In the United States in 2008, an anticipated 400,000 people will die from cardiovascular disease. Looking worldwide of course it will be far, far greater.

These animals have been used extensively for malaria research. While not of foremost importance in the United States, malaria remains one of the most devastating diseases worldwide. Mortality in 2008 is expected to be almost 3 million people, and 75% of those who die from malaria are women and children. Half of the children in Africa that die before the age of 5 die from complications from malaria.

Finally, these animals are important in studies of hepatitis B and C. Although there is now a vaccine for hepatitis B, these diseases remain a big problem. Tamarins were very important in the development of hepatitis A vaccine, and they may provide answers to some questions about hepatitis C. It is hard to determine numbers for the impact of hepatitis B and C worldwide, but it is probably on the order of 3 million or more people, and people who survive with hepatitis C for 25 years have a very, very high incidence of hepatocellular carcinoma and hepatomas. So it is also a risk factor in cancer.

I want to thank Jim Taylor, Don Bordine, and Alfie Caesar, who helped me with some numbers, as well as Larry Williams and Laura Zapalac in my department.

Challenges in Outsourcing Studies

An Academic Perspective

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A paradigm shift is beginning to occur with regard to academic collaborations across borders. Historically there has been a lot of collaboration between US academic institutions and those in the United Kingdom, Canada, and Europe. There was certainly a comfort zone in these interactions in terms of animal care and use regulations—they are not the same in each area, but clearly they functionally accomplished the same things.

More recently, countries such as China and India have the scientific and the physical infrastructure to perform cutting-edge science. With China as an example, there is technology developed there that is innovative and when attached to an NIH individual or program project application makes it very attractive for funding. So the academic agency has to determine how to best collaborate with this other institution. Unlike a CRO, it is not necessarily a choice of the institution but a choice of the research.

The problem is that our academic institutions do not have much experience with the local animal care and use regulations, especially in countries like China and India. Thus the two central questions that need to be considered are: Is the animal care and use being performed under reasonably appropriate conditions in a humane and ethical way? And are the resulting data of acceptable quality and integrity? There have been some recent updates in regulations regarding human clinical studies, which center on the last point and probably apply to animal studies as well.

In an academic institution, oftentimes most of the funding is predicated on the US Public Health Service (PHS). The following is a scenario outlining the institution’s responsibility when there is a PHS award with a foreign component. That foreign component is usually executed through a subaward or subcontract. A foreign component is defined as performing a significant element of the project outside the United States. It is performed either by the grantee or an individual working for the foreign institution, and funds do not necessarily change hands. For example, an investigator may be listed as key personnel under a grant. Even though the investigator might not be getting paid for it, it still can be a foreign component as long as there is a significant element in the work that is being performed for that project. So a foreign component involves human or animal subjects. It also includes what we would consider field studies, if somebody is going to a foreign site and collecting samples from animals. If the investigator is acting as a consultant, the institutions must grapple with that, because consultants are not included in the NIH foreign component entity.

Looking at the terms or conditions of a subaward or subcontract language related to animals, there are several points to consider. One is that the foreign entity must file a PHS assurance or provide evidence that acceptable standards for the humane care and use of animals will be met. All performance sites have to be operating under an assurance and there has to be verification of an IACUC approval. What does the foreign assurance entail? It is essentially a one-page document with three major components: a statement that the institution must comply with whatever the local regulations are; the institution needs to be guided by the International Guiding Principles for Biomedical Research Involving Animals issued by the Council for International Organizations of Medical Sciences (CIOMS), which are very similar to the US Government Principles; and the institution has to make a reasonable effort to ensure that the people doing the work understand the regulations and their responsibilities.

The foreign assurance is now in the process of revision. In contrast to a domestic assurance, the foreign assurance does not have a statement about the Animal Welfare Act, does not mention the need for accordance with the Guide for the Care and Use of Laboratory Animals, does not address lines of authority for administering a program, does not ask for the qualifications of the veterinarian, and does not have reporting requirements. The IACUC review, reporting and understanding the qualifications, falls to the primary recipient, which is the institution receiving the grant.

From an institutional perspective, the initial challenge is knowing that there is a grant with a foreign component. In an IACUC protocol, the investigator may forget to check the box for off-site research or may forget to indicate all the locations where the research will be done. There also may be some confusion as to whether the work being performed off-site has to be listed in the IACUC protocol.

The IACUC protocol is often one way to monitor off-site research, but the key is to ensure that your institution is doing a congruency review, i.e., certifying that what is in the grant matches the IACUC protocol. When doing a congruency review, the person reviewing the grant will see the subcontract including a description of the work and the justification for having it done off-site. The reviewer will determine whether there are procedures in the grant that are not in the IACUC protocol. So this is a very good protection mechanism that needs to occur.

Another important issue to consider is export control, not necessarily with respect to animals but other things that can go back and forth. This is highly 234 Animal Research in a Global Environment: Meeting the Challenges regulated by the US State Department, the Commerce Department, and the Treasury Department. Although most of these regulations do not apply here, and it is a low-risk situation, the consequences are very high if they are not followed. There may be fines up to a million dollars and imprisonment up to ten years. So it is critically important to determine that if there are to be animal-related items or products going back and forth, they are not on the commerce control list or part of any other export regulations.

Once an institution enters into an agreement to perform animal research at a foreign site, there needs to be a risk assessment to determine what the institution needs to do for monitoring and oversight. What kind of oversight is there? Is the institution AAALAC accredited? Are there local regulations? What infrastructure is available? What is the physical plant like? Are the human resources skilled or unskilled? What are the reporting lines of authority? There are also concerns about conflict of interest, e.g., is the person in charge of animal welfare reporting to the investigator doing the work? Also, the species involved may matter—the higher the species the more concern. Other concerns surround whether the procedures are invasive or noninvasive, the appropriateness of the number of animals, and whether the study is large or small. It is important to know whether the institution has a track record of collaborating with other institutions and whether any of their work has been published. If so, what does the materials and methods section say in the paper? This information can give a lot of insight into how the institution conducts its work.

After the risk assessment, a monitoring program needs to be implemented. There is an auditing clause in the subaward or subcontract, which primarily involves following the money to see how it is spent. However, it also gives the primary institution the ability to audit any documents related to regulations. In addition, the auditing clause allows the primary recipient to audit many aspects of the project according to the terms and conditions of the subcontract. The terms of auditing need to be very clear. If the institution wants to perform a specific document review, it needs to specify which documents should be kept and the frequency of the audit review.

Physical monitoring of the facility is the best option. There are multiple ways to do this, but the best is a site visit at least initially. Physical monitoring may also be done by requesting pictures and videos, or by looking through webcams. These methods all have security issues but as it has been said before, a picture is worth a thousand words, and going there is probably worth 10,000 words.

What happens if through the monitoring review noncompliance is observed? Who reports? Recall that the foreign assurance does not require that institution to report; reporting is the responsibility of the primary grant recipient. Who is held accountable for investigation and correction? Since the foreign country is out of OLAW’s jurisdiction, the main responsibility is on the primary institution. On the OLAW website there is a document that describes what happens during progressive noncompliance. Certainly one repercussion would be cessation of the financial support to the foreign institution if noncompliance was not resolved.

The last thing I wish to address is the recent trend with clinical trials. The FDA has put out new standards for the conduct of clinical trials. The new standards mandate that foreign clinical trials must now have an independent ethical committee and must be in compliance with the FDA’s good clinical practice. In the past, the standards were similar to what the requirements are for the foreign assurance now, i.e., the work must follow an international guideline. However, the stringency has increased to ensure that the data are reproducible and of appropriate quality to support a New Drug Application.

In an academic collaboration the onus is on the primary recipient to make sure that all of these things are occurring. If issues arise that are numerous and serious enough, it may be that this kind of regulation for animals will follow.

Perspective from China

.

To begin, I would like to say that I am not a specialist in laboratory animals but rather a biologist, with a specialty in stem cells. For the past eight years I have been working in a medical university in Beijing and I am currently involved in an effort to build a primate research facility in China from the ground up. I would like to tell our story of how to build such a facility.

In the past few days, almost all the talks mention China, and yet I am the only person who came from China, and I am not even a specialist in this particular area. At the end of my presentation, I would like to offer suggestions for those who are either planning on or now working with Chinese entities on scientific projects.

In 2003, most of my research [on stem cell therapy] was with mice. Before going to human trials I wanted to move to nonhuman primates. At that time the SARS epidemic rampaged through China and all animal transportation was stopped throughout the country. Consequently I wanted to find out where it might be possible to do NHP studies in China, i.e., where the monkeys were, where the good facilities were.

Most of the monkey breeders are in southern China; almost all the Chinese rhesus colonies or breeders are to the southwest. The area north of Vietnam is where many of the breeders of cynomolgus monkeys are located.

In visiting the area, I found many monkey breeders. For the bigger ones, the basic unit is 10,000, so they have 10,000 or 20,000 or 30,000 monkeys. But there were no good research facilities at all, and certainly not the type of facility we would like to have to do stem cell cultures or brain surgeries. So we decided to build our own.

We chose the city of Nanning for two reasons. One is that it is a small city by Chinese standards, with a million people, but the air is good, there is no traffic, and there are many direct flights to the big cities like Beijing, Shanghai, and Guangzhou. A second reason is that there are many good breeders in that general area, and most of them provide high-quality cynomolgus monkeys. Most of these facilities sell the monkeys abroad.

We talked to local people and rented space from them to set up our own facility. We immediately faced a problem that has already been discussed and that is an overall lack of awareness of animal welfare. Things have improved in the past two or three years, but it is still a problem. Also, there is a lack of expertise in veterinary care and technical skills. This is now recognized as a problem, and some remote education programs or lecture series have become available in China, but unfortunately at that time there were none.

Also, the quality of the animals is variable. Most of the breeders that sell to foreign countries are very good, but others are not, so we must stringently screen those animals.

All this is quite understandable. A quote from a commentary in Cell [129(6):1033–1036] published last year says: “There are 135 million Chinese living on less than $1 a day, which the World Bank defines as abject poverty. In comparison, ‘monkeys listen to music, have toys to play with and drink purified water’ in Wincon’s AAALAC-accredited lab.…” Even with the economic boom in the past few years, there are still many people at a very low standard of living. In such places it is difficult to provide care for our monkeys in such a way that they listen to music, have toys to play with, and drink purified water. With regard to purified water, I have a relevant personal experience. When we decided to install water purification systems for our monkeys, our technician came to me and asked if we could install a faucet in the office for the staff: people do not have purified drinking water—they normally boil the tap water for drinking. This small anecdote provides a view into the situation in China.

In developing our program, we decided to adopt a high standard, starting with the Guide. While this was a very good decision, in the beginning it was a very tough plan to carry through. Staff, including myself, had no experience with the Guide. It is embarrassing to say here that I became aware of AAALAC only in 2004. However, since we decided to go for this particular standard and apply for AAALAC accreditation, it has forced us to do everything properly and acceptably to the international community.

We were very fortunate to develop a collaboration with the University of Wisconsin, National Primate Research Center, and with Joe Kemnitz in particular. The center sends staff to our facility for days and sometimes weeks to help us implement the Guide in our facility and laboratories. This activity is continuing, but now people come not just to tell us what to do but also to collaborate with us on scientific experiments.

The third piece of developing our program involved the implementation of continuing education for our staff.

The final aspect of our program development was working with the local government to educate them and the local community. These efforts serve to bring support from the local community and funds from the local government.

It has been amazing how quickly things have progressed. In 2003 I visited Nanning and we were able to convince some local business people and the local government to put in some modest investment to rent a space on the second floor of a building beside a breeder, a big monkey farm. In 2004 we decided to work toward the standards set by the Guide, and in 2005 we had laboratory animal professionals from the University of Wisconsin come in to help us. By the end of 2005 we were able to apply for AAALAC accreditation, and we received it in 2006.

Since then everything has been progressing even faster, like everything in China nowadays. First, we immediately started getting phone calls from various pharmaceutical companies about our company. Second, we suddenly received investment money to build a new facility, which is to be completed by next year. Third, on a personal level, I have become one of the bigger clients of this company but am no longer involved with it. A large portion of my research grant goes into this company to support my study. But I feel happy about the outcome because I am a scientist, not a businessman.

Finally, I would like to offer a few additional suggestions for those planning to work with Chinese entities. The first is that it is important to spend more time going to China, and not just for site visits. It is important to spend time with the people who work there and this will help to solve a lot of problems such as language. Even though the English language capability of Chinese staff is not great, much may be accomplished just by working side by side. Also, it helps to build trust. Once everyone knows each other, it is possible to determine their trustworthiness, which is something that cannot be done by teleconference or videoconference.

Another consideration is that flying human primates is cheaper than flying nonhuman primates, given the restrictions with transportation. Even though travel to China is expensive, it is worth it, especially if one is working with non-human primates.

An additional suggestion is that people coming from abroad should work with the Chinese government, which, at the local or federal state level, is very receptive to advice from abroad and is also receptive to collaborations. In the last few years we were able to convince a major science funding agency in China to add requirements for major grants, mandating that facilities doing animal studies must comply with international standards, either by AAALAC accreditation or adherence to the Guide.

Finally, we are lobbying the Chinese government to support sequencing of the cynomolgus monkey genome so that we can compare the various sub-species as well as do genomic comparisons of Chinese and Indian rhesus. Working with the government may require additional effort, but it helps to tap into government resources.

Transportation Issues with Nonhuman Primates

.

I am going to focus on the transportation issues surrounding nonhuman primates (NHP). It is important to remember that almost 27,000 monkeys came into the United States in 2007.1 Even though there is a financial crunch and there is not as much money for research and fewer carriers are flying animals, there were still 27,000 monkeys that came into this country—and I am still worried about transporting animals.

Not only are there fewer carriers flying animals but there is no air transport within the US. We are converting to ground transport internally, and there are several companies that are very good at it.

It has been said previously at this conference that there are very few deaths during transport of NHP. But every year about 200 deaths occur in quarantine and it should not be considered a successful transport until the animals get out of quarantine. While some of these animals travel huge distances, even thousands of miles, a 1% death rate is still unacceptable. Facilities should be examined to find out why, if the animals are preconditioned and healthy before transportation, 1% of those animals die in quarantine.

There is a veritable cornucopia of laws and governing bodies that must be dealt with in order to move animals domestically or internationally and various agencies to enforce these laws and guidelines. Many times these regulations contradict each other and there may be [a lot of] ambiguity. Sometimes it is very difficult to know what the rules are. In addition, it is necessary to deal with officials at every one of these governing bodies and their interpretation of the laws. My plea to all of the attendees here is to get together and work with the agencies to develop an interagency agreement. The goal of such an agreement would be to bring all the documents together to give us better guidelines.

The difficulty in finding air carriers that will transport NHP has already been discussed. The profit margin for airlines to carry the animals is very low, and it costs them money to train their employees, put them at risk, and deal with the public relations aspect of it. It is likely that in the future there will be even fewer carriers that will transport these animals.

Good transport practices are based on common sense, on experience, and on knowledge of the animals. It is important to know the inspectors, know the rules, know all the officials, and know your shipping company, especially when it is a large or long shipment. Know what is going to happen with those animals every step of the way. Remember that regardless of how the animals are cared for in your facility, once they leave it they are under the control of others. One thing is to anticipate the weather, particularly in the summer, when there is cause for worry because of potentially high temperatures.

Another consideration is space allocation. While the animals are housed in a facility more space may be better, but during transport small is much better. Large spaces mean more chance of animals falling, of rolling, of problems with motion in transport. Food and water of course must be considered. Anorexia and adipsia may occur during transport. It is not prudent to include large volumes of water because it causes changes in temperature and bad sanitation in your transport. With regard to handling, it is extremely important to precondition and acclimate the animals. They should be prepared by becoming acclimated to the transport cages and to the food they will eat during the trip.

It is prudent to instruct the driver or whoever might be moving or handling the animals about how to act with them, what behaviors to look for, and to be careful with them, remembering that the transporter likely has little or no knowledge about the animals.

It is important to provide for a way to monitor the animals throughout the trip and to prepare emergency procedures for a worst-case scenario, such as the truck breaking down or the need to euthanize an animal. It may be necessary to have alternate places for the animals to go if the unexpected happens.

Other issues that should be considered are training, shipping containers, and biosecurity. Initial training and continuing education should be given to transporters. With regard to shipping containers, ideally each container should have an overcarrier, but this may not be feasible. However, it is necessary to ensure that the container will endure a trip of thousands of miles. This is particularly true when it comes to biosecurity. If urine or feces were to penetrate to the outside of the container, workers may be exposed to infectious agents the primate might be carrying. This also raises the issue of having the workers wear personal protective equipment. Ideally, they should, but doing so might raise concerns among the public who see them. The workers should ideally also be aware of biocontainment issues, but without specific training it is unlikely that they would be.

In summary, it is important to consider all of these issues before transporting animals in order to make it safe, especially for the animals.

The Future of the Use of Nonhuman Primates in the UK

.

This presentation will focus on what we have recently been doing in the UK in terms of reviewing the use of nonhuman primates and whether such use can be justified. It will consider the Weatherall report1, including the goal of that review, the methodologies, conclusions, and recommendations in the report, and the responses to the report. I will end with some personal ideas in terms of the way forward. I am taking the place of Professor Roger Lemmon who was unfortunately not able to be here.

A snapshot of primate use in the United Kingdom (from 2007 UK Home Office statistics) shows that use of primates is significantly less than in the United States. We performed about 4,000 procedures on primates in 2007, which constitutes about 0.1% of all procedures. The actual number of primates used was about 3,125, and most of those would have been Old World macaques, with a much smaller number of New World monkeys, primarily common marmosets. The number of animals and the number of procedures differ slightly because some animals are used in more than one procedure and are thus counted more than once.

The statistics indicate that 87% of animals used are in regulatory toxicology and about 13% in basic or applied research, which was the area of greatest interest to the authors of the Weatherall report; thus I will not say much about regulatory toxicology. The ratio of rhesus to cynomolgus macaques in the UK is slightly different from that in the US, where rhesus monkeys are used in most basic and applied research. The data show that the use of Old World monkeys has stayed relatively stable from 1995 to 2007. On the other hand, the number of New World monkeys seems to be on the decline.

The background to the generation of the Weatherall report was a report from the Boyd Group in 2002. The Boyd Group is a very diverse group of individuals from a range of backgrounds, including science, government, welfare, and antivivisection organizations. In 2002, they produced a report on the use of nonhuman primates in research and testing.2

That information was also then taken into consideration by the Nuffield Council on Bioethics, which was also a very interesting group of which I was privileged to be a member. We produced a report in 2005 on the ethics of research involving animals.3 I recommend that report to provide a breadth of understanding of the ethics of use of animals in research, which is an excellent starting point.

Arising from the realization in the Nuffield Council report that there were significant views being expressed about the ethics of using primates in research, the Royal Society and others in the UK set up the Weatherall Committee. It reported in December 2006 on the use of nonhuman primates in research. The focus of the report, however, was much more on the scientific justification as opposed to ethics.

The sponsors of the report were the Royal Society, which is somewhat the equivalent of the National Academies, the UK Academy of Medical Sciences, the Wellcome Trust, and the Medical Research Council, the last two being the major funders of basic and applied research involving primates. It was focused on hypothesis-driven research in academia and looked at the use of primates in communicable disease research, neuroscience, and reproductive biology. There was a small amount about fetal development research and aging, as well as a brief consideration of drug discovery and development. The report also considered alternatives, welfare issues, and ethics to an extent, but those were not major components.

The central goal of this study was to examine the scientific case for the use of nonhuman primates for research into the prevention and treatment of disease or for fundamental research that has the long-term potential for achieving the same end. This was a fairly unique approach to looking at the use of primates and justification for their use in research.

The methodology was to set up an “independent” committee. This means that all members of the nine-person committee were nonusers of primates in research, although some of them were academic researchers, including those from overseas, and there was also representation from lay people. There was a public call for evidence to which 62 responses were received. In addition the committee took oral evidence from 35 witnesses. Both breeding and using sites were visited by the committee. The committee sat for some 18 months, and took a fairly rigorous approach to writing the report.

This is an appropriate place to state that the UK regulatory control system is very stringent, with a requirement for three licenses for any primate use. There are also local ethical review processes.

Many recommendations emerged in this report. First, it concluded there was a strong scientific case for the carefully regulated use of nonhuman primates when there are no other means to address clearly defined questions of particular biological or medical importance.

The second recommendation reiterates that point in relation to the fields considered in the study—communicable diseases, neuroscience, and reproductive biology—confirming that nonhuman primates were needed at least for the immediate future. There is a sense in this report that there are developments occurring all the time that may or may not affect the justification for the use of primates in the longer term.

The third recommendation is that major specialist organizations should regularly collate information involving their fields, and the information should be disseminated to funding bodies, ethics committees, and regulatory agencies.

Fourth, the major funding organizations should undertake a systematic review of the outcome of all research using nonhuman primates supported over the last decade. That is being done by examining the benefits resulting from funding those areas of research.

The fifth recommendation refers to the development of alternatives, and there is strong support for greater funding to develop alternatives to the use of nonhuman primates both in research and in toxicology. Funders should expand their support for research into refining nonhuman primate research practices particularly in behavioral neurosciences.

A sixth recommendation related to retrospective reporting of severity of procedures. This would entail introducing a system to report severity actually incurred during procedures, either to a local ethical committee or more centrally. Obviously such reporting would take place after the procedures have been performed.

The next recommendation called for improvements in the training of research workers in nonhuman primate research.

The committee also addressed housing issues, specifically minimum cage sizes, avoidance of single housing, and how cage fittings and conditions can be accommodated to the purpose of the experiment, thereby relating the housing to the purpose of the research. They also called for better assessments of the advantages of things like access to outdoors and the general need for visual stimulation for primates.

The next three recommendations relate to regulatory toxicology, particularly in areas where alternatives may be feasible, and pursuing regulators to consider what may be unnecessary tests or duplication of tests.

There was a recommendation toward the end of the report that looked at the creation of UK centers of excellence, which I will address further when I talk about future activities.

The Weatherall report was produced in December 2006, and in June 2007 there was a flurry of activity in response to the report. The funders and government produced a combined response that was generally supportive of the recommendations and gave commitment to take them forward and to work together on the strategy of how to move forward.

Shortly thereafter, the UK National Center for the Three Rs (NC3Rs) published a critique of the report. It was a constructive critique that sought a more rigorous review and analysis of the use of primates in research. It talked about the need for a national strategy, which is something now being explored. It also mentioned that the NC3Rs has set up an annual meeting on the welfare of primates, which has been serving a very useful purpose. It draws a very diverse audience and serves as a very useful forum for comparing best practice across the community that is involved and interested in research using primates.

What is next then? We are embarking in various areas on thematic reviews of the use of primates. One area that needs to be explored is the use of primates in neuroscience. My team of inspectors in the UK looks at how the cost-benefit assessment is applied in those studies and how we can help our licensees to adopt best practice. Looking at retrospective severity is also an interesting exercise, including options for alternatives and how effectively those are being applied.

In addition, there are moves toward development of a national primate strategy, including determining the need for centers of excellence. In the UK there are far fewer centers that use primates than in the United States. Some question whether it is necessary to develop new centers of excellence rather than have existing centers become better networked together. The national primate strategy will also look at things like training and sourcing, which were not addressed in the Weatherall report but are nevertheless very important. Also, it will be important to heed the recommendations from [the] Weatherall [report] about media and public understanding about why primates are used.

But as already stated, the use of primates is a global issue, not solely a UK issue nor a US issue. While we do some small-scale breeding of primates in the UK, many of our primates are sourced from overseas, primarily China, Vietnam, and Mauritius.

It’s clear we have to think of primates as a global resource. We are currently competing with other countries for our needs; we should not be in competition but rather exploring the needs of science together. There are significant transport and welfare issues to consider as well. And there are significant opportunities to share best practice, especially between countries, such as the US and UK, with well-established programs of primate research and those that are emerging scientifically in this field.

Those are just some of the issues that come with the fact that the use of primates in research is not only a highly sensitive issue but also something that has global impact.

My conclusion is that this is an ideal opportunity for global collaboration and harmonization, so that we are not competing for use of these animals but truly ensuring that this global resource is being used as effectively as possible. We must achieve this by sharing our ideas and by sharing access to those resources.

Proposed International NHP Plan

.

In lieu of the last item on the agenda for this afternoon in terms of presentations,1 I will simply mention that the ILAR Council and staff would like to capture the content and the spirit of this afternoon’s session and use it to launch an international primate plan to enable the best use of global resources to maximize research progress that requires the use of nonhuman primates while minimizing the numbers used and the negative consequences for the animals.

We have a draft plan that is not completely polished. Our hope is to launch it within the year. We need some additional resources in order to do so. Then we have a time line that would call for completion of a written plan within two years.

Finally, I thank all of you who participated in this conference, especially the speakers, and very especially Joanne Zurlo and the ILAR staff as well as the sponsors of this meeting.

Text of Joseph Kemnitz’s Slides on the Proposed International NHP Plan

Background

First primate plan developed in 1978 by the Interagency Primate Steering Committee established by the Director of the National Institutes of Health (NIH).

Recommendations were made to ensure:

  • Expansion of domestic production of nonhuman primates (NHP)
  • Action to ensure effective use of NHP
  • Stable supply and long-term availability of NHP from countries of origin

The 1978 Plan was quickly outdated (e.g., ban on exportation from India, AIDS crisis). Great pressure was put on Indian-derived rhesus monkey resources.

A workshop on International Perspectives: The Future of Nonhuman Primates Resources was convened by ILAR in 2002.

  • Reports on NHP resources and programs in 16 countries
  • Updates on issues such as nutrition, genetics, microbiology and transportation

A companion workshop, Rhesus Monkey Demands in Biomedical Research, was convened by NIH’s Office of AIDS Research (OAR) and National Center for Research Resources (NCRR).

  • Emphasized pressure on Indian rhesus monkey supply
  • Encouraged use of alternative species
  • Develop a comprehensive plan to preserve and expand resources for biomedical research using NHP models

Rationale for a New Plan

  • Increasing need for human disease research and testing
  • Disease threats that compromise quality and supply of NHP
  • Globalization of research
  • Need for conservation
  • Need for renewed investment in infrastructure

Overall Scope

To address the current and future needs of NHP supply and use in biomedical research on a global level with consideration of multiple issues

Scope

  1. Supply and demand issues based on input from countries and facilities that are major producers and/or users of NHP
    • Projections for NHP demand in the US over the next ten years will be determined in part by examination of US Department of Agriculture data and import/quarantine information from the last 10–15 years and in part by examination of trends and anticipated future trajectories of those trends.
    • Assessment of needs for NHP in other countries by enlisting expertise from these countries in the project.
  2. Factors affecting the breeding of various species of NHP used in research
    • This will include breeding of NHP both in the US and abroad, and will address issues such as nutrition, age of dams, pregnancy success rates, genetic management.
  3. Infectious diseases affecting NHP and the standardization of microbial characterization of individuals and colonies with a focus on quality control and the development and use of reference reagents to minimize variability among laboratories and facilities.
  4. Genetic management of animals including either genetic diversity or genetic similarity, depending on the needs of the research with recommendations for standardizing practices.
  5. Behavioral management of the animals with recommendations for best practice in maintaining psychological well-being, optimal housing conditions and colony management.
  6. Transportation issues specific to NHP, including the control of microenvironment of the animals during shipping, transport of biological samples from NHP, and current international regulatory obstacles to importation and transportation of animals.
  7. Training of individuals involved with the care and use of NHP, including research and husbandry staff, and addressing the shortage of veterinarians specializing in NHP medicine.
  8. Recommendations for the conservation of NHP resources, including the creation of formal mechanisms to facilitate sharing of samples and animals, detailed databases of genomic information on individual animals and development of small animal models to replace NHP where appropriate.

Some additional issues to be addressed:

  • Elaborate on the translational value of research on NHP to human disease
  • Identify priority areas of basic research for which NHP resources will be essential

Footnotes

1

Data in this and the next paragraph are from an unpublished workshop presentation by Thomas Butler, DVM, DACLAM (currently Chair of the Board of Directors of Chimp Haven in Keithville, LA), “The Future of Chimpanzees in Biomedical Research,” on October 17, 2007.

1

Data extrapolated from USDA Report of Animal Welfare Act in these two years.

2

The numbers of NHP used in France were extrapolated from Chinese suppliers/breeders and the report from the European Commission to the Council and the European Parliament on Statistics on the Number of Animals Used for Experimental and Other Scientific Purposes (2002). I also referred to the Ethics of Research Involving Animals, Appendix 2: Statistic-Research Involving Animals in the UK, EU, USA, and Japan.

3

The numbers of NHP used in the UK were extrapolated from Home Office (2004) Statistics of Scientific Procedures on Living Animals Great Britain 2003 and from other sources, including the Ethics of Research Involving Animals, 2005.

4

The numbers of NHP used in Germany were extrapolated from Chinese export sources and from the European Commission report cited above.

5

The numbers of NHP used in Canada were extrapolated from Chinese export data and a personal survey of Canadian importers.

6

The numbers of NHP used in Japan were extrapolated from Chinese exporters’ information as well as information provided by Japanese users and from Chinese government records. I also referred to a survey from April 2001–March 2002, performed by the Committee for Laboratory Animal Care and Use (2003).

7

Author’s note: The UK, France, Germany, Canada, and Japan do not have yearly compulsory reports on the use of laboratory animals like the US. I believe that the extrapolated numbers of NHP used in 2007 in these countries are fairly close to the reality.

8

The total number of the macaques imported into the US in 2006–2007 was obtained from the CDC presentation at the annual Conference of the Association of Primate Veterinarians.

9

The numbers of cynomolgus macaques and of rhesus macaques were from CDC reports at APV meetings.

10

(1) Statute on Administration of Laboratory Animals (1988), issued by the Ministry of Science and Technology. (2) Project on Laboratory Animals during the Ninth Five Years (1997), issued by the Ministry of Science and Technology. (3) Guideline of Beijing Municipality on the Review of Welfare and Ethics of Laboratory Animals (2005), issued by Beijing Administration Office of Laboratory Animals. (4) Guideline on Humane Treatment of Laboratory Animals (2006), issued by the Ministry of Science and Technology. (5) Regulations on Punishment of Dishonorable Behavior in Science and Technology Projects (2006), issued by the Ministry of Science and Technology.

11

Furthermore, most CROs conducting animal studies or testing as well as all AAALAC-accredited primate facilities have an IACUC.

1

The Convention on International Trade in Endangered Species of Wild Fauna and Flora (www​.cites.org).

2

The NIH Computer Retrieval of Information on Scientific Projects system, since replaced by the RePORT Expenditures and Results (RePORTER) query tool (http:​//projectreporter​.nih.gov/reporter.cfm).

1

Data from G. Gale Galland, Nonhuman primate importation and quarantine, United States: 2007. 35th Annual Workshop of the Association of Primate Veterinarians. October 11–13, 2007; Charlotte, North Carolina.

1

The Use of Non-Human Primates in Research and Testing (2002). Jane A. Smith and Kenneth M. Boyd, ed.; the Boyd Group. Leicester: The British Psychological Society.

2

The Use of Non-Human Primates in Research (2006). A working group report chaired by Sir David Weatherall. London: The Royal Society, Academy of Medical Sciences, Medical Research Council, Wellcome Trust.

3

The Ethics of Research Involving Animals (2005). London: Nuffield Council on Bioethics.

1

This session reached the end of its allotted time and eclipsed Dr. Kemnitz’s presentation about the International Primate Plan; the text of the slides he prepared for presentation is included here.

Copyright © 2011, National Academy of Sciences.
Bookshelf ID: NBK91512

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