GLOBAL ISSUES: WORKING ACROSS DIFFERENT STANDARDS

Operational Challenges—Pharmaceutical Industry

Margaret Landi

My presentation is about possible solutions to different operational challenges that might exist in pharmaceutical industries, especially those that tend to work around the globe. I will cover four major topics: the challenges, the criticisms, the charge, the consensus.

The best way to start this topic is to make sure we are all working from the same dictionary, using the same definitions. As an example, the word “standard” is often used interchangeably with words like “principle” or “goal” or “objective.” A standard is something formally established as one moves forward in discussions on whatever aspect we are talking about; in this case we are talking about animal care and welfare in the pharmaceutical industry.

Sometimes we use the word “principles.” A principle is really a code of conduct. According to what principles are we going to perform studies in animals in multinational pharmaceutical companies?

The last word we often hear is “guidance.” Whether it’s the Guide for the Care and Use of Laboratory Animals, guidance, as you might suspect, deals with influencing, trying to influence a certain way, trying to achieve a particular outcome.

I will give you a perspective from my responsibility at GlaxoSmithKline (GSK), which spreads between the US and the UK and continental Europe. I also have fairly strong ties with our new R&D center in China, which, in turn, has ties with a site in Singapore where we are doing some animal research. We run the gamut from transgenic mice and transgenic rats to large nonhuman primates, macaque species.

What are the challenges when we address global guidance, how will we move forward? As you have probably heard or surmised already:



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GLOBAL ISSUES: WORKING ACROSS DIFFERENT STANDARDS Operational Challenges—Pharmaceutical Industry Margaret Landi My presentation is about possible solutions to different operational chal- lenges that might exist in pharmaceutical industries, especially those that tend to work around the globe. I will cover four major topics: the challenges, the criti- cisms, the charge, the consensus. The best way to start this topic is to make sure we are all working from the same dictionary, using the same definitions. As an example, the word “standard” is often used interchangeably with words like “principle” or “goal” or “objec- tive.” A standard is something formally established as one moves forward in discussions on whatever aspect we are talking about; in this case we are talking about animal care and welfare in the pharmaceutical industry. Sometimes we use the word “principles.” A principle is really a code of conduct. According to what principles are we going to perform studies in ani- mals in multinational pharmaceutical companies? The last word we often hear is “guidance.” Whether it’s the Guide for the Care and Use of Laboratory Animals, guidance, as you might suspect, deals with influencing, trying to influence a certain way, trying to achieve a particular outcome. I will give you a perspective from my responsibility at GlaxoSmithKline (GSK), which spreads between the US and the UK and continental Europe. I also have fairly strong ties with our new R&D center in China, which, in turn, has ties with a site in Singapore where we are doing some animal research. We run the gamut from transgenic mice and transgenic rats to large nonhuman pri- mates, macaque species. What are the challenges when we address global guidance, how will we move forward? As you have probably heard or surmised already: 41

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42 Animal Research in a Global Environment: Meeting the Challenges  There is a lack of consensus on what best practice is across various cul- tures.  The regulations differ across countries.  The regulations change.  There are differences in cultural thinking. For the last point, I would like to describe the main influences that drive differences in European versus American culture when it comes to animal re- search. In Europe, as opposed to the US, many things are uniform, because things are the equivalent of federally driven, whether it’s a speed limit that goes across the country, whether it’s VAT or sales tax across the country. In the US, every state is different. [For example,] the sales tax will be different—we all know the states that don’t have sales tax, and if you live near them you tend to visit them so you can get a break of 6 to 7 percent on whatever you are buying. There is a lot of diversity in the US as far as the way we expect things to hap- pen. I’m originally from New Jersey; I travel back there a lot for family. I can use a cell phone in the state of Pennsylvania, and the minute I cross the New Jersey state border I put it away because I’m not allowed to use it unless I have a hands-free model. This is an example of differences. Our way of living sometimes translates into the way we think about things. Generally speaking, in Europe, many things are consensus-driven— people say “let’s have a discussion.” Right now, there is the European Directive, driving similar practices in all EU countries. The US, for better or for worse, tends to work on threshold: We tolerate a lot, whether it’s national debt or hand- guns—whatever it happens to be—until a certain threshold is met, and then things happen. The good news is, when a threshold is met, something usually happens quickly. The bad news is that it generally takes a while to hit a thresh- old. The reverse would be in consensus: sometimes it takes a while to get to that outcome, but people are talking about a topic and thinking about it. To me, the important question is, Do the variations that exist really result in a big difference in the way we care for animals in different parts of the world? Is it possible to align principles, independent of differing standards, which are the more prescriptive way of looking at animals in research? Some of the differences, compared to academia:  Industry usually has a very large internal capacity, there are many things we can do internally. [For example,] we generally have the option to buy equipment if we feel it’s needed and we can defend the budget for doing so.  Industry tends to be a regulated environment. Even the earlier work has probably many more regulations than are normally seen in academia.  Industry has many different requirements because it spans different countries and includes different types of studies, from efficacy models in trans- genic animals to highly regulated GLP studies in macaques.  Of course, timelines are extremely important.

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Operational Challenges—Pharmaceutical Industry 43 What then is the criticism? I distilled it down to the concept that “what we think weighs more than what they think.” When we have conversations, when we have dialogues, we have already sort of made that internal critique. We need to move away from that preconceived notion before we can start to have the conversation. Otherwise, it will be hard to have consensus or even a conversa- tion. Again, using GSK as an example, we work across two main cultures, the US culture and the UK (we also have sites in continental Europe, but that is a more modest operation). We have opened some discussions to see if we could come to consensus on guiding principles for the use of animals in research. We did this because we felt it would provide a safe structure for having conversations and would allow the diversity of thought and opinion to come through and have a sub- stantive type of conversation, and try to get some alignment. Our desired outcome is to achieve alignment and articulate a set of foun- dation principles with regard to the animals, for us within the institution and also for work done for our institution by CROs, academic institutions, or other places. We started with dogs and monkeys, some of the more highly emotive species. We also defined what the undesired outcome would be. If we couldn’t come to some sort of understanding, that wouldn’t mean that differences in prac- tices or standards always equate to a difference in care. We wanted to avoid a perception of a dual standard—i.e., a practice done in one place means greater care, not doing it in another place means lesser care. Unfortunately, this is often the initial perception when working in different environments. Going back to the definitions, consensus, of course, means a general agreement and some sort of alignment or solidarity along a certain belief or sen- timent. When we achieve a consensus, I think we can start to move the scales— each side will continue to maintain its own thoughts, but we will get a little more alignment and a little more agreement to ask “What is our objective?” Our ob- jective is the care and welfare of the animals; it’s not to say that one side’s opin- ion is more important than the other. So let’s keep that in mind as we have the conversations. But the question always asked is, “Is it truly achievable?” Even in socie- ties where there are many consensus-driven processes it is sometimes difficult to achieve consensus. So my charge has been, How do we handle this? At GSK, we have certain principles by which we work. We adhere to the 3Rs and we meet all applicable rules and regulations regarding animals in re- search. We have also established seven core principles of animal care and wel- fare. These principles are used no matter where we are in the world—whether we do research in China, North Carolina, or Croatia. [This consistency] allows us to look at cultural differences in ways of working and accept that issues iden- tified as important to all groups might be emphasized differently in each place. So the objective was to find some commonality.

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44 Animal Research in a Global Environment: Meeting the Challenges Core Principles of Animal Care and Welfare  Access to species-appropriate food and water  Access to species-specific housing, including species-appropriate temperature and humidity levels  Access to humane care and a program of veterinary care  Ability to demonstrate species-specific behavior  Adherence to principles of replacement, reduction, and refinement in the design of in vivo studies  Commitment to minimizing pain and distress during in vivo studies  Study design reviewed by institutional ethical review panel There are those in some parts of my organization who say these core prin- ciples are not strict enough and should be stricter. Others say we are stating the obvious, so why even bother? We bother because these core principles have allowed a dialogue across countries, sites, and cultures. As an example, we require an ethical review proc- ess at each institution where animal work is done on behalf of GSK. There are many parts of the world where an ethical review process is not the norm. We are asking for that to be in place. The 3Rs are part of the discussion before animal research happens. Some principles are self-evident such as food and water and there needs to be some common sense applied to implementing them. Now that we have put together these principles we are audited to make sure we are complying with them by internal auditors who have little knowledge about animal research. They will ask us to prove how we meet the principles. So now we are working through the next level. Most pharmaceutical companies, like GSK, have something about animals in research on their websites. For pharmaceutical companies there are basically two options. One is to apply engineering standards, and apply the most stringent standards of all the countries no matter where we work. In the case of GSK, the UK has the most stringent standards. So if we are doing work in Croatia, Phila- delphia, or China, we will use [the UK] standards. This approach allows some comfort because it is very easy to measure and understand. However, it does not necessarily affect animal welfare proportionately as some would think. The other option is to use performance standards, such as the standards upon which our core principles are based, and to use international standards such as AAALAC. For GSK, working in multiple countries, it was necessary to have international standards. Why do we use [an international standard]? Here are some of the reasons. It is a global approach and in spite of the numerous regulations, this system works. Obviously, it’s voluntary and confidential. It involves looking at practice, not just engineering standards in the program.

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Operational Challenges—Pharmaceutical Industry 45 These standards require the use of professional judgment, which may make some people uneasy because of the uncertainty of the education, knowledge, or credibility of the person making the judgment. Professional judgment is the issue that usually causes the most difficulty in that one professional differs from another professional. It is said by nonveterinarians that if there are five veterinarians in a room, there will be 10 opinions. It is very difficult sometimes to get consensus and know what the right professional judgment is. But from our standpoint, the animals benefit if we avoid template think- ing. Temple Grandin, whom many of you may know, has written a number of books on animals. She is an autistic woman who has been very successful in the animal behavior/animal psychology field. She often discusses her visits to slaughter plants, where she conducts plant evaluations. She knows that when government inspectors come in they have a 100-step checklist. Temple goes in with five or 10 different things she examines from the animals’ perspective. From those few items, she can rapidly tell the state of the slaughterhouse. I be- lieve this is one of the best examples of why professional judgment is important. So there is a lot of oversight: Our wonderful core principles have now be- come a way to audit us, in addition to the USDA and GLPs. But that is acceptable in that there is constant challenge and a dialogue to help improve and refine the system. It is also important to recognize that we and other pharmaceutical companies conduct work outside our institutions. CROs are fairly straightforward, but aca- demic alliances and collaborations with biotech and other companies are not. So we have instituted a process by which we look at those aspects. Many wonder if that’s the best use of resources that might be better spent in hiring more veterinarians or vet techs. However, as stated earlier, it is a bal- ance. We can perform research because society as a whole has stated that re- search is important. So there is something the companies owe the public in re- turn. While the standards to which the company holds us may be surprising, it is also understandable that they want to build trust with stakeholders. They feel they must answer certain questions and I and my team have to provide that in- formation. What are my conclusions?  Always to remember that we are all in this together. Personally, I feel that the weakest link in all our conversations is the [conversation] we don’t have. It is much more important to talk and disagree than not speaking and believing that “never the twain shall meet.”  Standards, particularly engineering standards, should be based on science and show a clear benefit.  Principles keep both the science and the animal in mind and should allow diversity and professional judgment.

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Overcoming Challenges— Contract Research Organizations (CROs): Setting Up a CRO in a Foreign Country Bryan Ogden Thank you for the opportunity to travel back to the US. I have been in Singapore for four years having left an academic environment at the Oregon National Primate Research Center to help with a startup contract research or- ganization (CRO).1 I am going to use some of my experiences to illustrate some of the challenges, operationally, that we face as a CRO in working across differ- ent standards. Foreign CROs face the challenge of establishing credibility. Western com- panies have scrutinized the different CROs that are being established in Asia. There have definitely been some bad outcomes, some disappointing facilities and programs. Sometimes that record is used to make presumptive judgments about new CROs. I hope that most people know that Singapore is not in China, although if one were to ask where Singapore is there would be many different answers. Sin- gapore is located at the tip of the Malaysian Peninsula. The island where we have our breeding colony in Indonesia is a one-hour ferry ride across the South China Sea. This presentation will focus on the Singapore story. CROs face the challenge of being competitive. The pharmaceutical com- panies demand a certain standard and expect CROs to do things similarly to the way they are done in the pharmaceutical industry, which can be a challenge from one country to the next. If the CRO does not meet those standards, it will not get the business, and yet it has to be profitable. The general perception is that a young company in particular needs to be faster, better, cheaper. 1 CROs provide support to the pharmaceutical and biotechnology industries in the form of outsourced research services (for both drugs and medical devices) such as clini- cal trial development, management, and postapproval services. This presentation focuses on the challenges of outsourcing to CROs in other countries. 46

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Overcoming Challenges—Contract Research Organizations (CROs) 47 The question becomes, Should the CRO vie to be better than everybody else or just acceptable, to meet the minimum standards? And what would those standards be? Should the CRO appeal to a niche market or do a broad service offering? Most CROs realize that they will be expected to provide humane animal care and use. Certainly our CRO does not want to attract business from countries with tighter regulations with the intent of doing something more invasive or less humane in our country or in our facility. Certainly the pharmaceutical compa- nies and biotech companies would not want to be perceived as outsourcing to Asia, for instance, so that they can bypass humane care and use standards. There are also opportunities for preferred provider and partnership ar- rangements, collaborations. For instance, we have agreements with certain pharmaceutical companies to do some of their discovery work and perhaps some of the toxicology work. These kinds of arrangements occur in different countries in Asia and most likely in Europe and the US. Such studies are important to CROs for their survival and give them a core base of income. These partnerships sometimes also provide an opportunity to work together on novel model devel- opment. However, there are challenges with different standards across different countries and cultures. The problem may not always be due to differences in, or lack of, animal welfare regulation. There may be different government agencies that affect permits related to a CRO’s activities without specific laboratory ani- mal welfare regulations. I will give an example. The other issue is how the regulations are enforced. Do the regulators really understand the best standard of animal care, or at least best practice? Within a CRO, especially in a country where there is a diverse population, there are different cultural attitudes. For instance, some males will not take di- rection from a female superior or are less likely to—a technician who was raised in a household with a Filipina maid might not readily accept correction from a Philippine veterinarian. A CRO must deal with these and other interpersonal and cultural challenges. There is also the issue of the status of the animals in different cultures. What is acceptable use of an animal? In some cultures animals that are consid- ered pets in western culture are actually food. There are ethical considerations and compliance issues as well. Does the country have a culture of compliance, or even a culture of integrity or ethical principles of integrity? In some countries Westerners are walking wallets—it is common for people in those countries to charge Westerners several times what they would charge someone else for similar services or products. It is considered a real coup for them to cheat people. A particular concern with CROs is cultural attitude toward saving face versus disclosure. Mistakes on studies are inevitable. If the culture is focused on saving face, there may be a tendency to hide the mistakes, which could affect the data and the interpretation of the data. This could ultimately cause far-reaching

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48 Animal Research in a Global Environment: Meeting the Challenges negative effects during clinical trials. It is therefore essential to understand the ethical principles about disclosure as opposed to saving face. Work ethic across different cultures and countries is another challenge. In some countries the work pattern is for one person to do the work and several supervisors to stand around and watch. This is based on a concept of how many hours of actual work in an 8-hour workday the employer is entitled to. Another issue concerns the socioeconomic and human living conditions of the workers when compared to animal living standards. It is difficult to persuade a worker to implement sanitation practices for primates when the worker lives in a hut with a dirt floor, blue tarp walls, and a rusty corrugated metal roof. Pride in workmanship affects the quality of the facilities, and ultimately the quality of the care of the animals. My company can be used as a relevant case study in operational chal- lenges working across different standards. It started as a spin-off of Monash University in Australia, then moved to Singapore as a preclinical CRO in 2003. Between 2004 and 2005, facilities were designed, financing was obtained, facili- ties were constructed and then licensed to do research; in 2006, the programs were accredited by AAALAC and began to adhere to FDA GLP compliance. The facility was accredited by the OECD for GLP accreditation in 2008. In addition to the Singapore CRO facility, the company has a breeding fa- cility for primates in Indonesia. The Indonesian standards for animal care, or lack thereof, will be discussed in a moment. In 2000, the government of Singapore began an initiative to develop bio- medical sciences as a major hub of the economy, with the ultimate goal of be- coming the biomedical hub of Asia. They appointed an advisory committee and built some “Field-of-Dreams-style” facilities. That committee was called the National Advisory Committee for Laboratory Animal Research (NACLAR). NACLAR looked at standards across different countries, including the UK, Aus- tralia, New Zealand, Canada, and the US, and decided to adopt standards similar to those in the US that would enforce a self-regulation type of oversight of ani- mal care and use programs. They published their guide in October 2004. The Parliament passed an amendment to the Animal and Birds Act covering animals in research, effective November 2004. The Agri-Food and Veterinary Authority (AVA) was assigned a role similar to that of the USDA, overseeing the licensing and inspection of animal research facilities. Of the challenges mentioned earlier, some result from working across dif- ferent countries, but others are specific to Singapore. To meet those challenges in part, Maccine hired me, a US-trained, ACLAM board-certified veterinarian, since my career was based on the US standards Singapore was adopting. This helped provide credibility for the company to potential clients. The company also received some backing and support from Quintiles, a UK-based CRO, in- cluding some key staff. They recruited people from other countries, too, because there was not a base of study directors or technical staff with experience in labo- ratory animal care in Singapore.

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Overcoming Challenges—Contract Research Organizations (CROs) 49 Maccine has held the Indonesian facility to the NACLAR and AVA stan- dards. In fact, the IACUC in Singapore oversees the animal care and use pro- gram at the Indonesian facility, including twice-yearly inspections of the facility. AAALAC accreditation was very critical. We even invited the Singapore AVA to be at the AAALAC site visit in Indonesia, even though AVA had no regula- tory authority there. Training has been a key issue. Through the Singapore Association of Laboratory Animal Science, which we established in 2004, we have offered training for IACUC members, similar to what is done in the US with IACUC 101. The NACLAR guidelines are different in some minor ways from US regu- lations. While they are very similar overall, NACLAR does not reflect the dif- ference between the USDA Animal Welfare Act and Public Health Service pol- icy with regard to the definition of an animal: NACLAR guidelines cover all vertebrate animals and the AVA uses the NACLAR guidelines to measure com- pliance. Another difference is that the IACUC may not do a designated review. Also, to have a quorum of the IACUC, one of the people in attendance must be the nonaffiliated or the nonscientific member. Animal facilities are inspected by the IACUC and AVA only once a year, although the IACUC program review occurs twice a year. To facilitate the proc- ess, we have started doing our IACUC inspections at the same time as the pro- gram review, twice yearly. This is similar to what is done in the US and what our clients expect. AVA inspection is scheduled, as opposed to being unan- nounced as it is in the US. In fact, the AVA has begun to require something similar to an AAALAC program description prior to its inspection. It seems that the AVA is striving to hold facilities to a standard even beyond the regulations and guidelines. It is both good and challenging to have inspectors come to the facility who have both an intimate knowledge of the program and the regulatory power to enforce the regulations. NACLAR and the regulations under the Animal and Birds Act both re- quire training. IACUC members must receive formal training. Also, anyone who does research must attend a course on the responsible care and use of laboratory animals. The contrast between Singapore and Indonesia demonstrates an interesting continuum in the amount of regulation. Singapore is one of the most regulated countries with the highest standards in Asia, and Indonesia (and perhaps Malay- sia) are at the other end of the continuum. Malaysia is now working on setting up some national animal welfare standards for laboratory animals. As mentioned earlier, while Maccine has a facility in Indonesia where there are no laboratory animal welfare standards and therefore no government inspections, the company applies the same standards as in Singapore. Even though both countries are CITES members, one can get a CITES permit in three days in Singapore, while it can take weeks or months to get one in Indonesia. The timeline for CITES approval in Indonesia can depend on who you know and in some cases who you pay. In addition, both countries require import and ex-

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50 Animal Research in a Global Environment: Meeting the Challenges port permits. Again, the turnaround is very fast in Singapore and very long in Indonesia. Singapore is very diligent and efficient in both permitting and bureaucratic integrity. Indonesia still has not been able to eliminate influence peddling and under-the-table payments in order to get permits. Without payments, the waiting period can be extremely long. There was a challenge in Singapore with regard to GLP certification. When the company was started, Singapore was not an OECD member so there was no GLP monitoring authority. In 2006, the Singapore government assigned SPRING as the GLP monitoring authority and it began auditing for GLP com- pliance in 2008. Singapore became a provisional member of OECD in 2007. I would like to address a few other CRO challenges:  financing and cash flow, especially with a startup company;  design and construction;  SOP establishment—starting from scratch, then training and achieving compliance; and  good quality control and validation and quality assessment. Those are all challenges that are met to one degree or another in different coun- tries, in different CRO facilities. Credibility is an issue especially if the country is viewed similarly to its neighbors. For example, some people may be under the misconception that Sin- gapore is in China and, if they have heard horror stories about melamine in baby formula or colleagues have revealed their bad experiences in China, they may think that Singapore has the same negative issues. From my own experience, when we have been audited by pharmaceutical companies and biotech compa- nies, the auditors are greatly relieved when they see our AAALAC accreditation. An additional challenge is being competitive. Singapore does not have much in the way of rodent breeding and there is no commercial rodent vendor there. Within the next couple of years, the country plans to have its own national breeding center. Now, however, we have to import rodents, which is expensive, making it hard to be cost-competitive, especially in the toxicology area. Communication is another challenge because there is a 12- to 13-hour time difference with the East Coast of the US, so we must have late-night or early-morning conference calls. Language is not usually a significant problem because the official lan- guage of Singapore is business English, although sometimes the accents are dif- ficult to understand. In other countries, however, there are significant language and cultural barriers. Sourcing supplies and equipment can become a challenge as well as the function of the regulatory agencies with regard to shipping, bioanalysis, pathol- ogy. AAALAC accreditation was an important step to becoming a credible CRO

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Overcoming Challenges—Contract Research Organizations (CROs) 51 in order to meet the expectations of clients. For CROs doing toxicology, GLP certification is also necessary. There have been some frustrations in not being able to work with archi- tects, engineers, and contractors that have experience in building animal re- search facilities. Cost engineering is a problem everywhere, and unfortunately one of the first areas to be cut in building design is storage space. It is also a challenge to get quality materials and have them installed such that the epoxy floor does not come up, paint does not peel off the wall, or the walls don’t crack soon after you move in. In Asia, contractors tend to use unskilled labor. In China the laborers are uneducated ethnic minorities, and in Singapore it is the Bangla- deshis, Pakistanis, or people from other undeveloped countries. Even with the best epoxy products, inexperienced workers can make a real mess during instal- lation, which can of course also happen in the US. Here are some pet peeves of mine working in Asia. Workers cannot get a concrete slope floor to drain evenly—one gets pooling of water and water pour- ing from the room out into the corridor during hose-down washing. Another pet peeve has to do with improper surface preparation of floors for epoxy. There are often not good moisture membranes. There are problems with improper mixing so that a month later feet still stick to the epoxy floor and wheels leave indents. Of course, installation and maturing are issues here. Another pet peeve is the apparent inability to match paint in Asia, which should be possible with a simple computer program. But this does not seem to happen in Singapore. If you are lucky, when a crack is patched, the workers will put a geometric design over it, like a square or a long rectangle. If you are not lucky, it will just kind of patch the crack in a different color in an irregular pattern, maybe using a different tex- ture, maybe a flat paint as opposed to a gloss. There does not seem to be enough pride of workmanship in many parts of Asia. Simple jobs like applying grout or caulking that should produce a smooth line result in thumbprints, blobs, or smears and the workers appear to be satis- fied. It is a real challenge to find people who are qualified. There are the “sea turtles” coming back to China and other countries after working or studying in the US. Their competence in the CRO and in other environments using animals will depend on what their US experience was. In my experience in academia, foreign workers did not always get it, even after 10 years for some of them. If people like this return to their native country and are perceived as understanding animal welfare standards and ultimately become leaders in their companies, you can expect that things are not going to be harmonized. It is common to hire workers from outside the area, especially in Singa- pore, where there are only 4 million people and no farms or anyone with any agricultural background. We often hire from other countries and have a large number of employees, including some veterinarians, from India and the Philip- pines. Often it is most expedient, at least initially, to hire Westerners to help train employees and to help set the standard and maintain compliance. It is a problem to retain them, however, and it is necessary to make a plan for succession, so

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56 Animal Research in a Global Environment: Meeting the Challenges 1830s), a percentage larger than that of the US in the decades immediately after World War II. [After Mao’s Cultural Revolution and Great Leap Forward, China’s output dropped to only 1% of the world’s GDP in 1979. China has since rebounded to 5% and its spending on R&D has grown 19% annually over the past 10 years, a rate more than six times higher than in the US, which is still the world’s leader in yearly R&D expenditures.]4 This impressive heritage gives many Chinese citizens great pride and an ex- pectation that their country will eventually resume its global leadership in the sciences. Hence, domestic support for the pursuit of science and technology leadership will continue to be strong. Besides India, no other country comes close to matching China in this context. But because India has chosen to dis- courage the use of nonhuman primates in biomedical research,5 China is a logi- cal focus. By contrast, addressing the differences only between wealthy coun- tries with respect to laboratory animals and academic research is less compelling because those differences are minor in comparison with poorer nations. Fur- thermore, investment in animal-based biomedical research in China and other developing countries will likely accelerate. Current Drivers and Barriers Several years ago in his book The World Is Flat, Tom Friedman described how Tian Xu, a Yale professor and Howard Hughes Investigator, outsourced bench work and mouse studies to long-time colleagues at Fudan University in Shanghai while his laboratory analyzed the resultant data back in New Haven.6 Xu’s counterparts in China enjoyed new and expansive laboratories, ample fed- eral funding, and could remain in their country rather than traveling to the US for graduate or postdoctoral training. This arrangement permitted the American side to accomplish just as much research with trusted collaborators but at a frac- tion of the cost of performing that research in the US. At the same time, gradu- ate students in the partnering laboratory in China got access to cutting-edge re- search, with frequent exchanges of staff in both directions. [It is important to recognize how serious the Chinese government is about recruiting expatriates that historically have stayed abroad. A related trend is the dramatic increase in Chinese students receiving higher education—from 1.4% of the college-age 4 Philip Auerswald, “China’s quick fall, slow return to glory,” Boston Globe, August 11, 2008. 5 A.J. Rao. Use of nonhuman primates in biomedical research in India: Current status and future prospects. In International Perspectives: The Future of Nonhuman Primate Resources, Proceedings of the Workshop Held April 17-19, 2002, National Research Council. Washington: National Academies Press. 6 Thomas L. Friedman, The World Is Flat: A Brief History of the Twenty-first Century (New York: Farrar, Straus and Giroux, 2005), pp. 247-248.

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Global Issues: Operational Challenges in Academia 57 population in 1978 to 20% in 2005, resulting in almost half a million new un- dergraduates, 48,000 master’s degree graduates, and 8,000 new PhDs a year.7] Other scientists in advanced countries have recognized the same cost ad- vantages, even without close personal relationships, and these types of extramu- ral collaborations are becoming more popular. Consider that for the first nine months of 2004, 53% of the research papers published in Science and Nature from Chinese laboratories included American scientists as coauthors.8 When laboratory animals are involved, the cost differential may be even more striking when one appreciates the much greater investment made in each animal in bio- medical research today. For example, genetically engineered mice have proven to be a critical tool in dissecting the influences of various genes in diseases and other biological phenomena. But preparing for the actual experiment of interest involving a specific combination of multiple genotypes usually requires several generations of cross breeding, coupled with genetic analysis of every animal from each generation to make sure that the breeding scheme actually yields the genetic components of interest. The result is not only a mouse with a novel and precise mixture of genes but a mouse that represents an investment of perhaps tens of thousands of dollars before the experiment is ever conducted. Cost reali- ties like these in a tight funding environment are leading many to consider less expensive strategies abroad. Other drivers for transnational collaborations between developed and de- veloping countries involve access to patient populations or environmental cir- cumstances that are not as prevalent in wealthier nations. China is not unique in this regard, but some of its ethnic minorities with their relatively narrow genetic bases, isolated living conditions, and limited diets may offer science a better means of understanding nature versus nurture in specific diseases that also af- flict patients elsewhere. For example, Xinjiang Province in the northwest corner of China is home to thirteen nationalities. Here, Kazaks eat a very salty diet and have a high incidence of hypertension and esophageal cancer with short life- spans when compared to Uighurs, who eat primarily grains and fruit and have long lives with a very low incidence of cardiovascular disease.9,10 On the other hand, there are diseases relatively widespread in China but rare in most other parts of the world. One example is hydatid disease, a parasitic infection affecting 600,000 Chinese, with an additional 60 million estimated to be at risk. Treat- 7 Howard W. French, “China Luring Scholars to Make Universities Great,” New York Times, October 28, 2005. 8 Ya-Ping Zhang and Shigang He, 2004, editorial, Science 306: 1861. 9 He Bing-Xian and Zhang Jian-Yi, “Dietary habits and longevity along the Silk Road,” in Proceedings of the Symposium on New Horizons in Preventing Cardiovascular Diseases, Y. Yamori and T. Strasser, eds. New York: Excerpta Medica, 1988, pp. 89-93. 10 D. Rahmutula, et al. Angiotensin-converting enzyme gene and longevity in the Xin Jiang Uighur autonomous region of China: An association study. J Gerontol A Biol Sci Med Sci 57:M57-M60, 2002.

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58 Animal Research in a Global Environment: Meeting the Challenges ment is only 30% effective, leaving many to face premature death.11 Many sci- entists are studying this parasite-host interaction because it may provide insight into parasite immunology in general. Regardless of the increase in transnational research collaborations between developed and developing countries, there are significant risks involved. These include fraud, plagiarism, loss of intellectual property, and perhaps even crimi- nal acts involving theft or smuggling of protected natural resources. Most of these adverse consequences are very rare in contemporary science among wealthy countries, but lack of similar protections and an only recent respect for the ownership of ideas in less developed countries raise legitimate concerns. Other postulated incentives to increase academic collaboration between scientists in developed and developing countries are not as valid, at least here in the US. These include the avoidance of regulations and activist targeting pertain- ing to the use of animals in biomedical research. American scientists have be- come accustomed to established standards of laboratory animal oversight, and their respective institutions have administrative and physical infrastructures for compliance with regulations that have been in effect for many years. In fact, the biggest academic concerns to transnational collaborative research involving lab animals involve just the opposite situation, i.e., the lack of those same quality standards and safeguards that protect the health and welfare of today’s expen- sive animal models in developed countries. When coupled with an unprecedented level of scrutiny available via the Internet, the negative consequences of mere allegations of lab animal mistreat- ment involving a scientist in a developed country are greater than any theoretical advantage to be gained by conducting animal research in a less rigorous envi- ronment. Therefore, the biggest concerns to be resolved if such collaborations are to grow and succeed involve acceptable (i.e., Western) ethical values for and adequate oversight of animal research in developing countries. Additional con- cerns pertain to the adequacy of the knowledge base of local veterinarians in poorer nations with respect to lab animal biology and medicine, as well as the vested authority of those veterinarians to intercede on behalf of lab animals when (Western) limits on animal pain and distress have been exceeded. Some may claim that this smacks of cultural imperialism and imposition of one ethical standard at the expense of another that has just as much legitimacy. However, even in China, as a middle class becomes more established, pets are becoming more precious to their owners and this trend could expand to greater sensitivity for other animals.12 As a result, cultural attitudes toward animals may, indeed, converge as living standards rise and more persons gain access to the web and other global connections. 11 “Parasitic time bomb,” Scientific American, July 2005, p. 22. 12 Nicholas Zamiska, “Chinese Unleash a New Fondness for Their Dogs,” Wall Street Journal, August 7, 2006.

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Global Issues: Operational Challenges in Academia 59 Current and Future Safeguards At least two multinational approaches to address these major concerns are currently in effect. Both are laudable, but each has limitations. The first involves the NIH’s Office of Laboratory Animal Welfare (OLAW; http://grants.nih.gov/ grants/olaw/olaw.htm). OLAW is charged with obtaining official assurances that institutions accepting NIH research funds comply with contemporary standards for lab animal care and use. US institutions must submit a lengthy document every four years that details every aspect of their animal husbandry, veterinary care, occupational safety, and internal (IACUC) oversight programs, for review by OLAW staff before an assurance is approved. OLAW also expects to receive annual updates from those institutions as well as timely notification of any major adverse events affecting lab animal welfare. Foreign institutions that receive NIH research funds also are required to submit an animal welfare assurance, but that document is less stringent, to wit: When the grantee is a domestic institution (i.e., domestic grant with a for- eign component), PHS animal welfare requirements are applicable. Ac- cordingly, the grantee remains responsible for animal activity conducted at a foreign site and must provide verification of IACUC approval. That ap- proval certifies that the activity, as conducted at the foreign performance site, is acceptable to the grantee. The grantee IACUC may accept, as its own, the approval of a foreign entity’s IACUC; however, the grantee IACUC remains responsible for the review. Additionally, the foreign en- tity must complete the Statement of Compliance with Standards for Hu- mane Care and Use of Laboratory Animals by Foreign Institutions, avail- able from OLAW. This document certifies that the institution will comply with the applicable laws, regulations, and policies of the jurisdiction in which the research will be conducted, and that the institution will be guided by the International Guiding Principles for Biomedical Research Involving Animals. If the grantee is a foreign institution then IACUC ap- proval is not required. The institution completes the Statement of Compli- ance referenced above. OLAW encourages foreign institutions to use the standards in the Guide, which is available in a number of foreign transla- tions.13 Currently, institutions in 79 countries have an animal welfare assurance approved by OLAW.14 OLAW cannot impose US laws and regulations on for- eign entities, and regulatory site visits to those entities to ensure compliance with the Guide and other standards are impractical and unaffordable. Thus, the 13 PHS Policy on Humane Care and Use of Laboratory Animals, “Frequently Asked Questions” (http://grants.nih.gov/grants/olaw/faqs.htm, last revised February 26, 2008). 14 “Foreign Institutions with a PHS-Approved Animal Welfare Assurance” (http://grants.nih.gov/grants/olaw/assurance/500index.htm).

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60 Animal Research in a Global Environment: Meeting the Challenges resulting discrepancy allowed between US and foreign institutional oversight of lab animals can be wide. Lapses that affect scientific data or animal welfare could be subject to disciplinary enforcement in the US but may be deemed toler- able in another country. That would result in only the US collaborator being subject to punishment from either OLAW or the public. In addition, such a dou- ble standard leaves a US scientist at a disadvantage for research funding when competing against a foreign applicant or another US institution relying on a for- eign collaborator for its animal work, if all other aspects of their respective grant proposals are equal and if the first US institution is not able or willing to attain an acceptable assurance from OLAW. The second approach in effect today is the voluntary accreditation pro- gram conducted by the Association for Assessment and Accreditation of Labora- tory Animal Care International (AAALAC; www.aaalac.org), a laudable organi- zation that is well represented at this symposium. Over 750 institutions, including academic research centers, in 29 countries are currently AAALAC accredited. But AAALAC accreditation is entirely voluntary and its delibera- tions and communications with applicants are confidential. Thus, there may be just as much uncertainty about the relative quality and reliability of AAALAC- accredited institutions as there can be about US versus foreign assurances ap- proved by OLAW. However, the AAALAC approach is more rigorous than OLAW’s in that site visits are required every three years to maintain accredita- tion, regardless of past evaluations or parallel approval by OLAW or any other entity. Those site visits are conducted by an experienced team of lab animal spe- cialists to determine whether the institution remains in compliance with the Guide and other applicable standards of care and use as well as pertinent na- tional and other laws and regulations. One can envision AAALAC accreditation becoming an international standard of quality in the absence of national laws and regulations that are equal for all countries. In the meantime, there remains a need to upgrade global lab animal wel- fare standards not only to establish a more fair and consistent playing field be- tween scientists in developed and developing countries but also to ensure that lab animals used anywhere are provided protection consistent with evolving values. The often referenced International Guiding Principles for Biomedical Research Involving Animals was issued by the Council for International Organi- zations of Medical Sciences “as a result of extensive international and interdis- ciplinary consultations spanning the three-year period 1982-1984.”15 It continues to be used as an acceptable foundation to guide lab animal welfare around the world, but has not been upgraded or otherwise revised for the past 23 years. More recently, the predecessor of this conference16 and a similar one-day 15 www.cioms.ch/frame_1985_texts_of_guidelines.htm. 16 The Development of Science-based Guidelines for Laboratory Animal Care: Pro- ceedings of the November 2003 International Workshop, National Research Council.

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Global Issues: Operational Challenges in Academia 61 symposium at the AAAS annual meeting earlier this year17 compared and con- trasted various regulatory and cultural mores involving lab animal welfare among only developed nations. But neither gathering would or could go further to propose more modern goals for universal standards of lab animal welfare that would apply to research performed elsewhere. In light of these circumstances, combined with the need for more modern practices involving lab animals as more transnational collaborations arise, the following objectives are proposed, listed in no particular order:  Veterinarians responsible for laboratory animal health are sufficiently educated and trained in the biology, husbandry, handling and restraint, sponta- neous diseases, and veterinary medicine of the specific species under their care before they are assigned any such responsibility.  All laboratory mammals produced or used in research, testing, or edu- cation receive environmental enrichment unless enrichment is exempted for (valid) scientific reasons.  All laboratory mammals produced or used in research, testing, or edu- cation receive effective postoperative analgesic therapy unless exempted for (valid) scientific reasons.  Lethal endpoints are not permitted for laboratory mammals produced or used in research, testing, or education. Animals approved to decline to moribund endpoints are monitored frequently enough to ensure they are euthanized before they die.  Veterinarians responsible for laboratory animal health have authority without interference or penalty to intervene on behalf of animals experiencing unapproved or otherwise excessive pain or distress. These objectives will be presented to the American and European Colleges of Laboratory Animal Medicine for submission to the International Association of Colleges of Laboratory Animal Medicine, with a recommendation that they be adopted within five years. Summary We are witness to a rapidly changing environment for academic animal re- search in which comparable expertise and resources are available at lower costs in a more transparent and more knowledgeable global society. It is imperative that lab animal welfare standards be adjusted and universally adopted to ensure that good science and good animal care continue to go hand in hand everywhere lab animals are used. 17 “Optimal Laboratory Animal Care and Use: The Road to International Guidelines,” AAAS Annual Meeting, Boston, February 17, 2008.

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Overcoming Challenges—Academia in Europe Harry van Steeg My presentation will focus on an overview of the animal studies going on in our institute.1 Most of these studies are embedded in international collabora- tions, among others, with NIH support and grant money. Differences in stan- dards in animal testing are encountered especially in these international projects. Here is a brief overview of the studies being conducted and the areas of interest. There are two primary research fields. First, we are interested in develop- ing alternative test models for carcinogenicity and mutagenicity. In particular, we are interested in the mechanisms of nucleotide excision repair, or in general genome maintenance, and p53, the cell cycle control gene. In addition, we are involved in large survival studies in models that have a defect in genome main- tenance genes. In particular, what is the effect of this defect on survival and ag- ing in these models? We encountered some differences in regulations in these studies. Why are we interested in developing alternative tests for carcinogenicity testing? The gold standard is still the rodent two-year bioassay, which is very tedious and uses many animals—at least 500 rats and mice must be used to test one compound—and a very high dose is used, up to the maximum tolerated dose, which is totally irrelevant to human exposure. These assays also require long exposure times over the lifetime of the animals, which is two years or longer. Based on these dose-regimen protocols, these two-year bioassays often produce many false positive results. Thus, the results are not reliable, and these assays are very expensive. Therefore, we are interested in developing alternative test models to de- crease animal use and use lower, more relevant doses at lower cost. The idea was to make animal models that are more sensitive to carcinogens and in that way use fewer animals. In our institute in the Netherlands, we developed a DNA repair-deficient mouse model, XPA, and we combined it with a p53-deficient model, which was 1 The National Institute of Public Health and the Environment in Bilthoven, the Neth- erlands (www.rivm.nl). 62

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Overcoming Challenges—Academia in Europe 63 developed here in the US. Based on our preliminary results, this is a very inter- esting model, and we were invited by the International Life Sciences Institute and the Health and Environmental Science Institute (ILSI/HESI) to become a member of a global initiative to foster alternative testing in carcinogenicity. In this program, there were four different transgenic mouse models—among oth- ers, our XPA/p53 model. Twenty-one different carcinogenic and noncarcino- genic compounds were tested. Exposure time was six to nine months instead of two years. For each compound tested, there were only 120 animals, with 30 animals (15 males and 15 females) per dose group for each of three doses. In this global enterprise there were pharmaceutical industries, contract re- search organizations, governmental institutes like ours, and regulatory entities, like the US Food and Drug Administration (FDA) and the Committee for Pro- prietary Medicinal Products (CPMP) in Europe. In total, there were over 70 dif- ferent partners in a big program. The outcome of the study is that most of the known human carcinogens tested positive in our transgenic models. Some compounds were false positives, which are compounds that test positive but may not actually be carcinogenic to humans. They tested positive because of the dose regimen used in this rodent assay. These alternative transgenic models may prove to be very interesting if used as an adjunct to the two-year bioassay, which is what is currently happen- ing. Both the FDA and the CPMP in Europe allow the use of transgenic animals as an alternative to the mouse lifetime bioassay. The current test for pharmaceuticals still uses 500 rats with a two- to three-year exposure. There is an alternative test with the mouse, which uses only 120 animals and exposure times of only six to nine months. This clearly is a big advantage in terms of the 3Rs concept. The next part of this presentation will focus on the aging studies in the in- stitute. The basic research question is, Do DNA repair systems, or genome maintenance genes, have an effect on aging in terms of survival and pathology associated with aging? The experimental design included different mouse mod- els having one type of DNA repair defect. Every survival study used 50 males and 50 females. The controls were the C57BL/6 animals. In these aging cohorts, we do complete analysis of all the animals when they are still alive, of course. When they are dead, you cannot do autopsy on them and pathology…. In order to determine what happens during aging, cross-sectional studies were done. Samples were taken from many tissues from each of 15 males and 15 females at several time points. The time points were 13, 26, 52, 78, 91, 104, 117, and 130 weeks and the total number of animals was 200. These are very expensive experiments that we perform in conjunction with many American groups. In doing them, we discovered that there are different standards in the animal testing. As noted already, in the European Union animal experiments are performed based on engineering standards according to local and EU rules and regulations. Animal welfare is a critical issue and, at least in the Netherlands, we are required to prepare an animal welfare book. In the US

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64 Animal Research in a Global Environment: Meeting the Challenges the experiments are based more on performance standards, on scientific facts…; when projects are funded by NIH…the rules are more stringent. In Europe, there are two different regulations. One, designed by the Euro- pean Union, is the Council Directive 86/609, which is quite old, from 1986; it is currently being revised. This document was mainly based on economic and po- litical considerations, and not animal welfare; however, in the revision there will be attention paid to animal welfare issues. This law will apply to the 27 member states of the European Union. The other document, the European Convention for the Protection of Vertebrate Animals Used for Experimental Purposes (ETS 123) was passed by the Council of Europe, which comprises 47 member states. The focus of this organization is on social and cultural cohesion. The premise of this document is that humans have a moral obligation to respect all animals. While not all the member countries have ratified this document, our country did. Therefore, in Holland we obey both protocols. An overview of the animals used in the EU from 2005 shows that most are rats and mice as well as some cold-blooded animals. Very few nonhuman pri- mates are used. Research on nonhuman primates is still allowed in the Nether- lands, but it is not very common. In the Netherlands, about 50 percent of animal studies are for fundamental research or education; the other 50 percent are for testing pharmaceuticals, vaccines, or other toxicity tests. In total, there were about 600,000 animals used in 2006. In the EU the total was 12 million in 2005; worldwide, it was 100 million to 150 million animals, which is a large number. Most countries in the EU have signed on to those two documents. But as has already been discussed, Europe is divided on these issues. Some member states have refined the rules to make them more stringent; among those are the UK, Germany, the Scandinavian countries, and the Netherlands. The Nether- lands has its own animal welfare law as well, which was passed in 1977 and has been updated since. According to this Dutch law, I am obligated by my institute to submit all new projects. They must be reviewed by the ethical commission. When the project is granted, all individual experiments need to be reviewed as well. So there is very good oversight. (I must provide documents for the US projects to the NIH. I have an assurance based on time; mine is for four years, which is the duration of the project. We have not had a site visit by NIH.) So what is in the additional law? Nobody is allowed to do animal experi- ments unless the institute receives a license from the minister of health. Scien- tists are obliged to ask permission from the IACUC, otherwise we cannot do an experiment. The members judge whether the use of animals is legal, ethical, [and] justified, the number of animals proposed is appropriate, measures are taken to alleviate pain, and so on. Animal studies are prohibited when there is an alternative with respect to the 3Rs—there are no exceptions. Studies with great apes are prohibited, [but] experiments with other nonhuman primates are still possible. We have three levels of education on responsibilities for people who are involved in animal studies. We have the Article 9 officer, who is a scientist who took a course in animal studies, including statistics; this course only takes three

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Overcoming Challenges—Academia in Europe 65 weeks. The Article 9 officer designs experiments, which are assessed on their scientific content by an institutional scientific committee. The study design is assessed on ethical merits by the Article 14 officer and is approved by the IACUC. Then we have the Article 12 officer, who is an animal technician and has had a complete study on animal handling, animal anatomy, autopsy, and so forth. The duration of this study is three to four years. Article 12 concerns all animal handling, including breeding, maintenance, critical surveillance, autop- sies, and euthanasia. Finally, we have the Article 14 officer, who is an animal welfare officer with an academic education in a biological discipline and postdoctoral training in laboratory animal sciences. This person is not, per se, a veterinarian in our country, but is involved in all ethical and animal welfare issues. We are not allowed to let the animals die when they suffer, particularly in the longevity studies we are doing. We have criteria defined as to when we need to kill the animals. Those criteria are when there is extensive weight loss (10- 20% of the total weight within two weeks); when there are changes in behavior, such as lower mobility or hunched back; cyanosis; and tumors or ulcers. The final decision on euthanasia is made by the pathologist after consultation with the Article 14 officer. The Article 12 officer euthanizes the animal. At the end of the animal’s life, we prepare an animal welfare book de- scribing animal discomfort, if any. This report goes to the legislated inspection services for review, and information is used to adapt for future experiments. What does this mean for aging studies? One of the parameters of these studies, of course, is determination of the lifetime of the animals. This is a cru- cial parameter. However, when animals suffer—for example, when they develop ulcers or tumors—they need to be euthanized…. The Netherlands does not per- mit keeping the animals alive under those conditions. In housing, it is not permitted to keep the animals solitary. However, when the animals get older and older, every now and then there will be only one ani- mal in a cage, but because that is not allowed, buddy animals must be added. The question, of course, is, Do the animals live for shorter times in our hands? We do have one advantage in killing the animals earlier in that we can obtain more end-of-life pathology, and we can determine their causes of death. However, the survival is worse. The survival curve of C57BL/6 female mice shows that 50% survival is approximately 110 weeks; the survival curve of the XPD female mice with an accelerating aging phenotype shows a shorter survival compared to the C57BL/6 mice. According to the literature, C57BL/6 females typically live between 110 and 115 weeks and in our lab, the survival was about 110 weeks. Therefore, even with the requirement for humane endpoints, the survival did not differ sig- nificantly from that of animals who were allowed to die naturally. Based on these longevity studies I conclude that under our conditions we can still do reliable studies and that the studies are comparable to those of oth- ers. Euthanasia is not a restriction. Therefore, although restrictions concerning

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66 Animal Research in a Global Environment: Meeting the Challenges animal welfare are more stringent in our country as compared to the US, I be- lieve that the outcomes of our experiments are equally valid. Given the regula- tion, there is no restriction on the types of research or toxicology testing we do. We can do the studies we want, provided we go to the ethical commission. And our research is still competitive, given the fact that we get some financial sup- port also from the US. Given all of these points, I believe that we should take animal welfare into account. It does not compromise the experiment and it is beneficial to the ani- mal. Finally, I would like to mention our collaborators on the many projects, both nationally and internationally. I acknowledge the collaborators on our can- cer studies in the Netherlands, at the University of Amsterdam and Leiden, and those on our aging studies at the Erasmus University in Rotterdam. In the US, we collaborate with the Cancer Center at MIT, M.D. Anderson, and the Univer- sity of Cincinnati. We are intensifying our collaboration with the National Insti- tute of Environmental Health Services, to develop alternative tests for the Na- tional Toxicology Program (NTP) for carcinogenicity testing. We collaborate with the Albert Einstein Institute in New York, Lawrence Berkeley Laboratory, and the University of Texas on aging studies. Our financial support comes both from the EU and from the US with three NIH grants.