Today a great deal of basic pharmaceutical research, as well as product control, can be achieved without animal testing.

At Novo Nordisk we are constantly on the look-out for new ways to replace animal testing and reduce the number of animals needed. Animal experimentation remains, however, essential for the evaluation of the safety and efficacy of therapeutic compounds and is furthermore still a legislative requirement. We will do our best to ensure that only experiments that can contribute to new important knowledge are carried out. We will work to ensure the well-being of the animals used in-house and on a contract basis and we will work to refine the techniques employed so more knowledge is gained from each experiment and pain and discomfort are kept to an absolute minimum.

At Novo Nordisk, animals are used in the discovery and development of new pharmaceuticals as well as testing of the biological activity of some of our products. Our enzymes are also tested on animals to make sure that they do not pose a threat to consumers or to the people working with them.

15% increase in the number of animals used
In 1997 the number of animals used at Novo Nordisk rose by 15% compared to 1996. This is due primarily to an increase in research projects on diseases related to Type II diabetes that have reached the preclinical stage where drug candidates are screened in animals. Furthermore, our figures now include animals used at PPL Therapeutics PLC, our research partner on the development of transgenic animals for the production of pharmaceuticals.

Although it is our ultimate goal to reduce the number of animals needed for research, the absolute number used each year is determined primarily by the number of ongoing research projects coupled with the development phase of each particular project. in vitro methods are used mostly in the initial stages of drug discovery, after which preclinical trials can begin, starting with studies typically using a large number of rodents, followed by studies using fewer and larger animals such as pigs, dogs and primates.

Focus group on lab animal ethics
During the past five years a focus group on lab animal ethics has been effective in driving the organization toward developing an increased awareness of the importance of high standards in this area. Among the group's recent achievements are the preparation of:

• Policy on use of animals
• Position paper on transgenic animals
• In-house training course on animal testing and experimentation
• Brochure on use of animals at Novo Nordisk
• Video on use of animals at Novo Nordisk (to order a copy, please contact Per Fledelius at pfl@novo.dk)
• Guidelines for experiments on animals at Novo Nordisk, including responsibilities and obligations
• Home page on Novo Nordisk's Intraweb - our internal Internet

Over 90% of the animals used in our research and development projects are mice and rats. Testing on larger animals such as dogs is, however, necessary to investigate how pharmaceuticals are absorbed, metalolized and excreted by the body and whether they have any side effects.

Contract laboratories
Approximately 90% of all testing and experimentation on animals takes place at Novo Nordisk's own research and development facilities. Due to a lack of in-house capacity or expertise, some experiments are outsourced to contract research organizations.

During 1997, one of the contract research organizations we have used for many years was exposed in a TV documentary on the use of dogs in research experiments. The programme revealed scenes where animals were badly abused.

Since the incident we have received several reports describing what has been done to rectify and prevent recurrences in the future. The relevant authorities have inspected the lab on a number of occasions and granted them a new Certificate of Designation. We will, therefore, continue the collaboration with this partner and monitor them closely again in 1998.

"We need to tighten our practices to ensure that the contract labs we work with apply the same high standards we set for ourselves"
Karsten Skydsgaard, Director,
Preclinical Development

Ensuring uniform standards for animal welfare
This unpleasant experience has made us aware of the need to tighten our practices for ensuring that the standards for animal welfare we set for ourselves are also observed at the contract laboratories with which we cooperate.

New 1998 target: Develop best practice guidelines for monitoring animal welfare at contract research organizations.

Monitoring in-house compliance with our policy
During 1998, a pilot project will be carried out in order to define bioethical standards and to develop tools to assess the level of compliance with our policy on use of animals.

Transgenic animals
Transgenic animals are animals whose hereditary traits have been permanently altered by genetic engineering techniques leading to an incorporation of new genes or an inactivation of gene sequences.

Novo Nordisk uses transgenic mice as models for human diseases on which new drug candidates are tested. They are also used to test the identity and purity of proteins. Less than 2% of the animals used at Novo Nordisk in 1997 were transgenic.

Animals such as sheep, goats and cows can be induced to produce specific therapeutic proteins in their milk. Novo Nordisk owns 9% of the shares of the UK research company PPL Therapeutics PLC, a world leader in transgenic and cloning technology. We are cooperating with PPL Therapeutics on two potential pharmaceuticals: Fibrinogen to stop blood loss and Factor VIIa for the treatment of haemophilia. In 1997 100 mice and 3,160 sheep were used at PPL for these projects, whereof approximately a third were transgenic.

Cloned animals
By using cloning techniques it is possible to develop a set of animals that is genetically identical. By combining genetic engineering and cloning techniques it may in future be possible to develop many individuals producing sufficient quantities of exactly the same pharmaceutical product.

Apart from our financial interest in PPL, Novo Nordisk is not presently involved with specific projects on developing cloned animals. But we believe that it is an important new technology that needs to be assessed carefully before routine use is allowed. In general, we take a positive attitude towards the cloning of animals for the production of pharmaceutical products.

We recommend an open debate among laymen, specialists and politicians on this issue. We suggest that international guidelines on cloning be developed to ensure that the technique is not used unethically.

We are opposed to the use of cloning to reproduce human beings.

Examples of replacement, reduction and refinement

• Novo Nordisk has donated DKK 60,000 to a research project at the Danish Veterinary and Agricultural University which is to identify the level of discomfort for hypophysectomized rats used to test the potency of human growth hormone. The test is a regulatory requirement and in 1997 approximately 11,000 rats were used at Novo Nordisk for this purpose
• Antibodies are used widely in our discovery and development activities. Since 1990 we have exclusively used the in vitro method for our in-house production of monoclonal antibodies, whereby an estimated 1,500 mice are saved annually. There is currently a discussion in Europe of whether the production of monoclonal antibodies in viro should be banned
• New techniques for determining the blood concentration of compounds have been developed, requiring only minute quantities of blood from fewer animals, thus giving an estimated reduction of 25% animals per study
• Investigating the side effects of pharmaceuticals on the cardiovascular system is now performed by inserting small transmitters into test animals. The animals are able to move about freely with less discomfort. The quality of the data is improved and the animals can be used again so fewer animals are needed in this kind of experiment
• Some 30 rabbits are used each year by Novo Nordisk for skin and eye irritation testing of enzymes. But animal testing may in future become unnecessary if a project we are involved in - within the trade organization of enzyme producers (AMFEP)
  - succeeds in validating in vitro alternatives
• In our osteoporosis research, compounds were formerly tested in baby mice for their possible carcinogenic effect. These studies are now conducted in a cell culture, thereby saving approximately 80 mice per compound

Number of animals used at Novo Nordisk and at contract reseach organizations

Percentage of animals used in the three main areas

Number and species of animals used at Novo Nordisk and at contract reseach organizations in 1997

Biodiversity in practice