GxP-Blog

Introduction

In this modern age there are many topics that are controversial, emotionally charged, and loudly and fiercely debated. Animal testing is one such issue that polarizes society and sometimes tears open divides that cannot be bridged. Entire industries, including the pharmaceutical, the cosmetics, and the chemical industries, as well as companies that develop and manufacture medical devices, come under suspicion. Companies are anonymously targeted, but often the employees who work specifically on animals are the ones personally affected. Simple ignorance and a lack of understanding and knowledge of complex interrelationships often collide with the "Ivory Tower of Science" and create mistrust and fear. This calls for the scientific community to explain, clarify and present transparently, honestly and openly what goes on in the laboratories of its institutions. An excellent example is an initiative by Swiss, and now many German scientists, known as the "Basel Declaration" 1) (Figure 1). The Declaration transparently shows how experimental animals in science and industry contribute to saving lives, to our safety, and to improving the quality of life.

Medical devices may only be used on humans in Europe if they have been issued a CE certificate. Approval worldwide is subject to similar regulations. Medical devices must meet the fundamental requirements described in Annex 1 of Directive 90/385/EEC on active implantable medical devices, while taking into account the intended use of the device. Manufacturers must provide evidence that the fundamental requirements are met. Included in the fundamental requirements is the biological compatibility of the medical devices. Verification in accordance with Section 2 of the Directive on Medical Devices (MPV) 2) can currently only be demonstrated with animal testing. In vitro methods are also taken into consideration. But by the current state of scientific knowledge, animal  testing cannot yet be done away with. In order to comply with the requirements stipulated by law, research to be carried out is clearly described in DIN EN ISO 10993. In order to assess biological safety, it also clearly describes which materials, which design and which dimensions and precautionary measures must be taken and observed. A medical device, such as a device to be implanted in a muscle, must not damage the tissue into which it is implanted. Neither must operation of the implant jeopardize patient safety, but rather completely fulfill the function for which it was developed and increase patient quality of life. Safety and functionality are clear priorities. The series of standards for biological safety and tolerability, or in scientific terms the biocompatibility of medical devices, is logically divided into subgroups, for example, for cytotoxicity, blood compatibility, implantation of medical devices, skin compatibility and systemic toxicology, as well as fundamental issues such as general material properties and animal welfare. All of these sub-areas have more or less stringent requirements for biological safety, which must be demonstrated in animal testing.

But before scientists are even permitted to begin animal testing, legislation provides for another control mechanism to ensure that work is indeed being carried out in accordance with the latest scientific knowledge, and that only scientists who have the necessary training and experience are entrusted with animal testing.

Since 2013, provisions have been made to ensure ensure that, given our increasing global responsibility, a European harmonization of standards for the treatment of laboratory animals and for animal testing itself is observed. On July 13, 2013, the new Animal Welfare Act 3) entered into force in Germany. Its corresponding, completely new Animal Experiment Regulation 4) took effect on August 13, 2013. German law was thereby amended, in particular the revised EU Animal Welfare Directive of 2010 [EU Directive 2010/63/EC, 5)]. If all of these requirements are met, what is to be investigated is clearly described and it is absolutely impossible to use any other methods to demonstrate biocompatibility, animal testing can take place.

The animals used represent all laboratory animals that are generally recognized as the best possible laboratory animals for obtaining results comparable to humans. In 2012 approx. 8% of the total number of animals, including primates, used in experiments in Germany were for medical devices (see Fig. 2). In particular mice, rats, guinea pigs, and rabbits, as well as dogs, minipigs and, last but not least, primates are used. A variety of applications are relied on for assessing biocompatibility. These include, for example, testing for compatibility of materials on skin, where any changes to the skin is measured directly on the animal. Materials are implanted in various tissues in order to show, for example, tissue integration, cellular compatibility, and degradation processes for temporary implants. Finally, functionality tests of finished, complete medical devices show the flawless and safe functioning of a medical device, for example, artificial heart valves, stents or hip endoprostheses (for example in sheep, see Figure 3), and how the actual structurally identical medical device works when applied to and interacting with the organism.

Particularly noteworthy is the work of ISO/TC 194/WG 3 in the international harmonization process of the ISO 10993 standards for animal welfare. Recognized experts have been developing proposals that noticeably reduce stress on laboratory animals in all respects, especially in terms of 3R (Replace, Reduce, Refine). The requirements of the individual standards for animal testing are critically assessed and, in cooperation with the experts of the other groups, suggestions for improvement are discussed and, if generally accepted, implemented and applied. It should be noted that this process of harmonization goes beyond European notions, and the working group led by a Japanese colleague is staffed with colleagues from all continents and thus seeks to actively minimize the use of animals by ensuring that animal testing on medical devices is recognized by all authorities in the world. This is real and reasonable animal welfare!

Responsible researchers must find answers to the issues of modern society, on the one hand requiring continuous progress in medical care for the population and on the other, imposing high moral requirements for the treatment of animals. This is reflected in amended European and national legislation. Yet our efforts must also extend to establishing this globally and sensitizing all authorizing authorities worldwide to accept one standard. This requires new concepts and solutions, such as standardization of tests by the ISO organization, for example. Only then can it be ensured that patient safety is at the forefront of considerations when handling medical devices, while at the same time taking into account the best possible treatment of the animals used.

1) Basel Declaration, de.basel-declaration.org

2) Directive on Medical Devices (MPV), www.gesetze-im-internet.de/mpv_2002/

3) Animal Welfare Act (TierSchG), www.gesetze-im-internet.de/tierschg/

4) Regulation for the Welfare of Animals Used for Experimental or Other Scientific Purposes (TierSchVersV), www.gesetze-im-internet.de/tierschversv/

5) Directive for the Welfare of Animals Used for Scientific Purposes, www.bfr.bund.de/cm/343/5_Beratung_Anlage%203_2010-63-EU.pdf