Drug Development between Human and Animal Welfare

Abstract

Today’s drug developments face the challenge of protecting man while also promoting animal welfare. This article describes animal welfare practices in non-clinical drug development including initiatives to replace and reduce animal studies, the reduction of suffering, and the development of human-animal relationships through the refinement of methods. New legislative initiatives based on Directive 2010/63/EU may reduce animal ethics to a ‘check-the-box‘ procedures. This approach would endanger future research and the development of drugs in Europe, which is currently distinguished by high-quality and high ethical standards.

Keywords: animal welfare, human protection, non-clinical research, European legislation

Zusammenfassung

Die Arzneistoffentwicklung ist mit der Herausforderung konfrontiert, sowohl dem Wohl des Patienten als auch dem Tierschutz gerecht zu werden. In diesem Artikel werden bereits etablierte Maßnahmen für den Tierschutz in der nicht-klinischen Forschung und Entwicklung von Arzneistoffen unter Einbeziehung der ethischen Perspektiven vorgestellt. Dabei werden Methoden zum Ersatz und zur Reduktion, zur Vermeidung von Schmerz und Leid und zur Verfeinerung von Tierversuchen beschrieben. Ambitionierte nationale Gesetzesinitiativen zum Tierschutz könnten allerdings Tierethik zu einer formalen prozeduralen Methode reduzieren, verbunden mit großem Zeit- und Ressourcenaufwand. Diese Entwicklungen gefährden den Fortbestand der durch hohe ethische und qualitative Standards charakterisierten Forschung und Arzneistoffentwicklung in Europa.

Schlüsselwörter: Tierschutz, Schutz des Menschen, nicht-klinische Forschung, europäische Gesetzgebung

“Ebola drug saves infected monkeys”.¹ This title was published in Nature in August 2014 when Ebola was declared a public health emergency. The news on tests in monkeys would not have gained much positive attention if the Ebola outbreak in West Africa was not considered a global threat to humans. In fact, it appears that fear of this deadly disease initiated increased public communication on the drug development process overall.

The fundamental principle in drug research and development is based on the Hippocratic Oath: Primum non nocere. Guidelines on the ethics of clinical research, such as the Nuremberg Code, the Declaration of Helsinki, the Belmont Report, and the Convention on Human Rights and Biomedicine all stress the protection of humans’ health and dignity. In addition, regulatory authorities and international guidelines such as those of the ICH (International Conference on Harmonisation) and the ISO (International Organization for Standardization) standards 10993 require thorough safety and efficacy assessment of a potential drug candidate or medical device for first-in-human dose studies and market authorization of a new drug.²

The title cited above conceals one crucial fact, namely, that successful drug development for Ebola and all other diseases involves the sacrifice of animal health and life. The monkeys concerned were first deliberately infected and then treated in order to protect human life and not the monkeys’ lives.

Risk-benefit assessment of drugs for humans still relies heavily on non-clinical safety and efficacy studies performed in animals. ICH M3 (R2) summarizes the general principles for drug safety evaluation as follows: “The goals of the nonclinical safety evaluation generally include a characterisation of toxic effects with respect to target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility. This information is used to estimate an initial safe starting dose and dose range for the human trials and to identify parameters for clinical monitoring for potential adverse effects”.³

Developing a new drug nowadays involves more complicated issues than for the comparatively uncomplex drugs on the market. It takes 12 years on average to develop a new product, and only 1 in 10,000 compounds reach market approval.⁴ Recent advances in science, but also regulatory authority requirements, demand more and more data and consequently, more studies in animals. Laboratory animals are not only used for efficacy and safety testing of a new medicinal product, but also for quality batch control testing as part of the manufacturing process. Interestingly, regulatory safety studies for human and veterinary pharmaceuticals account for about 4.4% of experimental animals used; quality batch control testing requires 10.9% and 4% of experimental animals for human and veterinary drug products, respectively.⁵ The majority of animal studies are performed within basic research and to establish disease models to find an effective treatment therefore.

The title above also highlights the growing attention over the last 50 years for animal ethics and welfare in drug research and development. Since W. M. S. Russell and R. L. Burch published their principles of “replacement, reduction and refinement”, also called the “3Rs”, in 1959,⁶ criticism of cruelty against animals has produced numerous guidelines, legislations, and initiatives of non-profit organisations to save their lives and promote their welfare. These 3R principles focus on replacing animal experiments with alternative in vitro methods, reducing the number of animals used in a study, and refining techniques used to decrease the incidence or level of animal harm and distress.

Since the 1980s, pharmaceutical companies and contract research organisations (CROs) are increasingly establishing local animal ethics committees and hiring Animal Welfare Officers responsible for observing animal welfare during their housing period and during experimentation.⁷ In addition, companies can volunteer for accreditation by the AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care), a private non-profit organisation promoting the humane treatment of animals.⁸ The EU-Directive 2010/63/EU, which came into effect in 2013 and replaces EU Directive 86/609/EEC, aims to harmonize animal welfare for animals used for scientific purposes in all EU member states.⁹ In Austria, the new Tierversuchsgesetz 2012 (TVG 2012) regulates experiments on living animals.¹⁰ Both legal documents require assessment of the harm inflicted on animals during an experiment relative to the benefit for humans as a result of such experimentation. A set of criteria to objectify such a harm-benefit analysis is currently being developed for inclusion into applications for animal experimentation from 2016 onward.

1. The need for a two-fold effort

Drug development and the pharmaceutical industry are faced with two ethical challenges: To protect man and to promote animal welfare. This dilemma can only be solved if all parties involved possess 1) a profound and detailed knowledge of the drug development process, and 2) a critical ethical reflection of man’s dignity and of animals’ value. This two-fold approach must be incorporated on all the following levels, posing the following questions:

1. Philosophically/ethically: Which current methods are available to test drugs for toxicity and efficacy? Which are the most relevant tests for humans? Are alternative tests validated? Is it morally acceptable to weigh the suffering inflicted on animals in preclinical studies against the benefits for humans resulting from animal experimentation? If yes, how should this harm-benefit analysis be performed? Do humans and animals have the same or different moral significance when human health is at stake? Is it ethically acceptable to prohibit animal experiments at the risk of harming patients?
2. Legally: According to the EU Directive 2010/63/EU, whose normative nature is in many parts based on consequentialism, a harm-benefit analysis is required for each animal study within drug research and development. However, the directive cedes the method of analysis to the EU Member States. The parameters for assessing benefits are not yet defined and remain rather subjective. Which benefits are most relevant: Social, scientific, economic, or educational? As already pointed out by the European Commission, no single system of analysis will do justice to all projects.¹¹
3. In practice (drug development): Which initiatives are being taken by scientists and the pharmaceutical industry to promote animal welfare? How are the 3Rs being implemented? Is detailed evaluation of welfare parameters complemented by a sound ethics strategy of the drug development project as a whole? Can animal ethics be reduced to a check-the-box procedure without taking into account the responsibility of the individual researcher?

Taken together, the challenge for the pharmaceutical industry, which is an interface between science, technology, legislation, economy, and ethics, is: Who should be saved at what cost: Human or animal life?

2. The pharmaceutical industry’s approach to the life-boat situation

The basic dilemma of drug development is the so-called “life-boat situation”: Who should be saved? Man or animal?

Over the last 10 years, most international pharmaceutical companies have begun to incorporate animal ethics and welfare into corporate (bio)ethics policies, position statements, and annual sustainability reports. Independent animal welfare officers, mostly veterinarians, ensure that animal welfare is observed during the housing and experimental phase. Animal ethics committees, also called the Institutional Animal Care and Use Committee (IACUC), review animal study protocols. These committees consist of veterinarians, animal users, scientists of relevant research areas, independent lay persons, and (bio)ethicists when available. Animal facilities and programs are regularly inspected by government agencies. Studies that are outsourced to contract research organisations (CROs), as done by an increasing number of companies, must be also ethically justified, reviewed by an internal ethics committee, and regularly audited for animal welfare.

Most of these processes are incorporated into the companies’ quality system as Standard Operation Procedures (SOPs). This procedure-driven ethical approach should be supported by constant in-depth ethical and philosophical reflection. Awareness of the preliminaries which shape one’s perspective on evaluation of values, as well as continuous examination of the values at stake, i.e. animal welfare and protection of human subjects, however, are prerequisites for responsible personal ethical decisions. Such decisions are not only based on guidelines, but on a living relationship between researcher/animal caretaker and animal.

3. Perspectives, values, and practical implications in animal experimentation

The following sections describe current animal welfare practices in non-clinical drug development, taking into account perspectives and ethical values of animal care.¹²

3.1 Animal rights: The value of life - replacement and reduction in animal experimentation

Why do humans value animals? Because they are living beings. The value of life is fundamental and must be respected. However, the concept of animal rights, mainly influenced by T. Regan, virtually bars all use of animals in research because they are “subjects-of-a-life”.¹³ To kill an animal deprives it of its future. In Regan’s deontological perspective, animals, like humans, have a right to live which cannot be weighed against human interests.¹⁴ This thinking is reflected in the new EU Directive’s ultimate goal “of full replacement of procedures on live animals”.¹⁵

The scientist must consider alternative methods to replace animal experimentation. He must also provide evidence of an appropriate literature search to the internal ethics committee and the authorities approving the experiment. If the study is designed to test toxicity or safety pharmacology of a drug candidate, the proposed alternative method must be validated in order to be approved by regulatory agencies. Many large-scale international organisations, such as EURL ECVAM (The European Union Reference Laboratory for alternatives to animal testing), are involved in the development, validation, and dissemination of alternative methods. EURL ECVAM also provides a large database service for validated alternative methods.¹⁶

In vitro cell-based technologies, computational modelling, and many high throughput techniques are used to replace animal testing. Advanced alternative in vitro techniques can predict human oral absorption, distribution, metabolism, and excretion (ADME). Furthermore, new FDA and EMA guidelines recommend in vitro testing in human liver microsomes, hepatocytes, CaCo-2 cells, or other cellular systems to predict drug interactions prior to performing Phase III clinical trials.¹⁷ It is crucial that the in vitro metabolism is functional and comparable to that in vivo, or at least suitable for quantitative in vitro-in vivo extrapolation. The current in vitro system has limits as it does not yet represent a whole, intact organism including blood circulation, but only acute exposure. Therefore, it remains necessary to test even the pharmacokinetics of the drug candidate in animals before processing into clinical development.

As the American Medical Association stresses, virtually every advance in medical science in the 20th century, from antibiotics and vaccines to antidepressant drugs and organ transplants, has been achieved either directly or indirectly through the use of animals in laboratory experiments. The result is a longer, healthier, better life for humans with less pain and suffering. For many, it means life itself.¹⁸ Nevertheless, even the strongest advocates for animal experimentation acknowledge that especially mouse disease models have only limited relevance for humans. Mouse xenograft models, for example, are used to test the efficacy of drug candidates for oncology. This therapeutic area, however, has the largest number of failures, with only a 29% rate of success in Phase II and 34% in Phase III clinical trials.¹⁹ And yet, in vivo and in vitro non-clinical models mimicking the situation in humans are critically relevant for sound science.

To overcome the discrepancies between in vitro systems and the human body, the 6th and 7th Research Framework Programmes (FP6 and FP7) supported projects with human embryonic stem cells.²⁰ The question is, does the importance of respecting animal welfare outweigh human dignity and justify instrumentalization of the human embryo?²¹ In the meantime, many assays now use induced pluripotent stem cells (iPS); however, predictive cardiotoxicity assays involving human embryonic stem cell derived cardiomyocytes are still used for screening assays.²²

To replicate the organ complexity of the human body organs / tissues-on-a-chip are currently being developed with the aim of producing a human-on-a-chip. Advances in bioengineering and material sciences, microfabrication, and microfluidics technologies have led to the development of microsphysiological systems that mimic the functional units of an organ. Cellular environments and/or functional units of lung, heart, blood vessels, muscles, bones, liver, nervous system, gut, and kidney can now be engineered.²³ In 2012, the development of a two-organ-chip combining human liver and skin equivalents was achieved.²⁴ None of these methods are validated or accepted by regulatory authorities for testing potential drugs yet. Even the researchers involved in the design of “human-on-a-chip” systems admit that “it remains wishful thinking to expect such a “homunculus” (small man) on-a-chip to develop, for example, impaired consciousness or human-like myocardial infarction. One must always keep in mind that the term “human” in “human-on-a-chip” has the meaning of an artificial copy, effigy, or image. The uniqueness of a human being is inviolable.”²⁵

As a human-on-a-chip remains far from reality, one major objective of animal welfare is to avoid unnecessary animal experimentation, for example, duplication of animal studies.²⁶ Preclinical studies also require careful design based on statistical analysis to ensure that the number of animals per treatment group provides reasonable and interpretable results. However, statistical analysis should not divert the researcher’s attention from the fact that, like humans, animals experience pain and distress.

3.2 The pathocentristic perspective: The value of sensitivity

As laboratory animals cannot yet be excluded from preclinical research, one of the main tasks of animal welfare is to avoid inflicting pain and distress. Prevention of stress, suffering, and pain is at the heart of all animal welfare training and ethical review. The common understanding of animal protection groups and researchers is that animals are sensitive beings, capable of feeling pain. All animal welfare guidelines prescribe the use of species and procedure specific analgetics and anesthetics. Directive 2010/63/EU, Article 13.3 requires that “Death as the end-point of a procedure shall be avoided as far as possible and replaced by early and humane end-points”.²⁷

Despite granting animals the same moral status as humans due to their sensitivity to pain, P. Singer distinguishes between more evolved animals (monkeys and dogs) and lower animal species (rats, mice, and fish): The closer the evolutionary proximity to humans, the more morally relevant the animal.²⁸ This discrimination is also found in animal welfare legislations. Whereas the use of chimpanzees is forbidden by the EU Directive, and careful consideration and harm-risk analysis is required for inclusion of other non-human primates in research, using rats, mice and fish can more easily be ethically justified.²⁹ Also, companion animals such as dogs are increasingly being replaced by mini pigs in drug development.

Since several years, testing systems which avoid invasive procedures such as surgery are being established. For example, the development of biopharmaceuticals often requires the testing of cardiovascular pharmacology in non-human primates such as cynomolgus monkeys, as monkey data are most relevant to humans. In former years, surgery was necessary to obtain ECGs from animals with implanted telemetry. Approaches using Jacketed External Telemetry (JET) are now available and can also be used to record changes in ECG parameters without the need for invasive procedures. Before treatment, animals are habituated to the JET devices which look like small rucksacks. This method not only spares animals pain, but also provides a significantly higher quality of results.³⁰

In terms of animal suffering, is there really a difference between rats or dogs? Recent research shows pain-like states even in some molluscs.³¹ Therefore, suffering must be limited by defining humane endpoints for all animal species. According to the OECD Guidance Document on Humane endpoints, “a humane endpoint can be defined as the earliest indicator in an animal experiment of severe pain, severe distress, suffering, or impending death.³²

Study protocols for non-clinical toxicological or pharmacological assessment must include humane endpoints. Common humane endpoints are a decrease in body weight by a certain percentage and a defined maximum tumor volume in xenograft cancer models in mice. Such outcome measures require extensive training of all personnel involved in the performance of a study, i. e. the study director, who is responsible for the study design and monitoring, and interpretation of results; an independent veterinarian who advises in the event of clinical signs; and the animal caretaker/technician, who, by caring for the animals before, during, and after experimentation, develops the closest bond with them.³³

3.3 The concept of flourishing: The value of human-animal relationship-refinement

Refinement rules in the Guidelines for Accommodation and Care of Animals (ETS 123, 2007) refer to general rules for improved housing, such as a defined cage size, freedom of movement, social contact, meaningful activity, nutrition, and water, with restrictions only for a minimum of time and degree,³⁴ Enrichment basics include special bedding and nesting material. In Europe, laboratories must provide social/group housing for animals. Exceptions, mostly due to aggressive behavior of animals (e. g. male rabbits) or special procedures (metabolic cages), must be justified. For example, European facilities offer cages for group housing of monkeys, which are sometimes as high as three stories, and allow visual, acoustic, and/or olfactory contact between animals in different cages. A perch or ladder is provided to offer animals use of as much cage volume as possible. On the upper level, more than one perch must be provided to keep in line with the vertical flight reaction of primates and to reduce stress in the lower-ranking animals. A balcony offers animals a view into the neighbouring cages.³⁵ Some CROs even equip their monkey housing with swimming pools.

Most of the above discussed requirements are already defined before study initiation and rely on the application of theoretical principles. However, day-to-day animal care is more than a deductive exercise, but involves the relationship between caretaker/technician, veterinarian, and animal.

R. L. Walker discusses the concept of flourishing for animals, which includes a more comprehensive understanding of their well-being³⁶ than the exclusion of negative states such as pain and suffering only. For Walker, an animal “flourishes when it lives a life that is good for it, both as a particular kind and as a specific individual, where notions of “good for” are taken in part from a view of what is natural for it, and are assessed over its lifetime”.³⁷ This type of care can only be met by practicing virtues such as practical wisdom, patience, respect, care, friendship, compassion, justice, and reliability, depending on context.³⁸

An example for exercising patience and respect regarding the intrinsic value of each animal is by carefully assessing primates’ social ranking, which requires special training for animal caretakers. Animals delivered from breeding facilities are given sufficient time to acclimatize to the new situation. For primate housing, assessment of social ranking is of utmost importance: Aggressive and submissive behavior is monitored; the group’s hierarchical structure is defined by the frequency of submissive behavior toward peers. Animals that do not exhibit submissive behavior are considered alpha animals.³⁹ With time and daily interaction, the caretaker knows which of “his” animals are dominant, intermediate, or low ranking and their special needs. If animals do not get along, they are separated into different cages.

Positive reinforcement training is applied to improve husbandry and veterinary care, to increase the safety of the attending technicians, and to desensitize animals to fear of uncomfortable and stressful events. Gradually, animals learn to accept the caretaker; first by accepting treats from his hand, then by allowing the caretaker to touch them, and finally by permitting him to hold them during a procedure.⁴⁰ The development of an atmosphere of trust over a long, intensive period of care is necessary for a monkey to let itself be led by its caretaker to a ladder, sit down, and stretch its arm for injection of a drug candidate and blood sampling. A prerequisite for blood sampling is that an upper blood volume limit / defined time and an upper limit of stitch numbers/time is defined for each species to avoid stress or discomfort. This procedure requires much training, patience, and humility on behalf of the caretaker, whereby the human-animal bond is established via the sense of touch.

Day-to-day virtue ethics may also allow for more dynamic and positive animal welfare. Current animal welfare guidelines, such as the new EU Directive, focus on a static and negative concept, e. g. the avoidance of suffering and stress. This is certainly a basic requirement; however, a more flexible concept of welfare takes into account that each animal is able to interact and adapt to its given environmental setting.⁴¹ Good housing means not only that animals are provided a comfortable thermal environment and are able to move around freely,⁴² but that they can react freely to a change therein, e.g. find shelter when needed.⁴³

While 3R initiatives and day-to-day ethics in drug development are crucial, they become meaningless without a balance between the ethical justification for the drug development program as a whole and a detailed scrutiny of procedures.⁴⁴

4. The ethical challenge: Drug development between giving and receiving

The basic dilemma of drug development is the so-called “life-boat situation”. Man owes his life or health to the sacrifice of animals’ lives. This observation already was made by Anaximander: “Things owe each other their existence”.⁴⁵ Human and animal life is a gift which asks for an adequate response.⁴⁶ Therefore, the fundamental ethical question to the pharmaceutical industry is: What is your duty: To develop drugs to give what is due to the life/health of man and animal or to develop drugs to receive more and more profit? The basic ethical question to animal welfare advocates is: Do you consider man’s dignity besides the intrinsic value of the animal to give what is due to the life/health of man and animal? Or are you focused on animal welfare for the sake of receiving intellectual/ideological profit?

Finding a balance between giving and receiving is crucial during all phases of drug development, as addressed by the following questions:

4.1 What is the aim of drug development?

One of the basic decisions in drug development is which indications to pursue. Many pharmaceutical companies focus on developing “blockbuster drugs”, i. e. medications that yield a profit of more than a billion euros per year mostly due to the fact that they treat diseases prevalent in industrial countries.⁴⁷ With such drugs, companies can get their return on investment by the end of patent protection. Research for treatment of disease in developing countries is less attractive. However, in recent years, the development of orphan drugs for rare diseases has received increasing support by EMA and FDA.⁴⁸

Another crucial choice for companies is whether to develop life-style drugs or life-saving drugs, generic medication or urgently needed new treatment. These limited examples demonstrate that decisions in animal ethics and clinical ethics are linked to the company’s overall aim: Profit maximisation at the expense of man and animal, or health maximisation for man and animal?

Animal experimentation can be only justified by the prospect of protecting humans, but which patient group and which indication? Is economic profit not also a justifiable benefit if it allows the company to develop orphan drugs for rare diseases? The benefit/success of a project/animal study is proposed to be evaluated by a harm-benefit analysis as well as by its probability of success. No research and drug development would ever be initiated without the researcher/company’s belief in its success. If success were guaranteed, however, no research would be needed. The huge lack of clarity and the subjectivity in estimating the benefit of a project compromises every effort to objectify the benefit analysis by numeric evaluation. Animal ethicists and national legal intentions attempting to quantify benefits by factors and numbers⁴⁹ are cloaking this subjectivity with an objective system, an approach unfortunately founded on the consequentialist ethical perspective of the EU Directive which allows ethical evaluation based on calculations of the consequence.

4.2 How should ethical evaluation be performed?

Today, pharmaceutical companies’ high sales figures are often due to the acquisition of other companies or of drug candidates.⁵⁰ The factors driving such takeovers are also crucial for ethical evaluation: Is the quality of research and of the drug candidate in question relevant, or rather the marketing figures and gain in visibility for a certain indication? If market shares are the incentive behind the acquisition of a project, this may pose a challenge for those involved in the development of the drug candidate.

Drug development is heavily driven by timelines. To meet tight timelines and design scientifically and thus ethically reasonable animal studies, a sound toxicology and pharmacology evaluation of the drug is indispensible. Without this knowledge, creative further research involving additional time and resources is necessary. An animal study that fulfills all 3R animal welfare requests, but which lacks a sound scientific basis for the overall program, cannot be ethically justified. Thus, the question is whether to give preference to the value of creativity/time devoted to man and animal’s health and life or to the company’s market value?

Ethical analysis tools should enable the researcher to make well informed, responsible decisions. However, current legislative trends (e. g. harm-benefit analysis) may reduce such decisions to a time and resource consuming check-the-box process by introducing a set of criteria for the researcher/initiator of a project to complete for approval.⁵¹ Ethical evaluation should be transparent. Numeric evaluation lacking interdisciplinary appraisal is not only ethically questionable, but also legally, as the EU Directive does not explicitly demand this procedure. In addition, a static evaluation cannot cope with progressing knowledge in science and behavioral research in animals. Interdisciplinary ethics committees may be more suited to handle a complex harm-benefit analysis, which is the current approach in many EU member states.⁵² What has long been acceptable for evaluating clinical trials should also be sufficient for assessing animal studies.

4.3 How and where is drug investigation conducted?

Internal ethical review committees for animal studies, animal welfare officers, and governmental approval processes, are mandatory in all EU countries since implementation of the new EU Directive. However, if the entire drug development program is compromised, as outlined in the examples above, review may end up comprising a narrowed down check-the-box process. In addition, current incorporation of the EU Directive into national law will require more administrative resources not only in the pharmaceutical industry, but also within basic research, to comply with animal welfare regulations. This will only reinforce the following trend: To transfer research and development into countries with lower ethical standards, e. g. to Asian countries. As sound ethics are always linked to sound science, low quality of research and drug products will be the consequence.

An example for possible consequences of transferring drug development to countries with lower ethical/quality standards is the recent withdrawal of generic drugs for which results of bioequivalence trials performed in India were shown to be dubious.⁵³ Ambitious national legislative plans to introduce the highest animal welfare standards for drug development without taking into account the practical implications outlined above are short sighted. Animal welfare advocates should insist that animal experimentation only be performed in countries with high ethical standards. Only European animal welfare standards and continuous research in the EU will guarantee this.

5. Conclusion

The current focus on animal welfare in animal experimentation within drug development ensures high quality and ethical standards in this field in Europe. However, the trend of protecting animals against all harm and reducing animal studies at all costs may ultimately endanger patient safety. The following recent European and Austrian initiatives and legal implementations regarding the beginning and end of human life must also be taken into consideration: Euthanasia of animals and experimentation on animal embryos will be increasingly restricted, whereas human euthanasia and loss of human embryos by in vitro methods will receive more and more legal and ethical approval. If these tendencies continue, I may soon wish to be a dog and not a human.

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33. ebd., S. 12
34. Europarat, European Convention for the Protection of vertebrate animals used for experimental and other scientific purposes, ETS No. 123, Official Journal of the European Communities K (2007), Appendix A, S. 2525
35. Müller W., The new European housing regulations for nonhuman primates: Opportunities and challenges, in: Weinbauer G. F. , Vogel F. (Hrsg.), Critical contributions of primate models for biopharmaceutical drug development, Waxmann, Münster/New York/München/Berlin (2008), S. 53-74
36. Walker R. L., King N. M. P., Animal care and use in biodefense and emerging infectious disease research: Framing the ethical and policy issues, White Paper commissioned by Policy, Ethics, and Law Core of the Southeast Regional Center of Excellence for Emerging Infections and Biodefense (2010), www.serceb.org/documents/Animalresearchethics.htm
37. ebd., S. 76
38. ebd.
39. Müller W., siehe Ref. 35
40. ebd.
41. Ohl F. et al., Animal welfare: At the interface between science and society, The Vetrinary Journal (2012); 192: 13-19
42. Blokhuis H. J. et al., Animal welfare’s impact on the food chain, Trends in Food Science Technology (2008); 19: 79-87
43. Ohl F.et al., siehe Ref. 41
44. FELASA-Federation of European Laboratory Animal Science Associations, siehe Ref. 7, S.  8
45. siehe Gerl-Falkovitz H.-B., Verzeihung des Unverzeihlichen? Ausflüge in Landschaften der Schuld und der Vergebung, Verlag Text & Dialog, Dresden (2013), S. 62-69, hier S. 62
46. ebd.
47. Seeberger P. H., Warum die reiche Pharmaindustrie krank ist und Hilfe braucht, GEO 5 (2013); S. 50-51, hier S. 50
48. European Medicines Agency, Orphan designation, www.ema.europa.eu/ema/index.jsp
49. National Competent Authorities for the implementation of Directive 2010/63/EU on the protection of animals used for scientific purposes, Working document on Project Evaluation and Retrospective Assessment, Brüssel, 18.-19. September 2013, ec.europa.eu/environment/chemicals/lab_animals/pdf/Endorsed_PE-RA.pdf
50. Seeberger P. H., siehe Ref. 47, S. 51
51. Alzmann N. et al., The Austrian catalogue of criteria to objectify the harm-benefit analysis within the evaluation of projects using living animals, ALTEX Proceedings (2014); 3: 1/14, Prague 2014 and oral presentation on the 9th World Congress on Alternatives and Animal Use in the Life Sciences, Prague 2014
52. Guillen J. et al, Approaches to animal research project evaluation in Europe after implementation of Directive 2010/63/EU, Lab Animal (2015); 44(1): 23-31
53. Gopalakrishnan M., EU health agency questions Indian company’s research, DW-News, 5. Dezember 2014, www.dw.com/en/eu-health-agency-questions-indian-companys-research/a-18112673

Letzter Zugriff auf sämtliche Internetseiten am 6. August 2015.

Anschrift der Autorin:

Mag. pharm. Dr. Margit Spatzenegger, Lic. bioethics
Scheibenbergstraße 38, Top 2/21, A-1180 Wien
Margit.Spatzenegger(at)gmx.net