The long path to a medicine

Many years of high-precision work and interdisciplinary expertise go into a medicine. To ensure that medication is reliably effective in humans, research with animals is absolutely essential in the development of new medicines.

1. Medicine as high-tech product

A medicine takes almost as long as a human to mature. On average, it takes an active ingredient 13 years before it is granted regulatory approval, and a few more years before the medicine is established in day-to-day medical practice. Along the way, it may encounter blind alleys and find itself on the wrong track. But this is where the comparison with human development ends. A medicine is an industrial high-tech product whose development involves the participation of biologists, chemists, physicians, pharmaceutical experts and other specialists. Basic research and translational (applied) research prepare the ground for the development of medically useful substances, which have to be extensively tested in both the preclinical and the clinical phase, so that patients can benefit from new and more effective therapies.

2. Basic research requires animal models

A new medicine – or diagnostic agent to detect and identify diseases – starts with basic biomedical research, which looks for mechanisms that lie at the root of diseases at the level of cells, cell components or even individual molecules. Scientists deploy a wide range of modern methods for this, including animal models. These models enable scientists to reproduce life processes as they occur in humans and to understand diseases. With its insights, research establishes the requirements for actually searching for new medical substances. Only if you have a point of attack (usually a target molecule), you can search for a substance that actively interferes in the disease process. The search and “construction” of suitable substances is usually a process lasting several years that is made up of hundreds of individual steps. A great many substances are investigated to determine whether they show the characteristics required of a product. Computer-based procedures serve well here, replacing animal experiments today to a considerable extent.

3. Preclinical testing in the living organism

When substances have eventually arrived at the point where they have the potential to become a medicine, these drug candidates are tested for efficacy and safety in preclinical studies. Toxicologists and other specialists analyse them for toxicity to rule out the possibility that they may trigger diseases such as cancer or cause genetic damage. Computer simulations are used for these investigations such as bacteria, cell and tissue cultures or isolated organs. Tests with rats or mice, in relatively rare cases also with non-rodents, are necessary to study interactions of promising substances with cells and organs in the living organism. Tests of this kind are absolutely essential, for example, to determine whether a substance remains in the body long enough to achieve the desired medical effect. Tests with at least two animal species (e.g. rats and dogs) are required by law for clarifying certain issues. All tests are always conducted in accordance with internationally recognized standards.

4. Clinical trials in humans

Only drug candidates that have proved safe and effective in animals are approved for trials in humans. The clinical trial is a lengthy and organizationally challenging process. In a first step, the results obtained for example in animal studies on tolerability, absorption, distribution, metabolism and elimination of drug candidates are verified in a limited number of healthy human subjects (Phase I trials). These are followed by Phase II trials in a manageable number of patients, which yield information in particular about efficacy, side effects and the appropriate dose of the substance. The findings are verified in Phase III trials involving thousands of patients. Thanks to the large number of participants, rare side effects can also picked up in these trials. In parallel with the clinical trials in humans, further studies are carried out in animals, with which side effects during long-term use or impairment of fertility can be established, for example.

5. Animal-free alternative methods have priority

If a substance has successfully passed all the tests, it is approved by the authorities– following a detailed review of the test results – for use in patients. After the market launch, experience with the medicine is systematically recorded and analysed. Further clinical trials yield information about very rare side effects (Phase IV trials). Animal studies may become necessary in this phase as well if a product is to be approved for further diseases (indications) or in a different dosage form and new clinical Phase II or Phase III studies are required. In this case, the principle that animal experiments are only carried out if they are absolutely essential and no alternative methods are available applies throughout the entire cycle of drug development. Every animal experiment requires approval, and everyone who works with animals is required to undergo continuing education.

6. Excursion: interview with Prof. Michael Hottiger

“New medicines are inconceivable without basic research.“

Prof. Hottiger, what role does basic research play in the development of new medicines?

Basic medical research investigates the complex functions in both the healthy and the sick body. The findings obtained here ideally – but by no means always – establish the basis for new therapies. If this results in a new medicine, its development will last several years. New medicines are inconceivable today without basic research. Almost all our medicines stem from the insights obtained in basic research.

What part do animal experiments play in basic research?

Certain animal species are very similar to humans in terms of bodily functions or organ structure. Basic research exploits this similarity to understand the pathological process. The models developed in the animal can be drawn on to clarify scientific questions. Thanks to animal models we can study, describe and understand disease mechanisms that are relevant to humans without having to undertake irresponsible interventions in the human body.

Would it not be possible to use animal experiments only in applied research?

It is in the nature of basic research not to develop a medicine directly. If we confined ourselves to translational research, we would lose an important supplementary source of knowledge in the longer term. Additional insights on the functions of our body would then no longer be possible, and medical progress would find itself blocked. For this reason, it would be devastating if animal experiments were banned in basic research.

Can you illustrate this using an example from your own research?

We’re studying how inflammation occurs, how it alters the tissue or organ and how it subsides again. Our insights, for example, offer an in-depth understanding not only of bacterial infections, but also of non-bacterial, sterile inflammatory conditions, which as far as we know today play an important role inthe aging of the body or in the development of cancer, among other things. Inflammations of this kind are always associated with complex interactions between various blood cell types and the organs. This dynamic process cannot be studied in a cell culture or in organ-like microstructures. For this we need animals. Inflammation research – even if it uses cutting-edge technologies, as we do at our institute – is reliant on living organisms.

To what extent can animal experiments in basic research be replaced by alternative methods?

The principle of the 3R is of central importance. We systematically apply the principle in our research. Before I submit an application for approval by the cantonal committee for animal experiments, I give an account of the advantages and disadvantages that an animal model has and whether an animal experiment is really necessary, or whether there are alternative methods available to achieve the same level of knowledge gain.If I can do without an animal experiment, I also do so not only for animal welfare and ethical reasons, but also because it is one of the most expensive methods you can use in basic research.To satisfy animal welfare requirements as best as possible, for example, we also freeze the organs of killed animals so that we can use them again in later experiments and research. From today’s perspective, I cannot imagine that we will one day be able to avoid animal experiments completely. But by continuing to validate animal models and strictly applying the principle ofthe 3R, we can achieve further progress for animal welfare.