For an active ingredient to be approved, it must pass a variety of test phases. Initially, tests are conducted only with cell cultures or in laboratory animals, based on the . If they are successful, they are first tested on just a few humans, and then ‒ if the benefit is deemed large and the risk small ‒ gradually on an increasing number of humans.
Nearly one-third of new potential medicinal products already fail preclinical safety tests (i.e., studies with animals), because they prove to be ineffective or too unsafe. Many more substances do not pass various later clinical trial phases for a number of different reasons. That a substance is not launched on the market is often due to it being considered too dangerous for humans in animal tests. This means the end of any further development of the substance.
Before a medicinal product is approved by the authorities, it passes through the following phases, with further development being contingent upon the successful completion of each phase.
Cell or tissue cultures are used in screenings to examine how a substance works. Animal testing is conducted if there are reliable indications that it is theoretically effective in an organism. This provides answers to the following questions: "Is there a possible therapeutic benefit?", "Is the substance safe enough to be used on humans in Phase I?". In addition, analyses of the pharmacology and pharmacokinetics (dose/effect) are conducted with animals. The purpose of the subsequent preclinical development is to carry out tolerability tests and to rule out foetal malformations with animal subjects.
This is the first investigation involving humans. Tests are conducted with only a few persons and under strict restrictions, with rigorous observation as to whether an active ingredient delivers a successful therapy outcome and is safe enough. These tests are usually conducted with six to ten healthy volunteers or with severely ill patients for whom no other treatment options are available.
Questions researchers hope to answer in Phase I include: "What effects does the active ingredient have on humans", "What kinds of side-effects occur?", "Is a medicinal product safe enough to be tested on a larger group of patients?".
If Phase I supplied sufficient evidence that the product achieves a benefit and no reasons for safety concerns have been identified, the active ingredient can be studied further in clinical Phase II. It is now investigated in a small number of selected patients. Depending on the condition for which the active ingredient is used, a Phase II study is conducted with from twenty to three hundred study subjects. The focus is on exploring questions such as: "How is the treatment’s success dependent on the dosage?" or "What is the most effective therapy scheme?".
Parallel studies with animals are still conducted in this phase, in order to study the effect of the product on reproduction.
If the results of Phases I and II are encouraging, clinical Phase III will start, in which a new medicinal product is studied in more detail in a large group of patients under practice-oriented conditions. From three hundred to three thousand, or even more, study subjects are used for these analyses. Phase III is primarily intended to determine the following: "Is the safety and efficacy of the new product better than, worse than or identical to comparable established treatments?", "How does the active ingredient behave when combined with other medicinal products?" or "What is the best option for prescribing the medicine to patients?".
Parallel animal tests are likewise carried out in Phase III, in order to rule out carcinogenic effects following long-term use.
After the successful completion of Phase III, the medicinal product can be approved, although it will be monitored further in the context of clinical Phase IV studies, with the documentation and evaluation of side-effects. A very large number of patients take the product on a routine basis, and as a result, a large amount of data on efficacy and long-term safety is gathered. This also makes it possible to identify rare or very rare side-effects.