Every year huge amounts of medicines are prescribed and taken. In Germany alone, about 40, 000 medicines are on the market. Medicines should be effective and harmless, quality assured and reproducible. For this reason, a drug must be tested in Germany since 1978 for these characteristics.
Effective, tolerable and safe - these are the characteristics that you take for granted as a patient, even as a patient. For pharmaceuticals to be officially certified by the Federal Institute for Drugs and Medical Devices (BfArM) and thus approved for use on humans, they have to go the long way in the proving process.
This is regulated in detail by the provisions of the German Medicines Act (AMG; §§ 21-37 and §§ 40-42), which essentially correspond to the principles revised by the World Medical Association 1964 in Helsinki. All clinical trials must be reviewed and approved before the start of ethics committees consisting of physicians, lawyers and lay people.
The drug law
The currently valid version of 19.10.1994 regulates as a legal requirement the marketing of medicines. It contains provisions concerning their quality, efficacy, testing, approval and prescription, as well as the liability for damage to medicines. The Medicines Act states that only those medicines that are effective and harmless may be marketed.
Also included are provisions for the protection of subjects undergoing a clinical proving, as laid down in the Declaration of Helsinki and also assessed by an ethics committee. In addition, regulations are also laid down to inform consumers, for example in the form of the leaflets.
The phases of proving
Before the effect of new substances in humans is tested, the "preclinical examination" takes place. This is followed by the "pre-approval clinical trial" in three phases; the 4th phase takes place as a post-admission clinical trial:
After synthesizing a new substance in chemical laboratories, the preclinical phase involves determining their physical and chemical properties, demonstrating the principle of action, and identifying dangerous side effects and toxic reactions. For this purpose, tests are carried out in a test tube, on cell cultures and in animal experiments.
A preclinical test provides first indications of the mechanism of action, the dosage, tolerability and safety of the substance. Only in the case of a promising result does the actual drug proving take place on humans. "Clinical study" refers to the systematic investigation of an active substance.
Pre-admission Clinical Trial - Phase 1-3
Only results obtained from chemical or animal experiments are not easily transferable to humans. Therefore, in order to be able to declare drugs as effective and harmless, studies on humans are necessary. These examinations are performed and documented by doctors according to very strict, well-defined rules. They are officially and scientifically closely monitored.
The test is carried out on volunteers: first to healthy people, only in the next step to patients.
Phase 1 trial: Assessment as a first-time application to a small number of healthy, mostly younger volunteers or, in exceptional cases, selected patients (eg, AIDS or cancer drugs). It serves for the preliminary evaluation of the compatibility and harmlessness as well as the first assessment of side effects. Effective doses can be determined and uptake, metabolism and excretion of the substance can be determined.
Only about 10% of new medicines show that they are safe and thus make the leap into the next phase.
Phase 2 study: Now the drug is being tested for the first time in patients who have the disease. The test is performed on a smaller number of patients (about 30-300), who are mostly recruited in hospitals. There are different ways to test the effectiveness. For example, a group of patients receiving the new drug is compared to a control group with the same disease but no or no therapy.
In this phase, it should come to a first assessment, above all the effectiveness and effect, as well as the relative harmlessness and a further assessment of the side effects.
Phase 3 Study: This phase will not be followed until phase 2 has confirmed efficacy and relative safety. The application is made in a large collective of several hundred to several thousand people in clinics and medical practices ("multicentre study") and often takes several years. Efficacy and tolerability should be confirmed and the type, duration and frequency of adverse drug reactions should be recorded.
In addition, it is now also recorded to what extent interactions with other drugs or problems in certain diseases occur. If, after these three phases, compatibility, efficacy, dosage and safety have been tested and assessed as positive, approval for the substance can be sought from the competent authorities.
Post-approval clinical examination - Phase 4
Even after approval, the safety of a drug continues to be followed for years. Thus, even in patients who had not previously participated in the studies (eg, elderly or patients with multiple diseases) can be ensured that no adverse effects occur.
Phase 4 study: The application is carried out on a very large number of patients (up to more than 10, 000). Again, patients come from both the hospital and doctors' offices. The objective of this review is to ensure that the drug is effective and well tolerated, to accurately characterize it with its risks, to detect drug interactions, and to identify and evaluate rare side effects.
Even after completing these four phases, the new drug will be observed in routine use in clinics and doctors' offices. In these so-called application observations (observational studies) further findings are collected and compiled.
The planning and execution of studies
For clinical studies to be meaningful, they must be carefully planned, performed and documented. In particular, the comparability of the results is important. For external influences must be excluded or unified. Factors such as gender, age, constitution, pre-existing illness or previous history, and last but not least, personal attitudes play an important role.
To minimize these influences, there are a number of possibilities. This includes, for example, random distribution (randomization), the administration of dummy drugs (placebos), double-blind studies (makes the result independent of expectation, because the subject does not know which group he belongs to) and others.
The study participants
Every person participating in the study must give written consent. Mandatory for this is a detailed explanation by the investigator. This patient information includes the following items:
- Overview of the indication, ie in which disease the new substance should be used
- a brief description of the study, test substance, and tests to be performed
- Indication that the test substance is not an approved drug but a substance under development
- possible risks that may arise from the test substance or the associated examinations
- Tasks of the study participant
- Reference to examinations being performed (eg blood samples for HIV infection)
- Indication of the likelihood of which treatment the patient will be assigned to and how the assignment will be made (in placebo / comparator trials)
- alternative treatment options for study treatment
- Note on patient insurance (address, telephone number of the insurance)
- Information on data protection, ie how to deal with the personal data of the patient.
This information must be written in a manner understandable to the layman. The subject or patient has the right at any time to withdraw his consent to the study.