Huge amounts of medicines are prescribed and taken every year. In Germany alone, there are about 40,000 drugs on the market. Medicines should be effective and harmless, and their quality should be guaranteed and reproducible. Therefore, for a drug to be approved, it must be tested for these characteristics in Germany since 1978.
High requirements
Effective, tolerable and safe – these are the characteristics that are taken for granted for medicines to be taken, even as a patient. In order for drugs to be officially certified by the Federal Institute for Drugs and Medical Devices (BfArM) and thus approved for use in humans, they must undergo the long process of drug testing. 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 in Helsinki in 1964. All clinical trials must be reviewed and approved by ethics committees composed of physicians, lawyers, and lay persons before they begin.
The Medicines Act
The currently valid version of 19.10.1994 regulates as a legal regulation the circulation of medicinal products. It contains provisions concerning their quality, efficacy, testing, approval and prescription, as well as the liability of damage caused by medicines. The Medicinal Products Act stipulates that only medicinal products that are effective and safe may be placed on the market. Also taken into account are regulations on the protection of subjects undergoing clinical drug trials, as laid down in the Declaration of Helsinki and in each case also assessed by an ethics committee. Also stipulated are regulations on consumer information, e.g. in the form of package inserts.
The phases of drug testing
Before the effect of new substances is tested in humans, “preclinical testing” takes place. This is followed by the “pre-approval clinical trial” in three phases; the 4th phase takes place as the “post-approval clinical trial.”
Preclinical testing
After a new substance has been synthesized in chemical laboratories, the preclinical phase involves determining its physical and chemical properties, demonstrating the principle of action, and identifying dangerous side effects and toxic reactions. To this end, tests are carried out in test tubes, on cell cultures and in animal experiments. Preclinical testing provides initial information on the mechanism of action, dosage, tolerability and safety of the substance. Only if the results are promising does the actual drug trial in humans take place. “Clinical trial” in this context refers to the systematic investigation of an active substance.
Pre-approval clinical trial – phase 1-3.
Results obtained only from chemical or animal experiments are not easily transferable to humans. Therefore, in order to declare drugs as effective and safe, studies in humans are necessary. These studies are conducted and documented by physicians according to very strict, precisely defined rules. They are strictly monitored by the authorities and by scientists. The tests are carried out on volunteers: first on healthy people, and only in the next step on patients. Phase 1 trial: tolerability testing as initial application in a small number of healthy, usually younger volunteers or, in exceptional cases, selected patients (e.g., for AIDS or cancer drugs). It is used for the preliminary evaluation of tolerability and safety as well as the initial assessment of side effects. Effective doses can be established and absorption, metabolism and excretion of the substance can be determined. Only about 10% of new drugs show that they are safe and thus make it to the next phase. Phase 2 trial: now the drug is tested for the first time in patients who have the disease in question. Testing is done in a smaller number of patients (about 30-300), usually recruited in clinics. There are different approaches to testing efficacy. For example, a group of patients receiving the new drug is compared to a control group with the same disease but different or no therapy.This phase is intended to provide an initial assessment of efficacy and efficacy in particular, as well as relative safety and a further assessment of side effects. Phase 3 study: This phase will follow only after efficacy and relative safety have been confirmed in phase 2. The application is carried out in a large collective of several hundred to several thousand persons in clinics and medical practices (“multicenter study”) and often lasts several years. Efficacy and tolerability are to be confirmed and the type, duration and frequency of adverse drug reactions recorded. In addition, the extent to which interactions with other drugs or problems with certain diseases occur is now also recorded. Once tolerability, efficacy, dosage, and safety have been tested and positively evaluated after these three phases, an application for approval as a drug can be submitted to the relevant authorities for the substance.
Post-approval clinical trial – phase 4
Even after approval, the safety of a drug continues to be monitored for years. This helps to ensure that no adverse effects occur, even in patients who had not previously participated in trials (e.g., the elderly or patients with multiple diseases). Phase 4 study: The application is carried out on a very large number of patients (up to more than 10,000). Again, patients are from both hospital and physician offices. The purpose of this trial is to continue to ensure that the drug is effective and tolerable, to characterize it accurately with its risks, to detect interactions with other drugs, and also to record and evaluate rare side effects. Even after these four phases have been completed, the new drug is observed in routine use in clinics and doctors’ offices. In these so-called observational studies (Anwendungsbeobachtungen), further findings are collected and compiled.
The planning and conduct of studies
For clinical trials to be meaningful, they must be carefully planned, conducted, and documented. In particular, comparability of results is important. To achieve this, external influences must be excluded or standardized. Factors such as gender, age, constitution, previous illnesses or history and, last but not least, personal attitude play an important role. In order to minimize these influences, a number of possibilities exist. This includes, for example, distribution at random (randomization), the administration of placebo, double-blind studies (makes the result independent of expectations, since the subject does not know to which group he belongs), and others.
Study participants
Each person participating in the study must give written informed consent. Mandatory for this is detailed patient information provided by the investigator. This patient information includes the following items:
- Overview of the indication, i.e. for which disease the new substance is to be used.
- A brief description of the study, test substance, and investigations to be performed.
- Indication that the test substance is not an approved drug, but a substance under development
- Potential risks that may be posed by the test substance or associated investigations
- Tasks of the study participant
- Reference to tests that will be performed (e.g., blood tests for HIV infection).
- Reference to the likelihood of which treatment the patient will be assigned to and how the assignment will be made (in studies with placebo/comparative drugs)
- Alternative treatment options to the study treatment.
- Reference to patient insurance (address, telephone number of insurance company).
- Information on data protection, that is, how to handle the patient’s personal data.
This information must be written in a form understandable to the layman. The subject or patient has the right to withdraw consent to the study at any time.
