Authorization of medicinal products: possibilities and criteria

If a pharmaceutical company wishes to bring a medicinal product to market, it usually has to apply for authorization to do so. The authorization gives the company state approval to market the medicinal product. Within the scope of the authorization process, the pharmaceutical company provides evidence of the quality, efficacy and safety of the medicinal product. In this context, safety means that, if used as intended, a medicinal product does not have any harmful effects that go beyond what is reasonable according to the findings of medical science.

The therapeutic efficacy and safety of the medicinal product are determined in studies: from simple laboratory tests in a test tube to animal testing (if necessary) and clinical trials involving healthy participants or patients. The most important criterion for authorization is that the benefit of the medicinal product outweighs its potential risks.

Pharmaceutical companies must provide precise evidence that the medicinal product is effective with regard to the relevant illness and does not harm patients.

On applying for authorization, pharmaceutical companies submit extensive documentation on quality, efficacy and safety. This is then reviewed by the relevant authorization authority. The authority has a maximum of 210 days to review the documentation.

There are various application procedures within the European Union:

National procedure

If a medicinal product is only intended for the German market, it can be authorized using the national procedure. Depending on the type of medicinal product, the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI) is responsible for this.

Decentralized procedure (DCP)

With the decentralized procedure (DCP), a medicinal product is authorized in several EU countries at the same time: a new authorization is applied for in several European countries at the same time, one of which takes charge of the review.
This procedure is used for most imitation products (generics).

Mutual recognition procedure (MRP)

With the mutual recognition procedure (MRP), national authorization has already been granted in one country. This can be expanded to other countries using the MRP.

Centralized procedure

With the centralized procedure, the pharmaceutical company applies for authorization for the entire European Economic Area. The procedure is coordinated by the European Medicines Agency (EMA). The scientific review of the documents submitted is performed by experts from national authorities and the EMA’s Committee for Medicinal Products for Human Use (CHMP). The authorization is issued by the European Commission. Certain medicinal products, for example new active substances for combating cancer, diabetes, autoimmune diseases or rare diseases, can only be authorized using this procedure.

The scope of the documents to be submitted and reviewed primarily depends on the newness of the medicinal product. Under certain circumstances, special authorization procedures can be used for medicinal products, for example if a particular product is required particularly urgently. If the efficacy and safety of an active substance are already well-known, medicinal products can be authorized with less extensive documentation.

Accelerated procedure at the EMA

The European Medicines Agency (EMA) also has accelerated authorization procedures. These are used if medicinal products are required urgently, for example to close therapeutic gaps in the case of severe illnesses or if there is a pressing need to act during a pandemic. Despite the accelerated process, the data is reviewed just as carefully as with the regular authorization process. The quality, safety and efficacy requirements are as high as ever.

Orphan drugs for rare conditions

It is often not particularly profitable for pharmaceutical companies to develop medicinal products for conditions that only affect a few people. Such products are known as orphan drugs. To enable them to be developed and authorized despite this obstacle, the EMA offers a free authorization procedure for medicinal products for rare conditions. The criterion for this is that the condition does not affect more than 5 in every 10,000 people in the EU. If authorization is granted, the company has exclusive marketing rights for a period of ten years. This should offset the cost of the research and development work.

Medicinal products for children

Most medicinal products are designed for adults and not specially tested and authorized for use by children. In many cases, the dosage of an active substance is therefore adapted to children’s bodies on the basis of experience. According to Regulation (EC) No 1901/2006, for a new medicinal product to be authorized, the suitability for children and adolescents must also be proven through the use of appropriate studies.

Authorization for generics and biosimilars

Generics and biosimilars are imitations of medicinal products that have already been authorized. When applying for authorization, reference can therefore be made to the authorized original medicinal product (reference medicinal product).

In the case of generics that are essentially identical to the reference medicinal product, no further separate clinical trials on efficacy and safety are required. However, the pharmaceutical company must prove that the new product affects the body at a comparable speed and to a comparable extent to the reference medicinal product.

A reference medicinal product can also be used in the case of biosimilars. However, biosimilars are usually complex biological medicinal products that are not completely identical to the reference medicinal product. Separate laboratory studies and clinical trials are therefore required for the authorization process to prove that the effect is comparable.

Almost all new medicinal products have to be authorized. However, there are exceptions where a registration procedure can be used as a simplified format. Certain medicinal products are also exempt from the need for authorization (standard authorization).

Registration

A registration procedure is used for homeopathic medicinal products without a defined area of use as well as for traditional herbal medicinal products.

Even with registration, the pharmaceutical quality and safety of the medicinal product must be proven. With traditional herbal medicinal products, the efficacy and safety are demonstrated in the evidence of traditional use: the traditional herbal medicinal products must have been safely used for medicinal purposes for at least 30 years, including for at least 15 years in the European Union. Unlike with an authorization, no clinical trials are required to prove the efficacy.

Standard authorizations

Standard authorizations release certain medicinal products from the mandatory requirement to be authorized if the requirements with regard to the necessary quality, efficacy and safety have been proven to have been met. This is subject to the criterion that there are no potential risks to people. For example, standard authorizations have been issued for many herbal medicinal teas or medicinal products that are individually prepared for patients in pharmacies.

Clinical trials assess the quality, efficacy and safety of new medicinal products. They are a prerequisite for the authorization of new active substances. Before a clinical trial begins, data is collected from laboratory tests on cells and animals. These tests are known as preclinical studies. They are primarily used to ensure that medicinal products are not carcinogenic, mutagenic or teratogenic (toxic to reproduction).

If the results of the preclinical studies are promising, an application can be submitted to the responsible higher federal authorities (BfArM or PEI) for the performance of the clinical trials. The clinical trials can only begin once approved. They usually involve four consecutive development phases, which often overlap in newer clinical trials so clear lines can no longer be drawn between them.

Phase 1 trial

A phase 1 trial usually involves a small number of healthy volunteers. It does not yet matter whether the active substance to be trialled is actually effective against a particular illness. Certain indications such as cancer are exceptions to this: as it is not possible to perform tests on healthy people, affected patients are involved right from the start.

The aim of phase 1 is to investigate the safety of the active substance for humans. As such, participation in a phase 1 trial is not completely without risk and not recommended for everyone.

In addition to safety, the phase 1 trial also looks at the metabolization of a new active substance in the body to determine the optimum dose range.

Phase 2 trial

If the phase 1 trial is successful, the phase 2 trial can begin. This trial phase investigates for the first time whether the active substance is actually effective against the illness. The participants are therefore patients with a certain health condition. Between 50 and 500 people usually take part. In addition to the efficacy, phase 2 is also used to determine common side effects.

Phase 3 trial

Once the phase 2 trial has proven good efficacy and that there are no unacceptable side effects, the phase 3 trial begins. This phase is used to test the efficacy and side effects on a larger number of patients – usually more than 1,000. This makes it possible to further expand the range of data on efficacy. It is also possible to determine rare side effects, which did not show up in phase 2 due to the smaller number of test subjects. If phase 3 is successful, the manufacturer can apply for authorization.

Phase 4 trial

During a phase 4 trial, the medicinal product has already been authorized and is on the market. Despite this, even after the authorization, medical questions can still arise or affect certain groups of patients and need to be investigated within the scope of further clinical trials.

In phase 4, it is also possible for extremely rare side effects that affect less than one in every 10,000 people to be reported and registered for the first time.

Quality criteria for clinical trials

Good, trustworthy clinical trials should fulfill certain quality criteria. These include there not only being a treatment group but also a control group: subjects in the control group received a sham medicinal product (placebo) or an already established medicinal product – ideally without knowing this. The people who administer the substance should also be unaware of which medicinal product is being administered unless they need to know for safety reasons. This ensures that all participants are treated the same. This “blinding” – i.e. not knowing whether the new medicinal product or the placebo/control medicinal product is being administered – is an important quality criterion.

Subjects should be assigned to the different groups at random. The voluntary participation of the subjects is a further key principle of clinical trials: no-one has to take part in a clinical trial if they do not want to. Participants can also withdraw from the trial at any time without repercussion.

A newly granted authorization is usually valid for five years or one year in the case of conditional authorization. Once this period has elapsed, experts review whether the medical benefit of the medicinal product still outweighs its risks. If, after the first five years, there are no safety concerns on the basis of the experience gained, the authorization is generally extended for an unlimited period.

Monitoring authorized medicinal products

The relevant higher federal authority precisely monitors the side effects of authorized medicinal products. In other words, this is done by the Federal Institute for Drugs and Medical Devices (BfArM), the Paul Ehrlich Institute (PEI) in cooperation with the European Medicines Agency (EMA) or other EU authorization authorities. Very rare side effects sometimes only occur after authorization, when the medicinal product is used by a larger number of patients. If these are serious side effects and the benefit therefore no longer outweighs the risks, the medicinal product may no longer be used. In such cases, the authorization can be permanently revoked or temporarily withdrawn.

If changes to the medicinal product are required after authorization, the pharmaceutical company must report these to the responsible authority. In the event of major changes, these can only be implemented with the responsible authority’s consent.

Black triangle symbol

Medicinal products containing new active substances, biological medicinal products and medicinal products with a conditional authorization are monitored particularly carefully. They are labeled with a black triangle as less information is often available about them than about other medicinal products. This can be because there is not yet sufficient data about their long-term use, for example. It does not, however, mean that such a medicinal product is unsafe.

Further information about the black triangle can be found on the BfArM website.

Cost coverage by health insurance providers

If a medicinal product has been authorized in Germany, health insurance providers will reimburse the cost of it. In the first year following authorization, the manufacturer can set the price itself. After that, the Federal Joint Committee (G-BA) decides on an appropriate price within the scope of the early benefit assessment.

The Federal Institute for Drugs and Medical Devices (BfArM) has compiled a list of frequently asked questions (FAQ) about medicinal products and their authorization on its website.