Searching for the “target”
Even before tests are carried out with new substances, the researchers consider what properties the substance they are looking for has or what reaction it should trigger in the body. This could be, for example, the lowering of blood pressure, the blocking of a certain messenger substance or the release of a hormone.
Researchers are looking for a suitable “target”, i.e. a point of attack in the disease process where an active substance can be applied and thus have a positive influence on the disease process. In most cases, the target is an enzyme or a receptor (docking site on cells for hormones or other messenger substances). Sometimes the patient also lacks a certain substance. In this case, it quickly becomes clear that the drug being sought is intended to compensate for this deficiency. A well-known example is insulin in diabetes mellitus.
Search for the active ingredient
The test substances are usually chemically – i.e. synthetically – produced. For some time now, however, genetically engineered substances have also been gaining in importance. They are obtained using genetically modified cells (such as certain bacteria) and form the basis of biopharmaceuticals (biological drugs).
Optimization
In most cases, the “hits” found still need to be optimized. Sometimes, for example, the effectiveness of a substance can be increased by slightly changing its structure. In these experiments, scientists often work with computer simulations, which can be used to estimate the effect of a chemical change to the substance in advance. If the prediction is good, the substance is adapted in real life, i.e. in the laboratory. Its effect on the target is then examined again.
In this way, the researchers gradually improve a new active substance, which usually takes several years. In the best case scenario, they eventually reach the point where the substance is ready for the next step: it is registered for a patent and then subjected to preclinical studies as a so-called drug candidate.
Preclinical studies
- How is it absorbed?
- How is it distributed in the body?
- What reactions does it trigger?
- Is it metabolized or broken down?
- Is it excreted?
Secondly, the scientists investigate exactly what effect the substance has on the target, how long this lasts and what dose is required.
Above all, however, preclinical studies serve to answer questions about the toxicity of the drug candidate. Is the substance toxic? Can it cause cancer? Is it capable of altering genes? Can it damage an embryo or fetus?
Many drug candidates fail the toxicity tests. Only those substances that pass all safety tests are allowed to enter the next development phase with studies on humans (clinical trials).
Whenever possible, preclinical tests are carried out in test tubes, for example on cell cultures, cell fragments or isolated human organs. However, some questions can only be clarified in tests on a living whole organism – and this requires animal experiments.
Clinical studies
In clinical trials, the drug candidate is tested on humans for the first time. A distinction is made between three study phases, which build on each other:
- Phase I: The drug candidate is tested on a small number of healthy volunteers (test subjects).
- Phase III: Testing is now being carried out on a large number of patients.
Each study phase must be approved in advance by the competent authorities: On the one hand, this includes the responsible national authority – either the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI), depending on the drug candidate. Secondly, every clinical trial requires the approval of an ethics committee (consisting of doctors, lawyers, theologians and laypersons). This procedure is intended to provide the best possible protection for trial participants in particular.
The pharmaceutical manufacturer that has developed the drug candidate can carry out the clinical trials itself. Or it can commission a “Clinical Research Organization” (CRO) to do so. This is a company that specializes in conducting clinical trials.
Phase I studies
The test subjects in phase I are usually 60 to 80 healthy adults who have volunteered to take part. After the study participants have been fully informed and have given their consent, they are initially only administered a small amount of active substance.
Tablet, syringe or ointment?
Once phase I has been successfully completed, the so-called galenics come into play: the scientists are now working on the optimal “packaging” for the active ingredient – should it be administered as a tablet, capsule, suppository, syringe or infusion into the vein?
The answer to this question is very important: the form of administration has a significant influence on how reliably, how quickly and for how long the active ingredient can fulfill its task in the body. It also influences the type and strength of possible side effects. For example, some active ingredients are much better tolerated as an injection than if they enter the body in tablet form via the gastrointestinal tract.
Galenicians also check whether and which excipients should be added to the new preparation. For example, this may be something that improves the taste of the medicine or serves as a carrier or preservative.
You can read more about the search for the right “packaging” for a new active ingredient and suitable excipients in the article Galenics – the manufacture of medicinal products.
Phase II and phase III studies
After the healthy volunteers in Phase I, it is the turn of patients to test the drug candidate from Phase II onwards:
- Phase III: The same is tested here as in Phase II, only on considerably more patients (several thousand). In addition, attention is paid to possible interactions with other drugs.
In both phases, different treatments are compared with each other: Only some of the patients receive the new drug, the rest receive either a usual or customary standard drug or a placebo – a drug that looks exactly like the new drug but contains no active ingredient (placebo). As a rule, neither the patient nor the treating doctor know who is receiving what. Such “double-blind studies” are intended to prevent hopes, fears or skeptical attitudes on the part of doctors and patients from influencing the outcome of the treatment.
Granting approval
Even if a new drug has passed all the prescribed studies and tests, it cannot be sold just like that. To do this, the pharmaceutical company must first apply for marketing authorization from the competent authority (see below: Approval options). This authority carefully examines all study results and then, in the best case scenario, grants the manufacturer permission to launch the new drug on the market.
Phase IV
If necessary, the regulatory authority then requires the manufacturer to draw attention to these newly discovered side effects in the package leaflet. However, it can also impose restrictions on use: If, for example, rare but serious side effects in the kidney area have been discovered, the authority can decree that the drug may no longer be used in people with existing kidney disease.
In extreme cases, the authorities can also withdraw a drug’s approval completely if unacceptable risks have been identified over time. Sometimes, however, the manufacturer voluntarily withdraws such a preparation from the market.
Doctors also record in protocols how the new drug proves itself in everyday use by their patients. The manufacturer uses the results of such observational studies, for example, to improve the dosage or dosage form of the preparation.
Sometimes it also turns out in everyday practice that the active ingredient also helps against other diseases. The manufacturer then usually conducts further research in this direction – with new phase II and III studies. If successful, the manufacturer can also apply for approval for this new indication.
Approval options
In principle, a pharmaceutical company can apply for marketing authorization for a new drug either for the entire EU or just for a single member state:
Applications for marketing authorization are submitted directly to the European Medicines Agency (EMA). The regulatory authorities of the EU member states are also involved in the subsequent review. If the application is approved, the product can be sold anywhere in the EU. This approval procedure takes an average of one and a half years and is mandatory for some medicinal products (e.g. for biotechnologically produced preparations and cancer drugs with new active ingredients).
National authorization procedure
The application for authorization is submitted to national authorities and therefore only in the country concerned. In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI) are responsible for this. The BfArM is responsible for the majority of medicinal products for human use, the PEI for sera, vaccines, test allergens, test sera and test antigens, blood and blood products, tissues and medicinal products for gene therapy and cell therapy.
Drug authorization in several EU countries
In addition, there are two further options if a pharmaceutical company wishes to obtain marketing authorization in several EU countries:
- Mutual recognition procedure: If there is already a national marketing authorization for a medicine in a country of the European Economic Area, this can be recognized by other member states as part of the “Mutual Recognition Procedure” (MRP).
Applying for marketing authorization for a new drug is very expensive for pharmaceutical companies. For example, processing a marketing authorization application for a completely new active substance at the EMA costs around 260,000 euros in the simplest case.
Standard authorization
Some drugs are released for sale via a standard marketing authorization: These are not newly developed preparations, but those whose manufacture is based on certain monographs laid down by the legislator. In addition, these medicinal products must not pose a risk to humans or animals. In a monograph (e.g. for paracetamol suppositories 250 mg), the composition and dosage of the preparation in question is precisely defined – as is the area of application.
Pharmacists, for example, may also prepare and then sell a saline solution according to the instructions in the relevant pharmacopoeia monograph. However, they must declare the use of such a standard authorization to the regulatory authority and the competent state authority.
Other routes for medicinal product authorizations
In addition to the conventional authorization procedure, the EU also offers options for making a new medicinal product available earlier than usual. These are not just fast-track authorizations. Rather, there are various ways of ensuring that patients can benefit from active substances even without traditional drug approval. Experts speak of so-called adaptive pathways:
Hardship programs (compassionate use)
Here, very specific patients receive medication that is actually still undergoing clinical trials. The prerequisite is that there is no other treatment option and the patient cannot take part in a corresponding study on this medication. These exemptions must be applied for separately for each individual patient.
Conditional approval (conditional approval)
- The conditional marketing authorization is limited in time.
- The manufacturer must provide the missing evidence required for a regular marketing authorization
Conditional approval is used in pandemics, for example, in order to quickly provide a suitable drug against the infectious disease.
Drug approval under exceptional circumstances (approval under exceptional circumstances)
This special procedure is used for rare diseases, for example. As there are only very few patients, it is not possible for the pharmaceutical company to submit the amount of data otherwise required for testing. With this type of drug approval, however, the manufacturer must generally check annually whether new data and findings are available.
Accelerated drug approval (accelerated assessment)
Here, the approval documents are reviewed and assessed more quickly by the responsible EMA committee – in 150 days instead of the usual 210. This route is possible if there is a promising active substance for a disease that has not yet been properly treated.
Priority medicines (PRIME)
Rolling review
In the case of urgently needed medicinal products and vaccines, the EMA can – as already mentioned – approve the active substances “conditionally” or work with the manufacturers at an early stage before final approval. In important cases, the so-called rolling review procedure begins before these approvals. The experts evaluate existing data before the manufacturer can submit all other relevant documents for approval. In addition, they continuously review all new results that emerge from further studies.
For example, the EMA used the rolling review procedure for the conditional approval of the viral drug Remdesivir during the coronavirus pandemic. As part of the approval process for coronavirus vaccines, the experts also reviewed the results already available and then obtained during ongoing phase III trials.
Medicines for children
New drugs usually undergo several studies before they are allowed to be launched on the market. However, one patient group has long received less attention in research: Children and adolescents. For the treatment of minors, the dosage of a drug tested on adults was often simply reduced.
The approval tests on minors make sense because the bodies of children and adolescents often react differently to a drug than those of adults. Efficacy and tolerability can therefore be different. The dosage therefore usually has to be adjusted for minors. In many cases, a different dosage form is also necessary for medicines for children – for example drops or a powder instead of the large tablets that adult patients receive.
Herbal medicines
When developing new herbal medicines (phytotherapeutics), proof of efficacy, as required in the form of clinical studies, is difficult:
While chemical medicines usually contain no more than one or two pure substances, each plant produces a mixture of active ingredients. In most cases, this mixture also varies in the different parts of the plant. For example, stinging nettle herb can have an effect on the kidneys, while stinging nettle root has an effect on the hormone metabolism of the prostate. In addition, these mixtures of active ingredients vary greatly depending on the origin and preparation of the plant, which also influences their effectiveness.
As the monographs of Commission E have not been updated since 1994, the monographs of the Committee on Herbal Medicinal Products (HMPC) are now used instead. This is the committee of the European Medicines Agency responsible for herbal medicinal products. It is responsible for the scientific evaluation of such medicinal products.
Traditional herbal medicinal products are to be distinguished from modern herbal medicinal products: Instead of an authorization, a registration is required here. More on this in the next section.
Registration instead of authorization
As “special therapeutic indications”, traditional herbal medicinal products, like homeopathic preparations, are exempt from the obligation to obtain a marketing authorization. Instead, they require registration:
As with the authorization of “normal” medicinal products, proof of the safety and appropriate pharmaceutical quality of the homeopathic or traditional herbal medicinal product must be submitted.
On the other hand, clinical studies to prove efficacy, as required by traditional drug approval, are not necessary for either homeopathic or traditional herbal medicines to be sold by a company.
In contrast to traditional medicines used in conventional medicine, alternative remedies usually lack extensive scientific evidence of efficacy, especially as no complex drug approval procedure is required.
