Orphanet: About orphan drugs
About Orphan Drugs

What is a clinical trial ?

A clinical trial is a medical study conducted to test the effects of a new or already existing drug, of a biological treatment or of a medical device that might treat or curb a disease already identified. The main goal of a clinical trial is to compare two or several groups of subjects, by using two or several treatments in order to determine the efficacy of a drug or of a biological treatment.

Clinical trials are carefully and ethically conducted in order to protect patients against unwanted adverse reactions and to allow collection and accurate analysis of the information concerning the disease.

Four key points on clinical trials :

  1. The aims of a clinical trial are, on the one hand, to make sure that the new treatment that is to be tested is safe and, on the other hand, that it shows therapeutic efficacy in a given indication.
  2. Drugs are tested in humans only after pre-clinical trials (carried out in vitro and on experimental models), which is a prerequisite necessary to study the pharmacology (study of therapeutic effects) and toxicology of the active substance.
  3. People wishing to participate in a clinical trial must be well informed about the study, including about the side effects and benefits they may get from research. The physician responsible for the trial is in charge of explaining the protocol, answering all the questions and obtaining the 'informed consent' of the participants.
  4. The patient can refuse to participate or leave a clinical trial at any time and this shall not be detrimental to the relationship between the patient and the physician.

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What is a protocol ?

All the clinical trials are based on a protocol that is well defined and written down.

The methodology for the trial is accurately described. It mentions the different protagonists of the trial :
the sponsor, the main investigator and the persons participating in the trial. It gives details on the various methods used in the trial, as well as its assessment criteria which are the same for all the participant in the trial and which respect 'good clinical practice'. At each phase, evaluation allows researchers to assess the efficacy (and the tolerance) of the active substance. This evaluation must be easy, reproducible and sensitive enough in order to detect low level variations. The conditions and techniques of evaluation are standardised, and criteria are measured at the same time for everyone.

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What are the purposes of a clinical trial ?

The two main purposes of a clinical trial are the determination of the safety, the tolerance and then the efficacy of a drug.

How is it tolerated ?

When a drug is active, it is, by definition, 'potentially dangerous' and its misuse may trigger relatively minor disorders (vertigo, nausea, dryness of the mouth) or accidents that may be more serious (cardiac disorders, anaemia, haemorrhage). A new drug is tested in humans only after toxicology and pharmacology studies have been performed on laboratory animals.

Is the drug effective ?

When a symptom disappears, it does not mean that the drug is effective. This improvement or recovery may be due to other causes: the natural course of disease, an underlying pathology, another therapeutic effect or a 'placebo effect'.

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What are the different phases in a clinical trial ?

Clinical trials for testing a new molecule are normally conducted in three phases, each involving a larger number of people. When a molecule is already known in another therapeutic indication, phase I is not carried out.

Phase IV studies are the longest and start once the drug is on the market (post marketing studies). It aims at determining the adverse reactions and pharmaceutical proprieties that would not have been found during the first three phases.

Phase I :

Studies aimed at assessing the safety of a drug and knowing its pharmacokinetics (i.e. what happens to the drug in the human body: absorption, metabolism, elimination and excretion).

These studies are generally short (lasting from some days to some months) and involve a small number of healthy volunteers (people with no disease diagnosed wishing to participate in a clinical trial). They are hospitalised during the trial so as to be closely followed-up. It aims at determining the maximum dosing level of drug tolerated as well as side effects that occur as dosage levels are increased.

About 70 percent of experimental drugs pass the initial phase of testing.

Once the drug has been shown to be safe, it must be tested for efficacy.

Phase II :

These studies last from some months to 2 years and are performed on a small homogeneous group of patients (10 to 40 patients).

They aim at studying the efficacy of the product and determining the smallest efficacious dosing level and the best posology for phase III.

Only one-third of experimental drugs successfully complete both phase I and phase II studies.

Phase III :

They are comparative studies conducted on several hundreds of patients. This comparison is based on randomisation of treatments. They are double-blinded studies.
The treatment that is being tested is compared either to a placebo, or to a reference drug for the therapeutic indication studied. These phase III studies allow researchers to determine the tolerance and the efficacy of the product and therefore to assess the benefit/risk ratio of the drug.
They are large-scale studies conducted most of the time during one or several years. Relying on the results obtained after phase III, the pharmaceutical industry can submit an application for marketing approval to the relevant health authorities.

Seventy to 90% of drugs entering phase III will be candidates for a marketing approval application.

Phase IV (post marketing) :

These studies allow researchers to have a better knowledge of the drug by :

  1. comparing the drug to other products already on the market ;
  2. assessing the long-term effects on the patient's life quality ;
  3. determining the cost-effectiveness of the treatment compared to others.

These studies are on-going and allow the pharmaceutical industry to have arguments for the review of the marketing approval every 5 years.

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What is a placebo ?

In a therapeutic trial, the placebo (noun derived from Latin and meaning 'I will be liked') is a substance that resembles the drug that is being tested, but which contains no active substance. Therefore its potential effect is independent of the active substance that is to be tested.

During the trial, the drug tested must be compared to another treatment. When no effective reference treatment exists or is available in the disease concerned, the drug tested is compared to a placebo. One group of subjects receives the drug while the other receives the placebo.

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What is the placebo effect ?

It is the difference between the change noticed (global therapeutic effect that can be clinically assessed) and that attributed to the pharmacological effect of the treatment (specific effect or pharmacodynamic effect when it is a drug).

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What is a comparative trial ?

The evaluation of a therapeutic process is usually done through a comparative trial : the 2 groups only differ with regard to the treatment administered (active substance or placebo). This trial usually corresponds to phase III.

The phase of recruitment is particularly difficult, because the subjects included in a comparative trial must form a homogeneous group defined by specific criteria: they have to be affected by the same disease and present with similar symptoms. The rarer the disease is, the more difficult it is to find people. This is why research teams belonging to different research centres are often involved (multicentre study).

The people participating in a comparative trial are divided into two groups, each receiving a different treatment :

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What is a controlled or randomised trial ?

A controlled trial allows scientific objectivity. One of the control methods is randomisation, which is the random distribution of patients into different groups. Scientifically speaking, it is referred to as a 'randomised comparative trial'.

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What is a blinded or double-blinded trial ?

A blinded trial is a trial in which participants do not know to which group they belong: either to the group receiving the drug tested, or to the control group. No patient knows the type of treatment he is receiving.

During a double-blinded trial, neither the patients nor the medical team know the type of treatment administered. Therefore the human factor that may influence the results of the trial is eliminated. When needed, the composition of the groups and of the corresponding treatments may be disclosed.

This type of trial is the only procedure scientifically recognised which allows researchers to draw conclusions on the effectiveness of the product independently of the placebo effect. However, it cannot always be carried out (very complex organisation, the use of a placebo is sometimes impossible).

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What is informed consent ?

Before initiating a clinical trial the sponsor must get the informed consent of all the participants. This principle aims to make sure that each participant is sufficiently informed so as to be free to choose to participate or not to participate in the clinical trial. When people give their informed consent, they must have been informed at least about:

All the information is given orally and written down on a document delivered to the person that gives his/her consent. In addition, a physician is present during each interview to answer all his/her questions.

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