Good Clinical Practice (GCP) is defined in the International Conference on Harmonisation (ICH) guideline as an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. This standard ensures that the rights and safety of the trial subjects are protected and that the trial results are credible. This Entry explains how ICH-GCP is applied and how a new drug reaches the market.

Clinical Trials

Before a new drug can be released onto the market, it needs to go through a series of several stages, which of course takes some time. In general, it takes between 12 and 15 years, from discovery of the drug to approval by the regulatory body¹. Most applications for new drugs are submitted to the US Food and Drug Administration (FDA), since this has great authority and, because of the International Conference on Harmonisation, other countries will accept the new drug as well.

The time it takes for a new drug to be approved can be divided into two main stages: the pre-clinical stage and the clinical stage. During the pre-clinical stage, the drug is developed up to the point where it can be tested on humans. This means that there are no human subjects involved during the pre-clinical stage and all testing and experimenting is done in vitro or on animals. The pre-clinical stage can last up to six years. When it is deemed safe and the drug developed enough, the switch is made to human subjects and the new drug enters the clinical stage, which can last from six to nine years. The main activity during these years is the clinical research, which can be divided into four phases. At the same time other minor research activities concerning the new drug also occur.

Definitions

Since you need to talk the talk before you can walk the walk, some explanation of the terminology would seem to be in order, before discussing clinical research itself:

• Placebo: a substance with no pharmacological activity, which is made up to look like the active drug and is used to compare with and so test the efficacy of the active drug.

• Randomisation: assigning patients to a treatment group in an unpredictable manner.

• Open Label: a trial in which both the patient and the investigator/doctor know what treatment the patient is receiving.

• Single Blind Label: a trial during which either the investigator or the patient (but not both) is aware of the nature of the treatment.

• Double Blind Label: in which neither the investigator nor the patient is aware of the nature of the treatment.

• Parallel Treatment: group A receives treatment A and group B receives treatment B for the duration of the trial.

• Cross-over Treatment: group A receives treatment A at the start of the trial, but after some time switches to treatment B, at which point group B, having previously received treatment B, switches to treatment A.

• Control Group: a group of subjects who are neither treated nor receive a placebo.

• Pharmacokinetics: the study of the effects of the body on the drug (by absorption, distribution, etc).

• Pharmacodynamics: the study of the effect of the drug on the body.

• Submitting: making up the necessary paperwork and getting it to the appropriate regulatory body for review and approval to market the new drug.

Four Phases of Clinical Research

Phase I

The first phase of the clinical stage consists of a trial carried out on healthy volunteers, usually a small number (between 20 and 80 subjects). For some types of drugs, patient volunteers may be used - in studies of cancer drugs or HIV medication, for instance. The aim of the study is to assess the tolerability of the patients and the safety of the new drug. Also, a pharmacokinetic and pharmacodynamic profile is made. A first assessment of the dose range - whether to use single or multiple doses - is investigated. The design of a Phase I-study is quite simple: it can be either open or blind label, with a single dose (sometimes it increases over the course of the study) and a repeated administration (the drug is administered more than once).

Phase II

During Phase II, the subjects are persons who have the disease or condition which the active ingredient is intended to treat. Though the number of patients is still relatively small (a few hundred), there will still be more than in a Phase I-study. Safety (short-term) is assessed and the pharmacological activity of the drug is demonstrated. Most importantly, it is during this study that the efficacy of the drug is examined. Does the drug treat the disease for which it has been developed? Besides the efficacy, dose/response relationships are part of the aim of a Phase II-study. Often, these studies are referred to as 'dose-finding-studies', designed to investigate which dose has the best efficacy/safety ratio. This is also why the subjects participating in such a study are usually very ill with the studied disease, so that it is easier to detect an effect of the drug. The design of such a study is more elaborate than in Phase I: patients are intensely monitored and placebo groups are used alongside several different treatment groups, with one group for dose X, another for dose Y and so on.

Phase III

Phase III studies are the most important for the development of a new drug. A large number of subjects (several thousands) are recruited and the drug is tested in normal conditions: the subject population should be a representative sample of the patient population (every person who suffers from the disease for which the drug is being developed).

Short and long-term safety and efficacy and the balance between these two are assessed. These studies are mostly comparative: the new drug's efficacy is compared with a placebo or with that of existing drugs. This also means that these studies are double blind in 99% of cases. Something to note: because of the large number of subjects that need to be recruited, Phase III studies are multinational and multi-centred (a centre can be, for example, a hospital).

Phase III studies can occur right before submitting to the regulatory body, such as the FDA, or immediately after submitting. The first are called IIIa studies, the latter IIIb studies.

Phase IV

Phase IV studies happen after approval by the regulatory body has been granted and the drug has already been marketed. These studies are mostly orientated towards marketing. Long-term effects such as morbidity, prophylaxis² or long-term tolerance are the most important objects of investigation in Phase IV-studies. Alongside this, information can be collected to see if the new drug can be used for other indications³, which has to be approved by the regulatory body first. The study population is large (on the same scale as Phase III or bigger) and consists of 'general subjects', having broad inclusion and exclusion criteria. More information is gathered and physicians get more experience with the new drug, but still under controlled circumstances. The design of this type of study is quite simple: fewer safety assessments are done and the focus is on the efficacy of the drug.

Minor Research Activities

At the same time as these four phases, other activities, necessary for the development of the new drug, are going on.

When the molecule - the active component of the new drug - is fully developed in the chemical lab, methods are devised to produce the drug on an industrial scale. At the same time, the packaging and dosages are thought out. When the drug is put into its final form, long-term stability tests are done in order to see how long the molecule keeps its potency, before it is administered to the patient and an expiration date is determined. Interactions with other drugs and substances such as alcohol are investigated and chronic toxicology and carcinogenic tests are run. A final set of tests is carried out to determine the effect of the human body on the drug (pharmacokinetic testing). Throughout this time, a team of administrators is busy compiling the file that needs to be submitted to the regulatory body. This consists mainly of the results of all the testing and the several clinical trials (Phases I to III). Other documents such as the investigator's brochure and any correspondence with the Ethics Committee are also included. At about the 11th year after the drug was first synthesised and testing on animals began, the necessary paperwork is delivered to the regulatory body and after about three years an answer is received, either an approval or a dismissal.