Clinical pharmacology or evaluation of drugs in humans
At the end of the study in animals, one will decide if the molecule under investigation deserves to be tested in humans or must be dropped out. A complete analysis of all the results obtained is necessary to evaluate the efficacy/toxicity ratio. Starting trials in humans will depend on this ratio and its comparison with similar drugs already marketed. This experimental file constitutes the requirements for beginning trials in humans.
Clinical pharmacology evaluates the properties of drugs (efficacy, tolerance, pharmacokinetic characteristics…) very often in healthy people and always in patients.
This evaluation is carried out by trials whose protocols must have a sufficient rigor to lead to the aim without harming the volunteers, healthy and patients, who accept to participate in. The trials must be in conformity with the ethics.
The person who takes the initiative of a clinical trial is called promoter. The people who direct and supervise the realization of trials are called investigators.
The written informed consent of the volunteers is needed before their incorporation in the trial: it requires a clear information about the course of the study and its possible risks.
Four phases are distinguished.
Phase I is the first administration of the compound under investigation to the man. It is carried out in a small number of healthy volunteers by increasing, by stages, the administered dose to determine those which are tolerated without adverse effect. The dose initially tested is determined according to the results of the animal experimentation, by taking a sufficient safety factor to avoid any serious risk.
It is not however licit to give drugs having an important toxicity, such as the anticancer drugs, to healthy volunteers; these drugs are tested in patients with the disease.
Blood and urine sampling is made during this phase I to obtain the first pharmacokinetic data.
Phase II is carried out in patients, in general a small number, having a well characterized disease and likely to be improved by the compound under investigation. The goal of this phase is to check the therapeutic activity expected from the data of the animal experimentation, and to determine the effective dosage.
This study can be carried out comparatively to a placebo or a reference drug, for example the efficacy of a new analgesic could be compared with that of acetaminophen.
The clinical expertises are carried out on a great number of patients during a relatively long time, sometimes several years.
The aim of this phase is to specify the therapeutic efficacy of the product, at determined dosages, comparatively to a placebo or a reference drug and to assess the importance of adverse effects.
It is generally necessary to resort to multicenter studies to find a number sufficient patients suffering from the target disease.
New drug approval, NDA
When the pharmaceutical laboratory estimates to have collected sufficient data for introducing its investigational product on the market, it files with the administrative authorities ( for example FDA, Food and Drug Administration; EMEA, European Medicines Evaluation Agency; AFSSAPS, Agence Française de Sécurité Sanitaire des Produits de Santé….), a request for new drug approval. This file includes all the data obtained during the investigations. The competent authorities can refuse or accept this new drug approval.
The active molecule, in addition to its chemical name generally too complex to be retained, has an international non-proprietary name, a brand name also called trade name under which it will be marketed. Thus the brand name Inderal* corresponds the generic name propranolol and a chemical name. The international non-proprietary name of a drug belonging to a class of drugs has generally an evocative suffix: thus the generic names of proton pump inhibitors end in “prazole”, that of beta-blockers in “olol”, derivatives of heparin in “parin”, HIV protease inhibitors in “navir” etc
For each new drug approved, a text called “Summary of Product Characteristics”, or drug label, is retained. This text mentions composition, pharmacological and pharmacocinetic properties, clinical uses, contraindications, possible warnings, adverse effects and other instructions.
Phase IV or postmarketing
The drug which received its New Drug Approval, is marketed by the pharmaceutical industry, prescribed by the doctors and dispensed by the pharmacists. Postmarketing monitoring, or phase IV, is necessary to better determine the therapeutic efficacy and the tolerance of drug under the usual conditions of use in patients different by their age, their various diseases and the other drugs used concomitantly. Some rare adverse effects are detected only during this phase or only after a few years of use.
Notice: Generic drugs
An active principle already marketed under a brand name but whose protection by the patents has expired, can be marketed as a generic drug which must have the same characteristics as the original drug. The time of protection is generally 20 years, after the date of the deposit of the patent of the original molecule and not the date of first marketing. After expiry of protection of the reference drug, a pharmaceutical laboratory can obtain the approval to market it as a generic drug, by establishing a relatively simple file involving a study of bioavailability showing that the new generic is in conformity with the already marketed reference drug.