Since the most extensive clinical research is done in the USA, the following is related to the regulation by the FDA. Regulations in other countries usually follow similar principles but vary from place to place.
An application to the USA Food and Drug Administration (FDA) for the authorization to administer a new drug to humans in clinical trials. Following authorization the drug can move into a phase I clinical trial.
Phase I: Evaluation of clinical pharmacology
The main goal is to study the safety and tolerability of the drug. The drug is given in several dosages and information is obtained on the drug characteristics including: absorption levels and time course, distribution in the body, break down in the body, and excretion. Drug interaction with food and other drugs is also tested. In most cases phase I is done in healthy volunteers, normally 20 to 50 individuals. Treatment durations range from a single dose to 2 weeks.
Phase II: Initial evaluation of efficacy
The trial is conducted in a relatively small number of patients (few hundreds at most) having a specific illness (the “indication”). The main aim is to establish the proof that a new drug is clinically effective in the treatment of the particular disease. In addition, drug’s safety is continuously checked and optimal dosages are determined. Phase II lasts from six months to two years.
Phase III: In-depth confirmation of the drug’s therapeutic benefit
A drug will move into phase III clinical trials only when phase II results have established the proof of concept for short term efficacy and safety. The efficacy is tested by comparing to reference treatments (if available) or to a placebo. The main aim is to provide substantial evidence of the efficacy and safety of the drug by testing in up to few thousands of patients and for longer treatment periods.
The formal application to the FDA for the approval of the drug for sales and marketing in the USA. The application includes the results of all clinical trials as well as the data gathered during animal studies in the pre-clinical research.
The NDA is reviewed by the Center for Drug Evaluation and Research (CDER). Experts from various relevant fields evaluate the application. Medical/clinical reviewers, which are almost exclusively physicians, have the lead role and are responsible for synthesizing the results of the animal toxicology, human pharmacology and clinical reviews to formulate the overall basis for a recommended Agency action on the application. Pharmacokinetic experts evaluate the relevant pharmacokinetic profile of the drug. A review team of pharmacologists and toxicologists evaluate the relevant profile of the drug. Statisticians evaluate the statistical relevance of the data including the methods used. Their input is critical mainly (but not only) for the evaluation of the drug’s efficacy. A team of chemists is employed and is responsible for reviewing the chemistry and manufacturing control sections of drug applications. When the NDA involves anti-infective drugs the specific section in the NDA is reviewed by appropriate specialists.
Following the review process, an approval, approvable, or non-approvable recommendation is reached by the reviewers and their supervisors, the decision must be evaluated and agreed to by the director of the applicable drug review division or office. Once the division director (or office director, as appropriate) signs an approval action letter, the product can be legally marketed starting that day in the United States.
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