Clinical Trials

Clinical trials are investigations with human participants to discover or verify the clinical, pharmacologic, or other pharmacodynamic effects of an investigational drug product. A clinical trial also characterizes absorption, distribution, metabolism, and excretion of a drug product with the object of determining its safety and efficacy.

Approval of a preclinical submission by a regulatory agency, usually the submission of an investigational new drug (IND) application, determines the start of clinical trials. The design of clinical trials is related to the particular type drug under investigation.

A clinical program starts with three main strategic phases and a postmarketing phase, each with its own specific set of objectives.

The phases are as follows:

• Phase I. This phase is intended for the initial testing in healthy normal volunteers. These studies usually consist of shorter studies in a small number of participants (20 to 80), to determine the levels of toxicity, absorption, pharmacologic effects, drug interaction, metabolic effects, dose ranges, and the preliminary evidence of effectiveness.
• Phase II. These studies are usually larger than Phase I trials and are required to determine effectiveness and relative safety of the drug product. They are the first controlled studies, and they are intended to discover whether a new drug is effective for one or more clinical indications, at a specified dose and frequency of administration. The studies are usually employed as doubleblind, placebo-controlled trials and include anywhere from 100 to 200 patients on the drug. These trials are intended to establish primary efficacy end points, to help design the Phase III trials. After completing phase II trials, the drug company usually arranges a meeting with the regulatory agencies to get the agencies’ “buy-in” (agreement to proceed) on the Phase III program.
• Phase III. These studies are expanded controlled and uncontrolled trials after preliminary evidence of effectiveness and safety has been established in the previous phases. This phase establishes the clinical requirements of regulatory agencies and provides the company's marketing department with information on which to base marketing themes.
• Phase III studies are usually double-blind, placebocontrolled trials that include an increase in patient number, exposure, and length of drug administration. It is important during Phase III studies to arrange several meetings with the regulatory agencies to discuss the [Page 78]format of the registration application, any new indications, and the core of the clinical submission.
• Phase IV. The fourth phase is intended for postmarketing trials to elucidate the incidence of adverse reactions, and explore specific pharmacologic effects. Phase IV studies can also supplement premarketing data, study new patient populations, and explore other indications.

The sponsor should acquire qualified individuals (biostatisticians, clinical pharmacologists, physicians) throughout all phases of the clinical trials, to determine the design of the protocols, case report forms, and establish the appropriate clinical end points. It is also recommended that sponsors submit the appropriate chemistry, manufacturing, and controls documentation during Phase II and Phase III studies.