Clinical drug development, four phases

Clinical drug development follows a sequential process. By convention, development of a new drug in humans is divided into four phases preapproval segments (Phases 1 through 3) and a postapproval segment (Phase The definitions of the three preapproval... 

Clinical drug development is generally divided into four phases Phase I through Phase 4. For each study conducted within a particular phase, specific information is collected according to the requirements for individual drugs being developed. Collection of safety, efficacy, and pharmacokinetic data is the focus of most clinical trials. Although these topics appear to be distinct disciplines. 

The clinical development of new drugs usually takes place in steps or phases conventionally described as clinical pharmacology phase I), clinical investigation (phase II), clinical trials (phase III), and postmarketing studies (phase IV). Table 1.1 summarizes the four phases of clinical evaluation. 

Initial clinical work focused on a product that would be used to convert patients who were hospitalized for recent-onset AF as an alternative to a cardioversion procedure. Cardiome partnered with Fujisawa (now Astellas Pharmaceuticals) for the clinical development of a vernakalant (1), which produces robust AF conversion rates and none of the ventricular conduction abnormalities associated with less selective agents.35 By the close of 2009, vernakalant had been in 5 large trials and several smaller trials, including a total of over 1200 AF patients. Four Phase III studies—Atrial Arrhythmia Conversion Trials (ACT 1, 2, 3, and 4) —examined patients with recent onset AF (< 45 days) and the measured the rate of conversion to NSR in various periods after drug administration.36 38 The conversion rate was 45-63% in these studies, which tended to exclude patients with more compromised heart function or a history of heart failure. While there has been no specific study looking at QT prolongation, monitoring in both patients and in healthy volunteers showed only modest increases in the QT interval with no directly associated incidents of TDP across all trials. 

The safety of medicines is under evaluation throughout the drug development cycle. This process starts before humans are exposed, and continues during the clinical development and post-marketing phases. Broadly, the safety of a medicine is tested in four phases, each of which produces different types of data. These are as follows ... 

The aim of any clinical trial is to have small Type 1 and n errors and consequently sufficient power to detect a difference between treatments, if it exists. Of the four factors that determine sample size, the power and significance level are chosen to suit the level of risk felt to be appropriate the magnitude of the effect can be estimated from previous experience with drugs of the same or similar action the variabiUty of the measurements is often known from published experiments on the primary endpoint, with or without drug. These data will, however, not be available for novel substances in a new class and frequently the sample size in the early phase of development is chosen on a more arbitrary basis. As an example, a trial that would detect, at the 5% level of statistical significance, a treatment that raised a cure rate from 75% to 85% would require 500 patients for 80% power. 

Table 8.2 shows the trends in investigational new drug (IND) filings for four new cheinical entity (NCE) approval phases.Clinical development and US approval phases by FDA therapeutic rating (priority or standard) show that priority times have decreased and standard times have been stable since 1970s until very recently. 

---