Planning and Design of Clinical Trials: 2nd Articulation

1. Phase I and II Trials
   1. A clinical trial is a prospective study which is designed to determine the effectiveness of a particular treatment, a surgical procedure or a therapeutic regimen administered to patients with a pinpoint disease. Usually, the new drug or surgical procedure is first experimented on test animals. If a tolerable dose can be determined and the drug or surgical procedure is considered to have potential efficacy, clinical trials on humans are permitted. We focus our attention on therapeutic clinical trials of drugs.
   2. A phase I, or early trial, is an exploratory investigation of one of many surgical procedure or therapeutic regimens with different types of patients totally free of unrequired side effects or without any side-effects to the patients. For example, almost all anti-cancer drugs which are specifically designed to destroy cancer cells are harmful to normal cells too. Obviously, the practicable hazards, for example, toxicity, of a treatment may need to be considered in relation to the dangers of the disease itself. A phase I trial is aimed to calculate a safe dose for further studies of a therapeutic efficacy.
   3. In general, the major aim of phase I trial is to establish a maximum tolerated dose (MTD) for a new drug. The MTD will then be used in subsequent clinical trials to determine the efficacy (phase II) and also to compare them with other drugs (phase III). In order to decipher the new drug, qualitative and quantitative toxicity of the new drug are also investigated in phase I trials. Although efficacy is not the dominant concern of phase I trials, but the investigator would not totally ignore its importance. In addition, some of the basic pharmacology of the drug, including uptake, metabolism and organ dissemination of the drug, are often investigated.
   4. The type of surgical operation or dose of drug to be used initially may be selected from antecedent experiments with laboratory animals. It was found by Freireich et al. (1966), for illustration, that, for cancer agents, MTD in humans is comparable to that in five animal species which are mouse, rat, hamster, dog and monkey when dosage was demonstrated per unit of the surface area.
   5. In a drug trial, the patient is started at a particular dosage level (usually low). For example, some phase I cancer trials use (1/3) TDL, where TDL is the toxic dose low in most sensitive large animal species, denoted in milligrams per square meters. Another initiating dose is (1/3) LD₁₀ (in mice), where LD₁₀ is the lethal dose for 10% of the experimental animals, expressed in milligrams per square meters. Many of the current cancer trials have used (1/10) LD₁₀ (in mice) or (1/3) TDL (in dogs). The amount of drug per dose in then increased gradually, the trial duration increased, or the number of doses per unit time increased until a safe dosage level can be calculated. For example, in the modified Fibonacci scheme (Carter et al. 1977, Hansen 1970), the starting dose is increased 100% initially, and subsequent dose levels are increased by 67, 50, 40 and 33% consecutively. Eventually, a dosage regimen that can be tolerated by a majority of patients is chosen as the MTD.

    

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