Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 28

Phase I trials (“First in Human” or FIH, sometimes also called “First in Man”) actually belong to human pharmacology, in contrast to animal pharmacology. These are the first steps in determining the profile of both the beneficial and the untoward effects in humans. They are designed mainly to find the maximum tolerated dose and the pathways for metabolizing and eliminating the drug. Safety is more important in this phase than efficacy. The first study is often a single-dose trial in a small number (e.g., a dozen) of healthy, often male (to avoid any possible pregnancy issues), volunteers. If tolerated, a multiple-dose study and a rising-dose study follow. The aim of phase I trials is to study Absorption, Distribution in the body, Metabolism, and Excretion (the so-called “ADME” studies), as well as safety and toxicity.

Other things that may be examined include the proposed formulation to be used in subsequent trials and marketing (as they may be different, and usually are) and the dosing frequency or schedule. Drug interaction studies may be done in phase I or later in phase II. If the drugs are known to be toxic or have severe and predictable ADRs, these studies are often done for ethical reasons in patients with the disease to be treated rather than in healthy volunteers, e.g., cancer chemotherapy or AIDS. Each study is short, often running no more than a few days to a few weeks at most. The trial design is usually simple and open label. They may or may not be controlled. Several phase I studies often take a year or so and may include around 100 patients in total.

There is usually no benefit to the subjects in the trial, and they participate either because of generosity of spirit or because they are paid. Because there is no gain to the individual subjects, all efforts are made to minimize the risk of toxicity. Serious adverse events (SAEs) are usually rare in phase I trials and, if SAEs occur, they often result in suspension or modification of the study protocol (sometimes an SAE will stop further development of a compound.) Subjects are often “housed” for these studies in special clinical research centers run by academic medical centers or clinical research organizations (CROs). These research centers provide for constant supervision and subjects are carefully monitored. Note that the term subjects in this context usually refers to “normal people”, not patients. However, the term subjects is ordinarily also used to refer to people, with the disease in question, who are enrolled in clinical trials.

Hence, phase I trials usually involve healthy subjects, and phase II, III, and IV trials involve subjects with the disease to be studied. This distinction is not always followed, and some use the terms patient and subject interchangeably. For example, it is common to refer to any person enrolled in any study phase to be referred to as a study subject. These two terms will be used interchangeably in this book to refer to an individual in a trial. The preferred use is “subject” for anyone in a study and “patient” for anyone otherwise seeking or receiving care in the healthcare system.

Adverse events (AEs) seen in phase I trials are always noteworthy because the subjects are usually normal and a low starting dose of the drug in question is usually used. Because few subjects are studied in phase I, any AE should be investigated thoroughly. SAEs and the rare death seen in phase I trials should be looked at immediately and consideration should be given to stopping further dosing or enrollment.

Some countries now require that the next subject is dosed only when the previous subject ends the surveillance period scheduled in the protocol; this allows the avoidance of tragic adverse experiences in several subjects at the same time. Note that the FDA now requires all SAEs (whether labeled or not, whether felt to be due to the drug or not) to be submitted as expedited reports. In addition to the toxicity of the drug preparation, subjects have been known to hide serious medical problems or medical history to participate in the study, especially if the subjects are compensated.