Purpose of Clinical Trials
Clinical trials are needed to assess the efficacy and safety of a drug or procedure before it is brought into widespread clinical use. Clinical trials are tightly regulated to ensure that there are no safety or ethical breaches. The trials may only begin once sufficient information has been gathered supporting the non-clinical safety of the drug or procedure; this is often through the use of animals, a highly controversial subject. Clinical trials are normally funded by the pharmaceutical company intending to bring the product to market.
Phases of Clinical Trials
There are typically four phases to a clinical trial, of which I, II and III must be passed for the drug or procedure to enter clinical use. The fourth stage is a post approval stage.
This phase is designed to test the toxicity, the efficacy and the pharmacokinetics of the drug, and is normally both in vitro (i.e. in a test tube), and in vivo (i.e. animal testing), using a wide range of doses. These tests are undertaken by pharmaceutical companies in order to determine whether there is potential for a compound to become an investigational new drug.
This is a recent phase which is often referred to as a microdosing study, and is used to facilitate the process of developing a beneficial new drug quickly. This phase is used to establish the pharmacokinetics and pharmacodynamics of the drug. A very small dose is used so that there is negligible danger to the participants; therefore, although no data can be collected on the safety or efficacy of the drug, pharmaceutical companies can ensure that the mechanism of the drug in human is as expected from pre-clinical trials.
Phase 0 trials must be undertaken in accordance with rules imposed by regulatory bodies such as the FDA in the USA.
This is the first stage at which the drug is tested in humans, and normally involves a small number of individuals; 20-80 participants who have volunteered. Normally these volunteers are healthy participants, but there may be some trials in which patients are used, such as those with an end-stage terminal disease. The participants are often monitored full-time until the drug is almost entirely eliminated from the system. A range of doses may be tested, which must be much lower than those that caused harm in animal studies. Subjects are usually paid for their participation. The phase I trials test the safety, pharmacodynamics, pharmacokinetics, and tolerability of the drug.
There are three main types of phase I trial. The first is a food effect trial. This tests whether ingested food has any interaction with the pharmacokinetics of the drug. A crossover study is used to compare the effect when a subject has eaten or fasted.
Besides food effect trials, phase I trials can be single ascending dose, or multiple ascending dose trials. Single ascending dose (SAD) trials are where a single dose is given to a small number of participants, and the effects of the drug are observed. If the drug is tolerated, then the dosage is increased, and given to a new group of participants. This is continued until intolerable side effects are observed or the pre-calculated maximum safe dose is reached; this dosage is termed the maximum tolerated dose, or MTD.
Multiple ascending dose trials (MAD) are those in which a small number of people are given multiple low doses of the drug. The ability of the body to process the drug is assessed through measurements made from blood plasma and other fluids across time as the multiple doses are given. If the dosage is regarded as safe, it may be increased and a new group will receive multiple administrations of the new dose. This is continued, as in SAD trials, until severe adverse side effects begin or a pre-calculated safety level is reached.
If a drug is to fail in clinical trials, it is normally at this stage, as this is where adverse effects of the drug begin to be observed, or the drug fails to work as planned. A larger number of participants are recruited, and the trial proceeds as in phase I. Phase II can be divided into two sections; IIA and IIB. Phase IIA is to determine the dosages of the drug required. Phase IIB is used to determine how effective the drug is at the prescribed dose.
These are normally controlled, randomised trials at multiple centres; i.e. patients are given either the drug or a placebo (or standard treatment). The patient is unaware which treatment they are receiving. Phase III is usually the last phase before the drug is approved for use by a regulatory body, but often at least two successful phase III trials are required.
Phase IIIB trials are those which continue whilst the process of approval is ongoing, and are to allow patients to receive potentially beneficial treatment whilst the drug is being considered for market, and to explore the possibility of label expansion. Label expansion is when the drug is shown to have unforeseen benefits for other symptoms or diseases besides the disease the drug was originally intended to treat.
These are post-marketing surveillance studies, which may be required by the regulatory authority, or may be undertaken voluntarily by the producing pharmaceutical company in order to explore the possibility of new markets for the drug. A drug company may also conduct studies to ensure the safety and efficacy of the drug in different population groups, such as pregnant women (who are unlikely to be tested in drug trials), and to monitor drug interactions. In a larger population and over a longer time-scale than is feasible for phase I-III clinical trials, previously non-apparent adverse side-effects or toxicity may emerge, which results in the withdrawal of the drug from the market; this occurred with the specific COX-2 inhibitor Vioxx, and the statin cerivastatin (Lipobay)
It is vital that acceptable informed consent is gained from all participants before beginning the trial. Patients must be made aware of all potential risks and benefits of the treatment, and the relative risk of any adverse effects. This may be difficult when conducting a trial in a different country using a foreign language, or with children, the mentally ill, or patients unable to communicate. It is vital that subjects are aware that they are able to leave the study at any time, and that they will not be punished.
The likelihood of benefit from the drug or procedure must outweigh the risk to the subject, and the design of the trial must be such that meaningful results may be obtained to ensure that participants are not at risk for no potential benefit. It is important that all subjects are monitored adequately throughout the trial to minimise the likelihood of harm resulting from administration of the drug. All trial designs and plans must be submitted to ethical boards before they begin to ensure that ethical standards are met.
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