Phase I trials were formerly referred to as “first-in-man studies” but the field generally moved to the gender-neutral language phrase "first-in-humans" in the 1990s;[6] these trials are the first stage of testing in human subjects.[7] They are designed to test the safety, side effects, best dose, and formulation method for the drug.[8] Phase I trials are not randomized, and thus are vulnerable to selection bias.[9]
Normally, a small group of 20–100 healthy volunteers will be recruited.[2][7] These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organization (CROs) who conduct these studies on behalf of pharmaceutical companies or other research investigators. The subject who receives the drug is usually observed until several half-lives of the drug have passed. This phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. Phase I trials normally include dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer.[10] The tested range of doses will usually be a fraction[quantify] of the dose that caused harm in animal testing. Phase I trials most often include healthy volunteers. However, there are some circumstances when clinical patients are used, such as patients who have terminal cancer or HIV and the treatment is likely to make healthy individuals ill. These studies are usually conducted in tightly controlled clinics called CPUs (Central Pharmacological Units), where participants receive 24-hour medical attention and oversight. In addition to the previously mentioned unhealthy individuals, “patients who have typically already tried and failed to improve on the existing standard therapies"[11] may also participate in phase I trials. Volunteers are paid a variable inconvenience fee for their time spent in the volunteer center.
Before beginning a phase I trial, the sponsor must submit an Investigational New Drug application to the FDA detailing the preliminary data on the drug gathered from cellular models and animal studies.
Phase I trials can be further divided:
Single ascending dose (Phase Ia)
In single ascending dose studies, small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time to confirm safety.[7][12] Typically, a small number of participants, usually three, are entered sequentially at a particular dose.[11] If they do not exhibit any adverse side effects, and the pharmacokinetic data are roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose.[11] This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)). If an additional unacceptable toxicity is observed, then the dose escalation is terminated and that dose, or perhaps the previous dose, is declared to be the maximally tolerated dose. This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity. Variations of this design exist, but most are similar.[11]
Multiple ascending dose (Phase Ib)
Multiple ascending dose studies investigate the pharmacokinetics and pharmacodynamics of multiple doses of the drug, looking at safety and tolerability. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.[7][12]
Food effect
A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.
In the United States, any company developing new drugs must submit the results of pre-clinical studies to the FDA as a part of an investigational new drug application, or IND, which application must become effective before it can begin clinical trials in the United States. An IND becomes effective 30 days after receipt by the FDA unless the FDA objects to it and the IND must be annually updated. Typically, clinical evaluation involves a time-consuming and costly three-phase process.
Phase I refers typically to closely monitored clinical trials and includes the initial introduction of an investigational new drug into human patients or normal healthy volunteer subjects. Phase I clinical trials are designed to determine the safety (metabolic and pharmacologic actions of a drug in humans), the side effects associated with increasing drug doses and, if possible, to gain early evidence on effectiveness (inductions of antibodies in our case). Phase I trials also include the study of structure-activity relationships and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. During Phase I clinical trials, sufficient information about a drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase II studies. The total number of subjects and patients included in Phase I clinical trials varies but is generally in the range of 20 to 80 people. Bioanalyses on the clinical trial samples in different in vitro assays must be conducted under good laboratory practice (GLP). At this stage, all techniques must be qualified according to standard operating procedures (SOPs) but it is not required to have the assays validated. Validating an assay consists of analyzing or verifying the 8 or 9 assay parameters as described in the US pharmacopeia or the ICH guidelines: 1) accuracy; 2) precision; 3) limit of detection; 4) limit of qualification; 5) specificity; 6) linearity and range; 7) robustness; and 8) system suitability.
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