Phases of clinical research

The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases start with testing for drug safety in a few human subjects, then expand to many study participants to determine if the treatment is effective. Clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays.

Description

Clinical trials testing potential medical products are commonly classified into four phases. The drug development process will normally proceed through all four phases over many years. When expressed specifically, a clinical trial phase is capitalized both in name and Roman numeral, such as "Phase I" clinical trial.
If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are 'post-marketing' or 'surveillance' studies conducted to monitor safety over several years.

Phase	Primary goal	Dose	Patient monitor	Typical number of participants	Success rate	Notes
	Testing of drug in non-human subjects to gather efficacy, toxicity and pharmacokinetic information	Unrestricted	Scientific researcher	No human subjects, in vitro and in vivo only		Includes testing in model organisms. Human immortalized cell lines and other human tissues may also be used.
	Pharmacokinetics; particularly oral bioavailability and half-life of the drug	Small, subtherapeutic	Clinical researcher	10 people		Often skipped for Phase I.
	Dose-ranging on healthy volunteers for safety	Often subtherapeutic, but with ascending doses	Clinical researcher	20–100 normal healthy volunteers	Approx. 52%	Determines whether drug is safe to check for efficacy.
	Testing of drug on participants to assess efficacy and side effects	Therapeutic dose	Clinical researcher	100–300 participants with a specific disease	Approx. 28.9%	Determines whether drug can have any efficacy; at this point, the drug is not presumed to have any therapeutic effect
	Testing of drug on participants to assess efficacy, effectiveness and safety	Therapeutic dose	Clinical researcher and personal physician	300–3,000 people with a specific disease	57.8%	Determines a drug's therapeutic effect; at this point, the drug is presumed to have some effect
	Post marketing surveillance in public	Therapeutic dose	Personal physician	Anyone seeking treatment from a physician	N/A	Monitor long-term effects

Preclinical studies

Before clinical trials are undertaken for a candidate drug, vaccine, medical device, or diagnostic assay, the product candidate is tested extensively in preclinical studies. Such studies involve in vitro and in vivo experiments using wide-ranging doses of the study agent to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist the developer to decide whether a drug candidate has scientific merit for further development as an investigational new drug.

Phase 0

Phase 0 is a designation for optional exploratory trials, originally introduced by the United States Food and Drug Administration's 2006 Guidance on Exploratory Investigational New Drug Studies, but now generally adopted as standard practice. Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects to gather preliminary data on the agent's pharmacokinetics.
A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.

Phase I

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; these trials are the first stage of testing in human subjects. They are designed to test the safety, side effects, best dose, and formulation method for the drug. Phase I trials are not randomized, and thus are vulnerable to selection bias.
Normally, a small group of 20–100 healthy volunteers will be recruited. 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 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, 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. The tested range of doses will usually be a fraction 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 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" 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:

Phase Ia

Single ascending dose : 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. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. 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. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up. 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.

Phase Ib

Multiple ascending dose : 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 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.

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.

Phase II

Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect. Phase II trials are performed on larger groups and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Genetic testing is common, particularly when there is evidence of variation in metabolic rate. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.
Phase II studies are sometimes divided into Phase IIa and Phase IIb. There is no formal definition for these two sub-categories, but generally:

Phase IIa studies are usually pilot studies designed to find an optimal dose and assess safety.
Phase IIb studies determine how well the drug works in subjects at a given dose to assess efficacy.