phases of clinical research 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 (potentially tens of thousands) to determine if the treatment is effective. clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays. for broader coverage of this topic, see clinical trial. summary 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. 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. summary of clinical trial phases phase primary goal dose patient monitor typical number of participants success rate notes preclinical 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. phase 0 pharmacokinetics; particularly oral bioavailability and half-life of the drug small, subtherapeutic clinical researcher 10 people often skipped for phase i. phase i dose-ranging on healthy volunteers for safety often subtherapeutic, but with ascending doses clinical researcher 20–100 normal healthy volunteers (or cancer patients for cancer drugs) approx. 52% determines whether drug is safe to check for efficacy. phase ii 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 phase iii 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 phase iv post marketing surveillance in public therapeutic dose personal physician anyone seeking treatment from a physician n/a monitor long-term effects preclinical studies main article: preclinical development 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 (test tube or cell culture) and in vivo (animal model) 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 recent designation for optional exploratory trials conducted in accordance with the united states food and drug administration's (fda) 2006 guidance on exploratory investigational new drug (ind) studies. 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 (10 to 15) to gather preliminary data on the agent's pharmacokinetics (what the body does to the drugs). 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 in order 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 (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. 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 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" 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. 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 (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. 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. food effecta 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 (50–300) 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 demonstrate clinical efficacy or biological activity ('proof of concept' studies); phase iib studies determine the optimal dose at which the drug shows biological activity with minimal side-effects ('definite dose-finding' studies). trial design some phase ii trials are designed as case series, demonstrating a drug's safety and activity in a selected group of participants. other phase ii trials are designed as randomized controlled trials, where some patients receive the drug/device and others receive placebo/standard treatment. randomized phase ii trials have far fewer patients than randomized phase iii trials. example: cancer design in the first stage, the investigator attempts to rule out drugs that have no or little biologic activity. for example, the researcher may specify that a drug must have some minimal level of activity, say, in 20% of participants. if the estimated activity level is less than 20%, the researcher chooses not to consider this drug further, at least not at that maximally tolerated dose. if the estimated activity level exceeds 20%, the researcher will add more participants to get a better estimate of the response rate. a typical study for ruling out a 20% or lower response rate enters 14 participants. if no response is observed in the first 14 participants, the drug is considered not likely to have a 20% or higher activity level. the number of additional participants added depends on the degree of precision desired, but ranges from 10 to 20. thus, a typical cancer phase ii study might include fewer than 30 people to estimate the response rate. efficacy vs effectiveness when a study assesses efficacy, it is looking at whether the drug given in the specific manner described in the study is able to influence an outcome of interest (e.g. tumor size) in the chosen population (e.g. cancer patients with no other ongoing diseases). when a study is assessing effectiveness, it is determining whether a treatment will influence the disease. in an effectiveness study, it is essential that participants are treated as they would be when the treatment is prescribed in actual practice. that would mean that there should be no aspects of the study designed to increase compliance above those that would occur in routine clinical practice. the outcomes in effectiveness studies are also more generally applicable than in most efficacy studies (for example does the patient feel better, come to the hospital less or live longer in effectiveness studies as opposed to better test scores or lower cell counts in efficacy studies). there is usually less rigid control of the type of participant to be included in effectiveness studies than in efficacy studies, as the researchers are interested in whether the drug will have a broad effect in the population of patients with the disease. success rate phase ii clinical programs historically have experienced the lowest success rate of the four development phases. in 2010, the percentage of phase ii trials that proceeded to phase iii was 18%, and only 31% of developmental candidates advanced from phase ii to phase iii, in a large study of trials conducted over 2006–2015. phase iii this phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice. phase iii studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective