Phases of clinical research

Clinical trials involving new drugs are commonly classified into four phases. Individual trials may encompass more than one phase. A common example of this is combined phase I/II or phase II/III trials. Therefore, it may be easier to think of early phase studies and late phase studies.[1] 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 are 'post-approval' studies.

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive preclinical studies. These involve in vitro (test tube or cell culture) and animal experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug.

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.[3] 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).[4]

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 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;[5] these trials are the first stage of testing in human subjects.[6] They are designed to test the safety, side effects, best dose, and formulation method for the drug.[7]

Normally, a small group of 20–100 healthy volunteers will be recruited.[2][6] 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.[8] 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"[1] 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.[6][9] Typically, a small number of participants, usually three, are entered sequentially at a particular dose.[1] 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.[1] 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.[1]

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.[6][9]

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.

Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect.[1] Phase II trials are performed on larger groups (100–300) 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.[1] 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 2 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 look to find the optimum dose at which the drug shows biological activity with minimal side-effects (‘definite dose-finding’ studies).

Some trials combine Phase I and Phase II, and test both efficacy and toxicity.

Trial design

Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of patients. 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 which 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.[1]

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 patients 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 patient 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 patient 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.

Some researchers argue that phase II studies are generally smaller than they ought to be.[1]

This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice.[1] 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 the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. Phase III trials of chronic conditions or diseases often have a short follow-up period for evaluation, relative to the period of time the intervention might be used in practice.[1] This is sometimes called the "pre-marketing phase" because it actually measures consumer response to the drug.

It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorized as "Phase IIIB studies."[12]

While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), or the EMA (European Union).

Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities[13] in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug.

Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines through a New Drug Application (NDA) containing all manufacturing, preclinical, and clinical data. In case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.[14]

A Phase IV trial is also known as postmarketing surveillance trial, or informally as a confirmatory trial. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold (e.g. after approval under the FDA Accelerated Approval Program).[17] Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials).[2][6] The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials.[6][17] Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses; recent examples involve cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx). The minimum time period mandatory for Phase IV clinical trials is 2 years.

The entire process of developing a drug from preclinical research to marketing can take approximately 12 to 18 years and often costs well over $1 billion.[18][19]