The phases of clinical research are the stages in which scientists conduct experiments with a
health intervention
A public health intervention is any effort or policy that attempts to improve mental and physical health on a population level. Public health interventions may be run by a variety of organizations, including governmental health departments and n ...
to obtain sufficient evidence for a process considered effective as a
medical treatment
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
.
For
drug development
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...
, the clinical phases start with testing for 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
A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
candidates, new medical device
A medical device is any device intended to be used for medical purposes. Significant potential for hazards are inherent when using a device for medical purposes and thus medical devices must be proved safe and effective with reasonable assura ...
s, and new diagnostic assays.
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.][
]
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
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...
.[ Such studies involve '']in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' (test tube
A test tube, also known as a culture tube or sample tube, is a common piece of laboratory glassware consisting of a finger-like length of glass or clear plastic tubing, open at the top and closed at the bottom.
Test tubes are usually placed in s ...
or cell culture
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
) and ''in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' (animal model
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
) experiments using wide-ranging doses of the study agent to obtain preliminary efficacy
Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a pragmatic clinical trial#Efficacy versu ...
, toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
and pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
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
Microdosing, or micro-dosing, is a technique for studying the behaviour of drugs in humans through the administration of doses so low ("sub-therapeutic") they are unlikely to produce whole-body effects, but high enough to allow the cellular resp ...
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
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
(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
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
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
Gender-neutral language or gender-inclusive language is language that avoids bias towards a particular sex or gender. In English, this includes use of nouns that are not gender-specific to refer to roles or professions, formation of phrases in a c ...
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
Selection bias is the bias introduced by the selection of individuals, groups, or data for analysis in such a way that proper randomization is not achieved, thereby failing to ensure that the sample obtained is representative of the population int ...
.
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 In the life sciences, a contract research organization (CRO) is a company that provides support to the pharmaceutical, biotechnology, and medical device industries in the form of research services outsourced on a contract basis. A CRO may provid ...
(CROs) who conduct these studies on behalf of pharmaceutical companies
The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate symptoms. ...
or other research investigators. The subject who receives the drug is usually observed until several half-lives
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
of the drug have passed. This phase is designed to assess the safety (pharmacovigilance
Term Given By Tushar Sharma (UPES Batch 2025)
Pharmacovigilance (PV, or PhV), also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharma ...
), tolerability, pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
, and pharmacodynamics
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...
of a drug. Phase I trials normally include dose-ranging A dose-ranging study is a clinical trial where different doses of an Biological agent, agent (e.g. a drug) are tested against each other to establish which dose works best and/or is least harmful.
Dose-ranging is usually a clinical trial#Phase I, p ...
, 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
Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
. Phase I trials most often include healthy volunteers. However, there are some circumstances when clinical patients are used, such as patients who have terminal
Terminal may refer to:
Computing Hardware
* Terminal (electronics), a device for joining electrical circuits together
* Terminal (telecommunication), a device communicating over a line
* Computer terminal, a set of primary input and output dev ...
cancer or HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
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
Adverse or adverse interest, in law, is anything that functions contrary to a party (law), party's interest. This word should not be confused with wikt:averse, averse.
Adverse possession
In property law, adverse possession refers to an interest i ...
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
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
(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 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
In medicine, a crossover study or crossover trial is a longitudinal study in which subjects receive a sequence of different treatments (or exposures). While crossover studies can be observational studies, many important crossover studies are cont ...
, with volunteers being given two identical doses of the drug while fasted
Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see "Breakfast"), or to the metabolic state achieved after co ...
, 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
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
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
A case series (also known as a clinical series) is a type of medical research study that tracks subjects with a known exposure, such as patients who have received a similar treatment, or examines their medical records for exposure and outcome. Ca ...
, demonstrating a drug's safety and activity in a selected group of participants. Other Phase II trials are designed as randomized controlled trial
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
s, where some patients receive the drug/device and others receive placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
/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 trial
A multicenter research trial is a clinical trial conducted at more than one medical center or clinic. Most large clinical trials, particularly Clinical trial#Phase III, Phase III trials, are conducted at several clinical research centers.
Benefit ...
s 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. 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."
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
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(US), 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[The regulatory authority in the US is the ]Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
; in Canada, Health Canada
Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the Structure of the Canadian federal government#Departments, with subsidiary unit ...
; in the European Union
The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...
, the European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
; and in Japan, the Ministry of Health, Labour and Welfare
The is a cabinet level ministry of the Japanese government. It is commonly known as in Japan. The ministry provides services on health, labour and welfare.
It was formed with the merger of the former Ministry of Health and Welfare or and the ...
in different countries. They will review the submission, and if it is acceptable, 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.
Adaptive design
The design of individual trials may be altered during a trial – usually during Phase II or III – to accommodate interim results for the benefit of the treatment, adjust statistical analysis, or to reach early termination of an unsuccessful design, a process called an "adaptive design". Examples are the 2020 World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
''Solidarity Trial
The Solidarity trial for treatments is a multinational Phase III-IV clinical trial organized by the World Health Organization (WHO) and partners to compare four untested treatments for hospitalized people with severe COVID-19 illness. The tria ...
'', European ''Discovery trial'', and UK ''RECOVERY Trial
The Randomised Evaluation of COVID-19 Therapy (RECOVERY Trial) is a large-enrollment clinical trial of possible treatments for people in the United Kingdom admitted to hospital with severe COVID-19 infection. The trial was later expanded to In ...
'' of hospitalized people with severe COVID-19 infection, each of which applies adaptive designs to rapidly alter trial parameters as results from the experimental therapeutic strategies emerge.
Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.[
]
Success rate
For vaccines, the probability of success
Probability is the branch of mathematics concerning numerical descriptions of how likely an event is to occur, or how likely it is that a proposition is true. The probability of an event is a number between 0 and 1, where, roughly speaking, ...
ranges from 7% for non-industry-sponsored candidates to 40% for industry-sponsored candidates.
A 2019 review of average success rates of clinical trials at different phases and diseases over the years 2005-15 found a success range of 5-14%. Separated by diseases studied, cancer drug trials were on average only 3% successful, whereas ophthalmology
Ophthalmology ( ) is a surgical subspecialty within medicine that deals with the diagnosis and treatment of eye disorders.
An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a medic ...
drugs and vaccines for infectious disease
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
s were 33% successful.[ Trials using disease ]biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s, especially in cancer studies, were more successful than those not using biomarkers.[
A 2010 review found about 50% of drug candidates either fail during the Phase III trial or are rejected by the national regulatory agency.
]
Phase II/III cost
The amount of money spent on Phase II/III trials depends on numerous factors, with therapeutic area being studied and types of clinical procedures as key drivers. Phase II studies may cost as much as $20 million, and Phase III as much as $53 million.
Phase IV
A Phase IV trial is also known as a postmarketing surveillance Postmarketing surveillance (PMS), also known as post market surveillance, is the practice of monitoring the safety of a pharmaceutical drug or medical device after it has been released on the market and is an important part of the science of pharmac ...
trial or drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test.[ Phase IV trials involve the safety surveillance (]pharmacovigilance
Term Given By Tushar Sharma (UPES Batch 2025)
Pharmacovigilance (PV, or PhV), also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharma ...
) and ongoing technical support of a drug after it receives regulatory approval to be sold.[ 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).][ 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.][ Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include ]cerivastatin
Cerivastatin ( INN, brand names: Baycol, Lipobay) is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing w ...
(brand names Baycol and Lipobay), troglitazone
Troglitazone is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for people with diabetes mellitus type 2.
It was patented in 1983 and approved for medical use in 1997. It ...
(Rezulin) and rofecoxib
Rofecoxib is a COX-2 inhibitor, COX-2 selective nonsteroidal anti-inflammatory drug (NSAID). It was marketed by Merck & Co. to treat osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, acute pain conditions, migraine, and dysmenor ...
(Vioxx).
Overall cost
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.
References
{{Drug design
Clinical research
Design of experiments
Life sciences industry