Phases of clinical research

{{Short description|Clinical trial stages using human subjects}} {{broader|Clinical trial}} {{Use dmy dates|date=October 2025}} {{cs1 config|name-list-style=vanc|display-authors=6}}

[[File:What are clinical trial phases.webm|thumb|National Cancer Institute video on clinical trial phases]]

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.<ref name="fda-dd">{{cite web |title=The drug development process |url=https://www.fda.gov/patients/learn-about-drug-and-device-approvals/drug-development-process |archive-url=https://web.archive.org/web/20190826022421/https://www.fda.gov/patients/learn-about-drug-and-device-approvals/drug-development-process |url-status=dead |archive-date=26 August 2019 |publisher=US Food and Drug Administration |access-date=17 August 2020 |date=4 January 2018}}</ref><ref name="nih">{{cite web |title=NIH Clinical Research Trials and You: The Basics |url=https://www.nih.gov/health-information/nih-clinical-research-trials-you/basics |publisher=US National Institutes of Health |access-date=8 September 2025 |date=2025}}</ref> 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.<ref name=fda-dd/> 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.<ref name=fda-dd/> When expressed specifically, a clinical trial phase is capitalized both in name and Roman numeral, such as "Phase I" clinical trial.<ref name=fda-dd/>{{Failed verification|date=September 2025}}

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.<ref name=fda-dd/> Phase IV trials are 'post-marketing' or 'surveillance' studies conducted to monitor safety over several years.<ref name=fda-dd/>

{| class="wikitable" |+ Summary of clinical trial phases |- ! Phase ! Primary goal ! Dose ! Patient monitor ! Typical number of participants ! Success rate<ref name="Clinical Development Success Rates 2006-2015">{{cite web|url=https://www.bio.org/clinical-development-success-rates-and-contributing-factors-2011-2020|title=New Clinical Development Success Rates 2011–2020 Report|publisher=BIO, Informa Pharma Intelligence, and QLS Advisors |date=Feb 2021}}</ref> ! Notes |- | {{ClinicalStudyInfo|phase=pre|align=mc}} | 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. |- | {{ClinicalStudyInfo|phase=0|align=mc}} | Pharmacokinetics; particularly oral bioavailability and half-life of the drug | Small, subtherapeutic | Clinical researcher | 10 people | | Often skipped for Phase I. |- | {{ClinicalStudyInfo|phase=1|align=mc}} | 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. |- | {{ClinicalStudyInfo|phase=2|align=mc}} | 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 |- | {{ClinicalStudyInfo|phase=3|align=mc}} | 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 |- | {{ClinicalStudyInfo|phase=4|align=mc}} | Post marketing surveillance in public | Therapeutic dose | Personal physician | Anyone seeking treatment from a physician | N/A | Monitor long-term effects |- |}

==Preclinical studies== {{main|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.<ref name=fda-dd/> 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.<ref name=fda-dd/>

==Phase 0== Phase 0 is a designation for optional exploratory trials, originally introduced by the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies, but now generally adopted as standard practice.<ref name=cder2006>{{cite web| date = January 2006 | title = Exploratory IND Studies, Guidance for Industry, Investigators, and Reviewers | publisher = Food and Drug Administration | url = https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078933.pdf | archive-url = https://web.archive.org/web/20090709180549/http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078933.pdf | url-status = dead | archive-date = 9 July 2009 | access-date = 15 June 2010 | author-link = Center for Drug Evaluation and Research }}</ref><ref>{{Cite web |last=Mandal |first=Ananya |date=13 March 2023 |title=What is a Phase 0 Clinical Trial? |url=https://www.news-medical.net/health/What-is-a-Phase-0-Clinical-Trial.aspx |access-date=28 June 2024 |website=News-Medical |language=en}}</ref> 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).<ref>{{cite journal | title = Phase 0 trials: a platform for drug development? | journal = Lancet | volume = 374 | issue = 9685 | pages = 176 | date = July 2009 | pmid = 19616703 | doi = 10.1016/S0140-6736(09)61309-X | s2cid = 30939770 | last1 = The Lancet | doi-access = free }}</ref>

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.<ref>{{Cite journal|last1=Burt|first1=Tal|last2=Young|first2=Graeme|last3=Lee|first3=Wooin|last4=Kusuhara|first4=Hiroyuki|last5=Langer|first5=Oliver|last6=Rowland|first6=Malcolm|last7=Sugiyama|first7=Yuichi|date=2020|title=Phase 0/microdosing approaches: time for mainstream application in drug development?|journal=Nature Reviews Drug Discovery|language=en|volume=19|issue=11|pages=801–818|doi=10.1038/s41573-020-0080-x|pmid=32901140|issn=1474-1784|doi-access=free}}</ref>

==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;<ref>{{cite journal | vauthors = Fisher JA | title = Feeding and Bleeding: The Institutional Banalization of Risk to Healthy Volunteers in Phase I Pharmaceutical Clinical Trials | journal = Science, Technology, & Human Values | volume = 40 | issue = 2 | pages = 199–226 | date = March 2015 | pmid = 25914430 | pmc = 4405793 | doi = 10.1177/0162243914554838 }}</ref> these trials are the first stage of testing in human subjects.<ref name="acs">{{cite web|url=https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/what-you-need-to-know/phases-of-clinical-trials.html|title=Types and phases of clinical trials|publisher=American Cancer Society|date=18 August 2020|access-date=15 September 2020}}</ref> They are designed to test the safety, side effects, best dose, and formulation method for the drug.<ref>{{Cite web | url = https://www.cancer.gov/publications/dictionaries/cancer-terms/def/phase-i-clinical-trial | title = NCI Dictionary | publisher = National Cancer Institute| date = 2 February 2011 }}</ref> Phase I trials are not randomized, and thus are vulnerable to selection bias.<ref>{{cite journal | vauthors = Van den Eynde BJ, van Baren N, Baurain JF |doi=10.1146/annurev-cancerbio-030419-033635| doi-access=free| title=Is There a Clinical Future for IDO1 Inhibitors After the Failure of Epacadostat in Melanoma?| year=2020 | journal=Annual Review of Cancer Biology| volume=4| pages=241–256| hdl=2078.1/232835| hdl-access=free}}</ref>

Normally, a small group of 20–100 healthy volunteers will be recruited.<ref name="fda">{{cite web|url=https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm|archive-url=https://web.archive.org/web/20141122080847/http://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm|url-status=dead|archive-date=22 November 2014|title=Step 3. Clinical research|publisher=US Food and Drug Administration|date=14 October 2016|access-date=1 February 2017}}</ref><ref name=acs/> 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.{{citation needed|date=November 2023}}

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.<ref>{{cite journal | vauthors = Shamoo AE | title = The myth of equipoise in phase 1 clinical trials | journal = Medscape Journal of Medicine | volume = 10 | issue = 11 | pages = 254 | year = 2008 | pmid = 19099004 | pmc = 2605120 | url = http://www.medscape.com/viewarticle/582554_2 }}{{registration required}}</ref> The tested range of doses will usually be a fraction{{quantify|date=November 2011}} 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"<ref name="DeMets">{{Cite book | vauthors = DeMets D, Friedman L, Furberg C | year = 2010 | title = Fundamentals of Clinical Trials | publisher = Springer | edition = 4th | isbn = 978-1-4419-1585-6}}</ref> 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.<ref name=fda-dd/>

Phase I trials can be further divided:

===Phase Ia=== 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.<ref name=acs/><ref name="p1ct">{{cite book | first1 = Elizabeth | last1 = Norfleet | first2 = Shayne Cox | last2 = Gad | chapter = Phase I Clinical Trials | veditors = Gad SC | title = Clinical Trials Handbook | isbn = 978-0-470-46635-3 | date = 2009 | page = 247 | publisher = John Wiley & Sons }}</ref> Typically, a small number of participants, usually three, are entered sequentially at a particular dose.<ref name="DeMets" /> 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. {{citation needed|date=November 2023}}

If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose.<ref name="DeMets" /> 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.<ref name="DeMets" />

===Phase Ib=== 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.<ref name=acs/><ref name="p1ct"/>

===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.<ref name="DeMets" /> Phase II trials are performed on larger groups (50–300 individuals) 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.<ref name="DeMets" /> 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.<ref name="sun">{{cite journal |vauthors=Sun D, Gao W, Hu H, Zhou S |title=Why 90% of clinical drug development fails and how to improve it? |journal=Acta Pharmaceutica Sinica. B |volume=12 |issue=7 |pages=3049–3062 |date=July 2022 |pmid=35865092 |pmc=9293739 |doi=10.1016/j.apsb.2022.02.002 |doi-access=free}}</ref>

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 ('dose finding' studies).<ref name="gardp">{{cite web |title=Phase 1, 2, 3, 4 trials |url=https://revive.gardp.org/resource/phase-1234-trials/ |publisher=Revive, Global Antibiotic Research and Development Partnership |access-date=24 October 2023 |date=2023}}</ref> * Phase IIb studies determine how well the drug works in subjects at a given dose to assess efficacy ('proof of concept' studies).<ref name=gardp/>

===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.<ref name=fda-dd/>

====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.<ref name="DeMets" />

====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.<ref name=sun/>

===Failure rate=== Phase I trials historically have experienced the lowest success, having about a 66% failure rate due mainly to adverse effects and other toxicity concerns.<ref name=sun/> A 2022 review found that about 90% of drug candidates fail over the course of Phases I-III, mainly due to absence of therapeutic efficacy, toxicity, non-specific drug properties, poor strategic planning, and recognition that the compound will not succeed commercially.<ref name=sun/>

==Phase III== This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice.<ref name="DeMets" /> 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.<ref name="DeMets" />

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."<ref>{{cite web|url=https://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html|archive-url=https://web.archive.org/web/20010506012400/http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html|url-status=dead|archive-date=6 May 2001|title=Guidance for Institutional Review Boards and Clinical Investigators|access-date=27 March 2007|date=16 March 1999|publisher=Food and Drug Administration}}</ref>

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, to obtain approval from the appropriate regulatory agencies such as FDA (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<ref name="reg-auth">The regulatory authority in the US is the Food and Drug Administration; in Canada, Health Canada; in the European Union, the European Medicines Agency; and in Japan, the Ministry of Health, Labour and Welfare</ref> 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.<ref>{{cite book |title=Pharmacotherapeutics for Advanced Practice: A Practical Approach |last1=Arcangelo |first1=Virginia Poole | first2 = Andrew M. | last2 = Peterson | name-list-style = vanc |year=2005 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-5784-3 |url-access=registration |url=https://archive.org/details/pharmacotherapeu02edunse }}</ref>

===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".<ref name="vannorman">{{cite journal | vauthors = Van Norman GA | title = Phase II trials in drug development and adaptive trial design | journal = JACC. Basic to Translational Science | volume = 4 | issue = 3 | pages = 428–437 | date = June 2019 | pmid = 31312766 | pmc = 6609997 | doi = 10.1016/j.jacbts.2019.02.005 }}</ref><ref name="fda-adaptive">{{cite web |title=Adaptive Designs for Clinical Trials of Drugs and Biologics: Guidance for Industry |url=https://www.fda.gov/media/78495/download |format=PDF |publisher=U.S. Food and Drug Administration |access-date=3 April 2020 |date=1 November 2019}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}</ref><ref name="pallmann">{{cite journal | vauthors = Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, Holmes J, Mander AP, Odondi L, Sydes MR, Villar SS, Wason JM, Weir CJ, Wheeler GM, Yap C, Jaki T | display-authors = 6 | title = Adaptive designs in clinical trials: why use them, and how to run and report them | journal = BMC Medicine | volume = 16 | issue = 1 | article-number = 29 | date = February 2018 | pmid = 29490655 | pmc = 5830330 | doi = 10.1186/s12916-018-1017-7 | doi-access = free }}</ref> Examples are the 2020 World Health Organization ''Solidarity trial'', European ''Discovery trial'', and UK ''RECOVERY Trial'' 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.<ref name="miller">{{cite news |first1=Alan |last1=Kotok | name-list-style = vanc |title=WHO beginning Covid-19 therapy trial |url=https://sciencebusiness.technewslit.com/?p=38676 |work=Technology News: Science and Enterprise |access-date=7 April 2020 |date=19 March 2020}}</ref><ref name="inserm-disc">{{cite web |title=Launch of a European clinical trial against COVID-19 |url=https://presse.inserm.fr/en/launch-of-a-european-clinical-trial-against-covid-19/38737/ |publisher=INSERM |access-date=5 April 2020 |date=22 March 2020|quote=The great strength of this trial is its "adaptive" nature. This means that ineffective experimental treatments can very quickly be dropped and replaced by other molecules that emerge from research efforts. We will therefore be able to make changes in real time, in line with the most recent scientific data, in order to find the best treatment for our patients}}</ref><ref name="RECOVERY Home">{{cite web |title=RECOVERY Trial |url=https://www.recoverytrial.net/ |access-date=17 June 2020}}</ref>

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.<ref name=pallmann/>

===Failure rate=== Some 90% of drug candidates fail once entering Phase I trials.<ref name=sun/> 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 only 5–14% overall.<ref name="Wong">{{cite journal | last1=Wong | first1=Chi Heem | last2=Siah | first2=Kien Wei | last3=Lo | first3=Andrew W | title=Estimation of clinical trial success rates and related parameters | journal=Biostatistics | volume=20 | issue=2 | date=31 January 2018 | issn=1465-4644 | doi=10.1093/biostatistics/kxx069 | pages=273–286| pmid=29394327 | pmc=6409418 | s2cid=3277297 |url=https://academic.oup.com/biostatistics/article/20/2/273/4817524| doi-access=free }}</ref> Separated by diseases studied, cancer drug trials were on average only 3% successful, whereas ophthalmology drugs and vaccines for infectious diseases were 33% successful.<ref name=Wong/> Trials using disease biomarkers, especially in cancer studies, were more successful than those not using biomarkers.<ref name=Wong/> A 2010 review found about 50% of drug candidates either fail during the Phase III trial or are rejected by the national regulatory agency.<ref>{{cite journal | vauthors = Arrowsmith J | s2cid = 39480483 | title = Trial watch: phase III and submission failures: 2007–2010 | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 2 | pages = 87 | date = February 2011 | pmid = 21283095 | doi = 10.1038/nrd3375 | doi-access = free }}</ref>

For vaccines, the overall probability of success ranges from 7% for non-industry-sponsored candidates to 40% for industry-sponsored candidates.<ref name="vaccine-trial-pos">{{cite journal |last1=Lo |first1=Andrew |last2=Siah |first2=Kien |last3=Wong |first3=Chi | name-list-style = vanc |title=Estimating probabilities of success of vaccine and other anti-infective therapeutic development programs |url=https://hdsr.mitpress.mit.edu/pub/pnp0pr4j/release/1 |journal=Harvard Data Science Review |issue=Special Issue 1 – COVID-19 |publisher=MIT Press |doi=10.1162/99608f92.e0c150e8 |quote=we can see that the overall probability of success (PoS) for industry-sponsored vaccine development programs is 39.6%... In contrast, non-industry-sponsored vaccine development programs have an overall PoS of only 6.8%|date=14 May 2020|access-date=11 August 2020|doi-access=free |hdl=1721.1/129805 |hdl-access=free }}</ref>

==Cost of trials by phases== {{see also|Cost of drug development}}

From discovery in the laboratory of a molecule with drug potential through the years-long process establishing an approved drug, the overall cost of development through all the stages of preclinical and clinical research is about $2 billion.<ref name=sun/><ref name="hinkson">{{cite journal |vauthors=Hinkson IV, Madej B, Stahlberg EA |title=Accelerating Therapeutics for Opportunities in Medicine: A Paradigm Shift in Drug Discovery |journal=Frontiers in Pharmacology |volume=11 |issue= |article-number=770 |date=2020 |pmid=32694991 |pmc=7339658 |doi=10.3389/fphar.2020.00770|doi-access=free}}</ref>

In the early 21st century, a typical Phase I trial conducted at a single clinic in the United States ranged from $1.4 million for pain or anesthesia studies to $6.6 million for immunomodulation studies.<ref name="key">{{cite journal | vauthors = Sertkaya A, Wong HH, Jessup A, Beleche T | s2cid = 24308679 | title = Key cost drivers of pharmaceutical clinical trials in the United States | journal = Clinical Trials | volume = 13 | issue = 2 | pages = 117–26 | date = April 2016 | pmid = 26908540 | doi = 10.1177/1740774515625964| doi-access = free }}</ref> Main expense drivers were operating and clinical monitoring costs of the Phase I site.<ref name=key/>

The amount of money spent on Phase II or III trials depends on numerous factors, with therapeutic area being studied and types of clinical procedures as key drivers.<ref name=key/> Phase II studies may cost as low as $7 million for cardiovascular projects, and as much as $20 million for hematology trials.<ref name=key/>

Phase III trials for dermatology may cost as low as $11 million, whereas a pain or anesthesia Phase III trial may cost as much as $53 million.<ref name=key/> An analysis of Phase III pivotal trials leading to 59 drug approvals by the US Food and Drug Administration over 2015–16 showed that the median cost was $19 million, but some trials involving thousands of subjects may cost 100 times more.<ref name="moore">{{cite journal |vauthors=Moore TJ, Zhang H, Anderson G, Alexander GC |title=Estimated costs of pivotal trials for novel therapeutic agents approved by the US Food and Drug Administration, 2015–2016 |journal=JAMA Internal Medicine |volume=178 |issue=11 |pages=1451–1457 |date=November 2018 |pmid=30264133 |pmc=6248200 |doi=10.1001/jamainternmed.2018.3931 |url=}}</ref>

Across all trial phases, the main expenses for clinical trials were administrative staff (about 20% of the total), clinical procedures (about 19%), and clinical monitoring of the subjects (about 11%).<ref name=key/>

==Phase IV== A Phase IV trial is also known as a postmarketing surveillance trial or drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test.<ref name=fda-dd/> Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives regulatory approval to be sold.<ref name=acs/> 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).<ref name=fda/><ref name=acs/> 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.<ref name=acs/> 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 (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).<ref>{{Cite web |last=Bhattacharya|first=Shaoni|title=Up to 140,000 heart attacks linked to Vioxx |url=https://www.newscientist.com/article/dn6918-up-to-140000-heart-attacks-linked-to-vioxx/|date=2005-01-25 |access-date=2026-02-16 |website=New Scientist |language=en-US}}</ref>

==Overall cost== The entire process of developing a drug from preclinical research to marketing can take approximately 12 to 18 years and may cost about $2 billion.<ref name=sun/><ref name=hinkson/><ref>{{cite journal | doi = 10.5912/jcb588 | title = Fixing a broken drug development process | year = 2013 | last1 = Holland | first1 = John | name-list-style = vanc | journal = Journal of Commercial Biotechnology | volume = 19}}</ref><ref>{{cite journal | vauthors = Adams CP, Brantner VV | title = Estimating the cost of new drug development: is it really 802 million dollars? | journal = Health Affairs | volume = 25 | issue = 2 | pages = 420–8 | year = 2006 | pmid = 16522582 | doi = 10.1377/hlthaff.25.2.420 | doi-access = free }}</ref>

==See also== * Lists of investigational drugs

== References == {{Reflist}}

Category:Clinical research Category:Design of experiments Category:Life sciences industry