Phases of clinical research

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Phase I clinical trial
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National Cancer Institute video on clinical trial phases

The phases of clinical research are the stages in which scientists conduct experiments with a

drug safety in a few human subjects, then expand to many study participants (potentially tens of thousands) to determine if the treatment is effective.[1] 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.

Roman numeral, such as "Phase I" clinical trial.[1]

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.[1] Phase IV trials are 'post-marketing' or 'surveillance' studies conducted to monitor safety over several years.[1]

Summary of clinical trial phases
Phase Primary goal Dose Patient monitor Typical number of participants Success rate[2] Notes
Preclinical Testing of drug in non-human subjects to gather
pharmacokinetic
information
Unrestricted Scientific researcher No human subjects, in vitro and in vivo only Includes testing in
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

Before clinical trials are undertaken for a candidate drug, vaccine, medical device, or diagnostic assay, the product candidate is tested extensively in

investigational new drug.[1]

Phase 0

Phase 0 is a recent designation for optional exploratory trials conducted in accordance with the United States

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 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.[5]

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;[6] these trials are the first stage of testing in human subjects.[7] They are designed to test the safety, side effects, best dose, and formulation method for the drug.[8] Phase I trials are not randomized, and thus are vulnerable to selection bias.[9]

Normally, a small group of 20–100 healthy volunteers will be recruited.

pharmaceutical companies or other research investigators.[citation needed
]

The subject who receives the drug is usually observed until several

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.[11] The tested range of doses will usually be a fraction[quantify] 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"[12] 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.[citation needed]

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.[7][13] Typically, a small number of participants, usually three, are entered sequentially at a particular dose.[12] 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]

If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose.

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.[12]

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.[7][13]

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.[12] 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.[12] 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.[citation needed]

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).[14]
  • Phase IIb studies determine how well the drug works in subjects at a given dose to assess efficacy ('proof of concept' studies).[14]

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.[citation needed]

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.[12]

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.[citation needed]

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%,[15] and only 31% of developmental candidates advanced from Phase II to Phase III in a study of trials over 2006–2015.[16]

Phase III

This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice.

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.[12] This is sometimes called the "pre-marketing phase" because it actually measures consumer response to the drug.[citation needed
]

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."[17]

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[18] 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.[19]

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".[20][21][22] 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.[23][24][25]

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.[22]

Success rate

For vaccines, the probability of success ranges from 7% for non-industry-sponsored candidates to 40% for industry-sponsored candidates.[26]

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%.

infectious diseases were 33% successful.[27] Trials using disease biomarkers, especially in cancer studies, were more successful than those not using biomarkers.[27]

A 2010 review found about 50% of drug candidates either fail during the Phase III trial or are rejected by the national regulatory agency.[28]

Cost of trials by phases

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.[29] Main expense drivers were operating and clinical monitoring costs of the Phase I site.[29]

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.[29] Phase II studies may cost as low as $7 million for cardiovascular projects, and as much as $20 million for hematology trials.[29]

Phase III trials for

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.[30]

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%).[29]

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.[1] Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives regulatory approval to be sold.[7] 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).[10][7] 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.[7] 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).[citation needed]

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.[31][32]

References

  1. ^ a b c d e f g h i "The drug development process". US Food and Drug Administration. 4 January 2018. Retrieved 17 August 2020.
  2. ^ "New Clinical Development Success Rates 2011–2020 Report". BIO, Informa Pharma Intelligence, and QLS Advisors. Feb 2021.
  3. ^ "Exploratory IND Studies, Guidance for Industry, Investigators, and Reviewers" (PDF). Food and Drug Administration. January 2006. Retrieved 2010-06-15.
  4. S2CID 30939770
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  7. ^ a b c d e f g "Types and phases of clinical trials". American Cancer Society. 18 August 2020. Retrieved 15 September 2020.
  8. ^ "NCI Dictionary". National Cancer Institute. 2011-02-02.
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  10. ^ a b "Step 3. Clinical research". US Food and Drug Administration. 14 October 2016. Retrieved 1 February 2017.
  11. )
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  14. ^ a b "Phase 1, 2, 3, 4 trials". Revive, Global Antiobiotic Research and Development Partnership. 2023. Retrieved 24 October 2023.
  15. ^ "New drugs failing Phase II and III clinical trials". MedCity News. 2011-06-02.
  16. ^ "Clinical Development Success Rates 2006–2015" (PDF). bio.org. Retrieved 2018-02-11.
  17. Food and Drug Administration
    . 1999-03-16. Retrieved 2007-03-27.
  18. Ministry of Health, Labour and Welfare
  19. .
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  21. ^ "Adaptive Designs for Clinical Trials of Drugs and Biologics: Guidance for Industry" (PDF). U.S. Food and Drug Administration. 1 November 2019. Retrieved 3 April 2020.
  22. ^
    PMID 29490655
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  23. ^ Kotok A (19 March 2020). "WHO beginning Covid-19 therapy trial". Technology News: Science and Enterprise. Retrieved 7 April 2020.
  24. ^ "Launch of a European clinical trial against COVID-19". INSERM. 22 March 2020. Retrieved 5 April 2020. 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
  25. ^ "RECOVERY Trial". Retrieved 17 June 2020.
  26. hdl:1721.1/129805. Retrieved 11 August 2020. 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%
  27. ^ .
  28. .
  29. ^ .
  30. .
  31. .
  32. .