Jan 27

Before clinical research studies about a new drug is approved regulatory authorities, pharmaceutical companies have to conduct extensive pre-clinical studies.

Clinical research studies are classified into four phases (Phase I-IV). Each phase is viewed as a distinct clinical trial. While Phase I, Phase II and Phase III of a clinical trial have to be approved by the regulatory authorities  before they can take place, Phase IV are ‘post-approval’ studies.

Each phases consists of an accumulation of many studies (see Article «Clinical trial design – Studies»).

Phase I
The Phase I of clinical research studies constitute the first set of testing of a new drug into humans. They typically include studies grouped under Human Pharmacology. Phase I  clinical research studies have non-therapeutic objectives and are therefore not usually used for treatment of a disease. They are conducted on a small group of healthy volunteer subjects or on certain types of patients (such as patients with mild hypertension) .  The participants often need to stay overnight at the trial center to be closely monitored and observed. However, drugs that are known to have a high potential of toxicity (such as cytotoxic drugs used in chemotherapy in cancer) are usually studied in patients.

The Phase I of a clinical trial design can be open, meaning that both researcher and subject may know the details of the treatment. Phase I studies can also be baseline controlled: there is an assessment of the volunteer before and after treatment. Randomisation and blinding may also be used. In this case, there is a random allocation of the treatment, without the researcher and/or the subject knowing what treatment is being administered, which lead to more accurate results. The clinical trial design Phase I can involve:

(a)Estimation of Initial Safety and Tolerability is ,used to determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected.

(b)Pharmacokinetics information is used to characterize the profile of the new drug about its absorption, distribution, metabolism, and excretion by the human body. Although predominant in Phase I of clinical trials, PK are studied throughout the trial, and other PK studies are carried during Phase II, Phase III and even Phase IV.

(c)Assessment of Pharmacodynamics, to provide an early idea of the activity and the potential efficacy of the new drug. PD can also guide the dosage of the drugs in later studies.

(d) Early Measurement of Drug Activity. Although usually done in later phases, it is possible to carry preliminary studies about drug potential therapeutic benefit in Phase I of a clinical trial, as a secondary objective.

Phase II
Clinical research studies Phase II can be initiated after enough information have been collected from Phase I and safety been confirmed. Their primary objectives are to explore therapeutic efficacy in patients. Phase II studies are used to evaluate how well the drug works, and also to collect additional safety data in a larger group of volunteers and patients. While early studies of Phase II may include be baseline controlled, later studies of Phase II are usually randomized with a placebo control, to evaluate the efficacy of the new drug and its safety under specific conditions or indications.

In Phase II, the therapy or drug is usually administered on a relatively uniform patient population, and groups are larger than those of Phase I. Subjects are closely monitored and information collected is important to determine the doses and treatment indications that will be used during Phase III. More studies under Phase II may be used to assess potential study endpoints, therapeutic restrictions (such as simultaneous or concomitant medications) or target populations (such as mild versus severe disease) for further studies.

Phase III
Phase III studies in clinical trials complete the information needed for the actual drug marketing approval, and give the official product information. For a drug to be approved, it typically has to undergo at least two successful Phase III trials, showing that the drug is safe for human use and its efficacy in the targeted population.

Phase III studies aim to confirm the therapeutic benefits of the new drug on the targeted population, and also to confirm previously collected evidence about drug safety. Additional Phase III studies may be used to research the dose-response relationship or the drug’s use in wider populations, in different stages of disease, or in combination with another drug.

Phase III studies are done on large group patients and are randomized controlled multicenter trials. The size and the relatively lengthy duration of Phase III trials make them notably expensive and time-consuming. Phase III trials can be difficult to design and run, especially in therapies for chronic medical conditions (ICH E1 and ICH E7). Trials involving extended exposure to the drug may be started in Phase II of the clinical trial.

Phase IV
Phase IV studies are post-approval studies and include therapeutic use type of studies. Clinical research studies  Phase IV are not mandatory for drugs and therapies approval, but can be important to optimize their use. Clinical trial Phase IV can be used to refine the dosing recommendation of a drug or to identify rare side effects. Mortality and morbidity or epidemiological studies are other examples of a clinical trial Phase IV studies. Some Phase IV studies have lead to the findings of harmful side effects, and the discontinuation or use restriction of some drugs.
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References:
(1) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Topics 1,5,7
(2) Health Canada
(3) U.S. Food and Drug Administration (FDA)

For more information, visit http://www.clinical-trials-info.com/.

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