trails phases

The clinical testing (investigation) of experimental drugs (previously unproven in humans, therefore "experimental") in humans is normally done in three phases (Phase I, II and III) with more and more people included in each subsequent phase. Before moving to the next phase of development the data are carefully analyzed to ensure the experimental drug is at least safe and well tolerated. After successful completion ofPhase I-III testing, a company will submit the results of all of the studies to the FDA or TPD to obtain a New Drug Approval (NDA). Once the FDA or TPD grants a company with a NDA, the company can market the drug (medication) to the public. Additional testing (post-marketing or late phase III/phase IV) to look at the ongoing-term safety continues.

Phase I Studies

Phase I studies are primarily concerned with the drug's safety, and are the first time the drug is tested in humans. These studies are typically done in a small number of healthy volunteers (20-100), usually in a hospital setting where they can be closely watched and treated should there be any side effects. These volunteers are usually paid for their participation and for the most part tend to be men approximately 30 years of age on average. (Women and children would be involved only in latest phases of clinical trial and only if substance in question is designed to be used in this groups of population.) The purpose of Phase I studies is to determine how the experimental drug is absorbed, metabolized, and excreted in humans. Additionally, they seek to determine what types ofside effects occur as the dosage of the drug is increased. Any beneficial effects of the drug are also noted. Phase I studies test a particular treatment in humans after it has been studied in the laboratory. The purpose of Phase I studies is to determine the maximum tolerated dose or amount of the treatment and answer questions about the best way to give the new treatment. Drugs that can cause seriousside effects are not tested on healthy humans, for example drugs for treating cancer. Phase I of these studies is carefully controlled by Cancer Therapy Evaluation Programs.

The following pre-clinical studies must be completed before phase 1 studies can begin in the United States.


Single dose toxicity in two mammalian species.Safety pharmacology studies to include assessment of effects on vital functions.Pharmacokinetic studies (ADME)Repeated dose toxicity studies in two species (one non-rodent) for two to four weeks, providing phase 1 studies will not exceed two weeks.Local tolerance studies using route of administration relative to propose clinical administration.In vitro tests for evaluation of mutations and chromosomal damage (genotoxicity)Carcinogenicitystudies (only if there is cause for concern)

Source: Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, U.S. Department of Health and Human Services and the FDA (CDER and CBER), July 1997, ICH.


Phase II Studies

Once Phase I studies have been completed and a dosage level is known, Phase II studies can start. Once an experimental drug has been proven to be safe and well tolerated in healthy volunteers, it must be tested in the patients that have the disease or condition that the experimental drug is expected to improve/cure. In addition to ensuring that the experimental drug is safe and effective in the patient population of interest, Phase IIstudies are also designed to evaluate the effectiveness of the drug. The second phase of testing may last from several months to a few years and may involve up to several hundred patients. Most Phase II studies are well controlled, randomized trials. That is, one group of patients (subjects) receives the experimental drug, while a second "control" group receives a standard treatment or placebo. Placement of the subject into the drug treatment or placebo group is by random chance (as if by the flip of a coin). Often thesestudies are "double-blinded", that is, the patient nor the researchers (investigator, coordinator, etc.) know who is getting the experimental drug. Additionally, Phase II studies are often designed to determine the correct dosage, that is the dosage with the least number of side effects that is most effective. These are often referred to as dose-ranging studies. In general, the purpose of Phase II studies is to provide the pharmaceutical company and the FDA in USA and TPP/TPD in Canada with comparative information about the relative safety of the experimental drug, the proper dosage needed to treat the condition, and the drug's effectiveness. Only about one-third of experimental drugs successfully complete bothPhase I and Phase II testing.

Pre-clinical requirements before initiating phase II studies in the U.S.:
Repeated dose toxicity studies in two species (one non-rodent) for a period of time equivalent to the length of the phase II studies. Six-month rodent and chronic non-rodent studies will support clinical trials of six months’ duration in the U.S. Studies of longer treatment duration are supported by nine- to twelve-month long pre-clinical studies.

Source: Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, U.S. Department of Health and Human Services and the FDA (CDER and CBER), July 1997, ICH.

Phase III Clinical Studies

If the treatment is found to be effective, Phase III studies compare it to the standard treatment. This is done by having two or more "arms" of treatment in which patients are randomly selected to participate. The arm in which the patient participates is decided by chance (by a computer), not choice. This randomization assists in making the groups as equal as possible so that sound conclusions can be drawn from study results. Patients are randomized by a number of factors that may affect the outcome of the study (age, performance status, stage of disease, etc.). In all treatment arms, patients should receive the best care available. The Data Monitoring Committee oversees all Phase III studies conducted by Sponsor. In a Phase III study, an experimental drug is tested in several hundred to several thousand patients with the disease/condition of interest. Most Phase III studies continue to be randomized and blinded. The large-scaletesting provides the pharmaceutical company as well as the FDA with a more thorough understanding of the drug's effectiveness, benefits/risks, and range/severity of possible adverseside effects. Phase III studies typically last several years. Seventy to 90 percent of drugs that enter Phase III studies successfully complete this phase of testing.

Pre-clinical requirements for initiation of phase III studies in the U.S.:

Repeated dose toxicity studies in two species (one non-rodent) for a period of time equivalent to the length of the phase III studies. Six-month rodent and chronic non-rodent studies would support clinical trials exceeding six months.Carcinogenicity studies if the duration of treatment of the drug is expected to be six months or longer or if intermittent exposure is equal to six months of continuous exposure, or if there is a cause for concern. Carcinogenicitystudies are not required if the patients receiving the drug have life expectancy of less than two years.Fertility studies in males.Repeated dose toxicology studies that include an evaluation of female reproductive organs must be done if women of non-childbearing potential are used.Assessment of female fertility and embryo-fetal development if women of childbearing potential will be included.All reproduction toxicitystudies and the standard and the standard genotoxicity tests should be completed if pregnant women will be included.

Source: Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, U.S. Department of Health and Human Services and the FDA (CDER and CBER), July 1997, ICH.

Phase IV Marketing of New Drugs and Post - Marketing Surveillance
After successful completion of Phase I-III testing, a company submits the results of all of the studies to the FDA to obtain a New Drug Application (NDA). Once the FDA grants a company with a NDA, the company can market the drug (medication) to the public. Additional testing (post-marketing or late phase III/phase IV) to look at the long-term safety continues. Kriger Research Center has a couple of full scale independent projects andstudies on several groups of new drugs in post-marketing stage. FDA (in USA) or TPD (in Canada) may require that sponsor would do a long term safety study - epidemiological post-marketing surveillance, as a condition of approval, These may be required because there have been seen problems with similar compounds in the past, or because the compound is novel and additional safety information will be beneficial.