Clinical Trials

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Different phases I-IV of a clinical trial
Clinical Trials/Studies in Humans 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 of Phase 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 of side 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 serious side 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)Carcinogenicity studies (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 II studies 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 these studies 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 both Phase 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-scale testing 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 adverse side 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. Carcinogenicity studies 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 nonchildbearing potential are used.Assessment of female fertility and embryo-fetal development

if women of childbearing potential will be included.All reproduction toxicity studies 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 and studies 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.

Clinical Trials A clinical trial is designed to answer specific questions about new drugs, medical devices, or new ways of using known treatments. Clinical trials are used to determine whether the new drug or treatment is safe, and whether it works. Clinical trials consist of four phases: Phase I tests a new treatment on a small group, and concentrates on safety; Phase II deals with safety and efficacy, and expands the study to a larger group of people (several hundred); Phase III expands the study to an even larger group of people (thousands), and is designed to determine conclusively whether or not the treatment is effective; Phase IV takes place after the drug has been licensed, to monitor the drug for long-term effects. The randomized, double-blind, placebo-controlled (or active-comparator-controlled) trial offers the strongest evidence that a treatment is effective. The number of participants also considerably effects how reliably the trial can determine the effects of a treatment. Clinical trials must be consistent with good clinical practice (GCP), a rigorous set of guidelines designed to protect the participants’ safety and the integrity of the trial data. The FDA requires pharmaceutical companies and contract research organizations to conduct rigorous clinical trials verifying the safety and efficacy of the new drugs before granting approval for marketing.

The trial objectives and design are usually documented in clinical trial protocols. Once the objectives are determined, case report forms must be carefully designed to gather complete, unambiguous data from the trial. During the trial, the data management team must continually monitor and verify the data to ensure that they are accurate and consistent. Any missing or inconsistent data must be investigated and corrected. Phase (in relation to Drug Development): Drug development is divided into phases that are determined by the main objectives of the drug development process.
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Preclinical: Laboratory or animal studies to show biological activity of the compound against the targeted disease, with the compound evaluated for safety and possible formulations. Phase 1 : A Phase 1 clinical trial is the first step in testing a new investigational medication (or new use of a marketed drug) in humans. Phase 1 studies are mainly concerned with evaluating a drug’s safety profile, including the safe dosage range. The studies also determine how the drug is absorbed and broken down by the body, what is the best way to give the drug to a patient (for example by mouth, or by injection), what side effects may be likely, and how the drug is absorbed, distributed, metabolized, and excreted as well as its duration of action. Except for drugs used to treat cancer, Phase 1 clinical trials are usually conducted in healthy individuals and are not intended to treat disease or illness. Because cancer can be such a lifethreatening condition, Phase 1 trials with anti-cancer drugs are usually carried out in patients who already have the disease. Phase 1b : Phase 1b studies are usually conducted in patients diagnosed with the disease, or condition for which the study drug is intended, who demonstrate some biomarker, surrogate, or possibly clinical outcome that could be considered for "proof of concept." Proof of concept in a Phase 1b study typically confirms the hypothesis that the current prediction of biomarker, or outcome benefit is compatible with the mechanism of action. Phase 1/2 : Phase 1/2 trials combine a Phase 1 and a Phase 2 trial of the same treatment into a single protocol. First the Phase 1 part of the trial is done - to determine the Maximum Tolerable Dose (MTD). Then, more patients are treated at the MTD, in the Phase 2 portion of the study, to further evaluate safety and/or efficacy. Phase 2 : Phase 2 clinical trials involve volunteers who have the disease or condition to be treated. These trials help physicians and researchers begin to learn more about the safety of the new drug treatment and how well the drug treats the targeted disease or condition. Several different doses of the drug may be looked at to see which dose has the desired effects. Patients are monitored for side effects and for any improvement in their illness, symptoms, or both. Phase 3 : After a drug has been shown to have positive results in small groups of patients, it may be studied in a larger Phase 3 trial to confirm efficacy and identify adverse events from long-term use. A Phase 3 trial usually compares how well the study drug works compared with an inactive placebo and/or another approved medication. One group of patients may receive the new drug being tested, while another group of patients may receive the comparator drug (already-approved drug for the disease being studied), or placebo. Phase 4 : Phase 4 clinical trials are sometimes called "post-marketing" trials because these studies begin after the Phase 1 – 3 study results have been given to the FDA for evaluation. These studies may be done to determine if the drug is effective against other disease states, or to test different ways of taking the drug such as tablets, time-release capsules or syrups, or to look for adverse events in larger populations over longer periods of time.

Investigational New Drug Application (IND): After completing preclinical testing, a company files an IND with the U.S. Food and Drug Administration to begin to test the drug in humans. The IND becomes effective if FDA does not disapprove it within 30 days. The IND shows results of previous experiments; how, where and by whom the new studies will be conducted; the chemical structure of the investigational drug; how it is thought to work in the human body; any toxic effects found in the animal studies; and how the compound is manufactured. All clinical trials must be reviewed and approved by the Institutional Review Board (IRB) where the trials will be conducted (in Europe, the Ethics Review Board, or ERB). New Drug Application (NDA): Following the completion of all three phases of clinical trial development, a company analyzes all of the data and files an NDA with the U.S. Food and Drug Administration if the data successfully demonstrate both safety and effectiveness. The NDA contains all the scientific information that the company has gathered on the investigational drug. NDAs typically run 100,000 pages or more and can take up to a year or longer to review by the FDA, on average. Once FDA approves an NDA, the new medicine becomes available for physicians to prescribe. Open-label Study: A study in which the investigator and the study participant are aware of the drug therapy received during the study. Single-Blind Study: A study in which the treatment group assignment is not revealed to the study participant but is known by the investigator. Double-Blind Study: A clinical trial in which neither the investigator nor the study participant is aware of the treatment received. Unblinding: The act of providing visual or verbal access to the study participant, study drug treatment. Washout: A period of time during a clinical study when a participant is taken off of a study drug or a medication that is not allowed during the study. Food and Drug Administration (FDA): A branch of the U.S. Department of Health and Human Services primarily responsible for regulating the approval and use of drugs, medical devices, cosmetics, and foods. Good Clinical Practice (GCP): A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial participants are respected and protected. Institutional Review Board, or IRB: Also known in some countries as Ethics Review Board, or ERB. This is the scientific institution that is independent of the sponsor of the clinical trial that reviews and approves the study protocol on ethical treatment grounds and ensures that each participant enrolled in the trial has given their informed consent to participate. The IRB or ERB monitors the clinical trial from inception through completion.

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