Information AboutClinical Trials |
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Clinical trials can be divided into observational and interventional studies. Observational studies are those in which individuals are observed and their outcomes are measured by the investigators (e.g., Natural Experiment ). These researchers do not actively manage the experiment; they merely observe the effects of pre-existing factors. Interventional studies are those in which the research subjects are given a particular medicine or other intervention, and their subsequent health outcomes are measured. Interventional clinical trials are used to study the effects of a particular treatment upon a Disease or other pathological condition. Well-run clinical trials use defined techniques and rigorous definitions to answer the researchers' questions as accurately as possible. Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever reaching clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. For example, a new cancer drug has, on average, at least 6 years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about 8 years pass from the time a cancer drug enters clinical trials until it is approved. Drugs for other diseases have similar timelines. Why so long? To establish a drug's safety and effectiveness, researchers look at each new treatment in several different studies. Only certain people are eligible to take part in each clinical trial. And cancer trials, by their very nature, take years to complete. It takes months, if not years, to see if a cancer treatment works in any one person. For other drugs that target narrow groups of people and are not expected to have a strong effect, recruiting enough patients to test the drug's effectiveness can take several years. The most commonly performed clinical trials evaluate new Drugs , medical devices, Biologics , psychological therapies, or other interventions on patients in strictly scientifically controlled settings, and may be required for regulatory authorityThe regulatory authority in the USA is the Food And Drug Administration ; in Canada, Health Canada ; in the EU, the European Medicines Agency ; in Japan, the Ministry Of Health, Labour And Welfare ; the Health Sciences Authority (HSA) in Singapore. approval of new therapies. Trials may be designed to assess the safety and efficacy of an experimental therapy, to assess whether the new intervention is better than standard therapy, or to compare the efficacy of two standard or marketed interventions. The trial objectives and design are usually documented in a Clinical Trial Protocol . HISTORY Perhaps the first ever clinical trial was James Lind 's demonstration in 1753 that Citrus Fruits cure Scurvy 2. He compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of afflicted sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days. TYPES The most commonly performed clinical trials evaluate new Drugs , medical devices, Biologics , or other interventions on patients in strictly scientifically controlled settings, and are required for regulatory authority approval of new therapies. NIH organizes trials into five (5) different types:
Trials may be designed to assess the safety and efficacy of an experimental therapy, to assess whether the new intervention is better than standard therapy, or to compare the efficacy of two standard or marketed interventions. The trial objectives and design are usually documented in a Clinical Trial Protocol . In the U.S. there is a 50% Tax Credit on certain clinical trials.3 To be ethical, they must involve the full and Informed Consent of participating human subjects. They are closely supervised by appropriate regulatory authorities. All interventional studies must be approved by an Ethics Committee (in the U.S., this body is the Institutional Review Board at the investigator's hospital or institution) before permission is granted to run the trial. The study design that provides the most compelling evidence of a causal relationship between the treatment and the effect is the Randomized Controlled Trial . Observational Studies in Epidemiology such as the Cohort Study and the Case-control Study are clinical studies in that they involve human participants, but provide less compelling evidence than the randomized controlled trial. The major difference between clinical trials and Observational Studies is that, in clinical trials, the investigators manipulate the administration of a new intervention and measure the effect of that manipulation, whereas Observational Studies only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. These are fundamental distinctions in Evidence-based Medicine . Currently some Phase II and most Phase III drug trials are designed to be randomized, Double-blind , and Placebo -controlled. This means that each study subject is randomly assigned to receive one of the treatments, which might be the placebo. Neither the subjects nor scientists involved in the study know which study treatment is being administered to any given subject; and, in particular, none of those involved in the study know which subjects are being administered a placebo. This is to prevent biases in the administration of the drugs, since a physician may feel more useful to give the drug to a patient who could more easily benefit of it, and the placebo to a more advanced case. Moreover, it has been assessed how there can be a "placebo effect" that can cause tumor responses in the order of roughly 10%. A specialized form of double-blind study called a "double-dummy" design allows another measure of insurance against bias or placebo effect. Here, all patients are given both placebo and active doses in alternating periods of time during the study. Of note, during the last ten years or so it has become a common practice to conduct "active comparator" trials (also known as "active control" trials) - in other words, when a treatment exists that is clearly better than doing nothing (''i.e.'' the placebo) for the subject, the alternate treatment would be a standard-of-care therapy. While the term clinical trials is most commonly associated with large randomized studies, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. Other clinical trials require large numbers of participants followed over long periods of time, and the trial sponsor is more likely to be a commercial company or a government, or other academic, research body. It is sometimes necessary to organize Multicenter Trial s. Often the centers taking part in such trials are in different countries (in which case they may be termed international clinical trials). The number of patients enrolled in the study has a large bearing on the ability of the trial to reliably detect an effect of a treatment. This is described as the ". However, in designing a clinical trial, this consideration must be balanced with the greater costs associated with larger studies. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated and control groups. For example, a trial of a Lipid -lowering drug with 100 patients per group might have a power of .90 to detect a difference between active and placebo of 10 mg/dL or more, but only have a power of .70 to detect a difference of 5 mg/dL. PHASES Pharmaceutical clinical trials are commonly classified into four phases, and the drug-development process will normally proceed through all four stages over many years. If the drug successfully passes through the Phases I, II, and III, it will usually be approved for use in the general population. Before Pharmaceutical Companies start clinical trials on drugs, extensive Pre-clinical Studies are conducted. Pre clinical studies Pre-clinical studies involve '' In Vitro '' (''i.e.'', test tube or laboratory) studies and trials on animal populations. Wide ranging dosages of the compounds are introduced to the animal subjects or to an ''in-vitro'' substrate in order to obtain preliminary Efficacy and Pharmacokinetic information and to assist pharmaceutical companies in decisions regarding further development of the test compound, test item or test article. Phase 0 Phase 0 is a recent designation for exploratory, First-in-human Trial s conducted in accordance with the Food and Drug Administration’s ( FDA ) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies.4 Phase 0 trials are designed to expedite the development of promising therapeutic or imaging agents by establishing very early on whether the agent behaves in human subjects as was anticipated from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of investigational agent to a small number of subjects (10 to 15) to gather preliminary data on the agent's Pharmacokinetic and Pharmacodynamic properties and mechanism of action. Phase I Phase I trials are the first stage of testing in human subjects. Normally a small (20-80) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety ( Pharmacovigilance ), tolerability, Pharmacokinetics , and Pharmacodynamics of a therapy. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. The subject is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging, also called dose escalation, studies so that the appropriate dose for clinical use can be found. The tested range of doses will usually be a fraction of the dose that causes harm in animal testing. Phase I trials most often include healthy volunteers, however there are some circumstances when patients are used, such as with end-stage disease without other treatment options. This exception to the rule most often occurs in oncology (cancer) and HIV drug trials. There are different kinds of Phase I trials: ;SAD: Single Ascending Dose studies are those in which small groups of patients are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any Adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of patients is then given a higher dose. 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) ). ;MAD: Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, whilst samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level. ;Food effect: a short trial designed to investigate any differences in absorption caused by eating pre-dose, and its effect on the pharmacokinetic profile. These studies are usually run as a Crossover Study , with volunteers given two identical doses of the drug on different occasions; one while fasted, and one after being fed. Phase II Once the initial safety of the therapy has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20-300) and are designed to assess the activity of the therapy, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. The development process for a new drug commonly fails during Phase II trials due to the discovery of poor activity or toxic effects. Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase IIA is specifically designed to assess dosing requirements, whereas Phase IIB is specifically designed to study efficacy. Some trials combine Phase I and Phase II into a single trial, monitoring both efficacy and toxicity. Trial design Some phase II trials are designed as Case Series , demonstrating safety and activity in a selected group of patients. Other phase II trials are designed as Randomized Clinical Trial s, complete with a treatment arm and a comparison arm. Randomized phase II trials have far fewer patients than randomized phase III trials. Phase III Phase III studies are randomized controlled trials on large patient groups (300–3,000 or more depending upon the condition) and are aimed at being the definitive assessment of the efficacy of the new therapy, in comparison with current 'Gold Standard' treatment. Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic conditions. Once a drug has proven satisfactory over 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 various regulatory authorities in different countries for marketing approval. It is also common practice with many drugs whose approval is pending, that certain phase III trials will continue. This typically serves to provide lifesaving products after involvement in a clinical trial until the marketed product can be obtained. Other reasons for performing trials at this stage include attempts at "label expansion” to prove additional efficacy for uses beyond the original use for which the drug was designed, to obtain additional safety data, or to support marketing claims. Studies in this phase are by some companies categorised as "Phase IIIB studies."56 While not required in all studies, it is typically expected that there be at least two successful phase III trials, proving a drug's safety and efficacy, for approval from the standard regulatory agencies (FDA, TGA, EMEA, etc.). Though the current trend in recent months seems to be a move toward adaptive (live, changing) studies to expedite the process, there are no formal regulations for these trials in the pharmaceutical industry as of yet. Phase IV Phase IV trials involve the post-launch safety surveillance and ongoing technical support of a drug. Phase IV studies may be mandated by regulatory authorities or may be undertaken by the sponsoring company for competitive 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). Post-launch safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and timescale than was possible during the initial clinical trials. Such adverse effects detected by Phase IV trials may result in the withdrawal or restriction of a drug - recent examples include Cerivastatin (brand names Baycol and Lipobay), Troglitazone (Rezulin) and Rofecoxib (Vioxx). ACCIDENTS In March 2006 the drug TGN1412 caused catastrophic systemic failure in the subjects during its first human clinical trials (phase I). Following this, an Expert Group on Phase One Clinical Trials published a report. 7 REGULATION AND APPROVAL International Conference Of Harmonisation Guidelines For Good Clinical Practice (ICH GCP) is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure that the "rights, safety and well being of trial subjects are protected". SEE ALSO
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