Clinical Trials

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In medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is the application of the scientific method to human health. Researchers use clinical trials to test hypotheses about the effect of a particular intervention upon a pathological disease condition. Well-run clinical trials use defined techniques and rigorous definitions to answer the researchers' questions as accurately as possible.

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. 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

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Perhaps the first ever clinical trial was James Lind's demonstration that citrus fruits cure scurvy. 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 of Clinical Trials

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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. 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.

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) 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 trials. 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 "power" of the trial. It is usually expressed as the probability that, if the treatments differ in their effect on the outcome of interest, the statistical analysis of the trial data will detect that difference. The larger the sample size or number of participants, the greater the statistical power. The number of patients required to give a statistically significative result relates also to the question the trial wants to answer: to show the efficacy of a new drug in a non-curable disease as metastatic kidney cancer requires many fewer patients than in a highly curable disease as seminoma. 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

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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.

Phase 0 (Pre Clinical Studies)

Phase 0 trials are actually non-clinical studies involving 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 pharmacokinetic information and to assist pharmaceutical companies in decisions regarding further development of the test agent.

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 almost always conducted in an inpatient clinic, where the subject can be observed by full-time medical staff. The subject is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging studies so that doses for clinical use can be refined. The tested range of doses will usually be a small 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 oncology (cancer) and HIV drug trials. In Phase I trials of new cancer drugs, for example, patients with advanced (metastatic) cancer are used. These trials are usually offered to patients who have had other types of therapy and who have few, if any, other treatment choices.

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 clinical efficacy 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 efficacy 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 efficacy in a selected group of patients. Other phase II trials are designed as randomized clinical trials, 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[1] 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."

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 Clinical Trials

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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.


(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Clinical_trial)