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Many of the drugs that are used today have been discovered by chance or often by mere providence. The first clinical trial was conducted accidentally by the Renaissance surgeon Ambroise Parè in 1537.1 He used a mixture of turpentine, rose oil and egg yolk to prevent the infection of battlefield wounds, identifying that the new treatment was much more effective than the conventional formula. One of the most famous clinical trials was James Lind's demonstration in 1747 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.2 Since 1800, clinical trials began to grow and more attention was paid to study design. Placebos were first used in 1863, and the idea of randomization was introduced in 1923. The Food and Drug Administration (FDA) was founded in 1862 as a scientific body and became a law enforcement organization after the US Congress passed the Food and Drugs Act in 1906.3 Since 1945, the ethical impact of clinical trials has become increasingly important, resulting in strict regulation of medical experiments on human subjects. These regulations have been conserved in documents such as the Nuremburg Codex (1947) and the Declaration of Helsinki (1964, amended in 1975, 1983, 1989, 1996, 2000 and 2001). The first trial using appropriately randomized treatment and control groups was carried out in 1948 by the Medical Research Council, and concerned the use of streptomycin to treat pulmonary tuberculosis.4 This trial also characterized blind assessment (where neither the researchers nor the patients knew which treatment group each patient was in at the time of the study) enabling unbiased analysis of the results. In 1980s, harmonization between Europe, Japan and the United States led to a joint regulatoryindustry proposal on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).5 At present, most clinical trial plans follow ICH guidelines, intended at "ensuring that good quality, safe and effective medicines are developed and registered in the most competent and cost-effective manner. The design and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan has been consistent to follow Good Clinical Practice (GCP) guidance issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Regulatory authorities in India, Canada and Australia also follow ICH guidelines.
administer the treatment(s). (One of the IRB's main purposes is guaranteeing that potential patients are sufficiently . To be principled. Ethical Conduct in clinical trials Clinical trials are intimately monitored by appropriate regulatory authorities. diagnostics. Depending on the type of product and the stage of its development. Clinical trials can vary in size from a single center in one country to multicenter trials in multiple countries. followed by larger scale studies in patients that often contrast the new product with the currently prescribed treatment. but some sponsors permit the use of a central (independent/for profit) IRB for investigators who work at smaller institutions. concentration of the study drug in the blood. the Department of Veterans. The local ethics committee has prudence on how it will administer noninterventional studies (observational studies or those using already collected data).3 Most IRBs are situated at the local investigator's hospital or institution. In setting up a clinical trial. medical institutions and foundations.. Except for very small trials restricted to a single location. this body is called the Institutional Review Board (IRB). These trials can acquire place only after satisfactory information has been assembled on the quality of the non-clinical safety. and collect data on the patients' health for a distinct period of time. the Department of Defense. the sponsor decides what to compare the new agent with (one or more existing treatments or a placebo).. and Health Authority/Ethics Committee consent is granted in the country where the trial is taking place. or action plan. therapy protocols). In harmonization with a panel of expert investigators (usually physicians well known for their publications and clinical experience). how it will be conducted. and ensures that researchers in different locations all perform the trial in the same way on patients with the same characteristics. devices. the sponsor or investigator first identifies the medication or device to be tested. In the U. investigators enroll healthy volunteers and/or patients into small pilot studies at first. and private industries such as pharmaceutical and biotech companies. The researchers drive the data to the sponsor who then analyzes the shared data using statistical tests.5 Clinical trials are sponsored by the federal government such as the National Institute of Health. drugs. and why each part of the study is necessary. These data include measurements like vital signs. The protocol is the 'operating manual' for the clinical trial. for conducting the trial. Every clinical trial has a protocol. The plan portrays what will be done in the study. and what kind of patients might benefit from the medication or device.g.Clinical trials are conducted to allow safety and efficacy data to be collected for health interventions (e. During the clinical trial. All studies that appoint a medical or therapeutic intervention on patients must be permitted by a supervising ethics committee before consent is granted to conduct a trial. and whether the patient's health improves or not. researchers must obtain the full and informed consent of participating human subjects. the clinical trial design and objectives are written into a document called a clinical trial protocol.S. the investigators: recruit patients with the encoded characteristics.
The researchers do not vigorously manage the study. Clinical trial management systems (CTMS) are frequently used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial. In an interventional study.S. occasionally wireless ePRO (or eDiary) devices. The U.) If the patient is incapable to consent for him/herself. Usually. monitors the sites for compliance with the clinical protocol. National Institutes of Health (NIH) organizes trials into five (5) different types:7 . they evaluate the treated subjects to subjects who receive no treatment or standard treatment. It recruits participating researchers. grants them with supplies. Types of Clinical trials One way of classifying clinical trials is by the way the researchers perform. The guiding principle aim to guarantee that the "rights.informed about the clinical trial. and make sure that the sponsor receives 'clean' data from each and every site. researchers can seek consent from the patient's legally authorized representative. Patient-reported outcome measures are being increasingly collected using hand-held. The previous decade has seen a detonation of use of information technology in the planning and conduct of clinical trials. the local IRB must endorse researchers and their staff before they can conduct clinical trials. International Conference of Harmonisation Guidelines for Good Clinical Practice (ICH GCP) is a set of standards used internationally for the conduct of clinical trials. trains them. Web-based electronic data capture (EDC) and clinical data management systems (CDMS) are used in a greater part of clinical trials to collect case report data from sites.S. Another way of classifying trials is by their function. mainly with respect to investigational sites. safety and well being of trial subjects are protected". locations. manage its quality and organize it for analysis. y y In an observational study. the investigators monitor the subjects and measure their outcomes. Then the researchers compute how the subjects' health changes. the investigators give the research subjects a defined medicine or other intervention. Information technology in clinical trials A clinical research organization or contact research organization (CRO) is an organization that is contracted to execute all the managerial work on a clinical trial. Statistical software is used to examine the collected data and prepare it for regulatory submission. In some U.6 Interactive voice response systems (IVRS) are used by sites to catalog the enrollment of patients using a phone and to allocate patients to a particular treatment arm. synchronizes study administration and data collection. sets up meetings. They must comprehend the federal patient privacy (HIPAA) law and good clinical practice.
Phase I Phase I trials are the first stage of testing in human subjects. Phase IV are the 'post-approval' studies. Different Phases of clinical trials Clinical trials are generally classified into four phases. Before pharmaceutical companies start clinical trials on a drug. Normally. and pharmacodynamics of a drug. Normally. These trials are frequently conducted in an inpatient clinic. since the dose is too low to cause any therapeutic effect. new combinations of drugs. These trials may include medicines. If the drug effectively passes through Phases I. These studies are both short and long-term. vaccines. tolerability. and III. where the subject can be observed by fulltime staff. a small (20-100) group of healthy volunteers will be chosen. Quality of life trials: investigate ways to progress comfort and the quality of life for individuals with a chronic illness.y y y y y Prevention trials: look for improved ways to prevent disease in people who have never had the disease or to prevent a disease from recurring. they conduct extensive pre-clinical studies. This includes trials designed to assess the safety (pharmacovigilance). A Phase 0 study will not give data on safety or efficacy. Phase 0 Phase 0 is a recent explanation for exploratory. it will generally be approved by the national regulatory authority for use in the general inhabitants. Screening trials: test the finest way to detect certain diseases or health conditions. or lifestyle changes. The subject who receives the drug is usually observed until several half-lives of the . minerals. pharmacokinetics. Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body). vitamins. Treatment trials: test investigational treatments. first-in-human trials also known as human microdosing studies. The drug-development process will usually proceed through all four phases over many years. In this phase. Diagnostic trials: performed to find better tests or procedures for diagnosing a specific disease or condition. Each phase of the drug approval process is measured as a separate clinical trial. the drug is tested in a rodent and non-rodent since a drug may affect different species in different ways. the toxicity and pharmacological effects of the drug are evaluated through in vitro and in vivo animal testing. These studies support pharmaceutical companies to decide whether a drug candidate has scientific value for further development as an investigational new drug. or new approaches to surgery or radiation therapy. Pre-clinical studies This stage is designed to review the chemical properties of the new drug as well as to determine the steps for synthesis and purification. II.
Phase I trials most often include healthy volunteers. The dose is subsequently escalated for additional groups. up to a predetermined level.drug have passed. and test both efficacy and toxicity. there are some conditions when real patients are used. Phase I trials also usually include dose-ranging. or intolerable side effects start screening up (at which point the drug is said to have attained the Maximum tolerated dose (MTD). Phase IIB is particularly planned to study efficacy (how well the drug works at the prescribed dose(s)). studies so that the suitable dose for therapeutic use can be found. with volunteers being given two similar doses of the drug on different instances. Some trials combine Phase I and Phase II. caused by eating before the drug is administered. This is sustained until pre-calculated pharmacokinetic safety levels are attained. while samples (of blood and other fluids) are collected at various time points and analyzed to understand how the drug is routed within the body. Phase II trials are conducted on larger groups (20-300) and are planned to evaluate how well the drug works. Multiple Ascending Dose (MAD) studies are conducted to better know the pharmacokinetics & pharmacodynamics of multiple doses of the drug. y y Phase II Once the early safety of the study drug has been confirmed in Phase I trials. Because of their size and relatively long duration. and if the pharmacokinetic data is within the predicted safe values. Food effect . Phase III Phase III studies are randomized controlled multicenter trials on large patient groups (300±3. a group of patients receives multiple low doses of the drug.000 or more depending upon the disease/medical condition studied) and are intended at being the definitive assessment of how effective the drug is. y y Phase IIA is particularly planned to assess dosing requirements (how much drug should be given). In these studies. The tested dose ranges will usually be a fraction of the dose that causes harm in animal testing. . There are different kinds of Phase I trials: y Single Ascending Dose (SAD) studies are those in which small groups of subjects are given a single dose of the drug and they are observed and tested for a period of time.A short trial planned to investigate any differences in absorption of the drug by the body. such as patients who have fatal cancer or HIV and lack other treatment options. Phase III trials are the most expensive. Phase II studies are occasionally divided into Phase IIA and Phase IIB. time-consuming and complicated trials to design and run. in contrast with current 'gold standard' treatment. If they do not show any adverse side effects. and a new group of subjects is then given a higher dose. These studies are usually conducted as a crossover study. However. as well as to go on with Phase I safety assessments in a larger group of volunteers and patients. and one after being fed. one while fasted. especially in therapies for chronic medical conditions. also called dose escalation. the dose is escalated.
This is planned to detect any rare or long-term adverse effects that were not detected during the Phase I-III clinical trials. Obtain skilled medical care at leading health care facilities during the trial. including a technically competent workforce. low costs and a friendly drug-control system. serious or even life-threatening side effects to experimental treatment. formulation details. essential. more treatments. Gain access to new research treatments before they are extensively accessible. 20 crores to Rs. and. Benefits of participating in a clinical trial y y y y Play a dynamic role in their own health care.Once a drug has proved acceptable after Phase III trials. or on certain population groups such as pregnant women. including trips to the study site. of course. Phase IV trials engage the safety surveillance (pharmacovigilance) and continuing technical support of a drug after it obtains consent to be sold. patient availability. The clinical research industry in India has been growing rapidly. 5. troglitazone (Rezulin) and rofecoxib (Vioxx). Risks of participating in a clinical trial y y y There may be disagreeable. Help others by contributing to medical research.000 . hospital stays or complex dosage requirements. manufacturing procedures. give the sponsor approval to market the drug. the trial results are typically combined into a large document containing a complete report of the methods and results of human and animal studies. During the last 3 years it has increased from Rs. This compilation of information makes up the "regulatory submission" that is provided for evaluation to the appropriate regulatory authorities in different countries. The protocol may need more of their time and attention than would a non-protocol treatment. the drug may not have been tested for interactions with other drugs. 100 crores. Clinical trials are. but they come with an overwhelming price mark.8 India has become the preferred destination for global clinical trials today because of several reasons. by the year 2010 the industry is expected to grow up to Rs. The experimental treatment may not be effective for the participant. it is expected. pharma companies are spending between $100 and $800 million per each drug molecule. and shelf life. Phase IV studies may be mandatory by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example. who are doubtful to subject themselves to trials). According to a recent McKinsey report.3 Phase IV Phase IV trial are also known as Post Marketing Surveillance Trial. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold. They will review the submission. On average. or limited to certain uses: recent examples involve cerivastatin (brand names Baycol and Lipobay).
7. 6. Internet Res. 2009.al. Vol 11: No. 5. ³The use of electronic data capture tools in clinical trials.gov Pharmainfo. Robert Fee.com Ngppharma.com Fda.9 India is gearing up to attract more and more researchers from around the world to conduct their clinical trial studies in India. Clinicaltrials. 3. Drug discovery and development.net Ich. 9.crores.´ Jr. 2007: ³The cost of clinical trials´. References 1. 2. Clinasia. of Med. The Hindu.gov 8.org Khaled El Emam et.1. . December 15th 2008: Seeking the right formula. 4.
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