a guide to clinical drug research
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a guide to clinical drug researchIt continues to provide a wealth of practical advice, ranging from the conception of an idea, planning a study and writing a protocol, through to the conduct of a study, data collection and analysis, and publication. It tells investigators what information they should expect sponsoring companies to provide, particularly when there is only limited information available about a new drug. Unlike other currently available texts on clinical trials and pharmaceutical medicine, A Guide to Clinical Drug Research concentrates on the needs of the practising clinician and research team. It is not restricted to drug investigation, and is relevant to all those involved in clinical research in a variety of settings. Audience: Required reading for clinical researchers and others involved as investigators in a drug project, often sponsored by a pharmacuetical company, plus agents of the sponsoring companies themselves. Please try again.Please try again.Please try again. It continues to provide a wealth of practical advice, ranging from the conception of an idea, planning a study and writing a protocol, through to the conduct of a study, data collection and analysis, and publication. Audience: Required reading for clinical researchers and others involved as investigators in a drug project, often sponsored by a pharmacuetical company, plus agents of the sponsoring companies themselves. Then you can start reading Kindle books on your smartphone, tablet, or computer - no Kindle device required. Full content visible, double tap to read brief content. Videos Help others learn more about this product by uploading a video. Upload video To calculate the overall star rating and percentage breakdown by star, we don’t use a simple average. Instead, our system considers things like how recent a review is and if the reviewer bought the item on Amazon. It also analyzes reviews to verify trustworthiness.http://nakajima-ya.com/user_data/image/easy-lam-ii-manual.xml
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This allows for better planning and prioritization, and can lead to more effective and successful clinical trials. With practical examples, checklists and forms, this book is a useful guide for planning and conducting clinical trials from beginning to end. Show more A Comprehensive and Practical Guide to Clinical Trials provides an overview of the entire process of clinical research in one thorough and easy-to-read handbook that offers those involved in clinical research a clear understanding of how the components of a study are related. It focuses on the practical aspects of the preparation and execution of a clinical trial and offers tools and resources to help the entire team understand how their responsibilities tie together with the tasks and duties of other members. All rights reserved. Imprint Academic Press You currently don’t have access to this book, however youPurchase the book Editors Delva Shamley The Clinical Research Centre at the University of Cape Town, Cape Town, Western Cape Province, South Africa Brenda Wright The Clinical Research Centre at the University of Cape Town, Cape Town, Western Cape Province, South Africa About ScienceDirect Remote access Shopping cart Advertise Contact and support Terms and conditions Privacy policy We use cookies to help provide and enhance our service and tailor content and ads. By continuing you agree to the use of cookies. March 4, 2013CRC PressWhere the content of the eBook requires a specific layout, or contains maths or other special characters, the eBook will be available in PDF (PBK) format, which cannot be reflowed. For both formats the functionality available will depend on how you access the ebook (via Bookshelf Online in your browser or via the Bookshelf app on your PC or mobile device). Designed to be a teaching aid and reference guide, A Practical Guide to Human Research and Clinical focuses on ethics, regulations, and guidelines.http://sneps-cftc.org/imagesArticles/easy-heat-fts-1-manual.xml The book explains the intricate details of the subject to readers by citing concrete cases, exercises, and templates along with the theoretical aspects. Prof. M.U.R Naidu and his co-authors address all aspects of clinical trials from clinical research, drug development, and quality to methodology, biostatistics, and pharmacovigilance. To learn how to manage your cookie settings, please see our. Masks are required at all of our locations and other safety protocols are in place. Click here to learn more. Such studies test new or improved therapies in volunteer participants, first determining whether they are generally safe, then whether they are effective. Although clinical trials are governed by extensive regulations to ensure that they are ethical and as safe as possible, individuals considering clinical trials should carefully weigh the possible risks of participation against the potential benefits. Increasingly, they are designed by computers to meet certain structural or functional specifications. Promising compounds are then subjected to extensive testing. The first step involves in vitro (Latin for “in glass”) testing in a laboratory. For example, a potential antiretroviral compound may be added to a culture in a petri dish containing human cells and HIV to see whether the agent slows viral replication. Laboratory testing also cannot conclusively show that an agent is safe, although it can provide important information about its effects on cells. The next step in testing usually involves animal studies. Typically, drug candidates are first tested in mice or rats, then often in dogs, then sometimes in primates. Animals are not people, however, and many agents have been shown to be more or less safe or effective in different species. Finally, if a candidate still looks promising after laboratory and animal studies, it may advance to testing in humans. Researchers must submit an application to the FDA, the federal agency that regulates drugs and medical devices. If approved, the experimental agent is designated an investigational new drug (IND) and may enter clinical trials. The FDA may grant accelerated approval for agents that treat serious illnesses for which there are few or no other therapeutic options. However, the agency still requires pharmaceutical companies to complete the clinical trial process and provide longer-term data before drugs are granted final traditional approval. In 1987 the FDA instituted the Treatment Investigational New Drug (TIND) category to provide early access to promising medications for individuals with serious or life-threatening conditions and no good treatment options. For an agent to qualify as a TIND, there must already be some evidence that it is safe and effective. In addition to enabling more people to access experimental drugs, TINDs also provide information on safety and efficacy under “real world” conditions. Participants’ regular physicians dispense the drug and provide such data to the manufacturer. In effect, TINDs and EAPs act as open-label studies that do not involve blinding, randomization, or matched control arms. The clinical trial process is divided into four phases, each of which includes a larger number of participants. The aim is to detect any obvious toxicities (side effects or adverse events) before many subjects are put at risk. Usually subjects are exposed to the new agent for a short period, perhaps only a few days. These studies evaluate a compound’s pharmacokinetics —how it is absorbed, metabolized, processed, distributed, and eliminated by the body. At this stage researchers also try to determine an optimal amount of the agent that will offer the most benefit without unacceptable toxicity, a process known as dose-ranging. While there may be some early indications that a compound works, determining efficacy is not the goal of Phase I trials. These studies also provide preliminary data on a candidate’s efficacy (activity, or how well it works). Sometimes these trials are divided into Phase IIa (pilot studies) and Phase IIb (small controlled trials). The study period is longer than for Phase I trials, usually several months to two years. This stage is where most drug candidates are weeded out; only about one-third of experimental agents successfully make it through Phase II studies. These trials usually last at least a couple of years, and often considerably longer. The most rigorous type of study is the prospective, double-blind, randomized, controlled trial (described in detail below), which compares a candidate drug against either a placebo (dummy drug) or a currently available therapy. During this stage, researchers continue to monitor the agent’s safety, since some toxicities may become apparent only after a drug is used in larger groups or over longer periods. Data from the final Phase III studies—called pivotal trials—may be submitted to the FDA as part of a New Drug Application (NDA) to be considered as evidence for approval. Importantly, postmarketing studies also look for uncommon or long-term toxicities that did not show up in earlier trials (as was the case for metabolic side effects associated with the first protease inhibitors). Over time, more information may be revealed about interactions with other drugs and use in different populations, such as people with coexisting conditions. Each trial begins with a protocol, a written description of what hypothesis the researchers wish to test and what methods they plan to use. This includes details such as drug dosages, administration routes, schedule of clinic visits, and what monitoring tests will be performed. All aspects of a trial should be set forth in the protocol; many of these will determine how useful the trial is and whether its results will be regarded as credible. Characteristics and qualifications that a prospective subject must have are known as inclusion criteria, while those that disqualify a subject are called exclusion criteria. Enrollment criteria may include demographic characteristics (e.g., sex, age), behavioral factors (e.g., injection drug use), disease status (e.g., CD4 cell count, HIV viral load), and current or past medical history (e.g., kidney dysfunction, use of cancer chemotherapy). In addition, trials are regarded as “cleaner” if they eliminate any potentially confounding factors that could affect the study’s outcome. For example, many trials exclude subjects who have coexisting conditions such as active opportunistic illnesses (OIs) or chronic hepatitis C. Concurrent use of other medications is also often excluded because they might interact with the experimental agent, potentially impairing its activity or causing unforeseen side effects. Another common exclusion criterion is active substance use, since many researchers assume that alcohol and drug users have chaotic lives and are less likely to achieve optimal adherence. Otherwise, treatments may appear much more promising when tested in an “ideal” subject population than when used under real-world conditions. Since then women, people of color, injection drug users, and other marginalized populations and their advocates have pressed for broader inclusion in clinical trials, and competent researchers recognize the importance of including a representative cross-section of people affected by a disease. Recent research has shown, for example, that people of African descent as a group metabolize efavirenz (Sustiva) more slowly than white individuals, and thus achieve higher blood levels of the drug. More recently, a consensus has emerged that drugs should be studied in both sexes. However, pregnant and breast-feeding women are still typically excluded, unless the trial is for an immediately life-threatening condition or for a pregnancy-specific intervention. In addition, women “of childbearing potential” (meaning there is a chance they could become pregnant), as well as male partners of such women, may be required to use at least one form of effective contraception during and for some time after a trial. A majority of HIV trials specify that subjects must be at least 13 or 18 years of age. In the meantime, many physicians use drugs approved for adults “off label” to treat pediatric patients, making educated guesses about pharmacokinetics and optimal dosing. The lead researcher typically works with a team of health professionals, social workers, and others. There is often a study coordinator who oversees the administration of a trial. In many cases a study nurse will be the main person with whom trial participants interact on a regular basis. This can help ensure that nothing done during the study will unexpectedly interfere with ongoing treatment, and vice versa. If possible, laboratory results obtained during the trial (e.g., CD4 cell count, HIV viral load) should be available to subjects’ regular health-care providers. Every time we’re successful, it’s because somebody went first.” While it may take only a few subjects to uncover major toxicities, many more participants are needed to determine conclusively that an agent works. With a small number of subjects, there is always the possibility that an outcome could be the result of chance rather than being a true effect of an experimental therapy. Researchers, therefore, try to include enough subjects in their trials so that the results will be considered statistically significant, or very unlikely to be due to chance alone. The ability of a study to produce statistically significant data is known as its power. Longer trials, not surprisingly, provide more data than shorter ones. In addition, as noted above, some adverse events show up only with prolonged use of a drug (e.g., type 2 diabetes mellitus, heart attacks). Conversely, some side effects may improve over time (e.g., gastrointestinal symptoms). On the other hand, it may take time for a drug to become effective (as is the case with some antidepressants), so it should not be rejected too soon. If preliminary data indicate that an agent is either quite harmful or very beneficial, the trial may be halted prematurely. For example, in 1986 Phase II testing of the first approved anti-HIV drug—AZT (zidovudine, Retrovir)— was halted six months after it began when 19 subjects in the placebo arm had died compared with just one in the AZT arm. Interventional trials test new drugs or other types of therapies, or determine whether already approved therapies can be used in new ways. Observational trials look at certain factors or outcomes (e.g., disease progression) over time. Other studies examine what risk factors are associated with the development of a condition. As noted above, the “gold standard” for clinical trials is the prospective, double-blind, randomized, controlled trial with clinically meaningful endpoints. Often, however, one or more of these criteria cannot be fulfilled. Typically, a study cohort is selected and followed for a predefined period, sometimes several years. A retrospective study is one that looks backward at events that happened in the past. Such a study might, for example, analyze medical records or stored blood samples. In a controlled trial, one group of subjects receives the agent under study (the experimental arm), while another arm does not (the control arm). Some trials have complex designs with multiple experimental arms. This is done to minimize the influence of a phenomenon known as the placebo effect, whereby the treatment process itself—receiving a pill, injection, or other intervention—can make a person feel better or experience side effects (including changes in biological markers), even if he or she receives an agent that has no therapeutic value or toxicity. Thus, experimental agents are now usually compared with either the standard-of-care or the best available known treatment.If the experimental arm contains all women and the control group all men, for example, it would be impossible to say whether any differences in outcome were solely due to the treatment or were influenced by the sex of the participants. This means that any prospective participant has an equal chance of ending up in either arm (or in any one of multiple arms). In a two-arm trial, this would be like flipping a coin for each subject and assigning “heads” to one group and “tails” to the other. This is done to minimize selection bias. If it were up to investigators to choose which participants were placed in which study arm, they might, for example, tend to assign sicker subjects to receive the therapy they think will work best; conversely, they might favor healthier participants who are likely to respond better and make the experimental agent look good.In a single-blind (or simply, blind) study, the subjects do not know whether they are receiving the experimental agent, an existing standard therapy, or a placebo. In a double-blind study, the investigators do not know either. For example, in an unblinded study, if an investigator believes the experimental agent is superior to an existing drug, she might have a tendency to emphasize positive outcomes associated with the new therapy while minimizing negative ones. Likewise, if a subject thinks the experimental agent is more risky than standard therapy, he might tend to over-report side effects associated with the new drug or under-report those linked to the old one. Traditionally, trials have employed clinically meaningful endpoints, for example, disease resolution, progression to an AIDS-defining illness, or death. For that reason, contemporary trials often use surrogate markers, which are usually laboratory findings that are assumed to predict clinical outcome. Likewise, elevated cholesterol and blood pressure are considered surrogate markers for cardiovascular disease risk, although the true outcomes of interest are heart attacks, need for cardiac surgery, and death. The FDA may approve drugs based on surrogate marker data alone. Treatments of the future are totally dependent on the successful conduct of clinical studies today.” Before a clinical trial gets underway, its protocol must be extensively reviewed to see that its benefits outweigh its risks. Reviewers include FDA officials and Institutional Review Boards (IRBs), committees at each research institution comprised of physicians, other health-care professionals, statisticians, ethicists, local community members, patient advocates, and people with the disease under study. IRBs not only approve studies before they begin, but also monitor their progress until completion. In addition to federal requirements, some states also have their own regulations governing human research. Finally, international agreements such as the Nuremberg Code, the Declaration of Helsinki, and the International Code of Medical Ethics put forth principles for conducting ethical research. All prospective subjects (or their parent or guardian, if the participant is a minor) must sign an informed consent document that describes the nature of the study, the therapy being tested, known or potential risks, the subject’s rights, and who to contact in case of problems. Prospective subjects should also be informed of other options that exist if they decide not to enroll in a trial. The study should also be verbally explained to the subject, who should be encouraged to ask questions (see sidebar above). The prospective subject may take the document home to discuss with family and friends. Researchers must inform subjects of any important changes in the study design or new information about the experimental agent that becomes available during the course of the study. Importantly, an informed consent document does not waive the participants’ legal or medical rights, and researchers remain liable for damages due to negligence. The informed consent document is also not a contract; participants may discontinue a study at any time for any reason. A trial’s informed consent document should disclose all funding sources. In addition, all investigators must file financial disclosure statements explaining their financial relationship with the sponsor. The federal government and some states have various laws and policies concerning conflicts of interest, for example, when a researcher leads a trial of a drug produced by a company in which he owns stock. Many studies also cover monitoring tests and other types of medical care. However, some observational trials—including studies comparing various new dosing schedules or combinations of approved agents—do not provide free drugs. Health insurance regulations differ widely, but many insurers do not cover treatments or monitoring tests that are considered experimental. These can be used to reimburse participants for expenses such as transportation or childcare, or to compensate subjects for their time and inconvenience. Some researchers provide other forms of compensation, such as bus tokens or meals, especially if they are trying to include study participants from low-income and otherwise marginalized populations. However, it is illegal and unethical to pay people to join a trial, or to use stipends to persuade unwilling subjects to enroll. How do a trial’s advantages and benefits stack up against its inconveniences, discomforts, and potential risks. Trials of new drugs—and especially novel drug classes—can offer few guarantees. Researchers cannot be sure how effective a treatment will be, nor can they rule out unforeseen toxicities and side effects. First, they provide early and usually free access to the newest therapies. Sometimes subjects are given continued access to experimental medications even after the study period ends. Early in the epidemic, before many antiretroviral medications were approved, trial participation was often the only way to obtain drugs. This is no longer the case, but clinical studies remain at the forefront. For individuals who have developed resistance to the three major classes of antiretroviral drugs, trials can provide the first access to agents that work by entirely different mechanisms. In particular, trial participants typically receive frequent, intensive health monitoring using the latest testing methods (usually at minimum regular CD4 cell counts and viral load assays).This may be especially problematic for individuals who continue to work or have returned to work, and for those who must arrange for childcare. Trials may also involve a certain amount of discomfort, for example, frequent blood draws. These may range from temporary gastrointestinal distress to elevated blood cholesterol to life-threatening Stevens-Johnson syndrome (a type of serious hypersensitivity reaction characterized by severe rash). No matter how promising an agent looks in laboratory and animal studies, it may still cause unacceptable toxicities in humans. Some side effects may not appear right away, but only after prolonged use, and some may not diminish immediately (or ever) after a drug is discontinued. Participants in a trial should always be given information about what to do and whom to contact if they experience unexpected or serious reactions. With the growing awareness of the importance of choosing optimal individualized regimens, avoiding resistance, and sequencing successive regimens in order to extend effective treatment, prospective subjects may be less willing to leave their therapy to chance, and more inclined to rely on the expertise of experienced physicians and the latest treatment guidelines. In many cases, participating in a clinical study was the only way to obtain treatment, and doing so was a matter of life and death. Also, many HIV-positive people have returned to work and fuller lives since the advent of HAART, and no longer have time for extra clinic visits and meetings. Trials still provide access to innovative treatments, including new classes of drugs for individuals who require salvage therapy. Clinical studies also provide the information needed to make adjustments to treatment strategies that may ultimately benefit all people with HIV. Finally, clinical trials are the only way to discover better immune-based therapies and effective HIV vaccines, not to mention the ultimate achievement: a cure for AIDS. Click here to download a PDF of the original article, which first appeared in the Summer 2005 issue of BETA. Our Federal EIN is 94-2927405 and our California corporation number is C1241510. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices ) and known interventions that warrant further study and comparison.Clinical trials can vary in size and cost, and they can involve a single research center or multiple centers, in one country or in multiple countries. Clinical study design aims to ensure the scientific validity and reproducibility of the results. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory.Other clinical trials pertain to people with specific health conditions who are willing to try an experimental treatment. Pilot experiments are conducted to gain insights for design of the clinical trial to follow. Neither is an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is intended to be used, what other treatments are available, and the severity of the disease or condition.If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study.Data include measurements such as vital signs, concentration of the study drug in the blood or tissues, changes to symptoms, and whether improvement or worsening of the condition targeted by the study drug occurs. The researchers send the data to the trial sponsor, who then analyzes the pooled data using statistical tests.Jenner failed to use a control group. For instance, Lady Mary Wortley Montagu, who campaigned for the introduction of inoculation (then called variolation) to prevent smallpox, arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life. Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor. He divided twelve scorbutic sailors into six groups of two. They all received the same diet but, in addition, group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol ( sulfuric acid ), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by then one sailor was fit for duty while the other had almost recovered.The trial, carried out between 1946 and 1947, aimed to test the efficacy of the chemical streptomycin for curing pulmonary tuberculosis. From the 1920s, Hill applied statistics to medicine, attending the lectures of renowned mathematician Karl Pearson, among others. He became famous for a landmark study carried out in collaboration with Richard Doll on the correlation between smoking and lung cancer. They carried out a case-control study in 1950, which compared lung cancer patients with matched control and also began a sustained long-term prospective study into the broader issue of smoking and health, which involved studying the smoking habits and health of more than 30,000 doctors over a period of several years.These approaches may include drugs, vitamins or other micronutrients, vaccines, or lifestyle changes. Each phase of the drug approval process is treated as a separate clinical trial.If the study is double-blind, the researchers also do not know which treatment a subject receives. This intent is to prevent researchers from treating the two groups differently. In this kind of study, all patients are given both placebo and active doses in alternating periods. In trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness.Genetic testing enables researchers to group patients according to their genetic profile, deliver drugs based on that profile to that group and compare the results. Multiple companies can participate, each bringing a different drug. The first such approach targets squamous cell cancer, which includes varying genetic disruptions from patient to patient. Amgen, AstraZeneca and Pfizer are involved, the first time they have worked together in a late-stage trial.It is prepared by a panel of experts. All study investigators are expected to strictly observe the protocol.Details of the trial are provided in documents referenced in the protocol, such as an investigator's brochure.The protocol also informs the study administrators (often a contract research organization ). Journals such as Trials, encourage investigators to publish their protocols.