CLINICAL TRIALS The history of drug discovery is often mesmerizing. 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.
Clinical trials are conducted to allow safety and efficacy data to be collected for health interventions (e.g., drugs, diagnostics, devices, therapy protocols). These trials can acquire place only after satisfactory information has been assembled on the quality of the non-clinical safety, and Health Authority/Ethics Committee consent is granted in the country where the trial is taking place. Every clinical trial has a protocol, or action plan, for conducting the trial. The plan portrays what will be done in the study, how it will be conducted, and why each part of the study is necessary. Depending on the type of product and the stage of its development, investigators enroll healthy volunteers and/or patients into small pilot studies at first, followed by larger scale studies in patients that often contrast the new product with the currently prescribed treatment. Clinical trials can vary in size from a single center in one country to multicenter trials in multiple countries. In setting up a clinical trial, the sponsor or investigator first identifies the medication or device to be tested. In harmonization with a panel of expert investigators (usually physicians well known for their publications and clinical experience), the sponsor decides what to compare the new agent with (one or more existing treatments or a placebo), and what kind of patients might benefit from the medication or device. During the clinical trial, the investigators: recruit patients with the encoded characteristics, administer the treatment(s), and collect data on the patients' health for a distinct period of time. These data include measurements like vital signs, concentration of the study drug in the blood, and whether the patient's health improves or not. The researchers drive the data to the sponsor who then analyzes the shared data using statistical tests. Except for very small trials restricted to a single location, the clinical trial design and objectives are written into a document called a clinical trial protocol. The protocol is the 'operating manual' for the clinical trial, and ensures that researchers in different locations all perform the trial in the same way on patients with the same characteristics.5 Clinical trials are sponsored by the federal government such as the National Institute of Health, the Department of Defense, the Department of Veterans, and private industries such as pharmaceutical and biotech companies, medical institutions and foundations. Ethical Conduct in clinical trials Clinical trials are intimately monitored by appropriate regulatory authorities. 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. The local ethics committee has prudence on how it will administer noninterventional studies (observational studies or those using already collected data). In the U.S., this body is called the Institutional Review Board (IRB).3 Most IRBs are situated at the local investigator's hospital or institution, but some sponsors permit the use of a central (independent/for profit) IRB for investigators who work at smaller institutions. To be principled, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main purposes is guaranteeing that potential patients are sufficiently
informed about the clinical trial.) If the patient is incapable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In some U.S. locations, the local IRB must endorse researchers and their staff before they can conduct clinical trials. They must comprehend the federal patient privacy (HIPAA) law and good clinical practice. 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 guiding principle aim to guarantee that the "rights, safety and well being of trial subjects are protected". 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. It recruits participating researchers, trains them, grants them with supplies, synchronizes study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and make sure that the sponsor receives 'clean' data from each and every site. The previous decade has seen a detonation of use of information technology in the planning and conduct of clinical trials. 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, mainly with respect to investigational sites. 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, manage its quality and organize it for analysis.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. Patient-reported outcome measures are being increasingly collected using hand-held, occasionally wireless ePRO (or eDiary) devices. Statistical software is used to examine the collected data and prepare it for regulatory submission.
Types of Clinical trials One way of classifying clinical trials is by the way the researchers perform.
In an observational study, the investigators monitor the subjects and measure their outcomes. The researchers do not vigorously manage the study. In an interventional study, the investigators give the research subjects a defined medicine or other intervention. Usually, they evaluate the treated subjects to subjects who receive no treatment or standard treatment. Then the researchers compute how the subjects' health changes.
Another way of classifying trials is by their function. The U.S. National Institutes of Health (NIH) organizes trials into five (5) different types:7
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. These trials may include medicines, vitamins, vaccines, minerals, or lifestyle changes. Screening trials: test the finest way to detect certain diseases or health conditions. Diagnostic trials: performed to find better tests or procedures for diagnosing a specific disease or condition. Treatment trials: test investigational treatments, new combinations of drugs, or new approaches to surgery or radiation therapy. Quality of life trials: investigate ways to progress comfort and the quality of life for individuals with a chronic illness.
Different Phases of clinical trials Clinical trials are generally classified into four phases. Each phase of the drug approval process is measured as a separate clinical trial. The drug-development process will usually proceed through all four phases over many years. If the drug effectively passes through Phases I, II, and III, it will generally be approved by the national regulatory authority for use in the general inhabitants. Phase IV are the 'post-approval' studies. Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-clinical studies. 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. In this phase, the toxicity and pharmacological effects of the drug are evaluated through in vitro and in vivo animal testing. These studies are both short and long-term. Normally, the drug is tested in a rodent and non-rodent since a drug may affect different species in different ways. These studies support pharmaceutical companies to decide whether a drug candidate has scientific value for further development as an investigational new drug. Phase 0 Phase 0 is a recent explanation for exploratory, first-in-human trials also known as human microdosing studies. 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). A Phase 0 study will not give data on safety or efficacy, since the dose is too low to cause any therapeutic effect. Phase I Phase I trials are the first stage of testing in human subjects. Normally, a small (20-100) group of healthy volunteers will be chosen. This includes trials designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are frequently conducted in an inpatient clinic, where the subject can be observed by fulltime staff. The subject who receives the drug is usually observed until several half-lives of the
drug have passed. Phase I trials also usually include dose-ranging, also called dose escalation, studies so that the suitable dose for therapeutic use can be found. The tested dose ranges 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 conditions when real patients are used, such as patients who have fatal cancer or HIV and lack other treatment options. 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. If they do not show any adverse side effects, and if the pharmacokinetic data is within the predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is sustained until pre-calculated pharmacokinetic safety levels are attained, or intolerable side effects start screening up (at which point the drug is said to have attained the Maximum tolerated dose (MTD). Multiple Ascending Dose (MAD) studies are conducted to better know the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, 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. The dose is subsequently escalated for additional groups, up to a predetermined level. Food effect - A short trial planned to investigate any differences in absorption of the drug by the body, caused by eating before the drug is administered. These studies are usually conducted as a crossover study, with volunteers being given two similar doses of the drug on different instances; one while fasted, and one after being fed.
Phase II Once the early safety of the study drug has been confirmed in Phase I trials, Phase II trials are conducted on larger groups (20-300) and are planned to evaluate how well the drug works, as well as to go on with Phase I safety assessments in a larger group of volunteers and patients. Some trials combine Phase I and Phase II, and test both efficacy and toxicity. Phase II studies are occasionally divided into Phase IIA and Phase IIB.
Phase IIA is particularly planned to assess dosing requirements (how much drug should be given). Phase IIB is particularly planned to study efficacy (how well the drug works at the prescribed dose(s)).
Phase III Phase III studies are randomized controlled multicenter trials on large patient groups (300±3,000 or more depending upon the disease/medical condition studied) and are intended at being the definitive assessment of how effective the drug is, in contrast with current 'gold standard' treatment. Because of their size and relatively long duration, Phase III trials are the most expensive, time-consuming and complicated trials to design and run, especially in therapies for chronic medical conditions.
Once a drug has proved acceptable after Phase III trials, the trial results are typically combined into a large document containing a complete report of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This compilation of information makes up the "regulatory submission" that is provided for evaluation to the appropriate regulatory authorities in different countries. They will review the submission, and, it is expected, give the sponsor approval to market the drug.3 Phase IV Phase IV trial are also known as Post Marketing Surveillance Trial. Phase IV trials engage the safety surveillance (pharmacovigilance) and continuing technical support of a drug after it obtains consent to be sold. 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, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are doubtful to subject themselves to trials). This is planned to detect any rare or long-term adverse effects that were not detected during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or limited to certain uses: recent examples involve cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx). Benefits of participating in a clinical trial y y y y Play a dynamic role in their own health care. Gain access to new research treatments before they are extensively accessible. Obtain skilled medical care at leading health care facilities during the trial. Help others by contributing to medical research.
Risks of participating in a clinical trial y y y There may be disagreeable, serious or even life-threatening side effects to experimental treatment. The experimental treatment may not be effective for the participant. The protocol may need more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements.
Clinical trials are, of course, essential, but they come with an overwhelming price mark. On average, pharma companies are spending between $100 and $800 million per each drug molecule.8 India has become the preferred destination for global clinical trials today because of several reasons, including a technically competent workforce, patient availability, low costs and a friendly drug-control system. The clinical research industry in India has been growing rapidly. During the last 3 years it has increased from Rs. 20 crores to Rs. 100 crores. According to a recent McKinsey report, by the year 2010 the industry is expected to grow up to Rs. 5,000
crores.9 India is gearing up to attract more and more researchers from around the world to conduct their clinical trial studies in India.
References 1. 2. 3. 4. 5. 6. Clinasia.com Ngppharma.com Fda.gov Pharmainfo.net Ich.org Khaled El Emam et.al, 2009, ³The use of electronic data capture tools in clinical trials.´ Jr. of Med. Internet Res. Vol 11: No.1. 7. Clinicaltrials.gov 8. Robert Fee, 2007: ³The cost of clinical trials´. Drug discovery and development. 9. The Hindu, December 15th 2008: Seeking the right formula.