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What is a clinical trial? Clinical Trials are experiments in human beings designed to answer questions about possible therapeutic interventions. Clinical trials answer questions about the safety and / or benefit of the intervention to determine whether or not it might be useful for future treatment of patients. Clinical trials are NOT confirmatory exercises designed to reproduce findings from non-clinical and animal model studies. While it is easy to get caught up in the excitement around findings of non-clinical studies, we must be aware that non-clinical studies are completed to provide the supporting rationale for conducting human experiments. Studies show up to 50% of clinical trial participants incorrectly believe that the experimental drugs being administered during clinical trials already have proven benefits, when in fact proving whether they work or not is the intent of the clinical trial itself. In addition, participants often do not have a clear understanding about the potential risks of experimental drugs. Both of these issues are called “therapeutic misconception”. It is important to be aware that the results of human clinical trials are the primary basis of determining benefit and safety for FDA approval. Past analysis of drug approval rates in the US show less than 20% of drugs that begin human clinical trials ultimately receive marketing approval. This is true for both orphan (less than 200,000 patients in the US) and non-orphan diseases. For information on clinical trials:
http://clinicaltrials.gov/ct2/info/understand An Introduction to the Clinical Research Process A clinical trial is a research study that is performed in humans to determine if a new drug or therapy is both safe and effective for treating a disease or condition. All clinical trials are based on a set of rules called a protocol. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. Clinical trials are carried out in steps called phases. Patients may be eligible for studies in different phases, depending on their general condition, the type and stage of their disease, and what therapy, if any, they have already had. Trial participants are seen regularly by research staff to monitor their health and to determine the safety and effectiveness of their treatment. On average, it takes twelve years for a drug to travel through the clinical testing phases to reach the patient population. Approximately one in five drugs that enter clinical testing are ultimately approved for patient use. The following is a description of what makes up each stage in the U.S. clinical trial process: Pre-clinical Testing
Before a drug can be tested in humans, pre-clinical testing is required. Laboratory studies are conducted to demonstrate safety in humans and the drugs’ ability to fight against a targeted disease. Once the drug has been determined to have strong potential, it begins to be prepared for human delivery. Pre-clinical testing takes approximately three to four years. Investigational New Drug Application (IND)
After completing pre-clinical testing, an IND must be filed with the regulatory agency, the U.S. Food and Drug Administration (FDA). The IND outlines the results of pre-clinical testing and clearly defines how future studies will be conducted. The FDA has thirty days to review the IND. If they do not disapprove the IND (clinical hold) within that time period, the drug can move on to a phase 1 trial where it can be tested in humans. FDA caution is not unusual for new therapeutic approaches. A potential outcome from an IND application with a very novel approach like stem cell therapy is that the trial will be placed on clinical hold by the FDA. A clinical hold is an order that the FDA issues to a sponsor to delay a proposed trial. Each of the previous applications that have been submitted in this very new field of investigational stem cell treatments has been placed on clinical hold for approximately a year after the IND was filed. Once the FDA approves an IND application, a formal approval process must also occur at the institutes conducting the trials by a group called the Institutional Review Board, which often takes several months to complete. Phase 1
In a phase 1 clinical trial, the primary goal is to assess the drug's safety. For the first time, the drug is introduced to humans, with tests occurring in a small number of healthy volunteers (20 to 100). The study is designed to determine how the human body reacts to the drug and, specifically, what side effects occur as dosage levels are increased. This initial phase of testing typically takes several months to a year. About 70 percent of experimental drugs pass this initial phase. Phase 2
Once a drug has been shown to be safe, it must be tested for effectiveness. Most phase 2 studies are randomized trials. This means, one group of patients will receive the experimental drug, while a second "control" group will receive a standard treatment or placebo. Often these studies are "blinded"--neither the patients nor the researchers know who is getting the experimental drug. In this manner, the study can provide the pharmaceutical or biotechnology company and the regulatory agency comparative information about the relative safety and effectiveness of this new drug. This second phase of testing may last from several months to two years, and involve up to several hundred patients. Only about 30 percent of experimental drugs successfully complete both phase 1 and phase 2 studies. Phase 3
In a phase 3 study, a drug is tested in several hundred to several thousand patients. This large-scale testing provides the pharmaceutical or biotechnology company and the regulatory agency with a more thorough understanding of the drug's effectiveness, benefits, and the range of possible adverse reactions. Most phase 3 studies are randomized and blinded trials.
Phase 3 studies typically last several years. Seventy to 90 percent of drugs that enter phase 3 studies successfully complete testing. Once a phase 3 study is successfully completed, a company can request marketing approval for the drug from the U.S. Food and Drug Administration. New Drug Application (NDA) / Biologics License Application (BLA)
Once all three clinical trial phases are complete and if the data demonstrates that the drug is safe and effective, an NDA/BLA is filed with the U.S. Food and Drug Administration (FDA). This NDA/BLA must contain all of the scientific information compiled over the course of the trials. The FDA is allowed at least six months to review the NDA/BLA. However, this review process can sometimes take up to two years depending on the procedures set forth by a specific country. Approval
Once the U.S. Food and Drug Administration approves the NDA/BLA, the drug becomes available for physicians to prescribe. Although the product is approved, it must continue to comply with regulatory requirements over time. For example, all cases of adverse events caused by the drug must be reported and quality control standards must be met. In some cases, the regulatory agency will also require post-marketing studies to evaluate the long-term effects of the drug.
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