There are five basic stages of development that a novel treatment must pass through before approval. Many good ideas for novel treatments don't even make it through these stages due to a variety of factors such as incomplete paperwork or lack of funding. A collaboration involving researchers, doctors, regulators, and the private company that owns the patent on the medication or device determine how the trials are set up. Although clinical trials for device approval typically require enrolling fewer patients than do drug trials, this gap has been narrowing as device trials are subject to increasingly rigorous scientific standards.
The five key stages of clinical trials that a novel device or medication must pass through before — and after — it reaches the market include:
Preclinical: The safety and effectiveness of experimental medications or devices are evaluated in test tubes, computer models, and often on animals. For medicines, this involves assessing how the compounds move through living organisms and what impact they have against the disease target. Likewise, devices also must be evaluated for how compatible they are with the human body and how they work within the body. The main goal of preclinical studies is to rigorously assess safety before human tests begin; this is why preclinical studies often take three to six years (or longer) to conduct. Some preclinical safety tests continue even after the start of clinical trials to help identify any long-term adverse effects. Once ready for the next stage of testing on humans, the researcher or scientist must file an investigational medicine or device application with the FDA before human testing may begin. The application must show:
- Results of preclinical experiments;
- The chemical structure of the compound or design of the device;
- How it is thought to work in the body;
- Any side effects found in animal studies; and
- How it will be manufactured.
The application must also include a detailed plan of how, where, and by whom the clinical trial will be conducted. In addition, all clinical trials must be approved and monitored by an Institutional Review Board (IRB), a committee that reviews biomedical and behavioral research involving humans. An IRB is typically set up by academic institutions and medical facilities, but they can also be created by for-profit companies and are called independent or commercial IRBs. The aim of the IRB is to protect the rights and welfare of those involved in the study. Progress reports on clinical trials must be submitted at least annually to IRBs and the FDA.
Pilot, or Phase 1: Researchers first test an experimental medication or device in a small group of people to evaluate its safety, determine a safe dosage range, and identify side effects. To establish the safety profile of an experimental medication and determine how it moves through the body, a pilot study may involve 20 to 100 healthy volunteers. Somewhat fewer participants (a dozen or more) are needed for devices. This process can take from six months to a year to complete.
Feasibility, or Phase 2: The experimental medication or device is given to a larger group of patients who have the disease or condition to test whether it is effective and further evaluate its safety. For medications, these trials can involve 100 to 500 participants. Typically the group is divided in two, with one half given a placebo (an inactive substance, often called a "sugar pill"), and the other given the "active" medication. The placebo group is referred to as the "control group."
In device trials, rather than implant an inactive device, the control group typically receives the standard treatment for the disease or condition. The goal of this phase is to prove whether the therapy effectively treats the disease. Researchers continue to evaluate the safety of the medication or device, look for side effects, and adjust the therapy (such as dosage level). These studies also typically take from six months to a year.
Pivotal, or Phase 3: This is the phase of clinical trials designed to evaluate safety and effectiveness (efficacy) on a wide sampling of participants — from hundreds to 5,000 or more — of the target patient group. For medications, these are large, randomized (that is, the participants are randomly assigned to one of two or more treatment "arms," or groups), placebo-controlled trials that generate statistically significant data, meaning the results are unlikely to have been reached by chance or coincidence. Researchers closely and regularly monitor patients to confirm effectiveness and identify adverse events or side effects. They compare the safety and effectiveness of the new therapy to treatments already in common use for the targeted disease or condition. These studies can take from one to four years to complete, depending on the design of the study and how long it takes to recruit enough patients to meet the minimum size requirements established for the trial.
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Once the three phases of the clinical trials are complete, the data are analyzed to determine if the experimental medication or device is safe and effective. If it is, a new medication or device application is filed with the FDA. FDA scientists review the study results and determine whether the medication or device is safe and effective enough to be "cleared for marketing." In some cases, an Advisory Committee composed of FDA-appointed experts is convened to review the application and recommend whether it should be approved and, if so, under what conditions. The FDA is not required to accept an Advisory Committee's recommendations, but it typically does accept them. It took an average of 16.9 months for the FDA to review each medicine it approved in 2003. The proportion of applications rejected at this point in the approval process has remained constant over the years at about 10-15 percent.
Once cleared for marketing, the medication or device is available to physicians and patients. In the United States, FDA regulations permit doctors and other health care providers to prescribe approved medications and devices for indications other than the disease or condition for which they are approved; this is called off-label use.
Off-label use does not mean unsafe use. The FDA allows doctors to make informed decisions about the best medication or device to treat their patients, and doctors may prescribe a medication or device in a way that has demonstrated positive outcomes but is not "indicated" or FDA-approved for that specific use. If doctors were not allowed to prescribe off-label, lengthy FDA approval processes for each medication or device might prevent patients from receiving life-saving therapy. It is important for doctors and patients to discuss the best method of treatment and all medications and devices available to treat a condition. However, device and pharmaceutical companies are prohibited from promoting their products for any other purpose unless they first receive FDA approval for a new indication.
Post-marketing, or Phase 4: Patients participating in the clinical trial are followed for a year or more — sometimes many years — after a medication or device receives regulatory approval to monitor for safety and effectiveness and to gather additional information about risks, benefits, and optimal use. Since a much bigger and more diverse group of patients is now likely to take the medicine or have the device, researchers may detect side effects or adverse events that were not apparent during clinical trials. This is why researchers must submit regular reports to the FDA detailing complications they observe. These studies also help researchers better assess how the medication or device affects a particular group of patients based on such criteria as age, sex, race, or condition.