Clinical Trials: FDA Approval

Clinical trials
Clinical trials are the process by which a new drug's safety and effectiveness are tested as part of the FDA approval process. When a company discovers and develops a new drug, they must first run extensive pre-clinical trials prior to testing the drug candidate on people. This pre-clinical development process serves to determine a drug's safety, the best starting dose for human clinical trials, and the interaction between the body and the drug. Once pharmaceutical companies have enough information about the drug, they can apply for approval to run clinical trials on humans. Development and testing of medical treatments demands both high standards of scientific rigor and safety monitoring because of the unique ethical roles of humans as research subjects and as patients who will eventually receive a treatment. While observational studies such as case reports, surveys, and cohort studies may be relatively easy to conduct, their results are subject to bias because these studies cannot control the administration of a treatment to demonstrate cause and effect decisively. Results from experimental studies can be more valid; these include laboratory studies (on cell cultures, pathological specimens, or animal models) and clinical trials involving human subjects. Pre-clinical laboratory studies can provide information about pharmacology and toxicology of a newly designed drug. However, clinical trials are the only process by which a company or researcher can demonstrate that a drug, device, or biologic (a vaccine or treatment synthesized from living organisms) is safe and effective, and thus approvable by the Food and Drug Administration (FDA). A primary goal of a clinical trial is to establish cause and effect. In order to reach this goal, the study must isolate the effect of a treatment and rule out factors that could lead to misleading findings. This may include the elimination or at least minimization of bias, confounding (where the estimate of the treatment effect is distorted due the impact of another influential variable), and randomness. A clinical trial is a prospective study (a study that is planned in advance in which data are then collected in the future, as opposed to using data that has already been collected), and so it permits manipulation and measurement of a treatment in a controlled setting and thus provides the optimal strategy to avoid bias and confounding, minimize randomness, and quantify the uncertainty in the study outcome. If done properly, therefore, it is highly likely that the results will be considered valid. Disadvantages of clinical trials, beyond their infeasibility in some situations due to ethical concerns, include their costly and time-consuming nature. From the synthesis of a new drug to its appearance on the market can take approximately seventeen to twenty years, and cost from 0.8 to 1.7 billion dollars. After an experimental drug has been shown to be promising in laboratory and animal studies, an Investigational New Drug (IND) application may be filed with the FDA, requesting to begin experimentation in human subjects. If the IND application is approved, then a fourphase series of clinical trials progressively examines the optimal dose, safety, short-term and long-term effects on the body, and ultimately the effectiveness of an experimental therapy in humans.
Pharmaceutical companies Clinical trials can only come after extensive pre-clinical testing and development, which can be costly. Additionally, clinical trials themselves are very expensive to conduct. If a company's drug reaches a late-stage clinical trial and fails, the money spent up until that point will be lost. Any pharmaceutical company involved in the development of new drugs can be significantly impacted by the results of clinical trials, either positively or negatively. Major pharmaceutical companies include:

AstraZeneca (AZN) Bristol-Myers Squibb Company (BMY) Eli Lilly and Company (LLY) GlaxoSmithKline (GSK) Merck (MRK) Pfizer (PFE) Sanofi-Aventis SA (SNY)
As shown in the graph, these companies have anywhere from 20 to 140 new products in various stages of development. In general, Phase II is the most common place for drug candidates to fail. As such, companies with a higher percentage of products that either are in Phase III clinical trials or for which they've already filed a new drug application (NDA) are at somewhat lower risk of failing a clinical trial. Manufacturers of medical equipment, such as Advanced Medical Optics, are impacted by clinical trials as well.
Clinical testing process

Clinical trials are generally divided into four phases, though the FDA did establish a new Phase 0 designation for initial human trials. Including this recent addition, the five phases of clinical trials are:
Phase 0 o This phase is aimed at determining whether a drug will behave in humans in the way that pre-clinical testing indicated. A small dosage, below the amount expected to be used therapeutically, is given to a small number of subjects to determine if the drug will act on the part of the body on which it was designed to act. For example, a drug designed to lower cholesterol would be tested to see if it acts on particular parts of the body (blood vessels, the heart, etc.) and to see if that interaction is in line with expectations. This can prevent further, unnecessary testing in the event of a drug's not acting as predicted. Phase I
This is the first major stage in the clinical testing process. The drug is administered to a small group of subjects in an inpatient clinic, where the subjects can be monitored constantly. The main purpose of Phase I trials are to determine several things about a drug candidate, including its toxicity, side effects, interaction with the body, and proper dosage levels. There are a few different types of Phase I trials, but the basic premise is that the subjects receive an increasing dosage of the drug while being monitored for side effects. Other factors are also tested, such as the impact of food consumption on the drug's effectiveness, etc.
Phase II
o
After a drug's initial safety has been established, Phase II trials are commenced. In this stage, the drug is administered to a larger group of people, allowing further study of a candidate's effectiveness. Phase II trials also continue the safety assessments started in Phase I. The main purpose, however, is to determine a drug's efficacy, or whether its effect on the body is significant enough to warrant further testing.
Phase III
o
Phase III trials are generally the last stop on a drug's way from the lab to the pharmacy. These trials involve large subject groups and are designed to be the final assessment of a drug's efficacy and side effects. Phase III trials go one step further by comparing the drug candidate to the current standard treatment for a particular condition. If a drug is effective but shows no significant benefits over a treatment already in use, it can still be approved for production, though sales might not be as high as its developer had hoped. In the news, a drug that is proven to be safe and effective but that doesn't offer any advantages over the current "gold standard" treatment is often said to have "failed" the Phase III trials. While this something of a misnomer, it reflects the importance for pharmaceutical companies to develop innovative drugs that improve on existing treatment options.
Phase IV
o
Phase IV clinical trials occur after the approval and release of a new drug. These trials, which are sometimes not required, are used to further understand a drug's mechanism of action. For example, Phase IV trials often test the drug's interactions with other drugs and its effectiveness in certain populations that were not present in previous clinical trials. Additionally, drugs in this phase are monitored for long-term side effects that clinical trials were unable to detect. This can be important, since the relatively short duration of the clinical testing process doesn't allow for the observance of a drug's long-term impact on subjects. Vioxx, the blockbuster osteoarthritis drug made by Merck (MRK), is a well-known example of a drug recalled as a result of continual monitoring for safety.

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Clinical testing process

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