Clinical research is designed to determine both the safety and efficacy of a product that is hypothesized to have a health benefit. By determining the safety and efficacy of the product, the sponsor of clinical research is also able to determine optimal dosages, understand the conditions of use, prepare an accurate set of written directions for use, warn users of the product about potential adverse reactions, provide supporting documentation for health claims, and, in certain cases, protect patent claims. One approach to conducting clinical research is to perform a clinical trial. A clinical trial is, in essence, a well thought out, carefully orchestrated experiment designed to clearly determine the safety and efficacy of a product in humans. In this article, the basic form of a clinical trial is discussed.

A clinical trial requires the input of several types of participants. There is the sponsor of the clinical trial that provides the funding. The sponsor is generally a company, government or other organization that wishes to gather safety and efficacy data regarding a specific product. There are the clinical investigators who actually provide the product to patients and gather data according to the study protocol developed for a specific clinical trial. Finally, there are the subjects who are the patients participating in the clinical trial; that is, the safety and efficacy studies are performed in the subjects. Other participants are those who provide the variety of services required to conduct the clinical trial. Such services include designing the study, selecting the study locations and personnel, collecting, collating, and interpreting the data, responding to ethical questions, complying with Institutional Review Board (IRB) regulations, writing the reports, dealing with government regulations etc. These services are often provided by a "clinical research organization" often referred to as a CRO.

Interventional Clinical Research

For the purpose of this article, the discussion of clinical trials will center on what is known as an interventional study. In an interventional study, subjects (that is, the patients enrolled in the clinical trial) are purposely given the product being tested for safety and efficacy. Another type of study, an observational study, is performed when interventional studies can not be done. Observational studies will be discussed in a future article.

Randomized, Double-Blinded, Placebo Controlled Clinical Trial

All clinical trials must have an outcome that can be measured. Measured outcomes can include the ability of a product to treat or cure a condition, prevent a condition from occurring, or to improve the quality of life of an individual.

The strongest evidence supporting the efficacy and safety of a clinical trial is derived from a type of clinical trial known as the "randomized, double-blinded, placebo controlled clinical trial." Each of the key terms in this phrase has significant meaning. Placebo is a substance that does not contain the active product under study. A placebo is meant to be inactive for the condition targeted in the clinical trial. The placebo allows the active product to be compared to a product that is not active and thus forms the baseline for the untreated condition. It is the comparison of active product to placebo, that is treatment to no treatment, that allows a statistical comparison to be made and the efficacy and safety of the product to be determined.

In some cases, the control is not an inactive substance, but a competing product. This allows for a head-to-head comparison of two products designed for the same purpose. A determination as to which product has a greater effect or is safer can then be made. Often in clinical trials, the current standard of care approach is included in the clinical trial. In these cases, the product being tested is either compared to the current standard of care or is tested for its usefulness as a complementary treatment to current treatment protocols.

Two other significant terms in the phrase "randomized, double-blinded, placebo controlled clinical trial" are randomized and double-blinded. Randomized means that each subject participating in the clinical trial is randomly assigned to either the treatment arm or the control arm. The clinical trial is defined as being double-blinded if neither the subject nor the investigator knows into which treatment arm the subject is enrolled. When a clinical trial is randomized and double-blinded, the direct participants in the trial (the subjects and the investigators) are unable to bias the results.

Clinical trials are conducted in a series of phases which are performed after pre-clinical studies are completed. Pre-clinical studies generally involve work in a laboratory using cell culture and animal studies. Pre-clinical studies are designed to determine if the product is likely to be effective and safe, to identify potential toxicities, and to get an idea of the dosage required. Once the pre-clinical studies are completed, a decision can be made regarding the product's worth for testing in a clinical trial.

Not all clinical trials need to be blinded or controlled. The need for a control or blinding a clinical trial will depend on the questions that need to be answered about the product safety and efficacy, the results of clinical research that has already been completed, and which phase clinical trial is being conducted.

Phases 0 through IV

Clinical trials are conducted in a series of studies known as phases. Thus far, five phases, designated as phases 0 through IV, have been established. Not all clinical research requires all five phases to be performed. Each product and condition presents a unique set of requirements; therefore in some cases, phases of clinical research may be combined or skipped depending on the question being asked.

A phase 0 (zero) clinical trial, when performed, generally involves doses of active product that are purposely sub-therapeutic. Phase 0 allows for the gathering of some basic pharmacokinetic (how a compound is metabolized) and pharmacodynamic (how a compound is working, that is, the compound's mechanism of action) data. Generally, data on efficacy and safety are not collected since the dosages employed are sub-therapeutic.

A phase I clinical trial is generally designed to determine the safety of a product. Phase I allows for testing a product's maximum tolerated dose, common adverse events, as well as pharmacokinetics and pharmacodynamics. In a model phase I clinical trial, several doses of the active compound are examined in a small number of subjects. Sometimes, the effects of other events on a product's pharmacokinetics and pharmacodynamics are studied. Such events may include the intake of food on the product's bioavailability or the interaction of other substances with the product under study. Phase I clinical trials are generally not controlled or blinded.

A phase II clinical trial is designed to determine the efficacy of a product and to determine the optimal dose and regimen. During phase II, the product's safety continues to be assessed. Often, phase I and phase II studies can be combined as a phase I/II clinical trial. Phase II clinical trials are often controlled, but not always blinded.

Phase III studies provide the statistical data that clearly shows the extent of a product's efficacy and safety. Phase III studies generally involve the largest number of enrolled subjects and are often performed at more than one study location. These parameters are determined by the exact nature of the efficacy question being answered. Phase III clinical trials are often, but not always, controlled and blinded.

Phase IV clinical trials are for products that are already in use and on the market. Phase IV clinical trials allows for both continued study of the product's safety as used by consumers in the market and for the development of additional uses of the product that have not been previously explored. Because of the nature of a phase IV clinical trial, they are neither directly controlled nor blinded.

Final Notes

The advantages of a well performed clinical trial are many. Data that support efficacy and safety claims are collected, patent positions can be strengthened and consumers can be informed about how a product works. However, determining exactly how a clinical trial should be designed and gathering all the resources required can be a complex task. Sometimes the services of consultants are needed. These services can be provided by a CRO. A CRO will design a clinical trial that fits within a budget, makes use of the appropriate phases of a clinical trial for the product under study, and will advise on the need for controls and whether a clinical research study should be blinded. A CRO will also deal with selection of clinical study sites and will collect, collate, interpret and report data. Finally, ethical questions and the protection of the subjects enrolled in a clinical trial by an Institutional Review Board (IRB) are also critical to the trial's success. (A future article will deal with how the IRB protects subjects enrolled in a clinical trial while providing an environment for the collection of safety and efficacy data). Bringing all these concepts and parameters together will result in successful clinical research that will provide evidence that backs claims made for a product.