Drug Development research: The Process

Otolaryngologists often are involved in clinical trials, and nearly all of us read publications based on pharmaceutical research. However, many physicians who are not involved routinely in drug development may be unfamiliar with the stages in the drug development process, and with related terminology. Understanding such information helps interpret literature.

Briefly, there are several stages in the drug development process. The first stages are preclinical. Once an idea has been put forth for a new product (the creation of new product concepts will not be addressed in this editorial), the investigator and/or sponsor initiates research by testing the new product in vitro. In vitro studies are followed by animal studies designed to provide information about toxic effects and the pharmacologic nature and behavior of the investigational drug. Following successful preclinical research, clinical research may be initiated.

The first step in clinical research is to apply to the U.S. Food and Drug Administration (FDA) for an Investigational New Drug (IND) application. This is a complex application. Before issuing an IND number, the FDA reviews all preclinical research data, scientific information on the formulation of the investigational drug, manufacturing procedures and expertise, the qualifications of the proposed investigator, and the proposed clinical protocol. An IND is required not only for investigational drugs proposed by pharmaceutical companies or other private entities, but even for those proposed by federal agencies or the National Institutes of Health (NIH) intramural programs, prior to human use.

Phase I trials involve a small number of subjects, usually between 10 and 100. These trials may include patients or normal volunteers. If the drug involves substantial risk or is likely to cause harm (such as immunosuppressive therapy or cytotoxic chemotherapy), it is appropriate to use patients, so long as they are fully informed and give their consent. Typically, unless the drug is targeted specifically for women's health concerns, Phase I trials seek normal male volunteers to assess the investigational drug's initial exposure to an entire population. Phase I trials reveal information about pharmacologic action, metabolism, and toxicity in humans and help create a preliminary, dose-related profile of side effects.

Phase II trials are tightly controlled studies with strict inclusion and exclusion criteria. They include a larger but still a relatively small number of subjects, not exceeding several hundred. Phase II trials evaluate the effectiveness of the drug in treating a particular condition in patients, and they provide further information about short-term side effects and risks.

Phase III trials may include thousands of patients. Generally, they are designed for rapid recruitment of subjects and are approved only after data from Phase II trials indicate that the drug is effective for the condition under study. Phase III trials provide greater insight into safety and efficacy, as well as risks, effects, and side effects. The risks/benefits information developed from Phase III trials affect FDA-approved labeling of the drug when it is brought to market.  An investigational drug can be brought to market if Phase III studies indicate adequate safety and efficacy. In order to obtain permission to market a new pharmaceutical product, a New Drug Application (NDA) is required. This is also a complex and exhaustive application that includes all clinical data, all safety data from clinical studies, drug formulation and manufacturing information, and the results of at least two substantive Phase III trials.

Phase IV trials may be conducted by a pharmaceutical company after a product is available on the market and has received FDA approval. Phase IV trials are prudent and informative, but they typically are not required by the FDA. A company or investigator may choose to perform Phase IV studies to investigate the effects of different doses or dosing schedules from those used in Phase II and Phase III trials; to determine the behavior of the drug in different patient populations or in patients with earlier or more advanced stages of disease; to monitor long-term effectiveness of the new agent; to compare the drug with other drugs available on the market; or to compare the cost effectiveness of the drug with that of other products.  There is an analogous, similarly rigorous process required for development of devices that has been required by the FDA since 1980. That process will not be discussed in detail in this editorial, but it is important to recognize that devices also must undergo clinical trials before they can be brought to market. The rigor and expense of the clinical trials process varies depending upon whether the device is determined to be a “significant risk device” or “nonsignificant risk device.” Otolaryngologists should be aware that such regulations exist and may influence greatly the viability of creative new device concepts (including surgical instruments and, particularly, implants) because the costs associated with federal approval can be prohibitive. Physicians interested in more information on device development can probably obtain it most easily through their institutional review boards.