The process that occurs from the conceptualization of a new drug to its use by physicians to treat patients with targeted diseases is extraordinarily complex, involving several levels of study of preclinical and clinical safety and efficacy. Not surprisingly, this process consumes a great deal of time and financial resources. Indeed, the average time from the conception of a new drug to its approval for general use by physicians is more than 10 years, with accumulated costs of more than $500 million. It has been estimated that the time required to complete the drug discovery period is 3 to 4 years and to complete the clinical trials (phase I, II, and III) period is approximately 8 years, although the period of time required is becoming shorter with newer FDA regulations. Most agents, therefore, have at least 5 years left on their patent prior to generic manufacture
Drug Discovery Process
The process of drug discovery (or research and preclinical development) has been performed in various ways, depending on the technology available to medicinal chemists. Earlier in the 20th century, drugs were developed by "trial and error" testing, with compounds being screened on the basis of changes in phenotypic activity in patients. Subsequent evolution of knowledge about the mechanism of action of various pharmaceutical agents, which occurred via investigations of functional groups, has allowed a more sophisticated understanding of how drugs work and what modifications alter important pharmacodynamic interactions (eg, ligand-receptor affinity). More recently, medicinal chemists have been able to use newer techniques for drug discovery, including combinatorial chemistry (which can generate whole classes of compounds quickly), genomics (which allows a greater understanding of disease targets at the molecular and cellular level), biotechnology (which enables development of more sophisticated and complete screening methods), and high throughput screening (which uses robotics to screen and obtain data on compound activity). The combination of these techniques allows more compounds to be applied to more targets more rapidly, thus generating a large amount of data about compounds and classes of compounds that may be useful in treating disease.
Drug Development Process
Investigational New Drug Application
In the United States, any company wishing to test a new pharmacologic agent in humans must submit an investigational new drug application (IND) with the FDA prior to administration of the agent to human subjects. An IND sets forth the company's plan for conducting the human trials and for the manufacture of the compound to be evaluated. This plan, called the study protocol, is paramount in the success of a new drug candidate, because applicants must anticipate what data and results are needed for final approval by the FDA. The FDA has 30 days to review the IND and decide whether the new drug candidate has been adequately tested for safety and whether the supplemental material on manufacture and clinical testing in humans is appropriate. If the FDA does not respond to the IND after 30 days, clinical trials may begin. However, if the FDA has objections, a clinical hold is initiated until perceived problems are resolved.
Clinical Trials
After the IND is approved by the FDA, clinical trials are begun to evaluate specific aspects of the candidate drug. There are 4 "phases" of trials, which represent the sequential determination of safety, distribution, and efficacy of the candidate drug in normal volunteers and in small and then large numbers of patients.
Phase I trials. A phase I trial is the first introduction of the candidate drug into humans. This type of trial is conducted either on normal volunteers or patient subjects, depending on the disease that is the target indication. Usually 20 to 80 persons participate in phase I trials, which are used to determine a safety profile and obtain dosage information. These trials are also used to determine the pharmacokinetics of the candidate drug (ie, the absorption, distribution, and elimination of the agent being tested) using blood and urine samples as well as other potential surrogate markers. Phase I trials are typically performed at a limited number of sites, are closely monitored, and have an average duration of 1 year.
Phase II trials. A phase II trial assesses the safety and efficacy of the candidate drug using the doses obtained in the phase I trial. Phase II trials are typically conducted on a relatively small number of patients (100 to 200) who have the disease that is the selected target indication; results in these patients are compared with those in either "active" (ie, a separate arm of patients not receiving the drug) or "historical" (ie, patients with the same disease state from other studies in the medical literature) controls. Phase II trials offer the first evidence that a candidate drug has clinical efficacy and often represents the most rigorous initial demonstration of the drug's efficacy. Phase II trials also provide additional safety data and are the impetus to move on to phase III trials. Phase II trials typically last approximately 2 years.
Phase III trials. Phase III trials are conducted in a large number of patients with the targeted indication to verify efficacy and safety in a longer-term setting. Typically, several hundred to several thousand patients participate, depending on the target disorder. The information obtained in a phase III trial is often used to provide information for package labeling. These trials last several years, because of the need to randomize patients to different treatment arms and to stratify them by clinical characteristics (eg, age, sex, grade of disease). Either during or after the phase III trial, the pharmaceutical company may prepare and submit a new drug application (NDA). An NDA is a proposal for the new drug candidate to be approved for marketing. This application relies on the clinical trial data to substantiate claims that a specific new compound is safe and effective for a proposed use in an extensive number of human subjects with a target indication. In general, it includes the results of all preclinical and clinical studies as well as detailed descriptions of the new drug candidate's chemical composition (with data on how this composition was elucidated). In addition, it will include the methods, facilities, and controls used in the product's manufacturing, processing, and packaging. These applications are a very large endeavor, with most comprising 100 to 200 volumes and an average of 70,000 to 90,000 pages. The application is evaluated by a panel of reviewers at the FDA-including medicinal chemists, pharmacologists, medical officers, and statisticians-as well as by other administrative and scientific staff. The FDA must issue a decision on an NDA within 180 days of submission. However, extensions to the review are allowed when updates or amendments are made to the NDA. The average time taken by the FDA to evaluate an NDA is 12 months. After the review is complete, an "action letter" is sent to the pharmaceutical company containing a written decision (approved, approvable, or not approvable). The "approvable" decision either specifies minor changes to be made to the NDA or indicates where clarification is required.
Phase IV trials. These trials are performed for several reasons. For example, the FDA may require that a sponsoring pharmaceutical company continue to conduct postmarketing studies to monitor long-term risks and benefits or to study different dosage levels and evaluate different safety and efficacy levels in target patient populations. However, these trials take place after the drug is approved for marketing by the FDA.
