Many of the drugs in current use were discovered by experiments conducted in animals and humans. However, many drugs are now being designed with the specific disorder in view. Abnormal biochemical and cellular changes caused by disease are identified, and then compounds that may specifically prevent or correct these abnormalities (by interacting with specific sites in the body) can be designed. When a new compound shows promise, its structure is usually modified many times to optimize its ability to target the intended site (selectivity—see Site Selectivity), remain attached to the site (affinity—see Drug Action : Affinity and Intrinsic Activity), and optimize its strength (potency), efficacy, effectiveness (see Drug Action : Potency, Efficacy, and Effectiveness), and safety (side effects—see Drug Effectiveness and Safety). Other factors, such as whether the compound is absorbed through the intestinal wall and whether it is stable in body tissues and fluids, are also considered. These factors involve what the body does to the drug (drug kinetics—see see Introduction to Administration and Kinetics of Drugs) and what the drug does to the body (drug dynamics—see see Definition of Drug Dynamics).
Ideally, a drug is highly selective for its target site so that it has little or no effect on other body systems—that is, it has minimal or no side effects (see Overview of Adverse Drug Reactions). The drug should also be very potent and effective so that low doses can be used, even for disorders that are difficult to treat. The drug should be effective when taken by mouth (for convenient use), absorbed well from the digestive tract, and reasonably stable in body tissues and fluids so that, ideally, one dose a day is adequate.
During drug development, standard or average doses are determined. However, people respond to drugs differently. Many factors, including age (see Aging and Drugs), weight, genetic make-up, and the presence of other disorders, affect drug response (see Overview of Response to Drugs). These factors must be considered when doctors determine the dose for a particular person.
From Laboratory to Medicine Cabinet
After a drug that may be useful in treating a disorder is identified or designed, it is studied in laboratory animals (a phase called early development). Early development gathers information about how the drug works, how effectively it works, and what toxic effects it produces, including possible effects on reproductive capacity and the health of offspring. Many drugs are rejected at this stage because they are shown to be too toxic or not effective.
If a drug seems promising after early development, a program describing the clinical study must be approved by an appropriate institutional research board (IRB) and an investigational new drug application is filed with the Food and Drug Administration (FDA). If the FDA approves the application, the drug is allowed to be tested in people (a phase called clinical studies).
These studies occur in several phases and only in volunteers who have given their full consent.
Phase 1 evaluates the drug's safety and toxicity in people. Different amounts of the drug are given to a small number of healthy, young, usually male people to determine the dose at which toxicity first appears.
Phase 2 evaluates what effect the drug has on the target disorder and what the right dose might be. Different amounts of the drug are given to up to about 100 people who have the target disorder to see whether there is any benefit. Just because a drug is effective in animals in early development does not mean it is effective in people.
Phase 3 tests the drug in a much larger (often hundreds to thousands) group of people who have the target disorder. These people are selected to be as similar as possible to the people who might use the drug in the real world. The drug's effectiveness is studied further, and any new side effects are noted. Phase III tests usually compare the new drug against an established drug, a placebo, or both.
In addition to determining a drug's effectiveness, studies in people focus on the type and frequency of side effects and on factors that make people susceptible to these effects (such as age, sex, other disorders, and the use of other drugs).
If studies indicate that the drug is effective and safe, a new drug application (including data from the animal and human tests, intended drug manufacturing procedures, prescribing information, and product labeling) is filed with the FDA, which reviews all the information and decides whether the drug is sufficiently effective and safe to be marketed. If the FDA approves, the drug becomes available for use. The whole process usually takes about 10 years. On average, only about 5 out of 4,000 drugs studied in the laboratory are studied in people, and only about 1 out of 5 drugs studied in people is approved and prescribed.
Phase 4 (postmarketing):
After a new drug is approved, the manufacturer must monitor the use of the drug and promptly report any additional, previously undetected side effects to the FDA. Doctors and pharmacists are encouraged to participate in the ongoing monitoring of the drug. Such monitoring is important because before the drug is marketed, even comprehensive studies can detect only relatively common side effects (that occur about once in every 1,000 doses). Important side effects that occur once in every 10,000 (or more) doses can be detected only when a large number of people use the drug, that is, after it is on the market. The FDA may withdraw approval if new evidence indicates that a drug may cause severe side effects. For example, the diet aid fenfluramine was withdrawn from the market because some people who took it developed serious heart disorders.
Laboratory settings (such as cell cultures and animals)
To determine the chemical and physical characteristics of the drug and to assess the safety and effects of the drug in living organisms
20–80 healthy volunteers
To establish basic safety and blood levels achieved with different doses of the drug
Up to 100 people who have or who might develop the disorder being studied
To establish the drug's effectiveness and dosage range and to identify side effects
300–30,000 people who have the disorder being studied
To confirm the most effective dosage regimen, to obtain more information about the drug's effectiveness and side effects not seen during phases 1 and 2, and to compare the drug with existing drugs, a placebo, or both
Government review of all information from early development and clinical studies
To determine whether the drug has been proved to be effective and safe
Phase 4 (postmarketing surveillance)
All people taking the drug, particularly subgroups such as pregnant women, children, and older people
To identify any problems that did not occur in phases 1, 2, or 3, such as those that take a long time to appear and those that occur rarely
Last full review/revision July 2013 by Daniel A. Hussar, PhD