Drug Regulation

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The road to drug development is a long and demanding process that can take up to 15 years. Before a substance is deemed "safe" it must go through the series of phases shown in Figure 1. These phases are called: discovery; preclinical testing (in animals); phase I; phase II; phase III; review by the U.S. Food and Drug Administration (FDA); and phase IV.


A new drug may be "discovered" by numerous methods, as listed below.

Testing traditional or folk medicine. The root of the plant Podophyllum peltatum was traditionally used by North American aboriginal people to treat warts. The active chemical, called podophyllotoxin, was isolated in 1940, and was found to have anticancer activity. Etoposide, a semisynthetic chemical made from podophyllotoxin, is used in the treatment of some cancers.

Accident or serendipity. The anticancer activity of the chemicals found in the rosy periwinkle (Catharanthus roseus ) was discovered accidentally. Native people in Africa, Australia, India, and South Africa traditionally used the rosy periwinkle to treat diabetes. Two scientists tested the extract to find out whether it was useful in lowering blood sugar, and found that it was not. Something in the extract was found to reduce the number of white blood cells in test animals, however, and two chemicals, called vincristine and vinblastine, were isolated and are still used as anticancer agents in the treatment of leukemia today.

Random sampling of chemicals. After the discovery of penicillin by Dr. Alexander Fleming in 1928, the screening of chemicals found in nature became an important way to find new drugs.

Rational drug design. Cimetidine is a chemical that is used to treat stomach ulcers. It is not known how ulcers start, but it is known that the amount of acid in the stomach makes the ulcer worse. To design cimetidine, chemists first had to understand how the stomach produces acid. They then had to design a chemical that blocks the acid production so that the stomach has a chance to heal. Cimetidine was the result of rational drug design.

Preclinical testing

To find out whether a substance that is thought to have medicinal values is safe to use and effective, information on how it affects the body must be gathered. It therefore enters a phase called preclinical testing. Here, scientists from many disciplines must study the chemical and biological properties of the substance. Pharmacology, in its broadest sense, includes the study of how a substance is absorbed, distributed, metabolized or processed, and excreted by the body. These studies are done on small animals in the laboratory.

Substances can be given by mouth (oral), applied to the skin (topical), or be injected or inhaled (parenteral). Absorption studies determine how much of a compound is absorbed after it is given. Some compounds may be destroyed in the stomach by stomach acid so that very little reaches the site where it is needed. How quickly a compound gets to the part of the body where it exerts its effect is called absorption and distribution.

Different substances produce different effects on different parts of the body. Some substances affect only the heart; some, the muscles; and some, the kidneys. This depends on the shape and size of the substance. Correlation between the size and shape of a substance and its effect on the body is called its structure-activity relationship.

Drug metabolism is the study of how a substance is altered or processed in the body so that it can be removed or eliminated (excreted) by the body in the urine or feces.

This information is obtained by giving the substance to a test animal. Samples of blood, urine, and feces are collected at specific times, and the amount of substance present is recorded. All of this information is called the pharmacologic profile of the substance. An autopsy is also done to examine all organs and tissues to give more data. Special studies are also done to see whether the substance is found in the milk of nursing animals. In pregnant animals, studies are done to see if it reaches the developing baby.

Toxicology deals with the unwanted effects of substances. Toxicological studies determine whether a substance can cause nausea, vomiting, changes in eating or drinking habits, weight change or changes in behavior. Work is also done to see if the it can cause cancer (carcinogenic) or produce birth defects (teratogenic).

The manufacture of a substance into a tablet, capsule, or liquid preparation is called formulation. For a substance to be formulated into a suitable dosage form for human use, requires consideration of whether the compound is a solid or liquid, whether it is stable at room temperature, and whether it smells or tastes bad.

Phase I

Once a substance has completed preclinical testing, the manufacturer files an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration (FDA). The IND becomes effective if the FDA does not disapprove of it within thirty days. The IND allows scientists investigating the drug to distribute it to responsible investigators for use in clinical trials that will involve humans. All clinical trials must be reviewed and approved by the Institutional Review Board (IRB) of the medical institution that will be conducting the clinical trial.

Normal, healthy volunteers are used in Phase I clinical trials. Phase I studies are several months in duration, and the size of the group can range from twenty to eighty subjects. The purpose of these trials is to determine the safety profile or benefit to risk assessment for use in humans, including the safe dosage range; and absorption, distribution, metabolism, and excretion in humans.

Phase II

In Phase II, one hundred to three hundred subjects with the targeted disease are selected. These patients cannot have other medical conditions that might complicate the assessment. For example, if a drug is being tested to reduce blood pressure, the subject cannot have high blood pressure and diabetes.

Phase II trials are randomized, double-blind, placebo-controlled, clinical trials. Randomization is the process of assigning the subjects in the trial into two groups, the control group and the treatment group, in a random manner. This helps to eliminate bias when assigning patients to each group. Double-blind means that neither the subjects nor the people giving the drug know to which group each subject has been assigned. Placebo-controlled means that the control group receives a placeboa pill that does not contain the drugwhile the test group receives a pill with the drug. All these provisions help to eliminate bias that may skew the results of the trial.

Phase II clinical trials are several months to two years in duration. They are carried out to determine the best dosage for the drug, look for unwanted effects (adverse effects), and to evaluate the efficacy of the drug; that is, whether it is useful to treat the target disease.

Phase III

This phase involves 1,000 to 3,000 subjects with the targeted disease. The disease condition can range from being mild to severe, and the subjects may have other complicating medical conditions. These trials are done in different locations across the country (multicentre). Phase III clinical trials are one to four years in duration, and are done to confirm dosage, monitor unwanted or adverse effects, look for unwanted effects from long-term use, establish the safety profile of the drug, and confirm the efficacy of the drug.

Review by the U.S. Food and Drug Administration

The FDA evaluates the data presented from the clinical trials in the New Drug Application (NDA) submitted by the manufacturer. The application consists of the application form and data from preclinical testing, chemistry and manufacturing data, clinical trials, samples and product labeling, and relevant publications.

The FDA evaluates the safety and efficacy of the drug and the quality of the data supporting the claims being made by the manufacturer. If approved, the product goes to market and enters Phase IV clinical trials.

Phase IV

During Phase IV the drug becomes available for physicians to prescribe, but the manufacturer must continue to submit reports to the FDA that evaluate the effectiveness of the drug, monitor drug interactions, provide data that compare the drug with other drugs that are used for the same purpose, evaluate the cost-effectiveness of the drug, and provide long-term safety and efficacy data. This ongoing monitoring is called post-marketing surveillance.

Age factors

When a new drug enters clinical trials, special attention is given to older adults (65 years or older) because they often develop unwanted effects to drugs at levels that are well-tolerated by younger persons. This may be caused by agerelated sensitivity to the drug, or because the metabolism and excretion of the drug is slower in the older adult.

In all phases of clinical trials, the risks and benefits to susceptible populations must be evaluated. These populations include infants, young children, pregnant women, nursing mothers, and older adults.

Clinicians who are experts on the disease being treated are used as investigators during Phase I and Phase II clinical trials. In Phase III, the usefulness of the drug in an expanded patient base is evaluated and adverse effects that may not have appeared in the previous two phases may become apparent during this period. The drug may be withdrawn from testing at any time if the risk to patients outweigh the benefits.

When the drug enters Phase IV, any adverse event reported to the manufacturer must be reported to the FDA within fifteen days after initial receipt of the information. This allows for continued evaluation and, if necessary, warnings to be issued by the FDA to prescribing physicians, pharmacists, and the public. In extreme cases, it may warrant the removal of the drug from the market.

The FDA requires that postmarketing adverse drug events be reported at quarterly intervals for three years from the date of approval of the NDA, and then at annual intervals. This provides an ongoing evaluation of the benefit-to-risk ratio of new drugs. It also gives recognition to the rights of all patients who participate in clinical drug studies in all stages of development.

Time and cost

From discovery to FDA approval of a drug takes about fifteen years and costs about $500 million. From the 5,000 to 10,000 new chemicals that are screened, about two hundred and fifty enter preclinical testing. Of this 250, only five enter clinical testing, and only one is approved and marketed.

M. B. Thadani

See also Drugs and Aging; Evidence-Based Medicine; Herbal Therapy.


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Gennaro, A. R., ed. Remington: The Science and Practice of Pharmacy, 20th ed. Philadelphia, Pa.: Lippincott, Williams & Wilkins, 2000.

Guarino, R. A., ed. New Drug Approval Process, 3d ed. New York: Marcel Dekker, 2000.

Patrick, G. L. An Introduction to Medicinal Chemistry. Oxford, U.K.: Oxford University Press, 1995.

Thadani, M. B. Medicinal and Pharmaceutical Uses of Natural Products, 2d ed. Winnipeg: Cantext Publications, 1998.

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Drug Regulation

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