Chapter 5. Drug Evaluation & Regulation

The sale and use of drugs are regulated in almost all countries by governmental agencies. In the United States, regulation is by the Food and Drug Administration (FDA). New drugs are developed in industrial or academic laboratories. Before a new drug can be approved for regular therapeutic use in humans, a series of animal and experimental human studies must be carried out.

New drugs may emerge from a variety of sources. Some are the result of identification of a new target for a disease. Rational molecular design or screening is then used to find a molecule that selectively alters the function of the target. New drugs may result from the screening of hundreds of compounds against model diseases in animals. In contrast, many (so-called "me-too" drugs) are the result of simple chemical alteration of the pharmacokinetic properties of the original, prototype agent.

Because society expects prescription drugs to be safe and effective, governments regulate the development and marketing of new drugs. Current regulations require evidence of relative safety (derived from acute and subacute toxicity testing in animals) and probable therapeutic action (from the pharmacologic profile in animals) before human testing is permitted. Some information about the pharmacokinetics of a compound is also required before clinical evaluation is begun. Chronic toxicity test results are generally not required, but testing must be underway before human studies are started. The development of a new drug and its pathway through various levels of testing and regulation are illustrated in Figure 5–1. The cost of development of a new drug, including false starts and discarded molecules, is often several hundred million dollars.

The animal testing that is required before human studies can begin is a function of the proposed use and the urgency of the application. Thus, a drug proposed for occasional nonsystemic use requires less extensive testing than one destined for chronic systemic administration.

Because of the urgent need for new agents, anticancer drugs and anti-HIV drugs require less evidence of safety than do drugs used in treatment of less threatening diseases. Urgently needed drugs are often investigated and approved on an accelerated schedule.

Acute Toxicity

Acute toxicity studies are required for all new drugs. These studies involve administration of incrementing doses of the agent up to the lethal level in at least 2 species (eg, 1 rodent and 1 nonrodent).

Subacute and Chronic Toxicity

Subacute and chronic toxicity testing are required for most agents, especially those intended for chronic use. Tests are usually conducted for 2–4 weeks (subacute) and 6–24 months (chronic), in at least 2 species.

Tests done with animals usually include general screening tests for pharmacologic effects, hepatic and renal function monitoring, blood and urine tests, gross and histopathologic examination of tissues, and tests of reproductive effects and carcinogenicity.

Pharmacologic Profile

The pharmacologic profile is a description of all the pharmacologic effects of a drug (eg, effects on cardiovascular function, gastrointestinal activity, respiration, renal function, endocrine function, CNS). Both graded and quantal dose-response data are gathered.

Reproductive Toxicity

Reproductive toxicity testing involves the study of the fertility effects of the candidate drug and its teratogenic and mutagenic toxicity. The FDA uses a 5-level descriptive scale to summarize information regarding the safety of drugs in pregnancy (Table 5–1). Teratogenesis can be defined as the induction of developmental defects in the somatic tissues of the fetus (eg, by exposure of the fetus to a chemical, infection, or radiation). Teratogenesis is studied by treating pregnant female animals of at least 2 species at selected times during early pregnancy when organogenesis is known to take place and by later examining the fetuses or neonates for abnormalities. Examples of drugs known to have teratogenic effects include thalidomide, isotretinoin, valproic acid, ethanol, glucocorticoids, warfarin, lithium, and androgens. Mutagenesis is induction of changes in the genetic material of animals of any age and therefore induction of heritable abnormalities. The Ames test, the standard in vitro test for mutagenicity, uses a special strain of salmonella bacteria that naturally depends on specific nutrients in the culture medium. Loss of this dependence as a result of exposure to the test drug signals a mutation. Many carcinogens (eg, aflatoxin, cancer chemotherapeutic drugs, and other agents that bind to DNA) have mutagenic effects and test positive in the Ames test. The dominant lethal test is an in vivo mutagenicity test carried out in mice. Male animals are exposed to the test substance before mating. Abnormalities in the results of subsequent mating (eg, loss of embryos, deformed fetuses) signal a mutation in the male's germ cells.

Carcinogenesis

Carcinogenesis is the induction of malignant characteristics in cells. Carcinogenicity is difficult and expensive to study, and the Ames test is often used to screen chemicals because there is a moderately high degree of correlation between mutagenicity in the Ames test and carcinogenicity in some animal tests, as previously noted. Agents with known carcinogenic effects include coal tar, aflatoxin, dimethylnitrosamine and other nitrosamines, urethane, vinyl chloride, and the polycyclic aromatic hydrocarbons in tobacco smoke (eg, benzo[a]pyrene) and other tobacco products.

Human testing of new drugs in the United States requires approval by institutional committees that monitor the ethical (informed consent, patient safety) and scientific aspects (study design, statistical power) of the proposed tests. Such testing also requires the prior approval by the FDA of an Investigational New Drug Exemption application (IND), which is submitted by the manufacturer to the FDA (Figure 5–1). The IND includes all the preclinical data collected up to the time of submission and the detailed proposal for clinical trials. The major clinical testing process is usually divided into 3 phases that are carried out to provide information for a New Drug Application (NDA). The NDA includes all the results of preclinical and clinical testing and constitutes the request for FDA approval of general marketing of the new agent for prescription use. A fourth phase of study (the surveillance phase) follows NDA approval.

Phase 1

A phase 1 trial consists of careful evaluation of the dose-response relationship and the pharmacokinetics of the new drug in a small number of normal human volunteers (eg, 20–100). An exception is the phase 1 trials of cancer chemotherapeutic agents and other highly toxic drugs; these are carried out by administering the agents to volunteer patients with the target disease. In phase 1 studies, the acute effects of the agent are studied over a broad range of dosages, starting with one that produces no detectable effect and progressing to one that produces either a significant physiologic response or a very minor toxic effect.

Phase 2

A phase 2 trial involves evaluation of a drug in a moderate number of patients (eg, 100–200) with the target disease. A placebo or positive control drug is included in a single-blind or double-blind design. The study is carried out under very carefully controlled conditions, and patients are closely monitored, often in a hospital research ward. The goal is to determine whether the agent has the desired efficacy (ie, produces adequate therapeutic response) at doses that are tolerated by sick patients. Detailed data are collected regarding the pharmacokinetics and pharmacodynamics of the drug in this patient population.

Phase 3

A phase 3 trial usually involves many patients (eg, 1000–5000 or more, in many centers) and many clinicians who are using the drug in the manner proposed for its ultimate general use (eg, in outpatients). Such studies usually include placebo and positive controls in a double-blind crossover design. The goals are to explore further, under the conditions of the proposed clinical use, the spectrum of beneficial actions of the new drug, to compare it with older therapies, and to discover toxicities, if any, that occur so infrequently as to be undetectable in phase 2 studies. Very large amounts of data are collected and these studies are usually very expensive.

If the drug successfully completes phase 3, an NDA is submitted to the FDA. If the NDA is approved, the drug can be marketed and phase 4 begins.

Phase 4

Phase 4 represents the postmarketing surveillance phase of evaluation, in which it is hoped that toxicities that occur very infrequently will be detected and reported early enough to prevent major therapeutic disasters. Manufacturers are required to inform the FDA at regular intervals of all reported untoward drug reactions. Unlike the first 3 phases, phase 4 has not been rigidly regulated by the FDA in the past. Because so many drugs have been found to be unacceptably toxic only after they have been marketed, there is considerable current interest in making phase 4 surveillance more consistent, effective, and informative.

A patent application is usually submitted around the time that a new drug enters animal testing. In the United States, approval of the patent and completion of the NDA approval process give the originator the right to market the drug without competition from other firms for a period of 20 years from the patent approval date. After expiration of the patent, any company may apply to the FDA for permission to market a generic version of the same drug if they demonstrate that their generic drug molecule is bioequivalent (ie, meets certain requirements for content, purity, and bioavailability) to the original product.

See Chapter 2.

What type of dose-response curve is appropriate for the determination of the therapeutic index of a new drug in mice? What type of dose-response determination is needed for the determination of the minimum effective dose and the maximal efficacy of the drug in humans?

In the United States, many laws regulating drugs were passed during the 20th century. Refer to Table 5–2 for a partial list of this legislation.

An orphan drug is a drug for a rare disease (one affecting fewer than 200,000 people in the United States). The study of such agents has often been neglected because the sales of an effective agent for an uncommon ailment might not pay the costs of development. In the United States, current legislation provides for tax relief and other incentives designed to encourage the development of orphan drugs.

Chapter 2.

The therapeutic index is the ratio of the median toxic dose, (TD50) or median lethal dose (LD50) to the effective dose in half the population (ED50), determined in a population of subjects. Thus, quantal dose-response experiments are needed to ascertain the therapeutic index. The minimum effective dose and the maximal efficacy of a drug are determined by gradually increasing the dose and noting the responses produced. Graded dose-response experiments are needed for these measurements.

When you complete this chapter, you should be able to:

• □ Describe the major animal and clinical studies carried out in drug development.
• □ Describe the purpose of the Investigational New Drug (IND) Exemption and the New Drug Application (NDA).
• □ Define carcinogenesis, mutagenesis, and teratogenesis.
• □ Describe the difference between the FDA regulations for ordinary drugs and those for botanical remedies