Drug Development and Safety

Overview

The arrival of a new drug launched with a massive advertisement campaign and clever commercials does little to illuminate the highly regulated process that drugs go through to make it to the market. The overwhelming success in modern pharmacotherapy in treating disease states attests to the safety and efficacy of prescribed agents. However, drugs can also be poisons causing unwanted adverse effects, and drugs can kill. This chapter begins with a description of drug development and the processes for evaluating drug safety and efficacy and then discusses the various types of adverse effects and interactions that are caused by drugs. Considerations for specific populations, such as the neonate and the elderly, are highlighted, and the laws relating to drug use and abuse are briefly reviewed.

Drug Development

Drug development in most countries has many features in common, beginning with the discovery and characterization of a new drug and proceeding through the clinical investigations that ultimately lead to regulatory approval for marketing the drug. Steps in the process of drug development in the United States are depicted in Figure 4-1.

Discovery and Characterization

New drug compounds are synthesized de novo or are isolated from a natural product, or a combination of the two as in semisynthetic compounds. Synthetic drugs may be patterned after other drugs with known pharmacologic activity, or their structure may be designed to bind a particular receptor and based on computer modeling of the drug and receptor. Because the likely activity of some new compounds is relatively uncertain, they must be subjected to a battery of screening tests to determine their effects. There are cases in which a particular pharmacologic activity of a drug was discovered accidentally after the drug was administered to patients for other purposes. For example, the antihypertensive effect of clonidine was discovered when the drug was tested for treatment of nasal congestion and a profound hypotensive episode ensued. This led to the subsequent development of clonidine for treating hypertension.

Preclinical Studies

Before a new drug is administered to humans, its pharmacologic effects are thoroughly investigated in studies involving animals, called preclinical testing. The studies are designed to (1) ascertain whether the new drug has any harmful or beneficial effects on vital organ function, including cardiovascular, renal, and respiratory function; (2) elucidate the drug’s mechanisms and therapeutic effects on target organs; and (3) determine the drug’s pharmacokinetic properties, thereby providing some indication of how the drug would be handled by the human body. Although a few people object to using animals, there are even fewer willing to refuse all medical treatment and pharmacotherapy that result from animal testing.

Federal regulations require that extensive toxicity studies in animals be conducted to predict the risks that will be associated with administering the drug to healthy human subjects and patients. The value of the preclinical studies is based on the proven correlation between drug toxicity in animals and humans. As outlined in Table 4-1, the studies involve short-term and long-term administration of the drug and are designed to determine the risk of acute, subacute, and chronic toxicity, as well as the risk of teratogenesis, mutagenesis, and carcinogenesis. After animals are treated with the new drug, their behavior is assessed and their blood samples are analyzed for indications of tissue damage, metabolic abnormalities, and immunologic effects. Tissues are removed and examined for gross and microscopic pathologic changes. Offspring are also studied for adverse effects.

TABLE 4-1

Drug Toxicity Studies in Animals

TYPE OF STUDY	METHOD	OBSERVATIONS
Acute toxicity	Administer a single dose of the drug in two species via two routes.	Behavioral changes, LD₅₀,* and mortality.
Subacute toxicity	Administer the drug for 90 days in two species via a route intended for humans.	Behavioral and physiologic changes, blood chemistry levels, and pathologic findings in tissue samples.
Chronic toxicity	Administer the drug for 6-24 months, depending on the type of drug.	Behavioral and physiologic changes, blood chemistry levels, and pathologic findings in tissue samples.
Teratogenesis	Administer the drug to pregnant rats and rabbits during organogenesis.	Anatomic defects and behavioral changes in offspring.
Mutagenesis	Perform the Ames test in bacteria. Examine cultured mammalian cells for chromosomal defects.	Evidence of chromosome breaks, gene mutations, chromatid exchange, trisomy, or other defects.
Carcinogenesis	Administer the drug to rats and mice for their entire lifetime.	Higher than normal rate of malignant neoplasms.

^*The LD₅₀ (the median lethal dose) is the dose that kills half of the animals in a 14-day period after the dose is administered.

Studies in animals may not reveal all of the adverse effects that will be found in human subjects, either because of the low incidence of particular effects or because of differences in susceptibility among species. This means that some adverse reactions may not be detected until the drug is administered to humans. However, because studies of chronic toxicity of new drugs in animals may require years for completion, it is usually possible to begin human studies while animal studies are being completed if the acute and subacute toxicity studies have not revealed any abnormalities in animals.

The Investigational New Drug Application

The Food and Drug Administration (FDA) must approve an application for an investigational new drug (IND) before the drug can be distributed for the purpose of conducting studies in human subjects. The IND application includes a complete description of the drug, the results of all preclinical studies completed to date, and a description of the design and methods of the proposed clinical studies and the qualifications of the investigators.

Federal Drug Laws and Regulations

There are two major types of legislation pertaining specifically to drugs. One type concerns drug safety and efficacy and regulates the processes by which drugs are evaluated, labeled, and marketed. The other type focuses on the prevention of drug abuse. In both cases the laws and regulations reflect the concern of society for minimizing the harm that may result from drug use while permitting the therapeutic use of safe and beneficial agents.

Drug Safety and Efficacy Laws

Pure Food and Drug Act

The Pure Food and Drug Act of 1906 was the first federal legislation concerning drug product safety and efficacy in the United States. The Act was passed in response to the sale of patent medicines, often by so-called “snake-oil salesmen,” which contained toxic or habit-forming ingredients. The legislation required accurate labeling of the ingredients in drug products and sought to prevent the adulteration of products through the substitution of inactive or toxic ingredients for the labeled ingredients. Because the Act did not regulate fraudulent advertising, the legislation was only partially successful in eliminating unsafe drug products.

Food, Drug, and Cosmetic Act

The Food, Drug, and Cosmetic (FD&C) Act of 1938 came in response to a tragic incident in which over 100 people died after ingesting an elixir that contained sulfanilamide, used to treat streptococcal infections, in a solution of ethylene glycol. The legislation, which is still in force today, made major strides by requiring evidence of drug safety before a drug product could be marketed, by establishing the FDA to enforce this requirement, and by giving legal authority to the drug product standards contained in the United States Pharmacopeia (USP).

First compiled in 1820, the USP has been updated and published at regular intervals by a private organization that is called the United States Pharmacopeial Convention and is composed of representatives of medical and pharmacy colleges and societies from each state. The USP contains information on the chemical analysis of drugs and indicates how much variance in drug content is allowable for each drug product. For example, the USP states that aspirin tablets must contain not less than 90% and not more than 110% of the labeled amount of acetylsalicylic acid (aspirin). In addition, the USP outlines standards for tablet disintegration and many other aspects of drug product composition and analysis.

Provisions of the Food, Drug, and Cosmetic Act

The FD&C Act prohibits the distribution of drug products that are adulterated or misbranded (mislabeled) or that do not have an approved NDA. The Act requires that drug product labels contain the name, dosage, and quantity of ingredients, as well as warnings against unsafe use in children or in persons with medical conditions for whom use of the drug might be dangerous. A drug product is said to be adulterated if it does not meet USP standards or if it is not manufactured according to defined “good manufacturing practices.”

Amendments to the Food, Drug, and Cosmetic Act

The FD&C Act has been amended many times. The Durham-Humphrey Amendment was passed in 1952 and created a legal distinction between nonprescription and prescription drugs. Prescription drugs are labeled “Rx Only.” Agents that are classified as prescription drugs are those that are determined to be unsafe for use without the supervision of a designated health care professional. After a new drug has been marketed for a period of time or if it is found to be safe enough to be used without physician supervision, the FDA may reclassify the drug as a nonprescription drug, known as an over-the-counter (OTC) drug. For example, topical cortisone products, antifungal drugs for treating candidiasis, proton pump inhibitors for treating acid reflux such as omeprazole (PRILOSEC), and antihistamines such as loratadine (CLARITIN) were originally classified as prescription drugs but are now available as OTC nonprescription drugs.

The Kefauver-Harris Amendments were passed in 1962, largely in response to reports of severe malformations in the offspring of women in Europe who took thalidomide for sedation during their pregnancy. In fact, thalidomide had not been marketed in the United States, because a female scientist at the FDA, Frances Kelsey, held up approval of thalidomide. Nevertheless, the shocking pictures from Europe of deformed babies spurred Congress to more strongly regulate drug development. Congress passed amendments that required the demonstration of both safety and efficacy in studies involving animals and humans before a drug product could be marketed. Although the processes of new drug development and testing have not changed substantially since this amendment was passed, the FDA review of new drugs has been streamlined in recent years.

The Orphan Drug Act was passed in 1983 to provide tax benefits and other incentives for drug manufacturers to test and produce drugs that are used in the treatment of rare diseases and are therefore unlikely to generate large profits. The Act appears to have been successful, as several hundred orphan drugs are now available. Examples are drugs used for the treatment of urea cycle enzyme deficiencies, Gaucher disease, homocystinuria, and other rare metabolic disorders.

Drug Price Competition and Patent Term Restoration Act

The Drug Price Competition and Patent Term Restoration Act of 1984 extended the patent life of drug products (which at that time was 17 years) by adding the amount of time required for regulatory review of an NDA. It also accelerated the approval of generic drug products by allowing investigators to submit an abbreviated NDA in which the generic product is shown to be therapeutically equivalent to an approved brand name product. Therapeutic equivalence is demonstrated on the basis of a single-dose oral bioavailability study that compares the generic drug with the brand name drug. If the variance is within a specified range (usually ±20%), the generic drug may be approved for marketing. The cost of such a study is relatively small compared with the millions of dollars required for the development of a completely new drug.

In 1992, accelerated drug approval was authorized for new drugs to treat life-threatening conditions such as acquired immunodeficiency syndrome (AIDS) and cancer. Under the new regulations, patients with these conditions can be treated with an investigational drug before clinical trials have been completed.

Drug Abuse Prevention Laws

Harrison Narcotics Act

The Harrison Narcotics Act of 1914 was the first major drug abuse legislation in the United States. It was prompted by the growing problem of heroin abuse, which followed the synthesis of this potent and rapid-acting derivative of morphine. The Act sought to control narcotics through the use of tax stamps on legal drug products, a practice similar to the use of tax stamps on alcoholic beverages today. The Harrison Narcotics Act had a profound and controversial effect on the treatment of substance abuse in that it prohibited physicians from administering opioid drugs to drug-dependent patients as part of their treatment program.

Comprehensive Drug Abuse Prevention and Control Act

During the 1960s the prevalence of drug abuse increased, especially among adolescents and young adults, who were using a wide range of drugs that included prescription sedatives and stimulants as well as substances such as lysergic acid diethylamide (LSD), marijuana, and other hallucinogens. Believing that the drug abuse problem required a new approach, members of Congress passed the Comprehensive Drug Abuse Prevention and Control Act of 1970. This law is often called the Controlled Substances Act (CSA).

The CSA classified drugs with abuse potential into five schedules, based on their degree of potential for abuse and their clinical usage (Fig. 4-2). Schedule I drugs are classified as having high abuse potential and no legitimate medical use, and their distribution and possession are prohibited. Schedule II drugs have high abuse potential but a legitimate medical use, and their distribution is highly controlled through requirements for inventories and records and through restrictions on prescriptions. Schedule III, IV, and V drugs have lower abuse potential and decreasingly fewer restrictions on distribution. The CSA requires that all manufacturers, distributors, physicians, and medical researchers using controlled drugs register with the Drug Enforcement Administration (DEA), which is responsible for enforcing the Act.