Figure 4–1 Steps in the process of drug development in the United States. IND = investigational new drug; NDA = new drug application.
Discovery and Characterization
New drug compounds are either synthesized de novo, isolated from a natural product, or a combination of the two as in semi-synthetic 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 submitted 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 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 (a) ascertain whether the new drug has any harmful or beneficial effects on vital organ function, including cardiovascular, renal, and respiratory function; (b) elucidate the drug’s mechanisms and therapeutic effects on target organs; and (c) 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 also are 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 (IND) 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.
Clinical Trials
Phase I clinical trials seek to determine the pharmacokinetic properties and safety of an IND in healthy human subjects. In the past, most of the subjects were men. Today, women are included in Phase I studies to determine if gender has any influence on the properties of the IND. The subjects typically undergo a complete history and physical examination, diagnostic imaging studies, and chemical and pharmacokinetic analyses of samples of blood and other bodily fluids. The pharmacokinetic analyses provide a basis for estimating doses to be employed in the next phase of trials, and the other examinations seek to determine if the drug is safe for use in humans.
Phase II clinical trials are the first studies to be performed in human subjects who have the particular disease for which the IND is targeting. These studies use a small number of patients to obtain a preliminary assessment of the drug’s efficacy and safety in diseased individuals and to establish a dosage range for further clinical studies.
Phase III clinical trials are conducted to compare the safety and efficacy of the IND with that of another substance or treatment approach. Phase III studies employ a larger group of subjects, often consisting of hundreds or even thousands of patients and involving multiple clinical sites and investigators. Phase III clinical trials are rigorously designed to prevent investigator bias and include double-blind and placebo-control procedures. In a double-blind study, neither the investigator nor the patient knows if the patient is receiving the new drug or another substance. Placebo control design includes a group receiving an identical formulation but with no active ingredients. With some diseases, it is unethical to administer a placebo because of the proven benefits of standard drug therapy. In such cases, the new drug is compared with the standard drug for treatment of that disease. Phase III trials often involve crossover studies, in which the patients receive one medication or placebo for a period of time and then are switched, after a washout period, to the other medication or placebo.
In many cases, the data are analyzed statistically at various points to determine whether the IND is sufficiently effective or toxic to justify terminating a clinical trial. For example, if a statistically significant greater therapeutic effect can be demonstrated after 6 months in the group of patients who are receiving the new drug, it is unethical to continue giving a placebo or a standard drug to the control group, the members of which could also benefit from receiving the new drug. A clinical trial is also stopped if the new drug causes a significant increase in rate of mortality or serious toxicity.
The New Drug Application (NDA) and Its Approval
After Phase III clinical trials are completed and analyzed, the drug developer may submit a new drug application (NDA) to the FDA to request approval to market the drug. This application includes the results of all preclinical and clinical studies, as well as the proposed labeling and clinical indications for the drug. The NDA typically constitutes an enormous amount of written material.
The FDA often requires a number of months to review the NDA before deciding whether to permit the drug to be marketed. Approved drugs are labeled for specific indications based on the data submitted to the FDA. Some drugs are found to have other clinical uses after the drug has been introduced to the market. These indications are known as unlabeled or “off-label” uses. For example, gabapentin (Neurontin) was initially approved for treating partial seizures but was used “off label” for preventing migraine headaches and treating chronic pain. In some cases, manufacturers will seek a revised labeling of an approved drug for another indication and establish a new trade name. This was done for the antidepressant bupropion, the exact same drug marketed as Wellbutrin for treating depression and Zyban for use in smoking cessation.
Postmarketing Surveillance
If a drug is approved for marketing, its safety in the general patient population is monitored by a procedure known as postmarketing surveillance, also considered Phase IV. The FDA seeks voluntary reporting of adverse drug reactions from health care professionals through its MedWatch program, and standard forms for this purpose are disseminated widely. Postmarketing surveillance is particularly important for detecting drug reactions that are uncommon and are therefore unlikely to be found during clinical trials.
FEDERAL DRUG LAWS AND REGULATIONS IN THE UNITED STATES
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 with 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 C9H8O4 (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, 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 classified as 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; as a result, 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 Amendments were 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’s disease, homocystinuria, and other rare metabolic disorders.
Drug Price Competition and Patent Restoration Act
The Drug Price Competition and Patent 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. Schedule I drugs were classified as 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 Agency, which is responsible for enforcing the Act.
ADVERSE EFFECTS OF DRUGS
Adverse effects, or side effects, can be classified with respect to their mechanisms of action and predictability. Those due to excessive pharmacologic activity are the most predictable and are often the easiest to prevent or counteract. Organ toxicity caused by other mechanisms is often unpredictable, because its occurrence depends on the drug susceptibility of the individual patient, the drug dosage, and numerous other factors. Hypersensitivity reactions are responsible for a large number of adverse organ system effects. These reactions occur frequently with some drugs but only rarely with others.
Excessive Pharmacologic Effects
Drugs often produce adverse effects by the same mechanism that is responsible for their therapeutic effect on the target organ. For example, atropine may cause dry mouth and urinary retention by the same mechanism that reduces gastric acid secretion in the treatment of peptic ulcer, namely, by muscarinic receptor antagonism. This type of adverse effect may be managed by reducing the drug dosage or by substituting a drug that is more selective for the target organ.
Hypersensitivity Reactions
Hypersensitivity reactions, or drug allergies, are responsible for a large number of organ toxicities that range in severity from a mild skin rash to major organ system failure. An allergic reaction occurs when the drug, acting as a hapten, combines with an endogenous protein to form an antigen that induces antibody production. The antigen and antibody subsequently interact with body tissues to produce a wide variety of adverse effects.
In the Gell and Coombs classification system, allergic reactions are divided into four general types, each of which can be produced by drugs. Type I reactions are immediate hypersensitivity reactions that are mediated by immunoglobulin E (IgE) antibodies. Examples of these reactions are urticaria (hives), atopic dermatitis, and anaphylactic shock. Type II reactions are cytolytic reactions that involve immune complement and are mediated by immunoglobulins G and M. Examples are hemolytic anemia, thrombocytopenia, and drug-induced lupus erythematosus. Type III reactions are mediated by immune complexes. The deposition of antigen-antibody complexes in vascular endothelium leads to inflammation, lymphadenopathy, and fever (serum sickness). An example is the severe skin rash seen in patients with a life-threatening form of drug-induced immune vasculitis that is known as Stevens-Johnson syndrome. Type IV reactions are delayed hypersensitivity reactions that are mediated by sensitized lymphocytes. An example is the ampicillin-induced skin rash that occurs in patients with viral mononucleosis.
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