Chapter 2

Drug Approval and Regulation

Outcomes
1. Identify key U.S. drug regulations that have provided guidelines for the safe and
effective use of drugs and drug therapy.

2. Discuss the role of the U.S. Food and Drug Administration (FDA) in the drug
approval process.

3. Explain the four phases of approval for therapeutic and biologic drugs.

4. Discuss how the FDA has increased the speed with which new drugs reach
consumers.

5. Identify the nurse’s role in the drug approval process and in maintaining safety
practices.

6. Explain the U.S. Controlled Substance Act of 1970 and the role of the U.S. Drug
Enforcement Administration in controlling drug abuse and misuse.

7. Discuss why drugs are sometimes placed on a restrictive list, and the controversy
surrounding this issue.

8. Explain the meaning of a controlled substance and teratogenic risk in pregnancy.

9. Identify the five drug schedules and give examples of drugs at each level.

10. Identify the five categories of teratogenic drug classification.

More drugs are being administered to patients than ever before. More than 3 billion
prescriptions are dispensed each year in the United States. About one half of all
Americans take one prescription drug regularly. One out of six persons takes at least
three prescription drugs. The potential for harmful drug effects are greater than ever
before.

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2.1 Drug Regulations and Standards
1. The first standard commonly used by pharmacists was the formulary, or list of
drugs and drug recipes. In the United States, the first comprehensive publication
of drug standards, called the U.S. Pharmacopoeia (USP), was established in 1820.
A pharmacopoeia is a medical reference summarizing standards of drug purity,
strength, and directions for synthesis.
2. From 1852 to 1975, two major compendia maintained drug standards in the United
States: the U.S. Pharmacopoeia, and the National Formulary (NF) established by
the APhA. All drug products were covered in the USP; pharmaceutical ingredients
were covered in the NF. In 1975, the two entities merged into a single publication,
the U.S. Pharmacopoeia–National Formulary (USP-NF). 
3. The USP provides a nationwide database of documented and potential medication
errors, as well as their causes. The U.S. Pharmacopoeia Medication Errors
Reporting Program (USPMERP) provides opportunities for health care
professionals to search out and report occurrences related to medication safety. 
4. In order to protect the public in the early 1900s, the United States began to
develop and enforce tougher drug legislation.

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2.2 The Role of the Food and Drug Administration
1. In 1988, the U.S. Food and Drug Administration (FDA) was officially established
as an agency of the U.S. Department of Health and Human Services (HHS). 
2. The Center for Drug Evaluation and Research (CDER), a branch of the FDA,
exercises control over whether prescription and over-the-counter (OTC) drugs
may be used for therapy. 
3. Any pharmaceutical laboratory, whether private, public, or academic, must solicit
FDA approval before marketing a drug.
4. In 1997, the FDA created boxed warnings in order to regulate drugs with “special
problems.” At the time no precedent had been established to monitor drugs with a
potential for causing death or serious injury. Black box warnings, named after
the black box appearing around drug safety information located within package
inserts, eventually became one of the primary alerts for identifying extreme
adverse drug reactions discovered during and after the review process.
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 5. Another branch of the FDA, the Center for Biologics Evaluation and Research
(CBER), regulates the use of biologics including serums, vaccines, and blood
products. One historical achievement involving biologics was the 1986 Childhood
Vaccine Act. This act authorized the FDA to acquire information about patients
taking vaccines, to recall biologics, and to recommend civil penalties if guidelines
regarding biologics were not followed. In 1996, the Health Insurance Portability
and Accountability Act (HIPAA) required health-related organizations and schools
to keep private all health information including vaccinations.
6. The FDA oversees administration of herbal products and dietary supplements
through the Center for Food Safety and Applied Nutrition (CFSAN). 
7. In 1998, the National Center for Complementary and Alternative Medicine
(NCCAM), now called the National Center for Complementary and Integrative
Health (NCCIH), was established as the federal government’s lead agency for
scientific research and information about complementary and alternative medicine
(CAM) therapies. Its mission is to define, through rigorous scientific investigation,
the usefulness and safety of complementary and integrative health interventions
and their roles in improving health and health care. Among several areas of focus,
this agency supports research and serves as a resource for nurses in establishing
which CAM therapies are safe and effective.

2.3Phases of Approval for Therapeutic and Biologic Drugs

1. Therapeutic drugs and biologics are reviewed in four phases: Preclinical

investigation, Clinical investigation, Review of the New Drug Application (NDA),

Postmarketing surveillance.

2. Preclinical investigation involves extensive laboratory research. Scientists

perform many tests on human and microbial cells cultured in the laboratory.

Studies are performed in several species of animals to examine the drug’s

effectiveness at different doses and to look for adverse effects. 

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 3. Clinical investigation, the second phase of drug testing, takes place in three

different stages termed clinical phase trials. Clinical phase trials are the longest

part of the drug approval process. Clinical pharmacologists first perform tests on

volunteers to determine proper dosage and to assess for adverse effects

4. The New Drug Application (NDA) review is the third phase of the drug approval

process. During this phase, the drug’s trade name is finalized. 

5. Postmarketing surveillance, the final phase of the drug approval process, begins

after clinical trials and the NDA review have been completed. The purpose of this

phase is to survey for harmful drug effects in a larger population. Some adverse

effects take longer to appear and are not identified until a drug is circulated to

large numbers of people.

2.4 Changes to the Drug Approval Process

1. The process of isolating or synthesizing a new drug and testing it in cells,

experimental animals, and humans can take many years. 
2. According to the Tuft’s Center for the Study of Drug Development, drug
manufacturers will likely spend more than 2.5 billion dollars within the next
decade in order to gain approval to sell one new prescription drug 
3. In the early 1990s, due to pressure from organized consumer groups and various
drug manufacturers, government officials created a plan to speed up the drug
review process. Reasons identified for delays in the FDA drug approval process
included outdated guidelines, poor communication, and insufficient staff to
handle the workload.
4. In 1992, FDA officials, members of Congress, and representatives from
pharmaceutical companies negotiated the Prescription Drug User Fee Act on a 5-
year trial basis. This act required drug and biologic manufacturers to provide

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 yearly product user fees. This added income allowed the FDA to hire more
employees and to restructure its organization to more efficiently handle the
processing of drug applications. The result of restructuring was a resounding
success. From 1992 to 1996, the FDA approved double the number of drugs while
cutting some review times by as much as half. 

2.5 Nurses, the Drug Approval Process, and the Need for
Effective Safety Practices
1. The postmarketing surveillance period (Phase 4) is when the nurse has the most
opportunities to participate in the drug approval process. While the nurse working
at a large, urban medical center may participate in administering medications
during Phase II and III trials, all nurses administering medications monitor for
therapeutic effects and adverse reactions from the drugs they give to their patients.
2. Whenever a possible drug reaction is noted, the nurse is responsible for reporting
the reaction to the prescriber and appropriate health care agency personnel (e.g.,
risk management, pharmacist).
3. By monitoring for and reporting adverse effects, the nurse can ensure better
postmarketing surveillance is achieved.
4. Organizations like the nonprofit Institute for Safe Medication Practices (ISMP),
the federal Centers for Disease Control and Prevention (CDC), and The Joint
Commission accreditation/certification agency play additional roles and are
resources for safety enhancement.
5. Sentinel Event Alerts from The Joint Commission for example, describe “an
unexpected occurrence involving death or serious physical or psychological injury,
or the risk thereof that may or may not be directly related to administration of
medications.” 

2.6 Controlled Substances, Drug Schedules, and Teratogenic

Risks

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 1. Some drugs are frequently abused or have a high potential for addiction.
Technically, addiction refers to the overwhelming feeling that drives someone to
use a drug repeatedly.
2. Dependence is a related term, often defined as a physiological or psychological
need for a substance. Physical dependence refers to an altered physical condition
caused by the adaptation of the nervous system to repeated drug use. In this case,
when the drug is no longer available, the individual expresses physical signs of
discomfort known as withdrawal.
3. In contrast, when an individual is psychologically dependent, there are few signs
of physical discomfort when the drug is withdrawn; however, the individual feels
an intense compelling desire to continue drug use.
4. In the United States, a controlled substance is a drug whose use is restricted by
the Controlled Substances Act of 1970 and later revisions. According to this law,
drugs that have a significant potential for abuse are placed into five categories
called schedules.
5. These scheduled drugs are classified according to their potential for abuse:
Schedule I drugs have the highest potential for abuse, and Schedule V drugs have
the lowest potential for abuse. Schedule I drugs are restricted for use in situations
of medical necessity, if at all allowed. They have little or no therapeutic value or
are only intended for research purposes. Drugs in the other four schedules may be
dispensed only in cases in which therapeutic value has been determined. Schedule
V is the only category in which some drugs may be dispensed without a
prescription because the quantities of the controlled drug are so low that the
possibility of causing dependence is extremely remote.
6. Table 2.1 gives the five drug schedules with examples. Not all drugs with an abuse
potential are regulated or placed into schedules; tobacco, alcohol, and caffeine are
significant examples.

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The Controlled Substances Act is also called the Comprehensive Drug Abuse Prevention
and Control Act. Hospitals and pharmacies must register with the Drug Enforcement
Administration (DEA) and use their assigned registration numbers to purchase scheduled
drugs.
Hospitals and pharmacies must maintain complete records of all quantities purchased
and sold. Health care providers, nurse practitioners, and others with prescriptive
authority must also register with the DEA and receive an assigned number before
prescribing these drugs. Drugs with higher abuse potential have more restrictions. For
example, in many states, a special order form must be used to obtain Schedule II drugs,
and orders must be written and signed by the health care provider. Telephone orders to a
pharmacy are not permitted. Refills for Schedule II drugs are not permitted: patients must

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visit their health care provider first. Those convicted of unlawful manufacturing,
distributing, or dispensing controlled substances face severe penalties.

A teratogen is a substance that has the potential to cause a defect in an unborn child
during pregnancy. A small number of drugs have been shown to be teratogenic, either in
humans or in laboratory animals. Classification of teratogenic risk places drugs into
categories A, B, C, D, and X. Category A is the safest group of drugs while Category X
poses the most danger to the fetus. Birth defects are most probable in the first trimester;
thus, nurses must be mindful of the various drug risks during this time.