Drug Approval & Regulation

Pharmacology for Nurses: A Pathophysiologic
Approach
Fifth Edition
Chapter 2
Drug Approval and
Regulation
Copyright © 2017, 2014, 2011 Pearson Education, Inc. All Rights Reserved
Prior to 19th Century
• Few standards or guidelines to protect the public

– Some drugs contained hazardous levels of
▪ Dangerous substances
▪ Addictive substances
Early Drug References
• The first standard commonly used by pharmacists was

the formulary, or list of drugs and drug recipes
• A pharmacopoeia is a comprehensive medical reference
summarizing and publishing drug standards
United States Pharmacopoeia (USP), 1820
• First comprehensive publication of drug standards

• Summarized standards of drug:
– Purity
– Strength
– Directions for synthesis
American Pharmaceutical Organization (APhA)
• National professional society of pharmacists, established

1852
• Maintained the national compendia of drug standards, the
National Formulary (NF)
• National Formulary competed with other compendia, U.S.
Pharmacopeia (USP)
USP and NF Merged in 1975
• Formed United States Pharmacopeia–National

Formulary (USP-NF)
• Official monographs and interim announcements
published regularly
• Available in print and online
United States Develops and Enforces
Tougher Drug Laws, 1900s (1 of 2)
• Biologics Control Act, 1902

– Standardized serum and blood-related products
• Pure Food and Drug Act, 1906
– Established government control of labeling medicines
• Sherley Amendment, 1912
– Prohibited drugs labeled with false therapeutic claims
United States Develops and Enforces
Tougher Drug Laws, 1900s (2 of 2)
• Food, Drug, and Cosmetic Act (1938) and amendments

– Thorough testing of drug
– Proof of safety and efficacy of drug
• Dietary Supplement Health and Education Act, 1994
– Controls misleading industry claims
Figure 2.1 Medication with the USP label (1 of 2)
Source: Practice Label “for educational purposes only.”

Figure 2.1 Medication with the USP label (2 of 2)
Source: Practice Label “for educational purposes only.”

Food and Drug Administration (FDA)
• Officially established in 1988

• Agency of U.S. Department of Health and Human
Services
Figure 2.2 A Historical Timeline of Regulatory
Acts, Standards, and Organizations (1 of 3)
Time Line Regulatory Acts, Standards, And Organizations

1820 A group of health care providers established the first comprehensive publication of drug
standards called the U.S. Pharmacopoeia (USP).
1852 A group of pharmacists founded a national professional society called the American
Pharmaceutical Association (APhA). The APhA then established the National
Formulary (NF), a standardized publication focusing on pharmaceutical ingredients.
The USP continued to catalogue all drug-related substances and products.
1862 This was the beginning of the Federal Bureau of Chemistry, established under the
administration of President Lincoln. Over the years and with added duties, it gradually
became the Food and Drug Administration (FDA).
1902 Congress passed the Biologics Control Act to control the quality of serums and other
blood-related products.
1906 The Pure Food and Drug Act gave the government power to control the labeling of
medicines.
1912 The Sherley Amendment made medicines safer by prohibiting the sale of drugs
labeled with false therapeutic claims.

1938 Congress passed the Food, Drug, and Cosmetic Act. It was the first law preventing
the marketing of drugs not thoroughly tested. This law now provides for the requirement
that drug companies must submit a New Drug Application (NDA) to the FDA prior to
marketing a new drug.
1944 Congress passed the Public Health Service Act, covering many health issues
including biologic products and the control of communicable diseases.
1975 The U.S. Pharmacopoeia and National Formulary announced their union. The USP-N
F became a single standardized publication.
1986 Congress passed the Childhood Vaccine Act. It authorized the FDA to acquire
information about patients taking vaccines, to recall biologics, and to recommend civil
penalties if guidelines regarding biologic use were not followed.
1988 The FDA was officially established as an agency of the U.S. Department of Health and
Human Services.
1992 Congress passed the Prescription Drug User Fee Act. It required that nongeneric
drug and biologic manufacturers pay fees to be used for improvements in the drug
review process.

1994 Congress passed the Dietary Supplement Health and Education Act that requires
clear labeling of dietary supplements. This act gives the FDA the power to remove
supplements that cause a significant risk to the public.
1997 The FDA Drug Modernization Act reauthorized the Prescription Drug User Fee Act.
This act represented the largest reform effort of the drug review process since 1938.
2002 The Bioterrorism Act implemented guidelines for registration of selected toxins that
could pose a threat to human, animal, or plant safety and health.
2007 The FDA Amendments Act reviewed, expanded, and reaffirmed legislation to allow for
additional comprehensive reviews of new drugs and medical products. This extended
the reforms imposed from 1997. The FDA’s Critical Path Initiative was a part of this
reform.
2011 Provisions of the Health Care Reform law allowed the FDA to approve generic versions
of biologic drugs. Additional drug rebates and benefits were provided to the American
public. The FDA Food Safety Modernization Act represents the largest reform effort of
food safety review since 1938.
Center for Drug Evaluation and Research
(CDER)
• Branch of FDA
• Determines safet and efficacy of drugs
y
• Pharmaceutical laboratories must solicit approval from

FDA before marketing a drug
Black Box Warnings
• One of the primary alerts for identifying extreme adverse

drug reactions discovered during and after the review
process
Center for Biologics Evaluation and
Research (CBER)
• Branch of FDA
• Regulates use of biologics (serums, vaccines, and blood
products)
• 1986 Childhood Vaccine Act result of CBER work
Center for Food Safety and Applied
Nutrition (CFSAN) (1 of 2)
• Branch of FDA
• Oversees herbal and dietary products
Center for Food Safety and Applied
Nutrition (CFSAN) (2 of 2)
• Enforces 1994 Dietary and Supplemental Health and

Education Act
– Regulation not as close as Food, Drug, and Cosmetic
Act
– Herbal and dietary supplements can be marketed
without prior approval from FDA; package inserts
monitored once product is on market
Four Stages of Approval for Therapeutic
and Biologic Drugs
• Four stages:
– Preclinical investigation
– Clinical investigation
– Review of new drug application (NDA)
– Postmarketing surveillance
• Amount of time for approval varies
Figure 2.3 A New Drug Development Time
Line with the Four Phases of Drug Approval
Preclinical Investigation
• Involves laboratory research

• Tests done on cells and animals
• Determines drug-dose range
• Examines adverse effects
• Results considered inconclusive
FDA Critical Path Initiative
• In 2007, FDA restated its concern that a number of

innovative and critical medical products had decreased
since the 1990s
– Critical Path Initiative was initiated to modernize the
sciences to enhance the use of bioinformation to
improve the safety, effectiveness, and
manufacturability of candidate medical products
Clinical Investigation
• Takes place in three different stages termed clinical

phase trials
• Longest part of approval process
• Evaluates human benefits
• Tests on healthy humans first, then on those with the
target ailment
Review of New Drug Application (NDA)
• If results of clinical investigation are positive, even if

precautions are noted, a New Drug Application (NDA) is
next step
• NDA is third step of drug approval process
• Average review time 17–24 months
• Drug approved: process continues
• Drug rejected: process suspended
Investigational New Drug Application (IND)
• May be submitted for Phase I clinical trials when it is

determined there are significant therapeutic benefits, and
the product is reasonably safe for initial use in humans
Postmarketing Surveillance (1 of 2)
• New drug placed on market

• Surveyed for harmful effects in larger population
– Diabetes drug troglitazone (Rezulin) is an example of
a drug that did not exhibit harmful effects until the
year after release
– COX-2 selective nonsteroidal anti-inflammatory drugs
celecoxib (Celebrex) still being analyzed after others
in its group were withdrawn
Postmarketing Surveillance (2 of 2)
• FDA holds annual public meetings

– Will withdraw a drug if serious problem found
The Lengthy FDA Drug-Approval
Process (1 of 2)
• NDAs can be massively long and FDA review can take

several years
• Pharmaceutical manufacturer expenses for creating and
marketing a new drug can be in the millions of dollars
• Core FDA goal is to ensure drugs are safe for the public
The Lengthy FDA Drug-Approval
Process (2 of 2)
• In 1990s, delays in process determined to be caused by

– Outdated guidelines
– Insufficient staff
– Poor communication
Prescription Drug User Fee Act, 1992
• Established on five-year trial basis

• Drug and biologic manufacturers provide drug-user fee
• FDA hired more employees
• FDA restructured organization
Results Successful
• Doubled the number of drugs approved

• Some review times cut by half
FDA Modernization Act, 1997
• Reauthorized Prescription Drug User Fee Act

• FDA Amendments Act expanded the reforms in 2007
Research Shows
• Adverse drug events are reported to the FDA

• Nurses should constantly review literature for drugs that
have been recalled or reported dangerous
Nurses and the Drug Approval Process
• Nurses participate most in the drug approval process

during the postmarketing surveillance period of Phase IV
• All nurses administering medications monitor for
therapeutic effects and adverse reactions from the drugs
• Responsible for reporting adverse reactions
Addiction and Dependence (1 of 3)
• Addiction
– The overwhelming feeling that drives someone to use
a drug repeatedly
• Dependence
– A physiological or psychological need for a substance
• Physical dependence
– An altered physical condition caused by the
adaptation of the nervous system to repeated drug
use
• When the drug is no longer available, the individual
expresses physical signs of discomfort known as
withdrawal
• Psychological dependence
– Few signs of physical discomfort when drug is
withdrawn, but intense compelling desire to continue
drug use
Controlled Substances (1 of 2)
• Controlled substances are drugs that:

– Are restricted by the Controlled Substances Act of
1970 and later revisions
– Are frequently abused
– Have a high potential for addiction or dependence
– Have restricted use
– Are placed into one of five schedules
Controlled Substance Act of 1970
• Also known as Comprehensive Drug Abuse Prevention

and Control Act
• Restricts use of drugs with potential for abuse
• Restricted drugs placed into the five schedules
• Hospitals and pharmacies must maintain complete
records of scheduled drugs
Drug Enforcement Administration (DEA)
Regulates Controlled Substance Act
• Hospitals and pharmacies must register with DEA

– Must use assigned registration number to purchase
scheduled drugs
Controlled Substances (2 of 2)
• Anyone convicted of unlawfully manufacturing,

distributing, or dispensing of controlled substances faces
severe penalties
Scheduled Drugs
• Drugs that have a significant potential for abuse are

placed into five categories called schedules
– Schedule I drugs have the highest abuse potential,
Schedule V the lowest
Table 2.1 U.S. Drug Schedules and
Examples
Schedule I Drugs
• Restricted to situations of medical necessity, if allowed at

all
• Little or no therapeutic value; mostly used for research
Examples of Schedule I Drugs
• Heroin
• Lysergic acid diethylamide (LSD)
• Methaqualone
Schedule II-V Drugs
• May be dispersed only in cases where therapeutic value

has been determined
• Some Schedule V drugs may be dispensed without a
prescription
Not All Drugs with Abuse Potential Are
Regulated
• Tobacco, alcohol, and caffeine
Schedule II Drugs
• High abuse potential

• High potential for physical and psychological dependence
• Therapeutic use with prescription
• Some drugs no longer used
Schedule II Drugs Have More Restrictions
• Need special order form to obtain

• Orders must be written by health care provider
• Orders must be signed by health care provider
• Telephone orders to pharmacies are not permitted
• No refills are permitted; patient must see health care
provider first
Schedule III Drugs
• Moderate abuse potential

• Moderate physical dependence
• High potential for psychological dependence
• Some drugs no longer used
Examples of Schedule III Drugs
• Anabolic steroids
• Buprenorphine products
• Ketamine
• Benzphetamine
Schedule IV Drugs
• Lower abuse potential

• Lower potential for physical and psychological
dependence
Examples of Schedule IV Drugs
• Alprazolam
• Clonazepam
• Clorazepate
• Diazepam
• Lorazepam
Schedule V Drugs
• Lowest abuse potential

• Lowest physical and psychological dependence
• Therapeutic use without prescription
• Examples:
– OTC cough medicines with codeine
Teratogenic Drug Classification
• Five categories of risk that a drug poses to a fetus in the

case of a pregnant woman taking the drug
• A, B, C, D, and X
Category A Drugs
• Controlled studies in women fail to show a risk to the

fetus, and the possibility of fetal harm appears unlikely
Category B Drugs
• Animal reproduction studies have not shown a fetal risk

or adverse effect. Risks have not been confirmed in
controlled studies in women
Category C Drugs
• Either studies in animals have revealed adverse effects

on the fetus and there are no controlled studies in
women, or studies in women and animals are not
available
Category D Drugs
• There is confirmation of human fetal risk, but the benefits

from use in pregnant women may be acceptable despite
the risk
– Examples:
▪ In a life-threatening situation
▪ For a serious disease for which safer drugs cannot
be used
Category X Drugs
• Animal and human studies have shown fetal

abnormalities
• The drug is contraindicated in women who are or may
become pregnant
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Pharmacology for Nurses: A Pathophysiologic

• Few standards or guidelines to protect the public

• The first standard commonly used by pharmacists was

• First comprehensive publication of drug standards

• National professional society of pharmacists, established

• Formed United States Pharmacopeia–National

• Biologics Control Act, 1902

• Food, Drug, and Cosmetic Act (1938) and amendments

Source: Practice Label “for educational purposes only.”

Source: Practice Label “for educational purposes only.”

• Officially established in 1988

Time Line Regulatory Acts, Standards, And Organizations

Time Line Regulatory Acts, Standards, And Organizations

Time Line Regulatory Acts, Standards, And Organizations

• Pharmaceutical laboratories must solicit approval from

• One of the primary alerts for identifying extreme adverse

• Enforces 1994 Dietary and Supplemental Health and

• Involves laboratory research

• In 2007, FDA restated its concern that a number of

• Takes place in three different stages termed clinical

• If results of clinical investigation are positive, even if

• May be submitted for Phase I clinical trials when it is

• New drug placed on market

• FDA holds annual public meetings

• NDAs can be massively long and FDA review can take

• In 1990s, delays in process determined to be caused by

• Established on five-year trial basis

• Doubled the number of drugs approved

• Reauthorized Prescription Drug User Fee Act

• Adverse drug events are reported to the FDA

• Nurses participate most in the drug approval process

• Controlled substances are drugs that:

• Also known as Comprehensive Drug Abuse Prevention

• Hospitals and pharmacies must register with DEA

• Anyone convicted of unlawfully manufacturing,

• Drugs that have a significant potential for abuse are

• Restricted to situations of medical necessity, if allowed at

• May be dispersed only in cases where therapeutic value

• Tobacco, alcohol, and caffeine

• High abuse potential

• Need special order form to obtain

• Moderate abuse potential

• Lower abuse potential

• Lowest abuse potential

• Five categories of risk that a drug poses to a fetus in the

• Controlled studies in women fail to show a risk to the

• Animal reproduction studies have not shown a fetal risk

• Either studies in animals have revealed adverse effects

• There is confirmation of human fetal risk, but the benefits

• Animal and human studies have shown fetal

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