Sept. 5, 2012
Chapter 2 a.
Federal Regulation of
Medications: Development,
Production, and Marketing
Pages 39-68
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History of Major Legislation
(Not Including Controlled Substance Laws)
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Pure Food & Drug Act 1906
Food, Drug, and Cosmetic Act 1938 – Sulfanilamide; Safe, Misbranding/Adulteration;
Durham-Humphrey Amendment 1951- Rx/Otc; Oral Rxs; Refills
Food Additives Amendment 1958
Color Additive Amendments 1960
Kefauver-Harris Amendment 1962 – Thalidomide; Safe AND effective
Medical Device Amendments 1976 –Dalkon Shield
Orphan Drug Act 1983
Drug Price Competition Act 1984
Prescription Drug Marketing Act 1987
Safe Medical Devices Act 1990
Generic Drug Enforcement Act 1992
Prescription Drug User Fee Act 1992
Nutrition Labeling & Education Act 1990
Dietary Supplement Health & Education Act 1994; Reduced FDA authoride (food vs. drug)
Food & Drug Administration Modernization Act 1997
Food & Drug Administration Amendments Act 2007
Food & Drug Administration Safety and Innovation Act of 2012
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Food and Drug Administration Safety and
Innovation Act (FDASIA) of 2012
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The Food and Drug Administration Safety and Innovation Act (FDASIA), signed into
law on July 9, 2012, gives FDA the authority to collect user fees from industry to
fund reviews of innovator drugs, medical devices, generic drugs and biosimilar
biologics. It also reauthorizes two programs that encourage pediatric drug
development.
"Support for FDA user fees is a testament to the important role FDA plays in
America’s healthcare continuum. FDA’s medical product decisions sit at the
intersection of public health, innovation, and commerce and touch the lives of
nearly every American every day," said FDA Commissioner Margaret A. Hamburg,
M.D.
This is the fifth reauthorization of the Prescription Drug User Fee Act or PDUFA,
first enacted in 1992, and the third reauthorization of the Medical Device User Fee
Act, or MDUFA, first enacted in 2002. Both programs have provided steady and
reliable funding to maintain and support a staff of trained reviewers who must
determine whether a proposed new product is safe and effective for patients and
do so within a certain time period. The new user fee programs for generic drugs
and biosimilar biologics build on the successes of these two established user fee
programs
ALSO: REQUIRES INQUIRY INTO WHETHER TO MAKE HYDROCODONE COMBOS Cii
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FDASIA (HYDROCODONE PROVISION)
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SEC. 1139. SCHEDULING OF HYDROCODONE.
(a) IN GENERAL.—Not later than 60 days after the date of
enactment of this Act [October 1, 2012], if practicable, the Secretary of Health and
Human Services (referred to in this section as the ‘‘Secretary’’)
shall hold a public meeting to solicit advice and recommendations
to assist in conducting a scientific and medical evaluation in connection
with a scheduling recommendation to the Drug Enforcement
Administration regarding drug products containing hydrocodone,
combined with other analgesics or as an antitussive.
(b) STAKEHOLDER INPUT.—In conducting the evaluation under
subsection (a), the Secretary shall solicit input from a variety of
stakeholders including patients, health care providers, harm prevention
experts, the National Institute on Drug Abuse, the Centers
for Disease Control and Prevention, and the Drug Enforcement
Administration regarding the health benefits and risks, including
the potential for abuse and the impact of up-scheduling of these
products.
(c) TRANSCRIPT.—The transcript of any public meeting conducted
pursuant to this section shall be published on the Internet
Web site of the Food and Drug Administration
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Regulation of Drugs
How and When (Cont’d)
-MAJOR LEGISLATION CORE OF TODAYS LEGISLATON
FOOD, DRUG AND COSMETIC ACT
OF 1938
(21 U.S.C. §301 et seq.)
Several amendments to the core act
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FOOD, DRUG AND COSMETIC ACT
OF 1938
 No “new drug” could be introduced into interstate commerce
unless first proven ‘safe’ for labeled indication. (Pre-1938
drugs on market exempt from proving safe).
– Established New Drug Application/Approval Process (NDA)
– Required ‘adequate directions for use’ and other labeling
requirements …
• Unless dispensed pursuant to prescription from state-authorized
prescriber
– Required labeling for habit-forming drugs (no longer because of
FDAMA of 1997)
 Applied to cosmetics as well as food and drugs, but not to
devices until 1976 (Dalkon Shield, IUD).
 Creates two major offenses: adulteration and misbranding
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FOOD, DRUG AND COSMETIC ACT
OF 1938
 Did NOT establish prescription-only/OTC status of drugs. Drug manufactured determined
status of drug by its label (if sold OTC, had to have “adequate directions for safe use by
consumer”).
 Exemption from labeling with “adequate directions” if drug dispensed on written a
prescription, but didn’t create prescription only category of drugs
 Regs issued in 1938 shortly after passage of act allowed for prescription only category of
drugs if not necessary for public safety (i.e., if had prescription-only warning, shipped for
prescription sale only, and had labeling not easily understood by layperson)
 So, manufacturer could create prescription-only class by simply labeling it as such
 Did not required drugs to be ‘effective’ for intended purposes
 Recognized “Official Compendia,” privately published, that standardized drug quality
– USP/NF Monographs
• Chemical characteristics and quality standards of listed drugs
• USP/NF merged
– Homeopathic Pharmacopoeia of the United States
 Anything published in official compendia is a drug
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Prohibitions
Its is unlawful to introduce into interstate
commerce and article that is
– Adulterated or
– Misbranded
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Adulteration
Adulterated drugs and devices. A drug or device shall be deemed to
be adulterated:
501(a) (1) If it consists in whole or in part of any filthy, putrid, or
decomposed substance; or (2)(A) if it has been prepared, packed,
or held under insanitary conditions whereby it may have been
contaminated with filth, or whereby it may have been rendered
injurious to health; or (B) if it is a drug and the methods used in, or
the facilities or controls used for, its manufacture, processing,
packing, or holding do not conform to or are not operated or
administered in conformity with current good manufacturing
practice, or (3) [container composed of poisonous or dangerous
substance]; or (4) … [unsafe coloring additive if for coloring only]…
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Adulteration
• …(b) If it purports to be or is represented as a
drug the name of which is recognized in an
official compendium, and its strength differs
from, or its quality or purity falls below, the
standards set forth in such compendium… No
drug defined in an official compendium shall be
deemed to be adulterated under this paragraph
because it differs from the standard of strength,
quality, or purity therefore set forth in such
compendium, if its difference in strength, quality,
or purity from such standards is plainly stated on
its label.
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Adulteration
• Whenever a drug is recognized in both the
United States Pharmacopeia and the
Homeopathic Pharmacopeia of the United
States it shall be subject to the requirements
of the United States Pharmacopeia unless it is
labeled and offered for sale as a homeopathic
drug, in which case it shall be subject to the
provisions of the Homeopathic Pharmacopeia
of the United States and not to those of the
United States Pharmacopeia.
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Adulteration
(c) If it is not subject to the provisions of
paragraph (b) of this section and its strength
differs from, or its purity or quality falls below,
that which it purports or is represented to
possess.
(d) If it is a drug and any substance has been (1)
mixed or packed therewith so as to reduce its
quality or strength or (2) substituted wholly or
in part therefor.
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Misbranding
 Labeling must not be false or misleading, including
healthcare economic information
 Labeling must include a listing of active ingredients and
quantity and listing of inactive ingredients in alpha
order
 Labeling must contain “adequate directions for use”
and “adequate warnings against use” by children and
others for whom use might be dangerous
 If drug cannot be labeled with “adequate directions for
use”, it must contain “adequate information for use”
 It is misbranding if a drug imitates another drug
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Misbranding
P. 64
 Where adulteration deals with strength, purity and quality,
misbranding focuses on representations made by
manufacturer on label or labeling. FDA must approve
labeling/label. Can’t be false or misleading.
 Before 1997 FDAMA “Habit-forming” on label.
 List active ingredient and quantity (unless for non-human)
and inactive ingredient alphabetically (unless for nonhuman or if an OTC cosmetic).
 Adequate directions for use and warnings against use.
 Adequate “information” for use if drug can not be labeled
to protect consumer (i.e., rx drugs, see Durham-Humphrey)
 It is misbranding if a drug imitates another drug (otc’s
looking like controlled substances)
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Federal Food And Drug
Administration (FDA)
P. 45
• Housed under the Department of
Health & Human Services (DHHS)
• Authority for administering the FDCA
• FDA secretary appointed by President
with confirmation of Senate
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Functions of FDA
• Rulemaking
• Issue guidance documents
• Incorporate advice from standing
advisory committees of outside experts
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What is a Drug?
• Articles recognized in the USP or Homeopathic
Pharmacopeia
• Articles intended for use in diagnosis, cure, mitigation,
treatment or prevention of disease (Part B)
• Articles other than food intended to affect the structure
or function of the body (Part C)
• Definition is intentionally broad to include almost
anything with an intended therapeutic purpose or
purpose of altering the structure or function of the
body
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Evidence A Product is a Drug
• Labeling
• Advertising
• Nature of product
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Food or Drug?
P.46
• Generally depends upon intended use
• Food definition not very helpful in itself
• Congress likely intended the meaning of food
in the exclusion from part C of drug definition
to apply to food used for its ordinary purpose
and in an ordinary manner.
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SEC. 201. [21 U.S.C. 321] CHAPTER II—DEFINITIONS 1
SEC. 201. [21 U.S.C. 321] Definitions; generally
For the purposes of this Act— 2
(e) The term "person" includes individual, partnership, corporation, and association.
(f) 1 The term "food" means (1) articles used for food or drink for man or other
animals, (2) chewing gum, and (3) articles used for components of any such article.
(g)(1) The term "drug" means (A) articles recognized in the official United States
Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or
official National Formulary, or any supplement to any of them; and (B) articles
intended for use in the diagnosis, cure, mitigation, treatment, or prevention of
disease in man or other animals; and (C) articles (other than food) intended to affect
the structure or any function of the body of man or other animals; and (D) articles
intended for use as a component of any article specified in clause (A), (B), or (C). A
food or dietary supplement for which a claim, subject to sections 403(r)(1)(B) and
403(r)(3) or sections 403(r)(1)(B) and 403(r)(5)(D), is made in accordance with the
requirements of section 403(r) is not a drug solely because the label or the labeling
contains such a claim. A food, dietary ingredient, or dietary supplement for which a
truthful and not misleading statement is made in accordance with section 403(r)(6) is
not a drug under clause (C) solely because the label or the labeling contains such a
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statement.
Is it a drug?
• Do Cats Make Terrible Pets
• Diagnose, cure, mitigate, treat or prevent disease
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D – Diagnose
C – Cure
M – Mitigate
T – Treat
P – Prevent
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Health or Disease Claims for
Foods
• A health claim for a food made by a manufacturer could
result in the product being considered a drug
• The Nutrition Labeling & Education Act of 1990 and
subsequently FDAMA allows foods to contain health
claims if approved by the FDA by regulation or by the
“significant scientific agreement” test
• Manufacturer must submit considerable evidence to
support the claim to obtain FDA approval
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P. 50
What is DSHEA?
The Dietary Supplement Health and Education Act of 1994, which spells out
regulations regarding the manufacture and sale of dietary supplements, defines
a dietary supplement as “a product (other than tobacco) intended to
supplement the diet that bears or contains one of more of the following dietary
ingredients: (A) a vitamin, (B) a mineral, (C) an herb or other botanical, (D) an
amino acid, (E) a dietary substance for use by man to supplement the diet by
increasing the total dietary intake; or a concentrate, metabolite, constituent,
extract, or (F) concentrate, metabolite, constituent, extract or combination of
any ingredient noted in clause (A), (B), (C), (D), or (E).”
The act defines permissible labeling claims and places the burden of proof on
the Food and Drug Administration to show that a product is unsafe. It also
outlines safety requirements for new dietary ingredients.
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Are Dietary Supplements Unregulated?
No. DSHEA grants the FDA the authority to regulate dietary supplements in two important
respects.
First, the FDA regulates product labeling. Whenever a marketer wants to make a claim about
a supplement, it must submit the proposed claim to the FDA within 30 days after its first
use. Claims are limited to “general structure function” and as a rule may not assert that a
product prevents or treats disease. The FDA may stop the manufacturer from advertising
the claim if it is deemed impermissible.
Second, DSHEA holds supplement manufacturers to what are known as “good
manufacturing practices” (i.e., industry standards for maintaining product quality). In
addition, the Federal Trade Commission maintains authority over supplement advertising:
Manufacturers must report truthfully what their products contain and must have proof
backing up any claims they make.
Additionally, the Dietary Supplement and Nonprescription Drug Consumer Protection Act of
2006 requires what’s known as “adverse event reporting,” the FDA’s way of informing the
public about any incidents related to a product once it is on the market. This is the same
system of reporting used for FDA-approved drugs and biologics.
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Nutritional or Structure/
Function Claims
• DSHEA permits 4 types of nutritional support claims:
– Benefiting a classical nutrient deficiency disease
– Describing to role of the DS in affecting the structure/function of
the body [this is an exemption to the definition of “Drug” under
the FDCA 21 USC Sec. 321(g)(1)(C). ]
– Characterizing the mechanism by which a DS act to maintain the
structure or function
– Statements of general well-being
• Claims must be substantiated as truthful and not
misleading
• Label must contain disclaimer
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Health or Disease Claims
• DSHEA only permits DS manufacturers to make health
claims if either the FDA approves the claim by regulation or
by the significant scientific agreement test.
• Pearson v. Shalala, however, held that DS manufacturers
could make health claims not approved by the FDA provided
they are not false or misleading and accompanied by a
disclaimer
• FDA now allows qualified and unqualified health claims
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Dietary Supplements Containing
Drugs
• DSHEA excludes an article as a DS if it
was approved as a drug prior to it
being marketed as a DS
• Pharmanex case (Cholestin®, had lovastatin in it (made
from a fungus), same drug as Mevacor) establishes that
DSs cannot be specially manufactured
to concentrate the natural drug
ingredient
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Safety Issues
• FDA can only remove a DS on the basis the product is
adulterated, defined as presenting “significant or
unreasonable risk of illness or injury under the conditions
of use recommended or suggested in the labeling”
• Ephedrine Alkaloid DS example
• Dietary Supplement & Nonprescription Drug Consumer
Protection Act requires manufacturers to report serious
adverse events
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Implications of DSHEA for
Pharmacists
• Product selection
• Education of patients as opposed to
promotion of products
• Restrictions regarding the display of DS
publications
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Drug and/or Device?
Medical Device Amendment (MDA) of 1976
• Historical approach of the FDA prior to the
Medical Device Amendment was to declare
devices as drugs when necessary
• Definition of device excludes articles that
achieve their purpose through chemical
action and metabolism.
• Whether a device containing drugs is a drug
or device is dependent on various factors
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Drug and/or Cosmetic?
P. 55
• Definition of cosmetic generally includes
topical articles intended for cleansing,
beautifying or altering appearance
• A cosmetic can become a drug if the seller
makes a health or structure/function claim
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Labels and Labeling PAGE 56
• The term “label” means a display of written, printed
or graphic matter upon immediate container….
• The term “labeling” includes labels and other written,
printed or graphic matter upon any article or any of its
containers or wrappers OR ACCOMPANYING SUCH
ARTICLE.
• Labeling is defined as written or printed or graphic
matter “accompanying” the article.
• Courts have defined accompanying (p. 56) (is it an
“integrated distribution program”)
• If the written, printed or graphic matter is not
labeling, it is advertising
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• USP
Official Compendia
– Published by the USPC
– Sets uniform standards
– USPC works closely with the FDA but is private
• HPUS
– Publishes standards for homeopathy products by the
HPCUS, a private organization
– Role and legal authority of HPUS
• Pursuant to FDCA, if a drug is recognized in USP or HPUS the drug
product must meet all standards of the compendia
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Prohibited Acts
• Most prohibited acts involve misbranding or
adulteration
• Violation of FDCA is subject to strict liability
– Good faith excuse applicable (SEE 21 USC 303(c) )
• Applicable to pharmacies
– The mere receipt and subsequent delivery of an
adulterated or misbranded drug (§301(c))
– The doing of any act which causes a drug to be counterfeit
(§301(i)(3))
– The alteration, mutilation, etc. of the labeling (§301(k))
– (what about filling an otc drug as a prescription???)
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FDA Enforcement Authority
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Injunction
Criminal action
Seizure of products
Warning letters
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Product Recalls
• FDAAA established FDA authority to order
drug recalls
• Three classes of recalls
• Manufacturers responsible for notifying seller
and seller for notifying consumers if
necessary
• Pharmacists responsible for knowing of
product recalls
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Nonprescription Drug Labeling
• User friendly format including pharmacological category or
principal intended use, cautions and warnings, adequate
directions for use, and a “Drug Facts” panel
• Pharmacies that relabel or repackage must conform to the
same labeling requirements as manufacturers
• Professional OTC labeling may be published by manufacturers
for indications not appropriate for lay diagnosis or treatment.
• Drugs that are both OTC and prescription exist when some
indications can be labeled with adequate directions for use and
some cannot. (i.e., Zantac, Prilosec)
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Review Question
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A manufacturer of catsup advertised that its
particular brand of catsup would effectively treat gouty
arthritis. Which of the following would be correct:
a.
b.
c.
d.
The catsup is likely a food
The catsup is likely a drug
The catsup is likely both a food and a drug
The catsup is likely neither a food nor a drug
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Review Question
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A manufacturer of catsup advertised that its
particular brand of catsup would effectively treat gouty
arthritis. Which of the following would be correct:
a.
b.
c.
d.
The catsup is likely a food
The catsup is likely a drug
The catsup is likely both a food and a drug
The catsup is likely neither a food nor a drug
• ANSWER: C.
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Review Question
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Which of the following can make
structure/function claims without being
considered a drug.
a.
b.
c.
d.
e.
Vitamin D
Lipstick
Breakfast cereals
A&B
A&C
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Review Question
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Which of the following can make
structure/function claims without being
considered a drug.
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a.
Vitamin D
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b.
Lipstick
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c.
Breakfast cereals
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d.
A&B
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e.
A&C
• ANSWER: A
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