Food and Drug Outline
Adams/Safir
Spring 2013
1. INTRODUCTION
a. THE 1938 FDCA Act gave FDA authority over food, drugs, cosmetics and medical devices
i. It gained more and gave up some over the years
b. The Scope of the FDAs power is defined almost entirely by the list of product categories over which it
has jurisdiction
i. Definitions delineate the outer boundaries
ii. Greater authority over drugs, devices, and biological products then over food and cosmetics
iii. Category of the product largely determines regulatory scheme over it
c. Definitions are broad, confer jurisdiction over a vast range of goods
i. Sometimes interprets definitions broadly, sometimes narrowly
d. The FDA as an Agency
i. 25 cents of every consumer dollar regulated by the FDA
1. Often the focus of intense Congressional and public scrutiny
2. Budget less than 1 aircraft carrier, including industry user fees
ii. Affects everything you do
1. Nutrition, safety, availability, information access (many other agencies don't do this), also
protection of human subjects
iii. FDA is a part of DHHS
1. Commissioner is a 3d tier position, requires appt by President and recently requires the
approval of Senate
2. No independent authority to bring suit, goes through DOJ
iv. Science Side of FDA
1. Center for Food Safety and Applied Nutrition
2. Center for Drug Evaluation and Research (CDAR)
3. Center for Devices and Radiological Health (CDRH)
4. Center for Tobacco
5. Center for Vet
v. Enforcement Side
1. Office of Global Regulatory
2. Number of district and local offices on the enforcement side
e. History of the FDA and the FDCA:
1. Mission of the FDA: science + law enforcement
2. FDA regulation usually comes from fatal or near fatal events
3. First regulation came after 11 ppl died in STL, all biological products need to be
registered
4. Then came The Jungle era: food safety became a huge concern-what exactly was going in
our processed foods?!
5. 1906 Act: gave the feds the power to proceed against adulterated or misbranded products
[CRIMINAL STATUTE]
6. 1938 Act: Alixir came out, an alcohol based solution, created a drug that was essentially
antifreeze
a. 90 ppl died in the first month CONGRESS STEPS IN: FDCA (as amended
today)
7. 1958: Food Additive Acts
a. Preservatives, colors, stabilizers, etc
8. 1962 Drug Amendments
a. Drug developed in Europe that was a "safer" sleeping pill
b. Only problem was pregnant women that took this pill in first trimester had
children born with flippers instead of arms and legs
9. 1976: Now Congress and the FDA turn to devices
a. FDA started stretching the drugs part of the Act to apply devices
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b. SC agreed with them, Congress stepped in
10. Hatch-Waxman Act
a. First amendment that was economic NOT caused by a tragic event
b. Opened up the pathway for generic drugs to be approved
c. No reason for generics to have to get approved AGAIN after a patented product
lost its patent after 20 years of safety
d. Led to major litigation because it was so poorly written
11. 1902 Nutritional Labeling and Education Act
a. Allowing food companies making health claims about food
b. Created the food labels that we see today
12. 1994 Dietary Supplements Health Education Act
a. First time that power was taken away from FDA
b. “Favorite child of the law" you can do and say things with dietary supplements
you CANNOT do with drugs
2.
BASIC JURISDICTION
a. FOOD, DRUG, DEVICE
i. FOOD
1. Whether a product is a drug or a food often decides the fate of it since drugs are subject
to pre-market approval and food is not
2. Nutrilab Inc v. Schweiker (7th Circ 1983)
a. Facts: P manufacturers and markets a product known as starch blockers which
block the human body's digestion of starch as an aid to controlling weight
i. Blocker protein is extracted from a certain type of raw kidney bean, FDA
classified them as drugs and wants them to be removed from market until
FDA approval
b. H: Language of 321 g 1 c makes the definitions of food and drugs mutually
exclusive. Common sense definition of food is whether it is used for TASTE,
AROMA, or NUTRITIVE VALUE
i. Nutritive value is a value in sustaining human existence by such
processes as promoting growth, replacing loss of essential nutrients, or
providing energy
ii. Doesn’t matter if its derived from food, what the labeling says, or what
the manufacturers intent is since not in food statute.
iii. Starch blockers are drugs under this definition, intended to affect
digestion.
c. ***DHEA dramatically altered the categorization for products like starch
blockers, now dietary supplements are automatically foods, regardless of whether
they pass this test.
3. American Health Products v. Hayes: Court rejected FDA argument as to dual
classification because of parenthetical C in the statute
a. FDA later said things can be dual classified if it’s a food making therapeutic
claims.
4. Caffeine
a. Regulated as a drug when it’s a standalone stimulant but not regulated when
added to food
ii. Other Food Definitions
1. Subcategory of Food Additives
a. Any substance the intended use of which results of may reasonably be expected
to result, directly or indirectly, in becoming a component or otherwise affecting
the characteristics of any food if such substance is not generally recognized to be
safe under the conditions of its use
b. Some GRAS foods are exempted
c. Food additives can include migrating substances from the packaging
2. Chewing gum is a good
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3. Unfit food is still considered a food even if it is unfit for eating by the time FDA
institutes legal action.
b. DRUGS and DEVICES
i. Drugs
1. 201 g 1 A: USP, National Formulary
2. 201 g 1 B: Articles intended for the use or treatment of disease
3. 201 g 1 C: Intended to change the structure or function of the body
ii. Devices
1. 201 h: Devices-instrument, apparatus, similar, related
2. h 1: USP
3. h2: Intended-diseases/conditions
4. h 3: Intended to change the structure or function of the body
5. Looks like drug def NOT does not achieve primary purpose through chemical interaction
on or within the body
6. Meant by congress to be a different category of regulation
iii. United States v. An Article of Drug...Bacto-Unidisk (1969)
1. Issue: scope of the statutory definition of drug in the FDCA and the extent of the Sec's
regulatory authority
2. Facts: Product is an antibiotic sensitivity disc used as a screening test to determine the
proper antibiotic to administer
a. If drug, then needs premarket approval; if device, then only subject to
misbranding and adulteration proscriptions; or if no definition, then act doesn't
apply
3. H: Although there is overlap between the definition of device and drug, the natural way
to draw the line is in light of the statutory purpose to protect the PH + certify
product safety and efficacy
a. Since the patient will tend to derive less benefit and perhaps some harm if it got
the wrong antibiotic, it is entirely reasonable for the Sec to determine that the
disks are drugs and subject to preclearance
iv. Inclusion in Official Compendia
1. Although section 321 g 1 A on its face appears to give FDA the power to treat any item
listed in there, it has generally not been read so expansively by the courts
a. US Pharmacopeia and National Formula is a compendium of standards for drug
strength, quality, purity, packaging, labeling, and storage published by USP
(NGO)
b. Homeopathic Pharmacopeia contains many herbal products
2. An article in USP or NF must meet privately designated standards for quality and
strength or otherwise be subjective to misbranding or adulteration action
3. Recognition of an item in the USP + a label indicating compliance with standards makes
a prima facie case that it’s a drug only, adverse party can come forward with contrary
evidence
a. Some item recognized in the USP is not a drug if put into IC without a label such
as USP or NF to imply that is intended for medicinal use
4. US v. Ova II (NJ DC 1975)
a. H: When considering the regulatory status of a pregnancy test, the official
compendia provision of the drug definition cannot be taken literally because
literal interpretation would run afoul of the principle that a legislative body
many not lawfully delegate its functions to a private citizen or organization
v. Intended Use and the Food-Drug Spectrum
1. Most important similarity between the definitions of drug and device is their common
reference to "intended use"
2. FDA Intended Use Definition Since 1952
a. Refer to the objective intent of the persons legally responsible for the labeling of
the drugs
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b. Determined by their expressions or circumstances surrounding distribution of the
article
i. Labeling claims, advertising matter, or oral or written statements by
persons or reps
ii. Circumstances that show that with the knowledge of such persons or
their reps that the product offered and used for a purpose for which it is
neither labels nor advertised
iii. Once they know or should know that it is used for this purpose, then
must supply adequate labeling
c. FDA usually reluctant to attempt to classify a product as a drug or device in the
absence of relevant reps from manufacturer or distributor
vi. National Nutritional Foods Assn v. Mathews (2nd Circ 1976)
1. Facts: Involved high dose vitamin supplements, usually classified as food unless
therapeutic claims were made. People were experiencing toxic effects from large doses of
Vitamin A and D. FDA came out with regs for these levels of vitamins [later revoked],
manufacturers challenged.
2. H: Vendor's intent in selling the product to the public is the key element in this statutory
definition. FDA is not bound by the manufacturer's subjective claims of intent but
can find actual therapeutic intent on the basis of objective evidence including
labeling, promos, advertising, or ANY RELEVANT SOURCE of if the manufacturer
knows or has reason to know that people are using it differently
a. Toxicity is not included as an element in the stat def of a drug, only relevant to
the extent that constitutes objective evidence of therapeutic intent.
b. In this case, no evidence of intent to market these vitamins at these levels. Mere
inclusion in USP or NF is not enough.
3. I: Since this decision, the FDA has rarely asserted its drug or device jurisdiction over a
product without manufacturers reps but still have authority to establish intended use
based on circs surrounding the distribution of the article
a. In 2001 the US brought criminal charges against a number of individuals selling
unlabeled balloons containing nitrous oxide outside a rock concert
i. H: Court said intent for use can be determined by the environment
between the buyer and seller
vii. United States v. Articles of Drug...Neptone (DC NDCA 1983)
1. Facts: Neptone is a freeze dried powdered green mussel, that came with literature in
health stores that set it was full of certain elements that made it prevent certain diseases
2. H: Court said these promotional claims made it a drug, but if they stopped it would be a
food again.
viii. Classification of Products as Drugs and Devices and Additional Product Classification
Issues (June 2011)
1. What does FDA Consider in Determining Drug or Device?
a. Statutory definitions, as as applied to scientific data available to FDA
b. If you meet def of device, the product also meets definition of drug since drug
def scope is bigger
i. If a product meets both definitions, FDA generally intends to classify
product as a device
ii. If the product meets drug definition, but there is uncertainty about
whether it meets the device definition also, then FDA generally intends
to classify as a drug
2. How does FDA interpret "similar or related article" in the definition of a device?
a. Issue is in regards to products in liquid, semi liquid, gel, gas, or powder form; i.e.
wound covering gels, gasses used as space filers, etc
b. Such products may be classified as devices as long as they satisfy the remainder
of the device definition, including the chemical action exclusion
3. How does the FDA interpret "does not achieve its primary intended purposes through
chemical action within or on the body of man" in the definition of device?
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a. Even if a product exhibits a chemical action can still meet the exclusion if the
chemical action contributes to an effect other than the primary intended purpose
of the product
b. If it has multiple therapeutic effects, each would be a primary intended purpose
c. Also if it achieves its primary intended purpose through chemical action it still
meets the device definition provided that the chemical action does not occur
within or on the body of man or other animals
3.
JURISDICTION ISSUES
a. CONSTITUTIONAL LIMITS
i. United States v. 23...Articles (1951)
1. Facts: FDA sought seizure and condemnation of certain phonograph records entitled
Time to Sleep
2. H: Obviously records are devices, and were intended for the use in the cure, mitigation,
treatment or perhaps prevention of insomnia. Even though experts at trial said insomnia is
a symptom not a disease, sleep is a function of the body, and this device is meant to
induce sleep so it fulfills the device definition.
ii. United States v. Undetermined Quantities of Article of Device (1982)
1. Facts: FDA seeking condemnation and forfeiture of 32 self hypnosis tapes, with
accompanying literature leaving an impression that the tapes will allow the subconscious
mind to bring around the change the person desires using magic. Recently added a "no
therapeutic claims" disclaimer to catalogue.
2. H: The tapes, couple with the literature making therapeutic claims can be condemned.
Without the claims, however, the tapes do no more than communicate certain ideas about
hypnosis using a tape as toll of communication.
a. Court also needs to balance philosophical freedom and practical need to
protect citizens from hypnosis scams.
iii. Draft Policy Guidance for Regulation of Computer Products (1987)
1. When a computer product is a component, part, or accessory of a product recognized as a
medical device in its own right, the computer component is regulated according to the
requirements for the parent device
2. Those that are not components, but are themselves medical devices are regulated with the
least degree of control necessary to provide reasonable assurance of safety and
effectiveness
a. Expert and knowledge based systems are exempt
3. Updated Policy:
a. Any software that meets med device definition is a device subject to applicable
FDA medical device regulations
b. Standalone Software and Competent Human Intervention
i. Standalone medical software is medical software which is neither a
component nor an accessory to another device, gets med data as input
gives output results to health care user
ii. Previously, "unclassified information management products that were
decision support systems intended to involved competent human
intervention before any impact on human health occurs" were proposed
to be exempted from active regulations
c. Need for clarification:
i. Software decision process must be completely clear to the user, with a
reasonable opportunity for challenging the results
ii. Must be adequate time available for reflection, ie not in surgery
iii. More complex tech makes it questionable whether a practitioner can
reasonably exercise competent human intervention
iv. So now FDA is reexamining criteria for exemption from active
regulation
d. Recall Watson computer software that won Jeopardy
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i. In the past didn't regulate software that had human intervention before
any human impact
ii. The more complex the software, the less able the doctor will be to
understand or check the algorithm
1. Even if it’s going to be hard for doc to check, don't want to
regulate all software
iii. Key issue is competent human intervention
iv. The Verichip and Letter from Troy:
1. 2002 Letter from FDA to Lawyer for Devices asked whether Verichip, an implantable
scannable chip contains medical information, is a medical device
a. When used as a health information application setting, then it is a medical device
b. When used for security, financial or personal id or safety then it is not covered by
FDCA, even though it is an implant
i. Thus even if it changes the structure of the body, it is not intended to
ii. Intent based on marketing representation and objective intent of
manufacturer
b. STRUCTURE AND FUNCTION AND INTENDED USE
i. Intended Use Rule:
1. Remember the circuits are split on whether you only use manufacturer’s objective intent
or consider the circumstances as well
ii. Dual Use Products
1. FDA has set forth the following policy for products with both medical and non medical
uses
2. Will regulate if intended for medical purpose based on expression of person legally
responsible for its labeling and the circs surrounding its distribution
a. Labeling, ads, and other reps accompanying the product
3. Products that have med uses only are clearly intended for med purposes and will be
regulated as med devices whether or not med claims are made for them
4. Exercise equipment: Only regulated if therapeutic claims are made from them
5. Some items clothes have med claims made (ie protects from suns rays etc) so those are
med devices
c. LABELING
i. Scope of Labeling
1. Kordel v. United States (1948)
1. Facts: Kordel was marketing his own health food products which included
literature, some sold with products some displayed in stores where it was sold,
some independent of the product, that made statements about efficacy
2. I: Whether the separate shipment of literature saved the drugs from being
misbranded within the meaning of the FDCA
3. H: If drugs and literature have common origin, were used in the sale of the drugs
and explained their uses and were thus interdependent then they are considered
labeling
1. FDCA 201 m 2 doesn't require physical attachment
2. In another case, leaflets shipped at a different time nonetheless
accompanied the device
2. United States v. 24 Bottles Sterling Vinegar and Honey (2nd Circ 1964)
1. Facts: A number of books and bottles of V and H were condemned on the
grounds that the books were labeling the bottles and were misleading. Balanced
Foods sold a book that promoted V and H for a number of medicinal uses, also
sold premixed V and H without claims on the bottle.
2. H: Labels are presented to a customer, in some manner or another, in immediate
connection with his view and purchase of the product.
1. No evidence that there was joint promotion of the products or that
Balanced Foods did more than carry 2 related products.
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a. But see in another case, a book was considered labeling because customer were
referred to the book when purchasing a molasses product
ii. DSHEA Rule for Dietary Supplement Labeling:
1. In order to not be labeling it must:
a. Not be false and misleading
b. Cannot promote a particular manufacturer or brand of a dietary supp
c. Must be delayed or presented with other items on the subject matter for a
balanced view
d. Physically separate from dietary supplements
e. Many not have appended to it any information by sticker or any other method
2. Stores usually put these books in their reference section now
3. Even if you fail to meet all five of these doesn't automatically mean its labeling
iii. United States v. Articles of Drug...Century Food Co (SD Ill 1963)
1. Facts: FDA alleging misbranding from various pamphlets and articles of literature
accompanying several drug products containing false and misleading reps of vitamins
and minerals in the cure of serious diseases. Author of the book intervened alleging he
had no knowledge of the books being used as labeling for these products and that his
book shouldn't be condemned because it is sold else where
2. H: Court held that FDA cannot condemn the use of a book in other stores or outlets
where it is not acting as labeling BUT where the book is converted to labeling then the
FDA can seize them
iv. Ass'n of Am Physicians and Surgeons (DDC 2002)
1. I: challenging the authority of the FDCA to regulate based on the Pediatric rule
1. Facts: Pediatric Rule requires manufacturers to test products for use on children, even if
such a use is not prescribed, recommended or suggest by the product's label. Requires
testing even if the label specifically says don't use on kids. FDA believes that since
pediatric use is suggested use, the FDA has power to regulate it, under its authority.
2. H: Most cases say look at manufacturers intent and not further. FDA says some
cases you can look at customer intent, and whether the vendor is aware of off label
use.
1. These cases don’t apply to this case where we are not looking at whether
something is a drug, but just at the FDCA labeling section.
2. Requires that a drug be safe and effective for those uses "prescribed,
recommended or suggested in the proposed labeling"
3. If we allowed FDA meaning, then all off label used of drugs would be subject to
regulation and there would be no limit to FDA's authority
4. FOOD ADULTERATION
a. FOOD SANITATION
i. Filth
1. United States v. 484 Bags, More or Less (5th Circ 1969)
a. I: Whether molded green coffee is adulterated within the meaning of 21 USC
342 a 3
b. F: Coffee came in from Brazil to New Orleans, there was a hurricane the beans
got wet, they were run through a dryer and resacked. Although Act allows Sec to
exclude ALL food products containing filth, Sec gets discretion to adopt
tolerances. Here, adopted tolerance of 10% moldy beans, and the beans were
above this.
c. H: Two clauses of the statute are independent: either filthy or unfit for food are
sufficient, doesn't have to be both to be condemned.
i. If taken literally the first clause would ban all processed food from
IC, but samples here were above the permitted tolerance level.
ii. Tolerance levels weren't published but it doesn't matter since if the Court
thinks that the statute applies, they can always enforce a stricter tolerance
than the Secretary does
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ii. De Minimis Filth
1. US v. 1500 Cases of Tomato Paste (7th Cric 1957)
a. H: Congress set a standard of purity above that which is fit for food in order to
protect public health from a greater number of "slips" below tolerance level
i. FDA uses the expansive language reasonably, unclear why Congress put
“otherwise unfit for food” in there
ii. Ordinary consumer usually needs protection from what he cannot detect
in his food, not from what he can detect
2. United States v. Capital City Foods, Inc (D.N.D. 1972)
a. Facts: Ds charged with putting adulterated butter into IC
b. H: Since the FDA has not promulgated standards of allowable foreign matter in
butter, is that not itself a standard of zero allowance? Looks to the court like the
number of insect parts found in the butter was trifle without a standard
established by the FDA.
i. Court can then set its own standards, found the filth to be de
minimis and found for Ds.
3. Public Availability of Filth Standards
a. FDA now makes public all its filth guidelines, posts them on their website
i. Mold, insect fragments, hair/scales, stems would qualify for natural
filth guidelines
ii. Predaceous insects- no natural defect guidelines b/c not natural or
unavoidable and may be considered either a pesticide or a food additive.
b. Also important that even if the food isn't filthy, if the conditions are that can
make it enough for action to be taken against it
c. Defect levels set by the Sec represent a level below which the defect is both
unavoidable under current tech and presents no health hazard
d. Judicial review available to review defect action levels for arbitrary and
capricious
iii. Decomposition
1. United States v. An Article of Food...915 Cartons of Frogs Legs (SDNY 1981)
a. Facts: FDA chemist and organoleptic examiner broke shrimp open and smelled
it to determine if it was rotten. allowed organoleptic (smell the shrimp) testing to
decide whether shrimp is decomposed. Here, 4/18 samples is action level; this
batch had 7/18 decomposed so more than de minimis decomposition level.
b. H: Court concludes that the organoleptic test is appropriate, and more than a de
minimis amount of decomposition was present in the frozen shrimp and that it is
adulterated within the meaning 21 USC 342 a
iv. Insanitary Conditions
1. United States v. 1200 Cans...Pasteurized Whole Eggs, etc (NDGA 1972)
a. Facts: Actions brought to condemn and destroy as adulterated lots of
pasteurized frozen whole eggs and sugar yolks processed and introduced into IC.
b. H: Court condemns the egg address three FDA theories
i. Poisonous substances under 21 USC 342 a 1
1. Salmonella is a well recognized pathogen that is a serious threat
to PH; discovered in eggs, can be condemned on that
ii. Decomposed Substances under 21 USC 342 a 3
1. Difficult to use smell test on pasteurized egg products
2. FDA wanted to use the Direct Microscopic Count method, but it
is not proven to be reliable in the detection of bacteria without
corresponding acid tests
iii. Insanitary Conditions under 21 USC 342 a 4
1. Even if the food isn't decomposed, if it is processed under
unsanitary conditions that would offend a consumer's basic sense
of sanitation and which would cause him to refuse them had to
been aware of the conditions under which they were prepared
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2. Also, high DMC test, although not sufficient on its own, its
further proof of unsanitary conditions
2. United States v. Certified Grocers Co-op (CA7 1976)
a. Facts: P in this case was charged with adulteration of flour in their warehouse.
Gov't found rodent pellets and hair in bags of flour, and evidence of rodents
through the warehouse
b. H: It was clear from the evidence that there were unsanitary conditions, and the
court does not agree with the lower court’s interpretation of the statute that
despite unsanitary conditions, no reason to suppose anything entered the
packages and conditions were below tolerable levels.
3. United States v. 298 Cases Ski Slide Brand Asparagus (D.Ore. 1949)
1. Facts: D is an asparagus packer, the US found that his center cut spears are
fibrous and woody and beyond the permissible limits of the FDCA. Three
witnesses agree with the gov't, saying 25% of cuts were inedible.
2. H: Judge ate a can and agreed with the sole witness that they were edible, minus
a piece or 2 here or there. Since not everyone can afford the best cut of
asparagus, this is a nutritious and cheap option for the rest of the American
public.
b. SAFETY OF CONSTITUENTS
i. One of FDA's most controversial activities is the regulation of the safety of food constituentsmaterials that occur naturally in agricultural commodities, that are intentionally added to food
during processing, or that migrate to food as the result of industrial activity
ii. There is no single food safety standard-over 100 years of regulation
iii. 1938 Act thus contained three standards applicable to potential toxic substances in food
1. Section 402 a 1 ordinarily injurious standard applied to constituents that were not added
2. Section 402 a 1 may render injurious standard applied to added constituents that were
neither necessary nor unavoidable
3. Section 406 FDA could set tolerances for the protection of public health for added
constituents whose use was necessary in the production of food or whose occurrence was
unavoidable by good manufacturing practice
iv. Amendments:
1. ***None of the amendments cover exogenous substances like PCBS or mercury whose
occurrence in food is unintended and undesired
2. Miller Pesticide Amendments of 1954 which added section 406 of the Act
a. Created elaborate procedure for the establishment of tolerances for residue of a
pesticide on food
b. Doesn't cover pesticides that contaminate foods for which their use is not
approved, which often occurs as a result of drift during application
3. Food Additives Amendment (409)
a. Establishes a licensure scheme, similar to that for pesticide residues, for
substances that are intended to be used as ingredients in formulated food
b. Also applies to packaging material that comes into contact with food or is
reasonably expected to become components of food
c. There are some exceptions, such as food generally recognized as safe by experts
(GRAS), ie salt and sugar, and substances that were sanctioned prior to 1958
4. Delaney Clause
a. Precludes FDA from approving safe any food additive found to induce cancer in
man or animals
5. Color Additive Amendments
a. Apply to all substances used primarily for the purpose of importing color to food
b. Color additives need to be approved by FDA
c. Delaney Clause also applies here
6. Animal Drug Amendments of 1968
a. Applies to the food that animals eat that then get eaten by man
b. Delaney Clause also apply
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7. DSHEA
a. Congress recognized dietary supplements as a distinct subcategory of food and
established separate safety criteria for dietary ingredients
i. Still subject to 402 a 1
b. Also prohibits the marketing of any dietary supplement or dietary ingredient that
presents a significant or unreasonable risk of illness or injury
c. No GRAS exceptions from premarket notification for new dietary ingredient
d. Anyone who proposes to market a new dietary ingredient must notify FDA at
least 75 days in advance
v. Poisonous or Deleterious Substances
1. Section 402 a 1 defines as adulterated any food that contains an added poisonous or
deleterious substances which way render it injurious to health or a non-added poisonous
or deleterious substance which ordinarily renders it injurious to health
a. Contains no definition of the term "added"
2. Added Substances
a. United States v. Lexington Mill & Elevator Co
i. Facts: FDA sought to seize and condemn flour from the D who had
treated it with the Alsop process, which mixed nitrogen peroxide gas
with the atmospheric air which was brought into contact with the flour.
FDA said this made flour adulterated.
ii. H: Language says that if any added poisonous or deleterious ingredient
render an article injurious to health, then it can be condemned. Needs
to be both added and injurious.
b. Definitions:
i. INJURIOUS:
1. May render injurious standard takes into account QUANTITY
under may render injurious standard, which also takes into
account vulnerable segments of the population (as opposed to
ordinarily injurious)
ii. ADDED: has to be added, mixed is different (trinkets and candy case)
3. Non-Added Substances
a. United States v. 1231 Cases American Beauty Brand
i. Facts: FDA wanted to condemn oysters that contained shell fragments,
that were dangerous because they could cut the mouth and esophagus.
Current tech made it impossible for all shell fragments to be removed
from oysters, but clear that the shells were not artificially added
ii. H: Clear that the statute contemplates that there may be necessity of food
products containing deleterious substances, as long as they were not
injurious to health. In this case, the gov't says that in the case its the
character, not the quantity of this substance that controls its ability
to injure- but that goes against what the state says, it’s all about
quantity!
1. Can’t remove fragments from oyster, if FDA says they are
unsafe, then have to remove all oysters from marketUNLIKELY.
4. Naturally Occurring Environment Contaminants
a. To facilitate enforcement, FDA has sought to regulate a number of naturallyoccurring environmental contaminants of food as added rather than non added
substances
b. No provision of the FDC Act explicitly provides a mechanism for regulating
substances that become constituents of food through environmental
contamination
i. Yet such materials may pose serious risks to human health
ii. Controlling their occurrence in food raises difficult scientific and
economic and admin issues
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iii. FDA needs to use formal rulemaking to set tolerance levels, informal
rulemaking for action levels thus only a few tolerance levels have been
set
c. Poisonous or Deleterious Substances in Food: NPRM
i. Added is a statutory term of art encompassing all ingredients which are
not inherent and intrinsic parts of food
ii. Doesn't actually have to be added, just inherent in natural state and
increased by mishandling or intervention
iii. Only thing excluded from additives are those which cannot reasonably be
expected to become a component of food
iv. Action levels are just published in fed registrar, no rulemaking is used.
d. MERCURY
i. In 1970, FDA established and began to enforce an action level of .5 ppm
mercury in fish, resulting in a virtual ban of swordfish
ii. Later clarified with regulations that only a substance that is an inherent
natural constituent of the food and is not the result of environmental,
agricultural, industrial or other contamination in a non-added substance
1. Under this definition, all mercury in fish is added
e. US v. Anderson Seafoods Inc (5th Circ 1980)
i. Facts: US sought injunction against Anderson Seafoods to prevent them
from selling swordfish containing more than .5 ppm of mercury, which it
considered adulterated . Anderson sought a declaratory judgment that
fish containing 2.0 ppm of mercury or less are not adulterated. DC
denied dec judgment, and decided on a 1.0 ppm standard.
ii. H: Three theories put forward about the meaning of the term added
1. FDA's theory is that an added substance is one that is not
inherent, not a naturally occurring poisonous or deleterious
substance
2. Anderson's theory is that a substance is not an added substance
unless it is proved to be present as a result of the direct agency of
man, and only that which can be traced back to man is considered
added
3. District court theory [Which was adopted by Court]
a. If a de minimis amount of the mercury in swordfish is
shown to result from industrial pollution, then all of the
metal in the fish is treated as an added substance and
may be regulated under the statute's may render injurious
standard
iii. Take Away: Now you are going to be eating twice as much mercury as
FDA said is safe
f. Young v. Community Nutrition Institute (1986)
i. Facts:
1. Section 346 states: any poisonous or deleterious substance added
to any food....shall be deemed to be unsafe....but when such
substance is so required or cannot be avoided, the Sec shall
promulgate regulations limited the quantity therein...
2. Since tolerance levels require formal rulemaking, FDA has set a
number of action levels
ii. H: FDA has the ability to determine when regs are necessary, they are
not required set tolerance levels for everything. Language is ambiguous
and thus we must uphold the FDA's reasonable interpretation so FDA
can choose whatever tolerance level it deems necessary or to not set one
at all
iii. Follow Up: FDA later said it would regard action levels as prosecutorial
guidelines and not binding rules
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5. FOOD ADDITIVES
a. Food Additives Amendment of 1958
b.
c.
d.
e.
i. Under existing law, fed gov’t is unable to prevent the use in foods of a poisonous or deleterious
substance until it first proves that the additive is poisonous or deleterious
1. Requires 2+ yrs of experimentation
ii. Two flaws in existing law
1. Need to require the processor who wants to add a new and unproven additive to accept
the responsibility now voluntarily born by all responsible food processors of first proving
it to be safe for ingestion by human beings
2. Permit use of such additives as technological scientists produce why may benefit people
and economy in safe amounts
iii. Incidental additives (reasonably expected to become a component of any food or to affect the
characteristics of any food) would also be covered by legislation
1. Wouldn't cover what accidentally gets into food, that would be covered by FDCA dealing
with poisonous and deleterious substances would be applicable
iv. Safety requires proof of a reasonable certainty that no harm will result from the proposed use of
an additive
1. Based on cumulative effect, educated estimates under likely patterns of use
2. Now usually tested on humans prior to FDA approval of food additive petition
3. FDA favors the current requirement that a food additive have a functional value, but
objected to additional requirements considering economic or social decisions
United States v. An Article of Food
i. Facts: Appeal from manufacturers of a coconut concentrate that contains potassium nitrate to
develop and fix a desirable color and flavor. Govt said potassium nitrate is an unsafe food,
making beverage adulterated and subject to forfeiture. Manufacturer submitted one affidavit
saying it was found safe for use, also said approved by FDA for use in curing meats.
ii. H: Statute says it has to be safe under the conditions of its intended use. No conclusive
scientific evidence here that it is safe in beverages, even if it is commonly used.
Proposal Regarding Regulation of Prior-Sanctioned Food Ingredients
i. A food ingredient subject to a prior sanction may not be regulated under the food additive
provisions of the law
ii. May instead be regulated under the general adulteration and misbranding provisions of the Act,
and in particular may be banned from food if found to be a poisonous or deleterious substance
iii. Not all sanctions and approvals can be ascertained because of destruction of old records and
retirement of personnel
iv. Final Regulations:
1. Afforded the FDA substantial control over prior sanctioned food ingredients
2. If prior sanctioned food is found to injurious to health, FDA can amend prior sanction or
implement an emergency action level
Monsanto v. Kennedy
i. Facts: Appeal of a DC decision finding that acrylonitrile copolymer found in unbreakable
beverage containers is a food additive. There is a residual level of the acryl that migrates from
wall of container into the beverage. FDA admin proceedings focused on a 3.33 ppm level, but
FDA prohibited manufacture of containers irrespective of RAN levels. FDA tried to conjecture a
linear relationship for RAN levels, unsupported by the evidence.
ii. H: Based on language of the statute we think that Congress did not intend that the component
requirements of a food additive would be satisfied by a mere recitation of the diffusion principle.
FDA needs to show that the substance migrates into food more than insignificant amounts
with a fair degree of certainty.
1. Here FDA determination okay, but it may be weakened or strengthened with time and
experience with the substance
Times this is Implicated:
i. Issues arose with microwaves, which could change the temps of packaging to much higher than
before, making good unsafe-FDA requested information
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ii. FDA doesn't regulate shopping bags since in contact with food for such short period of time
iii. FDA also considers environment, i.e. how much plastic waste is produced
iv. FDA later promulgated a regulation that migrating food is exempt from food additive regulate if
it is not a carcinogen and it results in concentrations at or below .5ppb
f. Food and Drug Modernization Act of 1997
i. Included an entirely new approach for handling direct food additives
1. 120 day pre market approval process
g. GRAS: Generally Regarded as SAFE
i. If an added ingredient is GRAS, it can escape being a food additive, which takes years and tons of
studies
ii. If you don’t have scientific evidence from outside, then you do a self-affirmation of GRAS with
your own experts
iii. If you can’t prove GRAS, and you have a food additive
1. Apply FDCA 409: File a petition with the FDA with all the information and studies
6. DELANEY CLAUSE
a. Precludes the approval of any food additive found to induce cancer in man or in animals
b. Delaney clause is in the Food Additives Amendment of 1958, the Color Additive Amendments of 1960,
and the Animal Drug Amendments of 1968
c. Generally thought to be a reasonable test-food fed to animals in amount and way it was intended
i. Not meant to be read literally and ban all carcinogens-FDA supposed to read through the lines
d. Applied to Constituents of Additives
i. FDA says that the detection of trace amount of known carcinogenic substance naturally present in
food or unavoidably added to a food does not invoke the anti cancer clauses
ii. Has to be the food itself, not a constituent of the food
1. Used to be opposite policy, but with technology now it’s easy to decrease magnitudes of
components to very low levels
2. Also large numbers of components have been found to be carcinogenic!
iii. Apply Monsanto Case, if FDA thinks it’s safe and no reasonable certainty of harm then it’s
ok
e. Scott v. FDA
i. Facts : Guy sued FDA saying that DC Green No 5 contains DC Green No 6, which has proven to
be a carcinogen. FDA found that No 5 as a whole is not a carcinogen, and thus not barred by the
Delaney Clause. FDA extrapolated the max life time average annual exposure to the carcinogen
in DC Green No 5 and found that there was not a reasonable certainty of harm
ii. H: Court upholds FDA as a reasonable interpretation. Delaney not intended to apply to
constituents.
7. FOOD LABELING
a. Statute: label shall be found false or misleading if label is false or misleading in the particular
b. GENERAL: Regulation of Food Labeling
i. Focuses on government efforts to protect the economic expectations of both consumers and food
distributors
ii. Historical Overview
1. Section 403 of FDCA itemizes circs under which a food will be considered misbranded
2. Most of the forms of misbranding relate to info included in or omitted from the label or
labeling
3. Forced to tell the suppliers the truth about their products
4. Additional provisions prohibit other types of affirmative deceptions regarding quality,
quantity, or identity
5. Other provisions force manufacturers to provide info they might otherwise omit
6. Stat provisions enacted by Congress in 1938 to regulate food misbranding have remained
virtually the same, thus history reflected evolving admin policy of FDA
7. Two eras: before and after the White House Conference on Food, Nutrition and
Health in 1969
a. 1939-1969
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b. Following enactment of the FDCA in 1938, FDA relied primarily upon 5 stat
provisions to regulate food misbranding
i. Mandatory info required on labels
ii. Mandatory standards of identity for food products
1. FDA adopted the policy of establishing recipe standards for
identity, under which every permitted ingredient was specifically
listed in the standard
iii. Labeling of imitation food as an imitation
1. SC overruled FDA policy that any imitation of a standardized
product was inherently illegal, but agreed that once the FDA
had established a standard of identify, the standard could not be
evaded by adding non permitted ingredients and revising the
name of the food to reflect change
iv. Nutrition information for Special Dietary Food
v. Prohibition of any False or Misleading claims related to medical benefits
c. White House Conference on Food, Nutrition and Health
i. Nixon announced the conference in response to charges of hunger and
malnutrition but had an unexpected impact on FDA policy
ii. Announced need for sound and affordable nutrition, with technology to
fill that need, and increased info on nutrition
iii. Coupled with a huge overhaul of FDA personnel
d. 1969-1989
i. White House Conference represented the end of the restrictive approach
to food regulation proposed by FDA during the 1960s
1. Mandatory food labeling
a. Same four statutory categories of mandatory info remain
but with some changes
b. Standardized food is not required to include on the label
any mandatory ingredient in food, only optional
c. Also promulgated new regulations governing the names
used on the labels for food products
i. Must accurately identify or describe the basic
nature of the food or its characterizing properties
or ingredients and distinguish food from others
2. Food Standards
a. Began to eliminate the old recipe approach and permit
any safe and suitable functional ingredients
b. Limits on fortified foods have been abandoned
3. Imitation Foods
a. FDA says rather than calling it imitation, make up its
own name for it (ie margarine instead of imitation
butter)
4. Special Dietary Foods
a. Final special dietary food regulations have now been
promulgated for hypo-allergenic food, infant food,
weight control food, diabetic food, and low sodium food
5. Prohibition of False or Misleading Claims
a. Specific claim about prevention of disease are permitted
if they are recognized as valid by qualified experts, they
emphasize that good nutrition is a function of the total
diet, the claims are reasonably uniform within the
marketplace, and they do not result in dietary power
races
6. Slack Fill and Deceptive Packaging
a. FDA hasn't done anything about slack fill
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iii. Food Standards
1. Nothing in statute provides for mandatory standards, FDA implemented some
2. Federal Security Admin v. Quaker Oats Co
a. Facts: FDA promulgated regs establishing standards of identity for various wheat
products. Excluded vitamin D from the defined standard of farina and permitting
it only in enriched farina, which also had to contain a number of other vitamins
and minerals. Quaker Oats was selling farina enriched with vitamin D, but not
the other vitamins.
b. H: Since Consumers can get confused and are subject to exploitation by the sale
of foods described as enriched but of whose inferior unsuitable quality they are
not informed not unreasonable to not allowed vitamin D to be added to reg farina
but allowed to be added to enriched farina with the other ingredients.
3. Columbia Cheese Co v. McNutt
a. Facts: FDA proposed definition and standard of identity for cream cheese,
differentiating between cream cheese, neufchatel and creamed cottage cheese.
These different cheeses have different water and fat contents although they
appear and are used similarly
b. H: FDAs standards for different names for different ratios of fat and water
content are reasonable
4. FDA has only ever revoked one standard-the one for soft drinks
c. Scope of Labeling
i. All of them involve health food products against which the FDA took action because of their
therapeutic claims
1. Kordel v. United States (1948)
3. Facts: Kordel was marketing his own health food products which included
literature, some sold with products some displayed in stores where it was sold,
some independent of the product, that made statements about efficacy
4. I: Whether the separate shipment of literature saved the drugs from being
misbranded within the meaning of the FDCA
5. H: If drugs and literature have common origin, were used in the sale of the drugs
and explained their uses and were thus interdependent then they are considered
labeling
1. FDCA 201 m 2 doesn't require physical attachment
2. In another case, leaflets shipped at a different time nonetheless
accompanied the device
3. United States v. 24 Bottles Sterling Vinegar and Honey (2nd Circ 1964)
1. Facts: A number of books and bottles of V and H were condemned on the
grounds that the books were labeling the bottles and were misleading. Balanced
Foods sold a book that promoted V and H for a number of medicinal uses, also
sold premixed V and H without claims on the bottle.
2. H: Labels are presented to a customer, in some manner or another, in immediate
connection with his view and purchase of the product.
1. No evidence that there was joint promotion of the products or that
Balanced Foods did more than carry 2 related products.
a. But see in another case, a book was considered labeling because customer were
referred to the book when purchasing a molasses product
4. DSHEA Rule for Dietary Supplement Labeling:
1. In order to not be labeling it must:
1. Not be false and misleading
2. Cannot promote a particular manufacturer or brand of a dietary supp
3. Must be delayed or presented with other items on the subject matter for a
balanced view
4. Physically separate from dietary supplements
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5. Many not have appended to it any information by sticker or any other
method
2. Stores usually put these books in their reference section now
3. Even if you fail to meet all five of these doesn't automatically mean its labeling
5. United States v. Articles of Drug...Century Food Co (SD Ill 1963)
1. Facts: FDA alleging misbranding from various pamphlets and articles of
literature accompanying several drug products containing false and misleading
reps of vitamins and minerals in the cure of serious diseases. Author of the book
intervened alleging he had no knowledge of the books being used as labeling for
these products and that his book shouldn't be condemned because it is sold else
where
2. H: Court held that FDA cannot condemn the use of a book in other stores or
outlets where it is not acting as labeling BUT where the book is converted to
labeling then the FDA can seize them
ii. Labeling Requirements of Section 403
1. Section 403 contained two quite different types of provision
2. Those that prohibit certain types of representations and those that require disclosure of
specified info
3. Prohibited Reps
a. 403 a prohibits statements in labels or labeling that are false or misleading in any
particular
b. US v. 95 Barrels of Apple Cider Vinegar
1. Facts: FDA condemned 95 bottled of vinegars whose package said they
were made from selected apples, when in reality made from dried or
evaporated apples.
2. H: If an article is not the identical thing that the brand indicates it to be,
it is misbranded. Here the label is misleading, dried apples that are
rehydrated-->vinegar is not the same thing as apple cider vinegar
3. MISBRANDING CASE
2. US v. 432 Cartons of Candy Lollipops
1. Facts : Candy lollipops were labeled with names of liquor, but the list of
ingredients made it clear that there wasn't actually liquor in the lollipops.
2. H: Labeling statute is stricter than advertising, requires only that the
labeling be false or misleading in any particular v. advertising, which
must be misleading in a material respect. True statements don't cancel
out false ones, but taken as a whole the packaging is not misleading in
the particular.
1. The fact that purchasers have not been mislead is not a defense.
3. APPLE CIDER VINEGAR RULES NOT ABSOLUTE
3. Brand Names
1. While a brand name may be misleading, the courts have been reluctant
to require abandonment of a brand name
4. US v. an article of food...Manischewitz Diet Thins
1. Facts: Gov't says the thins are misleading because they give the
consumer the misleading impression that the matzos are lower in caloric
content when really they are just thinner. Only difference was use of
enriched flour.
2. H: Gov't doesn't need to prove that all the label reps are both false
and misleading, only that any one is false OR misleading.
1. Test: Not the effect on a reasonable customer, but upon the
ignorant, the unthinking and the credulous consumer (i.e.
those trying to lose weight).
d. Labeling of Genetically Modified Food
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1. Genetically modified food came about after the structure of DNA was discovered-more food
more productive, more resistant, or more nutritious
1. Can be invisible to consumer, but have cost savings and product improvement effects
2. FDA became involved:
1. Section 403 j of the act requires the producer of a food to describe the product by
its common or usual name or in appropriately descriptive terms and reveal all
facts that are material in light of reps made or suggested by labeling
2. Thus consumers must be informed if a food derived from a new plant variety
differs from its traditional counterpart such that the common or usual name no
longer applies or if a safety or usage issue exists
3. Use of biotechnology does not need to be disclosed on label
1. International Dairy Foods Association v. Amestoy
1. Facts: VT state says that you have to put a sticker on engineered
cow milk, without a safety or PH argument.
2. H: State is requiring speech, apply four-part Hudson test
1. Whether the expression concerns lawful activity and is
not misleading
2. Whether the gov'ts interest is substantial
1. Fails here, they claim the interest is strong
consumer interest and right to know NOT ph
and safety
3. Whether the labeling law directly serves the asserted
interest
4. Whether the labeling law is no more extensive than
necessary
2. Alliance for Bio-Integrity v. Shalala
1. Facts: Ps challenging the FDA May 1992 Statement of Policy's
failure to require labeling for genetic engineered foods, for
which FDA says they are GRAS.
2. H: FDA’s interpretation of the word MATERIAL in 321 n is
reasonable.
3. Reasonable for FDA not to considered consumer interest as a
reason for labeling when they said they are safe.
2. Frankenfoods and the FDA
1. 2002 FDA came out with a Draft Guidance
1. Name must be changed if the products name no longer adequately describes the
product
2. Also important to remember that when you use different genes, like peanut gene
in a tomato, then you have to label it because there is a potential for allergies
3. Also can't say GMO free if there’s GMO food in that category
1. FDA is discouraging people from making any kinds of statements about
biotech unless 100% true
2. If a label says GMO free the problem is even if it’s actually GMO free
the label may lead consumers to think that GMO free goods are superior,
which the agency has not found to be true misleading
8. HEALTH CLAIMS
a. STRUCTURE/FUNCTION CLAIMS
i. US Gov’t Regulation of Food with Claims for Special Physiological Value
1. Because of the statutory exclusion of food from the structure/function portion of the drug
definition, s/f claims can lawfully be made for food without making it a drug
a. But food industry is conservative so they generally haven’t made many claims
b. FDA made new approach official in 1994 wish DSHEA, saying that both food
and dietary supplements could make s/f claims
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c. Proposed to distinguish between a permitted s/f claim for conventional food to
those that directly relate to nutritive value of food but these are not enforceable
d. S/F Claims made about conventional foods are usually called functional foods
ii. Food v. Dietary Supplements:
1. Remember that food is still subject to food additive clause of FDCA, while DSHEA
applies to dietary supplements and is more flexible
2. Dietary Supplements need disclaimer and are sent to FDA, unlike foods
iii. Examples of Acceptable Claims:
1. Statements of nutritional support should provide useful information to consumers about
the intended use of a product
2. Statements of nutritional support should be support by scientifically valid evidence
substantiating are truthful and not misleading
3. Statements indicating the role of a nutrient or dietary ingredient in affecting the structure
or function of humans may be made when the statements do not suggest disease
prevention or treatment
4. Statements that mention a body system, or function can b e appropriate when the
statements do no suggest disease prevention or treatment or use for a serious health
condition
5. Statements should not be made that products restore normal or correct abnormal function
when the abnormality implies the presence of disease
6. Health claims that characterize the relationship between a nutrient or a food component
and a specific disease or health-related condition
7. Statements of nutritional support are not to be drug claims, can’t refer to specific
diseases, disorders, etc
iv. FDA concluded that it is not appropriate to treat common non-serious conditions associated with
natural states as diseases, ie adolescence or old age
1. Later removed pregnancy claims from the list of acceptable natural states for fear of
endangering unborn children
v. Use of heart symbol: FDA said heart symbol could be used in labeling of dietary supp in
conjunction with s/f claim relating to maintenance of health circ or some other function that does
not imply treatment or prevention of disease
vi. Submitting your health claim: when you send it your claim within 30 days, if FDA objects they
will send you a courtesy letter
b. Disease Prevention Claims
i. General Principles
1. FDA always said no disease claims for dietary supplements until Congress authorized the
Nutrition Labeling and Education Act of 1990 and the FDA Modernization Act of 1997
a. Explicitly permitted claims that characterize the relationship of a nutrient to a
disease or health related condition
i. If they are approved on the basis of significant scientific agreement
ii. Or approved in authoritative statements by other federal agencies or
National Academy of Science
2. After this, FDA required mature science-a virtually scientific consensus
3. Difficult to overcome, no emerging science
ii. Pearson v. Shalala(DDC 2000)
1. Facts: Marketers of a dietary supplement failed to persuade the FDA that the claim they
wanted to make had sign scientific agreement. Four claims linked the consumption of a
particular supplement to the reduction in risk of a particular diseases: consumption of
antioxidant vitamins may reduce the risk of certain kinds of cancer, .8mg of folic acid in
a dietary supp is more effective in reducing the risk of neural tube defects than a lower
amount in foods in common form, etc.
2. H: Restrictions on health claims are evaluated under the commercial speech
doctrine, must apply a three Central Hudson test.
a. Is gov’t interest substantial? Protection of public health and prevention of
consumer fraud
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b. Whether the reg directly advances the gov’t interests asserts? Not saying this is a
threat to health, but rather a threat to common sense judgment
c. Whether the fit between the ends and means is not necessarily perfect, but
reasonably? There is a preference for disclosure over suppression, disclaimer
may be appropriate in this case
3. Remember a disclaimer will never overcome a false or misleading statement!
4. Follow Up:
a. FDA construed this mandate narrowly and continued to disapprove proposed
diseases claims, apply a weight of the evidence test
b. Until this case:
iii. Whitaker v. Thompson(DDC 2003)
1. Facts: Ps challenge the FDA decision prohibiting dietary supplement labels from
including the health claim that “Consumption of antioxidant vitamins may reduce the risk
of certain kinds of cancers”. The court in Pearson 1 strongly suggested that it was
unconstitutional for the FDA to refuse to authorize a claim that was potentially
misleading, as opposed to inherently misleading. Resulted in Pearson II and III, both
finding for the P against the FDA. Established a heavy burden from a D who wants to
totally suppress a particular health claim: must show with empirical evidence that
disclaimers would bewilder consumers and fail to correct for deceptiveness.
2. H: Here the FDA has again failed to comply with the Pearson I decision. The claim
is not inherently misleading, so FDA erred by not considering a disclaimer. Where
credible evidence supports a claim, that claim may not be absolutely prohibited.
3. Follow Up:
a. After this case, FDA forced to change its strategy
i. Created 2 separate and different standards for disease claims for food
ii. Sign scientific agreement for unqualified disease claims AND credible
scientific evidence for qualified disease claims
c. Unqualified Disease Claims
i. FDA has promulgated regulations approving 12 unqualified disease claims, i.e. calcium and
osteoporosis, etc
ii. Food Labeling; General Requirements for Health Claims For Food
1. The proposed definition establishes that a claim must have at least 2 basic elements for it
to be regulated as a health claim:
a. Must be about a substance
b. Must characterize the relationship of the substance to a disease or health related
condition
2. Claims relating to a broad range of substances are potentially subject to regulation
3. Leg history shows that Congress intended whole foods to be subject of claims regulated
under the act
a. Doesn’t apply to broad classes of food, i.e. fruits and vegetables
4. Includes both risk factors and claims about a disease
a. BUT Doesn’t apply to classical deficiency diseases
5. Under Nutrilab, a substance whose uses do not include taste, aroma, or nutritive value is
not a foods
a. Thus dietary supplements are usually not considered to be a food because not
taken for above reasons
iii. Misnomer to consider the 12 unqualified phrases that have been approved unqualified, since they
all include qualifications
iv. Jelly Bean Rule
1. No food may make a disease claim unless it contains ten percent or more of the reference
daily intake or the daily reference value for vitamin a, c, iron, calcium, protein, or fiber
per reference amount customarily consumed prior to any nutrient addition
2. A lot of times fruits and vegetables don’t qualify!
v. Disqualifying Macronutrient Levels
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1. Can’t make a disease claim if food contains 13 grams fat, 4 grams sat fat, 60 mg of
cholesterol, 480 mg of sodium
vi. All info required in disease claim must appear together in one place without other intervening
material
d. Qualified Disease Claims
i. Evidence based ranking system used to evaluate the scientific evidence relevant to a disease claim
1. Four levels of disease claims based upon the rank of evidence
a. High: sign scientific evidence (unqualified disease claim)
b. Moderate: sci evid is not conclusive
c. Low: evidence is limited and non conclusive
d. Extremely low: little sci evid supporting this claim
2. Difficult for consumers to distinguish between these claims
3. FDA exercises enforcement discretion with these claims
9. DIETARY SUPPLEMENTS
a. THINGS TO LOOK FOR
i. Prior approval as a drug....what does that mean for the dietary supplement?
ii. Prior marketing clause?....FDA will call it a drug if we try to market it as a dietary supp
b. Dietary Ingredients in Dietary Supplements
i. FDA and dietary supp industry have always been in a regulatory war
ii. FDA was finally defeated in 1994 with DSHEA
1. Congress exempted the dietary ingredients in supplements from the food additive
requirements of FDCA + more flexible food safety provisions
2. Broadly defined dietary supplements and authorized strong new claims
3. Pre 1994 ingredients used in supplements are ok as long as FDA can't prove a significant
or unreasonable risk of illness or injury
a. FDA has taken the position that the mere incidental presence of components of a
dietary ingredient as inherent components of a food market in the US before
1994 does not satisfy this requirement
b. Has to be that the dietary ingredient itself was used as a food or food ingredient
without chemical alteration
4. New post 1994 ingredients that have not previously been markets or present in food
supply are subject to 75 days pre market approve
a. FDA can take action if there is inadequate info to prove reasonable assurance
b. Basically a premarket notification process, instead of approval requirements
c. DSHEA: FDCA 402 f
i. US has burden of proof, basically FDA has much less authority to regulate the safety of dietary
supps than the safety of conventional foods
d. Pharmanex
i. Issue: the scope of 321 ff 3 B as it relates to the FDA's power to regulate dietary supplements
ii. Facts: P markets a product, Cholestin that is intended to promote healthy cholesterol levels.
Contains mevinolin, which is chem = lovastatin that is in a prescription drug and approved for
treatment of high cholesterol in 1987. FDA advised Pharmanex that it considered Cholestin to be
a drug which may not be marketed without FDA approval.
iii. H: Chevron applies, so first determine if Congress unmbiguously manifested its intent to exclude
only finish drug products (rather than ingredients) from the definition of dietary supplements. To
permit manufacturers to market dietary supplements with components identical to active
ingredients in prescription drugs would contravene the incentive structures in place in the
FDA.
e. Pharmanex on Remand
i. Arguments
1. Pharmanex: Claims that even if the relevant article is lovastatin, it was market as a
dietary supplement or was a food prior to its approval as a new drug, and thus qualifies as
a dietary supp
a. It is present in red rice yeast, oyster mushrooms and other foods
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f.
b. Argues that FDA has misinterpreted the second portion of the exclusionary
clause, reading into the prior market clause as an extra statutory requirement of
promoting the food based on the property at issue or must have increased or
optimized the concentration at issue prior to approval as a new drug
2. FDA: Pharmanex failed to show that lovastatin was previously marketed as a dietary
supp, food, or component of food, thus Cholestin does not qualify as a dietary
supplement. Market as is ambiguous so FDA can interpret it however they like.
ii. H: Court holds for FDA. FDA construction of the market as language to mean more than
mere presence in a food is rational and consistent with statute.
Dietary Supplement Structure/Function Claims Guidance (Jan 2000)
i. Summary
1. FDA is issuing final regulations defining the types of statements that can be made
concerning the effect of a dietary supp on the structure or function of the body
2. Establish criteria for determining when a statement about a dietary supp is a claim to
diagnose, cure, mitigate, treat, or prevent disease
3. Intended to clarify the types of claims that may be made for dietary supplements without
prior approval by FDA and the types of claims that require prior authorization as health
claims or prior approval as drug claims
ii. Certain Types of Statements for Dietary Supplements
1. Structure/Function Statements
a. May bear statements that describe the role of a nutrient or dietary ingredient
intended to affect the structure or function in humans or that characterize the
documented mechanism by which it is to maintain such structure (as long as not
disease claims)
i. If its a disease claim-->drug unless it is an authorized health claim
b. Disease=damage to an organ, part, strucure, or system of the body such that it
does not function properly or a state of health leading to such disfunctioning,
except essential nutrient deficiencies
c. A health claim is a claim that characterizes the relationship of any nutrient in the
food to a disease or health related condition
2. DSHEA specifically authorized certain types of claims about the uses of dietary
supplements that would have formerly been required to be reviewed by FDA
a. Okayed statements that describe the role of a nutrient or ingredient intended to
affect the structure or function in humans
b. OR that characterizes the documented mechanism by which a nutrient or dietary
ingredient acts to maintain such structure or function
3. Still can't be misleading, must be truthful
a. Needs substantiation
b. Needs disclaimer: This Statement has not been evaluated by the FDA. This
product is not intended to diagnose, treat, cure or prevent any disease.
c. Must notify FDA no later than 30 days after the first marketing of the dietary
supplement with the statement
4. There may be cases however in which a statement of health maintenance can be
understood only as a claim of prevention of a specific disease, which case it will be
considered a disease claim
a. IE by use of terms that are so closely identified with a specific disease or that so
clearly refer to a particular at risk pop that the FDA would consider it an implied
disease prevention claim
b. Claims concerning maintenance of normal cholesterol levels are not necessarily
implied disease claims
i. But lowers cholesterol is, as is promotes cholesterol clearances
5. A commenter said the court of appeals First Amendment ruling in Pearson requires the
agency to permit health claims that do not satisfy the significant scientific agreement
standard as long as the claim can be rendered non misleading by requiring a disclaimer
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a. This is untenable, don't want companies avoiding time and expense of drug
provisions by smacking on a disclaimer
10. DRUG APPROVAL
a. THE BASICS
i. Pioneer applies for NDA
1. Has patents for drug and method of Use
a. Give this info to FDA when you apply, they put it in the Orange Book which
includes all approved drugs, exclusivities, and patents
ii. Generic comes in at end of patent with ANDA with paragraph IV certification where there is a
relevant patent, there can be a patent infringement case
1. If the Pioneer gets on it with 45 days, there’s a 30 mo stay on the approval of the ANDA
iii. ANDA allows you to piggy back off NDA
1. Sameness in active ingredient, dose, etc.
a. Can petition FDA for a variance on these
2. Bioequivalence
iv. If a Pioneer wants to improve the product but not reinvent the wheel
1. They can’t do a ANDA, but they do a paper 505 b2 NDA
a. Technically its an NDA but its different: applicant doesn't have right of reference
or own all the info on the NDA
b. subject to same exclusivities and patent certifications (so its just like an NDA)
v. If a Pioneer wants to keep generics out, keep changing your product, get patents on new stuff,
make it more difficult for generic to copy things (ie score your pills)
1. Known as “life cycle management”
2. FTC going after this for AT reasons
b. NEW DRUG DEFINITION
i. US v. Articles of Drug...Hormonin (DC NJ 1980)
1. Facts: Hormonin 1 is a fixed combo of three unconjugated estrogens. Hormonin 2 has
the same active ingredients as 1, in double dosage. Case over whether they are new drugs
as defined by 21 USC 321 p.
2. H: Definition of new drug must be liberally construed in order to effectuate the policy of
the statute and protect ph and safety. Situations in which a drug product is not a new drug
are narrowly defined, manufacturers nor the courts can substitute their opinions for that
of the FDA.
a. The plain language of the statute mandates that a manufacturer establish:
i. that the drug product is generally recognized as safe and effective by
qualified experts under the conditions prescribed and
ii. Genuine dispute or unawareness of the drug product among qualified
experts precludes a finding of general recognition
iii. Need substantial evidence of adequate and well controlled investigations
by qualified experts to conclude the effectiveness of the drug and
publication in scientific lit
1. The mere fact that a drug product has been marketed for an
extended period does not preclude a finding of new drug status.
Also need to find SE of the safety and efficacy of the combo, not
just the component.
b. OTC Drugs: with respect to OTC drugs, approval is contingent upon controlled
clinical investigations unless waived on a showing that it is not reasonably
applicable to the drug or essential to the validity of the investigation and an
alternative method of investigation is adequate to substantiate effectiveness
ii. Statute 201 p: Defines new drug
1. If its recognized already as safe and effective....
2. Not GRAS/E, by qualified experts, for labeled use....
a. Doesn't have to go through the approval process if it fills this definition
c. NEW DRUG APPROVAL PROCESS
i. Safety Standard
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1. Section 505 d of the FDCA directs FDA to withhold approval of an NDA unless the
sponsor's evidence shows the drug to be safe by all methods reasonably applicable to
show whether or not such drug is safe for use under the conditions of use
prescribed, recommended or suggested in the proposed labeling
2. Act doesn't say how safety is to be determined
a. Unlike with food, FDA has relatively consistently taken into account a product's
potential benefit
i. But many fairly innocuous new drugs offered for ailments that were not
life-threatening for evaluation without evidence they would do what the
label claimed
3. In evaluating risk, FDA needs
a. Interaction of drug with body processes
b. Manner in which the drug is absorbed and distributed in body
c. Whether active compounds arise from the metabolism of the drug
d. Influence of other chemicals
e. How the activity of drug in animals compares with its activity in man
4. General marketing of a new drug is essentially the final step in testing of a product, since
no clinical investigation could show those kind of results
5. Note that the FDA has a tough job-if it only allows drugs that are "safe" there
would be no drugs!
ii. Effectiveness Standard
1. Section 505 d also specifies that the FDA shall withhold approval of a new drug
unless the sponsor provides substantial evidence that the drug will have the effect it
purports or is represented to have under the conditions of use prescribed,
recommended, or suggested in the proposed labeling
iii. The Test:
1. Substantial evidence is evidence consisting of adequate and well-controlled
investigations including clinical investigations by qualified experts where it can be
fairly and responsibly be concluded by such experts the drugs will have the effects
they purport
2. What are adequate and well controlled studies?
a. Provide the primary basis for determining whether there is substantial evidence
to support effectiveness claims
b. Should provide sufficient details of study design, conduct and analysis:
i. Clear statement of objectives, summary of propose or actual methods of
analysis
ii. Study design that permit a valid comparison with a control to provide a
quantitative assessment of effect
1. Placebo concurrent control (randomization + double blind)
2. Dose comparison control (rando + double blind)
3. No treatment control (rando)
4. Active treatment concurrent control (rando + double blind)
a. Where no placebo or no treatment would be contrary to
patient interests
5. Historical Control-special circumstances only
a. Results of treatment with test drug are compared with
experience historically derived from the adequate
documented natural history of the disease or condition
b. Studies of diseases with high and predictable mortality,
studies in which the effect of the drug is self-evident,
anesthetics
iii. Method of selection of subjects to assure they have disease or condition
studied, or evidence of susceptibility and exposure
iv. Method of assigning patients to treatment and control groups minimizes
bias and is intended to assure comparability of the groups
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v. Min bias on the part of subjects, observers, and analysts
vi. Methods of assessment are well-defined and reliable
vii. Analysis of the results of study adequate to assess effects of drugs
3. What is Substantial Evidence?
a. SUBSTANTIAL EVIDENCE WAS ADDED BY THE SC TO THE DRUG
APPROVAL DEFINITION!
b. Senate Report said that if a drug has been adequately tested by qualified experts
and has been found to have the effect claimed for it, this claim should be
permitted even thought there may be preponderant evidence to the contrary based
upon equally reliable studies
i. Doesn't matter if only a few scientists agree, or docs deny effectiveness,
or won't be effective in other cases
c. FDA usually requires at least 2 studies, but when there is only 1 with a stat sign
at the .005-.001 level that’s ok
d. FDA does not refuse to approve a drug on the ground of relative efficacy, i.e. that
a more effective drug is available
i. But it has disapproved drugs on grounds of relative safety
e. To min bias, FDA has an intent to treat analysis
i. Includes subjects that don't perfectly adhere to their treatments as part of
the study result
ii. Accurately reflects actual populations sometimes, otherwise it can be
misleading if real pops would adhere more
f. Ultimate endpoint of interest is the survival of patient
i. Where that cannot be determined, researchers seek surrogate endpoints
that will demonstrate, at a much earlier stage, whether the drug is
effective
ii. Typically physiological parameters that correlate with the processes of
disease
g. FDA regs permit agency to exempt a drug from requirement of controlled
studies, ie for AZT use in kids with AIDS
h. Usually long term studies are used to study safety, not effectiveness
iv. Balancing Benefit and Risk:
1. Under the 1938 Act, an applicant had to submit sufficient data to demonstrate the safety
of the new drug
2. Requirement was not amended with the Drug Amendments of 1962 that added the
effectiveness requirement so there are two independent and separate requirements
3. FDA chose to make the benefit-risk determination themselves, rather than allow the doc
and patient to do it
a. Denies patients who might rationally want to have available for their own
individualized disease situation, even if the drug might be regarded as unsafe or
ineffective for other patient pops or for the country as a whole
d. GENERAL DRUG APPROVAL
a. Zeneca v. Shalala (2000)
i. Facts: Zeneca manufactures Diprivan, approved by FDA. Gensia Pharmaceuticals manufactured
a generic of the drug, changing the inactive preservative to sulfite. FDA said ok as long as there
was a label warning people with sulfite allergies. Zeneca challenged FDA approval of the generic.
ii. H: Once a drug is approved by the FDA, generic manufacturers can piggy back off the clinical
findings of the first NDA; but still needs to prove to FDA that the generic is bioequivalent, its
active ingredients, route of admin, strength and dosage are the same, and its inactive ingredients
are not unsafe.
1. Most inactive generic ingredients must be same as inactive pioneer ingredients,
differences in preservatives, buffers, or antioxidants are permitted as long as they
do not affect safety of drug. Sulfites are considered safe, FDA allowance of a
warning for people with allergies is not plainly erroneous.
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2. The warning does not violate the regulation generally requiring a generic drug's
labeling to be the same as its pioneer counterpart.
iii. Three Types of Applications For a New Drug (NDA)
1. Application that contains full reports of investigations of safety and effectiveness
(505 b 1)
2. Application that contains full reports of investigations of safety and effectiveness but
where at least some of the info required for approval comes from studies not
conducted by applicant and for which the applicant has not obtained a right of
reference (505 b 2)
a. Permits reliance on studies published in scientific lit to demonstrate safety and
effectiveness of duplicates
i. Can rely on publish lit
ii. Agency's finding of safety and effectiveness for an approved drug
1. Intended to encourage innovation in drug development without
requiring duplicative studies to demonstrate what is already
known about a drug while protecting the patent and exclusivity
rights for the approved drug
b. Can either be an application for
i. New chemical entity (NCE)/New molecular entity (NME)
1. Likely that the data would be derived from published studies
2. If the applicant has all the right of reference to underlying data, it
would be considered a 505 b 1 application
c. Changes to a previously approved drug
i. Should file a 505 b 2 if seeking approval of a change to an approved drug
that would not be permitted under section 505 j, because approval will
require the review of clinical data
3. Application that contains information to show that the proposed product is identical
in active ingredient, dosage form, strength route of admin, labeling, quality,
performance characteristics, and intended use, to a previously approved product
(505 j)
a. Generic drugs, duplicates based on chemistry and bioequivalence data
iv. Glossary
1. Active ingredient (21 CFR 60.3 b 2): any component that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease, or to affect the structure or any function of the body
of man or of animals. The term includes those components that may undergo chemical
change in the manufacture of the drug product and be present in the drug product in a
modified form intended to furnish the specified activity or effect.
2. Active moiety (21 CFR 314.108 a): the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt (including a salt with
hydrogen or coordination bonds), or other noncovalent derivative (such as a complex,
chelate, or clathrate) of the molecule, responsible for the physiological or
pharmacological action of the drug substance.
3. Suitability petition: a citizen petition to Agency seeking permission to file an
abbreviated NDA for a change from a listed drug in dosage form, strength, route of
admin, or active ingredient in a combo product
v. Exclusivities
1. Hatch Waxman Compromise of 1986
a. 5 yr exclusivity "NCE" (new chemical entity)-<20/year
i. Delays the application of an ANDA
ii. What’s an NCE? New active moiety that’s never been approved before,
it’s the part of the active ingredient that causes the drug reaction
b. 3 yr exclusivity
i. Delays approval ANDA
1. New clinical investigation
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2. Pediatric Exclusivity under Section 505 A
a. Delays approval of ANDA, extends other exclusivity by 6 mos AND also
delays patents
b. Normally no incentive to do pediatric data, because docs will still prescribe,
hard to do, hard to get kids, just going to cost money
i. Now you can get exclusivity it leads to pediatric data for docs to help
their decision making
c. Will attach exclusivity and patent protection listed in the Orange Book for any
drug product containing the same active moiety as the drug studied and for which
the party submitting the studies holds the approved new drug application
d. For studies conducted on an unapproved drug, pediatric exclusivity will also
attach to any exclusivity or patent protection that will be listed in the Orange
Book upon approval of that unapproved drug
e. Will attach PA at any time as approved
i. 6 mos of exclusivity, not a patent term extension, but rather extends the
period of time during which the approval of an abbreviated new drug app
may be not made effective by FDA
f. Section 505 A permits certain applications to obtain an additional six months of
exclusivity if, the sponsor submits requested info relating to the use of the active
moiety in the pediatric pop
g. Will qualify if all the following have occurred:
i. Agency issued a Written request for pediatric studies
1. Before the approval of a NDA submitted under 505 b 1 or
2. for an active moiety approved for adults and/or part of the
pediatric population for an approved indication that occurs in the
pediatric pop and appears on the List of Approved Drugs for
Which Additional Pediatric Information May Produce Health
Benefits in the Pediatric Population
ii. Sponsor submitted reports of the requested studies to the NDA after the
Agency made the Written Request
iii. Sponsor submitted studies that responded completely to the Written
Request
e. GENERIC DRUG APPROVAL
f. Abbreviated NDAs
i. Drug Price Competition and Patent Term Restoration Act of 1984 supersede all FDA
action that came before it
1. Under the Act, the FDA may approve an abbreviated NDA for a generic version of a
pioneer new drug after
a. All relevant product and use patents have expired for the pioneer drug
b. All relevant periods of market exclusivity for the pioneer drug have also
expired
ii. In the FDA Modernization Act of 1997, Congress expanded the length of protection granted
pioneer drugs by providing an extra 6 months of market exclusivity at the end of the extended
patent term when the sponsor conducts pediatric testing requested and approved by FDA
iii. Two types of situations where an abbreviated NDA may be submitted
1. Where the generic version is the same as the pioneer version in all material respects
a. Simply submits the abbreviated NDA, and FDA may approve it without
further consideration about the basic safety and effectiveness of the drug
2. Where the generic version is different from the pioneer drug in any significant
respect
a. i.e. Different active ingredients, route of admin, dosage form or strength
b. Then they must first submit to FDA a suitability petition demonstrating that
the difference between the drugs is not sufficient to preclude an abbreviated
NDA and that additional studies to show safety and effectiveness are not
needed
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c. If FDA grants the suitability petition, an abbreviated NDA may be submitted
i. If denied, the applicant must submit either a section 505 b 2 or a full
NDA
3. Unlike a pioneer NDA, which must contain full animal and human data to establish the
safety and effectiveness of the drug, an abbreviated NDA need only contain sufficient
info to demonstrate that the generic is bioavailable and bioequivalent
a. Established three new stat protections for pioneer manufacturers
i. Protection against release safety and effectiveness info
1. Can't be released to public but can be used by FDA to approve
generic
ii. Protection against an abbreviated NDA becoming effective before all
relevant product and use patents for the pioneer drug have expired
1. Can approve it but it won't be effective
iii. Protection against an abbreviated NDA becoming effective during
specific periods of market exclusivity that are independent of the patent
status of pioneer drugs
1. Generics can challenge a product or use patent by submitting an
abbreviated NDA and the necessary details to the FDA
2. Pioneer must respond within 45 days
3. If so FDA is precluded from making the abbreviated NDA
effective for a period of 30 months, if nothing comes of case then
FDA can approve
iv. Bioequivalence
1. Bioequivalence if the rate and extent of absorption of the drug do not show a significant
difference from rate and extent of absorption of the listed drug or if the extent of
absorption does not show significant difference and the different in rate of absorption is
intentional, reflected in the proposed labeling, and medically insignificant
2. The typical test to determine the bioequivalence of a generic drug involves giving oral
doses to 24-36 healthy human volunteers
a. A approval means its bioequivalent
b. B is not and therefore is its not therapeutically equivalent to pioneer
3. Alternative Methods of Demonstrating Bioequivalence
a. In determining whether an active ingredient is the same as a previously approved
active ingredient or is a new active ingredient, the statute refers to the substance
as it is formulated in the drug product and not as it is subsequently metabolized
in the gut
4. Pioneers and their Patents
a. Under the new statute, which amends patent law, the patent for any drug
approved by FDA after the date of enactment is potentially eligible for patent
term extension
i. The decision as to which patent to extend is up to the owner
1. Can't be extended more than once
2. Marketing or use of the product permitted by the reg review must
represent the first permission for that marketing or use
3. May be obtained for the length of the reg review period subject to
three important limits
a. Reg review period is defined as half the human clinical
study time, plus the whole time during which FDA is
reviewing the NDA
b. First under no circs may it exceed five years
c. Second, total effective patent life may not exceed 14
years
d. Reg review period is to be reduced by any amount of
time during which the NDA applicant has not exerted
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due diligence (usual industry practice) in attempting to
obtain FDA approval of NDA
4. In order to obtain patent term restoration, the patent holder must
submit an app to the Patent office within 60 days
v. Other Notes on Pioneers and Generics
1. When a pioneer is withdrawn from marketing by its manufacturer for reasons of safety, it
can no longer be subject to abbreviated NDA
2. First generic only results in 5% reduction in price, second 50%, 6th 25%, can reach 10%
or lower
a. Development of pioneer drug takes 15 years, 1.5 billion; generic 3-5 years at
500k cost
b. Questionable whether pioneer drug industry can sustain current level of research
and development when the average patent life is only 11-12 years
3. First generic to apply for a Paragraph IV cert gets 180 days of market exclusivity for its
generic; extremely valuable
a. When a generic applies, they file a certification
i. There are no patents
ii. Patent has expired
iii. We'll wait for patents to expire
iv. One or more patent is not valid or not infringed (AKA para IV certcreates all the litigation)
b. Pioneers usually submit citizens petition asking FDA to adopt rigorous testing
requirements for a generic applicant to demonstrate bioequivalence
i. FDA usually denied on same day it approves abbreviate NDA, pioneer
usually brings suit for a temp restraining order
c. When two abbreviated NDAs are submitted on the same day, each will share 180
market exclusivity
d. Have to file with FTC and DOJ
4. Biological products are excluded from 505 b2 and j
a. Except HGH, recombinant DNA, and insulin
vi. Key Cases
1. Fed Circ said that patent perm restoration is precluded for a second approved use after the
new drug was initialy approved for another use + allows a manufacturer to test a patent
holder's device or drug to obtain information to support FDA approval of a substitute
product
2. Pioneer drug company sought to prevent a generic competitor from using copyrighted
materials developed for its non prescription drug product subject to NDA
a. Law requires that the generic uses same labeling as pioneer drug even if that use
may infringe a copyright held by the pioneer drug co
b. Pioneer co may not obtain damages
3. Usually when a pioneer is about to lose patent, a common response by the pioneer is to
license it to generic drug co immediately to preserve s much of the market as possible
a. Limits the 180 market exclusivity of other generic firms
4. It is common for pioneer drug manufacturer to seek FDA approval of new indications
through submission of supplemental NDAS
a. Doc may prescribe generic for all its indications, so this makes it useless unless
there is a substantial amount of patent protection time remaining on the original
NDA
5. Patents used to be 17 years, now 20
vii. In 2003, FDA amended its regulations on Orange Book listings and the availability of 30
mo stays on the approval of ANDAs containing paragraph IV certifications
1. Permitted only one 30 mo stay per NDA
2. Prevented the submission of info on patents claiming packaging, intermediates or
metabolites
28
3. Permitted the submission of patents claiming alternate polymorphic forms of the active
ingredient found in the NDA and requires information demonstrating that a drug product
containing the polymorph will perform the same as the drug product in the NDA
4. Amended the patent info required to be submitted to FDA and only those patents
claiming the approved drug product and its approve uses are list in the Orange Book
5. **All designed to reduce what FDA regarded as abuse of the 1984 Act by the pioneer
pharma industry
b. GENERIC DRUG V. GENERIC DRUG
a. MMA Provisions re 180-day Exclusivity
i. Medicare Prescription Drug, Improvement, and Modernization Act of 2003 modified
certain provisions of the Hatch-Waxman Act
1. Significant changes have been made to provisions governing 180 day exclusivity
awarded to each ANDA applicant submitting a paragraph IV certification for the
same drug with regard to any patent on the first day that any ANDA applicant
submits a paragraph IV certification for the same drug
2. 180 day exclusivity period begins on the date of firm commercial marketing of
the drug by any of the first applicants
ii. First applicant may forfeit its exclusivity when
1. Failure of first applicant to market its drug by the later of 2 dates calculated as
follows
a. 75 days after approval or 30 mos after submission of the ANDa,
whichever comes first
b. 75 days after each patent for which the first applicant is qualified for 180
day exclusivity is either
i. the subject of a final court decision holding that the patent is
invalid, not infringed, or unenforceable
ii. withdrawn from listing with FDA
2. Withdrawal of the first applicant's ANDA
3. Amendment or withdrawal by the first applicant of each patent certification for
which the applicant is eligible for exclusivity
4. Failure of the first applicant to obtain tentative approval within 30 mos after the
app is filed unless failure is caused by a change in or a review of requests for
approval
5. An agreement between first app and ND holder, the patent owner, or another
ANDA applicant that is determined to violate antitrust laws or section 5 of FTC
Act
6. Expiration of all the patents for which the applicant is eligible for exclusivity
b. Teva v. Sebelius (DDC 2010)
i. Background
1. Filing paragraph IV cert comes with a risk, it constitutes an act of patent
infringement, with the hazard of sparking costly litigation
2. In order to compensate generic manufacturers for the list right, the statute
provides that the first company to file an ANDA containing a paragraph IV cert
earns an exclusivity period of 180 days, during which the FDA may not approve
for sale any competing generic version of the drug at issue
3. Potential bug in the system is the ability of a brand manufacturer, after a generic
has filed a para IV cert, to announce that the challenged patent is not one that
protects the drug at issue and ask the FDA to delist the patent
4. In Ranbaxy, we considered whether the FDA may delist a patent upon the request
of the brand manufacturer after a generic manufacturer has filed an ANDA
containing a paragraph IV cert so that the effect of delisting is to deprive the
applicant of a period of marketing exclusivity
a. We said no, since it is inconsistent with the structure of the statute
b. FDA ruled that the 2003 MMA amendments required a different
outcome from the one Ranbaxy ordered under the old version of the law
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ii. Facts: Teva filed the NDAs at issue in this case with paragraph IV certs targeting
Merck's patent. Merck didn't sue for patent infringement, but instead asked FDA to delist.
iii. H: The argument that the plain language of the stature imposes no limit on the circs in
which the agency many effectuate delisting requests fails. We see nothing in the 2003
amendments to the FDCA that changes the structure of the statute such that brand
companies should be newly able to delist challenged patents, thereby triggering a
forfeiture event that deprives generic companies of the period of marketing exclusivity
they otherwise deserve. For that reason the interpretation of the statute that the FDA has
adopted fails at Chevron step one.
1. Apotex v. Sebelius (Civil Action, DC DC 2010)
1. FDA informed the Court that it had learned that the Merck '075 patent had actually expired prior
to the filing of Teva's lawsuit, due to Merck's failure to pay maintenance fees to the US Patent
and Trademark Office after it delisted the patent.
1. FDA argued that patent expiration is another and separate basis on which, under the Act,
it might be found that Teva had forfeited marketing exclusivity.
2. FDA urged the Court to withhold its remedy order for Teva until after FDA decided the
question of statutory interpretation
3. However, because Teva had persuaded the circuit to expedite its appeal and the mandate,
in light of the anticipated expiration of the lack Merck patent
2. FDA issued a letter to ANDA applicants and notified them that, while it disagreed with the
Circuit opinion, it had applied the Circuit's reasoning to answer no to the question of whether a
brand name drug manufacturer could unilaterally cause its patent to expire and thus force a
forfeiture of a first ANDA applicant's right to marketing exclusivity for 180 days
3. Therefore, FDA announced it would not prevent the first ANDA applicant, Teva, from enjoying
its 180-day marketing exclusivity for its generic losartan drugs, and would not approve any other
ANDA application during that time period
2. FTC: Pay for Delay in the Pharma Industry
1. Consumers lose when branded drugmakers use illegal tactics to keep generic alternatives off the
market
2. FTC sues drug companies that pay off the makers of competing drugs not to bring their products
to market
3. Loophole in current law allows for generics to be blocked; also supports leg to end such pay for
delay settlements
4. Costs consumers 3.5 billion per year
1. Hurt competition and consumers right to choose a cheaper alternative form of
medication
2. 17 mos longer to get generics on the market then when no pay for delay payment [could
be up to 48 mos]
3. Generic can reduce the price of a branded drug by up to 90%
4. Share their illegally obtained monopoly revenues
5. Under the Medicare Modernization Act, drug companies are required to report certain court
settlements to the FTC, which issues a report on these settlements each year
6. Ending this will also reap significant savings for the federal gov't which pays approximately 1/3
of all script drug costs
1. Approx $12 billion in savings
7. Most agreements still in effect, protect at least $20 billion in sales of brand name pharma
2. EXPEDITED DEVELOPMENT OF LIFESAVING DRUGS
1. Faced with the Aids epidemic, FDA promulgated an interim regulation to establish an official policy on
expedited development of new drugs for life-threatening and severely debilitating diseases
2. Investigational New Drug, Antibiotic and Biological Drug Product Regs: Procedures for New Drugs
Intended to Treat Life-Threatening and Severely Debilitating Illnesses
1. Expedite development of drugs intended to treat these types of illnesses, especially where no
satisfactory alternatives exist
2. Applies to new drugs, antibiotics, and biological products that are being studied for their safety
and effectiveness
30
1. Life-threatening means likelihood of death is high unless course of disease is interrupted
and diseases or conditions with potentially fatal outcomes where the endpoint of clinical
trial analysis is survival (increased survival in heart attack patients)
2. Severely debilitating means diseases or conditions that cause major irreversible morbidity
3. Key component is early consultation with the FDA to seek agreement on the design of necessary
preclinical and clinical studies needed to gain marketing approval
1. Seek agreement after phase 1 testing on proper design of phase 2 testing to be adequate to
provide sufficient data on the product's safety and effectiveness
2. After phase 1, they submit treatment protocol for phase 2
3. After phase 2, FDA evaluates the data using a medical risk-benefit analysis; taking into
account the severity of the disease and the absence of satisfactory alternative therapy
4. May also seek agreement from sponsor for phase 4 post-marketing studies to delineate
additional info about drug benefits, risks, and optimal use
3. FAST TRACK
1. As part of FDA Modernization Act of 1997, Congress added section 506 to FDCA codifying the fast
track program
1. Benefit is that the FDA will accept a continuous marketing application under which reviewable
units of an NDA may be submitted before the full NDA is prepared
2. Frequent scientific feedback and interactions between FDA and applicant
2. Facilitates expedited development during the IND phase of a new drug
3. Provides the opportunity to submit what is often called a rolling NDA
4. Fast track program is open to any drug that is intended to address an unmet medical need
1. Only if available treatments are unapproved use of approve drugs or are approved under the
accelerated approval program in Subpart H
5. Only applies to specific indication of specific drug for serious, life threatening condition
1. Similar to priority review, infra
6. Drugs for Serious or Life Threatening Conditions
1. Sometimes were going to work with you and consolidate phase 2 and phase 3
2. In terms of risk benefit, were going to consider severity of disease, absence of alternatives, need
to address less safety issues since people are going to die anyway, maybe look at phase 4 testing
3. Usually want 2 studies for replication of results...maybe here they are ok with 1
4. Came up with FAST TRACK
4. CLINICAL TESTING CONDUCTED OVERSEAS
1. May be used in clinical trials abroad when
1. If the drug is manufactured abroad or for a US company, it is not subject to the FDCA and must
meet only the foreign country requirements
2. If the drug is manufactured in US, it may be exported under Section 802 c of the FDCA, to any
countries listed without need to comply with any of the US investigational drug provisions
2. FDA made it clear that there would be no discrimination against foreign clinical trials submitted to
support NDAs as long as the trails were conducted under the ethical standards of the Declaration of
Helinski
3. A lot of pharma moved trials to US, less regs + easier to get participants=costs less
1. Some people question safety of human subjects and quality of trials
5. USE OF INVESTIGATIONAL DRUGS FOR THERAPY
1. It was never intended to authorize the use of investigational drugs for treatment of ill patients outside a
clinical trial, but has been widely used to do so
2. FDA has taken the position that an unapproved new drug may not lawfully be commercialized prior to
approval
1. Agency's regulations specified that investigational drugs were solely to be made available for
clinical trials
1. INDs could be terminated if FDA found applicants had sold or distributed drugs for
commercial purposes beyond the trial
3. FDA discarded the rule that an investigational drug could not be used for treatment purposes when new
drugs began to be developed to treat serious diseases for which no alt existed AKA expanded access
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4. New FDA proposal contained new sections on treatment use (later promulgated into final detailed rule for
AIDS patients) and emergency use
5. Individual Patient Aid
1. FDA has long granted single patient exceptions to allow the use of investigational drugs outside
protocols of the approved IND
2. Agency can disallow a single patient exception for any investigational drug (Smith v. Shalala)
3. Anyone can ask a drug sponsor for access to investigational drug if there is no satisfactory alt
therapy available, there is sufficient evidence of safety and effectiveness, FDA determines that
provision of the drug won't interfere with clinical investigations, and sponsor submits a clinical
protocol consistent with INC regulations
6. Emergency Use Aid
1. FDA may authorize shipment of investigational drugs or devices for treatment of serious disease
or condition in emergency situations
2. Exempt from prior IRB approval and sometimes informed consent
3. Congress okayed for declared domestic, military, or national security emergency
7. Treatment IND
1. Another component of 1997 Act authorizes the use of an investigational drug under a treatment
protocol for the treatment of a serious or immediately life threatening disease or conditions
2. Sponsor can charge if not being commercially promoted or advertised and the sponsor of the drug
is actively pursuing marketing approval with due diligence
3. Can't charge more than to recover your costs BUT CMS and 3d party payors don't pay, so rare
4. Some people want drugs offered even earlier, before shown to be safe and effective at all
1. This has led to bad results in underground studies because it helps in short run, ie for
AIDS patients, but not in long-run
8. Parallel Track IND
1. Permits the use of investigational drugs by people with AIDS and HIV who are both unable to
benefit from existing standard therapies and unable to participate in clinical studies
2. Starts after Phase II clinical trials, must comply with FDA protocols
9. Group C Cancer Treatment IND
1. Most promising investigational drugs, called Group C drugs, are used to treat patients by
qualified docs
2. Appear in a Master File submitted to FDA
1. Includes only drugs likely to obtain NDA approval
3. Eligible for Medicare reimbursement
4. Not charged for drugs
10. Open Label IND
1. Never been codified; two types:
1. Placebo controlled clinical trial is completed and there is no formal follow-up as a part of
the protocol, it is common to continue the treatment arm and switch the placebo arm to
treatment under an open label protocol
2. An open label protocol is used under a variety of other circumstances for the treatment of
ill patients
11. Compassionate Use IND
1. Broad and undefined term
2. Applies to situations in which the use of an investigational new drug for patient therapy does not
fall within any other specific expanded access IND program
3. FDA has taken liberal and flexible approach, as long as prelim data that new drug is effective
12. Orphan Drug IND
1. Orphan drugs are drugs for rare diseases or conditions, and seldom proceed from an IND to an
approved NDA
1. Too few patients to satisfy testing requirements
2. Market for new drugs too small to justify investment
2. Regulated under continuing IND status that FDA and sponsor agree will be perm, still around
13. Tropical Drug IND
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1. FDA has long permitted drugs for tropical diseases to be subject of clinical US trial, there are
rarely approved NDAs
2. IND assumed permanent
3. However, now more people travel so reasoning for not approving INDs is disappearing
14. Special Exception IND
1. When an individual is ineligible to enroll in a clinical trial of an investigational drug, the sponsor
may request that FDA permit a special exception from the IND protocol to permit the excluded
individual to receive treatment
2. Excluded from reported study results
15. Constitutional Right to Expanded Access
1. Small companies can't afford to provide free drugs to terminally ill patients, yet demand is so
great
2. FDA Act of 1997 says any person acting through a doc may obtain an investigational drug from
the sponsor if all the requirements of an individual patient IND are met....which says you can't
charge
3. Thus if you have to charge you need a full written explanation of why you are charging; needs of
desperately ill patients are not considered
16. Abigail Alliance for Better Access to Developmental Drugs v. Von Eschenbach
1. Facts: AA seeks to enjoin FDA from barring the sale of new drugs that the FDA has determined
after Phase 1 to be safe and effective for expanded human testing. Says that policy violates due
process rights to privacy, liberty, and life of terminally ill members.
2. H: Gov't has not blocked access to new drugs throughout the greater part of Nation's history. If
you have a due process right to refuse life sustaining medical treatment, you should have the right
to access the medication where no alt gov't approved treatment exists. Gov't shouldn't interfere.
3. Follow Up:
1. This was appealed, Court of Appeals said the opposite and overturned the decision
2. Doesn't believe there was a fundamental constitutional right
3. It may just be what's better for greater man, by having more studies and figure out the
answers, rather than help one person
1. Societal imperative v. imperative for the individual
17. Comment: Future of FDA Personal Import Policy
1. Personal import-bringing in drugs from other country yourself, ie Canada
2. FDA thinks the Personal Import Policy should be drastically reduced or eliminated; especially in
light of drastic price differences in other countries
3. HHS has resisted this change however-compromised with Canada, allowing ppl to bring in 90
day supply of any drug except controlled substance or a biological product
18. Clinical Trials Databank
1. FDA began publishing a list of all AIDS drugs in clinical trial under an IND
2. NIH established a databank of information on clinical trials for drugs for serious or lifethreatening diseases and conditions
3. But no enforcement remedies for noncompliance so not a great success
1. Some journals say they won't allow for studies to be published unless data in a bank
2. Some companies have their own databanks
4. NY sued GSK for fraud for withholding data from clinical trials showing that Paxil was no
more effective than a placebo in teens, selectively publishing favorable data, making
inconsistent promotional claims
1. Settled with a 2.5 m fee + an online registry with summary of results
6. ORPHAN DRUGS
1. The requirements for approval of a new drug present special obstacles for the development of drugs
intended to treat rare diseases whose potential sales are not large enough to justify funding the tests
2. For many years FDA kept several such drugs indefinitely on orphan IND, allowing them to be used for
patient treatment
3. Congress enacted the Orphan drug Act to provide incentives
1. Tax credits for expenditures for clinical testing
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2. Added new section to FDCA like easier approval by FDA, and 7 years of post approval market
exclusivity for unpatentable orphan drugs
3. Also defined rare disease or condition as one that affects >200,000 persons in US-->greatly
expanded number of diseases that could be regarded as rare, and thus be considered orphan drugs
4. Pharma began to compete to become the first to obtain FDA approval of NDAs for lucrative orphan dru
5. In 24 years since this law was passed, 282 orphan drugs and biological products providing treatment for
more than 14 m patients in US have come to market
1. Go through same development process and must be show to be as safe and effective
2. May be even more so because of the small number of patients to test
6. Genetech Inc v. Bowen
1. Facts: Genetech, who makes HGH from recombinant DNA technology, alleges that the recent
decision of the FDA to approve a recombinant DNA HGH product manufactured by Eli Lilly
violated the APA, Orphan Drug Act, and 5th Amendment. FDA designated Genetch’s drug as an
orphan drug in 1985, granting it 7 years market exclusivity. One year later FDA designated an rHgH drug developed by Eli Lilly as an orphan drug for treatment of HGH deficiency which is
similar without an extra amino acid.
2. H: Without Eli Lilly’s drug, methionyl-free HGH wouldn't be available in this country. They are
different so FDA ok to allow Lilly designation.
7. BIOTECHNOLOGY DRUGS
1. Recombinant DNA tech and other forms of biotech have played sign roles in pharmaceutical research and
development
2. Explosive industry, 2k small companies
3. Believed that they could skip expensive NDA process, and target only drugs with high chance of success
1. Also believed FDA would help them out
2. They have been disappointed-FDA treats them no differently and costs are largely the same
4. Since the first biotech company went public 25 years ago, stock market investors have put close to 100 b
into the industry
1. But lost more than 40b....but still a good investment
1. Home runs are scarce but can be lucrative
5. Many thought since biotech drugs are often versions of the body's own proteins, the thinking was that
they would sail through safety tests- not the case
8. Priority Review
1. FDA has always regularly accorded expedited consideration to applications for important new medicine
2. Created a complex matrix to classify NDAs according to chemical type and therapeutic potential to
determine their priority for review
1. CDER Manual of Policies and Procedures 6020.3, Priority Review Policy
1. NDA classification system provides a way of describing drug apps upon initial receipt
and throughout the review process and prioritizing their review
1. Definitions
1. Designations Priority and Standard are mutually exclusive
2. Both original NDAS and effectiveness supplements receive a review
priority classification but manufacturing supplements do not
2. Priority Review
1. The drug product, if approved, would be a significant improvement compared to
marketed products in the treatment, diagnosis, or prevention of a disease
2. Can be demonstrated by increased effectiveness demonstrated, elimination or
substantial reduction of treatment limiting drug reaction, documented
enhancement of a patient compliance, or evidence of safety and effectiveness of a
new subpopulation
3. Standard Review: all non priority applications
3. Policy
1. Review priority classification should be determined and assigned at the 45 day
meeting if the app is to be filed
2. Final review classification of a new drug may change from P to S during course
of review of marketing app
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3. Will not change during first review cycle and user fee time frame of the original
review cycle will be that based on the original priority
4. Review priority classification determines the overall approach to setting review
priorities and use fee review time frames but is not intended to preclude work on
other projects
2. Accelerated Approval-Subpart H
1. In 1992, FDA promulgated regulations establishing two forms of accelerated approval of
an NDA
1. Approval based on evidence of the drugs effect on a surrogate endpoint that
reasonably suggests clinical benefit or on evidence of the drug's effect on a
clinical endpoint other than survival or irreversible morbidity
2. Approval of an effective drug that can be used safely only if distribution or use is
modified or restricted
2. In both situations, approval is determined by FDA to meet the requirements for safety
and effectiveness and thus is a full NDA approval under section 505 of FDCA
3. Approval Based on a Surrogate Endpoint
1. FDA has for many years approved NDAs based on validated surrogate endpoints
2. Accelerated approval, is based upon an invalidated surrogate endpoint that
nonetheless is reasonably likely to predict clinical benefit or on the basis of an
effect on a clinical endpoint
3. NDA approval will therefore be subject to the requirement of further clinical trial
to verify clinical benefit, when there is uncertainty as to the relation of the
surrogate endpoint to clinical benefit or of the observed clinical benefit to
ultimate outcome
4. Accelerated Approval of Oncology Products
1. Accelerated approval allows for approval of drugs for serious or life threatening
diseases if the drug appears to provide a benefit over available therapy and the
benefit is determined by the drug's effect on a surrogate endpoint that is
reasonably likely to predict clinical benefit or on evidence of an effect on a
clinical benefit other than survival
2. Effect on survival, relief of patient symptoms, objective response rates, time to
progression all been accepted as evidence of clinical benefits
3. Allows for 18 cancer products to get on the market fast
5. Approval Conditioned on Restricted Distribution
1. Second provision in Subpart H authorizes FDA to approve an effective drug than
can be used safely only if distribution or use is modified or restricted
2. FDA has no authority under FDCA to restrict distribution as a condition of NDA
approval, can only be invoked at the request of the NDA applicant
3. FDA has approved fewer than 10 drugs with restricted distribution programs
under subpart H
11. SPECIAL CLASSES OF DRUGS
a. OTC DRUGS
i. BACKGROUND
1. Script and OTC drugs are MUTUALLY EXCLUSIVE
a. Can't have the same drug marketed both ways
2. Set up about 30 panels, took them a few years
a. Decided to do it via regulation, vs case by case
3. Three categories
a. Safe and effective
b. Not safe or ineffective
c. Not certain
4. Now we have monographs for OTC drugs based on type of drug and ingredients listed
that are S and E
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a. If you have one of those ingredients and you use what are known as safe and
suitable inactive ingredients, you meet the CFR monographs
5. What do you need to show the FDA?
a. Needs to be for a condition that a consumer would be able to self diagnosis
i. That's why the box says if symptoms persist, go see a doc
6. If you are going to go generic because your patent is coming to an end...what do you
want to do?
a. GO OTC, you need to match the labeling except you can't because you get three
years of exclusivity to build brand SO no generics
b. Not the same money as a script, but its still a huge market
c. Plus you have brand recognition
d. Complicated strategy, some are not willing to do it OR can't
i. There was once an issue where they switched thinking they’d get 3 yrs
exclusivity BUT then FDA approved 6 OTCs-WHOOPS
7. INSURANCE COMPANIES ARE THE ONES THAT PUSH FOR OTC v. scripts-they
don't want to pay
ii. From the enactment of the 1938 Act, the FDA has drawn clear distinction between prescription
and non prescription drugs-ok OTC drugs
iii. OTC Drug Review
1. Prior to 1972, no country had ever attempted to conduct a systematic review of OTC
drugs or to establish a comprehensive regulatory program for these products
2. FDA realized it would be too difficult to go case by case to determine the safety and
effectiveness of every OTC drug
3. Proposed a rule making procedures for OTC classification
a. There are between 100k-500k OTC drugs, few have been approved through 505
new drug procedures
b. Some are excluded from the new drug definition because of the 1938 or 1962
grandfather clauses
i. Even exempt drugs, however, cannot be misbranded
c. FDA intends to require all unapproved new drugs and misbranded drugs either be
reformulated or relabeled to meet all requirements of act or be removed from
market
d. Decided on rulemaking because
i. Limited resources, litigation would be exhausting, inadequate consumer
protection produced by product-by-product review and litigation,
impossible to go after all manufacturers of similar drugs at same time
ii. Also, practically all OTC drugs are compounded from 200 active
ingredients
1. Thus they are the same or essentially the same
e. Thus FDA Commissioner seeks to create a rule that classifies OTC drugs as
GRAS and not misbranded under prescribed, recommended, or suggested
conditions of use
4. FDA received comments about their procedures and responded
a. Drug must be GRASE, not just safe and effective or would require a NDA
b. Necessary for studies to prove safety and effectiveness, unless there is a waiver
showing studies are unnecessary or inappropriate
c. May be that a drug is GRASE but has certain side effects that make it better for
scripts
d. FDA will not allow drugs that don’t meet these regulations to stay on the market
e. They have the power to make regulations under the act instead of using
adjudication
i. Fulfills APA and due process requirements
b. The OTC Rule
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i. Advisory Review Panel will be appointed by Commissioner, with input from manufacturers, to
evaluate safety and effectiveness of OTC drugs and labels and advice him on promulgation of
monographs establishing conditions under which OTC drugs are GRASE and not misbranded
1. The panel will review the data submitted to it and prepare a report with conclusions and
recommendations
a. Interested parties may request oral hearing, but panel can deny
b. Can submitted written materials
2. Standards
a. Safety means a low incidence of adverse reactions or significant side effects
under adequate directions for use and warnings against unsafe use as well as
low potential for harm which may result from abuse with widespread
availability
i. Proof of safety shall consist of adequate tests by methods reasonably
applicable to show the drug is safe under conditions of use
ii. Needs results of human experienced
iii. Can incorporate unpublished studies and other data
b. Effectiveness means a reasonably expectation that, in a sign proportion of
target pop, the pharmacological effect of the drug, when used under
adequate directions for use and warning against unsafe use, will provide
clinically significant relief of the type claimed
i. Shall consist of controlled clinical investigations, unless waived
c. Benefit to risk ratio of a drug shall be considered in determining safety and
effectiveness
d. OTC drug may combine two or more S and E ingredients and may be GRAS/E
when each active ingredient make a contribution to the claimed effect, when
combining doesn’t decrease the effect, and when the combination provides
rational concurrent therapy for target pop
ii. Panel Report
1. Recommends monograph covering the category of OTC drugs and establishing
conditions under which the drugs involved are GRASE and not misbranded
2. Statement of active ingredients, labeling claims, etc that are excluded from the
monograph since they would lead to drug not GRAS
iii. Commissioner must then publish in FR
1. Monograph, statement of conditions for those excluded because not GRASE or not
enough info, full report of panel
2. Then receives comments, and after reviewing all objections, and considering any
arguments made at any oral hearing, commissioner published a final order in FR
a. Appealable only by court
iv. FDA didn’t devote enforcement resources except
1. When an OTC drug would pose a significant health hazard or was likely to defraud
consumers
2. Not hesitate to deal with ingredient found to be health hazardous
v. Marketing of OTC drugs may begin before promulgation of a final monograph if it meets
requirements and Commissioner provides notice of that determination in FR
1. Panels are very flexible
2. Although a large number of important drugs have been switches from script to OTC
status through the NDA process, very few have been switched from NDA to monograph
status
3. Can’t mail OTC drugs unless there is child-resistant packaging
c. OTC Drug Time and Extent App
i. In 2002, FDA promulgated regulations establishing a new mechanism for adding foreign
ingredients to OTC drug monographs
1. Did so in response to 1983 FMALI Herb decisions, which held that marketing experience
abroad must be considered in determining whether a food is a food additive and in
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f.
recognition of the fact that there are safe and effective OTC drug ingredients that have
been marketed abroad for decades
ii. Under section 201 p2, a drug is a new drug even if it is generally recognized as safe and effective
based on scientific investigations if it has not been used to a material extent or for a material time
1. Thus the app under the new procedure is called a time and extent app or TEA
2. Info that must be included is voluminous and complex, at least 10 companies have done it
was some success
d. FDA Letter re Plan B
i. The resubmitted NDA provides for switch from Rx only statute to OTC status for women ages
16+
1. Plan B would remain Rx for women younger
ii. In addition you have proposed that both the Rx and OTC versions be marketed in a single
package
iii. CDER concluded safe for OTC for women 17+ but there are some other issues related to the
NDA
iv. Three difficult and novel issues
1. Whether can be marketed in same package
2. Whether a drug can be both Rx and OTC depending on age of patient and how to enforce
it
v. Decided to seek public comment to codify this interpretation-cannot legally market drug as OTC
at this time
e. Sebelius Letter re Plan B
i. Teva submitted a supp NDA for Plan B, to market it as OTC without any age restriction
ii. I have concluded that the data submitted for this product does not establish that script dispensing
requirements should be eliminated for all ages
iii. There are different cognitive and behavioral difference between older girls and the youngest girls
of reproductive age which are relevant
iv. I instruct the FDA to respond saying there is not sufficient evidence that the script should be
removed for all ages
BIOLOGICS
i. Background
1. Regulated under 262 Public Health Services Act, NOT FDCA
2. Used to have to have 2 licenses: biologics product license and establishment license-for
the facility!!
3. Now just one license: Biologics License App
a. Similar to NDA but different standards
4. Biosimilar Generics
a. So difficult to get a biologic that’s the same!!
b. Ended up coming up with the term biosimilar
i. It’s not the same as generics for regular drugs, it’s more of a "close
enough"
1. Close enough that we can rely on the S and E studies done by
pioneer, similar to Hatch-Waxman, when approving the
biosimilar
1. You are going to need to prove to this that you are
biosimilar, we are going to put out standards for this, we
also don't want to deal with the patents so we need to
come up with a way to do that
2. Wanted a better process than the drug generics
1. Didn't want to link patents to the approval process
2. Entirely different regime...no idea if it’ll work or not since nothings been
approved!!
3. How it works
1. Can file after 4 years, but can't be approved for 12
1. Leaves lots of time to litigate
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2. They go and ask pioneer how many patents they have
1. Then two sides agree on which patents they are going to
fight over (he doesn't know why they would ever agree)
2. If they can't agree, then pioneer can pick one and they
fight over that one
3. The other patents can't be argued until after there is
approval
3. PATENTS
1. Strong patents that cover composition of matter for REG DRUGS
1. No way to replicate the composition of matter patent WITHOUT
patent infringement
2. Biologic patents are much weaker-you can change some things and it’ll
be biosimilar!!
1. Still no generics right now, these companies have a forever
situation
2. They want some protection like the Hatch-Waxman great
compromise
3. Europe passes a biosimilar law
1. Gives 10 years exclusivity to pioneer
2. US debates the subject all over the place
3. Ended up with 12 years-eliminates a lot of patent fights
ii. 1972 GAO Report caused the regulation of biologics to move from DBS to FDA
iii. Licensing of Biological Products
1. No person shall introduce bio prod to IC unless
a. License in effect
i. Sec shall approve a license app on the basis that the product is
demonstrated to be safe, pure and potent and the facility where it is made
assures that the produce continues to be safe, pure and potent
b. If the applicant consents to the inspection of the facility
i. Sec shall prescribe requirements under which a biological product
undergoing investigation shall be exempt from the requirements of
paragraph 1
2. Biologics product means virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component, or derivative, allergenic product, or analogous product, or arsphenamine or
derivative or arspheanimine applicable to the prevent, treatment, or cure of a disease or
condition of human beings
a. FDCA still applies except 505
iv. Procedures for Review of Safety, Effectiveness, and Labeling of Biologics
1. Proposal will establish a procedure under which the S, E and labeling of all biological
products presently licensed under 351 of PHSA will be reviewed
2. Advisory review panels comprised of independent experts will provide conclusions and
recommendations to Commissioner of FDA who will review and implement them
3. FDA is aware of unique problem of proving substantial evidence of effectiveness to
biological products
a. Where adequate and well controlled studies are not feasible, and acceptable
alternative scientific methods of demonstrating effectiveness are available, the
latter is sufficient
b. Panels will initially develop the standards, subject to review by Commissioners
v. Generic Biologics
1. As therapies produced through genetic engineering approach the end of their patent
protection, interest has focused on the question whether Hatch-Waxman applies to
biologics AKA whether ANDAs can be approved for copies of biologic drugs
2. FDA wanted there to be one but nothing in the statute-unsure if they have the authority
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3. Traditional pharma is made up of small molecules, created through chemistry while
biologics are made up of proteins and glycoproteins made by biology
a. The biologic activity of an end product is largely dependent on the process used
to create that product-difficult to replicate
4. Leg intent showed that ANDAs were not supposed to apply to biologics
5. So what can the FDA do instead
a. Current capability of science and tech in relation to biologics is not sufficient to
determine the bioequivalence and pharmacologic equivalences of biologics
without extensive clinical testing
b. FDA instead presumes that drugs are the same if they have the same principal
molecular structure
i. Broad and arbitrary terms
ii. Makes a presumption of sameness between any two proteins that have
the same amino acid sequence
iii. To rebut this, one must show a clinical difference between or superiority
of the new biological drug and the one first to market
c. Difficult to replicate the manufacturing process of the pioneer, patent law doesn’t
require disclosure
d. Also costly and time-consuming-not really worth the investment
vi. Current Biosimilars Law
1. Biologics Price Competition and Innovation Act was passed by Congress in 2010 and
amended the PHSA to create an abbreviate approval pathway to follow-on biologics
2. Available for biosimilar products, aka those that are highly similar to biologics that have
been approved in biologic license applications under the PHSA notwithstanding minor
difference in clinically inactive components
3. Differs slightly from the ANDA process for drugs
a. The BPCIA provides a new type of application and new standards for approving
biologics based on either “biosimilarity” or interchangeability
i. Biosimilarity requires that that there be no “clinically meaningful
differences” between the biosimilar and reference products
1. Biosimilar to the ref product, sameness of strength, dose, admin,
mechanism of action, approval of ref product for indication
proposed, appropriate manufacturing facilitates
2. Based on demonstration using animal studies for toxicity, clinical
studies for safety, purity and potency for one or more appropriate
conditions of use for which licensure is sought and for which the
ref product is licensed unless FDA waives a requirement
3. Interchangeability requires a specific determination regarding the
effects of switching a patient from one product to another in
multiple-dose therapy
a. Will yield the same clinical result as the reference
product in any given patient
b. Must be substituted for the reference product without
intervention of a health care provider
b. Now also applies to proteins, which used to be covered under 505 of the FDCA
i. Grandfathered exception for biologics approved under 505, i.e. hormones
and insulin until March 2020
4. The new law provides an exclusivity protection to the first biosimilar product determined
by FDA to be “interchangeable” with the approved reference product, which delays
determinations of interchangeability between the reference product and other biosimilar
products.
a. The BPCIA provides two distinct exclusivity protections for reference products
that differ significantly from the exclusivity protections afforded to reference
drugs under the Hatch-Waxman scheme in section 505 of the FDCA
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i. The BPCIA first delays submission of a biosimilar application until four
years after the “date on which the reference product was first licensed.”
ii. The BCPIA then delays final (effective) approval of a biosimilar
application until twelve years after the first licensure of the reference
product.
iii. The first-licensure requirement precludes an additional period of
exclusivity for a supplement to the original application for the reference
product.
1. It also precludes exclusivity for an entirely new BLA in certain
circumstances. A new BLA submitted by a sponsor or
manufacturer of a previously approved biologic would not be
protected by exclusivity for (1) a non-structural change that
results in a new indication, route of administration, dosing
schedule, dosage form, delivery system, delivery device, or
strength or (2) a structural change that does not result in a change
in safety, purity, or potency.
2. As in the case of new drug applications approved under
section 505 of the FDCA, BLAs may be entitled to pediatric to
extend exclusivities by six months.
b. The BPCIA also provides exclusivity protections to reference products.
Biosimilar applications cannot be submitted until four years after approval of the
original application for the reference product and cannot be granted an effective
approval until twelve years after the original approval date.
5. A fourth key element of the biosimilar approval scheme is a mechanism for exchanging
patent information and litigating patents prior to approval of the biosimilar application
a. The process commences with the biosimilar applicant providing the reference
product sponsor with a copy of its application and information concerning its
manufacturing process within 20 days after FDA notifies the applicant that its
application has been accepted for review
i. The parties then go through a process of exchanging information on
patents that may be infringed by the biosimilar product
b. After exchanging this information, the parties must engage in good faith
negotiations to identify patents that will be litigated pursuant to an expedited
litigation procedure.
i. If the parties do not agree within 15 days, each must provide the other
with a list of patents it believes should be asserted.
ii. Although the biosimilar applicant may list as many patents as it wishes
for this expedited litigation, the reference product sponsor is restricted to
the number of patents listed by the biosimilar
c. Once there is agreement or the lists are exchanged, the reference product sponsor
must bring an infringement suit on all of the agreed upon or listed patents within
30 days. If the suit is not brought within this timeframe, relief in any
subsequently brought lawsuit will be limited to recovery of a reasonable royalty.
d. The PHSA provides the reference product sponsor with an opportunity to seek a
preliminary injunction with regard to other patents prior to the launch of the
biosimilar
i. The biosimilar applicant must provide notice to the reference product
sponsor 180 days before launching its product
g. COMPOUNDED DRUGS
i. Drug compounding is the process by which a pharmacist combines or alters drug ingredients
according to a doc script to create a med to meet the unique needs of an individual human or
animal patient
1. Usually for ppl allergic to certain things, ppl with cancer, kids, hospice care and
intravenous admixtures
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ii. Pharmacies have long compounded drugs before there were drug manufacturers, who didn’t
emerge until later half of 19th century
iii. Compounding still occurs today in pharmacies
1. Nothing excludes pharmacies from doing this in the FDCA
2. Have long been exempted from drug establishment regulation, but everything else applies
as long as the pharmacies does not manufacture, prepare, propagate, compound or
process drugs for sale other than in their regular course of business of dispensing or
selling drugs at retail
iv. Concerned with rogue pharmacies, FDA initially brought enforcement action and then issue
Compliance Policy Guide No 7132.16 which stated that lawful compounding consisted only of
filling an individual script as received
1. If a compounding pharmacy prepared a bulk quantity in anticipation of scripts, that drug
became an illegal new drug
v. When Congress was passing the FDA Modernization Act of 1997, pharmacies sought to obtain
explicit statutory recognition of compounding
1. The applicable provision was struck down by Western States case as violation of
1st amendment (about advertising)
2. Courts split about whether the phrase that was struck down is severable from the rest of
the act, if not the whole thing would be unconstitutional
vi. After the Western States case, the FDA issued a new CPG to replace the old one
1. CPG 460.200: Pharmacy Compounding (2002)
a. Under Section 503a of the FDCA, drug products that were compounded by a
pharmacist or doc on customized basis for an individual patient were entitled to
exemptions from
i. Adulteration provision
ii. Misbranding provision
iii. New drug provision of section 505
b. In order to exemptions to apply, there were a number of requirements
i. FDA believes SC decisions in Western State makes all of 503A invalid
ii. Traditional compounding still okay, this applies to activities outside the
bounds of the act
c. FDA will seriously consider enforcement action when
i. Compounding drugs in anticipation of receiving scripts, except in limited
quantities
ii. Compounding drugs that are withdrawn or removed from the market for
safety reasons
iii. Compounding finished drugs from bulk active ingredients that are not
components of FDA approved drugs without an FDA sanctioned IND
iv. Receiving , storing or using drug substances without first obtaining
written assurance from the supplies that each lot of the drug has been
made in an FDA registered facility
v. R, S, or U drug components not guaranteed or otherwise determined to
meet official compendia requirements
vi. Using commercial scale manufacturing or testing equipment for
compounding drug product
vii. Compounding drugs for 3d parties who resell
viii. Compounding drug products commercially available or essentially the
same
ix. Failing to operate in conformance with state pharma laws
vii. Med. Center Pharmacy v. Gonzales (2008)
1. Issue: the extent to which the FDCA permits the FDA to regulate compounding
2. Facts: For about 50 years after the FDCA enactment, the FDA did not seek to enforce
NDA requirements against compounding, left it to the states. In the early 1990s, FDA
became concerned however that some pharmacies were purchasing bulk quantities of
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f.
drug products, compounding them into specific drug products before receiving scripts
and marketing them to docs AKA manufacturing drugs.
3. H: It seems unlikely that Congress intended to force compounded drugs to undergo the
NDA process-which would make compounding impossible and thus nonexistent. After
Western State, FDAMA validity remains uncertain however the leg history and the
language of the act do not amount to strong evidence that Congress would not have
enacted the law without the advertising provisions that were struck down.
a. Compounded drugs are not subject to a general exemption from the
definitions of a new drug and animal drugs
b. But new human drugs that result from compounding are exempt from the
adulteration, misbranding, and NDA provisions of the statute.
HOMEOPATHIC DRUGS
a. Concept of homeopathy was invested by Hahnemann in late 1700s
b. Idea is that like cures like, and thus a drug that produces symptoms in a healthy subject is capable
of curing the illness underlying the same symptoms in a sick patient
a. Came to be known as the law of similar
c. Homeopathic drugs are subject to provings, where healthy volunteers take doses of the agent and
record their symptoms to help establish the drug’s full remedy picture
d. Not mentioned in FDA Act of 1906, but were added in the 1938 at as one of the three official
drug compendia recognized by statute
a. FDA basically exempts them all from drug regs, this was okay back then when they
started to disappear
b. Seen a resurgence lately-prob because of public interest and lack of FDA regs
c. FDA put out a CPG in 1988 saying they had the same labeling and manufacturing
requirements on OTC and script homeopathic
12. DEVICES
a. DEVICES, GENERALLY
i. Class I-General Controls
ii. Class II-Performance Standard
iii. Class III-PMA
1. Valid Sci Evidence
2. You get a 6 year exclusivity for first PMA
3. But remember NDA’s substantial evidence requirement-->clinical standard
a. Why is this different for devices? They wanted to make it easier for devices
v. drugs, it has been for a long time
iv. 501 k
1. Notification
2. Substantial equivalence: substantially equivalent to something on the market before
1976
3. Way to keep a new device from being auto classified Class III
v. THIS IS NOT AN APPROVAL, it’s a clearance
b. CLASSIFICATION
i. 1976 Medical Device Amendments and Later Amendments
1. Medical Device Amendments added more than a dozen provisions to the 1938 Act
2. 1976 Amendments revised the definition of a device to achieve 2 purposes
a. Intended to convert some medical products then being regulated as drugs into
device
b. Also broadened the definition to include products intended to diagnose
physiological conditions that are not ordinarily regarded as diseases, like
pregnancy
ii. Classification
1. FDA was required to classify all medical devices in accordance with the relative degree
of assurance of their safety and effectiveness
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a. Class I includes those devices for which neither special controls nor premarket
approval is warranted because the general regulatory controls available under the
FDCA are sufficient to assure safety and effectiveness
b. Class II includes those devices for which general controls are not sufficient but
for which enough information exists to develop special controls
i. Special controls include promulgation of performance standards,
postmarket surveillance, patient registries, development and
dissemination of guidelines, recommendations, and other appropriate
actions as deemed by the Secretary
ii. Guidance docs have proven to be more important than performance
standards
c. Class III includes those device for which general controls are not enough, and
there isn't enough info to establish performance standards
i. Also includes all devices introduced after the enactment of the 1976
Amendments that are not substantially equivalent to a device marketed
prior to the enactment
iii. Regulation of Market Entry
1. 1976 Amendments provide for comprehensive control over the market introduction of all
medical devices, a system which operates independently of the classification scheme
a. A device may lawfully be marketed in only of four ways
i. As a device for which FDA had cleared a section 501 k PMN
demonstration under section 513 f 1 that the device was substantially
equivalent to a preamendment Class I or Class II
ii. As a device for which FDA had cleared a 510 k notification under
section 515 b 1 that the device was substantially equivalent to a
preamendment Class III device on which the agency had not yet imposed
the PMA requirement
iii. As a class III device for which FDA has approved a premarket approval
application under section 515
iv. As a device that FDA had reclassified from Class III into Class I or II
pursuant to a section 513 f reclassification petition
b. Two classes of preamendemnt medical devices are subject to special
requirements
i. Class II medical device must comply with any special controls
established by the FDA under Section 514
ii. Class III device must be the subject of an application demonstrating its
safety and effectiveness and submitted once the agency promulgates a
regulation requiring the submission of applications for that type of device
c. All medical devices are subject to the general regulatory controls under the
FDCA
i. Include the basic adulteration and misbranding provisions as well as
applicable good manufacturing practice regulations, banned device
regulations, and notification and repaid, replacement, or refund
requirements
2. Under this regime, the 510 k notification demonstration substantial equivalence became
the dominant route of market entry to a degree never contemplated by Congress
a. Usually a faster and smoother route to market than any other pathway
3. In 1997, Congress passed FDAMA establishing two additional paths for introducing a
device into the market
a. 513 f 2 established a procedure for requesting that FDA initially classify a device
with no substantial equivalent predicate into Class I or Class II
b. Congress automatically exempted most Class I devices from the 510k premarket
notification requirement and authorized FDA also to exempt Class II devices
where appropriate
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i. FDA thus does not oversee the market entry of many low risk devices at
all
c. PMA v. PMN
i. Gaining PMA is not an easy process, obliged to include sufficient data to prove the effectiveness
and safety of the device aka conducting clinical trials
1. Need approval to conduct clinical investigation, then analyzed by sponsor, then reported
to FDA in a statistically significant way
2. FDA reviews for completeness, can request more info
3. Once complete, its referred to expert outside panel, who issues a report
4. FDA does its own review and when it decides to grant the app, it is published in Fed
Register and a summary of the evidence must be prepared
ii. Sometimes data needed to reclassify is tantamount to the PMA process anyway
iii. Less information is Required in a 510 k Submission
1. Need to provide information support the claim of substantial equivalence to a
preamendment device
a. Safety and effectiveness are not explicitly required
2. Better chance of getting accepted
3. Months faster than a PMA
a. PMN is 102 days, PMA is about 400 days
d. Patent Term Restoration
i. Drug Price Competition and Patent Term Restoration Act of 1984 offered patent term restoration
of up to 5 years for medical devices subject to a regulatory review period that would otherwise
reduce their effective patent life
ii. Some premarket approval devices have in fact been awarded extension of their patent life under
the statute
e. What is Substantial Equivalence?
i. 1976 Amendments didn't include a definition but leg history shows it was meant to assessed not
merely in terms of physical characteristics and intended use, but also in terms of safety and
effectiveness
ii. Left to FDA to interpret, created three principles in the regulatory structure
1. A postamendment device that is substantially equivalent to a preamendment device
should meet the same standards of safety and effectiveness as the predicate device on the
same schedule
2. A postamendment device without a predicate should get PMA before on the market
3. 510 k PMNs requirement should be established to allow FDA to review a manufacturers
decision to introduce a device and thereby prevent the introduction of novel devices that
have not undergone official assessment
iii. FDA released a policy statement saying that one device could be substantially equivalent to
another only if it had the same intended use
1. Could have different technological characteristics as long they didn't diminish safety or
effectiveness
iv. Later codified in the Safe Medical Devices Act of 1990
v. Now, many manufacturers for Class I and II devices determine substantial equivalence for
themselves
f. PMN statement is a certification that the 510k owner will provide safety and effectiveness info
supported the FDA finding of substantial equivalence to anyone within 30 days of written request
g. Special 510 Ks are for certain device modification
i. Apply to devices that are already in commercial distribution but are about to be significantly
changed or modified in designed, components, method of manufacturer, or intended use
ii. Not accepted for modifications that affect the intended use of the device or alter its fundamental
scientific technology
h. Piggybacking
i. Piggybacking or equivalence creep occurs when sponsors show SE to devices that are SE to
preamendment devices...leading to little resemblance between the new device and the original
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ii. 1990 Act specifically authorizes it: needs to be as safe and effective as a legally marketed
device....
i. PMA v. NDA
i. PMAs need to provide reasonable assurance of safety and effectiveness, this language is not in
the drug provisions
ii. For devices, FDA considers
1. Intended persons
2. Conditions of Use
3. Probable benefit to health from the use of the device weighed against any probable risk of
injury or illness
4. Tech none of these are in the drug provisions, although are routinely considered
iii. Device SE more flexible with clinical investigations, can use other valid scientific evidence
iv. Devices are not metabolized, so their interaction with the body tends to be less complex
1. Also can't do double blind placebo tests etc
j. Humanitarian Device Exemptions
i. Do the probable benefits outweigh the probable risks?
1. Reasonableness requirements
ii. In the 1990 Act, Congress added 520 m to encourage development of devices intended to benefit
patients in the treatment and diagnosis of diseases that affect fewer than 4000 individuals in the
US aka HUDs
iii. Still need to show reasonable assurance of safety, but only need to satisfy FDA that there is a
reasonable basis from which to conclude that the probable benefit to health outweighs the risk of
injury or illness, taking into account the probable risk and benefits of currently available devices
and alternative forms of treatment
1. Only need to include reasonably obtainable clinical data
2. No comparable device is available to treat or diagnose the condition
3. Not an investigational device, and does not require informed consent
4. FDA can provide grants to defray costs
k. Custom Devices
i. Section 520 b of the FDCA says that requirements of 514 performance standards and 515 PMA
do not apply to any device which, to comply with an individual doc or dentist, necessarily
deviates from an otherwise applicable performance standard or approved PMA application
ii. Custom device exemption applies only if the device is not generally available for purchase in
finished form and is either made according to specification for an individual patient or is intended
to meet the special needs of ordering doc
iii. Exempted from IDE requirement unless the device is being used to determine safety or
effectiveness for commercial distribution
iv. Contact lenses tried to fall under this category, show down by a court
1. FDA came out later saying that a custom device may not be a standardized modification
of a marketed device, may not be commercially distributed, and must be made in a
specific form for a patient named in the order of the doc to meet the special needs of such
doc in the course of his or her professional practice
l. Classification and Reclassification of Novel Devices
i. For a manufacturer, the question is whether section 513 f 3 reclassification or section 513 f 2
classification can be accomplished more speedily or with less S and E data than a PMA
ii. Reclassification of a new postamendment device by petition has rarely provided a shortcut to the
market
1. These are relatively minor ways of getting into the market
m. Restricted Devices
i. Sounds like what they are describing is a prescription drug
ii. Section 520 e of the Act provides that FDA by regulation require that a device be restricted to
sale, distribution, or use
1. Only upon the written or oral authorization of a practitioner licensed by law to administer
or use such device or
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2. Upon such other conditions as the Secretary may prescribe in such regulation if because
of its potentiality for harmful effect or the collateral measures necessary to its use, the
Secretary determines that there cannot otherwise be reasonable assurance of its S and E
iii. Thus analogous to a prescription drug but the language was crafted to allow FDA to control
distribution of a device in ways that it cannot control distribution of a drug
iv. Examples include drug abuse testing systems and hearing aids
v. Class II special controls can also be used to restrict sale and distribution, and many Class III
devices are prescription devices
13. COMBINATION PRODUCTS
a. GENERALLY
i. Both a drug and a device, regulated by primary mode of action
1. Assigning it for review for one area of FDA
2. Better to be regulated as a device-but have to convince them that that’s the primary
mode of action (which is doing the most???)
b. FDA Notice re Combination Products
i. FDA is announcing a public hearing to discuss the assignment, premarket review, and postmarket
regulation of combination products
ii. Combination products are products containing a combination of drugs, devices, or biological
products
1. Novel and have significant potential
2. Can compromise of two or more different regulated components, like a syringe prefilled
with a drug, or two or more separate products packaged together, like a kit with drapes,
needles, anesthetic, etc
3. Also defined to include a product that is intended for use only with an approved product
where both are required to achieve the intended use, indication or effect, and the labeling
of the approved product needs to be changed to reflect this use
4. Also includes any investigational product that is intended to be used only with another
investigational product
iii. Safe Medical Devices Act of 1990 explicitly recognized the existence of products that constitute a
combination of drug, device, or bio product and provided a mechanism for determining which
agency component would be assigned the admin responsibility of regulating a particular
combination product
1. Also refined the assignment process by providing a mechanism to request that the FDA
classify a product a certain way, and to determine which agency component will be
assigned to regulate it
2. Supposed to be assigned based on the product's primary mode of action
3. Involvement of more than one center presents unique challenges, the FDA can request
that separate applications are approved
iv. Issues involved include consistency, predictability, and transparency of the assignment
(jurisdiction) process, issues related to the management of timeliness of the review process when
two + FDA centers have review responsibilities, lack of clarity about post market controls, lack of
clarity regarding certain agency policies, such as when applications to more than one agency
component are needed
14. PREEMPTION
a. Medtronic v. Lohr (SC 1996)
i. I:Whether the Medical Device Amendments of 1976 preempt a state common law negligence
action against the manufacturer of an allegedly defective medical device
ii. Facts; Medtronic took advantage of 510ks expedited process when it notified the FDA that its
pacemaker lead as a device was SE to devices already on the market; FDA approved it. Lohr had
the pacemaker, it failed, and she filed suit in state court for negligence for breach of duty to use
reasonable care in the design, manufacture, assembly and sale of the subject pacemaker.
iii. H: Congress didn't want to add additional federal or state law, but it didn't mean to preempt pre
existing common law duties
1. Design Claim
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a. Medtronic exaggerates the importance of the 510k process and the FDA letter to
the company regarding the pacemakers SE to a grandfathered device
i. Just says its no more dangerous and no less effective than the earlier
device but if the earlier device was dangerous, this one could be too
b. Letter also said it did not denote FDA approval of the device
2. Identity of Requirements Claims
a. Nothing in 360k denies FL the right to provide a traditional damages remedy for
violations of common law duties when those duties parallel federal requirements
b. Its not a different or additional requirement, its another reason for manufacturers
to comply with identical existing requirements under federal law
c. Weight is given to the state that says in a provision that it does not preempt State
or local requirements that are equal to, or substantially identical to, requirements
imposed by or under the act
3. Manufacturing and Labeling Claims
a. Good Manufacturing Practices are enforced by the FDA against manufacturers
that violate them
b. State requirements for labeling, etc are only preempt when the particular state
requirement threatens to interfere with a specific federal interest
c. Need to compare the two requirements, and here they are not preempted
i. Federal requirements reflect important but entirely generic concerns
about device regulation generally, not the sort of concerns regarding a
specific device or field of device regulation that the statute or regulations
were designed to protect from potentially contradictory state
requirements, state requirements were also not developed with respect to
medical devices
iv. Takeaway: The FDA regs were specific to that device, but state laws are generally thus they
are not preempted
b. Wyeth v. Levine (SC 2009)
i. Facts: Directly injecting the drug Phenergan into a patient's vein creates a significant risk of
catastrophic consequences. Wyeth, the manufacturer or the drug, was found by a VT jury to have
failed to provide an adequate warning of that risk and awarded damages to Levine whose arm was
amputated. Warnings on the label had been deemed sufficient by FDA when it approved the NDA
in 1955 and again when it later changed its drug label. FDA told Wyeth to consider changing
their label, but when they tried to, FDA told them to stick with the old label.
ii. I: Whether the FDA's approvals provide Wyeth with a complete defense to Levine's tort claims
iii. H: Wyeth makes 2 separate pre-emption arguments, which both fail:
1. That it would have been impossible for it to comply with the state law duty to modify the
drug's labeling without violating federal law
a. Without clear evidence that the FDA would not have approved a change to the
drug's label, we cannot conclude it was impossible for Wyeth to comply with
both state and federal laws
2. That recognition of Levine's state tort action creates an unacceptable obstacle to the
accomplishment and execution of the full purposes and objectives of Congress because
its substitutes the jury's opinion for that of the FDA
a. They rely on an FDA preamble to a regulation that says the FDCA is both a floor
and a ceiling and preempts all State law that is conflicting or contrary
b. This goes against both the FDAs and Congress' position on the topic
1. FDA has limited resources, state tort suits uncover unknown drug hazards and
provide incentives for drug manufacturers to disclose safety risks promptly, also
serve a compensatory function
2. Dissent (Scalia): Only injured parties represented in court, not those who the drug helped
1. Also now getting 50 different opinions on a drug, instead of a cohesive federal one
3. Takeaway: Tort claims from the state are not preempted by the FDA labeling rules
1. Why did the FDA file a brief in favor of preemption?
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1. Previously had said it’s the manufacturers problem to fulfill the labeling
requirements, not theirs
2. But FDA had changed their policy, but didn't use formal rulemaking-so they
didn't get any deference
15. ENFORCEMENT AUTHORITY
a. CLASS NOTES:
i. FDA's enforcement authority begins with inspection power
1. The average company meets the FDA during the inspection process
2. Usually the first time for the food industry since they don't have a pre approval process
3. Supposed to occur every 2 years
ii. Section 704 is critical here: 704 a FDA official can enter any facility with presented of proper id
and notice at a reasonable time and can inspect such facility in a reasonable time, within
reasonable limits, in a reasonable matter
1. What can they look at?
a. Food finished product, process etc but can't look at the files or the formulas
b. Greater authority with drugs, medical devices, and tobacco-can look to see if
misbranded or adulterated
c. Can't look at financial or personnel data or pricing information, other than the
fact that the people are qualified
i. Can look at shipping records to see if entering IC
iii. Okay why didn't they need a warrant?
1. Pharma clearly heavily regulated, but what about food? Not nearly as heavily inspected
2. OSHA case that inspected a facility and found violations-Court agreed with 4th
Amendment argument that they could have gotten a warrant
iv. Inspectors put observations on a 483 form
1. District office then looks and sees if the agency thinks its a violation
2. Company has 10-15 business days to respond to the observations
a. I.e. We made corrective actions etc
b. SEIZURE
i. CLASS NOTES
1. Drug company messes up the labels on aspirin and acetaphamine (sp) and a patient takes
the wrong one, has an allergic reaction, dies
2. Pharma tells FDA, FDA goes down to warehouse seizes everything and essentially puts
them out of business
3. Drug company calls his lawyer and says what happened to the 4th Amendment, help!
a. What does the lawyer do? 4th Amendment protects against unreasonable search
and seizure, WITH A JUDGE-ISSUED WARRANT
i. They didn't get one here so it violates the 4th amendment...will this
work?
b. Under what statutory authority did FDA go in without a warrant
i. 304 b-you can seize products under libel of information (no mention of
warrants)
ii. Mentions admiralty law...what goes this say?
1. In actions by the US for federal statutory violations, a clerk can
issue a warrant instead of a judge (used to stop vessels at sea)
iii. Does it matter that this wasn't for a routine inspection but rather for a
specific seizure?
1. No, closely regulated industry they can go in any time
iv. What’s the adequate substitute for a judge-issued warrant?
1. Still need a clerk issued warrant, but its less than a judge
issued
2. Level of specificity required describing the seized goods
3. Preliminary report of public harm created
4. Seizure is a way of gaining jurisdiction over a product, but the manufacturer could still go
to court and try to get it back within 10 days
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a. Then you have a case to determine if product is adulterated or misbranded
b. If so, condemned by court and either destroyed or the company can then ask the
product be salvaged
c. Here the product is misbranded, possible that they could just switch the labels
i. Unlikely that the FDA would let them do that-how could you screw that
up?! They prob have other GMP violations, etc
5. OK but if they smell marijuana at the plant next door, can’t go get it with an in rem
warrant because they have no stat authority over it
6. Remember FDA cannot bring cases by themselves, they have to get the warrant give it to
the Marshall, and the DOJ has to sign off or AG
a. Therefore there is a check on the FDA, they don't just make up these decisions
i. All they need to find is probable cause and that satisfies due process
ii. And the DC doesn't have the power to review this decision of probable
cause
ii. Section 304 of the FDCA set forth a two step process for seizure:
1. Authorizes the US to proceed against adulterated or misbranded articles or unapproved
drugs on libel of information and seize the articles
2. Empowers the federal DCs, after trial, to decree the condemnation of such articles and
order them destroyed, sold, or returned to the owner for destruction, reconditioning or in
some instances, export
3. Extends to the product labeling as well as the article itself, as long as it has accompanied
the product in IC (promo materials may not count)
4. Removal of the illegal labeling before seizure does not render the device immune from
seizure and condemnation if it was misbranded when introduced into IC
iii. US v. Argent Chemical Labs (DC of WA 1996)
1. Facts: FDA seized adulterated products the premises of a regulated veterinary drug
manufacturer without obtaining a warrant from a judicial officer upon a finding of
probable cause. FDA agents inspected Argent several times to ensure compliance and
cited them for certain deficiencies; several months after the last inspection, the FDA got
an in rem warrant and seized over 100k worth of drugs.
2. H: The warrant in this case was issued in accordance with the Act, in rem warrants
can be obtained without review by a judicial officer or a finding of probable cause.
The argument that the seizure violated the 4th Amendment is defeated by the nature of its
business and the regulation to which it is subject .
a. Under the Colonnade-Bisewell exception, warrantless searches and seizures
on commercial property used in closely regulated industries are constitutionally
permissible.
b. This business is closely regulated AND
i. Substantial gov't interest that informs the regulatory scheme
pursuant to which the inspection is made [FDA regs vet drugs]
ii. Warrantless inspections must be necessary to further the regulatory
scheme [deterrent]
iii. Statute's inspection program, in terms of certainty and regularity of
its application must provide a constitutionally adequate substitute
for a warrant [inspections put them on notice]
c. C-B exception applies to both seizure and inspection without a warrant
iv. Ewing v. Mytinger and Casselberry Inc. (SC 1950)
1. Facts: Appeal for an injunction to restrain enforcement of a portion of the FDCA for
repugnance to the Due Process Clause. FDCA allows multiple seizures of misbranded
articles when the Administrator has probable cause to believe that the misbranded article
is dangerous to health or that the labeling is fraudulent or would be materially misleading
to the injury or damage of the purchaser or consumer. Sole claim is that the labeling (a
booklet) is misleading and therefore the product is misbranded. This was the
administrative finding behind eleven seizures resulting in 11 libel suits.
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2. H: Admin finding of probable cause required by 304 a is merely the statutory
prerequisite to the bringing of the lawsuit. When the libels are filed the owner has
an opp to appear as a claimant and to have a full hearing, which satisfies due
process. Just because seizures can hurt a business doesn't mean that due process
requires a hearing before the fact.
a. The FDA determination of probable cause has no binding legal consequence
and there is no judicial review available at that time
3. Takeaway: No Due Process needs to be accorded before the seizure.
v. Parke Davis and Co v. Califano (6th Circ 1980)
1. I: Whether the DC properly enjoined enforcement actions by the FDA which were
instituted as libels for the seizure of drugs in warehouses of PD.
2. Facts: Dispute concerns the right of PD to market an OTC product containing DPH.
FDA has originally approved the drug for Rx, and PD has tried to switch to OTC twice.
Began marketing it OTC after the OTC panel recommended that the product be
available OTC and FDA wrote a letter to PD saying that the agency was extremely
unlikely to initiate enforcement action. FDA then disapproved PDs SNDA and said it
would not accept the panels rec and would pursue seizure.
3. H: DC has no jurisdiction to review the decision of the FDA to initiate enforcement
actions. It was an abuse of discretion to enjoin the FDA in the circs of this case
where pending enforcement actions provided an opportunity for full hearing before
a court.
vi. US v. 893 One-Gallon Cans...Labeled Brown's Inhalant (City of Chicago, 2002)
1. Facts: A libel was filed which sought seizure and condemnation of certain cans
containing poultry medicine. Claimants denied that the product was misbranded, and the
claimants were permitted to discharge the property upon filing a bond as long as they
should not sell the property unless and until the labels were removed. Gov't moved to
amend the order to strike out portions returning the property.
2. H: D argues that this is a cause in Admiralty and they should be allowed to have
possession of the property before final hearing and decree according to the statute. But
Admiralty Rules only gives support for release of perishable goods.
a. Once a decision has been made by a Court determining the misbranding,
then the article can be released to the claimant or destroyed
3. Notes on Perishable Goods:
a. Seizure of perishable commodities may result in the articles destruction or a
reduction in their value even if the claimant ultimately prevails
b. If the seizure was reasonable however the claimant is not entitled to
reimbursement for any loss of value during storage
c. INJUNCTION
i. CLASS NOTES
1. When would FDA want to use injunction over seizure??
2. What do they have to show to get a preliminary injunction
a. Need to show irreparable injury
i. Unless there is a statutory violation, in which case the irreparable injury
is assumed
b. Need to show damage to D and balances of harm
3. Two types of typical PIs
a. Bad apples that are clearly not going to stop
b. Firms with bad manufacturing practices
i. Violate GMPs-if you don't make the product right using the right
controls, etc the product that comes out at the end is not good
1. Even if it passes every test at the end, you can't add in that quality
later
ii. They don't just want the stuff in the plant, they want them to fix it! We
aren't going to let you ship any more until you fix it
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ii.
iii.
iv.
v.
4. Then what happens is the good people fix this up go into court and say look what we've
fixed
a. Don't put us out of business-you'll put 5,000 people out of work
b. Judges usually want to side with this guy! And they are constantly making
improvements!
5. Now usually the FDA just threatens to shut the plant down until the company negotiates
a. Known as consent decrees
i. Also name certain people so that they can come after you if you violate it
ii. We want individuals to through them in jail instead of just getting a fine
from the company
iii. Go after the people they think are responsible for the problems
1. Usually name old head of quality AND the new guy
2. New guy ends up getting a lot of money to sign it
The 1906 Act did not authorize the FDA to seek injunctive relief against violators, but the 1938
Act did
1. This was to expedite action against violators and to avoid the hardship and expense of
seizure cases
Gov't started to use them, alone or with seizures as they had several distinct advantage:
1. Lower burden of proof in an injunction suit than in a criminal prosecution
2. An injunction can prohibit further violations , whereas a condemnation decree after
seizure cannot, since it applies to the product not the person
3. FDA can seek a prelim injunction or a temp restraining order to put a half to violative
conduct immediately before the court decides to award a perm injunction
a. Usually resolved by consent decree
A D is not entitled a jury trial in an injunction suit unless the violation also constitutes a violation
of the FDCA
1. Injunctions are usually non jury trials, but a company can request them
2. Rare that they do, since they are accused of adulterating drugs!
Preliminary Injunctions
1. US v. Odessa Union Warehouse Co-Op (9th Circ Case)
a. Facts: Gov't inspected Odessa grain warehouses and revealed violations of the
food contamination and adulteration standards including rodents and birds. As a
result of these inspections, the FDA has imposed embargoes on thousands of
bushels of wheat under Odessa's control. Gov't sought a prelim injunction to
enjoin the sale and movement of wheat held in Odessas elevators until they
complied with the FDCA standards . Prior to the court hearing, Odessa took
action to improve sanitation at its facilities, so DC denied the gov'ts motion for
preliminary injunction.
b. H: The Standards for Issuing a Preliminary Injunction are
i. Likelihood of P's success on merits
ii. Possibility of P's suffering irreparable injury if relief is not granted
iii. Extent to which the balance of hardships favors the respective
parties
iv. Whether the public interest will be advanced by the provision of
prelim relief
c. Moving party must show
i. Combination of probable success on the merits and the possibility of
irreparable injury
1. These represent two points on a slide scale in which the required
degree of irreparable harm increases and the probability of
success decreases
2. Because irreparable injury must be presumed in a statutory
enforcement action, the DC needed only to find some change of
probable success on the merits
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3. Record indicates that there is a substantial likelihood of success
on the merits in this action given the uncontested evidence that
Odessa remained in violation of the FDCA until the hearing
ii. That serious questions are raised and the balance of hardships tips
in its favors
d. Sliding scale is no longer the test in DC, usually just probability of success
on the merits
2. US v. Nutricology (9th Circ 1992)
a. Facts: Nutricology distributes and promotes a number of products labelled as
nutritional or dietary supplements promoted as useful to prevent and treat
numerous diseases and conditions. FDA notified the Ds in writing multiple times
that the FDA considered its products to be unapproved drugs and new drugs
under the FDCA. The gov't did not file this action until 3 years after the last
letter. DC granted the gov'ts ex parte request for a temp restraining order
enjoining D from further marketing of its 9 products, representing 80% of Ds
business, but then denied prelim injunction.
b. H: Where the gov't has only made a colorable showing, but not met the
probability of success prong, there must be further inquiry into the
possibility of irreparable injury
i. Because the gov't failed to demonstrate any harm to consumers and
because D submitted extensive evidence to the contrary, the DC did not
A its D when it denied the prelim injunction.
vi. Permanent Injunctions
1. US v. Laerdal Manufacturing Corp (9th Circ 1994)
a. Facts: D appeals the order of the DC that it be permanent enjoined. D
manufactures AEDs, and the court agreed with the FDA that the device may have
caused or contributed to a death or serious injury. D argues that the court
improperly imposed the injunction because there is no cognizable danger that D
would violate the MDR regulation in the future.
b. H: DC cannot issue an injunction unless there exists some cognizable danger
of recurrent violation, found here
i. May consider degree of scienter involved, isolated or recurrent nature of
the infraction, the D's recognition of the wrongful nature of his conduct,
the extent to which the Ds profession and personal characteristics might
enable or tempt him to commit future violations, the sincerity of any
assurance against future violations, and past wrongs
1. Court implicitly balances the PH against the burden placed upon
D, namely that it complied with gov't regs
2. US v. Sars of LA
a. Court denied an injunction with the D has complied with all FDA recs by the
time the case came to trial so violations not likely to occur
3. US v. Articles of Drugs, et al, Midwest Pharma (8th Circuit 1987)
a. Facts: DC found that the drugs were imitations of other drugs in and enjoined D
from selling or marketing any drug product similar in appearance and in effect to
the drugs seized. D is both a wholesale and retail distributor of generic OTC drug
products containing caffeine, ephedrine etc and also sells "incense". D usually
sells its products in bulk containers of 1k dosage units and advertises in
subculture magazines described as legal body stimulants and sleep aids, with
street names for illegal drugs. FDA sought an order enjoining D and its president
from selling or marketing the same or similar products in the future.
b. H: Injunction does have to identify the specific drugs prohibited. D also sells
that there’s no legal basis to enjoin the otherwise lawful sale of drug
products without the misbranding, but Gov't believe that even without
future advertising, D could continue to sell drugs from residual and repeat
orders.
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i. Here D had a pattern of violations, so DC did not A its Ds in issuing
its injunction
4. U.S .v. Syntrax (DC Case 2001)
a. Facts: Gov't seeking condemnation and destruction of Triax, which was being
sold as a weight loss dietary supplement but included an illegal drug. D's have
conceded the condemnation but object to several provisions of the condemnation,
forfeiture, and permanent injunction order.
b. H:
i. Gov’t injunction is not overbroad if it applies to marketing and sale
of associate drugs, i.e. Triax II and Triax. D cannot defend against
an injunction by asserting that the injunction will drive them out of
business.
ii. Order can grant the FDA the right to inspect the facilities to ensure
compliance with the injunction.
iii. Can also require them to pay for the gov’t’s cost incurred to ensure
compliance with the perm injunction.
1. But can’t impose despoition costs and travel expenses because
there was no discovery.
iv. Order can enjoin others in active concert or participation with them
as well.
v. Also okay to require notification to any purchasers, like most
injunction cases; and to shut down operations if they are found to by
violating the injunction.
1. However these determinations are subject to judicial review
for A and C.
d. DISGORGEMENT
i. Abott Labs case
1. They were the only guys who made the thing, but it took them years to try to fix stuff
under the consent decree
2. FDA said were over it will go for an injunction and Abott says if you stop us then
everyone’s gonna die because we are the only ones making these products
a. Bothered the FDA a whole lot so they came up with a scheme for Abott to pay a
disgorgement fee/fine for the time that they have been violating the law, and a
royalty fee for as long as you continue selling them
b. Basically you keep making them but you can't make any money off of them
c. Abott agreed to pay 100M and high royalties
3. FDA then began making these payments standard in consent decrees
4. Can also put monetary fines in the injunction to enforce deadlines
a. Avoids contempt of consent decree and having courts throw people in jail
ii. FDA has renewed a decades old pursuit of restitution and disgorgement to enforce violations of
the FDCA
iii. FDCA provides three judicial mechanisms to address violations
1. Seizure to remove non-compliant products from the market
2. Injunction to prohibit further manufacture or distribution of such products
3. Criminal Prosecution to punish the wrongdoer with fines and imprisonment
a. FDA rarely uses this for violations that were not willful and did not result in the
death or serious injury to or blatant fraud upon customers
iv. FDA found that these tools were not always appropriate or effective
1. Seizures and injunctions would remove essential products from the market
2. Instead turned to forward looking consent decrees of mandatory injunction while
ordering the Ds to remediate the noncompliance
a. Started getting claims from companies that their products were medically
necessary and they wanted these kinds of injunctions too
v. FDAs solution was to use disgorgement payments of significant size
1. Lump sum payment to US treasury
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2. Percentage of sales payment required if remediation is not achieved by decree deadline
3. Daily payments required for each product or process not brought into compliance within
specific deadlines determine pursuant to the decree
vi. Considered long recognized equitable remedy developed to prevent unjust enrichment and to
deprive a D of illgotten gains
1. Different than restitution where the money goes to the victim, disgorgement is to deter
violations by making them unprofitable
2. Unlike other agencies, FDA keeps the money and does not give it back to the victims
who suffered financial loss
vii. US v. Lane Labs-USA(3rd Circ 2004)
1. I: Whether a DC has the power under the FDCA to order a D found to be in violation of
the Act to pay restitution to consumers
2. Facts: Three products are the subject of this action, which D promoted as cancer and HIV
treatments. FDA filed a complaint for permanent injunction alleging that the D's
promotional claims brought their products under the definition of drugs and were
misbranded without adequate directions for use. DC ordered restitution to all purchasers
of the product, among other things.
3. H: Although the FDCA does not specifically authorize restitution, such specificity is
not required where the gov't properly invokes a court's equitable jurisdiction under
the statute. FDCA purpose is both to protect PH as well as the value that customers
perceive when they purchase products AKA health and pocketbooks. Putting customers
back in the same economic position they were in before strengthens financial protection
offered by the FDCA and enhances consumer confidence.
viii. Medical Device Amendments gave FDA restitution authority, as well as ability to order
repair or replacement of the device in question
e. CRIMINAL LIABILITY
i. Every violation of the FDCA is potentially a criminal violation
ii. Without intent-misdeamoner, with intent potentially a felony
iii. US v. Park (SC 1975)-PUTS THE FEAF OF GOD IN EVERY CEO IN FD INDUSTRY
1. Facts: Acme is a large national food chain, HQ with office of the President Park in
Philly. CEO gets warning letter that the FDA has checked out the Philly warehouse and
there are violations. Goes to his VP of Quality in Philly and says fix it. A year later FDA
goes to the Baltimore warehouse, sees issues sends CEO a letter. CEO tells MD VP to fix
it. FDA comes back 2 months later, see its improved, but not perfect, charges Park with
criminal violation under 301 a.
2. H: SC holds that the 1970 letter was notice that the CEO had a system that was not
working, and the 197 letter showed that he was still relying on the same system that
wasn’t working.
3. Takeaway:
a. Only way to combat this was if it was objectively impossible to fix it, aka
powerless
b. Doesn't usually work on CEO, lower level people don't usually have power to tell
others to fix stuff
c. Because of these cases new position created usually VP of Manuf. or Quality
who always had the final say on quality issues aka in charge of going to jail
d. These cases aren’t usually brought though because the DOJ wants “bad guys” not
CEOs
i. But it does make CEOs afraid of FDA
iv. Prosecutorial Discretion
1. FDA is expected to exercise reasonable discretion in invoking the Act's criminal
sanctions
2. Usually only applies to continuing violations of law, violations of an obvious and flagrant
nature, and intentionally false or fraudulent violations
3. Only applies to those who are in the position to and have the authority to correct
violations
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4. Usually only applies with an officer has been informed and failed to do anything
5. US v. Parfait Powder Puff Co (7th Circ 1947)
a. Ds argument that Helfrich was an independent contractor for whose acts it was
not responsible for was rejected by the court which reasoned that the D incurred
liability when it voluntarily selected H to manufacture and distribute a product it
knew would become part of interstate commerce.
6. In another case, court rejected Ds argument that he was not longer the responsible officer
because he had sold the plant and the title and control had passed to the purchaser right
before trial
7. Where Ds are convicted under the Park doctrine without criminal intent, the court is
reluctant to deny the D's motion to expunge their criminal records
8. The Defense of Impossibility
a. To advance the impossibility defense the D must come forward with sufficient
evidence of impossibility to warrant placing an additional burden on the gov't
(burden of establishing beyond a reasonable doubt that the D could have
prevented or corrected the prohibited condition through exercise of extraordinary
care)
b. Ds have trouble sustaining this defense, but doesn’t always fail
i. In one case the court said that the Ds were only helpless to maintain
sanitary conditions because they continued to use the same warehouse
ii. In another, where a company was going to build a wire cage around the
warehouse to keep out rodents but it hadn't arrived yet, the court said that
a wire cage is not a novel device and it would not have been objectively
impossible for the D to implement an effective solution earlier
iii. In another, the D worked in close proximity to the violations so even
though he had delegated the cleanup to the janitor he could observe that
it had not been completed
f.
RECALLS
i. Every company has to have a recall policy
1. Class 2: get stuff from manufacturers
2. Class 3: get stuff from retailers
ii. A market withdrawal is for lesser offenses: not going to hurt anyone, but maybe the tablets
are broken and not pharmacologically elegant
iii. Since before passage of the 1938 Act, FDA has used its own resources and encouraged
manufacturers to recall illegal products from the market
iv. As soon as the FDA learns that a potentially injurious product has been distributed, its efforts to
retrieve the suspect batches are abated only when every unit is accounted for
1. Sometimes even go into consumer channels
v. After the dangerous drugs have been accounted for, the firm is cited to a hearing with a view to
criminal prosecution if the error was one which could have been avoided by GMP or could have
been corrected at an earlier stage
vi. Almost always the recalls are “voluntary,” the FDA only seeks a court order when the
manufacturer refuses
1. They comply because of the threat of adverse publicity, and the need for FDA approval in
the future, as well as the implied threat for formal legal action
vii. Mandatory Recalls
1. FDA today has explicit statutory authority to mandate recalls in certain limited
circumstances but issued very few
2. Section 535 f of the PHSA gives FDA power to mandate the repurchase, repair or
replacement of radiation-emitting electronic products
a. FDA has always interpreted this to authorize recall orders as well
3. Section 351 d of the PHSA gives FDA the power to order recall of a biological
product that presents an imminent or substantial hazard to PH
4. Section 412 e 1 of the FDCA requires manufacturers take all actions necessary to
recall an infant formula if the FDA determines it presents a risk to human health
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5. Section 518 e of FDCA titled Recall Authority requires the FDA to order cessation
of the distribution of a device and notification of health professionals and user
facilities if the agency finds that the device would cause serious health consequences
or death
a. After an opportunity for informal hearing, the agency may amend the order to
include a recall for the device
6. BUT With regard to food, drugs, cosmetics and devices that do not pose a serious risk to
health, FDA does not itself have formal authority to demand a recall
a. Has successfully sought court orders under the 302 a injunction provision
b. Trend seems to be toward recognizing the court’s authority to require recalls
c. Also, consent decrees entered in DC by FDA and Ds sometimes require recall
i. The product have already been seized, but the D has to go out and get
everything back on the market
viii. FDA-initiated recalls
1. Two types
a. When the agency determines that a marketed product violates the law and so
informs the responsible firm, a later recall is considered an FDA-initiated recall
even though it has not been specifically requested by the agency
b. Formal notification from the commissioner when a product presents a danger to
health or significant consumer deception and immediate action is necessary
i. Can only be made by the Commissioner or his designee
ix. Firm Initiated recall
1. A firm may on its own initiative remove, correct, or otherwise dispose of an illegal
product that it has distributed in commerce
a. Firm should notify the FDA
2. A recall involved several separate but related steps taken by the FDA and the firm
a. Evaluation of the health hazard associated with the product being recalled
or being considered for recall
b. Developing and following a recall strategy
i. Depth of recall
1. Consumer or user level
2. Retail level
3. Wholesale level
ii. Public warnings
1. Purpose is to alert customers or users that a product presents a
serious hazard to health
iii. Effectiveness checks
1. Verification that recipients of a product being recalled
(consignees) have been notified and have taken appropriate action
2. For FDA to routinely carry out industry’s task of assuring recall
effectiveness would represent misuse of public funds
a. FDA will monitor to check
iv. Steps to follow:
1. Develop a contingency plan for recall
2. Develop the capability of tracing product distribution and
identifying the product being recalled
3. Promptly notify FDA when products are being removed or
corrected and provide the agency with pertinent info on these
actions
4. Initiate a recall when it is request by FDA
5. Develop and follow a recall strategy for handling any recall
situation
6. Assume the responsibility and expense of conducting all aspects
of a recall, including effectiveness checks
7. Notify all consignees of initiated recalls
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8. Evaluation the circs causing the violation and take steps to
prevent recurrence and future recalls
9. Provide periodic reports to FDA on the progress of the recall
10. When a recall is completed, certify to FDA that the recall has
been effective and that final disposition of the recalled product
has been made
c. Recall communications to a firm’s customers
d. Periodic reports on the progress of the recall
e. Termination of the recall and proper disposition or correction of the
violative product
g. DEBARMENT
i. Could also get at senior managers who were involved although not indicted if they had a
role in the activity
ii. For companies, you can't submit an application under 306
1. Can't use a debarred person in connection with your app and if you do, you could
be violating the law
2. Need to certify this, don't mess up
iii. For an individual, they can't provide services to anyone who has a pending or approved
drug application in any capacity
1. You can't work in drug development or regulatory affairs, you can't even be a
janitor at that company
2. You are out of the industry, can work for OTC companies
iv. What can you argue against this? Both Fail
1. Ex post facto
2. Double jeopardy-being punished for the same crime twice
v. Been used prob 100 times, but can't forget about it when you are working with a client in a
drug case
1. Bae v. Shalala (7th Circ 1994)
1. Facts: GDEA mandates permanent debarment for any individual convicted of a felony under
federal law for conduct relating to the development or approval or other regulation of any drug
product under the FDCA. Bae was debarred because of his 1990 felony conviction for aiding and
abetting interstate travel in aid of racketeering for providing an FDA official with a bribe, he got
formulation for generic drugs from other companies apps in return for 10k.
2. I: Whether and under what circs a civil debarment penalty may consisted retroactive punishment
prohibited by the Ex Post Facto Clause of the Constitution
3. H: The aim of the GDEA was to restore consumer confidence in generic drugs by eradicating the
widespread corruption in the generic drug approval process. A civil sanction that can fairly be said
solely to serve remedial goals will not fail under ex post facto scrutiny simply because it is
consistent with punitive goals as well. A deterrent purpose does not automatically mark a civil
sanction as a form of punishment.
1. Debarment, although harsh because permanent, is not disproportionate.
Upheld.
vi. Application Integrity Policy
1. Policy sets forth FDA’s general approach regarding applicants that seek to subvert the
agency’s review and approval processes for premarket approval
2. FDA developed an approach to ensure validity of data called into question by such
wrongful acts and to remove from the market products for which application approval
was based on fraudulent data
3. House Subcommittee and FDA did investigations and found four FDA employees had
accepted illegal gratuities from generic drug companies, and 11 drug companies were
found to have falsified data submitted in premarket applications to FDA
4. Prompted FDA to develop a program
a. To ensure the validity of data submissions called into question by the agency’s
discovery of wrongful acts such as fraud, untrue statements of material fact,
bribery, and illegal gratuities
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b. Withdraw approval of, or refuse to approve, applications containing fraudulent
data
c. Validity Assessment
i. FDA will conduct an investigation to identify all instances of wrongful
acts and to determine the extent to which the wrongful acts may be
affected approved or pending apps
ii. Scope of investigation will be based on the nature of the offense and
focus on the reliability of the applicant’s research and manufacturing
data
iii. If the wrongful acts have raised a significant question regarding
reliability of data in some or all of the applicant’s pending apps, FDA
ordinarily will conduct validity assessment of those applications
iv. FDA generally intends to defer substantive scientific review of the data
in a pending application undergoing a validity assessment until the
assessment is complete and questions regarding reliability of the data are
resolved
v. The principal basis for this determination is the data in the application;
therefore, the reliability of data is of critical importance
1. If the agency determines that the criteria for approval cannot be
met because of unresolved questions regarding reliability of data,
the agency will not approve the application
vi. When FDA finds, based on fraudulent data in an application, that the
data in the application are unreliable, the agency intends ordinarily to
exercise its authority to refuse to approve the application or to proceed to
withdraw approval regardless of whether the applicant attempts to
replace the unreliable data with a new submission in the form of an
amendment or supplement
vii. Thus, if the applicant wishes to replace the false data with a new
submission, the new submission should be in the form of a new
application
1. The new application should identify the parts of the original
application that were found to be false, certified by the president,
chief executive officer, or other official most responsible for the
applicant's operations
viii. FDA may also seek recalls, and other actions including seizure,
injunction, civil penalties, and criminal prosecution
5. Corrective Actions
a. The corrective actions an applicant will be expected to take will depend upon the
facts and circumstances of each case, the nature of the wrongful acts, the nature
of the data under consideration, and the requirements of the particular review
process. Applicants who engage in wrongful acts ordinarily will need to take the
following corrective actions to establish the reliability of data
i. Cooperate fully with FDA and other Federal investigations to determine
the cause and scope of any wrongful acts and to assess the effects of the
acts on the safety, effectiveness, or quality of products;
ii. Identify all individuals who were or may have been associated with or
involved in the wrongful acts and ensure that they are removed from any
substantive authority on matters under the jurisdiction of FDA;
iii. Conduct a credible internal review designed to identify all instances of
wrongful acts associated with applications submitted to FDA, including
any discrepancies between manufacturing conditions identified in
approved applications and manufacturing conditions during actual
production
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iv. Commit, in writing, to developing and implementing a corrective action
operating plan to assure the safety, effectiveness, and quality of their
products
v. FDA intends to reinspect applicants, and may be requested to recall
products
h. CIVIL PENALTIES
i. Can get a subpoena to impose civil penalties
ii. Mostly for devices
iii. Safir: Can't remember a case when they have done it, its in the statute but they never use it
iv. 1938 FDCA contained no provisions authorizing civil money penalties, so for many the only
authority the FDA had to seek penalties was under the Radiation Control Act
v. Now section 539 of the FDCA empowers the FDA to seek the imposition of civil penalties for
violations of the Radiation Act in federal DC
1. This power was repeatedly increased by Congress to give FDA authority to impose civil
money penalties for other types of violations
a. Vaccine Injury Law for violations of the biological product recall provision and
vaccine manufacturer recordkeeping requirements
b. Prescription Drug Marketing Act authorizes penalties from manufacturers or
distributers convicted of violations of the drug sample provisions of the FDCA or
parallel state laws
c. Safe Medical Devices Act authorizes civil penalties on any person who violates a
requirement of the Act which relates to devices
d. Generic Drug Enforcement Act added civil penalties for misconduct in
connection to an ANDA
e. Food Quality Protection Act authorizes them from people other than growers
who introduced food containing unsafe pesticide chemicals into IC
f. Mammography Quality Standards Acts includes CPs for various violations
regarding mammography facilities
vi. Guidance for FDA Staff: Civil Monetary Penalty Policy
1. Guidance on pursuing CMPs recommendations under the Safe Medical Devices Act
2. CMP cases should serve to eliminate the profit from violative activity and/or provide
non-compliant firms with the financial incentive to correct violations
3. CMP is considered to be a remedial action, not punitive-designed to influence future
conduct of that firm and similar firms directly or indirectly
4. When the monies spent on corrective actions will be deducted from the fine imposed,
CMP action can also provide non-compliant firms with a financial incentive to come into
compliance
5. First resolved by admin hearings, if requested, before a ALJ then appeals for to the HHS
Departmental Appeals Board, and then the US Circuit Court of Appeals
a. Can avoid hearings through consent decrees
vii. CMP may be considered in cases where
1. Other regulatory action is NOT appropriate
a. Current violations warrant consideration of seizure or injunction
b. Combo with CMP should be rare, only for egregious or flagrant violations
c. If other civil action is not appropriate, consider whether prosecution is
appropriate
i. CMP and prosecution will not be initiated for the same violative conduct
d. If none are appropriate, consider CMP for both current or continuing violations
i. Even if all violations have been corrected, but maybe they took a long
time
2. Prior warning has been given
a. Rare that CMP should be initiated without prior warning
3. FDA policy is clear and
a. The key is whether a neutral person would say that industry had or should have
had a clear understanding of FDA’s requirements
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i.
4. Statutory factors in Section 303 f support the case
a. FDA is required to consider
i. The nature, circs, extent, and gravity of the violations
ii. Ability to pay, effect on the ability to continue to do business, any
history of prior violations, degree of culpability and other such matters as
justice may require
iii. Nature of the violations refers to a general evaluation of the type and
seriousness of statutory or regulatory violations considered in the
abstract, not with the facts of this case
iv. General seriousness of the violation refers to the relationship of the type
of violation to the different purposes of the Act
v. Those that go to the core of the Act’s purposes are more serious, other
violations vary
vi. Circumstances of the violations refers to the context in which the
violations occur and to facts extrinsic to the legal elements of the
violations themselves
vii. May include both mitigating and aggravating factors
viii. Extent of the violations refers to the number and variety of document
violations and the length of time during which the violations continued
ix. Gravity of the violations refers to the consequences, actual or potential,
of the violations
x. Degree of culpability requires consideration of whether the violations
were intentional, reckless, careless or inadvertent
viii. FDA is required to reduction CPs for small entities, and adjust CMPs for inflation every 4
years
INFORMAL COMPLIANCE CORRESPONDENCE
1. Section 309 of the FDCA permits FDA to decline to institute formal enforcement
proceedings for minor violations of the Act whenever it believes that the public interest
will be adequately served by a suitable written notice or warning
2. Beginning in the 1970s, the agency developed regulatory letters and other informal
compliance correspondence as alternative to court enforcement
a. Regulatory letter (now Warning Letters) warned a violator that formal
enforcement was likely in the absence of voluntary compliance
b. Report of investigational Finding (Information Letter, now Untitled Letters)
requested voluntary correction but made no representation that formal
enforcement action was imminent
3. Warning Letters
a. It is the FDA’s practice to give individuals and firms the opportunity to take
voluntary and prompt corrective action before it initiates an enforcement action
b. Responsible officials in positions of authority in regulated firms have a legal duty
to implement whatever measures are necessary to ensure that their products,
practices, processes or other activities comply with the law
i. Under the law such individuals are presumed to be fully aware of their
responsibilities
ii. Shouldn’t assume you are going to get a warning letter before
enforcement action
c. Does not represent a commitment to enforcement action, but we still may come
after you
d. Issued by the district director, division director, or higher agency official
4. Untitled Letters
a. Cites violations that do not meet the threshold of regulatory significance for a
Warning Letter
b. Letter is not titled and does not include a warning statement that failure to take
prompt correction may result in enforcement action
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c. Letter requests a written response from the firm within a reasonable amount of
time, unless more specific instructions are provided in a relevant compliance
program
d. Any appropriate agency compliance official may issue an Untitled Letter
5. Comment: Mandatory OCC Clearance of Enforcement Correspondence
a. In 2001, HHS Sec directed FDA to submit all warning letters to the OCC prior to
issuance so that they can be reviewed for legal sufficiency and consistency with
agency policy
b. Since then, the number of FDA warning letters dropped
c. Even so, FDA does not consider warning letters to be final agency action on
which it can be sued
6. *** Now under Obama gave a lot more autonomy to district offices to issue them
j.
PUBLICITY
i. FDA will sometimes work with you to avoid publicity
1. May issue a bare bones complaint, without gory details of the violations to control
publicity
2. Need to work with them to get these results
ii. DOJ loves publicity so if you sign a consent decree with them likely to be publicized
iii. FDCA 705 expresses authorizes the issuance of information to the public
1. Obligates FDA to publish from time to time summaries of all formal enforcement actions
resolved in court
2. Also allowed FDA to disseminate information regarding regulated products in situations
involving imminent danger to health, or gross deception of the consumer
iv. Administrative Practices and Procedures: Publicity Policy (Withdrawn in 1991)
1. Issuing publicity is important to FDA fulfillment of its commitment to PH and honest
marketing of products
2. FDA seek publicity for several purposes
a. To warn against the use of marketed products that may be hazardous
b. To warn against gross economic deception
c. To encourage public comment on proposed regs or actions and other public
participation in FDA activities
d. To report to the public on adjudicated court proceedings
e. To present to the public FDA’s views on matters of public interest
f. To report on studies or investigations that may form the basis for an FDA
regulatory action
3. There are occasions when publicity can have a negative or adverse effect
a. Could create a greater hazard than the one proposed by the violation, causing
economic harm to both individuals and firms
4. FDA does not issue any publications or provide any information for the purpose of
seeking publicity in the news media
a. Public appearances by FDA employees are also not considered to be publicity
5. Personally disparaging or gratuitously critical remarks, not required in reporting the facts
of a situation, should be and will be avoided
6. Negative information and firm names will only be mentioned as deemed necessary
a. FDA will provide advance notice of the publicity to the firm before the general
public when the publicity will have adverse effects for that firm, giving them
time to have a media response
7. There are also policies for retraction and correction when needed
v. FDA has said that presses releases are issued when they feel that the scope of the problem
warrants more widespread publicity
1. Talk papers are used when the problem is of a narrower scope and available to the press
and used as source for news stories
vi. Hoxsey Cancer Clinic v. Folsom (DDC)
1. Facts: FDA has issued a circular, copies of which are posted in post offices, warning the
public that the Hoxsey cancer treatment has been found worthless insofar as internal
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cancer is concerned. Hoxsey brings this case to enjoin HHS and FDA from dissemination
of the poster.
2. H: There is no due process required when an agency is not making an order or issuing
directions, but instead is disseminating info and warning the public.
vii. FDA Officials Privilege in Defamation Suits
1. SC addressed this issue in Barr v. Mateo, a case involving a libel suit brought against the
Director of the Office of Rent Stabilization
a. Court embraced a broad version of the privilege, holding that executive officers
are absolutely immune from defamation claims if they issued the statements in
the appropriate discretionary exercise of their official duties
b. Applies to both high-ranking officials, and officers anywhere in the executive
hierarchy
k. DISCRETION
i. Heckler v. Chaney (SC)
1. I: Extent to which a decision of an administrative agency to exercise its discretion not to
undertake certain enforcement actions is subject to judicial review under the APA
2. Facts: Respondents are several prison inmates convicted of capital offenses and
sentenced to death by lethal injection of drugs. They petitioned the FDA that the use of
drugs in this way violated the FDCA, and requested enforcement action, FDA refused.
3. H: Case law leads us to the conclusion that an agency’s decision not to take
enforcement action should be preserved immune from judicial review.
ii. Heterochemical Corp v. FDA (Dist Crt case)
1. H: Only case since Chaney to reject agency’s argument that it had non-reviewable
discretion not to take enforcement action. Here, the court said where the agency had
already conducted an investigation and determined there as a violation, they had to
take action.
l. CONSTITUTIONAL LIMITS
i. US v. Jamieson-McKames Pharma
1. Facts: JM is a MO corp with POB in STL, manufacturing, purchasing, packaging,
labeling, distributing and selling drugs. Federal and state agents entered and searched
their premises and the Ds were later charged with an 11-count indictment with
counterfeit, adulterate, and misbrand drugs. Also charged that the Ds committed these
acts with the intent to defraud and mislead, rendering such felonies. Employee in charge
was given a notice to inspect, but no warrant to inspect was obtained.
2. H: An exception from the search warrant requirement has been delineated for
industries long subject to close supervision and inspect and pervasively regulated
businesses. Drug manufacturing industry is included in that class.
a. Next question is whether the D consented to the warrant, since a notice to inspect
is authorized only when there is valid consent
i. The question is whether appellants refused to permit entry or inspection,
if so FDA needed to get a warrant.
3. Takeaway: A warrant based on administrative showing of probable cause is valid in
this pervasively regulated industry where they have a lesser expectation of privacy.
ii. FDA’s Authority to Take Photos During an FDA Establishment Inspection Under Section
704
1. FDA MUCH MORE INSISTENT ABOUT PHOTOS THESE DAYS
a. Photos are much more effective in court
2. Manufacturers don’t like them, don’t want the evidence in
3. As a guide to FDA investigators, FDA maintains an Investigations Operations Manual
describing procedures to follow during these inspections
4. Photographs section discussing the taking of photographs and making of photocopies
during inspections
a. Every one of the photographs should be taken with a purpose
b. Investigators should assume that they have authority to take photos, don’t ask for
manager permission
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5. Inspections must be conducted during reasonable times, within reasonable limits and in a
reasonable manner, but Courts usually side with the agency when this is challenged
6. Whether a refusal to allow photos is an actual refusal of the inspection under 704 is not
settled
a. FDA may consider it to be, and if they feel that they cannot conduct their
inspection, they should contact their supervisor to determine if a warrant should
be requested
b. These warrants usually contain specific authorization to take pics
7. If managers refuse, the FDA is supposed to reference certain cases where the courts have
upheld taking of photographs-although none of them are on point, to either specifically
taking photos during an inspection or to the FDA
iii. U.S. v. Gel Spice (2nd Circ 1984)
1. Facts: DC found appellants guilty of all 10 counts of violating the FDCA. Gel Spice
contends that the FDA acted in bad faith by conducting four inspections without warrants
after having already made a decision to prosecute Gel Spice.
i.
H: When FDA decides to utilize its criminal enforcement option it may not abandon
its civil enforcement responsibilities and it is not thereby prohibited from any
further agency surveillance pending the conclusion of criminal proceedings. Thus
even though the FDA was pursuing criminal enforcement of the Act at the same time
as inspections does not imply bad faith.
a. LaSalle case that restricts issuance of a subpoena to the period before a criminal
investigation is not applicable here because the FDA’s power under the FDCA is
a general grant for criminal prosecution
1. Even if we did apply that here, we believe that the four inspections, as
found by the DC were conducted in good faith, ie pursuant to a valid
admin scheme and not for the purpose of fathering evidence for a
criminal prosecution
16. PROMOTION AND COMMERCIAL SPEECH
a. Want to inspect a drug facility?
i. You can use GMP (as opposed to a food facility where you couldn't use this)
ii. Also could look for labeling...say you find a bunch of books in there
b. Off-label promotion-->misbranding
i. 502 a: False or misleading in any particular
1. Newspaper article
2. Do you want to have to bring this into court every time with evidence trying to show
that experts say its false or misleading...wastes resources!
3. Do you need to prove all that stuff to show that this product is misbranded?
a. Is there another angle? Besides 502 a
b. INTENDED USE....intent to use it for unapproved use (besides what they
submitted to the FDA)
i. 502 f: adequate directions for use
1. didn't put adequate directions for any intended use
2. Alberty case-ALL intended uses
a. But is a newspaper ad labeling? NO but it doesn't
matter it’s not specified that it needs to labeling
ii. More often relied on by FDA since a lot easier for them to win this
case
1. It’s called the squeeze play...not approved for this...you
intended it to be used for this use...didn't put adequate
directions...we win
ii. What can be labeling?
1. Can a book be labeling?
a. May or may not be labeling
i. Depends on what it says, how it is presented etc
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ii. Sell them together, suggest that they be put together at a store etc etc
2. what about advertising materials?
a. if you saw a bunch of ad materials in the facility....could establish the intent
so you would have a legit regulatory interest in the materials
b. FTC deals with it though not FDA
3. Does FDA have expressed interest on drug advertising?
a. ONLY On prescription drugs
i. 502 n authority over prescription drug ads
1. not false or misleading
2. brief summary of side effects, etc basically the package insert
in an ad
c. Lets say you have a study that says you can use a drug for another use
i. What do you do with it???
1. Get it published in peer review journal, then docs will read it and prescribe it off
label
ii. 502 n doesn't define advertising
1. FDA has made a listing of things it considers advertising but otherwise hasn't
defined it, i.e. tv, radio, etc
iii. What about trying to get this study at a CME, press conference, seminar etc?
1. Docs don't pay the drug companies do, FDA really didn't want to do away with this
but needed to regulate it
2. Supporting CME
a. Look at a number of factors to consider to make sure there is enough
independence between drug company and CME
b. At what point is their influence too much?
i. So you can't pay for the doc to come and his spouse and have it in
Bermuda etc
ii. Need to live within the FDA rules, they know the rules and generally
stay within them now
iii. Not something that people really worry about now
d. SCOPE OF LABELING
i. Research Laboratories, Inc v. US (9th Circ 1942)
1. Facts: US Marshall seized 600 unites of Nue-Ovo and circulars entitled "information on
Nue-Ovo and its value in Arthritic and other Rheumatoid symptoms"
2. H: The materials used by the appellant in this case unfairly omitted unfavorable
comments regarding some of Nue-Ovo's ingredients. It was to cover precisely such tricky
omissions and suppressions that Section 321 n was designed.
a. Furthermore in any case where an article is alleged to be misbranded
because the labeling is misleading in any respect, it is made mandatory by
321 n itself that the jury shall take into account such omissions or
suppressions
3. Takeaway: This case demonstrates that the FDA may proceed against misleading claims
of therapeutic value masquerading as assertions of opinion.
a. Deception may results from label statements that are technically accurate but
misleading in overall impression, thus a disclaimer may not be availing
ii. Deceptive Names
1. The name of a product may imply a claim of effectiveness that, if false, may render it
misbranded
a. Can't escape liability by attributing false reps of a drug's effectiveness to 3d
parties
2. Another common deception has been found in labeling for products capable of treating
minor ailments such as constipation, whose labeling also proclaims an ability to relieve
symptoms that accompany more serious conditions for which the product is of no use
whatever
a. Section 201 n imposes affirmative disclosure requirements
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b. Any information on a company sponsored website is regarded by FDA as
labeling, advertising, or both
iii. Current FDA Enforcement Strategy
1. Court enforcement of section 502 a no longer plays a major role in the FDA's efforts
to combat false or misleading therapeutic claims for drugs because the Drug
Amendments of 1962 require premarket proof of the effectiveness of all new drugs
2. Rarely uses 502 j for enforcement because hard to prove
a. Have to submit labeling during NDA process and FDA can force a manufacturer
to recast or omit proposed labeling claims before allowing a drug to be marketed
b. Thus, enforcement usually charges a violation of the new drug provisions rather
than misbranding provisions
3. FDA usually just regulates prescription drug advertising, requiring the manufacturer to
disseminate corrective advertisement through the same channels as the original message,
which rarely goes to court
iv. FDA has priorities for initiating legal action against drug quackery
1. Direct health hazard
2. Indirect health hazard
3. Major economic fraud
4. Minor economic cheats
v. If a competitor is making claims that are false or misleading, including claims making
unjustified comparison against the company's own product, they can:
1. Complain to FDA request them to take appropriate reg action; very few resources, if it
does take action its usually limited to a warning letter
2. Complain to FTC which takes months and is not likely
3. Complain to the National Advertising Division of the Better Business Bureau, which
conducts a program under which the company may initiate a proceeding in which the
NAD reviews the competitive claim and offers an opinion on it
a. Party making the competitive claim will usually comply with the opinion, if not
they refer the case to the FTC and FDA where it gets a higher priority
4. Complain to Broadcast Media which produces faster action if the matter is clear cut, but
they can be brought into FTC cases so its own for clearly misleading advertising
5. Bring a Lanham Act Lawsuit: provides a private right of action for unfair competition
based on false or misleading claims in labeling or advertising
e. ADEQUATE DIRECTIONS FOR USE (502 f 1)
i. Alberty Food Products Co v. US (9th Circ 1950)
1. Facts: US filed a libel involving 33 bottles of Ri-Co tablets therein that the drug was
misbranded. The labeling of the drug failed to bear adequate directions for use since it did
not state the purpose or condition for which the drug was intended. Newspaper ads rec'd
the drug for use in the treatment, mitigation, and cure of arthritis and rheumatism.
Alberty says that the label doesn't require statement of the disease for which it is to be
used.
2. H: Newspaper ad didn't accompany the drug into IC nor were distributed by vendors or
otherwise to purchasers, like in Kordel. Users of the drug should be entitled to a chance
to somewhere find and examine a label which is complete enough to give them the info
which would lead them to purchase a drug for that purpose.
3. Follow Up:
a. In a later case Alberty argued that ad claims similarly cannot be considered in
determining the intended uses of a drug which the labeling must bear adequate
directions
b. Court said in order for the labeling of a drug to bear adequate directions for use it
must state the purpose and conditions for which the drug was intended and
sufficient information to enable a layman to intelligently and safely attempt self
medication
4. BUT If Alberty had tried to include info about arthritis on the labeling, FDA would
then have claimed that the produce was misbranded
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f.
a. Known as the squeeze play
5. Since 505 requires the introduction into IC, the FDA needs to use 501 and 502
misbranding and adulteration provisions when bringing an action against a person
selling within a state
ii. US v. Article of Drug Designated B-Complex Cholinos Capsules (3d Circ 1966)
1. Facts: Gov't charges misbranding because labeling of the products was not in compliance
with the act because it failed to bear adequate directions for use. Court found that the
vitamins seized were drugs since labeling consisted of a catalog of the vitamin and
mineral products offered for sale by claimant.
2. H: Whether labeling contains adequate directions for use of an article necessarily
depends upon what it is intended to be used for. Catalogs contained nothing whatever to
indicate for what disease or conditions the various preps were supposed to be beneficial
and nothing to show how they were to be used. Broadcast on radio by company
consultant was labeling.
3. Take Away: Pushed to its extreme, this decision would allow FDA to regulate all
therapeutic claims made in ads for OTC drugs
a. But FDA and FTC have agreed that FTC has primary jurisdiction over this kind
of advertising
iii. Current FDA Regulation of Adequate Directions for Use:
1. Adequate directions for use means directions under which the layman can use a drug
safely and for the purposes for which it is intended
2. Directions for use may be inadequate because of omission or incorrect specification of
a. Statements of all conditions, purposes or uses for which such drug is intended,
including conditions, purposes or uses for which it is prescribed, rec'd or
suggested in its oral, written, printed or graphic ads, and conditions, purposes or
uses for which the drug is commonly used; except that such statements shall not
refer to conditions uses or purposes for which the drug can be safely used only
over the supervisions of a doc
3. All labels must be in English, can include other languages
DRUG AND DEVICE PROMOTION
a. Promotion of Unapproved Uses
i. Dissemination by manufacturers of information about unapproved drugs or unapproved
uses of approved drugs has presented vexing problems for FDA
b. 202 1 e 4 provides that advertising cannot recommend or suggest any use that is not in the
labeling in an approved NDA
c. 312 7 a of the IND app regs, though prohibiting any representation in a promotional
context than an investigational drug is safe and effective, goes on to state:
i. Provision is not intended to restrict the full exchange of scientific information concerning
the drug, including dissemination of scientific findings and scientific or lay media
d. Difficult to reconcile these provisions
i. Promotional activities for prescription drugs have expanded far beyond the materials
traditionally thought of as advertising, now includes newspaper articles, talk shows,
seminars, etc
ii. Definitions for labeling and advertising can cover virtually all activities disseminating
information about a drug which are done by or on behalf of the manufacturer
e. Makes sense for information to flow freely during the IND process, since it is an investigational
phase
i. Firm should be able to communicant fully with their researches and investigators can
publish their results in journals and in seminars and symposia
ii. But a firm cannot disseminate any info it wishes simply because they disguise it as a
seminar or call it education
1. Then they are just trying to get the drug to be used for a wide variety of
unapproved uses
iii. Seminars should be run by professional or educational organizations responsible for
editing and disseminating written materials, not influenced by the firm
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iv. Essence of these regulations is that the information be accurate, truthful and balanced
1. Won't pursue action if the information is complete and balanced
2. FDA has issued a number of policy statements about which ad/promo practices
don't fall within the regs
3. Journal articles by independent publisher are not ads or labels if the manufacturer
makes no contribution to the article and doesn't use the article for promo
4. FDA will not regulate as labeling any info provided by a pharma company to a
doc in response to an unsolicited request
f. Washington Legal Foundation v. Henney (DDC)
i. Facts: Lower court held that the FDA was violating the 1st Amendment rights of P's
members by unduly limiting the manner in which drug manufacturers may disseminate
info relating to unapproved or off label uses of FDA approved drugs.
ii. H: Under Central Hudson:
1. Court looks first to determine whether the speech at issue is false or inherently
misleading
a. In this case the speech is not false or inherently misleading
b. FDA may not restrict speech based on its perception that the speech
could, may or might mislead-has to be more likely to mislead than to
inform
2. If not, the gov't must demonstrate a substantial interest that is directly advanced
by the reg without burdening substantially more speech than necessary
a. Ensuring that docs receive accurate and unbiased info upon which to
make prescription decisions
i. Unvailing, can't assume everyone is stupid
b. Encouraging drug manufacturers to seek FDA approval of off label uses
i. Substantial, and supported by FDAMA's supplemental
application for additional uses
ii. But this amount to constitutional blackmail-comply with the
statute or sacrifice your 1st Amendment rights
3. Court finds that the FDAMA unconstitutionally restricts protected
commercial speech
iii. Take Away: FDA shall not in any way prohibit, restrict, sanction or otherwise seek to
limit any pharm or med device manufacturer or any other person
1. From disseminating or redistributing to med professional any article published in
a peer reviewed professional journal
2. From disseminating reference textbooks or parts thereof
3. From suggesting content or speakers to an independent program provider in
connection with an education seminar even if they discuss unapproved uses
4. ***Doesn't apply of the material is false or misleading
iv. After the case the FDA said they still may proceed to determine from a manufacturer's
written materials and activities how it intends that its products be used since intent to
promote an unapproved use may be the basis for misbranding.
1. Later decided not to bring legal action against off label promotion
b. Good Manufacturing Practice
a. 501 a 2 explicitly declares a drug to be adulterated if it is not manufactured in conformity
with current GMP
b. US v. An Article of Drug...White Quadrisect (7th Circ 1973)
i. Facts: Lower court condemned the shipment because the D violated GMP: Failure to
keep basic production records, inadequate testing of active ingredients before use,
insufficient test of finished product prior to shipment. Appellant contents that the
provision is unconstitutional under the Due Process Clause because of its alleged
vagueness.
ii. H: Sustain the GMP provision, which the D violated.
c. FDA Policy on Industry Supported Educational Activities, Nov 1997
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a. Agency has traditionally recognized the important public policy reasons not to regulate all
industry supported activities as advertising or labeling
b. To permit industry support for the full exchange of views in scientific and educational
discussions, FDA has distinguished between non-promotional and otherwise independent from
the substantive influence of the supporting company activities and otherwise not
i. Those that are independent are not treated as advertising or labeling are not subject to the
agency's regulatory scrutiny
c. Companies and providers who wish to ensure that their activities will not be subject to regulation
should design and carry out their activities free from the supporting company's influence and bias,
based on a combination of these factors
i. Control of Content and Selection of Presenters and Moderators
ii. Disclosures . . . of: (1) The company's funding of the program; (2) any significant
relationship between the provider, presenters or moderators, and the supporting company
(e.g., employee, grant recipient, owner of significant interest or stock);
iii. The Focus of the Program . . . The agency will consider whether the intent of the
company and the provider is to produce an independent and nonpromotional activity that
is focused on educational content and free from commercial influence or bias
iv. Relationship Between Provider and Supporting Company . . . The agency will consider
whether there are legal, business, or other relationships between the company and the
provider that could place the company in a position whereby it may exert influence over
the content of the activity
v. Provider Involvement in Sales or Marketing
vi. Provider's Demonstrated Failure to Meet Standards
vii. Multiple Presentations
viii. Audience Selection
ix. Opportunities for Discussion
d. CONSTITUTIONAL ISSUES
a. Thompson v. Western (SC April 2002)
i. Facts: FDAMA, amending FDCA, exempts compounded drugs from FDCA's new drug
requirements. Script must be unsolicited and the pharmacy compounding may not
advertise or promote the compounding any drug, but can promote the compounding
service. Respondents are a group of pharmacies that specialized in drug compounding
and have prepared promotional materials to inform patients and docs of the use and
effectiveness of specific compounded drugs.
ii. H: Gov't asserts three substantial interests that underlie FDAMA
1. Preserving the effectiveness and integrity of the FDCA's new drug approval
process and the protection of PH
2. Preserving the availability of compounded drugs for patients who cannot use
commercially available FDA approved products
3. Achieving the proper balance between these two interests
iii. Wouldn't make sense to require compounded drugs to undergo new drug approval
process, pharmacies can't afford it and would just stop compounding; but refraining from
advertising is NOT an ideal way to permit compounding and guarantee that large scale
manufacturing doesn't happen
1. Can use less restrictive methods
iv. FDAMA's restriction on compounding advertising is unconstitutional
e. FDA Notice re First Amendment Issues (May 2002)
a. FDA is seeking public comment to ensure that its regs, guidance, policies and practices continue
to comply with First Amendment case law
b. Recent case law has emphasized the need for not imposing unnecessary restrictions on speech
c. Some statutory provisions that FDA enforces explicitly limit speech, much of the FDCA depends
on the use of words
i. SC struck down ban on advertising in Western States and lower courts have also held that
the FDA musts adhere to the First Amendment's guarantee of free speech
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d. To be sure, FDA will continue to regulate commercial speech as part of its mandate but has
questions for public
f. FDA Reprints Policy (Jan 2009)
a. Guidance is intended to describe the FDA's current thinking regarding Good Reprint Practices
with regard to the distribution by a drug or device manufacturer of medical journal articles and
scientific or medial reference publications that discuss unapproved new uses for approved drugs
or approved or cleared med devices marketed in US to healthcare professionals or entities
b. FDA recognizes the important PH and policy justification supporting dissemination of truthful
and non-misleading medical journal articles and medical or scientific reference publications on
unapproved uses of approved drugs/devices
c. Should follow these recs
i. Peer review
ii. Generally available in bookstores or other independent distribution channels and not
edited or significantly influenced by a drug or device manufacturer
iii. Should address adequate and well-controlled clinical investigations
iv. Must not be false or misleading or pose a significant risk to the PH if relied on
v. NO editing or highlighting, and must have additional information including bibliography
of studies reaching different conclusions and disclosure statement
d. If you follow these recs, then won't establish intent that the product be used for an unapproved
new use
g. US v. Caronia (2nd Circ 2012)
a. Facts: Orphan hired Caronia as a specialty sales consultant to promote Xyrem. Started Orphan's
speaker programs where he enlisted physicians to speak to other docs about FDA approved drug
use. Caronia and a doc were audio recorded on 2 occasions promoting the drug for off-label uses.
b. H: Gov't contends that Caronia was not prosecuted fro his speech but because his promotion
served as evidence of intent for off-label uses for which Xyrem's labeling failed to provide any
directions BUT the record makes clear that the Gov't prosecuted Caronia specifically for his
promotion and marketing efforts.
i. We decline the gov'ts invitation to construe the FDCA's misbranding provisions to
criminalize the simple promotion of a drug's off-label use
ii. Because the FDCA is content and speaker based it is subject to heightened scrutiny
1. Prohibiting the truthful promotion of off-label drug usage does not directly
further the gov'ts goals of preserving the efficacy and integrity of the FDA's drug
approval process and reducing patient exposure to unsafe and ineffective drugs
2. Could pursue several other alternative without excessive 1st Amendment
restrictions
a. More directly address off label use, guide physicians, cap off-label
scripts, prohibit off-label use altogether
iii. We construe the FDCA as not criminalizing the simple promotion of a drug's offlabel use because such a construction would raise 1st Amendment concerns
iv. Livingston Dissent (Adam’s thinks this is the correct interpretation):
1. Gov't must prove that the D conspired to introduce or cause to
be introduced a drug into IC AND that the drug was misbranded
2. Clearly Caronia was convicted for his conspiracy not his speech, speech was
evidence of that conspiracy
3. FDCA prohibitions on off label marketing advances the interest of not
wanting off-label use
a. Least restrictive way, other ways ineffective
v. **THE FDA AND MOST COURTS AGREE WITH THE DISSENT
1. Hot issue though, some people are learning towards majority.
17. TOBACCO
a. FDA v. Brown and Williamson Tobacco Corp (2000)
i. H: The FDA's claim to jurisdiction contravenes the clear intent of Congress
1. Apply Chevron, first step: did Congress speak directly on the issue?
a. Here Congress has and precluded the FDAs jurisdiction on tobacco products
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b. Congress has consistently considered and denied jurisdiction to the FDA to
regulate tobacco products
2. Purpose of FDCA is to make sure products are safe and effective, any harmful effect
must be offset by therapeutic ones
a. In that case, since the FDA has found tobacco products to be so unsafe, it is clear
that in regulating them they surely could not approve them for market
b. Family Smoking Prevention and Tobacco Control Act
1. Signed into law in 2009, provides the FDA with regulatory authority over virtually every aspect
of the design, production, marketing, and advertising of tobacco products
2. FDA will move expeditiously to implement Act
1. Already launched its new Center for Tobacco Products, with director Dr. Deyton
2. Also established the Tobacco Products Scientific Advisory Committee (TPSAC)
3. First lawsuit challenging constitutionality has already been filed, will be more
1. Section 2 sets out the findings of Congress to support the act, wanted it to be as strong as
possible
2. Discuss the many harms associated with tobacco use
1. Effect on children
2. Addictive power of nicotine
3. Impact of tobacco on healthcare costs
4. Risks posed by products marketed as modified risk products
5. Past efforts of industry to target youth
3. Section 3 sets out the purposes
1. Ensure that FDA has adequate authority to regulate tobacco products
2. Not intended to affect the growing, cultivation, or curing of raw tobacco
3. If it exceeds constitutional limitations, section 5 provides for severability of those
provisions
4. FDA required to issue a number of regs and take other actions in next few years
1. Section 6 delays implementation of provisions that imposed fixed deadlines on
agency actions
2. Statutory deadlines are to be determined by reference to the date on which FDA
beings to collect use fees, and the law allows for 90 days additional at FDA
discretion
3. Don't apply to FDA's reissuance of its final rule restricting tobaccos ads and
availability or to the revision of cigarette labeling and ad warnings
1. Also don't apply to actions required of industry
4. FDCA
1. FDCA amendments provide essential definitions, a comprehensive stat framework, and
conditions that would cause a tobacco product to be adulterated or misbranded,
subjecting the manufacturer and/or product to enforcement actions
2. FSPTCA 101 adds a new Chapter IX to FDCA
3. Section 203 contains conforming amendments to sections of the FDCA that address
seizure, injunction, and important detention, etc
4. 301 adds provisions intended to prevent illicit trade in tobacco products
5. Definitions
1. 101 rr 1 broadly defines tobacco product as any product made or derived from tobacco
that is intended for human consumption, including any component, part or accessory of a
tobacco product (except for raw materials other than tobacco used in manufacturing a
component part or accessory of a tobacco product)
2. Excluded are drugs, devices, and combo products which are subject to reg under FDCA
Chapter V
3. 101 a prohibits the marketing of a tobacco product in combination with other articles
subject to regulation under the FDCA (ie joint marketing of a cigarette and tobacco
cessation drug)
4. FDCA section 900 also puts forth other definitions
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1. Additive definition is similar to food additive definition, FDA can be expected to
consider prior admin and judicial interpretations of food additive in determining
how to apply the definition of a tobacco product additive
5. Chapter IX currently applies only to certain forms of tobacco: cigarettes, cigarette
tobacco, roll your own tobacco, smokeless tobacco
1. FDA can render Chapter IX applicable to other forms of tobacco by issuing a
regulation to that effect
2. Does not apply to producers of tobacco leaf, including tobacco warehouses
6. Adulteration and Misbranding
1. 902 sets out standards
1. Adulterated if t bears or contains any filthy, putrid, or decomposed substance, or
any added
poisonous or deleterious substance; it was prepared, packed, or held under
insanitary conditions whereby it may have been contaminated with filth or
rendered injurious to health; the methods, facilities or controls used for its
manufacture do
not conform to good manufacturing practices (GMPs); it does not comply with an
applicable product standard; it is marketed without an order where such an order
is required; or there has been a failure to pay a user fee
2. 908 FDA has authority to issue order public notification to eliminate an unreasonable risk
of substantial harm to the PH
1. Must first determine that notification is necessary to eliminate the risk, and that
no more practical means of doing so are available
2. If there is a reasonable probability that a tobacco product contains a
manufacturing or other defect not ordinarily contained in tobacco products on the
market that would cause serious, adverse health consequences or death, then the
FDA must issue an order immediately stopping distribution
1. Can also order recall
3. Number of new misbranding provisions under 903 a
1. A tobacco product is misbranded if its labeling: is false or misleading in any
particular; fails to include specified information (e.g., name and place of
business, and percent of tobacco used in the product that is domestic versus
foreign grown); fails to conspicuously bear required statements or any directions
for use or warnings required by regulation; or does not comply with an applicable
product standard.
2. A product is also misbranded if: its advertising is false or misleading; it is sold or
distributed in violation of advertising restrictions imposed by FDA; or its
advertising or printed matter fails to include the product’s established name, a
brief statement of warnings, or a description of the products components or
formula as required by FDA.
3. In addition, a product is misbranded if it is from an unregistered establishment or
otherwise does not comply with the requirements of section 905 (discussed
further below), or if there has been a failure to comply with requirements
pertaining to the submission of health information, notification and recall
activities, or reporting.
4. Not limited to the post market context
1. 903b grants FDA premarket approval authority over labeling to ensure
compliance with applicable requirements
2. It also grants FDA authority to subject advertising for modified risk products to
premarket approval
7. Adulterated or misbranded tobacco products are subject to the enforcement provisions of the
FDCA:
1. Seizure under 304
2. Detention under 801 a
3. Injunction 302
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4. Civil and Crim Liability under 303
8. FDA's access to Info
1. Chapter IX containers a number of provisions designed to keep FDA informed of which
manufacturers and importers are in op, and of which products are on the market and what
their attributes are
2. FDA also has authority to require the submission of information on the health effects of
tobacco products
9. Establishment of Standards
1. FDCA section 907 establishes a standard for cigarettes that prohibits the addition of
characterizing artificial or natural flavors, herbs or spices, with an exception for menthol.
Congress deferred action on menthol pending further study by
the TPSAC on the potential effects of prohibiting menthol-flavored cigarettes on
children and racial and ethnic minorities
2. Section 907 also authorizes FDA to modify the standard for cigarettes and to
establish standards for other tobacco products as “appropriate for the protection
of the public health.”16 The question of whether a standard is appropriate “for the
protection of the public health” must be determined by reference to
1. scientific evidence concerning the risks and benefits to the population as a whole,
including users and nonusers of tobacco products, of the proposed standard; the
increased or decreased likelihood that existing users of tobacco products will stop
using such products; and the increased or decreased likelihood that those who do
not use tobacco products will start using such products.
3. If the standard require the reduction or elimination of an additive, constituent or other
component on the ground that it may be harmful, then anyone objecting to the proposed
standard can submit evidence demonstrating that the proposed standard does not reduce
or eliminate risk of illness or injury
1. Could have the effect of curtailing FDA's use of standards because of the
resources needs to responds to objectors
4. Standard must includes provisions that are appropriate for the protection of the PH,
including provisions for nicotine yield and reduction of other constituents or harmful
components
5. Any provisions of a standard are subject to periodic reevaluation by FDA in light of new
scientific information or technological data, and FDA has authority to amend or revoke a
standard.
6. FDA must consider whether compliance with the standard is technically achievable
1. Whether the standard could have countervailing effects on tobacco users and non
users, ie creation of significant demand for contraband
7. May refer a standard related reg to TPSAC or at the request of an interested person for
good cause shown
1. TPSAC consists of 12 mems: 9 voting (seven scientists, one gov't official, and
one public rep) and 3 non voting (one manufacturing industry resp, one small
manufacturer rep, one grower's rep)
10. Things singled out for special consideration
1. Menthol cigs (1 year)
2. Dissolvable tobacco (2 years)
2. Discount Tobacco City & Lottery (6th Circ 2012)
1. Facts: tobacco companies brought action against FDA challenging the FSPTCA on free speech, due
process, and takings grounds
2. H: heightened scrutiny does not apply since SC Cipollone case said that cig manufacturers must disclose
serious risks.
1. Under the Modified Risk Tobacco Product Rule, Ps may only commercially market a product as
modified risk if, after app to the FDA, it is determined that the product, as used by consumers will
significantly refused harm and the risk of tobacco related disease to individual tobacco users and
benefit the health of the pop as whole taking into acct both users of tobacco products and persons
who don't currently use them
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1. Survives Central Hudson's fit and tailoring test
2. Affirm decision of DC upholding Act's restrictions on the marketing of modified risk
tobacco products, bands on event sponsorship, branding non tobacco merchandise, and free
sampling; and the requirement that tobacco manufacturers reserve packaging space for
textual health warnings
1. The ban of use of color and graphics in tobacco ads is vastly overboard and
therefore gov't doesn't meet the Central Hudson burden
3. Reverse DC's determination that the Act's restriction on statements regarding the relative
safety of tobacco products based on FDA regulation is unconstitutional and its
determination that the Act's ban on tobacco continuity programs is permissible under the
1st Amendment
3. R.J. Reynolds (DC of DC 2012)
1. Facts: Ps are five tobacco companies that manufacture cigs. FDA published a final rule requiring the
display of nine new textual warnings, along with certain graphic images on the top 50% of the front and
back panels of every cigarette package manufactured and distributed in the US . P alleges that many of
these images are technically manipulated, enhanced, or animate or that they depict actors to achieve the
desired image. FDA cited these nine images salience-defined as a warning's ability to evoke emotion-as a
primary selection criterion.
2. H: Heightened scrutiny does not apply, but it fails the Zauderer and Hudson test.
1. Narrow exceptions do exist in compelled commercial speech and allow the Gov't to require
certain disclosures to protect consumers from confusion or deception (Zauderer)
2. Neither designed to protect the consumer from confusion or deception, nor to increase consumer
awareness of smoking risks, rather they were crafted to evoke a strong emotion response to make
consumer stop or not start smoking
3. Gov't failed to carry its burden of demonstrating a compelling interest and its burden of
demonstrating that the Rule is narrowly tailored to achieve a constitutionally permissible
form of compelled commercial speech
4. Court concludes that these graphic images violate the 1st Amendment by unconstitutionally
compelling speech
4. Sottera v. FDA (DDC 2010)
1. Facts: electronic cigarettes are battery power products that allow users to inhale nicotine vapor without
fire, smoke, ash or carbon monoxide. Liquid nicotine uses is derived from natural tobacco plants. NJOY
imports and distributes e cigs since 1997, marketed and labeled for smoking pleasure, rather than as a
therapeutic or smoking cessation product. FDA ordered that a shipment of NJOY's e cigs be denied entry
into US asserting that they appeared to be adulterated, misbranded, or unapproved drug-device combos
under FDCA.
2. I: Whether the FDA can regulate e cigs under the FDCA's drug/device provisions or whether it can
regulate them only under the Tobacco Act
3. H: Together, Brown and Tobacco Act establish that the FDA cannot regulate customarily marketed
tobacco products under the FDCA's drug/device provisions, that it can regulate tobacco products
marketed for therapeutic purposes under those provisions, and that it can regulate customarily market
tobacco products under the Tobacco Act
4. Concurrence: I read the Tobacco Act as requiring the FDA to regulate products like e cigs under the Act,
rather than under the FDCA. More likely that 321 rr 2 is an expression of Congress' intent to preserve
Brown's holding that even a product made from tobacco remains a drug, device, or combo that can be
regulated under the FDCA if it is marketed for therapeutic purposes.
1. Thus, if it makes a therapeutic claim its not tobacco products under Tobacco Act meaning
and thus subject to drug/device provisions of FDCA
2. Anything regulated under Tobacco Act shall not be subject to the provisions of the FDCA
3. No Chevron deference to FDA
5. Notice re Tobacco Product Regulation
1. Tobacco product is any product that is made or derived from tobacco that is intended for human
consumption
2. FDA currently had the authority to regulate certain tobacco products and the power to issue regs to
subject other products that meet the definition of tobacco product
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1. Wants to extend the Agency's tobacco product authorities in Chapter IX to all produces that meet
the stat definition
2. Public will have opp to comment
3. Sottera said that products made or derived from tobacco can be regulated under FDCA's
tobacco product authorities unless they are market for therapeutic purposes, which the case they
are regulated as drugs and/or devices
6. Guidance re New Tobacco Products
1. Draft guidance is intended to assist persons submitting apps for new tobacco products under FDCA 910
2. Draft guidance does not establish legally enforceable responsibilities
3. Background
1. When you create a new tobacco product or modify a tobacco product in any way, you must obtain
an order from FDA authorizing the marketing of the product before the product may be
introduced or delivered for introduction into IC
1. Includes change in design, component, or any part/constituent (include smoke
constituent) or anything related to nicotine or other additive/ingredient
2. Where a new tobacco product is not substantially equivalent to a tobacco product
commercially marketed in the United States as of February 15, 2007
1. You must submit a premarket tobacco product application (PMTA) under section
910(b) of the FD&C Act and receive a marketing authorization order under
section 910(c)(1)(A)(i) prior to marketing the product.
2. Section 910(c)(1)(A)(ii) of the FD&C Act requires that FDA deny a PMTA and issue an
order that the product may not be introduced or delivered for introduction into interstate
commerce where FDA finds that:
1. You have not shown that the product is appropriate for the protection of the public
health;
2. The manufacturing methods, facilities, or controls do not conform to manufacturing
regulations issued under section 906(e) (21 U.S.C. 387f(e))
3. The proposed labeling is false or misleading; or
4. You have not shown that the product complies with any tobacco product standard
in effect under section 907 (21 U.S.C. 387g). (Section 910(c)(2); 21 U.S.C. 387j(c)(2))
3. Section 910(c)(1) of the FD&C Act requires that FDA issue an order stating whether the product
may be introduced into interstate commerce "[a]s promptly as possible, but in no event later than
180 days after the receipt of an application."
4. Under section 902(6)(A) of the FD&C Act (21 U.S.C. 387b(6)(A)), a tobacco product is deemed
adulterated if it is a new tobacco product and it "does not have an order in effect under section
910(c)(1)(A)(i)" as necessary under section 910(a) of the FD&C Act.
5. Under section 301(a) of the FD&C Act (21 U.S.C. 331(a)), the introduction or delivery for
introduction into interstate commerce of any adulterated tobacco product is a prohibited act.
6. Violations of section 910 are subject to regulatory and enforcement action by FDA, including but
not limited to, seizure and injunction.
4. Information to Support a Showing that the New Tobacco Product is Appropriate for the Protection
of PH
1. Should present data and info sufficient to enable FDA to made a finding that the marketing of a
new tobacco product is appropriate for the protection of the PH
2. Shall be determined
1. With respect to the risks and benefits to the pop as a whole, including users and nonusers
of tobacco and taking into account
1. increase or decreased likelihood that existing users of tobacco products will stop
using such products
2. increased or decreased likelihood that non users will start to use
3. FDA required to deny apps where there is a lack of showing that permitting such tobacco product
to be marketed would be appropriate for the protection of PH
1. Based on well controlled investigations
2. Include a detailed explanation of how the data and info provided support this finding,
compare new product with those on the market
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3. FDA requests comment on how to evaluate this
5. General Principles for Scientific Studies
1. Allow for an evaluation of the impact of new tobacco product on morbidity and mortality for the
pop as a whole
2. In demonstrating the public health impacts of the product, data from studies should address how
the new product will compare to other products, and how it will effect non smoking and smoking
populations.
7. Electronic Cigarettes:
1. Class Notes
1. If they are tobacco products, they are going to be new tobacco products
1. They are unlawful, adulterated not approved yet--->boom knocked off the market
2. Need to submit studies like the ones in the guidance
1. Scientifically different
2. FDA gets 180 days to approve, it but they never do
1. Safer than smoking cigs!!! can be used to reduce smoking---> is this a true ph
benefit? need fancy studies
2. Big uncontrolled experiment
3. But we have enforcement discretion don't need to go after them if we don't want them
1. Can't affirmatively grant permission to use this product-got sued for this
2. Can say its low enforcement priority
2. The electronic cigarette is a battery powered electronic nicotine delivery system that looks very similar to
a conventional cigarette and is capable of emulating smoking, but without the combustion products
accountable for smoking's damaging effects
1. Smokers that switch would achieve large health gains
2. Becomingly increasingly popular with smokers worldwide
3. Users report buying them to help quit smoking, to reduce cigarette consumption, to relieve
tobacco withdrawal symptoms due to workplace smoking restrictions and to continue to have a
'smoking' experience but with reduced health risks.
3. The status quo in smoking cessation presents smokers with just two unpleasant alternatives: quit or suffer
from the harmful consequences of continuing to smoke.
1. However, there is a third choice for smokers: switching to the electronic cigarette.
2. Currently, the electronic cigarette is continuously evolving, with new and improved models
making it to the market at a yearly rate.
3. Sufficient regulation of the electronic cigarette is currently lacking
4. Electronic cigarettes can substantially decrease cigarette consumption without causing significant side
effects, but large and carefully conducted controlled trials will be required before a definite answer about
the efficacy and safety of these devices can be formulated
Tobacco Hypo:
 Pig farmer feeding some stuff to his pigs, including tobacco
 Having chemical analysis done to his pigs...finding there now nicotinepig skins
 What does this sound like to you?
o If you're in the FDA Center for Drugs....only have jurisdiction if they say its for therapeutic reasons
 Drugs are approved to do this-smoking cessation
o Can he get it regulated as food??
 What about e-cigarettes??
 Now we have this new Tobacco Act to bear on these types of products
 Center for Tobacco Products: we have the power to create tobacco standards
 Age restriction
 GMP standards on the product
o Haven't done it yet but concerned about safety of constituents
o Statute said we cannot reduce the amount of nicotine in a product be reduce to zero-CONGRESS
MADE THIS CLEAR
 BUT wanted to be able to take it down to a less than addictive level
 Guidance for New Tobacco Products
 Anything different from something on market before Feb 2007
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






Congress reached back 2 YEARS before the statute was passed
Then we can require approval of it-if it’s not approved its adulterated
PMTA
 Whats the impact on smoking behavior? non smokers-->smoking and smokers--->stop smoking
 Here, eating a few pig skins is 1000s of times safer than smoking cigarettes
Let’s say FDA has done its deeming regulation
o Deemed the pig skins to be tobacco
o First thing we want to tackle is affirmative disclosures
 Letting people know what's in these pig skins-got to tell people that theres nicotine in them, warn
them
 Constitutional question....can you make someone say something about the risk of these
products
 DC Court Case, and the 6th Circ case, applied different standards
 Strict scrutiny: 6th circ general central hudson analysis...no strict scrutiny
 Reynolds court said something different!
What if FDA required pics of people suffering heart attacks, clogged arteries, etc on a package of pig skins
o Want to give the image that these are horrible products
o FDA may not make it under Reynolds court
 Strict scrutiny when you force people to put these pictures on their packages
 6th circ different standard
What about off-label use?
o Think Coronia
 Off label use case, can't you go out and get truth non misleading info out about your product
 **remember think about the dissent, how does it apply to this case
Adams had an op ed saying limit age for cigs with addicting levels of nicotine in them
o Would force cig companies to redo their marketingdidn't happen, not going to happen
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