Food and Drug OutlineAdams/SafirSpring 2013

1. INTRODUCTIONA. THE 1938 FDCA Act gave FDA authority over food, drugs, cosmetics and medical devices

i. It gained more and gave up some over the yearsb. The Scope of the FDAs power is defined almost entirely by the list of product categories over which it

has jurisdictioni. Definitions delineate the outer boundaries

ii. Greater authority over drugs, devices, and biological products then over food and  cosmeticsiii. 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 Agencyi. 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 subjectsiii. 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 DOJiv. Science Side of FDA 

1. Center for Food Safety and Applied Nutrition2. Center for Drug Evaluation and Research (CDAR)3. Center for Devices and Radiological Health (CDRH)4. Center for Tobacco5. Center for Vet

v. Enforcement Side 1. Office of Global Regulatory2. 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 enforcement2. 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

registered4. 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

antifreezea. 90 ppl died in the first month CONGRESS STEPS IN: FDCA (as amended

today)7. 1958: Food Additive Acts

a. Preservatives, colors, stabilizers, etc8. 1962 Drug Amendments

a. Drug developed in Europe that was a "safer" sleeping pillb. 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 in10. 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 approvedc. No reason for generics to have to get approved AGAIN after a patented product

lost its patent after 20 years of safetyd. 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 foodb. Created the food labels that we see today

12. 1994 Dietary Supplements Health Education Acta. 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 drugs2. 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 weighti. 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 foodii. 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 exemptedc. 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 Formulary2. 201 g 1 B: Articles intended for the use or treatment of disease3. 201 g 1 C: Intended to change the structure or function of the body

ii. Devices1. 201 h: Devices-instrument, apparatus, similar, related2. h 1: USP3. h2: Intended-diseases/conditions4. h 3: Intended to change the structure or function of the body5. Looks like drug def NOT does not achieve primary purpose through chemical interaction

on or within the body6. 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 authority2. Facts: Product is an antibiotic sensitivity disc used as a screening test to determine the

proper antibiotic to administera. 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 products2. An article in USP or NF must meet privately designated standards for quality and

strength or otherwise be subjective to misbranding or adulteration action3. 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 diseases2. 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 FDAb. If you meet def of device, the product also meets definition of drug since drug

def scope is biggeri. If a product meets both definitions, FDA generally intends to classify

product as a deviceii. 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, etcb. Such products may be classified as devices as long as they satisfy the remainder

of the device definition, including the chemical action exclusion3. 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 purposec. 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 ISSUESA. CONSTITUTIONAL LIMITS

I. United States v. 23...Articles (1951) 1. Facts: FDA sought seizure and condemnation of certain phonograph records entitled

Time to Sleep2. 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 exempt3. 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 resultsii. 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 interventioniv. 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 deviceb. 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 distributiona. 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 devicesC. 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 attachment2. 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 misleadingb. Cannot promote a particular manufacturer or brand of a dietary suppc. Must be delayed or presented with other items on the subject matter for a

balanced viewd. Physically separate from dietary supplementse. 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 rule1. 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 ADULTERATIONA. FOOD SANITATION

i. Filth1. 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 Filth1. 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 ICb. 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 websitei. Mold, insect fragments, hair/scales, stems would qualify for natural

filth guidelinesii. 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 Conditions1. 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 theoriesi. 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 31. 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 41. 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 CONSTITUENTSi. One of FDA's most controversial activities is the regulation of the safety of food constituents-

materials 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 regulationiii. 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 added2. Section 402 a 1 may render injurious standard applied to added constituents that were

neither necessary nor unavoidable3. 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 foodB. Also applies to packaging material that comes into contact with food or is

reasonably expected to become components of foodC. 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 19584. Delaney Clause

A. Precludes FDA from approving safe any food additive found to induce cancer in man or animals 

5. Color Additive AmendmentsA. Apply to all substances used primarily for the purpose of importing color to food B. Color additives need to be approved by FDAC. Delaney Clause also applies here

6. Animal Drug Amendments of 1968A. 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 ingredientsI. 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 ingredientD. 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 CoI. 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 market-UNLIKELY.

4. Naturally Occurring Environment Contaminants a. To facilitate enforcement, FDA has sought to regulate a number of naturally-

occurring 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 healthii. 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: NPRMi. 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. MERCURYi. 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 added1. 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 ADDITIVESa. Food Additives Amendment of 1958

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 experimentationii. 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 use2. 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 decisionsb. 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.

c. Proposal Regarding Regulation of Prior-Sanctioned Food Ingredientsi. A food ingredient subject to a prior sanction may not be regulated under the food additive

provisions of the lawii. 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 substanceiii. 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 leveld. 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

e. 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 timeiii. FDA also considers environment, i.e. how much plastic waste is producediv. 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 .5ppbf. 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 SAFEi. If an added ingredient is GRAS, it can escape being a food additive, which takes years and tons of

studiesii. 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 studies6. 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 1968C. 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 linesD. 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 levels2. 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 LABELINGa. 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 misbranded2. Most of the forms of misbranding relate to info included in or omitted from the label or

labeling3. Forced to tell the suppliers the truth about their products4. Additional provisions prohibit other types of affirmative deceptions regarding quality,

quantity, or identity5. Other provisions force manufacturers to provide info they might otherwise omit6. 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 1969a. 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 nutritioniii. 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 Standards1. Nothing in statute provides for mandatory standards, FDA implemented some2. 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 drinksc. 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 attachment2. 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 misleading2. Cannot promote a particular manufacturer or brand of a dietary supp3. Must be delayed or presented with other items on the subject matter for a

balanced view4. 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 provision2. Those that prohibit certain types of representations and those that require disclosure of

specified info3. 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 CASE2. 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 Names1. 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 effects2. 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 misleading2. 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 FDA1. 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 category1. FDA is discouraging people from making any kinds of statements about

biotech unless 100% true2. 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 CLAIMSA. STRUCTURE/FUNCTION CLAIMS

I. US Gov’t Regulation of Food with Claims for Special Physiological Value1. 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 druga. But food industry is conservative so they generally haven’t made many claimsb. 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 foodsii. 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 foodsiii. 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 Claimsi. 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 agreementii. Or approved in authoritative statements by other federal agencies or

National Academy of Science2. After this, FDA required mature science-a virtually scientific consensus3. 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 foodii. Sign scientific agreement for unqualified disease claims AND credible

scientific evidence for qualified disease claimsc. 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 Food1. 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 substanceb. Must characterize the relationship of the substance to a disease or health related

condition2. Claims relating to a broad range of substances are potentially subject to regulation3. Leg history shows that Congress intended whole foods to be subject of claims regulated

under the acta. Doesn’t apply to broad classes of food, i.e. fruits and vegetables

4. Includes both risk factors and claims about a diseasea. 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 Rule1. 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 Claimsi. 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 evidencea. High: sign scientific evidence (unqualified disease claim)b. Moderate: sci evid is not conclusivec. Low: evidence is limited and non conclusived. Extremely low: little sci evid supporting this claim

2. Difficult for consumers to distinguish between these claims3. FDA exercises enforcement discretion with these claims 

9. DIETARY SUPPLEMENTSA. 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 SupplementsI. FDA and dietary supp industry have always been in a regulatory war

II. FDA was finally defeated in 1994 with DSHEA1. Congress exempted the dietary ingredients in supplements from the food additive

requirements of FDCA + more flexible food safety provisions2. Broadly defined dietary supplements and authorized strong new claims3. Pre 1994 ingredients used in supplements are ok as long as FDA can't prove a significant

or unreasonable risk of illness or injuryA. 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 fI. 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 supplementsII. 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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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.

f. 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 claimb. 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 statement4. 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 clearances5. 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 APPROVALA. 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 ANDAiii. 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 NDAa. Technically its an NDA but its different: applicant doesn't have right of reference

or own all the info on the NDAb. 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 andii. Genuine dispute or unawareness of the drug product among qualified

experts precludes a finding of general recognitioniii. 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 drug1. 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

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I. Safety Standard 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 benefitI. 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 processesB. Manner in which the drug is absorbed and distributed in bodyC. Whether active compounds arise from the metabolism of the drugD. Influence of other chemicalsE. 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 onlyA. 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

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IV. Method of assigning patients to treatment and control groups minimizes bias and is intended to assure comparability of the groups

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 safetyE. 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 effectivenessIV. 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 APPROVALa. 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

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do not affect safety of drug. Sulfites are considered safe, FDA allowance of a warning for people with allergies is not plainly erroneous.

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 litII. 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 studies2. If the applicant has all the right of reference to underlying data, it

would be considered a 505 b 1 applicationC. 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. Exclusivities1. Hatch Waxman Compromise of 1986

a. 5 yr exclusivity "NCE" (new chemical entity)-<20/yeari. 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         

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i. Delays approval ANDA1. New clinical investigation 

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 moneyi. Now you can get exclusivity it leads to pediatric data for docs to help

their decision makingc. 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 approvedi. 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 or2. 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 APPROVALf. 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 drugb. All relevant periods of market exclusivity for the pioneer drug have also

expiredii. 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 strengthb. Then they must first submit to FDA a suitability petition demonstrating that

the difference between the drugs is not sufficient to preclude an abbreviated

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NDA and that additional studies to show safety and effectiveness are not needed 

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 bioequivalentb. 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 Patentsa. 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 owner1. Can't be extended more than once2. 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

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d. Reg review period is to be reduced by any amount of time during which the NDA applicant has not exerted 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 Generics1. When a pioneer is withdrawn from marketing by its manufacturer for reasons of safety, it

can no longer be subject to abbreviated NDA2. 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 costb. 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 patentsii. Patent has expired

iii. We'll wait for patents to expireiv. One or more patent is not valid or not infringed (AKA para IV cert-

creates 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 damages3. 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

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2. Prevented the submission of info on patents claiming packaging, intermediates or metabolites 

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 DRUGA. 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 firstB. 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 unenforceableII. withdrawn from listing with FDA 

2. Withdrawal of the first applicant's ANDA3. Amendment or withdrawal by the first applicant of each patent certification for

which the applicant is eligible for exclusivity4. 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 litigation2. 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

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B. FDA ruled that the 2003 MMA amendments required a different outcome from the one Ranbaxy ordered under the old version of the law

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

market2. FTC sues drug companies that pay off the makers of competing drugs not to bring their products

to market3. Loophole in current law allows for generics to be blocked; also supports leg to end such pay for

delay settlements4. 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 savings7. 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 diseases2. 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

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2. Applies to new drugs, antibiotics, and biological products that are being studied for their safety and effectiveness

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 morbidity3. 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 23. 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 use3. 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 drug3. Provides the opportunity to submit what is often called a rolling NDA4. 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 32. 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 OVERSEAS1. 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 so2. 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 trials1. INDs could be terminated if FDA found applicants had sold or distributed drugs for

commercial purposes beyond the trial

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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

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 IND2. 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 situations2. 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 diligence3. Can't charge more than to recover your costs BUT CMS and 3d party payors don't pay, so rare4. 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 docs2. Appear in a Master File submitted to FDA

1. Includes only drugs likely to obtain NDA approval 3. Eligible for Medicare reimbursement4. 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 term2. 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 program3. 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 requirements2. 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

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13. Tropical Drug IND 1. FDA has long permitted drugs for tropical diseases to be subject of clinical US trial, there are

rarely approved NDAs2. IND assumed permanent3. However, now more people travel so reasoning for not approving INDs is disappearing

14. Special Exception IND1. 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 results15. 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 decision2. 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 person1. 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 Canada2. FDA thinks the Personal Import Policy should be drastically reduced or eliminated; especially in

light of drastic price differences in other countries3. 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 product18. Clinical Trials Databank

1. FDA began publishing a list of all AIDS drugs in clinical trial under an IND2. NIH established a databank of information on clinical trials for drugs for serious or life-

threatening 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 results6. 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 dru5. 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 r-HgH 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

development2. Explosive industry, 2k small companies3. Believed that they could skip expensive NDA process, and target only drugs with high chance of success

1. Also believed FDA would help them out2. 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 medicine2. Created a complex matrix to classify NDAs according to chemical type and therapeutic potential to

determine their priority for review1. 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 exclusive2. Both original NDAS and effectiveness supplements receive a review

priority classification but manufacturing supplements do not2. 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 applications3. 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 H1. In 1992, FDA promulgated regulations establishing two forms of accelerated approval of

an NDA1. 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 Endpoint1. FDA has for many years approved NDAs based on validated surrogate endpoints2. 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 fast5. 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 DRUGSA. OTC DRUGS

I. BACKGROUND1. Script and OTC drugs are MUTUALLY EXCLUSIVE

A. Can't have the same drug marketed both ways2. Set up about 30 panels, took them a few years

A. Decided to do it via regulation, vs case by case3. Three categories

A. Safe and effectiveB. Not safe or ineffectiveC. 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 doc6. 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 genericsB. Not the same money as a script, but its still a huge marketC. Plus you have brand recognitionD. 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 Review1. 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 products2. FDA realized it would be too difficult to go case by case to determine the safety and

effectiveness of every OTC drug3. 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 misbrandedC. 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 becauseI. 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 sameE. 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 respondedA. Drug must be GRASE, not just safe and effective or would require a NDAB. Necessary for studies to prove safety and effectiveness, unless there is a waiver

showing studies are unnecessary or inappropriateC. May be that a drug is GRASE but has certain side effects that make it better for

scriptsD. FDA will not allow drugs that don’t meet these regulations to stay on the marketE. They have the power to make regulations under the act instead of using

adjudicationI. 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 denyB. Can submitted written materials

2. StandardsA. 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 experiencedIII. 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 waivedC. Benefit to risk ratio of a drug shall be considered in determining safety and

effectivenessD. 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 Report1. Recommends monograph covering the category of OTC drugs and establishing

conditions under which the drugs involved are GRASE and not misbranded2. Statement of active ingredients, labeling claims, etc that are excluded from the

monograph since they would lead to drug not GRASIII. 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 courtIV. 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 hazardousV. Marketing of OTC drugs may begin before promulgation of a final monograph if it meets

requirements and Commissioner provides notice of that determination in FR1. Panels are very flexible2. 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 packagingC. 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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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 TEA2. Info that must be included is voluminous and complex, at least 10 companies have done it

was some successD. 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 youngerII. In addition you have proposed that both the Rx and OTC versions be marketed in a single

packageIII. CDER concluded safe for OTC for women 17+ but there are some other issues related to the

NDAIV. Three difficult and novel issues

1. Whether can be marketed in same package2. Whether a drug can be both Rx and OTC depending on age of patient and how to enforce

itV. Decided to seek public comment to codify this interpretation-cannot legally market drug as OTC

at this timeE. Sebelius Letter re Plan B

I. Teva submitted a supp NDA for Plan B, to market it as OTC without any age restrictionII. I have concluded that the data submitted for this product does not establish that script dispensing

requirements should be eliminated for all agesIII. There are different cognitive and behavioral difference between older girls and the youngest girls

of reproductive age which are relevantIV. I instruct the FDA to respond saying there is not sufficient evidence that the script should be

removed for all agesF. BIOLOGICS

i. Background1. Regulated under 262 Public  Health Services Act, NOT FDCA2. 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 standards4. 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 generics1. Didn't want to link patents to the approval process2. 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 121. Leaves lots of time to litigate

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2. They go and ask pioneer how many patents they have1. 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 one3. The other patents can't be argued until after there is

approval3. PATENTS

1. Strong patents that cover composition of matter for REG DRUGS1. No way to replicate the composition of matter patent WITHOUT

patent infringement2. 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

situation2. They want some protection like the Hatch-Waxman great

compromise3. Europe passes a biosimilar law

1. Gives 10 years exclusivity to pioneer2. US debates the subject all over the place3. 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 FDAIII. Licensing of Biological Products

1. No person shall introduce bio prod to IC unlessA. 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 facilityI. 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 505IV. 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 CommissionersV. 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 biologics5. 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 termsII. Makes a presumption of sameness between any two proteins that have

the same amino acid sequenceIII. To rebut this, one must show a clinical difference between or superiority

of the new biological drug and the one first to marketC. Difficult to replicate the manufacturing process of the pioneer, patent law doesn’t

require disclosureD. 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 biologics2. 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 drugsA. The BPCIA provides a new type of application and new standards for approving

biologics based on either “biosimilarity” or interchangeabilityI. Biosimilarity requires that that there be no “clinically meaningful

differences” between the biosimilar and reference products1. 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 FDCAI. Grandfathered exception for biologics approved under 505, i.e. hormones

and insulin until March 20204. 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 DRUGSI. 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 pharmacies1. Nothing excludes pharmacies from doing this in the FDCA2. 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 one1. 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 provisionII. Misbranding provision

III. New drug provision of section 505B. In order to exemptions to apply, there were a number of requirements

I. FDA believes SC decisions in Western State makes all of 503A invalidII. Traditional compounding still okay, this applies to activities outside the

bounds of the actC. 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 resellVIII. Compounding drug products commercially available or essentially the

sameIX. 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 compounding2. 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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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.

F. HOMEOPATHIC DRUGSA. Concept of homeopathy was invested by Hahnemann in late 1700sB. 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 patientA. 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 regsc. 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, GENERALLYi. Class I-General Controls

ii. Class II-Performance Standardiii. Class III-PMA

1. Valid Sci Evidence 2. You get a 6 year exclusivity for first PMA3. 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. Notification2. Substantial equivalence: substantially equivalent to something on the market before

19763. Way to keep a new device from being auto classified Class III

v. THIS IS NOT AN APPROVAL, it’s a clearanceB. CLASSIFICATION

I. 1976 Medical Device Amendments and Later Amendments1. Medical Device Amendments added more than a dozen provisions to the 1938 Act2. 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 Entry1. 1976 Amendments provide for comprehensive control over the market introduction of all

medical devices, a system which operates independently of the classification schemeA. 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 pathway3. In 1997, Congress passed FDAMA establishing two additional paths for introducing a

device into the marketA. 513 f 2 established a procedure for requesting that FDA initially classify a device

with no substantial equivalent predicate into Class I or Class IIB. 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 report4. 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 Submission1. 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 accepted3. Months faster than a PMA

a. PMN is 102 days, PMA is about 400 daysd. 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 structure1. 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 market3. 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 requestg. 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. Piggybackingi. 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. NDAi. PMAs need to provide reasonable assurance of safety and effectiveness, this language is not in

the drug provisionsii. For devices, FDA considers

1. Intended persons2. Conditions of Use3. Probable benefit to health from the use of the device weighed against any probable risk of

injury or illness4. 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 evidenceiv. Devices are not metabolized, so their interaction with the body tends to be less complex

1. Also can't do double blind placebo tests etcj. 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 Devicesi. 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 court1. 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 Devicesi. 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 Devicesi. 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 devices13. COMBINATION PRODUCTS

A. GENERALLYI. Both a drug and a device, regulated by primary mode of action

1. Assigning it for review for one area of FDA2. 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 potential2. 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. PREEMPTIONa. 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 Claimsa. 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 interestc. 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 claimsiii. 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 topic1. 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 helped1. 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 rules1. 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 AUTHORITYA. 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 process3. 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 formulasB. Greater authority with drugs, medical devices, and tobacco-can look to see if

misbranded or adulteratedC. 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 inspected2. OSHA case that inspected a facility and found violations-Court agreed with 4th

Amendment argument that they could have gotten a warrantIV. Inspectors put observations on a 483 form

1. District office then looks and sees if the agency thinks its a violation2. Company has 10-15 business days to respond to the observations

A. I.e. We made corrective actions etcB. SEIZURE

I. CLASS NOTES1. Drug company messes up the labels on aspirin and acetaphamine (sp) and a patient takes

the wrong one, has an allergic reaction, dies2. Pharma tells FDA, FDA goes down to warehouse seizes everything and essentially puts

them out of business3. 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 warrantI. 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 timeiv. 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 goods3. 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 misbrandedB. If so, condemned by court and either destroyed or the company can then ask the

product be salvagedC. 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 decisionsI. 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 articles2. 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 warrantiv. 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 prevailsb. If the seizure was reasonable however the claimant is not entitled to

reimbursement for any loss of value during storageC. INJUNCTION

I. CLASS NOTES1. 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 injuryi. Unless there is a statutory violation, in which case the irreparable injury

is assumedb. Need to show damage to D and balances of harm 

3. Two types of typical PIsa. Bad apples that are clearly not going to stopb. 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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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 workb. 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 decreesi. 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 problems1. Usually name old head of quality AND the new guy2. New guy ends up getting a lot of money to sign it

ii. 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 

III. 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 prosecution2. An injunction can prohibit further violations , whereas a condemnation decree after

seizure cannot, since it applies to the product not the person3. 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 injunctiona. Usually resolved by consent decree

iv. 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 them2. Rare that they do, since they are accused of adulterating drugs! 

V. Preliminary Injunctions1. 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 areI. Likelihood of P's success on merits

II. Possibility of P's suffering irreparable injury if relief is not grantedIII. Extent to which the balance of hardships favors the respective

partiesIV. Whether the public interest will be advanced by the provision of

prelim reliefC. 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 Injunctions1. 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 LAa. 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 occur3. 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 case1. They were the only guys who made the thing, but it took them years to try to fix stuff

under the consent decree2. 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 productsa. 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 themc. Abott agreed to pay 100M and high royalties 

3. FDA then began making these payments standard in consent decrees4. Can also put monetary fines in the injunction to enforce deadlines

a. Avoids contempt of consent decree and having courts throw people in jailII. 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 products3. 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 effective1. Seizures and injunctions would remove essential products from the market2. 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 treasury54

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 lossvii. 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 violationii. Without intent-misdeamoner, with intent potentially a felony

III. US v. Park (SC 1975)-PUTS THE FEAF OF GOD IN EVERY CEO IN FD INDUSTRY1. 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

powerlessb. Doesn't usually work on CEO, lower level people don't usually have power to tell

others to fix stuffc. 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 jaild. These cases aren’t usually brought though because the DOJ wants “bad guys” not

CEOsi. 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

sanctions2. 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 55

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 faili. 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. RECALLSi. Every company  has to have a recall policy

1. Class 2: get stuff from manufacturers2. 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 channelsv. 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 Recalls1. FDA today has explicit statutory authority to mandate recalls in certain limited

circumstances but issued very few2. Section 535 f of the PHSA gives FDA power to mandate the repurchase, repair or

replacement of radiation-emitting electronic productsa. 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 provisionb. Trend seems to be toward recognizing the court’s authority to require recallsc. 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 recalls1. 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 designeeix. 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 FDA2. 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 strategyi. Depth of recall

1. Consumer or user level2. Retail level3. Wholesale level

ii. Public warnings1. Purpose is to alert customers or users that a product presents a

serious hazard to healthiii. 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 checkiv. Steps to follow:

1. Develop a contingency plan for recall2. Develop the capability of tracing product distribution and

identifying the product being recalled3. 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 FDA5. Develop and follow a recall strategy for handling any recall

situation6. Assume the responsibility and expense of conducting all aspects

of a recall, including effectiveness checks7. 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 recall10. 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 customersd. Periodic reports on the progress of the recalle. Termination of the recall and proper disposition or correction of the

violative productG. 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 law2. 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 companiesIV. What can you argue against this? Both Fail

1. Ex post facto2. 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 Policy1. Policy sets forth FDA’s general approach regarding applicants that seek to subvert the

agency’s review and approval processes for premarket approval2. 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 programa. 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 Assessmenti. 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 Actionsa. 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 penaltiesII. Mostly for devices

III. Safir: Can't remember a case when they have done it, its in the statute but they never use itIV. 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 ActV. Now section 539 of the FDCA empowers the FDA to seek the imposition of civil penalties for

violations of the Radiation Act in federal DC1. This power was repeatedly increased by Congress to give FDA authority to impose civil

money penalties for other types of violationsa. Vaccine Injury Law for violations of the biological product recall provision and

vaccine manufacturer recordkeeping requirementsb. 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 Policy1. Guidance on pursuing CMPs recommendations under the Safe Medical Devices Act2. CMP cases should serve to eliminate the profit from violative activity and/or provide

non-compliant firms with the financial incentive to correct violations3. CMP is considered to be a remedial action, not punitive-designed to influence future

conduct of that firm and similar firms directly or indirectly4. 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 decreesvii. CMP may be considered in cases where

1. Other regulatory action is NOT appropriatea. Current violations warrant consideration of seizure or injunctionb. Combo with CMP should be rare, only for egregious or flagrant violationsc. If other civil action is not appropriate, consider whether prosecution is

appropriatei. CMP and prosecution will not be initiated for the same violative conduct

d. If none are appropriate, consider CMP for both current or continuing violationsi. Even if all violations have been corrected, but maybe they took a long

time2. Prior warning has been given

a. Rare that CMP should be initiated without prior warning3. 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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4. Statutory factors in Section 303 f support the casea. FDA is required to consider

i. The nature, circs, extent, and gravity of the violationsii. 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 factorsviii. Extent of the violations refers to the number and variety of document

violations and the length of time during which the violations continuedix. Gravity of the violations refers to the consequences, actual or potential,

of the violationsx. Degree of culpability requires consideration of whether the violations

were intentional, reckless, careless or inadvertentviii. FDA is required to reduction CPs for small entities, and adjust CMPs for inflation every 4

yearsI. 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 Lettersa. 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 actionb. 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 official4. 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 Letter5. 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 droppedc. Even so, FDA does not consider warning letters to be final agency action on

which it can be sued6. *** 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

publicity2. 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 publicizedIII. 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 products2. FDA seek publicity for several purposes

a. To warn against the use of marketed products that may be hazardousb. To warn against gross economic deceptionc. To encourage public comment on proposed regs or actions and other public

participation in FDA activitiesd. To report to the public on adjudicated court proceedingse. To present to the public FDA’s views on matters of public interestf. To report on studies or investigations that may form the basis for an FDA

regulatory action3. 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 publicity5. Personally disparaging or gratuitously critical remarks, not required in reporting the facts

of a situation, should be and will be avoided6. 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 neededv. FDA has said that presses releases are issued when they feel that the scope of the problem

warrants more widespread publicity1. Talk papers are used when the problem is of a narrower scope and available to the press

and used as source for news storiesVI. 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 Suits1. SC addressed this issue in Barr v. Mateo, a case involving a libel suit brought against the

Director of the Office of Rent StabilizationA. 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. DISCRETIONI. 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 LIMITSi. 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 DAYSa. 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 inspections4. Photographs section discussing the taking of photographs and making of photocopies

during inspectionsA. Every one of the photographs should be taken with a purposeB. 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 pics7. 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 SPEECHA. 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-->misbrandingi. 502 a: False or misleading in any particular

1. Newspaper article2. 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 ab. 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 use2. 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 labelingi. 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 etc2. 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 FDA3. Does FDA have expressed interest on drug advertising?

a. ONLY On prescription drugsi. 502 n authority over prescription drug ads

1. not false or misleading2. brief summary of side effects, etc basically the package insert

in an adc. 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

labelii. 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 it2. 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 etcii. Need to live within the FDA rules, they know the rules and generally

stay within them nowiii. Not something that people really worry about now

D. SCOPE OF LABELINGI. 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 Names1. 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

parties2. 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 Strategy1. 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 provea. 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 marketedb. Thus, enforcement usually charges a violation of the new drug provisions rather

than misbranding provisions3. 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 quackery1. Direct health hazard2. Indirect health hazard3. Major economic fraud4. 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 likely3. 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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a. Known as the squeeze play5. 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 intended2. 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 f. DRUG AND DEVICE PROMOTION

A. Promotion of Unapproved UsesI. Dissemination by manufacturers of information about unapproved drugs or unapproved

uses of approved drugs has presented vexing problems for FDAB. 202 1 e 4 provides that advertising cannot recommend or suggest any use that is not in the

labeling in an approved NDAC. 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 mediaD. 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 balanced1. Won't pursue action if the information is complete and balanced2. FDA has issued a number of policy statements about which ad/promo practices

don't fall within the regs3. 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

misleadingA. In this case the speech is not false or inherently misleadingB. 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 stupidB. 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 thereof3. From suggesting content or speakers to an independent program provider in

connection with an education seminar even if they discuss unapproved uses4. ***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 Moderatorsii. 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 Presentationsviii. Audience Selection

ix. Opportunities for DiscussionD. 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 FDAMA1. Preserving the effectiveness and integrity of the FDCA's new drug approval

process and the protection of PH2. 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 methodsiv. 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 lawb. Recent case law has emphasized the need for not imposing unnecessary restrictions on speechc. Some statutory provisions that FDA enforces explicitly limit speech, much of the FDCA depends

on the use of wordsi. 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 recsi. 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 investigationsiv. Must not be false or misleading or pose a significant risk to the PH if relied onv. NO editing or highlighting, and must have additional information including bibliography

of studies reaching different conclusions and disclosure statementd. If you follow these recs, then won't establish intent that the product be used for an unapproved

new useg. 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 scrutiny1. 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 off-label 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 misbranded2. Clearly Caronia was convicted for his conspiracy not his speech, speech was

evidence of that conspiracy3. FDCA prohibitions on off label marketing advances the interest of not

wanting off-label usea. Least restrictive way, other ways ineffective

v. **THE FDA AND MOST COURTS AGREE WITH THE DISSENT1. Hot issue though, some people are learning towards majority.

17. TOBACCOA. FDA v. Brown and Williamson Tobacco Corp (2000)

i. H: The FDA's claim to jurisdiction contravenes the clear intent of Congress1. 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 Act1. Signed into law in 2009, provides the FDA with regulatory authority over virtually every aspect

of the design, production,  marketing, and advertising of tobacco products2. FDA will move expeditiously to implement Act

1. Already launched its new Center for Tobacco Products, with director Dr. Deyton2. Also established the Tobacco Products Scientific Advisory Committee (TPSAC)

3. First lawsuit challenging constitutionality has already been filed, will be more1. Section 2 sets out the findings of Congress to support the act, wanted it to be as strong as

possible2. Discuss the many harms associated with tobacco use

1. Effect on children2. Addictive power of nicotine3. Impact of tobacco on healthcare costs4. Risks posed by products marketed as modified risk products5. Past efforts of industry to target youth

3. Section 3 sets out the purposes1. Ensure that FDA has adequate authority to regulate tobacco products2. Not intended to affect the growing, cultivation, or curing of raw tobacco3. If it exceeds constitutional limitations, section 5 provides for severability of those

provisions4. 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 industry4. 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 FDCA3. Section 203 contains conforming amendments to sections of the FDCA that address

seizure, injunction, and important detention, etc4. 301 adds provisions intended to prevent illicit trade in tobacco products

5. Definitions1. 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 standards1. Adulterated if t bears or contains any filthy, putrid, or decomposed substance, or

any addedpoisonous 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 donot 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 recall3. 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 context1. 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 3042. Detention under 801 a3. Injunction 302

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4. Civil and Crim Liability under 3038. 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 Standards1. 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 bythe TPSAC on the potential effects of prohibiting menthol-flavored cigarettes onchildren and racial and ethnic minorities

2. Section 907 also authorizes FDA to modify the standard for cigarettes and toestablish standards for other tobacco products as “appropriate for the protectionof the public health.”16 The question of whether a standard is appropriate “for theprotection 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 achievable1. 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 shown1. 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 consideration1. 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 grounds2. 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 test2. 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 FDCA3. No Chevron deference to FDA

5. Notice re Tobacco Product Regulation1. Tobacco product is any product that is made or derived from tobacco that is intended for human

consumption2. 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 Products1. 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; or4. 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 determined1. With respect to the risks and benefits to the pop as a whole, including users and nonusers

of tobacco and taking into account1. increase or decreased likelihood that existing users of tobacco products will stop

using such products2. 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 products1. They are unlawful, adulterated not approved yet--->boom knocked off the market2. 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 this2. 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 worldwide3. 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 nicotinepig 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 constituentso 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 regulationo Deemed the pig skins to be tobaccoo 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 themo Would force cig companies to redo their marketingdidn't happen, not going to happen

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