Food and Drug - UVA Law by aflusche

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                                   Food and Drug Law – Lecture Notes
I. Introduction
     A. Course
        1. Why be interested in this course?
            a. Products regulated by FDA accounts for about 25% of GNP
            b. FDA is great example of administrative agency
        2. Sources
            a. Casebook – Foundation Press – 1991 – historical source = good
            b. Noah, Foundation Press – Law, Medicine, and Medical Technology
            c. Hilts, Protecting America‟s Health
            d. FDA Week
            e. Update: Food and Drug Law and Education – Food and Drug Law Institute
            f. FDA website – can even contact people – they like attention
        3. Requirements
            a. Discussion preparedness
            b. Paper
                i. Writing competition
                    (a) 2 prizes for short papers (< 40 pages)
                    (b) 2 prizes for long papers
                    (c) Both carry monetary prize + publication in F&D Law journal
        4. Office Times
            a. Tuesday is good
            b. Wednesday is awful
            c. Monday after class
        5. Research is different
            a. Not a lot of cases
            b. Raw materials might lie w/ FDA, parties seeking to influence FDA, etc
            c. More like a newspaper reporter than a law clerk
            d. Personal contact is encouraged
     B. FDA History and Organization
        1. Fed govt. has regulated food and drugs for 100 years
        2. 1906 – purely food and drug (not cosmetics or medical devices)
            a. Bureau of Chemistry, Dept. of Ag.
                i. Headed by Harvey Wiley
                    (a) Preoccupied w/ adulterated foods
                    (b) Tested things on their own people
                    (c) Intrepid – wore out his welcome
            b. Passed the same day as Meat Inspection Act – Dept. of Ag. can inspect meat (and now poultry)
        3. Meat inspection remains with USDA, but other foods with FDA
            a. Pizza rule - < 3% meat = FDA
        4. 1930, Food, Pesticide and Drug Admin, under Dept. of Ag.
        5. 193? – moved under Federal Security Admin (grab bag of govt. functions from New Deal)
            a. It seemed contradictory for the same dept. to regulate safety & proper labeling of food AND promote
               US agriculture
            b. Mostly changes of letterhead, reporting responsibility, and legal authority
        6. 1953 – Eisenhower created Dept. of Health, Education, and Welfare – FDA moved here
        7. 1977 – Carter – Education made its own Dept. – SSA made its own agency – Health made the core
        8. FDA‟s boss (Sec. of Health and Human Services) serves at will of President
        9. FDA headed by Commissioner of Food and Drugs
            a. Doesn‟t have to gain majority of commissioners (there aren‟t any)
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       b. But does have to satisfy FDA‟s boss AND President
   10. Lester Crawford
       a. Abruptly resigned, less than 1 month after being confirmed by Senate (acting commissioner for almost
          2 years)
       b. Suspicion: had something to do with Plan B
   11. Replaced, temporarily, by head of National Cancer Institute
   12. Rest is broken up into 6 units
       a. Biologics Evaluation and Research (CBER) – blood, vaccines, tissue, allergenics, etc
           i. Small copy of Drug Center
       b. Devices and Radiological Health (CDRH) – protects against man-made radiation
           i. In 1976, there were 4 people here – now > 1,000
       c. Drug Evaluation and Research (CDER) – new drugs, checks generics, monitors ads
           i. Largest part of agency
           ii. Great majority of employees is in Washington
       d. Food Safety and Applied Nutrition (CFSAN) – food additives, biotech foods, cosmetics, labeling
       e. Veterinary Medicine (CVM) – food and drugs for animals
       f. Toxicological Research (NCTR) – peer-reviewed research
   13. Problems are sent to the specific Center at issue
   14. FDA Com has complete authority over the Centers
   15. Sec. of H&HS v. Com.
       a. Authority given by 1938 statute is given to Secretary, not to Com
       b. Com gets authority from document executed by Secretary, conditioned upon exceptions
C. Overview of Food, Drug, and Cosmetic Act of 1938
   1. Basic architecture similar to present statute
   2. Size of Act has grown by 10 or 15 times
   3. Products under FDA jurisdiction
       a. Food, drugs, medical devices, cosmetics
       b. 1906 – only food & drugs
   4. Can‟t do or put into commerce anything adulterated or misbranded
       a. Adulteration – physical characteristics
       b. Misbranding – informational concept
   5. Why not just say, “you can‟t do X to your product”
       a. Congressional uncertainty about scope of fed commerce power
       b. Literal interstate transmission was clearly reachable
   6. What can FDA do if a product is A or M?
       a. Injunction – go to court – brought in name of U.S. – represented by DoJ
       b. Prison / fines – DoJ must prosecute responsible company
       c. Seizure – take physical custody of the product – in rem proceeding – U.S. Marshall enlisted
           i. Most of the time, responsible party lets goods go
               (a) If MM, sent to public institutions
               (b) If AA, destroyed
           ii. Sometimes, owner of goods contests – file a claim, saying the goods are ok, and should be released
   7. Main source of legal authority
   8. Additional authority through other statutes
       a. Public Health Service Act
           i. Main provision for FDA – regulate biological products (medical materials, therapeutic materials, etc)
           ii. Ex: blood, vaccines, human tissues, some genetically engineered products
           iii. Practically, these are also drugs, under F&D Act
   9. Amendments
       a. Mostly power-conferring – augmented jurisdiction & authority
       b. 2 have subtracted
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                i. 1976 – FDA may not regulate dietary supplements as drugs – they are subset of food
                ii. 1994 – Dietary Supplement Health & Education Act – requirements for labeling can‟t suppress
                   manufacturer‟s ability to tell consumers what products can do
       10. Authority – in Secretary of Ag. – now shifted to Secretary of Health and Human Services
       11. Commissioner – not in law until 1980 – delegated authority from Secretary to carry out Act
       12. Typical of New Deal legislation
       13. Unusual features:
            a. Nothing about agency organization – doesn‟t say “FDA” anywhere
            b. Bureaucratic organization isn‟t dictated by law
II. Definitions
    A. Jurisdiction defined by contours of products, defined by statute
       1. Limited by commerce power of fed govt – states can regulate in here
       2. Statutory carve-outs
            a. Water – divided between FDA (bottled water & bottle) and EPA (source of water)
            b. Alcohol
                i. 1970‟s, FDA asserted this was food, and should contain labels
                ii. Manufacturers complained and got concession from FDA that it wouldn‟t regulate
            c. Animal vaccines
            d. Dietary supplements – carved out from drugs, but subset of foods, different from regular foods
    B. Authority
       1. FDA has almost full range of regulatory tools that any agency might have
            a. Licensing – almost all drugs, life-sustaining medical products
            b. Regulations – production, packaging, labeling, shipment, storage, etc
            c. Policing
       2. But it doesn‟t have full range of authority over each CATEGORY of products
            a. > drugs … < cosmetics (law hasn‟t changed much since 1938)
       3. A form of what Congress has said, but potentially subject to its own authority (Congress was vague)
    C. Some products fall in 2 categories
       1. Food-looking product may be subject to regulation as a food, but (depending on marketing and labeling)
           might also be a drug
       2. Could be: device AND a drug
            a. Pre-filled syringe = medical device containing a drug
    D. Food
       1. Nutrilab (p. 2)
            a. Starch blocking tablets claimed to help with weight loss
            b. FDA adopted regulation – products like this (that interrupt metabolism of starch) are drugs
            c. Manufacturer claimed they are foods – no pre-approval required (unless food additive)
            d. Claim – “drug” = disease claim OR affecting structure or function of body (“other than food”)
            e. Shifts debate – is it a food?
                i. Company – comes from food source, ingested, look at use
                ii. FDA – doesn‟t serve common food functions (taste, nutrition)
            f. Ct – food is primarily for taste, aroma, or nutritive value
            g. In policing mode, FDA would have burden of proving that it doesn‟t work
            h. This way, company has burden of proving that it doesn‟t work
    E. Drug
       1. “Intended Use”
            a. Mathews (p. 9)
                i. Each tablet contains several times the nutritional value of vitamin A and/or D
                ii. FDA argues:
                    (a) Level of vitamin is therapeutic
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               (b) Everyone who buys these products intends them for therapeutic use – consumer understanding
                    may supply evidence of what product is intended for
           iii. Court
               (a) Evidence of consumer understanding must be nearly overwhelming
               (b) FDA‟s evidence is far short of the burden
           iv. What does FDA want here? – prescription only
               (a) Wanted to reduce sales
           v. FDA – argues that you can infer “intended use” from how consumers use the product
               (a) If evidence is overwhelming, this can work
               (b) At end of day, manufacturer‟s intent matters most
           vi. This theory underlay FDA attempt to regulate cigarettes
       b. Reclassification of products
           i. Primary reason to draw into “drug” – demand proof that product is safe & effective
           ii. But also shifting burden of demonstrating compliance to manufacturer
       c. Fairfax Cigarettes (p. 13)
           i. They claimed that they “may help you”
           ii. FDA able to seize them
       d. Tinted contact lenses w/out corrective power
           i. FDA would not regulate them as medical devices – no promised structural / functional benefit
           ii. Congress passed legislation bringing them under FDA authority
       e. Most examples of manipulability of statute – is it a drug or something else? OR is it also a drug?
F. Device or Drug
   1. Bacto-Unidisk (p. 26)
       a. It is a device, at least – but is it also a drug? – would require pre-market approval
       b. Way of identifying most successful antibiotic for infections
       c. FDA – called them drugs
       d. At the time, device said “other than a drug” – but hard to be both
       e. Most cited case by FDA lawyers
       f. Decided in 1969
   2. Bacto-Unidisk not the only product re-categorized by FDA
       a. Certain soft contact lenses were drugs
       b. Intera-occular lenses were drugs (tiny lenses implanted at back of eye)
       c. Copper 7 IUD – leeched copper into woman
   3. At hearing in House, FDA asked how this was possible
       a. Public health arguments – these devices need to be safe – only way to ensure safety is w/ pre-market
       b. But if Copper 7 IUD is a drug, why aren‟t others?
           i. Copper 7 hadn‟t been marketed yet
           ii. Others were in use by 1.5 million women – would need to be retrieved
   4. Cigarettes
       a. FDA was obstructed by its own statute
       b. If statute was elastic, FDA could say that they were drugs and must get pre-market approval
       c. But cigarettes would be withdrawn from the market – this would cause uproar
       d. FDA wanted to treat cigarettes as medical devices – don‟t all require pre-market approval
       e. Medical devices are enormous constituency that has enormously varied
       f. Question of pre-market approval was post-poned
       g. Brown & Williamson (p. 15)
           i. Relies on Mathews theory of intended use
           ii. Cigarettes are intended to affect structure / function of body – impart nicotine, which does affect
              structure / function of body
           iii. Intended use can be inferred by the actual use by consumers
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           iv. Ruling – “but it just doesn‟t fit”
               (a) The things said make them, if anything, drugs – yet FDA acknowledges they can‟t be regulated
                    as drugs
               (b) Cigarette regulation can‟t start & stop at Food & Drug Act – look at rest of U.S. Code
               (c) Congress has effectively immunized cigarettes from FDA regulation
G. Biological Products
   1. Organ Transplants
       a. 1983 – Congress looked at lack of supply of organs
       b. FDA never regulated this – people asked why
           i. Looked at possible statutory readings of how it could regulate
           ii. Device, drug, biological product, none
           iii. Never took or disclaimed authority
       c. Next year, Congress passed Organ Transplant Act
           i. Pretty good evidence that Congress wanted FDA out – effectiveness & safety aren‟t questions
           ii. But what about cadaver tissue?
               (a) Demineralized bone – used by dentists
               (b) Skin – burn treatment, cosmetics
               (c) In tact bone – hips, etc
           iii. Over 1m surgical procedures this year in U.S. using cadaver tissue
H. Two other limits
   1. Tape Recording Case (p. 20)
       a. Seizure of shipment of tape recordings
       b. Seller claims they will cure things
       c. FDA says the recordings are drugs or devices – not effective
       d. May be constitutional limitations on FDA‟s capacity to assert jurisdiction over things said about things
       e. FDA lost 3 cases w/in 20 years
       f. All prescription drugs have very detailed labeling – FDA approved
           i. FDA has always assumed essentially plenary authority for this labeling
           ii. DC Circuit – this isn‟t so – contours are limited – commercial speech
       g. 1st A – example of potential external constraint – GOOD PAPER TOPICS
   2. Dietary supplements
       a. Appears in statute in 1994
       b. 1938 Act – § 403(j) – FDA is empowered to prescribe labeling for foods of special dietary use
           i. Widely understood to be nutritional supplements (vitamins, minerals, etc)
           ii. FDA made manufacturers put % of minimal daily requirement
           iii. This invited manufacturers to put more than 100% in their food
       c. 1966
           i. Changed from “minimal daily requirement” to “recommended daily allowance”
           ii. If supplement has more than 150% of “recommended daily allowance” – that is a drug
               (a) Consumers will understand that it has a drug use – prevent dietary deficiency
           iii. Congressional opposition builds, due to widespread constituent upheaval
       d. Congress – dietary supplements aren‟t regulated by FDA, unless make explicit claims to treat disease
       e. FDA pursues other initiatives that reflect suspicion of these products
       f. 1990 – Congress imposed nutrition labeling requirements for foods generally – FDA can decide
          labeling for dietary supplements
           i. Can‟t make claims for dietary supplements that you couldn‟t make for foods
       g. 1994 – Congress stiffens FDA‟s authority
       h. Lessons
           i. Political potency of dietary supplement consumers & manufacturers
           ii. Some categories, or at least one, represents limitation of authority on FDA
               (a) Dietary supplements – evidences Congress‟ desire to limit regulation
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            i. Can FDA challenge dietary supplement quo supplement on the ground that it is categorically
                i. Ephedrine – enough people get hurt by taking it so that risks > benefits
                ii. Most manufacturers dropped it from their products
                    (a) Prepared to sacrifice a single ingredient to maintain political balance
                iii. But two manufacturers took FDA to court in Utah (center of dietary supplement production)
                    (a) FDA can‟t enact categorical ban
                    (b) Must demonstrate some sub-categories that can be individually evaluated
            j. Scope – matter of considerable uncertainty
III. Regulation of Food
     A. Preventing Adulteration of Food
        1. Intro
            a. American Chamber of Horrors (1936), Ruth Lamb – reprise of The Jungle, w/ broader scope
            b. Is regulation the only way to respond to the problem?
                i. Consumer watch dogs
                ii. Walk away from the foods
                iii. Products liability – but proof of causation is hard
                iv. Usual rule (until recently) – violation of FDA regulation is negligence per se – but compliance is
                   evidence of due care
                    (a) Now, case law upholds compliance as defense claims – mostly depending upon congressionally
                        added language
        2. Provisions
            a. § 342(a)-3 – if it consists in whole or in part of any filthy, putrid, or decomposed substance, or
               otherwise unfit for food
            b. (a)-4 – if it has been prepared, packing, or held under unsanitary conditions whereby it may have
               become contaminated
            c. Concerns: infection, unappetizing (aesthetic), bioterrorism (registration of all food people + budget)
            d. Why are they both here?
                i. (a)4 – “may” – the food might only be potentially contaminated
                ii. Could apply even if food is completely clean
                iii. Administrative efficiency – can‟t inspect everything all the time – lowers the burden – easier to
                   inspect processing establishments
            e. a3 – does govt. have to prove “unfit” to establish violation? – no – they are disjunctive
            f. Is every food adulterated?
                i. If construed literally, yes
                ii. But FDA has power to set working tolerances
            g. What must govt. prove after food is seized?
                i. Has FDA constrained itself w/ the working tolerances? – no
                ii. Just has to prove ANY filth
        3. USDA works side-by-side w/ FDA
            a. Distribution of resources isn‟t proportional to risk
            b. Proposals to combine two functions in single agency
            c. Senator Durbin – leading proponent right now
            d. Opposition
                i. FSIS inspectors – 10,000 unionized people
            e. USDA tried to change inspection methods
                i. Stop inspecting every carcass – start sampling
        4. Nova Scotia (p. 13)
            a. Case involves 342(a)(4) – condition of processing facility
            b. Facts
                i. Smoker of fish in metro NY
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        ii. FDA was concerned that some fish could contain spores that could proliferate if not neutralized –
           presents botulism risk
        iii. Solution – processing of fish – combination of salt, high temperature, and prolonged smoking
        iv. FDA adopted regulations framing the requirements
        v. Turned statutory regulation from negative (product shall not…) into positive (in order to comply,
           you must do…)
        vi. At adoption, FDA didn‟t believe this had any more legal status than working tolerances
        vii. NS is out of compliance – argued that “properly” cooked fish was unpalatable
        viii. NS had no adverse incidents
        ix. FDA brought suit for injunction
        x. NS – facility is fine – FDA is complaining about raw materials of the fish – no basis under statute
    c. Ruling
        i. FDA wins on the process issue
        ii. Are the regulations lawful?
            (a) NS – nobody will eat the food if regulations are followed – “expert” tester couldn‟t tell
            (b) Validity of regulations is dependent upon adequacy of FDA‟s justification at time of adoption
            (c) Regulations didn‟t comply with administrative procedure – persons outside didn‟t have access to
        iii. If FDA had complied with administrative procedure and considered palatability, would the
           regulations have been binding?
        iv. If the regulations are substantively valid, can they be binding?
            (a) FDA has been given authority for regs w/ respect to certain provisions of statute
            (b) § 371(a) – power to adopt regs for enforcement is vested in the Secretary
            (c) § 343(j) – misbranded, unless label contains proper info determined & regulated by Secretary
                   (1) Has no content until there are regs
            (d) But 342(a)(4) doesn‟t seem to need regs, and doesn‟t give Secretary the job of regulating
            (e) Statute confers rulemaking authority selectively
            (f) For food processing, responsibility is left ultimately to courts
    d. Judgment about importance of FDA‟s authority to issue regs might depend upon statutory language
    e. Recognition of FDA‟s authority to issue binding rules expands FDA‟s authority
    f. If FDA brings enforcement action, and regs don‟t have force of law, in court, FDA must convince judge
       or jury that language of the statute has been breached
    g. If regs are binding, FDA doesn‟t have to worry about statute itself (it is supplanted by regs) – just needs
       to show a violation of the regulations
    h. § 343(a) – food is misbranded if label is false or misleading
        i. FDA could adopt regulation that says “Food is misbranded if it fails to identify proper ingredients”
        ii. If FDA is clear enough in its rules, compliance is much more likely – particular becomes the law
    i. Court interprets FDA as having authority to adopt regs which have force & effect of law
    j. FDA adopted an avalanche of regs
    k. By 2000, it had become accepted that FDA‟s authority had been judicially confirmed
5. Merrill & Watts
    a. If no statutory signal about regs, can‟t allow adoption of regulation
    b. It‟s possible to look at statute as a whole and draw conclusion about congressional intent
6. Nova Scotia upholds FDA‟s authority to proscribe specific regulations
7. Result of these three cases – transforms the way FDA regulates generally
8. Merrill & Watts
    a. Think the courts got it wrong by upholding FDA‟s authority to regulate w/ force of law
    b. § 402(a)(4) doesn‟t have required intent ??
9. Procedures that FDA must follow to adopt rules
10. For our purposes, we can assume that FDA has the authority that Nova Scotia asserts
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B. Food Quality & Labeling
   1. Historical background
       a. Reduced fat milk
          i. Mechanical processes extract larger portion of butterfat – lower butterfat content
          ii. This was a diluted product
       b. Orange drink
          i. Beverage made from orange juice and water
          ii. To some, looked like diluted orange juice
       c. Margarine
          i. Vegetable oil based butter alternative
          ii. Lower in fat, cholesterol, and price
          iii. Dairy industry – claimed it was adulterated butter – successful for nearly half a century
       d. Bread Spread
          i. Sold in small jars (like jellies)
          ii. Consisted of less fruit than traditional jams, but more sugar (sugar was cheaper than fruit)
          iii. Manufacturer could market this at a lower price
          iv. Jam producers persuaded FDA to bring legal proceeding
              (a) Relying on 1906 Act language
              (b) Claim – adulteration includes selling of product that is a cheapened version
              (c) Court not persuaded
              (d) Bread Spread people aren‟t starting w/ jam and taking fruit out – they are starting w/ an empty
              (e) Relevant comparison is w/ Bread Spread itself, not w/ jam
          v. If you wanted to regulate Bread Spread, what could you empower FDA to do?
              (a) Clear labeling
              (b) Require maker to indicate that this isn‟t the old fashion product
              (c) Does “imitation” suffice?
                    (1) Jam makers – not a loud enough warning
                    (2) Bread Spread makers – you‟re killing our product – nobody will buy it – this suggests that
                        it is tainted in some form
                    (3) FDA did enforce the “imitation” label eventually – forced manufacturers back to the
                        drawing board
                    (4) What market might not worry about pejorative implications of “imitation”?
                       (i) People who service consumers who never see the label – restaurants, etc
   2. § 341 (or 401) – definitions and standards for food
       a. Secretary can promulgate regs establishing standards for: identity, quality, or fill of container
          i. This is like § 403(j), since until Commissioner promulgates standards, there is nothing for FDA to
       b. § 403g – food is misbranded if it purports to be a food, but doesn‟t conform to the standard
       c. What does standard of identity look like?
          i. Example: peanut butter – must contain 95% or more peanuts
          ii. Specify min or max amt of ingredients
          iii. Many standards go further – more like a recipe for the product
       d. Many standards of identity issued
          i. Lots of them are for dairy foods (ex: ice cream, ice milk, etc)
          ii. Cheese – style w/ respect to source of milk, etc
       e. Could someone sell peanut spread product that only has 90% peanuts?
          i. Competitors would try to keep it completely off the market
              (a) “purports to be or is represented as” – same size jar, same color, same purpose, same aisle
              (b) Could interpret this as “looks to be and serves same function as”
       f. Quaker Oats – parallel standards of identify
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    i. Farina v. enriched farina – must have entire portfolio of nutrients in the amounts required
    ii. Quaker has an intermediate product
    iii. Court – FDA is ok – entirely ok for FDA to promulgate standard of identity that makes marketing
       an intermediate product legally impossible
g. What is the consequence of these positions?
    i. Favors incumbents of the food making industry
    ii. Reduces availability of potentially more healthy foods
h. Process by which statute requires adoption of standards of identity
    i. Agency issues notice about proposed regulation (appears in Federal Register) – invites comments
       from public
    ii. Agency gets comments, and decides whether or not to adopt – regulation appears in Federal
    iii. Reagan wanted better control of rulemaking process – superimposed more stopping places
        (a) Before agency issues notice of proposed rulemaking, must submit draft to Office of
            Management & Budget – wait for approval
        (b) Same process must be done after agency digests public comments
    iv. Congress imposed more requirements for FDA adopting standard of identity
        (a) If there are objections to standard, agency must hold administrative hearing to adjudicate the
            correctness of those objections
    v. FDA began peanut butter standard process – took 5 years & 96 days of hearings before it was done
    vi. But same process was required to amend or repeal the standard – aren‟t added to or modified
i. White House Conference on Food Nutrition and Health (1970s)
    i. President Nixon – expectation that McGovern might be opponent in 1972
    ii. Central theme – FDA should relax control over composition of food products & enlarge kinds/types
       of info available to consumers about food products
    iii. FDA implemented some of these recommendations
        (a) Relabeled as optional some of the ingredients in food standards
              (1) Before, ingredients in standardized foods weren‟t required on the label
              (2) Now, only key ingredients are in the recipe – can use any others you want, as long as they
                  are safe
j. Seafood cocktail
    i. FDA convinced that there was a large # of diverse recipes on the market
        (a) Had different kinds of seafood
        (b) Varied of amount of seafood contained in them
    ii. FDA wanted to require that manufacturers simply label product w/ how much seafood it contains
    iii. But there is no provision of Food and Drug Act that speaks w/ enough clarity to allow FDA to
       require % labeling of any ingredient
        (a) Only requires: name of manufacturer, quantity of contents, ingredients if 2 or more & not
            standardized food, name of product
    iv. FDA gave seafood cocktails an official name – “seafood cocktail contains X % seafood”
    v. Industry takes FDA to court, and FDA wins
    vi. Then someone says, “why not do this for all of the ingredients”?
    vii. FDA doesn‟t see how they can stretch name into required disclosure for all components
    viii. Now, manufacturer can sell peanut spread as “peanut spread contains 80% peanuts”
k. FDA wanted to relieve manufacturers of new versions of standard foods that they might have to use
   “imitation” label
    i. Issued regulation interpreting 403(c), saying that product is an “imitation” only if the product is
       nutritionally inferior to the other product
    ii. Essentially cuts the guts out of “imitation” labeling requirement
l. Common policy thread
    i. FDA shifts from paternal strategy of determining contents to providing info to consumers
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           ii. Primary focus – economic choices
           iii. Not much attention to issue of nutrition
   3. FDA wanted food producers to put nutrition info on the labels
       a. FDA felt uncertain if they had legal authority to do this
       b. Presumably only some variant of the required disclosures that FDA can require
       c. § 201(n) – if article is alleged to be misbranded b/c of labeling, consideration can include whether label
          fails to reveal material facts w/ respect to claims made in the label
       d. FDA seized on this definition, saying it is an obligation to tell the whole story
       e. Adopts regulations requiring nutrition info on food labeling
       f. If you sell a food product, and provide nutrition info, here is how you must do it
       g. If you make a nutritional claim for your product, that is an incomplete statement of the nutritional
          properties of the food & you must provide full nutritional label – otherwise your label would be
       h. OR if you add to your product any nutrient, your label will be misleading for failure to provide info that
          is material w/ respect to the implicit representation
       i. This became standard for disclosure for much of food supply in 1970 – 1980s
   4. Pearson – FDA restrained by 1st A
C. Toxic Chemicals Added to Food
   1. Intro
       a. What kind of chemicals?
           i. Additives – perform some functional purpose (preservative, taste, color, form, etc)
           ii. Pesticides – could argue they are purposeful – but separately regulated
           iii. Pollutants
       b. Why separate chemicals? – separately regulated under F & D Act
       c. Historical background
           i. 1906 – adulterated if toxic ingredient is “added” that “may” be injurious
               (a) Draws line btw things “added” and naturally-occurring things (poisonous mushrooms)
               (b) FDA can‟t prove adulteration simply by showing that food contains poisonous chemical
               (c) Burden – FDA must show that it might be possible that people will get sick
               (d) No burden on manufacturers
           ii. 1938 – two safety standards
               (a) Added – adulterate if increased possibility of harm to consumers
               (b) Non-added – must be “ordinarily injurious” to health
           iii. Congress focuses on “added” substances, and focuses on different slices of that part of pie
               (a) Common theme – need govt. approval
           iv. Transformation of food supply during WW II – food needed to be durable
           v. Delaney‟s first law – pesticides
   2. Added Chemicals under the Food Additives Amendment
       a. Food Additives Amendment (1958)
           i. § 402(a)(2)(c) – enforcement provision – tells when a food is adulterated
               (a) Food = adulterated, if contains unsafe additive
               (b) Food additive = unsafe, if it lacks FDA approval
               (c) EASY burden for FDA to carry
           ii. § 201(s) – definition of food additive
               (a) Substance whose intended use may be expected to result (directly or indirectly) in its becoming
                   a component or otherwise affecting the characteristics of any food
               (b) Covers not only ingredients in a recipe
               (c) Also covers materials used in food processing that aren‟t part of the food – indirect food
               (d) EXCEPT: generally recognized as safe (GRAS)
                     (1) Don‟t want to reprove what is already known for much of food supply
                                                                                                       Flusche 11 of 32
                  (2) Potentially temporary – “is” GRAS
                  (3) Something might be GRAS, but later studied and found to be unsafe
            (e) OR: prior sanctioned use < 1958
                  (1) Focuses on reputation of chemical w/in regulatory community
                  (2) If additive is blest before, doesn‟t need to be blest again
                  (3) FDA will issue a “sanction letter” which constitutes prior approval
                  (4) This exception is permanent
                  (5) Speaks in terms of regulatory history, which doesn‟t change
                  (6) Important commercially
        iii. § 409(c) – criteria to be satisfied before FDA will approve additive
            (a) Persuade FDA that your food additive will be safe
            (b) If FDA agrees that additive will be safe – issues regs in Federal Register – can put limitations on
                it (amounts, in specific foods, for specific uses)
            (c) Generic approval
            (d) Gives FDA lots of leverage
    b. Process for getting approval
        i. Most of info that FDA uses is derived from toxicological studies and lab animals
        ii. Very rarely permit studies using human volunteers
        iii. Most studies will show some harmful effects – might find a No Observed Effect Level
            (a) Adjust for size (btw lab rats & humans) – use body weight or surface area – increases NOEL
            (b) ÷ 10 for diversity (humans are more varied then rats)
            (c) ÷ 10 for susceptibility (we might be more susceptible than test subjects)
            (d) Perhaps ÷ 10 again for children (1000 safety factor)
                  (1) Effect in animals is very worrisome – esp. birth defects
                  (2) Foods are preferentially consumed by children
        iv. FDA determines an “acceptable daily intake” (ADI) – NOEL ÷ 100 = ADI
            (a) Tries to take into account the higher servings that people actually consume
    c. System doesn‟t work if effects caused are cancer
    d. ADI assumes that consumption below this level will literally be safe for anyone consuming it
    e. § 403(c) – includes Delaney clause
        i. Doesn‟t speak in terms of risk of carcinogen
        ii. FDA has no authority to approve it, no matter what the cancer risk is
        iii. “No additive that produces cancer in man or other animals” – can‟t be approved
        iv. Controversial at time of adoption
        v. Colleagues in House wanted to memorialize Delaney‟s efforts in this area
        vi. Secretary testified – didn‟t object – it wouldn‟t approve chemicals that cause cancer anyway
        vii. More chemicals undergo testing for carcinogenic properties
        viii. This includes substantial # of already approved pesticides
        ix. There are a lot more industrial chemicals in food supply than we expected
        x. Universe of potential targets – getting larger
        xi. Carcinogen presents some risk at any level of exposure, risk that it presents is likely to be
           proportionate to amount of exposure
        xii. Exposure might be so low that risk will be trivial – not a plausible basis for disapproval
3. Pesticides
    a. Colors and drugs used to treat food animals will be forbidden if they cause cancer, unless no residue
       will be found in tissues taken for human consumption
        i. But how hard do you look for residue?
    b. Can‟t label environmental contaminants as “food additives” b/c then they would have to ban food
        i. § 406 of original 1938 statute – gives some ways around declaring a food unsafe
        ii. Gives Sec. authority to issue regs telling how much of the deleterious substance is allowed
                                                                                                        Flusche 12 of 32
           iii. One good example of a time when Sec. can do this if even good manufacturing practices can‟t
              eliminate the deleterious substance
       c. However, 1938 statute doesn‟t get around the problem of having the private sector do the research
       d. Another drawback – such regs would have to go through formal rule-making
       e. FDA has issued only one formal tolerance level – PCBs
       f. Other environmental contaminants FDA has informal tolerances – now called “action guides”
       g. Afflatoxin
           i. Mold that grows on nuts and grains
           ii. Rats get liver cancer from it
           iii. Humans are susceptible according to West Africa data
           iv. 15 ppb are allowed for corn
           v. FDA increased to 100 ppb if only used for livestock
           vi. Consumer group took FDA to court – claimed FDA was required by statute to pass a formal
           vii. SC said even “action guides” needed notice & comment b/c they act to form the FDA‟s
              enforcement policy
       h. Northeast – consumer advisory to pregnant women about mercury in fish, but no regulation
           i. Advisory is vague and hard to follow and most likely hard to find
           ii. But FDA has some general hurdles in regulating environmental contaminants
D. Genetically modified foods
   1. Should law require pre-market approval?
       a. EU – yes
       b. USA – not necessarily
   2. Does it need to be labeled as genetically modified?
   3. What risk of cross-contamination among plants?
   4. Rutabaga That Ate Pittsburgh – article that commented on the risk of allowing GM crops to be grown
   5. FDA has 4 avenues to regulate GM foods (§ 402(a)(1), 409, 403, 406
   6. Commercial issue – is there a market for these foods?
       a. Only 10 year-old issue
       b. EU – very hesitant
       c. Jury is out whether companies will find it a good investment
       d. Immediate beneficiaries – farmers – use less seed, use herbicides more effectively
   7. Labeling
       a. Is there a genuine consumer desire to know that food is GM?
       b. Does FDA have authority to require label disclosure of GM food?
           i. § 403 – misbranding – food = misbranded, if certain info is omitted
               (a) But list isn‟t very long
               (b) 1938 Act: name & address of manufacturer, name of food, ingredients (if >1), amount of food
                   in package)
               (c) 1990 – added nutritional properties
           ii. Given this framework, can FDA require GM labeling?
           iii. § 201(n) – FDA can require info, w/out which a label would be misleading
               (a) 1st prong – info must be “material” – influential for purpose or use
                     (1) Must be material in light of representations that seller of food makes
                     (2) Argument for consumers – when you say “milk,” consumers assume only the cow was
                     (3) FDA – as long as seller makes no claim other than “milk,” there is nothing to correct
                     (4) There would be no claim that needs correcting
               (b) 2nd prong = material w/ respect to the consequences that may result from use of food
           iv. Manufacturers and some users of Prosilac challenged statute – violates 1st A – required provision of
              info that seller doesn‟t wish to provide (but that‟s the whole point of the statute)
                                                                                                         Flusche 13 of 32
   8. Pre-Market Approval (not needed)
       a. Material that gets added to food is a gene – coloration, longer shelf-life, resistance to pesticides
       b. Everyone agrees that the gene is as safe as any other gene
       c. Protein that gene codes for – easy to classify as food additive
       d. Gene isn‟t a food additive, unless there are reasons to think that use or gene itself might not be unsafe
       e. No GM has gone through food additive process – all are GRAS
       f. Agency claims that every genetically modified food has first been discussed with FDA
       g. But FDA doesn‟t actually approve GM foods
       h. Domestic industry is in a pickle w/ foreign markets that require finding of safety
           i. Manufacturers want to have a document showing FDA‟s blessing
           ii. But they don‟t want FDA to abandon the categorical GRAS standard
       i. FDA proposal – if you don‟t consult, your product is a food additive
       j. To get to pre-market approval, we will probably need a “thalidomide looking episode” for GM food
       k. If pre-market approval is required, how would you test if it is safe?
   9. Segregation
       a. How do you keep GM crops from regular crops?
       b. Corn – Starling
           i. Company added foreign gene that killed major domestic pest threat (corn borer)
           ii. Inside the corn seed is a pesticide that kills the corn borer
           iii. Anything that is sold for eradication or control of pest = pesticide
           iv. Pesticide law is controlled by EPA
               (a) Can‟t sell for any use that EPA hasn‟t approved as safe
               (b) What do you do about pesticide residues after incorporated in crop, that remain when sold for
           v. FDA – don‟t know enough about possible remnant effects of this product
           vi. But there is a big market for corn – animal feed (60-70%), ethanol
           vii. Ok for animal food & ethanol product
           viii. Kraft taco shells contained trace levels of pesticide gene
           ix. Corn stubble remains on ground in the field
           x. If next season contains Starling-free corn, it will contain trace amounts of Starling from prior
           xi. Drift – Starling corn can drift across the fields
           xii. Bins – must remain segregated
           xiii. Cheating – costly & inconvenient to keep corn separate
   10. Questions (in priority order): approval, labeling
E. Dietary Supplements
   1. Dietary Supplement Health and Education Act of 1994 (DSHEA)
   2. Congress added to 4 basic categories (drug, device, cosmetic, food) a 5th: dietary supplement (DS)
   3. Statute also says that DS are subset of food – subject to many requirements generally applicable to foods
       a. Adulteration
       b. Misbranded
   4. Claim – DS not reliably produced in many markets
   5. Need uniformity and purity – levels of active ingredient need to be standardized & maintained
   6. Manufacturers – viewed this as a restraint (along w/ consumers – genuine consumer demand)
   7. FDA cannot:
       a. Classify common DS ingredient as a food additive (don‟t want FDA impeding sale of highly prized
       b. Challenge DS as a drug, when it makes label claims about health benefits
           i. Debate about what constraints FDA may impose
           ii. But DS can make at least “health promoting” statements
           iii. FDA could challenge a statement as misleading or false under § 403(a)
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8. Pre-1994 background
     a. Long-running acrimonious, bitter, frustrating struggle w/ DS
     b. FDA – you don‟t need DS, and if you‟re paying for them, you‟re being cheated
     c. 1938 Act – § 403(j) – FDA can require info about nutritional properties, on labels of foods sold for
        special dietary use
     d. FDA adopted regulations for pre-cursors to today‟s DS (vitamin-mineral pills)
         i. Tell consumer how much of nutrients are in the food
         ii. Tell how much is needed to support dietary health
     e. Industry grows over time
     f. FDA attempts to limit nutrients that can be added to DS to those for which there is a demonstrated
        dietary need
     g. FDA seeks to limit level of established nutrients that can be added to those that reflect basic nutrition
         i. Can‟t demonstrate that intended use of product is therapeutic, if manufacturer doesn‟t make
            therapeutic claims
     h. Proxmeyer Amendments (1976) – tried to defang FDA and release DS industry
         i. Can‟t limit amount of nutrient in DS based on utility, only on safety
         ii. Overwhelming vote of both houses from both parties
     i. FDA began series of cases challenging DS that they were unapproved food additives
         i. Black Current Oil (capsules)
             (a) FDA claimed it was food additive, requiring approval
             (b) 7th Cir – not a food additive, since it hadn‟t been added to anything
9. Important dates
     a. 1938 – Congress included § 403(j) in Food and Drug Act
         i. Authorized FDA to specify labeling info requirements for foods sold for special dietary use
     b. FDA thought the products were sold deceptively
10. FDA opposes statements regarding cholesterol & dietary fat – treated w/ suspicion
11. By 1980, FDA‟s posture – doesn‟t like label claims about disease avoidance – potentially drug claims
12. Two reports – lend credence to notion that foods are low-fat, high-fiber, etc are healthy and will reduce
    long-term risk of chronic disease
     a. These undermine FDA‟s historic posture
13. Kellogg‟s tried to label cereals w/ claims
14. Q shifts – are these claims to be treated as drug claims, or is there another role?
15. Particular issues: fresh foods – fruits, vegetables, meat; food consumed at home
16. FDA had to figure out what descriptors mean: “fat free,” “high fiber,” etc
     a. 18 months of rulemaking
     b. Dept of Agriculture – less enthusiastic than FDA, particularly regarding fat content
     c. USDA fought FDA about what “reference diet” ought to be used
         i. Rationale behind nutrition labeling – how much of consumer‟s daily need is being satisfied
         ii. Critically, what size diet should be used? – bigger diet means that good stuff counts more, bad stuff
            counts less
         iii. President ended up making the call, splitting the difference – 2,000
17. Where do dietary supplements come into this?
     a. Labeling for all foods potentially has applications for dietary supplements
18. Three categories where FDA had leverage under 1990 legislation:
     a. Content claims – presence & implicit utility of dietary constituent (ex: “good source of iron”)
     b. Function claims – (ex: “fiber aids digestive regularity”)
         i. Must be pre-approved by FDA before use
         ii. UNLESS seller of food can point to authority statement supporting the claim
             (a) Ex: chapter in National Academy of Science or National Institutes of Health
     c. Health claims – (ex: “diet high in fiber may reduce risk of cancer”)
         i. In another era, would‟ve been viewed by FDA as drug claims
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              ii. But central thrust of 1990 legislation – permit health claims that would otherwise be considered
                 claims for drugs
       19. What authority does FDA have to see to it that nutrients and other constituents in dietary supplement (DS)
          are safe for consumption?
           a. Congress, in 1994 DSHEA, said that constituent of DS may not be regulated as food additive
              i. BUT applies only to constituents of DS in use as of 1994
              ii. New ingredients in DS don‟t require pre-market approval, but manufacturer must alert FDA in
                 advance of plan to use new ingredient
              iii. For large universe of DS, this immunity of regulation as food additives means that FDA must resort
                 to other means of control
           b. § 402(f)(1) – DS adulterated if unreasonable risk of illness or injury
              i. “Unreasonable” – creates temptation to weigh risk v. benefits of consumption
              ii. Congress didn‟t set forth procedure for FDA to determine if DS presents unreasonable risk
                  (a) Ex: FDA went through rulemaking to ban DS containing ephedra
                        (1) Never went to ct, didn‟t seize anyone‟s product, didn‟t prosecute any sellers
                  (b) Judicial proceedings? – FDA would have burden to prove adulteration
              iii. What procedure would FDA prefer? – rulemaking
                  (a) Would all DS manufacturers immediately object?
                        (1) At least they would be on notice as to what is expected
                        (2) There is also safe harbor until the rule is finalized
                        (3) Can raise issues during comment period
                        (4) The manufacturers would be together – like a class action
                        (5) Manufacturers don‟t want to be singled out & named in ct case
              iv. In any proceeding:
                  (a) U.S. bears burden of proof on each element
                  (b) Court shall decide any issue on de novo basis
                  (c) Notice to respondent in any civil proceeding to enforce (f)(1)
                  (d) Secretary shall report to U.S. attorney
              v. What did Congress intend for procedure?
                  (a) Normal administrative rule challenge
                        (1) Challenger must show rule is arbitrary and capricious
                        (2) Court generally defers to record produced by agency
                  (b) Professor – Congress viewed enforcement of (f)(1) through court proceeding initiated by govt.
                  (c) Doesn‟t say “FDA‟s” burden of proof, but “U.S.” – U.S. is only in case if it is a ct case
           c. Case (ephedra, don‟t know the name)
              i. Govt. bears burden on every element
              ii. Ct looks at unreasonable risk statement (might be overturned on appeal – govt. lost ground)
                  (a) FDA categorically banned ephedra
                  (b) Govt. can‟t make risk assessment at that level of generality
                  (c) FDA cannot judge risks and benefits of ingredient abstractly – risks might go down
                  (d) Different formulas might produce different risks
           d. Manufacturers got out of the ephedra business
              i. Didn‟t want Congress to bolster the statute
IV. Drugs
    A. Basics of Drug Regulation
       1. Drug program gets lion‟s share of attention, especially from the press – analysts, lawyers, etc
       2. What kind of products?
           a. Definition of drug from F & D Act (s p. 1)
              i. Articles intended for use in diagnosis, cure, treatment … in man or animals
              ii. Articles other than food that intend to affect structure or function of body
           b. Product can be more than one category – ex: food / cosmetic may also be a drug
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    c. Elusive boundary btw DS and drugs
    d. Important Q, since drugs subjected to more stringent controls – FDA approval for safety &
       effectiveness before marketing (burden of proof on manufacturer)
3. Vioxx story
    a. Merck manufactured V and got approval from FDA in „99
    b. M sponsored clinical trials in ~5,000 patients (relatively large test)
    c. V approved b/c it offered unusually good relief from arthritis pain w/out gastrointestinal effects
    d. Clinical trials didn‟t reveal any significant elevation in cardiovascular risks while using drug
    e. FDA works w/ company to agree upon labeling (doesn‟t dictate)
    f. FDA oversees advertising of drugs that are sold by prescription – ensure conformity w/ labeling
    g. Marketing goes straight to consumers – sales soar
    h. M was selling $2b annually w/in 2 years
    i. M undertook post-approval trials to explore other uses for V – seeing if suppressing colon cancer
        i. This trial includes close evaluation of cardiovascular effects on patients
        ii. EE suggests that patients on V for 18 months or longer have significantly elevated incidence of
           heart attacks
        iii. M reports this data to FDA (maybe not as promptly as it should have)
    j. FDA assembles advisory committee – should V have a “black box warning”?
    k. M argues there are alternative interpretations – re-labeling isn‟t necessary
    l. At some point, M withdraws drug w/ FDA‟s approval (on market for 4 years)
    m. Soon (hours), M faced w/ 12,000 lawsuits
    n. Three cases resolved now – M lost first, won second two
    o. Federal CA judge – pressuring parties to settle
    p. National Academy of Sciences – commissioned by FDA to study system for approval and subsequent
       monitoring of prescription drugs
    q. How does the system work?
    r. Does it work?
4. History
    a. Three important dates
        i. 1906 – original F & D Act
            (a) Two kinds of offenses:
                  (1) Adulteration – dirty or dangerous
                  (2) Misbranded – misdescribed or lied about
            (b) SC considered whether govt. could challenge marketing of product on ground that it failed to
                perform as seller claimed it would
                  (1) Claims about products are assertions of opinion – gets into 1st A issues
                  (2) Early warning that there are Const. limits w/ respect to speech about health
            (c) FDA is tasked w/ role as police officer
            (d) No pre-market review or approval
        ii. 1938
            (a) Prohibition on misbranding is elaborated – makes it easier for FDA to punish unsupported
                claims of drug performance
            (b) Misbranded = label is false or “misleading”
            (c) Implicit affirmative disclosure obligation built into “misleading” language
            (d) Elixir sulfalidomide – incorporated ethylene glycol – poisoned 100 people in TN
            (e) Congress realized they should give FDA some teeth – limited pre-market authority
            (f) Mechanism created:
                  (1) Any co. seeking to introduce a “new drug” must notify FDA before marketing
                  (2) Must provide info on which notifying co. bases judgment that product will be safe
                  (3) FDA doesn‟t have to approve product before marketing
                  (4) No legal right of agency or obligation of company to wait for approval
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               (g) Focuses on safety of drug, and not on effectiveness, at least not overtly
               (h) Most drugs proffered by FDA as safe carry some side effects
           iii. Exploding growth
               (a) ~9500 “new drug” applications become effective btw ‟38 and „62
               (b) Indeterminate # of pre-‟38 drugs still on the market – FDA hasn‟t applied scrutiny for safety –
                   grandfathered in, if they don‟t change labeling
           iv. Two universes:
               (a) FDA “blessed” products
               (b) Shrinking # of old products – being replaced by new products
           v. Several thousand products enter marketplace after ‟38 w/out getting FDA‟s blessing as “safe”
               (a) Pioneer notifies FDA, and markets drug
               (b) Later company copies the drug, and FDA doesn‟t require another application
               (c) On average, for every pioneer product, there 10 “me too” products (i.e. generics)
           vi. Thalidomide horror – FDA didn‟t approve in U.S.
           vii. 1962 – § 505 of statute (s p. 130-57)
               (a) Requires pre-market approval by FDA
               (b) Approval can‟t be given unless FDA is satisfied that product is safe AND effective (for uses that
                   will appear in labeling)
               (c) Only applies to “new drugs”
               (d) Responsibility changed – no longer just police officer or umpire – now affirmatively responsible
               (e) Kind of EE to show effectiveness – § 505(d) – must be substantial EE – defined as EE derived
                   from adequate and well-controlled clinical studies
                     (1) Paid for by drug companies, not FDA or NIH, etc
           viii. Consequences:
               (a) Slow-pace of drug development and approval
               (b) Development = long, slow, and expensive
               (c) Clinical trials that must be done – long, slow, and $
               (d) Estimates for how much it takes to produce a drug: varies, but about $800m
                     (1) Much is direct cost for development & studies in laboratories
                     (2) A lot of the money is interest – time-cost of $ invested early on
               (e) Length – 7-10 years – most of this time is part of patent life of product
               (f) Lipitor (world‟s largest-selling drug) – over $8b per year sold
               (g) A lot of the work is done in public investment settings – NIH, govt. grants to researchers
               (h) In order to get approval, manufacturer must do lots of studies – take a lot of money
                     (1) Unclear who owns the studies after used by FDA for drug approval
                     (2) Companies who pay for these view them as proprietary – their property, on loan to govt.
                     (3) Companies don‟t want info given to anyone else, particularly competitors
B. Human Subjects Research
   1. Legal intro
       a. § 505(d) – drug can‟t be approved by FDA unless shown to be safe & substantial EE to support
       b. Substantial EE – including clinical evaluations
       c. Ordinarily, manufacturer of drug must ship it to investigator in another state
           i. But it would be illegal to ship un-approved drug in interstate commerce
           ii. § 505(i) – FDA authorized to make regulations for un-approved drugs being sent to clinical
       d. FDA regs set forth conditions of shipping un-approved drugs to investigators
           i. Proposed research protocols must be reviewed and approved by local institutional review committee
       e. Manufacturer pays for the studies
           i. Study results viewed by company as its property – on loan to FDA
   2. History
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     a. 1667 – Paris Ct – human experiments required consent of medical faculty
     b. 1947 – Nuremberg Code – “voluntary consent of human subject is absolutely essential”
     c. Three U.S. scandals
         i. Human radiation experiments
         ii. Tuskegee syphilis study
         iii. Willowbrook
     d. 1974 – National Research Act – requires entities to establish “institutional review boards”
     e. 1991 – “The Common Rule” – solidifies regs for FDA and HHS (generally)
3. Belmont Report – respect for persons (individual autonomy AND reduced autonomy), beneficence (do
    good), justice
4. Definitions
     a. Research – systematic investigation designed to develop or contribute to generalizable knowledge
     b. Human subject – living individual about whom an investigator obtains: data OR private info
5. Applicability:
     a. HHS – federally supported research OR research carried out w/ Multiple Project Assurance
     b. FDA – fit under regulated products, drugs, devices, biologics, food/color additives
6. Basic Protections
     a. Institutional Assurances
     b. IRB review
     c. Informed Consent
7. IRB decision matrix
     a. Benificence
         i. Risk / benefit analysis
         ii. Experimental design
         iii. Qualification of PI
         iv. (Non-malfeasance)
     b. Justice
         i. Subject selection
         ii. Inclusion / exclusion
         iii. Recruitment
     c. Respect for Persons
         i. Informed consent
         ii. Surrogate consent
         iii. Assent
         iv. Protection of subjects (esp. vulnerable populations)
8. IRB membership
     a. At least 5 members
     b. Both genders if possible
     c. Varied professions
     d. Member whose primary concerns are in nonscientific areas
     e. Member whose primary concerns are in scientific areas
     f. Member not otherwise affiliated w/ the institution
9. Types of Review
     a. Initial Review
     b. Continuation Review
     c. Amendment Review
     d. Adverse Events
     e. Noncompliance
10. Informed Consent – must make sure people understand it
                                                                                                         Flusche 19 of 32
       a. Basic elements: statement that it is research, procedures to be followed, risk / discomforts, benefits,
          alternative procedures, confidentiality description, if > minimal risk explanation of compensation &
          medical treatments, contact if questions arise, participation is voluntary
   11. Compliance
       a. Institutional Internal Audits
       b. Continuing review – over-enrollment or under-enrollment – is anyone publishing?
       c. Education
       d. External audits
       e. Audits by OHRP and FDA
   12. Failure to Comply
       a. Researcher
       b. Institution
   13. Examples
       a. A
           i. Power problem – 30 people isn‟t enough to see difference in results
           ii. Is animal data sufficient? – are pigs good enough? – probably – but is resection equivalent to the
              seizures the people are having?
           iii. Phase 1 – look for safety in healthy volunteers
           iv. Phase 2 – may involve placebo – bigger (30-100) – look for efficacy
           v. Should‟ve found out lethal dose in animals (maximum tolerated dose)
           vi. 5 week progression into max dose – pretty quick – how are the people being evaluated?
           vii. Ages – seems to young – usually make sure drug is safe in adults BEFORE testing children, unless
              there is a reason (seizure most suffered in pediatric population)
           viii. Investigator has conflict of interest ($20k invested in drug company)
               (a) Big question – what would general public view as significant?
               (b) Disclose conflict of interest to participant
           ix. Length – animals studies only went for 10 weeks, this is for 36 weeks
           x. Genetic data – should it be disclosed? – should child even participate in such a study?
C. Labeling
   1. Recap
       a. IRB‟s play an important role, not just for drug approval
       b. Primary focus – local ethical concerns, and less on quality of research
       c. Inquiry is chiefly whether the protocols protect welfare and autonomy of participants
       d. FDA – focus on whether research is a window on safety & effectiveness of drug, were it to be approved
       e. Mechanics of triggering the IRB process
           i. Sponsor of drug that needs FDA approval, submits Investigational New Drug Application (IND)
               (a) Inevitably the case that some of investigators are in other states – need approval to ship drug in
                    interstate commerce
               (b) IND is formal legal instrument by which that is given
           ii. Manufacturer gives FDA 30 days to veto plan as set forth in IND – if doesn‟t respond, commence
           iii. In theory, manufacturer could proceed w/out ever hearing from FDA
           iv. Pre-FDA meeting – what drug might be useful for, how they will test it, subjects involved, who
              investigators will be
               (a) Sponsor hopes that FDA will say this data will be definitive judgment about safety &
                    effectiveness of product
               (b) Sponsor doesn‟t want FDA to say “you should‟ve done another study”
               (c) FDA won‟t guarantee it
       f. FDA expects data to be able to identify EACH patient in the study
       g. During time of approval process, patents are running (get patent once you think you can get FDA
                                                                                                      Flusche 20 of 32
       h. Drug companies that make investment for approval, want that information treated as proprietary (not
          available to anyone else)
           i. FDA, almost from 1940+, has agreed w/ this
       i. Application
           i. Section in application on chemistry
           ii. Section on pharmacology & pre-clinical research
           iii. Section on manufacturing processes
       j. How much EE need be provided (§ 505(d))?
           i. Adequate and well controlled studies
           ii. FDA used to take position that sponsor must provide at least 2 phase 3 studies
           iii. FDA can now accept just one study, if it is good enough
       k. If FDA is going to turn down manufacturer, it must provide hearing
       l. There are no formal hearings – if manufacturer gets turned down, doesn‟t petition FDA for hearing
           i. Not likely to win hearings
               (a) Not much chance that you can persuade admin law judge that its administration made a mistake
               (b) Could take to ct, but judge probably won‟t find for manufacturer either
           ii. Concerns about cost
           iii. Manufacturers are repeat players – don‟t want to anger FDA
       m. What if manufacturer is already marketing drug, and FDA says it‟s not safe?
           i. Nation‟s doctor has said the drug is unsafe
           ii. Drug company doesn‟t have a strong enough voice to say that it‟s safe enough
           iii. Threat of liability suits
       n. What if FDA tells manufacturer that effectiveness isn‟t born out?
           i. Difficult to take off market & do a new study
           ii. Who benefits from amount of time taken doing study & new approval?
       o. Process that is utilized:
           i. Outward contours are increasingly public
           ii. Before drug approved, almost universally the case that advisory committee will be empanelled
           iii. If committee gives ok, almost certain that drug will be approved
   2. Labeling
       a. Addressed to physicians – professional labeling
       b. Before 1962, FDA had authority to regulate labeling – misbranding
           i. § 201(n) amplifies “misleading” prohibition – misleading if what it fails to say
           ii. § 502(f) – label of drug must bear “adequate directions for use” and “adequate warnings”
       c. FDA‟s determination that a drug is marketable is not about the chemical exclusively, just the chemical
          in respect to the way it is packaged, for particular usages
       d. Can a Dr. prescribe a drug for a different use than FDA approved?
           i. Ok to prescribe drug for use that FDA hasn‟t approved
           ii. But might be illegal under fed law to prescribe drug in face of specific warnings against it
           iii. Can manufacturer promote new uses of drug? – no, this violates statute
           iv. Washington Legal Foundation objects – FDA objected to manufacturers distributing copies of
              public domain info from doctors
               (a) WLF says this info is in public domain – free speech
               (b) Ct – holds that info that company wishes to disseminate is protected speech under 1st A
                     (1) Perhaps commercial speech, since reason for dissemination is commercial
                     (2) Govt. doesn‟t have significant reason for controlling
D. Prescription Drugs
   1. These are biologically active compounds – they intend to produce benefit in patients – but there are risks
   2. Players
       a. FDA – determines studies to be done, and decides what results signify
           i. Translates its view into a document – the label for the drug
                                                                                                      Flusche 21 of 32
        ii. Studies have as many as 5,000 people
        iii. Once a drug is approved, and manufacturer can ship it, potential population might be 1000 X the
           size of studies
    b. Patients – don‟t have const. right to medicine
        i. Can become spokesmen for drugs that do get approved
        ii. Determine whether drugs are taken at all, on time, in proper methods
    c. Manufacturers
        i. Learn about clinical trials – after original approval – must they keep FDA informed? – Vioxx
    d. Physician
        i. Person who actually prescribes the medicine
        ii. Learned intermediary – has capability to make wise judgments & has access to info about patient
    e. Pharmacist
        i. Place where drug is conveyed from commerce to the patient
        ii. Last barrier between patient and drug
        iii. Drugs have two names
            (a) Manufacturer name – market attire
            (b) Chemical name
        iv. If physician prescribes Vioxx, it would violate state law for pharmacist to dispense a generic
            (a) But physician can prescribe “whatever” version
        v. Some states prevent pharmacists from refusing to dispense certain drugs that are anti-ethical
3. PMA v. FDA (p. 103)
    a. What info should be provided to patients?
    b. Oral contraceptives – FDA required that package insert must be included
    c. Manufacturers – filed suit against FDA
        i. Liability? – could increase manufacturer liability – but not really
    d. Physician groups – didn‟t want anyone getting in the way of their dialogue w/ patient
4. Mazur v. Merck
    a. Vaccine administered as part of public health program
    b. Held – vaccinated child, who had adverse effect, should‟ve been advised directly by manufacturer
        i. There wasn‟t a genuine doctor-patient relationship here
        ii. Can‟t assume that the patient‟s needs and info are adequately satisfied by physician
        iii. Well recognized exception to the learned intermediary doctrine
    c. Merck entered into agreement w/ local public health authority – they were supposed to convey info on
       behalf of Merck – so Merck‟s duty was fulfilled
5. APhA v. FDA
    a. Methadone – agent in treatment of heroine dependence
    b. FDA wanted to deal w/ threat of theft
        i. Keep it in investigational status – only available through clinical trials noted to FDA – didn‟t work
        ii. Conditional approval scheme – only available in hospital pharmacies or licensed drug treatment
    c. Pharmacist‟s Association – sued b/c most of their members were cut out of the business – scared of
       slippery slope
    d. Held – once FDA determines drug is safe & effective, can‟t restrict access by pharmacy
6. Accutane
    a. FDA‟s concern – effects on children conceived while mother uses Accutane
    b. Now, concern is heightened – more patients are becoming pregnant & risk of defects is higher
    c. Should FDA have not approved Accutane at all?
    d. Example: Tysobril – multiple sclerosis
        i. People experienced PML – frequently fatal infection
        ii. FDA withdrew the drug
                                                                                                    Flusche 22 of 32
        iii. Two weeks ago, FDA convened advisory committee to determine if drug should re-introduce drug
    e. Are these cases different?
        i. Accutane presents 3rd party risk, while Tysobril is only risky to the patient
        ii. Accutane is a lifestyle drug
    f. Is either scheme lawful?
        i. APhA – if FDA determines the drug is safe & effective, it must be prescription or over-the-counter
        ii. Will probably be challenged
7. Off-Label Use
    a. Two propositions
        i. Manufacturer cannot promote off-label use
        ii. Not a violation for physician to prescribe drugs off-label
    b. Evers v. U.S.
        i. Only case where FDA has gone after physician for merchandising of off-label use
        ii. Dr. Evers was good businessman – advertised prominently for treatments in his clinic
        iii. FDA viewed Evers as being a wholesaler – distributing drug for unapproved uses
        iv. Shipment of drugs occurred w/ FDA approval
        v. No statutory remedy available to FDA
        vi. FDA doesn‟t pursue physicians for off-label uses
    c. Washington Legal Foundation v. FDA
        i. FDA announced it was inclined to view 2 industry practices as violating illegal promotion:
            (a) Sponsorship of educational programs, whose content largely controlled by manufacturer – which
                included off-label uses
            (b) Sending reprints of journal articles to the prescribing communities, which encourage off-label
        ii. Communications that manufacturers make like this are commercial speech, subject to certain
    d. Perspectives
        i. Congress has made determination in Food & Drug Act that all drugs on market shall have been
           demonstrated safe & effective before commercialized
        ii. Legitimate and powerful public interest in having all uses be shown to be safe & effective
            (a) WLF – credits this claim – but FDA hasn‟t demonstrated that restrictions are narrowly tailored
                to fulfill public objective
        iii. Physicians
            (a) It‟s good to have the authority to prescribe for whatever use
            (b) We‟re the ones best to judge
            (c) Presume that drug approved for use A is safe for use B, and physicians can judge if it‟s safe
        iv. Patients
            (a) Cancer patients think they benefit – 60% of therapeutic agents are off-label
            (b) Physician‟s freedom benefits patients
            (c) BUT, patients are exposed to things that haven‟t been evaluated as safe for B use
            (d) Benefit coterminous w/ the risk
        v. Manufacturers
            (a) Pretty clearly welcome opportunity to have usage of products expanded
            (b) Studies done for use A might not be sufficient for use B
            (c) Incur increased liability risk
        vi. Health insurers
            (a) Probably lies against manufacturers
            (b) Would prefer to not provide coverage for treatments that no one has found to be safe & effective
    e. U.S. ex rel Franklin v. Parke-Davis
        i. Franklin = nosy busy body w/ appetite for monetary recovery
                                                                                                   Flusche 23 of 32
        ii. Claim – claims are false, since U.S. is only supposed to pay for uses of pharmaceuticals that have
           FDA approval
        iii. Franklin is suing Parke-Davis, who “caused submission” of ineligible claims
        iv. Ruling
            (a) If the prescriptions were for indications that FDA had approved, there is no false claim
            (b) If you look on face of prescription, you don‟t find an indication of what it is for
        v. What does Prof think about no reimbursement for off-label uses?
8. Advertising
    a. Series of restrictions on advertising for foods, drugs, devices, and cosmetics – enforced by FTC
    b. Congress gave FDA authority to monitor advertising for…
    c. Later, Congress gave FDA authority for “restricted devices” – for us, this = prescription drug
    d. W/ respect to foods, other devices, cosmetics, and OTC – FDA has NO regulatory authority over ads
    e. Advertising agency monitors ads – responds to manufacturers when they fail the regs, or fall close to
       the line
    f. Direct-to-consumer advertising (DTC) – relatively new
    g. Commissioner of FDA wanted voluntary moratorium to consider what to do about DTC
        i. Use old regs
        ii. Make new ones
    h. Industry acceded to FDA‟s request, and didn‟t do DTC ads for another 3-4 years
    i. FDA determined it didn‟t need any new regs
    j. Electronic media exploded in late 1990‟s
    k. How should regs be applied to electronic DTC ads?
        i. Requirements: brief summary, side effects, contra-indications, and effectiveness
        ii. This requires more in way of text than is easily includable in TV commercial
        iii. FDA – core requirements needed, unless:
            (a) Major statement = in brief language describe utility and major risks
            (b) Adequate provision to make it possible to obtain official labeling
9. Prescription vs. OTC
    a. When original Food & Drug Act passed, didn‟t distinguish prescription v. OTC
    b. FDA adopted regulation that created division – interpreted § 502(f) – drug is misbranded unless it bears
       in label adequate directions for use
    c. FDA had to identify drugs whose utility couldn‟t be assessed or safety assured, & convert to
    d. Congress ratified FDA‟s authority, codifying the regulations FDA had adopted
    e. 1962 amendments
        i. Don‟t allow drugs on market, unless shown to be effective
        ii. FDA must review all drugs previously approved (between 1938 and 1962) to confirm effectiveness
           or remove from market, if not effective
    f. Some putative OTC drugs, FDA decided it wasn‟t feasible to go through them one-by-one – done
        i. FDA was to endorse a monograph – all of ingredients for each category that are safe & effective
        ii. If your product meets the monograph, you are automatically ok
        iii. But if you don‟t meet it, you need pre-market approval
        iv. Expectation – many products fit monograph (100,000), others didn‟t – but only a bare handful
           sought pre-approval
10. OTC Approval
    a. What criteria apply to the decision, and what processes does FDA use to decide?
    b. History – see 9, above
    c. Two universes of OTC drugs:
        i. Large – relatively small # of ingredients, been around for long time
        ii. Small – more ingredients, much newer, w/ initial stop at prescription status
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       d. Who has interest in OTC status?
           i. Drug companies
           ii. Doctors – serve gate-keeping role – cuts both ways – dr. doesn‟t have to spend time on patient, but
              doesn‟t get $
           iii. Insurers – won‟t have to pay if drug is OTC
       e. Example:
           i. 2nd generation antihistamines: Claritin, Zyrtec, Allegra (Rx only)
           ii. Claritin faces generic competition in short term – tries to get OTC status
           iii. What about Zyrtec and Allegra?
               (a) If they go over the counter, they‟re still competing w/ Claritin
               (b) They have substantial remaining patent life
       f. Example 2:
           i. Statins – blood pressure meds
           ii. Could users use these drugs safely themselves?
           iii. Liver risks, so must monitor this
       g. Example 3: Plan B
           i. Claim that more girls would take advantage of if
   11. Drug Lag
       a. Timeline = Year 1 ………….. Year 7 (IND) ….. Year 9 (NDA) …… Year 12 (FDA Approval)
       b. Real concern used to be about safety of the drugs
       c. $800 m to be successful in getting FDA approval (much of which = time value of money)
       d. How much of the process does FDA actually require vs. what independent investigators would say you
          should do?
       e. Heavy emphasis on patient population size w/ respect to which drugs to develop
       f. Drug prices are high
       g. Imagine that we duplicate Thalidomide every 2 years
       h. If one drug gets through that creates same Thalidomide problems, it‟s better to have 15 drugs that don‟t
          get through
       i. By 1998, U.S. realized that drug lag was a severe problem
       j. How could we solve the problem?
           i. Accept overseas studies as proof in our process
           ii. Accept overseas judgments about safety & effectiveness
       k. User Fees – charge companies lots of money, take it to hire more people to study applications
E. Generic Drugs
   1. Pioneer NDA
       a. Pioneer develops drug & gets initial patents on it
       b. Spends a lot of time and $ in ensuing years doing studies on drug
       c. § 505(c) of Food & Drug Act – requires submission of “full reports” of studies undertaken to evaluate
          safety & effectiveness of product
       d. Reports are in custody of FDA, who treats them as agency records (but won‟t release them to the
       e. At some point, patent on drug expires
   2. Generic Co comes along
       a. Wants to make a duplicate product (just as good, but ½ the cost)
       b. Expenses in entering marketplace are much less (esp. if it can get FDA to accept Pioneer‟s studies as
          showing safety & effectiveness of the drug)
       c. Needs FDA approval – must have § 505(c) requirements
       d. Generic must submit NDA that satisfies § 505
       e. Doesn‟t want to repeat Pioneer‟s studies
       f. Generic asks FDA to let them see the safety & effectiveness data – won‟t happen
       g. Generic asks FDA to rely upon Pioneer‟s data – can‟t do that either
                                                                                                   Flusche 25 of 32
    h. Extrapolation from first product to second is only possible if drugs perform the same way
    i. FDA requires bioequivalence of Generic to Pioneer
    j. Two statutes prohibit FDA‟s release of info, and one statute doesn‟t obligate FDA to release it
        i. Trade Secrets Act (18 USC 1001) – crime for fed employee to disclose confidential information
3. After 1962, FDA concludes that roughly ¼ of approved products don‟t work
    a. But this means that duplicates, which don‟t have approved applications, are not effective either
       (roughly 10,000)
    b. FDA wants to legitimate the 30,000 duplicates that mimic the 3,000 approved products that are ok
        i. This means giving them approved NDA somehow
    c. Abbreviated NDA = NDA that includes most of the key elements, but doesn‟t include full safety &
       effectiveness reports
        i. Appropriate vehicle for conferral of approval status on 30,000 mimic products
        ii. There is safety & effectiveness data in the public domain for these drugs
        iii. Need an application, b/c we need to know if makers of these products know how to make a viable
           product & we must be sure that these 30,000 duplicates are bioequivalent
    d. These products are from 1938 – 1962
    e. After 1962, originators of drugs are much more cautious about allowing public release of safety &
       effectiveness info
    f. Paper NDA – not used much – allows NDA to use a surrogate for safety & effectiveness data
4. Two phenomenon erode generic approval – lengthening of drug patents, + ?
    a. Sets stage for political deal
5. Hatch-Waxman Act
    a. Generic gets:
        i. FDA can rely on safety & effectiveness data already on file
        ii. Provided incentives to challenge patent claims of pioneer manufacturers (that might be spurious,
           invalid, inapplicable)
    b. Pioneer gets:
        i. FDA can extend patent term up to 14 years
        ii. Legal framework w/in which it can confirm validity of patents before generic competitors enter
6. Walk-through Process
    a. Pioneer NDA
        i. New requirement: must list all patents that it claims covers the product
        ii. When FDA approves product, it makes public all the patents that manufacturer has claimed
        iii. FDA makes no judgment about coverage or validity of the patents
    b. 5+ years later, Abbreviated NDA
        i. Generic asks FDA to approve its version of the product, based on bioequivalence & data submitted
           by Pioneer
        ii. Can be small differences, but they can‟t change effect of potential safety
        iii. Labeling must be the same – w/ a caveat
            (a) Suppose Pioneer has approval for heart attack & diabetes, w/ patents on both
            (b) Heart attack patent is new, and diabetes patent is old
            (c) Can ANDA application ask to just approve it for diabetes, not heart attack?
            (d) Pioneer strongly objects – destroys his patent protected market – Fed Cir said this is ok
        iv. W/ respect to each patent, Generic can say one of four things:
            (a) No patents in Orange Book
            (b) All patents in Orange Book have expired
            (c) By the time we get approval, the patents will have expired
            (d) Patent won‟t be infringed OR is invalid
    c. Pioneer gets notice, and has two options
        i. Wait (to see what FDA does)
                                                                                                           Flusche 26 of 32
           ii. File suit against Generic, disputing claims about patents – 30 month stay on FDA (to hopefully let
              case be adjudicated)
               (a) Filing of ANDA can be held to be constructive infringement, even though product not marketed
               (b) Sometimes, Generic wants to settle validity of patents up front – Congress allowed this
   7. Statute details
       a. First filer of ANDA, who claims inapplicability or invalidity of patent, gets 180 days of exclusivity if
          ANDA is approved
           i. Commences when Generic first markets its product
           ii. How is first ANDA filer going to price its product – pick a price just a bit lower than Pioneer
           iii. What can Pioneer do – separately incorporate and make an “authorized Generic”
               (a) Nothing in Hatch-Waxman to forbid FDA from approving this
               (b) Exclusivity promised to first ANDA filer is just against any other ANDA filer, not Pioneer
           iv. What else might Pioneer do?
               (a) Pay ANDA filer to stay out of market – can raise antitrust issues
               (b) If have # of patents, acquired over period of time – have 45 days to file lawsuit against ANDA
                      (1) Lawsuit automatically triggers 30 month stay on FDA‟s approval of NDA
                      (2) Pioneer could “stack” patents, so that it has renewed option of challenging ANDA filer
                      (3) NOW, Pioneer gets only ONE 30 month stay
F. Private Liability
   1. Tort law and FDA are complimentary in making sure drugs can be safe & still provide benefits
   2. Law strives for reasonable safety
   3. Couple of scenarios regarding the same drug
       a. FDA approves a drug, prescribes label content
       b. Sometime later, patient takes drug & suffers heart attack (which FDA didn‟t require manufacturer to
          warn about)
           i. Patient‟s lawyer claims that FDA should‟ve told dr. that there was a chance of heart attack
           ii. Is it appropriate for this claim to be recognized by ct applying state law, on premise that tort duties
              of manufacturers aren‟t exhausted by FDA?
           iii. Difficult to persuade fact finder that drug caused the heart attack
       c. Suppose FDA did require warning on label about heart attacks – but manufacturer ignored this
           i. Almost all jurisdictions would find manufacturer negligent (assuming causation is proven)
           ii. Ps and Ps‟ search for ways to argue that manufacturer violated FDA regs or Food & Drug Act
       d. Suppose P has heart attack, FDA required warning, & manufacturer did it
           i. D wants to show that manufacturer did its job
           ii. Fact finder can give this some weight, but doesn‟t preclude negligence by D
   4. Enterprise liability – study commissioned by ALI
       a. Legal apparatus as a whole should give a regulatory compliance defense
       b. Three criteria that ought to be satisfied before ct (in tort case) should give regulatory dispositive
           i. Compliance w/ all requirements
           ii. Full public disclosure
               (a) Manufacturer must provide regulatory agency every item of info it has about safety of product
                    (everything it had, and currently possesses)
           iii. Risk under regulation
       c. MacDonald v. Ortho (p. 323)
           i. M took oral contraceptive & had debilitating stroke
           ii. FDA published regs, saying exactly what insert should say
           iii. This was first drug where FDA required a patient package insert EVER
           iv. Insert said “abnormal blood clotting that could be fatal”
           v. Ct
                                                                                                          Flusche 27 of 32
                  (a) Jury was entitled to ask if something different should‟ve been said
                  (b) When claim = failure to warn, P must show that defect in warning caused him to take the
              vi. Should Ortho have defense under ALI study? – Is the risk under regulation?
                  (a) Maybe
                  (b) Would be safe if we had Federal Register doc where FDA explained why they chose “blood
                       clot” to represent “stroke”
                  (c) Pretty strong example of needing to accept ALI formulation
          d. Tobin v. Astra Pharmaceutical Products (p. 328)
              i. D complied w/ everything FDA required
              ii. Info on which tort litigation proceeds = info FDA used to approve product
              iii. Q – whether product was approvable
              iv. P is allowed to ask fact finder whether FDA should‟ve approved product in the first place
          e. Hypo – Vioxx
              i. 1999 – FDA approves, requires labeling about chiefly stomach bleeding
                  (a) No EE in studies about increased risk of heart attack
              ii. 2001, Merck‟s phase 4 study – trying to find out if Vioxx also controls colon cancer – suggestive EE
                 that risk of heart attack is significantly increased (about 2x)
                  (a) Assume Merck gave this info to FDA
              iii. Should a patient who took Vioxx during 12 month period before taken off market be able to recover
                 against Merck on failure to warn grounds?
                  (a) Merck is using precise label that FDA required & doing everything else FDA wants
                  (b) Full disclosure – Merck gave all info to FDA
                  (c) Under regulation? – FDA‟s decision could be not to act
          f. Nature of regulatory process & regulatory communication
              i. It‟s hard to know what agency is doing, or indeed whether it is doing anything
          g. Suppose P argues (against Vioxx) that Merck bribed FDA officials not to consider data & FDA didn‟t
              i. Does P get to go to jury to ask Q whether there was successful attempt to bribe FDA?
          h. Two puzzles
              i. Implicit in Vioxx example – frequently time lag btw approval of drug & hazard associated w/ use
                 becomes apparent
              ii. Difficulty of finding out what FDA thinks about EE in absence of some public, formal declaration
                 by agency
                  (a) Very reluctant to get involved in private litigation
                  (b) Warnings – no heart attack warning on Vioxx – FDA never decided about it
                         (1) Merck would have to show that FDA standards are floor and ceiling
                         (2) If a jury tried to require more, it would be in conflict w/ statutory language
                         (3) But practically, if manufacturer tried to make warning stronger, would FDA ever say “no”?
V. Biologics
   A. Introduction
      1. These products differ from others:
          a. Technologically
              i. Virtually all are derived from living organisms, not product of chemical synthesis
              ii. Origins are harder to define
          b. Institutionally
              i. All responsibility of another part of FDA
              ii. Shifted from Dept. of Biologics Standards of NIH
              iii. 1972, whole program got shifted to FDA
              iv. Impetus for change – polio vaccine by Cutter company was super-potent, actually causing polio
              v. Now, Center for Biologics Evaluation and Research
          c. Statutorily
                                                                                                        Flusche 28 of 32
           i. Public Health Service Act – basket of statutes among which is Biologics Act (§ 262)
   2. Biologic product (i) = virus, serum, toxin, antitoxin, vaccine, blood, allergenic product, or analogous
      product, or arsphenamine … applicable to the prevention, treatment, or cure of a disease or condition of
   3. Blood wasn‟t enumerated until 1950, when FDA‟s predecessor lost case attempting to regulate blood
   4. Requirements that FDA can impose:
       a. Must be licensed
           i. Confirms that product meets statutory requirements
           ii. Demonstrates that manufacturing facility is capable of producing the product
           iii. Requirements – safe, pure, potent
           iv. Batch certification
               (a) Production processes dependent upon living orgs, there is inherent difference btw different
               (b) Only way to make sure each batch is ok, is to sample it
           v. This brought FDA to stage of ultimate product approval, even more so than drugs (they don‟t even
              require batch certification)
           vi. Product can be BOTH a biologic and a drug
               (a) If biological product is both, it must satisfy Drug Act‟s requirements for EE of effectiveness
   5. FDA hasn‟t been prepared to extend Hatch-Waxman to biologics
       a. No clear benchmark to measure biological equivalence of generic products
C. Regulation
   1. National Performance Review
       a. Done by Al Gore
       b. Part examined FDA‟s fledgling regulation of human tissue
       c. Recommendations:
           i. Require all tissue banks to register w/ FDA
               (a) Just need to know who is in the business, where they are, & what they‟re doing
               (b) Added – for any agency distributing a tissue that is regulated as medical device, Food & Drug
                   Act provides independent statutory authority to require registration
           ii. Cadaver regulation
               (a) Screening function – sort-of like donation of whole blood – questions asked of next-of-kin
               (b) Working assumption – cadaveric tissues would be used by a stranger
                     (1) Reparative tissue AND reproductive tissue
                     (2) But for reproductive tissue, FDA didn‟t need to assume recipient was a stranger
           iii. Good tissue practices
               (a) Specifications (detailed) on how you run a tissue bank (p. 89)
               (b) FDA inspectors will check into tissue banks periodically
   2. FDA – might be need for more aggressive regulation, if tissue product takes on new form or function
       a. Two situations:
           i. Tissue has undergone more than minimal manipulation
           ii. Tissue other than for homologous use (different function in recipient than it was in donor)
       b. If FDA found it appropriate to increase requirements, it would “re-baptize” product as drug or device
       c. Agency tried to link-up functionality w/ being disease-free – having disease risk triggers agency
           i. Dropped all references to integrity or functionality
   3. Now, tissue is subject to 3 part tissue regulation – unless agency has concluded that form / function is
      sufficiently changed to justify pre-market approval as device or drug
   4. Reproductive tissue
       a. FDA said that regulations didn‟t apply to reproductive tissue
                                                                                                         Flusche 29 of 32
           b. Some people thought FDA was trying to stay out of political spotlight
           c. 1998 – proceeded to implement Gore‟s recommendations
               i. Good tissue practices – will apply to reproductive tissue
       5. Observations
           a. FDA banned selling pet turtles in 1972 – they carried salmonella – last time FDA used § 361
               i. But § came in handy in 1991 when FDA decided to regulate surgical use of donated tissue
    D. Gene Therapy
       1. Might be possible to isolate gene that can be injected into person w/ defective gene
       2. FDA has regulated clinical experimentation since 1982-3
       3. Testers must conform w/ IRB requirements & conform w/ consent for recipient
       4. RAC – established in early 1980‟s to oversee wide variety of experiments that use recumbent DNA
       5. For about 15 years, gene therapy experiments had to go through FDA and RAC
       6. FDA has proposed making results of clinical trials of gene therapy public as they are done
    E. Cloning
       1. Dolly was cloned several years ago – other species successfully cloned later
       2. Clinton Admin supported ban of reproductive cloning
       3. Worry that preventing cloning would limit use of therapeutic stem cells
       4. What options does FDA have to stop cloning?
           a. Tissue = egg; removing DNA from egg is major change
               i. But the risk is inheritable disease (§ 361 enables prevention of communicable diseases)
           b. Any solution that requires new regulations is politically deficient
           c. Is it intended to affect structure / function of body?
           d. Might argue that it treats infertility
    F. Reproductive Technologies
       1. Much controversy in this area
       2. FDA first said it wouldn‟t regulate in this area (donated reproductive tissue)
       3. Less than 10 years later, FDA changed its mind
           a. Registration requirements for tissue banks
           b. Donor screening requirements
       4. What about reproductive services?
           a. Drugs administered must be FDA approved for that purpose
           b. Special instrumentation must comply w/ medical device law requirements
           c. Clinics must report (on annual basis) their success & failure rates
    G. Xenografts
       1. Involves tissue or organs derived from animals being used in humans
           a. Horse heart valves are in use now
           b. Baboon heart implanted in young girl – survived several days – cause of death not related to heart
       2. FDA – must comply w/ investigational new drug / device / biologic regulations
       3. ~30 Stage I clinical trials currently underway
       4. Controversial, especially w/ animal rights‟ activists
VI. Medical Devices
    A. Intro
       1. Largest product sector of any FDA regulatory programs
    B. Medical devices used to not be subject to any pre-market approval – could only be challenged after-the-fact
       1. Practical implications until 1962 – not very important
       2. Medical technologies weren‟t very advanced
       3. But then tech really takes off
    C. FDA gradually began roping in certain devices as “drugs”
    D. People thought FDA didn‟t need any additional authority
    E. 1976 – Act signed by Ford – gives FDA authority over devices
       1. Clear, distinctive definition to separate devices from drugs
                                                                                                       Flusche 30 of 32
        a. Broad language sweeps in: computer programs
    2. Not all medical devices need pre-market approval for safety & effectiveness
        a. Calibrate risk to the product
        b. Classes
            i. Class 1
            ii. Class 2 – no individual evaluation & approval – performance standards = minimum requirements
               for all products in category
            iii. Class 3 – pre-market approval
    3. Pre-1976 universe of devices – unclear who is making what
        a. Could grandfather them all in
            i. But gives current devices equivalent or better market power than new devices
        b. FDA needed to prescribe comparable requirements for ALL devices (pre and post 1976)
        c. Divide up pre-1976 products into the 3 classes
        d. Pre – shrinking
        e. Post – growing
    4. Almost doubled length of Food & Drug Law
F. Turned out to be a lot of surprises
G. Passage was difficult – critics abounded
H. FDA can restrict a medical device to particular settings or particular people
    1. Previously, FDA had classified some medical devices as “prescription”
    2. FDA assumed that all prior prescription devices were restricted devices
I. Influence of design of law – experience of law governing drugs
    1. Produced drug lag
    2. Raised cost of drugs
    3. Patients couldn‟t get access to new drugs
J. Purposes
    1. Clear, distinctive definition to separate devices from drugs
        a. BUT fair number of devices possessed drug-like qualities – combination products
        b. Ex: pre-filled syringe – device containing a drug
    2. Calibrate the risk of device to the regulations for it – three categories of devices
        a. Treat similar products on a similar time table
K. Classification of devices
    1. Put device into one of 3 relevant categories
        a. 50% - I
        b. 40% - II
        c. 10% - III
    2. Once classified, people got a 30 day review period
    3. By early 1980s, FDA had finished classification, so ready to enforce regulations
        a. Class I – essentially business as usual – adulteration / misbranding, good manufacturing, restricted
            i. There were some devices that were put under Class II, but really needed to be here
        b. Class III – pre-market approval
            i. Two step process
                (a) Device is definitively classed in III
                (b) At time of FDA‟s choosing, it must file proposal to require pre-market approval app
                      (1) FDA must give the manufacturers 30 months before app is due
                (c) Ex: 16 years passed before FDA asked for pre-market approval for breast implants
    4. Some post-„76 devices will be essentially similar to pre-„76 devices
        a. If it is truly a mimic, it gets classified like the pre-‟76 device
    5. Others will be brand new technology
        a. Brand new, novel product assigned to Class III could seek reclassification by FDA
            i. But it‟s not likely that this will happen
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   6. Devices get squeezed – only two options: brand new, or already on market
L. Implementation
   1. § 510(k) – pre-market notification process
   2. Most important part of ‟76 amendments
   3. Mechanics:
       a. Notify FDA that you are planning to market new product – at least 90 days ahead of time
           i. Purpose: figure out which of two categories product fits
           ii. Manufacturer wants to persuade FDA that device falls into existing device group
       b. If FDA agrees that new product is substantially similar to existing product, it can be marketed
           i. FDA can impose any extra requirements on it and its counterpart
           ii. What does “substantially equivalent” mean?
               (a) Technology changes, so its difficult to know
               (b) Is it sufficient to show equivalence to any currently marketed device? – yes – piggybacking ok
               (c) BUT this could allow devices that are really not similar to pre-‟76 devices
               (d) Response – as long as its similar to an already-in-use device, that is ok
           iii. What can FDA ask you to provide (ex: clinical trials)?
               (a) If trials required – this would make “mini pre-market approvals” required for all devices
               (b) But not allowing FDA to ask for any data kind-of cripples its decision-making
               (c) On occasion, FDA does ask for clinical data
           iv. Similarity of use, similarity of features, different but equivalent safety & effectiveness
   4. 98% of devices currently on the market went through 510(k) process
   5. Process resembles, but is not a pre-market approval process
M. Buckman – preemption
   1. Whether P can sue manufacturer on grounds that they deceived FDA as to the intended use of the device
   2. Technique – spinal fusion – drive screws through pedicles of spine & use de-mineralized bone
   3. Claim – manufacturer lied to FDA about intended use
N. 510k
   1. Substantial equivalence needs to be shown
   2. People claim that FDA is responsible to the device lag
   3. Just b/c device is substantially equivalent doesn‟t mean that FDA can‟t require more of that product
       a. If Class II or Class III, more than possible that agency might establish performance standards years
O. Pre-Market Approval
   1. Slow, burdensome, contentious process
   2. Two universes of Class III products
       a. Result of classification & inventory of pre-‟76 products
       b. Post-‟76 devices, which have no on-the-market equivalent
   3. Patient populations are a lot smaller
   4. Devices can get “conditional approval” – requires further studies to be done
       a. Follow-up isn‟t usually very good
   5. FDA‟s determination about the type of product submitted doesn‟t dictate what part of agency will review it
      & have ultimate responsibility over it
P. Reclassification
   1. Agency has essentially un-reviewable discretion
Q. Tracking / post-approval
R. Preemption
   1. Medtronic
       a. P‟s claim would impose new obligations upon manufacturer, in addition to what FDA imposed
       b. Conflicting or additional requirements can only be instated at initiative of state
       c. All this device had to show was that it was substantially equivalent to already marketed device
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S. Restricted Devices (prescription)
   1. Why doesn‟t it use the same language? – could just say “prescription”
   2. Does this allow FDA to restrict advertising of devices?
        a. FTC really regulates products (except prescription drugs)
T. Cigarettes
   1. FDA & David Kessler sought to regulate cigarettes
   2. It was thought that Clinton would never support this
        a. It would politically shut down the Carolinas and Kentucky
        b. But it would substantially help California, New York, etc (blue states)
        c. Thought to be good politics to support this
   3. Thought that crucial point is 21 – if you don‟t start smoking young, you won‟t be smoking long
   4. But don‟t want adult smokers to think they will lose their cigarettes
   5. Strategy:
        a. Attack on advertising & promotion
        b. Assurances that cigarettes will continue to be available to adults
   6. Two analytical obstacles
        a. FDA had said (several times) that it lacked jurisdiction to regulate cigarettes
        b. Fair # of requirements for drugs & devices that are difficult to apply to cigarettes
            i. Both device & drug law require that products be shown to be safe
   7. Why study this?
        a. Important initiative of FDA
        b. Good example of good lawyering
   8. Hurdles to surmount – past denials by agency itself
   9. Is there a category into which cigarettes can be squeezed?
        a. Key word = “intended”
            i. Not much data about what manufacturers intended, except for relaxation
            ii. FDA argues that everyone uses them as drugs – but not enough EE of this
        b. Drugs – to say cigarettes are drugs and require NDA is to push them off the market
        c. Devices
        d. Cigarettes perform both functions – like a pre-filled syringe
   10. Devices – safe?
        a. Didn‟t classify cigarettes at first, so no affirmative showing of safety needed
        b. What requirements must manufacturers meet?
            i. Listing
            ii. Good manufacturing practices
            iii. Point of sale distribution limitations, restrictions on sponsorship
   11. O‟Connor‟s opinion
        a. Congress preempted the field – cigarettes can‟t be banned
   12. Cigarette companies sued 2 days after the proposed rules published
   13. Now, manufacturers are coming out w/ reduced tar & reduced risk cigarettes

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