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Transcript of Pharm Law-federal Drug Law
PHARMACY LAW & ETHICS
PCTH 7313
Fall 2009
FEDERAL DRUG LAW
CONTEXT OF EARLY FOOD & DRUG LAW
Excerpt from Upton Sinclair
The Jungle (1905) It was only when the whole ham was spoiled that it came into the department of Elzbieta. Cut up by the
two-thousand-revolutions-a-minute flyers, and mixed with half a ton of other meat, no odor that ever was in a ham could make any difference. There was never the least attention paid to what was cut up for
sausage; there would come all the way back from Europe old sausage that had been rejected, and that was
moldy and white--it would be dosed with borax and glycerine, and dumped into the hoppers, and made over again for home consumption. There would be meat that had tumbled out on the floor, in the dirt and
sawdust, where the workers had tramped and spit uncounted billions of consumption germs. There would
be meat stored in great piles in rooms; and the water from leaky roofs would drip over it, and thousands
of rats would race about on it. It was too dark in these storage places to see well, but a man could run his hand over these piles of meat and sweep of handfuls of the dried dung of rats. These rats were nuisances,
and the packers would put poisoned bread out for them, they would die, and then rats, bread, and meat
would go into the hoppers together. This is no fairy story and no joke; the meat would be shoveled into carts, and the man who did the shoveling would not trouble to lift out a rat even when he saw one--there
were things that went into the sausage in comparison with which a poisoned rat was a tidbit. There was
no place for the men to wash their hands before they ate their dinner, and so they made a practice of
washing them in the water that was to be ladled into the sausage. There were the butt-ends of smoked meat, and the scraps of corned beef, and all the odds and ends of the waste of the plants, that would be
dumped into old barrels in the cellar and left there. Under the system of rigid economy which the packers
enforced, there were some jobs that it only paid to do once in a long time, and among these was the cleaning out of the waste barrels. Every spring they did it; and in the barrels would be dirt and rust and
old nails and stale water--and cart load after cart load of it would be taken up and dumped into the
hoppers with fresh meat, and sent out to the public’s breakfast. Some of it they would make into “smoked” sausage--but as the smoking took time, and was therefore expensive, they would call upon their
chemistry department, and preserve it with borax and color it with gelatine to make it brown. All of their
sausage came out of the same bowl, but when they came to wrap it they would stamp some of it “special,”
and for this they would charge two cents more a pound.
Such were the new surroundings in which Elzbieta was placed, and such was the work she was compelled
to do.
2
FEDERAL REGULATION OF MEDICATIONS
I. HISTORICAL OVERVIEW
A. Pure Food and Drug Act of 1906
1. United States v. Johnson
B. The Federal Food, Drug, and Cosmetic Act of 1938 (FDCA)
1. United States v. Sullivan
C. Durham-Humphrey Amendment of 1951
D. Food Additives Amendment of 1958
E. Color Additive Amendments of 1960
F. Kefauver-Harris Amendment of 1962
G. Medical Device Amendments of 1976
H. Orphan Drug Act of 1983
I. Drug Price Competition and Patent Term Restoration Act of 1984
J. Nutrition Labeling and Education Act of 1990
K. Prescription Drug User Fee Act of 1992 (“PDUFA”)
L. Dietary Supplement Health and Education Act of 1994 (“DSHEA”)
M. Food and Drug Modernization Act of 1997
See Brief History of the Center for Drug Evaluation and Research (CDER) http://www.fda.gov/cder/about/history/default.htm; Milestones in U.S. Food and Drugs Law History
http://www.fda.gov/opacom/backgrounders/miles.html
II. DEFINING AND DISTINGUISHING DRUGS FROM FOODS, DEVICES AND COSMETICS
A. The Law
1. Statutory definitions of food, drug, counterfeit drug, device, cosmetic are found in 21 U.S.C.
§ 3211 and are recited in the textbook
B. Explanation of the Law
1. Crucial issue in determining if a product is a drug is whether the supplier makes a therapeutic claim (i.e., is the product intended to diagnose, cure, mitigate, treat, or prevent a disease and,
for products that are not a food, whether it is intended to affect the function or structure of the
body)
2. Action on Smoking & Health v. Harris 655 F.2d 236 (D.C. Cir. 1980) (held cigarettes are not
drugs unless a vendor makes therapeutic claims)
3. FDA v. Brown & Williamson 529 US 120 (2000)2 (after FDA promulgated regulation
designed to reduce youth smoking, court held the FDA does not have jurisdiction over
cigarettes)
4. National Nutritional Foods Ass’n v. Mathews 557 F.2d 325 3(high doses of vitamins A& D are not drugs without therapeutic claims)
1 http://www.fda.gov/opacom/laws/fdcact/fdcact1.htm 2 http://www.law.cornell.edu/supct/html/98-1152.ZS.html
3
C. Food Versus Drugs
1. Nutrilab, Inc. v. Schweiker 713 F.2d 335 (7th Cir. 1983) (2nd Cir. 1977) 4 Court held that a starch blocker is a drug because: (i) it was intended to affect the structure and function of the
body and (ii) was not a food. It did not fall within the definition of food simply because the
active ingredient was derived from kidney beans, which are food.
2. Special Dietary Foods
a. Distinguish dietary foods from dietary supplements
(i) See definition in textbook (also 21 U.S.C. § 350 (c ) (3)(A)) 5
(ii) Key aspect of the definition of “special dietary food” is that the food is for persons
with a particular “condition” (e.g., disease, convalescence, pregnancy,
overweight)—N.B. There is no such requirement for dietary supplements
3. Medical Foods
a. Foods formulated for oral use intended for management of a disease requiring specific dietary NUTRIENTS (H21 USC § 360EEH) (e.g., phenylketonuria)
4. Nutraceuticals and Functional Food
a. These terms have no legal meaning but are often used in the dietary supplement industry
5. Health Claims for Foods
(i) In U.S. v. Article of Drug Labeled as Exachol, 716 F.Supp. 787 (S.D.N.Y. 1989)
the court held that Exachol (which contained various compounds intended to prevent coronary thrombosis, arteriosclerosis, etc.) could be considered a drug and
a special dietary food
(ii) Because Exachol was intended for people who already have a heart condition or high cholesterol, it fell within the definition of special dietary food.
(iii) Exachol also fell within the definition of a drug
(iv) Because the FDA had previously allowed companies whose products were both special dietary foods and drugs to market their product without premarketing
approval as a new drug (e.g., Kellogg’s All Bran and fish oil products), the FDA
could not treat Exachol differently and Exachol could be marketed with these claims
b. Additional Resources
c. GAO Report on Functional Foods and Dietary Supplements @ http://www.nutriwatch.org/20pdfs/gaoff.pdf
d. What Can Your Food Do For You? (And Should FDA Let It?): An Overview of the Regulatory Regime (or Lack Thereof) Surrounding Functional Foods, Julie Melissa
Baher @ leda.law.harvard.edu/leda/data/754/Baher06.rtf (you may need to cut and paste
this link instead of simply clicking)6
3 http://www.altlaw.org/v1/cases/480567 4 http://bulk.resource.org/courts.gov/c/F2/713/713.F2d.335.82-2747.82-2746.html 5 http://www.law.cornell.edu/uscode/21/usc_sec_21_00000350----000-.html 6 For an excellent source of articles by law students on a wide variety of food and drug law topics, see
http://www.law.harvard.edu/faculty/hutt/table_of_contents_2002.html
4
D. Dietary Supplements
1. National Nutrition Labeling and Education Act of 1990 (NLEA): prohibits disease prevention
claim in food labeling unless the FDA promulgates a regulation approving the claim and defining the conditions under which the claim can be used. The FDA promulgated rules for a
variety of foods that contain disease prevention claims.
a. Examples: (i) certain high calcium foods can make limited claims regarding osteoporosis; (ii) certain low sodium foods can make claims that a low sodium diet can reduce the risk
of high blood pressure; (iii) certain fiber containing foods may reduce risk of cancer—see
the following website for description of permissible claims and citations to the regulation
in the CFR: http://www.cfsan.fda.gov/~dms/flg-6c.html
b. The Food and Drug Administration Modernization Act (FDAMA) changed the
requirements of the NLEA so that a food distributor can make claims without an FDA
regulation as long as there is “significant scientific agreement” as defined by the FDA.
2. Summary of Dietary Supplement Health Education Act (DSHEA): Sellers of certain products,
defined as dietary supplements, can make claims regarding a product’s effect on the structure
and function of the body without being considered a “drug” under the Food, Drug, and Cosmetic Act (“FDCA”).
a. Just like with foods, as described above, a seller of dietary supplements may make
“disease prevention” claims under NLEA and FDAMA if there is “significant scientific agreement” about the claim.
(i) In Pearson v. Shalala, 164 F.3d 650 (D.C. Cir. 1999), 7the court held that the FDA
unlawfully restricted sellers of certain dietary supplements from making disease prevention claims for antioxidant vitamins (cancer prevention), high fiber (cancer
prevention), omega-3 fatty acids (coronary heart disease), and folic acid (neural
tube defects). The court concluded that the standard for “significant scientific agreement” was too vague and that the FDA could regulate the commercial speech
with less burdensome means such as disclaimer that would say something like:
“The evidence is inconclusive because existing studies were performed with foods containing antioxidant vitamins and the results could be due to other components in
the food.”
3. Dietary Supplement Defined
a. A product intended for ingestion;
b. A Product to supplement the diet; and
c. A product that contains one or more of the following ingredients:
(i) a vitamin
(ii) a mineral
(iii) an herb or other botanical
(iv) an amino acid
(v) a dietary substance for use by man to supplement the diet by increasing the total dietary intake, or
(vi) a concentrate, metabolite, constituent, extract, or combination of the above
7 http://lw.bna.com/lw/19990202/985043.htm
5
4. The term “dietary supplement . . . does . . . include . . . an article that is approved as a new drug under section 355 of [the FDCA] . . . which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food . . . .”
a. Pharmanex v. Shalala 221 F.3d 1151 (10th Cir. 2000) 8— FDA claimed that red yeast rice containing lovastatin was not a dietary supplement because it contained an “article” that was not marketed as a dietary supplement prior to the time Mevacor was approved as a new drug; 10th Circuit agreed with FDA’s interpretation of DSHEA and remanded the case to district court for further determination. In other words, if the whole product or the active ingredient of a product has been approved as a new drug, the active ingredient cannot be marketed as a dietary supplement.
5. Under DSHEA, definition of “drug” in the FDCA was changed to exclude dietary supplements making certain types of claims.
6. Dietary supplements can be marketed in a variety of dosage forms including tablets, capsules, gel caps, liquids, etc.
7. Label must explicitly state that product is a “dietary supplement”
8. Depending on the claims made, a single product can be both a dietary supplement and a drug
9. Burden of Proof
a. FDA has burden to prove a dietary supplement is adulterated
10. Dietary supplement is adulterated if:
a. “It presents a significant or unreasonable risk of illness or injury under conditions of use. . . recommended in the product labeling,”
b. Secretary of HHS personally declares that an ingredient poses an imminent hazard to public health or safety, or
c. if product contains an ingredient that is poisonous or deleterious to health if used as directed
11. Labeling Exemption
a. Labeling for dietary supplements does not include publications printed in their entirety if it:
(i) is not false or misleading, (ii) does not promote a particular manufacturer, (iii) is presented with other subject matter to present a balanced view, (iv) is physically separate from the dietary supplement, and (v) does not have appended other information by a sticker or other method
8 http://ca10.washburnlaw.edu/cases/2000/07/99-4087.htm
6
12. Permissible Claims
a. A statement regarding dietary supplement may be made if the statement:
(i) claims a benefit related to a classical nutrient deficiency disease and discloses the prevalence of the disease in the U.S., or
(ii) describes the role of a nutrient or dietary supplement intended to affect the
structure or functions of the body
(iii) characterizes the documented mechanism by which a nutrient or dietary ingredient,
and
(iv) describes general well-being from consumption or a nutrition or dietary ingredient, and
b. Other conditions for permissible claims
(i) The manufacturer has substantiation that such a statement is truthful and not
misleading, and
(ii) The label states prominently and in boldface type “This product has not been evaluated by the Food and Drug Administration. This product is not intended to
diagnose, treat, cure, or prevent any disease.”
13. Safety Issues and Ephedra Products
a. Nutraceutical Corp. v. Von Eschenbach, 4459 F.3d 1033 (10th Cir. 2006) 9 (held FDA
met its burden to show all doses of Ephedra It presents a significant or unreasonable risk
of illness or injury under conditions of use. . . recommended in the product labeling)
E. Drugs vs. Devices
1. Definition of device attempts to distinguish drugs from devices by noting that a device does
not achieve any of its principal intended purposes through chemical action or depend on being metabolized to achieve of its principal intended purposes.
a. U.S. v. Article of Drug Bacto Unidisk, 394 U.S. 784 (1969) holding antibiotic sensitivity
disks are covered by definition of drug
b. U.S. v. Article of Drug Ova II, 414 F.Supp. 660 (N.J. 1975) pregnancy testing kit is not a
drug—excerpt from the court’s opinion below:
The condition of pregnancy, as such, is a normal physiological function of all mammals and cannot be considered a disease of itself. Pregnancy is an execution of an inherent
bodily function and implies no ailment, illness or disease. Both parties agree that this is
so.
It is also a fact that there is no occasion for anyone to perform a pregnancy test unless
there is a prior factual history to justify it. At least two events must have occurred before any question of a pregnancy can arise. One, there must have been a placing of male
sperm within the female genitals, and, two, there must have been thereafter an
interruption of the female menstrual cycle. There is only one widely recognized instance
of immaculate conception. All other mortals, burdened with original sin, must have these
two events occur before performing a pregnancy test for any purpose other than an
academic one.
A test for pregnancy, then, is not a test for the diagnosis of disease. It is no more than a
test for news, which may be either good news or bad news depending on whether pregnancy is wanted or not.
9 http://www.ca10.uscourts.gov/opinions/05/05-4151.pdf
7
2. The FDA uses several factors to decide whether a product is a device or a drug. These criteria are in the text.
F. Drugs vs. Cosmetics
1. Cosmetics become drugs when the manufacturer makes therapeutic clams
G. Label and Labeling
1. Label: a display of written, printed, or graphic matter upon immediate container
2. Labeling: all labels and other written material either upon container or accompanying an
article (broader term than label)
a. U.S. v. Guardian Chemical Corp., 410 F.2d 157 (2nd Cir. 1969) Court held that dairy
machine cleaning product became a drug when manufacturer provided brochures to
medical professionals promoting the product because the brochures accompanied the products and constituted labeling even though the brochures were not shipped with the
product.
H. Official compendia
1. United States Pharmacopoeia (USP/NF)
2. Homeopathic Pharmacopoeia of the United States (HPUS)
III. PROHIBITED ACTS, PENALTIES, AND ENFORCEMENT
A. Enforcement
1. Criminal penalties (fines and imprisonment)
2. Seizures
3. Injunctions
B. Corporate Officer Liability
1. Unlike most criminal statutes that require an intentional or knowing mens rea (state of mind
or guilty mind), the FDCA imposes criminal penalties on corporate officers even if they do
not have personal knowledge of violations.
a. U.S. v. Park,320 421 U.S. 658 (1975) President of national grocery company was
criminally liable even though president did not know of the violations because he had a
duty to seek out and correct violations of the law
b. U.S. v. Dotterweich U.S. 277 (1943) President of repackaging company was convicted of
adulteration and misbranding even though he had no personal knowledge of the wrongful
acts.
C. Product Recalls
1. FDA cannot force a recall, but if a manufacturer does not comply with recall request, FDA can use its seizure authority See FDA Website for recent product recalls.10
2. Classifications
a. Class I - Serious health effects or death
b. Class II - Reversible effects or remote chance of serious effects
c. Class III - Unlikely to cause adverse health effects
10 http://www.fda.gov/opacom/7alerts.html
8
D. Adulterated Drugs
1. Adulteration:
a. Decomposed, putrid, or filthy materials
b. Unsanitary conditions for packing, storage, etc.
c. Not manufactured in compliance with Good Manufacturing Practices (GMP)
d. Container consists of poisons that can leach into contents
e. Contains unsafe color additive
f. Drug varies from USP or HP unless the label states the deviation from compendial standards
g. Drug strength or purity differs from what it purports to be
h. OTC drug not in tamper-resistant container
(i) Tamper resistant package contains barrier which, if broken, gives visible evidence
of tampering
2. Explanation of Adulteration
a. Key concept for adulteration is to ensure purity
3. Current Good Manufacturing Practice (“CGMP”)
a. FDA GMP regulations can be found at:
http://www.fda.gov/CDRH/DEVADVICE/32.html
b. FDA warning letter index 11
c. Sample FDA warning letter for violation of GMP12
d. Intended to ensure that a drug is safe and meets the quality and purity requirements
e. CGMPs do not generally apply to pharmacists unless a pharmacist is manufacturing
f. Manufacturers generally inspected every 2 years
4. Product Tampering
a. A product packaged in violation of the tamper-resistant packaging regulations is
adulterated
b. Applies to OTC products
E. Misbranded Drugs
1. Misbranding:
a. Labeling is false or misleading in any particular
(i) Health care economic information presented to formulary committee in the course
of selecting drugs for managed care organizations is not considered false or misleading if the information relates directly to an approved indication and is based on competent and reliable scientific evidence.
b. Label does not state name and address of manufacturer and accurate statement of quantity
11 http://www.accessdata.fda.gov/scripts/wlcfm/indexdate.cfm 12 http://www.fda.gov/foi/warning_letters/s6873c.pdf
9
c. Required information not prominently displayed and written in a way likely to be understood by ordinary individual customer
d. Prescription drug omitting generic “established name” in type not less than one-half the size of trade name
e. Does not contain the proportion of each active ingredient and the proportion of certain
specific compounds listed in the law
f. Inadequate directions for use and inadequate warnings
(i) This requirement is not necessary for prescription drugs and forms the distinction
between OTC and prescription drugs
g. Drug listed in USP, but not labeled and packaged by compendial standards
h. Drug is subject to deterioration without precautions
i. Misleading packaging or imitation of another drug, or sold under name of another drug
j. Drug endangers health if used as labeled
k. Contains color additive and is not labeled or packaged in conformity with requirements of the FDCA
l. Drug and manufacturer not registered with FDA
m. Not packaged in accordance with Poison Prevention Packaging Act when applicable
n. Omits summary of side effects, warnings, etc. from advertisements and other descriptive
printed matter
o. Advertisement fails to include generic or established name or other required information
in type at least half as large as the brand name
p. If at any time prior to dispensing the label fails to bear, at minimum, the symbol “Rx only”
10
2. Explanation of Misbranding (concerns representations made by manufacturer)
a. False or Misleading Labeling
b. Habit Forming Drugs
(i) No longer required after FDAMA, but package insert must describe drug abuse and
dependence when applicable.
c. Established Names of Drugs
(i) Requires list of active ingredients for prescription and OTC products
(ii) Must also list inactive ingredients
d. Adequate “Directions” for Use
(i) This means the directions under which a layperson can a drug safely and for the
purpose for which it was intended.
(ii) Note the 6 pieces of information that are necessary for a drug to have adequate
directions for use (p. 58 of text)
e. Adequate “Information” for use
(i) Distinguish from adequate “directions” for use
(ii) If a drug cannot meet the “adequate directions for use” standard, the drug is a prescription drug and the labeling must contain Uinformation directed to the
prescriber, not the patient
(iii) Note the 6 categories of information that must be included in the labeling to meet the “adequate information for use” standard (p. 58-59)
f. Imitation Drugs
(i) See People v. Kenzia
(ii) Note the 3 factors that the court in U.S. v. Articles of Drug (Midwest
Pharmaceuticals), 825 F.2d 1238 (8th Cir. 1987) 13used to determine that tablets
containing caffeine, ephedrine, and phenylpropanolamine were imitation drugs
g. Batch Certification
(i) No longer required (previously required for insulin and antibiotics)
3. Nonprescription Drug Labeling
a. New user friendly labeling regulations for OTC products went into effect in 1999 and
have been modified from time to time since then
b. The general requirements are described in the text on pp.59-60 of the text.
c. Helpful websites for the rules and for questions and answers about OTC labeling are:
(i) OTC Labeling: Questions and Answers
www.fda.gov/cder/otc/label/quesanswers.htm
d. Professional Labeling
(i) This is a type of labeling provided to health professionals for use of OTC products
that are not safe for lay diagnosis or treatment
13 http://bulk.resource.org/courts.gov/c/F2/825/825.F2d.1238.86-1438.html
11
(ii) Normally, this labeling is provided to health professionals in the mail or in a communication that does not reach the public
(iii) Although a pharmacist can legally recommend an OTC product for a non-indicated use, a pharmacist should not give a patient professional labeling unless the patient
asks for it.
e. Drugs that are both OTC and Rx
(i) Some drugs are available in different strength with an Rx than when provided OTC
(ii) Some drugs are OTC with certain indications, but prescription for additional
indications
4. Prescription Drug Labels and Labeling
a. Commercial Container Label
b. See 21 CFR § 201.1,14 § 201.55,15 §201.100
c. Unit Dose Labeling
(i) The amount of information on the label of unit dose packages is more limited than for regular stock bottles. The required information is sufficient to provide an audit
trail of what the drug is and where it came from in case of a recall.
(ii) See FDA Compliance Policy Guide 71132b.1016
d. The Package Insert
(i) See 21 CFR § 201.56, §201.57, § 201.100 17
(ii) FDA finalized new requirements for package inserts in 2006
(a) 71 Fed. Reg. 3922-3997,18 71 Fed. Reg. 3998-3999,19 71 Fed. Reg. 3999-400020
(b) New inserts are supposed to reduce preventable adverse drug events by making drug information more easily accessible, more memorable, and less
complex.
(iii) Applies only to drug applications submitted after June 30, 2006 and will be phased in for drugs approved 5 years prior to June 30, 2006
(a) Changes include:
(1) Table of contents
(2) Highlights section
(3) Black Box Warnings
(4) Patient Counseling Information
(iv) Daily Med 21is an online clearinghouse for providing health professionals access to drug information
(v) Package insert intended to give the “learned intermediary” (the prescriber)
sufficient information to use the drug safely and effectively for individual patients.
(vi) Black Box Warnings
(vii) Pregnancy Warnings Categories A ->D and X 22
14 http://edocket.access.gpo.gov/cfr_2001/aprqtr/pdf/21cfr201.1.pdf 15 http://edocket.access.gpo.gov/cfr_2001/aprqtr/pdf/21cfr201.55.pdf 16 http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg430-100.html 17 http://edocket.access.gpo.gov/cfr_2001/aprqtr/pdf/21cfr201.100.pdf 18 http://edocket.access.gpo.gov/2006/pdf/06-545.pdf 19 http://edocket.access.gpo.gov/2006/pdf/06-543.pdf 20 http://edocket.access.gpo.gov/2006/pdf/06-544.pdf 21 http://www.fda.gov/cder/news/FactsatFDA.htm
12
5. National Drug Code Number (NDC)
a. Intended to facilitate automated processing of drug data by government agencies, drug
manufacturers, wholesalers, private insurers, and others.
b. NDC number identifies:
(i) drug manufacturer or distributor (labeler code)
(ii) drug name (product code)
(iii) package size (package code)
c. Ten character code
d. Drug Listing Act of 1972 required NDC for all drugs covered by FDCA
e. Now required as part of manufacturer’s prescription and OTC label
(i) NDC is required to be part of a linear bar code with the intention to reduce medication errors
(ii) Drug may have an NDC without an approved NDA
f. New FDA Drug Labeling Regulations— See FDA Press Release FDA Announces New
Prescription Drug Information Format to Improve Patient Safety 23January 18, 2006
IV. NEW DRUG APPROVAL
1. “New Drug” means:
2. Any drug . . . the composition of which is such that such drug is not generally recognized,
among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed,
recommended, or suggested in the labeling thereof, UexceptU that such a drug not so
recognized shall not be deemed to be a ''new drug'' if at any time prior to June 25, 1938, it
was subject to the Food and Drugs Act of June 30, 1906, as amended, and if at such time its
labeling contained the same representations concerning the conditions of its use; or
Any drug . . .the composition of which is such that such drug, as a result of investigations to determine its safety and effectiveness for use under such conditions, has become so
recognized, but which has not, otherwise than in such investigations, been used to a material
extent or for a material time under such conditions.
3. Summary of definition: a drug that is not generally recognized as safe and effective by qualified experts for use under the conditions recommended in the labeling.
4. Grandfathered drugs: Drugs marketed before 1938 are exempt from proving either safety or efficacy provided that it is marketed in accordance with the labeling requirements as then
existed.
5. Understanding the meaning of new drug is essential to understanding the overall FDA regulatory scheme.
22 http://www.perinatology.com/exposures/Drugs/FDACategories.htm 23 http://www.fda.gov/bbs/topics/NEWS/2005/NEW01272.html
13
B. Approved Drugs as “New Drugs”
1. Drug is also considered a new drug if it is:
a. Drug contains a new substance
b. New combination of approved drugs
c. The proportion of ingredients change
d. An established drug that is available in new dosage forms or at new dosage levels or is
packaged in novel materials such as plastic; or
e. An established drug with new medical claims (i.e. new intended uses)
2. U.S. v. Baxter Healthcare Corporation, 901 F.2d 1401 (7th Cir. 1990) 24
C. Road to Approved New Drug Application
1. Evidence of safety and efficacy must come from animal and human clinical studies, but new drugs cannot move in interstate commerce.
2. Notice of Claimed Investigational Exemption for a New Drug (also called Investigational New Drug Application (IND))
3. IND necessary before a manufacturer can ship drug in interstate commerce for clinical trials
4. IND is an exemption to FDCA law prohibiting interstate shipment of drugs unless proven safe and effective
5. Investigational New Drug Application
a. Contents of an IND
(i) Name of drug
(ii) Composition of drug
(iii) Methods of manufacturing and quality control
(iv) Information from preclinical (animal)studies
(v) Outline of proposed clinical trials
(vi) Experience and qualifications of clinical investigators
b. If FDA does not reject the IND within 30 days of submission, clinical trials may begin
c. Phases of clinical drug testing
(i) Phase I:25 small number of subjects, controlled studies, investigate toxicity,
metabolism, absorption, elimination, and route of administration
(ii) Phase II:26 initial trials on limited number of subjects for specific disease to
determine the efficacy of the drug and the dosages at which efficacy occurs
(iii) Phase III:27 large number of subjects, test for safety and efficacy—usually double-blinded and compared with a placebo control group
(iv) Postmarketing: information on further adverse effects, reporting other distribution information to FDA
d. Informed Consent
e. Participants must know the risks, possible benefits, and alternative course of treatment.
f. Investigational Review Board (IRB) must approve studies conducted in institutions. See
FDA Information Sheet Guidances for IRBs, Clinical Investigators, and Sponsors at
HUhttp://www.fda.gov/oc/ohrt/irbs/U
24 http://bulk.resource.org/courts.gov/c/F2/901/901.F2d.1401.89-2088.89-2087.html 25 http://www.fda.gov/cder/handbook/phase1.htm 26 http://www.fda.gov/cder/handbook/phase2.htm 27 http://www.fda.gov/cder/handbook/phase3.htm
14
6. Termination by FDA: The FDA may terminate a clinical trial any time if it appears too dangerous.
7. The New Drug Application (NDA)
a. NDA contains all of the information that the manufacturer has acquired during its
investigations
b. See FDA (CDER) website Drug approval Application Process http://www.fda.gov/cder/regulatory/applications/
c. FDA reviews the application and is required to act on it within 180 days, but delays often
occur.
d. During its review FDA determines risk vs. benefit of drug
e. Prescription Drug User Fee Act (PDUFA) has decreased the review time for NDAs—new drug applicant pays fees
(i) See http://www.fda.gov/CBER/pdufa.htm for details about PDUFA
Fee Category Fee Rates for FY 2008
72 Federal Register 58103-58106
APPLICATIONS
Requiring clinical data $1,178,000
Not requiring clinical data $589,000
Supplements requiring clinical data $589,000
ESTABLISHMENTS $392,700
PRODUCTS $65,030
8. FDA Drug Rating and Classification
a. System to classify drugs by chemical type and therapeutic potential
b. Priority (P) and Standard (S)
c. Six designations for chemical type
(i) Highest priority: Active moiety is a new molecular entity.
(ii) Lowest priority: Drug is a product previously marketed by the same firm (used
primarily for new indications)
d. For therapeutic potential , the FDA uses a two letter system:
(i) Priority (P) represents a therapeutic advance
(a) No other effective drug available
(b) It is more effective or safer than current drugs
(c) Drug has an important advantage
(ii) Standard (S) represents standard (i.e. replacing currently available agent)
(iii) The S & P system replaces the old A,B, C ratings.
15
e. Supplemental New Drug Application
f. Three categories
(i) “Prior approval” from the FDA is required for changes in production (e.g.,
synthesis, manufacturing process) and most labeling changes
(ii) “Change being effected” supplement allows manufacturers to implement a change before the FDA approves the change. Changes in this category include changes
that strengthen warnings or dosage and administration information, or for certain
changes in manufacturing (e.g., change in manufacturing facility where the new facility does not differ materially from the previous facility).
(iii) “Reported changes” are minor changes that the manufacturer only needs to report
in its annual report. Examples of such changes include editorial changes in labeling and changes in container size.
g. Supplemental NDAs have lower priority than new NDAs
9. Postmarketing Surveillance
a. Manufacturer must maintain post marketing records and reports and must submit reports
of serious adverse drug reactions and new information about safety and efficacy to the
FDA.
b. See FDA Postmarketing Surveillance Programs at
http://www.fda.gov/cder/regulatory/applications/Postmarketing/surveillancepost.htm
10. Phase IV Studies
a. Studies required by FDA and conducted to obtain additional data of a drug’s safety and
efficacy and to determine new uses for the drug.
V. GENERIC DRUGS AS NEW DRUGS
A. Drug Efficacy Study Implementation (“DESI”)
1. FDA commissioned National Academy of Sciences/National Research Council (NAS/NRC) See Marketed Unapproved Drugs—Compliance Policy Guide 28for more details about DESI
a. Review of several thousand drugs approved between 1938 and 1962 to determine
efficacy for indicated uses
(i) Remember: The definition of “new drug” means drugs “not generally recognized
as safe and effective.
(ii) New drug definition excludes drugs used prior to 1938 if such drugs are marketed in accordance with the labeling requirements prior to 1938.
(iii) Drugs approved after 1938 and before 1962 had to be safe, but no requirement to prove efficacy.
(iv) Thus, these 1938 to 1968 drugs were new drugs and had to be shown to be
effective.
28 http://www.fda.gov/cder/regulatory/applications/Postmarketing/surveillancepost.htm
16
b. Panel classified drugs according to efficacy
(i) UEffectiveU: Evidence justifies claim (ii) UProbably EffectiveU: More evidence is needed to support claim (iii) UPossibly EffectiveU: Substantially more research needed to support claim (iv) UIneffectiveU: (no acceptable evidence) (v) UEffective butU: Other more effective or safer drugs available (vi) UIneffective as a Fixed CombinationU: No added benefit of combination over
single ingredient
2. Three U.S. Supreme Court cases together held the FDA had authority to determine which drugs were new drugs and upheld FDA’s authority to retroactively require proof of efficacy for pre-1962 drugs.
a. HUCiba Corp. v. Weinberger, 412 U.S. 640 (1973)UH 29 b. HUWeinberger v. Bentex Pharmaceuticals, Inc., 412 US. 645 (1973)U
30 c. HUUSV Pharmaceutical Corp. v. Weinberger, 412 U.S. 655 (1973)U
31 d. FDA conducted DESI review for generic and for innovator drugs. The FDA
approved generic drugs with only bioavailability studies and eventually allowed some manufacturers to market generic drugs while final approval was pending.
3. In Hoffman LaRoche, Inc. v. Weinberger 425 F.Supp. 890 (D.C. Cir. 1975), the court held that FDA could not allow marketing of generic drugs until after the ANDA process had been completed.
4. HUU.S. v. Generix, 103 S.Ct. 1298 (1983)U
32H (the term “drug” was intended by Congress
to include the entire drug product, complete with active and inactive ingredients; therefore a generic drug is a drug under the FDCA and subject to the requirements for new drugs)
B. Paper New Drug Application
a. HUBurroughs Wellcome Co. Schweiker, 649 F.2d 221 (4th Cir. 1981)U
33H –The court
held the FDA had authority to create guidelines allowing paper NDAs that allow generic manufacturers to receive approval of their drugs based on previously published studies of safety and efficacy.
C. Drug Competition and Patent Restoration Act (Hatch-Waxman Act) 1984
1. Allows a manufacturer of a generic drug to obtain approval based on bioequivalence and bioavailability studies.
2. Extent and rate of absorption cannot be significantly different from innovator drug 3. Innovator company can obtain an additional 2 to 5 years of patent term extension for
some of the time the drug was in FDA review. 4. In Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493 (D.C. Cir. 1996), the court held
that FDA can approve a generic drug even if the innovator manufacturer had an additional indication that the generic company cannot include in its labeling.
5. The first generic drug company to market a drug has a 180-day exclusivity period.
29 http://caselaw.lp.findlaw.com/cgi-bin/getcase.pl?court=US&vol=412&invol=640 30 http://caselaw.lp.findlaw.com/scripts/getcase.pl?court=us&vol=412&invol=645 31 http://caselaw.lp.findlaw.com/cgi-bin/getcase.pl?court=US&vol=412&invol=655 32 http://caselaw.lp.findlaw.com/scripts/getcase.pl?court=us&vol=460&invol=453 33 http://www.altlaw.org/v1/cases/533850
17
D. Over-the-Counter Drug Review
1. The FDA evaluated OTC products marketed between 1938 and 1962 to evaluate whether the
products were effective.
2. Because there were between 100,000 and 500,00 OTC products on the market, the FDA did
not conduct a product-by-product review—instead the FDA evaluated the 200 active
ingredients on the market.
3. Instead the FDA evaluated “therapeutic categories.”
4. The FDA published monographs for each ingredient in the Federal Register.
5. If an ingredient was safe and effective, the monograph specified the permissible labeling for the drug including the indication, dosage, warnings, etc. See e.g., Regulatory History of
Pediatric Cough and Cold Products at
http://www.fda.gov/ohrms/dockets/AC/07/slides/2007-4323s1-02-FDA-Chang.ppt.
6. FDA created three categories of OTC products
a. Category I: ingredients generally recognized as safe and effective (GRAS)
b. Category II: Ingredients not GRAS
c. Category III: Insufficient data to determine if GRAS
d. Cutler v. Kennedy, 475 F. Supp 838 (D.D.C. 1979) (court held FDA could not promulgate regulations allowing drugs to stay on the market without evidence of safety
and efficacy (i.e., Category III))
E. Marketed Unapproved Drugs
1. Despite the FDA’s efforts, there are still thousands of drugs being marketed without FDA
approval. See FDA website Drugs Marketed in the United States That Do Not Have
Required FDA Approvalhttp://www.fda.gov/cder/drug/unapproved_drugs/
2. Case law
a. U.S. v. Rutheford, 442 U.S. 544 (1979):34 Court held that a compound intended to treat cancer (laetrile) was a drug because, even for terminally ill patients, the safety and
efficacy requirements of the FDCA have meaning. Defendants had argued that the safety
and efficacy standards had no meaning for terminally ill patients because they would
certainly die without the drug.
F. Patient Treatment with Investigational Drugs (§ 561)
1. Under FDAMA, the FDA can approve an investigational drug for Uwidespread access outside the controlled clinical trialsU to treat “serious” or “life threatening” diseases only if it
meets the following criteria:
a. Its use is for a “serious” or “immediate life threatening” disease
b. No comparable or satisfactory treatment is available
c. Drug is under investigation in clinical trials for the disease or the clinical trials have been
completed
d. Sponsor is actively pursuing FDA approval
e. The widespread use will not interfere with ongoing clinical trials
f. There is sufficient evidence of safety and effectiveness for use in a “serious” disease
34 http://caselaw.lp.findlaw.com/scripts/getcase.pl?court=US&vol=442&invol=544
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g. For “life-threatening” disease, there is a reasonable basis to conclude the drug may be effective and would not expose patients to unreasonable, significant risk
h. Sponsor has submitted a protocol to the FDA for this widespread use
G. Individual Patient Access to investigational Drugs for serious Diseases (Parallel Track
Policy) (§ 561)
1. A manufacturer, upon request of an individual acting through a physician, may provide an
investigational drug for treating a serious disease if the FDA determines:
a. The patient has no comparable or satisfactory alternative treatment and the risks from the
investigation drug are no greater that the probable risks from the disease
b. There is sufficient evidence of safety and effectiveness for use in a “serious” disease
c. The use of the drug will not interfere with clinical investigations being conducted to gain
approval
d. The manufacturer submits a protocol for treating individual patients.
e. There is no constitutional right to receive drugs in phase I or II trials. See Abigail
Alliance v. Von Eschenbach 445 F.3d 470 (C.A.D.C. 2006) 35
f. FDA issued Proposed Rules for Charging for Investigational Drugs and Expanded
Access to Investigational Drugs for Treatment Use 36 “Under the proposal, expanded access to investigational drugs for treatment use would be available to individual patients,
including in emergencies; intermediate-size patient populations; and larger populations
under a treatment protocol or treatment investigational new drug application. It is intended to improve access to investigational drugs for patients with serious or
immediately life-threatening diseases or conditions, who lack other therapeutic options
and who may benefit from such therapies.”
H. Expedited Approval of Drugs Intended to Treat Life-Threatening Disease (“Fast Track
Approval”) (§ 506) (See http://law.justia.com/us/cfr/title21/21-5.0.1.1.3.5.html)
1. FDAMA provided statutory language that provides for expedited approval of drugs intended to treat a life-threatening disease under the following conditions:
a. The drug is intended for treating a life threatening or serious disease and demonstrates a
potential to address an unmet need
b. The drug has an effect on a clinical endpoint or surrogate endpoint
VI. BIOLOGICALS
A. “Biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative
of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention,
treatment, or cure of a disease or condition of human beings. See 42 U.S.C. 262(i).37
1. Approved by the FDA
2. Licensed by the Public Health Service
3. No generic process.
35 http://pacer.cadc.uscourts.gov/docs/common/opinions/200611/04-5350b.pdf 36 http://www.fda.gov/Cder/regulatory/applications/IND_PR.htm 37 http://www4.law.cornell.edu/uscode/uscode42/usc_sec_42_00000262----000-.html
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VII. MEDWATCH VOLUNTARY REPORTING PROGRAMS
A. Voluntary Adverse Drug Reaction Reporting (MedWatch Program)
1. Drug Quality Reporting System (DQRS)38
a. Since the early 1970s, the FDA has operated the Drug Quality Reporting System (DQRS), which encourages health care professionals to voluntarily report observed or
suspected defects or quality problems with marketed drug products. The agency receives
reports through the MedWatch Program.
2. FDA MedWatch Home Page 39
VIII. MEDICAL DEVICE ACT (AMENDMENTS) OF 1976
A. Definition (see http://www.fda.gov/CDRH/DEVADVICE/312.html#link_2)40
1. A device is:
a. [A]n instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
b. recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
c. intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation,
treatment, or prevention of disease, in man or other animals, or
d. intended to affect the structure or any function of the body of man or other animals, and
which does not achieve any of its primary intended purposes through chemical action
within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.
2. FDA states: “This definition provides a clear distinction between a medical device and other
FDA regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug.”
3. Classifications:
a. Class I: Least regulated and “general controls” are adequate to ensure safety. Examples include needles, scissors, stethoscopes, and toothbrushes.
b. Class II: Must meet specific FDA performance standards. Examples include insulin
pumps and syringes, thermometers, tampons, and electric heating pads.
c. Class III: These devices are most regulated because they are life supporting and pose a
serious risk of injury. The law requires premarket approval.
(i) Note that there is an important process by which device manufacturers may market
medical devices without premarket approval.
(ii) 510K notification: A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is,
substantially equivalent, to a legally marketed device (21 CFR 807.92(a)(3)) that is
not subject to Premarket Approval (PMA). This means a device manufacturer does not have to obtain a PMA if it can show the new
38 http://www.fda.gov/cder/Offices/CRMS/DQRS.htm 39 http://www.fda.gov/medwatch/index.html 40 http://www.fda.gov/CDRH/DEVADVICE/312.html#link_2
20
(iii) devices is substantially equivalent to a device already on the market. See
http://www.fda.gov/cdrh/devadvice/314.html.
(iv) An important, recent U.S. Supreme Court case held the Medical Device Act and regulations preempts state laws (including tort lawsuits) that conflict with PMA
requirements. If a device comes to market by the 510K process, the manufacturer
can be sued for product liability or negligence if the device injures a patient. If the device has received a PMA, the manufacturer cannot be sued under state law tort
claims. See Riegel v. Medtronic, 200 U. S. 321 (2008)41
4. Medical device manufacturers must report deaths and serious injuries to the FDA.
5. Under the 1990 Amendments, a “device-user facility” (which includes hospitals, ambulatory
surgical facilities, nursing homes, and outpatient treatment facilities) must report any death,
serious injury, or serious illness related to a product.
6. For additional information about Medical Devices, see http://www.fda.gov/cdrh/devadvice/
IX. COSMETICS
A. Definition
1. Articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise
applied to the human body...for cleansing, beautifying, promoting attractiveness, or altering the appearance" See 21 USC §201(i).42
B. Overview
1. Premarket approval not necessary
2. Manufacturers must substantiate the safety of products and ingredients.
3. Compliance with GMPs is not necessary.
4. Cosmetics may be misbranded or adulterated.
X. DRUG ADVERTISING AND PROMOTION
A. The First Amendment to the U.S. Constitution
1. Know the test for determining if government action infringes on the First Amendment right in
the context of commercial speech.
2. Important First Amendment cases:
a. Central Hudson Gas v. Public Service Comm’n, 447 U.S. 557 (1980).43 The U.S.
Supreme Court articulated the test for determining when the government can regulate commercial speech. The Court held that truthful commercial speech that does not
promote unlawful activity can be limited only if it:
(i) Is not misleading or related to an unlawful activity;
(ii) Is in support of a substantial government interest;
(iii) Directly advances the government interest asserted; and (iv) Is not more extensive than is necessary to serve that interest.
41 http://www.supremecourtus.gov/opinions/07pdf/06-179.pdf 42 http://www.fda.gov/opacom/laws/fdcact/fdcact1.htm 43 http://caselaw.lp.findlaw.com/scripts/getcase.pl?navby=CASE&court=US&vol=447&page=557
21
b. HWashington Legal Foundation v. Friedman, 13 F.Supp.2d 51 (D.C. 1998)44 Court held
the FDA cannot prohibit distribution of peer-reviewed publications and textbooks that discuss off-label use of drugs. See also Washington Legal Foundation v.
Heney, 202 F.3d 331 (D.C. 2000).45
c. For more information see First Amendment Center.46
B. Prescription Drug Advertising: Manufacturer to Professionals
1. Applicable Statute and Regulations
a. A drug is misbranded unless the manufacturer includes a “true statement,” which
contains the following:
(i) Established name of the drug
(ii) Formula, showing quantitatively each ingredient
(iii) “Brief summary” of other information related to side effects, contraindications, and
effectiveness as required by regulations
b. Not applicable to “Reminder Advertisements”: True statement does not apply to
reminder ads that mention the drug, but that do not state the indications or dosage. See
21 C.F.R. §202.1(e)(2)(i).47
c. A manufacturer does not meet the true statement standard if the advertising:
(i) Is false or misleading
(ii) Does not present a “fair balance” between effectiveness and side effects and
contraindications
(iii) Fails to reveal a material fact
d. Fair Balance: An ad does not present a fair balance if:
It fails to present a fair balance between information relating to side
effects and contraindications and information relating to effectiveness of
the drug in that the information relating to effectiveness is presented in
greater scope, depth, or detail than is required by section 502(n) of the act
and this information is not fairly balanced by a presentation of a summary of true information relating to side effects and contraindications of the
drug; Provided, however, That no advertisement shall be considered to be in
violation of this section if the presentation of true information relating to side
effects and contraindications is comparable in depth and detail with the claims for effectiveness or safety.
e. An advertisement cannot:
(i) Contain any representations or suggestions about effectiveness, indications, or lack of side effects that have not been approved by the FDA
(ii) Suggest that a drug is better than other drugs unless such a claim is based on substantial evidence
(iii) Contain favorable information from an inadequate study
f. “Advertising” includes ads in journals and other periodicals, books, media, etc. for use by health care professionals.
44 http://lw.bna.com/lw/19990810/941306.htm 45 http://bulk.resource.org/courts.gov/c/F3/202/202.F3d.331.99-5304.html 46 http://www.firstamendmentcenter.org/speech/advertising/cases_resources_summary.aspx 47 http://edocket.access.gpo.gov/cfr_2003/aprqtr/pdf/21cfr202.1.pdf
22
g. “Labeling” includes brochures, booklets, mailing pieces, etc.
h. Same standards apply to both advertising and labeling, but the information in labeling
must be more comprehensive. Specifically, prescription drug advertising in broadcast media only include information about major risks instead of the entire “brief summary”
as long as there is adequate provision for providing labeling.
C. Industry-Supported Educational Programs
1. The FDA promulgated a guidance policy for industry sponsored programs in 1997. The
policy contained a number of factors that the FDA would apply to industry sponsorship of
programs to determine if the program was serving as a mouthpiece for the company and if the speakers were agents and representatives of the company. In other words, could any
statements about indications, safety, efficacy, etc. be attributed to the company and evaluated
under the FDCA?
2. Final Guidance on Industry Supported Scientific and Educational Activities 1997 at http://www.fda.gov/cder/guidance/isse.htm.
3. Office of Inspector General (OIG) issued guidance for pharmaceutical industry that
included advice that when a drug company provides funds to influence an educational
program it may violate antikickback laws
D. Prescription Drug Advertising: Manufacturer to Consumer
1. There are no specific regulations for Direct-to-Consumer advertising. The following
websites contain useful information for anyone interested in more detail:
http://www.fda.gov/cder/ddmac/globalsummit2003/ and www.gao.gov/cgi-bin/getrpt?GAO-03-177
2. DTC ads fall into two categories:
a. Educational: Does not mention the name of the drug, just the manufacturer
b. Product Specific: These are subject to regulations. The FDA encouraged the
dissemination of information to treat inadequately treated conditions, the FDA clarified
the distinction between product specific and educational ads in a draft guidance document: “Help-Seeking” and Other Disease Awareness Communications by or on
Behalf of Drug and Device Firms http://www.fda.gov/cder/guidance/6019dft.pdf
3. The following summarizes the status of guidelines for DTC ads:
a. Advertisers can provide summary of risks in audio or video form as long as the adequate
provision standard is met by providing consumer with full information from other
sources:
(i) Toll-free number
(ii) Internet address
(iii) Referral to currently running advertisement in a publication.
(iv) Referral to a health care provider
b. FDA Guidance 2004 Disclosing Risk Information in Consumer-Directed Print Advertisements http://www.fda.gov/cder/guidance/5669dft.pdf
23
c. Finally, the GAO issued a report in 2006 criticizing industry advertising.
PRESCRIPTION DRUGS Improvements Needed in FDA’s Oversight of Direct-to-
Consumer Advertising http://www.gao.gov/new.items/d0754.pdf
E. Promoting Prescription Drugs for Off-Label Uses
1. Prescriber can prescribe for unapproved uses and dosages
a. Law was not intended to limit MD’s ability to treat patients
b. Perhaps increased liability. See Package inserts and the standard of care, Proc (Baylor
Univ. Med Cent). 2003 October; 16(4): 502–504.48
c. Review Ramon v. Farr in the text.
2. FDAMA allowed dissemination of certain off-label uses to the following entities under several conditions:
a. Health care practitioners
b. PBMs
c. Health insurance plans
d. Group health plans
e. Government agencies
3. The information had to be in unabridged peer-review articles in scientific or medical journals
that had not been influenced by the company.
a. In order to provide this information, the company had to: (i) have filed an application for
the new indication, (ii) submit the information to the FDA 60 days before dissemination
for approval, and (iii) include a disclaimer on the material when disseminated
b. Some of these restrictions were unconstitutional under Washington Legal Foundation v.
Friedman.
F. Prescription Drug Advertising by Manufacturers
1. The FTC regulates OTC advertising by manufacturers
2. FTC is the Federal Trade Commission. The Division of Advertising Practices
3. From the FTC website:
a. Bureau of Consumer Protection: The Division of Advertising Practices49 is the
nation’s enforcer of federal truth-in-advertising laws. Its law enforcement activities focus on:
(i) Claims for foods, drugs, dietary supplements, and other products promising health
benefits.
(ii) Health fraud on the Internet.
(iii) Weight-loss advertising
(iv) Advertising and marketing directed to children.
(v) Performance claims for computers, ISPs and other high-tech products and services.
48 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1214572 49 http://www.ftc.gov/bcp/edu/pubs/consumer/general/gen03.shtm#bcp
24
(vi) Tobacco and alcohol advertising, including monitoring for unfair practices or
deceptive claims and reporting to Congress on cigarette and smokeless tobacco
labeling, advertising and promotion.
(vii) Protecting children’s privacy online.
(viii) Claims about product performance made in national or regional newspapers and magazines; in radio and TV commercials, including infomercials; through direct
mail to consumers; or on the Internet.
b. Bureau of Competition seeks to prevent anticompetitive mergers and other anticompetitive business practices in the marketplace
4. Werner-Lambert v. Federal Trade Comm’n, 562 F.2d 749 (D.C. 1977) Court ordered
company to stop making claims that Listerine was effective for preventing colds.
G. The Lanham Trademark Act
1. The federal law that prohibits false advertising or representations
2. This is the federal law that creates trademark rights.
a. A trademark protects words, names, symbols, sounds, or colors that distinguish goods
and services from those manufactured or sold by others and to indicate the source of
the goods. Trademarks, unlike patents, can be renewed forever as long as they are being
used in commerce.
b. Key to a trademark is that it informs the consumer of the source of product. If a mark by company “A” creates confusion about the source of a product so consumers think it is
produced by company “B” and company “B” has an existing trademark for its product,
company “A” likely infringes the trademark of company “B.”
c. FTC enforces the Lanham Act.
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FEDERAL REGULATION OF MEDICATION: DISPENSING
XI. DURHAM-HUMPHREY AMENDMENT
A. The Law
1. Creates the distinction between prescription (legend) drugs and OTC drugs by exempting
certain drugs from some labeling requirements
2. The law created this distinction by creating two classes of drugs.
a. OTC drugs were safe for use without medical supervision because the instructions and
warnings on the label of the product were adequate for the intended use. All the requirements for labels and labeling (e.g., adequate warnings) are required for the OTC
package the consumer receives.
b. Prescription (Legend) Drugs: are Uunsafe without medical supervisionU. Because a physician or other prescriber decides whether a patient receives the drug, the labeling
required by the FDA for manufacturers need not be on the package the consumer
receives.
c. In other words, the Amendment created a labeling exemption for prescription drugs such
that the package the consumer receives is not required to bear the information
manufacturers must provide with their products.
d. Prescription drugs must contain the legend “Rx only.” (The term legend drug derives
from the old legend that was required on prescription drug labels” “Caution: Federal law
prohibits dispensing without a prescription”)
B. Explanation of the Durham-Humphrey Amendment
1. Prescription Versus Over-the-Counter Drugs
a. The Amendment granted the FDA with authority to categorize drugs as prescription only if the drugs are:
(i) Unsafe for use except under the supervision of a practitioner based on toxicity, method of use, or collateral measurements necessary to use the drug
(ii) Subject to the new drug application process
b. U.S. v. Article of Drug—Decolin (involved dehydrocholic acid to be used for “indigestion . . . after-meal discomfort and fullness(particularly after fatty meals) . . . excessive
belching . . . constipation”)
(i) Court held FDA must prove two facts to change the status of a drug from OTC to prescription: (i) toxicity and method of use require supervision of a practitioner and
(ii) collateral measures necessary to use the drugs require supervision (e.g., if a
taking a drug causes delay in seeking treatment for a serious condition that the drug cannot cure)
2. Dispensing Written, Oral, and Electronic Prescriptions
a. The Amendment allows for oral transmission f a prescription drug order if the order is promptly reduced to writing. In fact, the purpose of the Amendment was to allow the
oral transmission of prescriptions and to allow pharmacists to honor refill information on
the original prescription.
26
b. Electronic signatures are now considered valid by passage of the Electronic Signatures in
Global and National Communications Act (E-Sign”), which allows electronic signatures
that meet certain requirements to be considered the same as physical signatures. See FTC web page at http://www.ftc.gov/os/2001/06/esign7.htm
3. Labeling Requirements
a. The Amendment exempts pharmacists from labeling prescriptions drugs except:
(i) Label cannot be false or misleading
(ii) Drugs cannot be imitation drug
(iii) Drug cannot be sold under name of another drug
(iv) Packaging and labeling must conform to compendial standards
(v) Drug must be packaged and labeled appropriately if subject to deterioration
(vi) Drug packaging must conform to Poison Prevention Packaging Act
b. Minimum federal standards for information on prescription drug label
(i) Prescriber’s name
(ii) Name and address of dispenser (pharmacy)
(iii) Serial number (Rx number)
(iv) Date of filling UorU date of prescription
c. Prescription label must include if stated on prescription:
(i) Name of patient
(ii) Directions for use
(iii) Cautionary statements
C. Expiration or Beyond Use Dating
1. Most states, but not the FDA, require expiration or beyond use dating.
2. USP sets the standards for expiration and beyond use dating.
a. For multiple-unit containers, like prescription containers, the beyond use date “shall not be later than (a) the expiration date on the manufacturer’s container, or (b) 1 year from
the date the drug is dispensed, whichever is earlier.”
b. For nonsterile solid and liquid drugs repackaged into containers, the pharmacist should include a beyond use date that is the earlier of one year from the date of repackaging o
the expiration date on the original bulk container.
D. Switch of Prescription Drugs to Over-the-Counter Drugs
1. Request switch with supplemental NDA
a. Note: Each company must receive approval of a switch to an OTC status. Thus, it may
be confusing when one manufacturer labels the same drug as Rx Only while another company distributes the same drug as an OTC product.
2. Petition FDA
3. OTC drug review process (monograph is published if the ingredient is approved as an OTC)
27
E. Professional Practice Considerations
1. Prescription Refill Authorization
a. Only a prescriber can authorize refills, but an employee can communicate or transmit
refill authorization with the pharmacist (Utah regulations have also specifically allowed
for this process).
b. How should pharmacists verify that the prescriber has actually authorized the refill?
2. Prescriptive Authority
a. State law governs who can prescribe
b. In Utah, the following have prescriptive authority
(i) Nurse practitioners & nurse midwives (CIIs and CIII in consultation with MD)
(ii) Dentists
(iii) Physician assistants (dependent on physician to prescribe)
(iv) Podiatrists
(v) Veterinarians
(vi) Osteopaths
(vii) Physicians
(viii) Optometrists (limited)
(ix) Naturopathic physician (limited to specific formulary)
c. Prescriptions must be within scope of practice of the prescriber (scope of authority)
3. Emergency Contraceptives (Plan B)
a. Plan B contains a high dose of levonorgestrel, which is normally used in lower doses in
oral contraceptives.
b. Plan B has been available since 1999 as a prescription drug.
c. 2003 Barr submitted SNDA to switch Plan B to OTC
d. Two advisory boards approved the switch, but the FDA rejected the application.
e. In 2004 Barr again submitted its application and the FDA initially rejected it.
f. In 2006, the FDA finally approved the switch to OTC, but only to be sold in pharmacies
by a pharmacist to a person who is at least 18 years old.
g. See FDA Website FDA’s Decision Regarding Plan B: Questions and Answers August 24,
2006.50
4. Conscientious Objection
a. There have been several cases litigated where states have passed laws or regulations to
govern dispensing post-coital contraceptives.
(i) Morr-Fitz, Inc. v. Blagojevich, 867 N.E.2d 1164 (Ill. App. March 19, 2007)
b. Brownfield v. Daniel Freeman Marina Hospital, 256 Cal. Rptr. 240 (1989) (court
concludes morning after contraception does not constitute abortion services under a law that protects religious organizations from providing services that are contrary to their
teachings).
50 http://www.fda.gov/CDER/DRUG/infopage/planB/planBQandA.htm
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c. Controversial proposed rule51 from HHS would define “abortion” to include IUDs and, perhaps, oral contraceptives. The regulation is intended to give health care providers the
right to object to providing abortion services. Thus, if abortion is defined broadly,
providers will be able to refuse providing services for a broader range of services.
“Abortion” means any of the various procedures—including the
prescription, dispensing, and administration of any drug or the
performance of any procedure or any other action—that results in the termination of the life of a human being in utero between
conception and natural birth, whether before or after
implantation.
Excerpt from Frye CA, An overview of oral contraceptives
Mechanism of action and clinical use, Neurology, 66:S29-S36, 2006.
Mechanism of action of hormonal contraception. Estrogen and
progestin are active components of hormonal contraception. Their primary mechanism of action is believed to be prevention of
ovulation. Estrogen prevents release of follicle-stimulating hormone
(FSH), thus inhibiting ovarian activity and preventing development of an ovum. Progestin has a variety of effects, including thickening
of cervical mucus, decreased tubal mobility, changes in the
endometrium, and prevention of ovulation. Thickening of cervical mucus hinders sperm penetration, whereas decreased tubal mobility
inhibits ovum transport and fertilization and may affect sperm
migration and activity. Finally, changes in the endometrium may
affect survival of a blastocyst within the uterus or prevent
implantation.
5. Collaborative Practice Agreements (basically a state law issue that will be addressed in the
Utah law portion of the course)
6. Authority to Dispense Prescription Drugs
a. The FDCA is silent about who can dispense drugs and leaves the decision to the states
F. Patient Package Inserts
1. FDA regulations require PPIs for certain hormonal products are required for (See
www.fda.gov/cder/guidance/6932dft.htm)
a. Oral contraceptives (21 C.F.R. § 310.105)52
b. Oral postcoital contraceptives (DES)
c. Injectable contraceptives (Medroxyprogesterone acetate)
d. Estrogens (12 C.F.R. § 310.515)53
e. Progestational drug products (21 C.F.R. § 310.516)54
2. The labeling for these drugs must include special patient labeling and must be given with
each package dispensed
51 http://www.rhrealitycheck.org/emailphotos/pdf/HHS-45-CFR.pdf 52 http://frwebgate.access.gpo.gov/cgi-bin/get-cfr.cgi?TITLE=21&PART=310&SECTION=501&YEAR=1999&TYPE=PDF 53 http://frwebgate.access.gpo.gov/cgi-bin/get-cfr.cgi?TITLE=21&PART=310&SECTION=515&YEAR=1999&TYPE=PDF 54 http://frwebgate.access.gpo.gov/cgi-bin/get-cfr.cgi?TITLE=21&PART=310&SECTION=516&YEAR=1999&TYPE=PDF
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3. Hospitals need only give information once every thirty days after first dose. See Schlieter v.
Carlos, 22 P.3d 682 (N.M. 2001) (giving PPIs to a physician in a hospital does not meet the
pharmacy’s duty to give each patient a PPI when patient received Premarin)
G. Medication Guides
1. The FDA has tried to create regulations that would require PPIs for every drug, but Congress eventually passed a law that prohibited the FDA from doing so if private industry could
achieve a plan whereby 95% of patients receive useful written information about their drugs
by 2006).
2. 2001 study showed only 89% of patients received written information and the information was useful only 50% of the time. See www.fda.gov/cder/reports/prescription
Info/default.htm)
3. In 1993, the FDA issued a regulation that required manufacturers to provide information for certain drugs, which each pharmacist must then provide to patients. See 63 Fed. Reg.
6637855H (Final Rule for Medication Guide Requirements).
a. Med Guides are required for drugs when:
(i) Patient labeling could help prevent serious adverse effects
(ii) The drug has serious risks relative to its benefits which the patient should know about when deciding whether to use the drugs, and
(iii) Patients’ adherence to the directions is crucial to the drug’s effectiveness.
b. A 2005 study found only1 of 25 pharmacies actually distributed the Med Guide for celexocib.
c. List of drugs required to have a Med Guide can be found at http://www.fda.gov/cder/offices/ods/medication_guides.htm
H. Risk Management Programs for Very High Risk Drugs
1. Accutane (iPledge – requires patients to register)
2. Plan B
3. Clozapine (Clozaril)
4. Olosetron (Lotronex)
5. Alendrinate (Fosamax)
I. FDA Consumer website to learn about drugs Drugs@FDA56
XII. APPROVED DRUGS FOR UNLABELED INDICATIONS
1. General Rule: Once a drug is in the pharmacy after shipment in interstate commerce, the
prescriber may, as part of medical or professional practice, lawfully prescribe a different dosage for a patient, or may otherwise vary the conditions of the use from those approved in
the package insert, without informing the FDA—that is, prescribers are free to prescribe
drugs for legitimate, clinically justifiable uses even if such uses are not indicated by the manufacturer
2. Mulder v. Parke Davis: court held that a physician’s deviation from recommendations of a
drug manufacturer in the package insert is prima facie evidence of negligence
3. Ramon v. Farr see text for summary
55 http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=1998_register&docid=98-31627-filed.pdf 56 http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
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4. Spensieri v. Lasky, 94 N.Y.2d 231 (1999).57
XIII. PHARMACY COMPOUNDING VERSUS MANUFACTURING
A. Pharmacies are exempt from registration as manufacturing if they
maintain establishments in conformance with any applicable local laws
regulating the practice of pharmacy and medicine and which are regularly engaged in dispensing prescription drugs or devices, upon prescriptions of
practitioners licensed to administer such drugs or devices to patients under the
care of such practitioners in the course of their professional practice, and which
do not manufacture, prepare, propagate, compound, or process drugs or devices for sale other than in the regular course of their business of dispensing or
selling drugs or devices at retail 21 U.S.C. § 360(g)58
1. In other words, pharmacies are exempt from registering as a manufacturer if they engage in the traditional practice of pharmacy.
2. Pharmacies that repackage OTC products or in any way change the container, wrapper, or
labeling of the products must register as a manufacturer
B. Chronology of Compounding Laws and Guidance
C. FDA 1992Compliance Guidelines
1. Based in part on judicial decisions
a. Cedar Towers Pharmacy v. U. S.: Court listed a number of factors to consider in
determining whether pharmacy qualifies for the exemption
b. The FDA stated that in determining whether to initiate an action against a pharmacy for
failing to register as a manufacturer it would consider whether the pharmacy engages in
certain activities:
(i) Soliciting business to compound specific drug products or therapeutic classes of
products
(ii) Compounding inordinate amounts of drugs that are commercially available
(iii) Receiving, storing or using drug substances from sources unapproved by FDA or
that do not meet official compendia requirements
(iv) Compounding with commercial scale manufacturing or testing equipment
(v) Compounding amounts of drugs far in excess of valid prescriptions
(vi) Offering compounded drugs at wholesale to others for resale
(vii) Distributing inordinate amounts of compounded products out of state; or
(viii) Failing to operate in conformance with applicable state law regulating the practice of pharmacy.
(ix) Other factors may be appropriate for consideration in a given case.
D. FDAMA’s Compounding Provisions
1. FDAMA exempted pharmacists from 3 provisions of the FDCA
(i) The adulteration provision that requires compliance with CGMP
(ii) The misbranding provisions that require labeling with adequate directions for use
(iii) The new drug provisions
57 http://www.law.cornell.edu/nyctap/search/display.html?terms=physician&url=/nyctap/I99_0168.htm 58 http://uscode.house.gov/uscode-cgi/fastweb.exe?getdoc+uscview+t21t25+181+1++21%3Acite%20w%2F3%20360
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2. In order to qualify, pharmacists had to meet certain conditions:
a. Products must be for individual an individual patient and cannot be resold
b. Limited quantities could be prepared in anticipation of legitimate prescriptions
c. Cannot compound commercially available products
d. Compounded product must be made from approved ingredients and not from products that appear on an FDA list of products withdrawn from the market
e. Prescriptions could not be solicited
f. No advertising for individual products
3. Thompson v. Western States Medical Center, 122 S.Ct. 1497 (2002):59 The Supreme Court
held that these final two conditions (e & f above) were unconstitutional restrictions on free speech
E. FDA 2002 Compliance Policy Guide
1. FDA drafted new compliance guidelines in reaction to the Thompson v. Western States decision
2. A copy of this compliance policy is included in the reading materials and can be found at
http://www.fda.gov/OHRMS/DOCKETS/98fr/02D-0242_gdl0001.pdf.
3. See also Compounding of Drugs for Use in Animals (CPG 7125.40)
http://www.fda.gov/ora/compliance_ref/cpg/cpgvet/cpg608-400.html.
4. FDA’s authority to inspect pharmacies was challenged by a compounding pharmacy where the FDA obtained a warrant and conducted an inspection. In the subsequent litigation, the
federal court held the FDA could inspect pharmacies to determine if the compounding
exemption applied, but that the FDA could not conduct a more thorough inspection if the initial inspection reveals the compounding exemption applies. See Wedgewood Village
Pharmacy v. United States, 421 F.3d 263 (3rd Cir. 2005).60
F. New Drug Issue
1. Remember the definition for “new drug” and consider whether a compounded drug is a new
drug.
2. The FDA has taken the position that all compounded drugs are new drugs. A federal court agreed with this position in a footnote in the 1995 case Professionals and Patients for
Customized Care v. Shalala, 56 F.3d 592 (5th Cir. 1995):
Although the Food, Drug, and Cosmetic Act does not expressly exempt “pharmacies” or “compounded drugs” from the new drug, adulteration,
or misbranding provisions, the FDA as a matter of policy has not
historically brought enforcement actions against pharmacies engaged in traditional compounding
3. FDAMA would have extended an exemption from the new drug provisions of the FDCA.
4. This summer (2008), the Fifth Circuit held that compounded drugs are new drug, but that FDAMA provides an exemption from the new drug provisions of the FDCA if
59 http://www.law.cornell.edu/supct/html/01-344.ZS.html 60 http://www.ca3.uscourts.gov/opinarch/041175p.pdf
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5. pharmacies comply with state laws governing compounding. Medical Center Pharmacy v.
Mukasey, No. 06-51583 (July 18, 2008).
6. See FDA statement of its interpretation of Medical Center Pharmacy v. Mukasey at http://www.fda.gov/cder/pharmcomp/medical_center_pharmacy.htm.
G. Patent Issues
XIV. THE ORANGE BOOK
A. FDA Approved Drug Products with Therapeutic Equivalents
1. Web links:
a. http://www.fda.gov/cder/ob/default.htm (search version)
b. http://www.fda.gov/cder/orange/obannual.pdf (includes entire text)
2. Most states use the Orange Book to determine whether a generic drug can lawfully be
substituted.
3. “A” rated drugs are generally bioequivalent and can be substituted.
4. See text for coding system.
B. Narrow Therapeutic Index (NTI) Drugs
1. Drug where there is less than a two-fold difference between the median lethal dose and the
median effective dose or less than two-fold difference between minimum toxic concentration
and minimum effective concentration in the blood.
2. See Therapeutic Equivalence of Generic DrugsResponse to National Association of Boards of
Pharmacy at www.fda.gov/cder/news/ntiletter.htm
XV. PRESCRIPTION DRUG MARKETING ACT OF 1987
A. Intent
1. 1. “[T]o restore the integrity and control over the pharmaceutical market necessary to
eliminate actual and potential health and safety problems before serious consumer injury results.”
2. To reduce public health risks from adulterated, misbranded, and counterfeit drug products
that infiltrate the legitimate drug market through the drug diversion market
B. Regulation of Prescription Drug Samples
1. Prohibits sale, purchase, or trade of samples
a. Except the following may receive drug samples upon written request:
(i) Prescribing Practitioners
(ii) Pharmacies of hospitals or health care entities
b. Retail pharmacies cannot possess drug samples; mere presence of a sample is evidence of
illegal acquisition
2. Samples can be provided only to prescribing practitioners who request them in writing
a. Form must contain practitioner’s name, address, title, amount and identity of sample,
name of manufacturer, and date
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3. Manufacturers are required to keep complete and accurate inventory and records
C. Purchases and Releases by Hospital and Health Care Entities
1. Prohibits hospitals, “health care organizations,” or charitable organizations from selling or
trading drugs
a. Exceptions
(i) Dispensing and distributing drugs pursuant to prescription
(ii) Purchases from buying group or from other member hospitals
(iii) Sales or purchases to nonprofit affiliates
(iv) Sales or purchases among hospitals or health care entities under common control
b. Sales or purchase for emergency medical situations
D. Product Returns
1. Because the wording of the PDMA is so broad, pharmacies were confused about whether and how to make returns to wholesalers. Eventually, the FDA issued regulations that allowed
returns with proper documentation. 21 C.F.R. Part 205. See also FDA Guidance on return
and disposal of drugs at http://www.uspharmd.com/pharmacist/FDA_Drug_Return_Policy.html
E. Wholesale Distributors
1. New regulations for wholesalers
a. Authorized and unauthorized wholesalers
2. Wholesalers must be licensed in every state in which it distributes drugs (Utah now regulates
wholesalers pursuant to this federal law)
F. Reimportation of Prescriptions Drugs
1. Prescription drugs manufactured in the U.S. cannot be reimported, except by manufacturer
a. Intended to stop the flow of foreign counterfeits
G. Penalties
1. Violations can be punished by fines or incarceration in accordance with penalties under the
FDCA
2. Violation of provisions dealing with reimportation, samples, resales, or wholesalers
punishable by up to 10 years in jail or $250,000 fine
3. Manufacturers & distributors:
a. Failure to maintain proper records - civil fine of $100,000
b. Violation of sample provisions carries up to $50,000 civil penalty Uper offense
c. Subsequent offenses punishable up to $1,000,000
4. Snitcher provision: informer can collect half of criminal fine up to $125,000
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XVI. INSPECTIONS UNDER THE FEDERAL FOOD, DRUG, AND COSMETIC ACT
XVII. USE OF ALCOHOL IN PHARMACY PRACTICE
XVIII. POISION PREVENTION PACKAGING ACT
A. Requires “household substances” to be packaged for consumer use in “child-resistant containers;”
the Act is intended to extend packaging requirements for household substances to prescription
and certain nonprescription drugs
1. All prescription drugs and all controlled substances must be packaged in child-resistant
packaging
a. A package fails if more than 20% of test group of children can open after visual demonstration, or
b. More than 10% of a test group of adults cannot open container
c. Unit does fails if one child can open more than eight individual units or the number of
units representing the toxic amount
2. Resale of plastic child-resistant containers is prohibited
3. 3Exceptions to the packaging requirements are listed in the texts
4. PPPA requires that most prescription drugs be packaged in child-resistant containers;
however when many drugs move from prescription to OTC child-resistant packaging is no longer required
5. Rules for aspirin and acetaminophen products
a. PPPA applies to APA with more than 1 gram in single package
b. Excludes effervescent tablets or granules containing less than 15% of drug
c. Excludes powdered ASA and APAP containing less than 13 grains of drug per unit dose
6. Each manufacturer can produce one single size package of an OTC drug if it bears the
warning “This package for households without young children”
7. Other OTC substances subject to the Act
a. Iron containing drugs: if preparation contains a total amount of elemental iron equivalent
to 250 mg or more in single package
b. Dietary supplements containing iron: same as for iron containing drugs
c. Diphenhydramine: oral dosage forms containing more than 66 mg of diphenhydramine in
single package
d. Ibuprofen: oral dosage forms containing more than 1 gram in single package
8. Exemptions
a. Patient or physician can request non-child-resistant container
b. Best to have written waiver
c. Patient can make a blanket request that all prescriptions be dispensed in noncomplying containers
d. Physician’s blanket request cannot be honored
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XIX. DRUG ADVERTISING BY PHARMACISTS
A. Advertising: Strict Liability
B. State Advertising Case: The Virginia Case and the First Amendment
1. In Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, the U.S.
Supreme Court held that the laws prohibiting the advertising prescription drug prices were
unconstitutional. The Court noted that the Board of Pharmacy cannot protect “its citizens by keeping them ignorant.”