FDCA and regulation of medication 2019 - outline

Question 1

Who/What regulates drugs- development, production and marketing of drugs?

Answer 1

1. FDA- primary enforcer of the FDCA.
2. Rulemaking authority- FDA promulgates regulations and guidance documents.
3. Enforcement Role- Can enforce FDCA with drug manufacturers, compounders, pharmacies using:

Question 2

1. FDA- primary enforcer of the FDCA.

Answer 2

1. Part of the US Department of Health and Human Services (DHHS)
   
   1. President appoints FDA commissioner with senate confirmation.
2. Five Centers share responsibility for scientific and regulatory evaluations and interpretations.
   
   1. Each center has a director and several managers.
3. Geographically, US is divided into fields- 6 regions with 20 district offices.
   
   1. The district offices inspect facilities and products and work cooperatively with state and local agencies (think boards of pharmacy, health departments, etc.)
4. Standing advisory committees- composed of scientific experts like physicians, nurses, pharmacists, statisticians, epidemiologists, and other professionals.

Question 3

b. Rulemaking authority- FDA promulgates regulations and guidance documents.

Answer 3

1. Guidance documents clarify laws or regulations, explain how to comply with laws and regulations, or to describe review and enforcement approaches.
   
   1. Not legally binding nor enforceable

Question 4

c. Enforcement Role- Can enforce FDCA with drug manufacturers, compounders, pharmacies using:

Answer 4

1. Seizures
2. Injunctions
3. Warning letters
4. Recalls
5. Drug product debarment

Question 5

How are drugs regulated? Through the FDCA

Answer 5

1. Pure Food Act 1906- .
2. FDCA of 1938- nucleus of today’s law:
3. Amendments
4. Durham-Humphrey Amendment 1951 (*aka prescription drug amendment
5. Food Additives Amendment of 1958-
6. Color Additive Amendments of 1960-
7. Kefauver-Harris Amendment of 1962- (*aka Drug Efficacy Amendment)-
8. Medical Device Amendments of 1976-
9. Orphan Drug Act of 1983-
10. Drug Price Competition and Patent Term Restoration Act of 1984 (*aka Waxman-Hatch Amendment)
11. Prescription Drug Marketing Act of 1987 PDMA-
12. Safe Medical Devices Act of 1990-
13. Generic Drug Enforcement Act of 1992
14. Prescription Drug User Fee Act 1992 PDUFA-
15. Nutritional Labeling and Education Act 1990-
16. Dietary Supplement Health and Education Act 1994-
17. Food and Drug Administration Modernization Act 1997-
18. Food and Drug Administration Amendments Act 2007-
19. FDA Safety and Innovation Act of 2012-
20. FDA Safety and Innovation Act of 2012:
21. Drug Quality and Safety Act of 2013 DQSA-
22. 21st Century Cures Act
23. FDA Reauthorization Act of 2017:

Question 6

1. Pure Food Act 1906- prohibited adulteration and misbranding of foods and drugs in interstate commerce.

Answer 6

1. 1. US. v. Johnson- held the misbranding provision didn’t prevent false or misleading efficacy claims- only prevented false statements only as to the drugs identity (strength, quality, and purity).
   2. Congress amended the Act in 1912 to prohibit false and fraudulent efficacy claims. – But still difficult to enforce.
   3. Required government to prove fraudulent intent of those who made the statement.
   4. Sulfanilamide- one of the first anti-infective sulfa drugs marketed- manufacturer who wanted to produce the drug in elixir form use diethylene glycol as solvent. This solvent was deadly poison and 107 deaths were attributed. The law hadn’t granted the FDA the right to ban unsafe drugs, so FDA had to remove the product on basis of technical misbranding- since elixir must contain alcohol and the product didn’t.

Question 7

2. FDCA of 1938- nucleus of today’s law: THREE KEY ELEMENTS:

Answer 7

1. (1) no new drug could be marketed until proven safe for use under the conditions described on the label and approved by the FDA;
2. (2) required labels must contain adequate directions for use, and warnings about the habit-forming properties of certain drugs; and
3. (3) applied to cosmetics and devices. BUT, exempted drugs marketed before 1938

Question 8

3. Amendments:

Answer 8

1. 1941-1945 allow the FDA to require batch certification of the safety and efficacy of insulin (and then penicillin) to ensure uniform potency. In 1997, FDA Modernization Act eliminated the batch certification requirement of insulin and antibiotics.
2. US. v. Sullivan- FDCA challenged by pharmacist on jurisdiction, he alleged he acts only affected intra-state transactions. SCOTUS held that the jurisdiction of the act extends to transactions between pharmacist and patient, so FDCA applies to all drugs held for sale in a pharmacy.

Question 9

4. Durham-Humphrey Amendment 1951 (*aka prescription drug amendment)-

Answer 9

1. When FDCA was passed, many drugs were not safe for use except under medical supervision- these drugs couldn’t meet the adequate direction for use requirement.
2. Amendment established two drug classes: prescription and over the counter.
   
   1. Prescription drugs did not need adequate directions for use, so long as they had: “Caution: Federal law prohibits dispensing without a prescription.” When dispensed by a pharmacist, the adequate description of use requirement was satisfied if the label included the directions from the prescriber.
3. Also authorized oral prescriptions and refills of prescription drugs.

Question 10

6. Color Additive Amendments of 1960-

Answer 10

6. Color Additive Amendments of 1960- require manufacturers to establish the safety of color additivities in foods, drugs, and cosmetics. Also contains a Delaney Clause (see Food Additives Amendment)

Question 11

7. Kefauver-Harris Amendment of 1962-

Answer 11

1. Transferred jurisdiction of drug advertising from Federal Trade Commission to FDA
2. Established Good Manufacturing Practices requirements
3. Added more extensive controls for clinical investigations by requiring the informed consent of research subjects and reporting of adverse drug reactions

Question 12

8. Medical Device Amendments of 1976

Answer 12

8. Medical Device Amendments of 1976- under 1938 Act, the FDA had no authority to review medical devices for safety/efficacy. In response to Dalkon Shield (intrauterine device)- required

1. Classification of devices according to function
2. Premarket approval
3. Establishment of performance standards
4. Conformance with good manufacturing practices (GWP)
5. Adherence to record and reporting requirements

Question 13

9. Orphan Drug Act of 1983

Answer 13

9. Orphan Drug Act of 1983- in response to complaints that new drug approval process was too expensive for drugs for diseases that affected few people.

1. Tax and exclusive licensing incentives for manufacturers to develop and market drugs or biologics for treatment of rare diseases/conditions (those affecting fewer than 200,000 Americans).

Question 14

10. Drug Price Competition and Patent Term Restoration Act of 1984 (*aka Waxman-Hatch Amendment)

Answer 14

10. Drug Price Competition and Patent Term Restoration Act of 1984 (*aka Waxman-Hatch Amendment) streamlined generic drug approval process while giving patent extensions, in certain cases, to innovator drugs. Intent- make generics more available, and incentivize development of new drugs. Compromise between generic vs. new drug manufacturers

Question 15

11. Prescription Drug Marketing Act of 1987 PDMA

Answer 15

11. Prescription Drug Marketing Act of 1987 PDMA- growing concern about a secondary or diversionary distribution system for prescription drugs. Establishes sales restrictions and recordkeeping requirements for prescription drug samples and prohibits hospitals and health care entities from reselling their pharmaceutical purchases to other businesses and requires state licensing of drug wholesalers.

Question 16

12. Safe Medical Devices Act of 1990

Answer 16

12. Safe Medical Devices Act of 1990- strengthened Medical Devices Act of 1976, FDA additional authority especially related to post-marketing requirements and pre-market notification and approval, while expediting pre-market device approval process.

1. Concern over the FDA’s ability to quickly learn when a medical device caused an adverse patient event, and to ensure that hazardous devices were removed from hospitals and other health care facilities in a timely manner. It gives the FDA the legal authority to directly regulate the use of medical devices in health care facilities. Among the Safe Medical Devices Act’s provisions are specific requirements for hospitals, health professionals, and other users of medical devices to report patient incidents involving medical devices to the manufacturer and to the FDA if a device caused or contributed to a serious injury, death, or other “adverse experience.”

Question 17

13. Generic Drug Enforcement Act of 1992

Answer 17

Generic Drug Enforcement Act of 1992- Background- FDA staff members (later convicted) accepted bribes from generic drug industry personnel to facilitate the approval process of certain drug products. This amendment authorized FDA to ban (debar) individuals or firms from participating in drug approval process if convicted of certain felonies or found to have engaged in certain types of conduct.

Question 18

14. Prescription Drug User Fee Act 1992 PDUFA

Answer 18

14. Prescription Drug User Fee Act 1992 PDUFA- requires manufacturers seeking new drug approval to pay fees for applications and supplements when the FDA must review clinical studies.

Question 19

15. Nutritional Labeling and Education Act 1990

Answer 19

15. Nutritional Labeling and Education Act 1990- mandates nutritional labeling on food products and authorizes health claims on product labeling, so long as they are compliant with FDA regulations.

Question 20

16. Dietary Supplement Health and Education Act 1994

Answer 20

Dietary Supplement Health and Education Act 1994- defines dietary supplements and permits manufacturers to make certain claims that would otherwise be illegal under FDCA- this treats supplements more like food than drugs.

Question 21

17. Food and Drug Administration Modernization Act 1997

Answer 21

17. Food and Drug Administration Modernization Act 1997- passed to streamline regulatory procedures.

1. Created fast-track approval process for drugs intended to treat life threatening or serious diseases, establishes a databank of information on clinical trials, authorizes scientific review panels for clinical investigations and expands the rights of manufacturers to disseminate unlabeled use information.
2. Expands FDA’s authority over over-the-counter drugs and established ingredient labeling requirements for inactive ingredients. States are pre-empted from establishing labeling requirements for OTC drugs and cosmetics when federal requirements exist.
3. Mandates priority review for breakthrough technologies in medical devices and allows the FDA to contract with outside scientific experts for review of medical device applications.

Question 22

18. Food and Drug Administration Amendments Act 2007-

Answer 22

18. Food and Drug Administration Amendments Act 2007- provided the FDA with new funding and more authority over drug safety.

1. Increased fees under Prescription Drug User Fee (PDUFA)
2. Enhanced responsibility and authority to regulate drug safety:
   
   1. Mandate label changes related to safety
   2. Require clinical trial data reporting and registries
   3. Require postmarket clinical studies to assess risks
   4. Require companies to implement risk evaluation and mitigation strategies when necessary.

Question 23

19. FDA Safety and Innovation Act of 2012

Answer 23

19. FDA Safety and Innovation Act of 2012- reauthorizes Prescription Drug User Fee Act,

1. Allows FDA to continue to collect fees from manufacturers seeking new drug approvals or medical device approvals, but also adds new user fees for generic drugs and biosimilars.
2. Provisions aimed at reducing drug counterfeiting, blocking the importation of adulterated products, detecting and reducing drug shortages, and enhancing the exchange of prescription drug diversion information across state lines.
3. Enables FDA to inspect foreign drug manufacturers more regularly and requires the agency to target problematic manufacturing sites.

Question 24

20. FDA Safety and Innovation Act of 2012:

Answer 24

20. FDA Safety and Innovation Act of 2012:

1. Reauthorizes PDUFA- allows FDA to continue to collect user fees from manufacturers seeking NDAs.
2. Creates GDUFA- generic drug user fee act, charges user fee for generics and biosimilars approvals
3. These user fees are intended to speed up the approval process, both PDUFA and GDUFA must be reauthorized every 5 years.
4. Grants FDA to inspect foreign drug manufacturers more regularly and requires agency to target problematic manufacturing sites.

Question 25

21. Drug Quality and Safety Act of 2013 DQSA-

Answer 25

21. Drug Quality and Safety Act of 2013 DQSA- compounding quality act; strengthens FDA oversight over pharmacies engaged in large scale compounding and shipping of sterile products to other licensed entities (think to entities other than patients/end users). Occurred in response to New England Compounding pharmacy and outbreak of fungal meningitis.

1. Creates designation of “outsourcing facilities”- entities that compounding sterile products may voluntarily register with the FDA and must comply with current good manufacturing practices (CGMP)
2. Adds track and trace requirements for all entities in the chain of distribution of pharmaceutical products

Question 26

22. 21^st Century Cures Act:

Answer 26

21^st Century Cures Act: created new clinical trial designs option and by accelerating approval pathways for drugs intended to treat certain life threatening or serious diseases.

Question 27

21. FDA Reauthorization Act of 2017:

Answer 27

FDA Reauthorization Act of 2017: reauthorizes PDUFA, GDUFA; creates a new category of OTC- hearing aids.

Question 28

food

Answer 28

The term “food” means: (1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article.

Question 29

drug

Answer 29

The term “drug” means- (A) articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any articles specified in clause (A), (B) or (C).

Question 30

counterfeit drug

Answer 30

a drug which, or the container or labeling of which, without authorization, bears the trademark, trade name, or other identifying mark, imprint, or device, or any likeness thereof, of a drug manufacturer, processor, packer, or distributor other than the person or persons who in fact manufactured, processed, packed, or distributed such drug and which thereby falsely purports or is represented to be the product of or to have been packed or distributed by, such other drug manufacturer, processor, packer, or distributor.

Question 31

device

Answer 31

means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is (1) recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, (2) 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 (3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its principal 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 principal intended purposes.

Question 32

cosmetic

Answer 32

means (1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles; except that such term shall not include soap.

Question 33

dietary supplement

Answer 33

(1) means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin; (B) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E);
(2) means a product that - (A)(i) is intended for ingestion in a form described in section 411(c)(1)(B)(i); or (ii) complies with section 411(c)(1)(B)(ii); (B) is not represented for use as a conventional food or as a sole item of a meal or the diet; and (C) is labeled as a dietary supplement; and
(3) does -(A) include an article that is approved as a new drug under section 505, certified as an antibiotic under section 507, or licensed as a biologic under section 351 of the Public Health Service Act (42 U.S.C. 262) and was, prior to such approval, certification, or license, marketed as a dietary supplement or as a food unless the Secretary has issued a regulation, after notice and comment, finding that the article, when used as or in a dietary supplement under the conditions of use and dosages set forth in the labeling for such dietary supplement, is unlawful under section 402(f); and (B) not include - (i) an article that is approved as a new drug under section 505, certified as an antibiotic under section 507, or licensed as a biologic under section 351 of the Public Health Service Act (42 U.S.C. 262), or (ii) an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food unless the Secretary, in the Secretary’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this Act. Except for purposes of section 201(g), a dietary supplement shall be deemed to be a food within the meaning of this Act.

Question 34

label

Answer 34

means a display of written printed or graphic matter upon the immediate contain of any article; and a requirement made by or under authority of this Act that any word, statement, or other information appearing on the label shall not be considered to be complied with unless such word, statement, or other information also appears on the outside container or wrapper, if any there be of the retail package of such article or is easily legible through the outside container or wrapper

a. This information is required on the container or wrapper.

Question 35

labeling

Answer 35

means any and all labels and other written, printed or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.

1. This information includes the label, it also applies to the information accompanying the article. Ex: package insert
2. If information accompanies (comes with the item) its labeling, if not, its advertising.
3. Are written materials part of an integrated distribution program, have a common origin and destination, and explain the drug.

Question 36

When is a product a drug?

Answer 36

1. Did supplier make a health or therapeutic claim or a structure/function claim? Was the article intended to diagnosis, cure, mitigate, treat, or prevent a disease or was it intended to affect the body structure or function?
2. Manufacturer/supplier’s intended use is key not the purchaser’s intent- mere use of an article for therapeutic purposes by purchasers, where supplier doesn’t intend the product to be used therapeutically or makes no therapeutic claims, doesn’t make the article a drug.

Look to the packaging of the article for therapeutic claims as well as advertising and marketing of the article- think of some TV commercials

Question 37

Food v. drug

Answer 37

1. Proliferation of dietary supplements, organic foods, etc.
2. Two categories of food: “special dietary foods” and “medical food”
3. Nutraceuticals and functional foods: some believe the FDA should recognize additional classifications of food products called nutraceutical and functional foods. This would include foods that provide health or medical benefits including the prevention and treatment of disease.
4. Health claims for foods-

Question 38

Proliferation of dietary supplements, organic foods, etc

Answer 38

1. Proliferation of dietary supplements, organic foods, etc
   * a. Nutrilab, Inc. v. Schweiker, 713 F.2d 335 (7^th Cir 1983). Question- is a weight reduction product labeled as a “starch blocker” a food or a drug? Plaintiffs argued food- derived from kidney beans. Court held no- people eat food for taste, aroma, or nutritive value.

Question 39

2. Two categories of food: “special dietary foods” and “medical food”

Answer 39

1. Special dietary food: those supplying a special dietary need that exists by reason of a physical, psychological, physiological, pathological, or other condition, including but not limited to the condition of disease, convalescence, pregnancy, lactation, infancy, allegoric hypersensitivity to food, underweight, overweight or the need to control the intake of sodium (21 U.S.C. § 411(3)(A)). Ex: artificial sweeteners, and caloric supplements.
2. Medical foods: include foods formulated for oral use under the supervision of a physician and that are intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements are established by medical evaluation (21 U.S.C. § 360(ee)). Ex: foods formulated without the amino acide phenylalanine for phenylketonuria and folic acid, B₆, or B₁₂ combination products for hyperhomocysteinemia.

Question 40

3. Nutraceuticals and functional foods

Answer 40

3. Nutraceuticals and functional foods: some believe the FDA should recognize additional classifications of food products called nutraceutical and functional foods. This would include foods that provide health or medical benefits including the prevention and treatment of disease.
4. Functional foods- foods that have been enhanced or fortified, often with a dietary supplement, like drinks with kava kava added or foods fortified with calcium, or yogurt with probiotics.

Question 41

4. Health claims for foods-

Answer 41

Health claims for foods- food manufacturers make health claims for foods (think of current television adds for common foods…) See hand out- Cheerios 2009

Question 42

Dietary supplements vs. drugs

Answer 42

To clarify the Nutritional Labeling and Education Act (1990), Congress passed Dietary Supplement Health and Education Act (1994) (DSHEA). – legally created the category of dietary supplement as a separate class of product.

1. FDA regulates dietary supplements more as a special type of food than a drug.
2. Does not require premarket approval
3. Manufacturer is responsible for determining if the product is safe and claims about the product are substantiated by adequate evidence. – but manufacturer doesn’t have to provide the substantiating evidence to the FDA.
   
   1. FDA has to prove an item is unsafe before it can remove an article from the market.
4. Key definitional components- a product intended for ingestion, intended to supplement the diet and contains any one of the following:
5. Vitamin, mineral, herb or other botanical, amino acid, a dietary substance of use by humans to supplement the diet by increasing the total dietary intake, or a concentrate, metabolite, constituent, extract, or combination of the previous.
6. Implications for pharmacists
7. Role- to provide accurate information to patients and assisting them in selecting products. Must present an informed and balanced view
   
   1. Using expertise and research

Question 43

Nutritional support- structure/function statements

Answer 43

1. FDA allows dietary supplement suppliers to make four types of statements
2. Health or disease claims
3. Dietary supplements containing drugs
4. Nonprescription drugs and dietary supplements
5. Drug v. Device- Medical Device Amendment
6. Drug v. Cosmetic
7. Official compendia

Question 44

1. FDA allows dietary supplement suppliers

Answer 44

1. FDA allows dietary supplement suppliers to make four types of statements, IF the seller has substantiation that they are truthful, and not misleading, and the label of the product contains the disclaimer “THIS STATEMENT HAS NOT BE EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE:
   
   1. That the product will benefit a classical nutritional deficiency disease as long as it also discloses the prevalence of the disease in the US
   2. That describe the role of the dietary supplement in affecting the structure or function of the body
   3. That characterize the documented mechanism by which a nutrient or dietary supplement acts to maintain structure or function
   4. That describe the general well-being from consumption of a nutrient or dietary ingredient (energizer, relaxant, muscle enhancement).
      
      1. Ex: promote cranberry tablets that increase the acidity of urine and help maintain a health urinary tract. But, if seller claims product prevents urinary tract infections then the product could be consider a drug.

Question 45

2. Health or disease claims-

Answer 45

2. Health or disease claims- the DSHEA-does not allow manufacturers to make unapproved health (disease) claims that fall under part B of the drug definition. Allows two types of health claims:
3. Unqualified- allowed if authorized by the agency pursuant to the significant scientific agreement test.
4. Qualified claims may be made when the claim does not meet the significant scientific agreement test and the claim would be misleading without the qualification. Allowed when there is more evidence for the claim than against it, and the claim must be truthful and not misleading and appropriate indicate the level of scientific support.
   
   1. Pearson v. Shalala, 164 F.3d 650 (1999)- 4 dietary supplement manufacturers, who had their health claims rejected by FDA, successfully argued that requiring pre-market approval of health claims violates 1^st Amendment and that FDA lacked sufficient criteria for explaining why a health claim does not meet the significant scientific agreement standard. SCOTUS agreed and instructed FDA to articulate clear standards as to what constitutes significant scientific agreement.
   2. This standard derives from 21 U.S.C. 343 (r)(3)(B)(i), which provides that FDA shall authorize a health claim to be used on conventional foods if the agency “determines based on the totality of the publicly available evidence (including evidence from well-designed studies conducted in a manner which is consistent with generally recognized scientific procedures and principles), that there is significant scientific agreement among experts qualified by scientific training and experience to evaluate such claims, that the claim is supported by such evidence

Question 46

3. Dietary supplements containing drugs

Answer 46

3. Dietary supplements containing drugs
4. What if a product contains dietary supplement and compound that was approved as a new drug?
   
   1. Ex: Cholestin, FDA decided it was a drug, Pharmanex v. Shalala- challenged decision that the product containing red yeast rice was a dietary supplement. Court upheld FDA’s decision since the product contain significant amounts of lovastatin, a drug approved in 1987 for lowering cholesterol. Moreover, Pharmanex included high levels of lovastatin not found in traditional red yeast rice.
5. Dietary Supplement and Nonprescription Drug Consumer Protection Act (2006)- ephedrine alkaloid dietary supplement products prompted Congress to enact adverse event reporting requirements for dietary supplement manufacturers.

Question 47

4. Nonprescription drugs and dietary supplements

Answer 47

4. Nonprescription drugs and dietary supplements- manufacturers, packers, or distributors whose name appears on the label must submit to Secretary of DHHS (through MedWatch Program), any report of a serious adverse event within 15 business days.
5. Also must submit any subsequent medical information received within 1 year of initial reported event.

Question 48

5. Drug v. Device- Medical Device Amendment

Answer 48

5. Drug v. Device- Medical Device Amendment – differentiates devices from drugs- a device does not achieve any of its principal intended purposes through chemical action and is not dependent on being metabolized for the achievement of any of its principal intended purposes.
6. Is the product intended to deliver drugs to the patient, but is not prefilled by the manufacturer? (ex: empty implantable infusion pump)
7. Is the drug component included only to make the drug safer (surgical drape impregnated with antimicrobial agents)?
8. Is the drug component intended to have a therapeutic effect (intrauterine contraceptive device that releases hormone)?

Question 49

6. Drug v. Cosmetic-

Answer 49

6. Drug v. Cosmetic- cosmetic may be a drug if the manufacturer promotes it for a therapeutic purpose despite the product chemistry. Ex: don’t say it gives a facelift without surgery.

Question 50

7. Official compendia

Answer 50

7. Official compendia
8. USP- Published by United States Pharmacopeial Convention, an independent, private organization founded by physicians and pharmacists. Elected experts to public the USP.
9. HPUS- established by the Homeopathic Pharmacopoeia Convention of the United States, private nonprofit organization of experts in homeopathy.

Question 51

Prohibited Acts, Penalties and Enforcement

Answer 51

1. Prohibited Acts- Two major prohibitions: adulteration and misbranding
2. Specific prohibitions:
3. Enforcement by FDA
4. Adulteration
5. GMP
6. Misbranding

Question 52

1. Prohibited Acts- Two major prohibitions: adulteration and misbranding

Answer 52

1. Prohibited Acts- Two major prohibitions: adulteration and misbranding
   
   1. Strict liability- liable regardless of intention or knowledge
   2. 21 U.S.C. §301(i)(3) illegal for pharmacist to make, dispense, or hold for dispensing a counterfeit drug- this includes dispensing a placebo or dispensing a drug labeled as another drug
   3. 21 U.S.C. §301(k)- for pharmacists who re-package or relabel drugs, either prescription or OTC, the new label must confirm to FDA specifications, or constitutes misbranding.

Question 53

2. Specific prohibitions:

Answer 53

2. Specific prohibitions:
3. The introduction, delivery, sale, receipt, or offer of delivery into interstate commerce of any food, drug, device, or cosmetic that is adulterated or misbranded.
4. Adulteration or misbranding of food, drugs, device or cosmetic
5. Refusal to permit access to or copying of records as required or the failure to establish or maintain records or reports
6. Refusal to permit entry or inspection
7. To manufacture food, drug, device, or cosmetic that is adulterated or misbranded.
8. Doing any act that causes a drug to be a counterfeit drug, or the sale or dispensing, or the holding for sale or dispensing of a counterfeit drug
9. Altering, mutilating, destroying, obliterating, removing, the whole or part of the labeling of a food, drug, device or cosmetic, if done during the sale (whether or not the first sale) after shipment in interstate commerce and results in the article being adulterated or misbranded.
10. Introducing or delivering into interstate commerce, a dietary supplement that is unsafe under section 413.
11. Penalty- up to 1 year imprisionment, and/or $1,000 fine; second offense or intent to defraud or mislead- up to 3 years and $10,000.

Question 54

3. Enforcement by FDA

Answer 54

3. Enforcement by FDA (and corporate officers can be convicted if other corporate employees violate FDCA- THIS IS CALLED PARK DOCTRINE)
4. Injunction- cause a violator to stop its illegal activity
5. Criminal proceedings- jail time and/or fines
6. Seize adulterated or misbranded food, drugs, cosmetics
7. Send warning letters
8. Corporate officer liability- officers can be convicted when their employees violate FDCA- without proof they acted intentionally or with negligence and even if they had no knowledge of the offense.
9. Product Recalls- FDA has authority or manufacturer can voluntarily recall; manufacturer responsible for contacting consumers. PHARMACIST responsible for knowing which drug products have been recalled. Pharm publications often list; available on FDA site: http://www.fda.gov/Drugs/drugsafety/DrugRecalls/default.htm
   
   1. Class I recall- reasonable probability that the product will cause serious, adverse health consequences or death
   2. Class II recall- product may cause temporary or medically reversible adverse health consequences, but the probability of serious adverse consequences is remote
   3. Class III recall- products not likely to cause adverse health consequences.

Question 55

4. Adulteration-

Answer 55

4. Adulteration-
5. Mostly applies to manufacturers, pharmacy may be deemed manufacturer if it repackages or compounds medications for sale; concerned with the facility and means of production rather than the product itself
6. Drug is deemed adulterated if it is:
   
   1. Prepared packed or held in conditions where it may have been contaminated
   2. Exposed to a container that may have contaminated it
   3. Manufactured under conditions that do not conform to current good manufacturing practices (GMP)
   4. Drug is adulterated if its strength, quality, or purity differs from those on the label or from compendia standards if it’s subject to compendia.

Question 56

5. GMP

Answer 56

5. GMP- set of regulations that establishes minimum requirements for the methods, facilities, or controls used in the manufacture, processing, packaging, or holding of a drug product.
6. Applies to manufacturers, not pharmacies, unless the pharmacy engages in activities where they could be deemed manufacturers
7. Manufacturers must be registered with the FDA and are normally inspected EVERY 2 YEARS
8. Confirm that the production and control procedures result in the proper identity, strength, quality and purity of the drugs
9. Identify deficiencies
10. Ensure correction of deficiencies
    
    1. Drugs subject to GMP are selected based on medical importance, market share, number of similar products in the marketplace, and previous compliance record of manufacturer

Question 57

6. Product tampering

Answer 57

6. Product tampering- (intentional contamination of Tylenol in early 80’s) Congress passed Federal Anti-Tampering Act (1982) making it federal offense to tamper with consumer products.
7. Tampering= improper interference with the product for the purpose of making objectionable or unauthorized changes
8. Certain drugs, cosmetics, devices be manufactured in tamper resistant packaging.
   
   1. One having an indicator or barrier to entry, which if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred.
9. Tamper resistant, not tamper proof!

Question 58

6. Product tampering

Answer 58

6. Product tampering- (intentional contamination of Tylenol in early 80’s) Congress passed Federal Anti-Tampering Act (1982) making it federal offense to tamper with consumer products.
7. Tampering= improper interference with the product for the purpose of making objectionable or unauthorized changes
8. Certain drugs, cosmetics, devices be manufactured in tamper resistant packaging.
   
   1. One having an indicator or barrier to entry, which if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred.
9. Tamper resistant, not tamper proof!

Question 59

7. Misbranding-

Answer 59

7. Misbranding- focuses on representations made by the manufacturer’s label or labeling
8. FDA must approve, as part of pre-market approval, the exact wording of a drug’s label and labeling
9. What is misbranded:
   
   1. False or misleading labeling
   2. Labels lacking: NAME and PLACE of business of the manufacturer, packer or distributor, and ACCURATE statement of the QUANTITY of the contents in terms of weight, measure, or numerical count.
   3. Labels of drug lacking: name of drug, the name and quantity (or if determined appropriate, the proportion of each active ingredient, and the established name of each inactive ingredient listed in alphabetical order on the outside container of the retail package for OTC
   4. Lacking: adequate directions for use
   5. Habit forming drug warning- up to manufacturer’s discretion for labeling, but required to describe the habit forming characteristics on the drug in the Drug Abuse and Dependence section of package insert
   6. Established name of drugs- law requires listing of any active ingredients for both prescription and nonprescription drugs and the quantity of each active ingredient. Usually need to include a list of the established name of each inactive ingredient in alphabetical order (unless nonprescription drug is also a cosmetic or not for human use).
   7. Adequate directions for use- labeling must include adequate directions for use and adequate warnings against use by children and others for whom it may be dangerous.
   8. Adequate labeling must include:
      
      1. Quantity or dosage for each intended use and for persons of different ages and physical conditions
      2. Frequency of administration/application
      3. Duration of administration/application
      4. Time of administration/application (in relation to meals, onset of symptoms, or other factors)
      5. Route or method of administration or application
      6. The preparation necessary for use (shaking, dilution, etc.)
      7. Adequate information for use- some drugs can’t be labeled adequately to protect the consumer (prescription drugs) which makes them exempt. Label must include:
      8. Drug’s indications
      9. Side effects
      10. Dosages
      11. Routes, methods, frequency, and duration of administration
      12. Contraindications
      13. Other warnings and precautions that enable a practitioner to administer, prescribe or dispense the drug safely
10. Imitation drugs are considered misbranded

Question 60

Nonprescription drug labeling requirements

Answer 60

1. General Provisions
2. Drug Facts
3. Active ingredient
4. Purpose or Purposes
5. Use or Uses
6. Warning or warnings
7. Includes normal dose for each intended use and doses for individuals of different ages/or physical conditions
8. Frequency and duration of administration or application
9. Administration or application in relation to meals, onset of symptoms, or other time factors
10. Route or method of administration or applications
11. Any required preparation for use (shake well, dilute…)
12. “Other information”, followed by additional information which is required by or is made optional under an applicable OTC drug monograph, other OTC drug regulation, or is included in the labeling of an approved drug application.
13. Required information about certain ingredients in OTC drug products (e.g., sodium, calcium, magnesium, and potassium in § 201.72(b))
14. “Inactive ingredients”, followed by a listing of the established name of each inactive ingredient
15. “Questions?” or “Questions or comments?”, followed by the telephone number of a source to answer questions about the product

Question 61

1. General Provisons

Answer 61

1. Drug must bear the name and place of business of the manufacturer, packer, or distributor.
   
   1. Manufacturer is the person who performs all of the following operations that are required to produce the product: (1) Mixing, (2) granulating, (3) milling, (4) molding, (5) lyophilizing, (6) tableting, (7) encapsulating, (8) coating, (9) sterilizing, and (10) filling sterile, aerosol, or gaseous drugs into dispensing containers.
2. Display panel-

Question 62

2. “Drug Facts”.

Answer 62

2. “Drug Facts”. If the drug facts labeling appears on more than one panel, the title “Drug Facts (continued)” shall appear at the top of each subsequent panel containing such information.

Question 63

3. “Active ingredient” or “Active ingredients”

Answer 63

3. “Active ingredient” or “Active ingredients” “(in each [insert the dosage unit stated in the directions for use (e.g., tablet, 5 mL teaspoonful) followed by the established name of each active ingredient and the quantity of each active ingredient per dosage unit.

Question 64

4.“Purpose” or “Purposes”

Answer 64

4.“Purpose” or “Purposes”, followed by the general pharmacological category(ies) or the principal intended action(s) of the drug or, where the drug consists of more than one ingredient, the general pharmacological categories or the principal intended actions of each active ingredient.

Question 65

5. “Use” or “Uses”

Answer 65

5. “Use” or “Uses”, followed by the indication(s) for the specific drug products

Question 66

6. Warning” or “Warnings”,

Answer 66

6. Warning” or “Warnings”, followed by one or more of the following, if applicable:
7. “For external use only” [in bold type] for topical drug products not intended for ingestion, or “For” (select one of the following, as appropriate: “rectal” or “vaginal”) “use only” [in bold type].
8. All applicable warnings listed in paragraphs (ex: Reyes syndrome, liver or sore throat, etc.) (iii) “Do not use” [in bold type], followed by all contraindications for use with the product. These contraindications are absolute and are intended for situations in which consumers should not use the product unless a prior diagnosis has been established by a doctor or for situations in which certain consumers should not use the product under any circumstances regardless of whether a doctor or health professional is consulted.
9. “Ask a doctor before use if you have” or, for products labeled only for use in children under 12 years of age, “Ask a doctor before use if the child has”, followed by all warnings for persons with certain preexisting conditions (excluding pregnancy) and all warnings for persons experiencing certain symptoms.
10. “Ask a doctor or pharmacist before use if you are” or, for products labeled only for use in children under 12 years of age, “Ask a doctor or pharmacist before use if the child is” [in bold type], followed by all drug-drug and drug-food interaction warnings.
11. “When using this product” followed by the side effects that the consumer may experience, and the substances (e.g., alcohol) or activities (e.g., operating machinery, driving a car, to avoid while using the product.
12. “Stop use and ask a doctor if” followed by any signs of toxicity or other reactions that would necessitate immediately discontinuing use of the product. For all OTC drug products under an approved drug application whose packaging does not include a toll-free number through which consumers can report complaints to the manufacturer or distributor of the drug product, the following text shall immediately follow the subheading: “[Bullet] side effects occur. You may report side effects to FDA at 1-800-FDA-1088.” The telephone number must appear in a minimum 6-point bold letter height or type size
13. Any required warnings in an applicable OTC drug monograph
14. The pregnancy/breast-feeding warning
15. The “Keep out of reach of children” warning and the accidental overdose/ingestion warning

“Directions”, followed by the directions for use described in an applicable OTC drug monograph or approved drug application

Question 67

Non-prescription drug labeling

Answer 67

1. OTC/Non-prescription drugs are those that are safe and effective for self-medication by consumers.
2. Look at image in outline
3. Drugs that are both OTC and RX: DIFFERENCE IS THE INDICATION FOR USE.
   
   1. Ex: meclizine- sold OTC for the indications of nausea, vomiting, and dizziness associated with motion sickness, sold RX for vertigo associated with diseases affecting the vestibular system.
4. Ex: differing strengths of ibuprofen determines OTC vs. RX.

Question 68

Package Insert-

Answer 68

Package Insert- pamphlet that must accompany the drug product and contains the essential scientific and medical information needed for safe and effective use of the drug by health care professionals.

1. Previous format- not user friendly, new regulations established in 2006
2. The new format requires that the prescription information for new drug applications submitted after JUNE 30, 2006, slowly phased in for drugs approved 5 years prior to June 30, 2006.
3. Some of the most significant changes include:
   
   1. a new section called Highlights to provide immediate access to the most important prescribing information about benefits and risks
   2. a Table of Contents for easy reference to detailed safety and efficacy information
   3. the date of initial product approval, making it easier to determine how long a product has been on the market
   4. a toll-free number and Internet reporting information for suspected adverse events, to encourage more widespread reporting of suspected side effects.
4. Items in package insert: a lot of info go to outline
5. Use of drug during pregnancy- look at pregnancy ranking
6. Draft pregnancy guidance:
7. Pregnancy exposure registry- if a registry is established for drug
8. Risk summary- statements that describe the risk of adverse developmental outcomes based on relevant human, animal data and drug’s pharmacology
9. Clinical considerations
10. Disease associated maternal or embryo/fetal risk
    
    • Dose adjustment during pregnancy and post-partum
    • Maternal adverse reactions
    • Fetal neonate adverse reactions
    • Labor or delivery
    • Data- from human and animal studies
    • Patient Counseling Information

Question 69

National Drug Code Number

Answer 69

1. Unique, 10 digit, 3 segment number (NDC): 4-4-2, 5-3-2, 5-4-1
2. First segment: assigned by FDA- identifies MANUFACTURER
3. Second segment: identifies a specific strength, dosage form, and formulation
4. Third segment: identifies package size and types.
5. NDC has 10 digits, billing and claims uses 11 digit- this is accomplished by adding a leading zero-
   
   • Added to the beginning of first segment (if it’s four numbers), added to the beginning of the second segment if it is three numbers) or added to the beginning of the third segment if it only has one number.