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Food and Drug Administration

- Component of the Department of Health and Human Services - led by Commissioner, who is appointed by the President (originally the Secretary), with Senate approval - authority to oversee safety of food, drugs, and cosmetics - is an administrative agency: can make rules - develops regulations based on the FDCA and other laws/amendments - functions: rule making issue guidance documents incorporate advice from standing advisory committees of outside experts

Dietary Supplement Containing a Drug

- DSHEA excludes this as an article as a dietary supplement if it was approved as a drug prior to being marketed as a dietary supplement - Pharmanex established that DS cannot be specifically manufactured to concentrate the natural drug ingredient

DSEHA (Dietary Supplement Health and Education Act of 1994)

- FDA must regulate dietary supplements as food rather than drugs - FDA cannot require pre-market approval for supplements - FDA is required to prove that a dietary supplement is unsafe before removing it from market - permits 4 types of nutritional support claims - claims must be substantial and truthful and not misleading - label must contain a disclaimer

Black Box Warning

- Labeling requirement that FDA may require - A warning for drugs that may lead to death or serious injury - May be required during the NDA review/approval process if risks are known or after approval based on post-market surveillance - Warning of the special problem in the package insert within a prominently displayed

Orphan Drug Act of 1983

- NDA process originally too expensive to warrant development and marketing of drugs for rare diseases - provides incentives for manufacturers to develop and market drugs and biologicals for the treatment of rare diseases/conditions - rare = affecting less than 200K Americans - includes tax and exclusive licensing incentives

Pure Food and Drug Act of 1906

- Prohibited the adulteration and misbranding of foods and drugs in interstate commerce - required drugs to meet standards - misbranding provision only prevented false claims regarding the drug's identify (strength, purity, quality) but not false or misleading efficacy claims - did NOT give FDA authority to ban unsafe drugs

Current Good Manufacturing Practices

- established in the Kefauver-Harris Amendment - ensures the proper design, monitoring, and control of manufacturing processes and facilities - adherence to these regulations assures the identity, strength, quality, and purity of drug products by requiring that drug manufacturers adequately control their operations - manufacturers must be registered with FDA and are inspected once every 2 years - non-compliance with this means drug is adulterated in which there is a recall, seizure of drug products, or litigation between manufacturer and FDA

Durham-Humphrey Amendment of 1951

- established two drug classes: Rx and OTC - amended the FDCA to say that only OTC drugs need to contain "adequate directions for use" since it is up to MD for Rx drugs - instead, Rx drugs must say "caution: federal law prohibits dispensing without a prescription" - allowed verbal prescriptions and refills over phone

Prescription Drug Marketing Act of 1987

- establishes requirements for Rx drug sample distributions - prohibits re-sale of pharmaceuticals by hospitals/other healthcare entities - requires state licensing of drug wholesalers

Generic Drug Enforcement Act of 1992

- felony to make false statement, bribe, fail to disclose material-related facts, etc. - due to FDA employees accepting bribes from generic drug companies

FDAAA (Food and Drug Administration Amendments Act of 2007)

- gave FDA enhanced authority to regulate drug safety - required REMS when necessary - FDA can make label changes related to safety - FDA has authority to require a drug product sponsor to establish procedures directed at patient safety

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

- goal: streamline generic drug approval process with some patent extensions to innovator drugs - intent: to make generic drugs more readily available to the public while providing incentives to manufacturers to develop new drugs - allowed for greater generic competition - created automatic approval for generic drugs by eliminating submission to FDA

Food, Drug, and Cosmetic Act of 1938

- no new drug can be approved until proven safe for use under the conditions of the label and approved by the FDA - as a response of sulfanilamide - expanded on definitions of misbranding and adulteration - required that labels must contain adequate directions for use and warning of habit-forming properties if applicable - includes cosmetics AND devices

FDA Safety and Innovation Act of 2012

- reauthorizes PDUFA (NDA requirements) - basically the PDUFA was going to expire in 2012, so this just reinforced it - but also adds user fees for generic drugs and biosimilars in order to speed the generic and biosimilar approval process

Prescription Drug User Fee Act of 1992

- requires manufacturer seeking NDAs to pay fees for their application - fees funding FDA to hire more reviewers, which also decreased NDA approval time - due to idea that private party should pay for the costs of an NDA, not the taxpayers

Kefauver-Harris Amendment of 1962

- response to thalidomide birth defects - required drugs not only be proven safe, but effective - established cGMP (good manufacturing practices) - required informed consent in clinical trials and the reporting of adverse effects - only affected drugs after 1938 (FDCA)

21st Century Cures Act of 2016

- streamlines and adds flexibility to the drug development and approval process - allows for more patient experience data during the process

Safe Medical Devices Act of 1990

- strengthens Medical Device Amendment of 1976 - gives FDA additional authority over post-marketing requirements of med devices - expedited pre-market device approval process

Medical Device Amendment of 1976

- under FDCA 1938, FDA had no authority to review med devices for safety and efficacy - this provide more extensive regulation and administrative authority regarding the safety and efficacy of med devices

Food and Drug Administration Modernization Act of 1997

- was passed to streamline regulatory procedures - expedited the availability of drugs and devices - created a fast-track process for drugs intended for serious or life-threatening illnesses - established ingredient-labeling requirements for inactive ingredients of OTC drugs

Label

A display of written, printed, or graphic matter: - upon the immediate container of any article (on the outside container or wrapper) - approved by the FDA - is a narrow term - controlled substances must have a "c" on this with their corresponding class since they are federally regulated

Misbranding

A drug is considered this if: - label or labeling is false or misleading - label or labeling does not include required elements - required label or labeling is not prominently displayed - an imitation of another drug (same shape, size, color, similar or almost identical in gross appearance, similar to effect in controlled substance) - its packaging does not conform to Poison Prevention Packaging Act 1970

Dietary Supplement

A product, other than tobacco, intended to enhance the diet that bears or contains one or more of the following dietary ingredients: - vitamins - minerals - amino acids - herbs - and/or other botanicals - dietary supplement for use by man to supplement the diet by increasing total dietary intake - concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E) - its manufacturers can only make a health claim if FDA approves the claim by regulation or by signifiant scientific agreement test (if not: disclaimer via Pearson vs. Shalala)

Drug

A) Article recognized by USP, Homeopathic Pharmacopeia of the US, or NF B) intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease C) intended to affect structure or function of human body/animals - if therapeutic or structure/function claim is being made, regardless of disclaimers made on the labeling

Federal Anti-Tampering Act

Act in response to Tylenol contamination - requires certain OTC drugs, devices, and cosmetics be manufactured in tamper-evident packaging: visible evidence to a consumer that tampering occurred - DOES NOT NEED TAMPER PROOF PACKAGING - made it a federal offense to tamper with consumer products

Labeling

All labels and other written, printed, or graphic matter upon any article or any of its containers or wrappers, or accompanying such article - sometimes manufacturers argue it's advertising, but FDA can say it is labeling if it is on the drug container

-Prescription (legend) and OTC (non-legend) -federal law prohibits dispensing w/o a prescription" -verbal prescriptions --- refills

Amendments Durham-Humphrey 1951 - The Durham-Humphrey Amendment established what 2 classes of drugs? -the FD&C Act of 1938 provided that prescription drug products labels need not contain adequate directions for use as long as they contain "caution: __________________________" - Allowed _____________ over phone and __________ called in from physician's office

Device

An instrument, apparatus, implant, machine, implement, or other related article that is: - recognized by USP/NF - intended for diagnosis, cure, treatment or prevention - intended to affect structure of human body - which does not achieve its primary intended purpose by chemical action and not dependent on metabolism to achieve its primary intended purpose (so not a food or drug)

Cosmetic

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 appearance, and intended for use as a component of any such articles; except that term shall not include soap - but if it states it affects structure/function: is a drug - follows the "ignorant, unthinking consumer" standard

Food

Articles used for food or drink for man or other animals, chewing gum, and articles used for components of any such article - can be considered a drug if it makes a therapeutic or health claim under part B of drug definition - excluded from Part C of drug definition

Drug Quality and Security Act of 2013

Compounding Quality Act - response to NECC meningitis outbreak - entities compounding sterile products may voluntarily register with the FDA and must comply with cGMP - established track and trace requirements for outsourcing facilities, a new sterile compounding entity

"Ignorant, unthinking consumer"

Cosmetics: -What is the standard of person that must understand cosmetic

-if the seller makes a health or structure/function claim -YES -YES

Cosmetics: -When can a cosmetic become a drug? -Can a product be a cosmetic and a drug? -Can a cosmetics be misbranded or adulterated?

-premarket approval --- CGMP -safety -misbranded --- adulterated --- health hazard -descending order of predominance --- warning

Cosmetics: Do cosmetics have the same approval process as drugs? -No premarket approval, nor conformance with CGMP -Manufacturers must substantiate product safety. -The FDA may remove if misbranded, adulterated, or a health hazard. -Must be labeled with list of ingredients in _________________ and appropriated ______________

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

Cosmetics: What 2 things define Cosmetics?

Hair dyes that contain coal tar

Cosmetics: What type of cosmetics are EXEMPT from the adulteration and color additive provisions of the law?

Pearson vs. Shalala

Court held that under first amendment FDA may not ban health claims simply because scientific literature is inconclusive - stated DS manufacturers could make health claims not approved by FDA, provided they are not false or misleading and contain a disclaimer

Nutritional Claims

DSHEA of 1994 allows dietary supplements to make 4 types of these: - benefitting a classical nutrient deficiency disease - role in dietary supplements affecting structure/function of body - characterizing mechanism by which a dietary supplement maintains structure/function - statements of general well-being

-USP/NF -diagnosis --- cure --- treatment --- prevention -structure -chemical --- metabolism

Device: a "device" is an instrument, apparatus, implement, machine, implant or other related article which is: -Recognized in the _________________ -Intended for ___________, ________, __________, or ________; or -Intended to affect the ______________ of human or animal body, and -which does not achieve its primary intended purpose by ______________ action and is not dependent on ______________ to achieve its primary intended purpose.

Adequate Directions for Use

Directions under which the layman can use a drug safely and for the purposes for which it is intended - OTC drugs Must include: - quantity or dosage for each intended use and for persons of different ages and physical conditions - frequency of administration or application - duration of use - time of administration or use - route of administration - necessary preparation instructions (e.g. shake well) reminder: D-H Amendment excluded Rx drugs from this

-generic drugs --- innovator drug products -submission to FDA -competition --- readily available -new drugs

Drug Price Competition and Patent Term Restoration Act of 1984 (a.k.a. Waxman-Hatch Amendment) - The Waxman-Hatch Amendment of 1984 facilitated the approval process of _____________ while affording patent extensions to _____________ products. - It created automatic approval for generic drugs by eliminating ___________________ - The Amendment allowed for greater generic _____________ and allowed generic drugs to be ore ____________ to public - Also provided incentives for manufacturer to develop ____________

Adulteration

Drug is deemed this if: - prepared, packaged, or held in conditions where it may have been contaminated - exposed to a container that may have contaminated it - manufactured under conditions that do not conform with cGMP - all of these say "MAY" because these are to regulate the facility/means of production rather than the product - contains unsafe color additive - strength, quality, or purity differs from those stated on the label

National Drug Code Number

Drug products are identified and reported using a unique 10-digit, 3-segment number - 1st segment: assigned by FDA and identifies the manufacturer or distributer - 2nd segment: identifies specific dosage form, strength, and formulation of a particular firm - 3rd segment: identifies package size and type - for Rx and OTC drugs - labeler, product code, package code - 4-4-2 - does NOT mean that the drug's NDA was approved

ASK ABOUT THIS

Drug vs Device FDA has stated many factors may determine whether a product is a drug or a device: -Is the product intended to deliver drugs to the patient, but is not prefilled by the manufacturer (e.g. empty implantable infusion pumps)? -Is the drug component included solely to make the product safer (e.g. surgical drape impregnated with antimicrobial agents)? -Is the drug component intended to have a therapeutic effect (e.g. intrauterine contraceptive device that releases a hormone?

(A) recognized by United States Pharmacopoeia (USP), official Homoeopathic Pharmacopoeia of the United States, or official National Formulary (NF) (B) intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease (C) (Non-food) intended to affect structure or function of human body/animals (D) intended for use as a component of A, B, or C above

Drugs: What 4 things define a drug?

-amendments of this act -Sulfanilamide elixir tragedy of 1937 -safe (not efficacious) --- FDA -adequate direction for use ---habit-forming properties

FD&C Act 1938 -All laws/amendments described after this act are __________________ - Prompted by the _________________ - No New Drug can be approved until proven _________ for use under the conditions described on the label and approved by the _________ (drugs that come after law was enacted are considered New Drug. Anything before this did not need to be proven safe before going to market) - Expanded definitions of misbranding and adulteration --> Required that labels must contain __________________ and warning about the __________________ of certain drugs

-habit forming -Drug Abuse and Dependence section of the package insert

Food and Drug Administration Modernization Act (FDAMA) of 1997 -This act made it discretionary to include ______(1)_______ warning on label -however, the manufacturer must still adequately describe the ______(1)_______ characteristics of the drug in the "_____________________________"

Drug vs. Device

Factors that differentiate the two: - product is intended to deliver drugs to the patient - but is not pre-filled by manufacturer - drug component included solely to make the products safer - drug component intended to have therapeutic effect The definition of a device excludes articles that achieve their purpose through chemical action and metabolism Drugs and Devices are approved via FDA, so FDA can help them determine if a drug vs. device

-phase IV clinical trials -safety information --- warnings postmarket -website

Food and Drug Administration Amendments Act (FDAAA) of 2007 -The FDAAA empowered the FDA to require manufacturers to conduct _____________________ when adverse event reporting or active surveillance is inadequate. Post marketing labeling: The FDAAA gave the FDA the authority to require manufacturers to add _______________ or ________________. The FDAAA required the FDA to develop and maintain a _____________ for patients and providers including labeling, safety information, REMS, guidance documents, etc.

-Sentinel Initiative -REMS (Risk Evaluation and Mitigation Strategies) -Medwatch number --- side effects

Food and Drug Administration Amendments Act (FDAAA) of 2007 The FDAAA also established "_____________" designed to detect early signs of a drug's risk. The FDAAA granted the FDA authority to require _____(1)______ as a condition for approval of an NDA or postmarket when the FDA believes it necessary to ensure benefits outweigh risks. Under _____(1)______ authority, the FDA can require a variety of procedures ranging from Medication Guides to limiting the drug to specified settings for dispensing. -The FDAAA requires pharmacies to provide patients with the _____________ and a statement about reporting _____________

(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.

Food: What 3 things define Food?

New Labeling

For drugs approved on or after June 30, 2015: - replaces former "letter category" risk levels - must include pregnancy, lactation, and reproductive subsection for males and females including pregnancy testing, contraception, and infertility as related to the drug - lactation section must include drug in breastmilk and potential effects to child

Unqualified Health Claim

Health claims that do not require a disclaimer - are allowed because the dietary supplement meets the significant scientific agreement test

Qualified Health Claim

Health claims that require a disclaimer - in response to Pearson - may be made when the claim does not meet the significant scientific agreement test and the claim would be misleading without the qualification - are only allowed when there is more evidence for the claim than against it - must be truthful and not misleading - must appropriately indicate the level of scientific support (ex. "scientific evidence suggests but does not prove")

HPUS

Homeopathic Pharmacopeia of the United States - defines homeopathy as the "art and science of healing the sick by using substances capable of causing the same sxs, syndromes, and conditions when administered to healthy people" - publishes standards for homeopathy products by a private organization

Tampering

Improper interference with the product for the purpose of making objectionable or unauthorized changes

-efficacy -1938

Kefauver-Harris 1962 -This amendment added the _________ requirement for drug products, which was made retroactive to 1938 -Drug products marketed prior to _______ remained exempted.

-effective --- safe -1938 -ANDA (Abbreviate New Drug Application) -bioequivalence --- manufacturing methods --- safety --- efficacy -generic drugs

Kefauver-Harris 1962 - Drug Efficacy Study Implementation (DESI) -Implemented in 1968 in response to 1962 Kefauver-Harris Amendment that required all drugs be ____________ and ____________. -The efficacy requirement was applied retroactively to all drugs marketed after __________ (innovator and generics). -Making the requirement retroactive for innovator and generics burdened the FDA. Several thousand drugs had been marketed between 1938-1962. -The FDA created the ____(1)_____ for generic drugs approved between 1938 and 1962. -The ____(1)_____ only requires evidence of ______________ and _________________ rather than proof of __________ and __________. -The U.S. Supreme Court ruled that _____________- are new drugs and subject to FDA approval.

Pregnancy

Labeling requirements require info regarding this and lactation; Classes A, B, C, D, and X

Official Compendia

Legal sources of drug standards; includes: - US Pharmacopeia-National Formulary (USP-NF) - Homeopathic Pharmacopeia of US (HPUS) - under the FDCA, drugs recognized under these must meet ALL compendium standards or else it would be considered misbranded or adulterated

Non-Prescription Drug Labeling

OTC label must have the following prominently displayed: - identity, including established name - name and address of manufacturer, packer, and distributer - cautions and warnings to protect consumer - adequate directions for use - drugs panel fact, which includes: - active ingredients, including dosage unit and quantity per unit - purpose - uses - directions - inactive ingredients (alphabetical order) - telephone Number for Consumer Questions

Recall

Occurs voluntarily by manufacturer, or via FDA request, or via FDA mandate - FDA has limited authority to do this to certain products such as medical devices, biological products, and foods, but not drugs - seizure or injunction action if FDA request for recall is ignored - a method of removing misbranded and/or adulterated products from the market to protect the public - FDA possesses mandatory authority to do this only with regard to four products: infant formula, medical devices, biologic products, and tobacco products - divided into 3 classes - manufacturer is in charge of notifying the seller of this

Controlled Substance

On the label of this, there must be a "c" with the corresponding class since this is federally regulated and is a REQUIREMENT to have on the label of this type of drug

Tamper-Evident Packaging

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 DOES NOT MEAN TAMPER PROOF PACKAGING

Package Insert

Pamphlet that must accompany drug product and contains essential scientific and medical info needed for safe and effective use of the drug by healthcare professionals - intended to be read by healthcare professionals - changes NDA: - reorganizes information to make it easily accessible, and less complex - table of contents - patient counseling section - newest update: must contain a highlight section - online access FDA - this new design is only applicable to drugs whose NDAs were submitted after 6/30/06, and will gradually apply to those submitted 5 years before 6/30/06 - must include info about drug during pregnancy and lactation

Class A

Pregnancy class in which adequate and well-controlled studies in pregnant women have NOT demonstrated a risk to the fetus

Class B

Pregnancy class in which animal studies have failed to demonstrate a risk to the fetus - statement must be included providing that the drug should be used in pregnancy "only if clearly needed"

Class C

Pregnancy class in which animal studies have shown an adverse effect on the fetus or there are no animal reproductive studies - and there are no adequate well-controlled studies in pregnant women - statement must be included that drug should be used in pregnancy "only if the potential benefit justifies the potential risk to the fetus"

Class D

Pregnancy class in which has positive evidence of fetal risk however potential benefits may outweigh potential risks - statement must be included in Warnings and Precautions section that the drug can cause fetal harm

Class X

Pregnancy class in which studies in animals or humans have demonstrated fetal risk and that risk in pregnant women clearly outweigh any benefits - must include statement that says "may cause fetal harm when administered to a pregnant woman"

Adequate Information for Use

Prescription drugs are intended to be administered under the supervision of medical practitioners and are exempt from "adequate direction for use" requirement Instead, they must include: - Indications, including all purposes for which it is advertised or represented - Side effects - Dosages - Routes, methods, and frequency and duration of administration - Other warning/precautions required to administer, prescribe, dispense the drug safely

-adulteration --- misbranding -USP/NF standards -drug identity (strength, quality, and purity) --- efficacy -unsafe drugs -cosmetic --- devices

Pure Food and Drug 1906 - Prohibited the ____________ and ____________ of foods and drugs in interstate commerce - Required drugs to meet _______________ - Misbranding provision only prevented false claims regarding the _________________ but NOT false or misleading ___________ claims. - Did not give the FDA authority to ban ___________ - Law failed to regulate ____________ or __________

REMS

Risk Evaluation and Mitigation Strategy - created via the FDAAA in 2007 - intended to manage known or potential serious risks of product

Unit Dose Packaging

Single dosage unit for direct administration used by hospitals and other institutions FDA Compliance document list the required label elements for the unit dose container* (solid or liquid dosage forms). Generally they include: - established drug name of drug - quantity of active ingredient per dosage unit - expiration date - lot or control # - name and address of manufacturer, packer, and distributor *The guidance contains additional requirements for more than one dosage unit per unit dose container and requirements for the outer package: - the number of dosage units contained, if more than one dosage, and the strength per dosage unit - the controlled substance symbol if required by the DEA - the statement "May be Habit Forming" where applicable* - Food and Drug Administration Modernization Act (FDAMA) of 1997 made it discretionary to include habit forming warning on label; however, the manufacturer must still adequately describe the habit-forming characteristics of the drug in the "Drug Abuse and Dependence section of the package insert

Food

The FDA must regulate dietary supplements as this rather than drugs

Federal Drug Regulation

The rationale for why drugs are monitored by the government (FDA) is for protection of the public against adulterated and misbranded drug products

Guidance Documents

These, which are created by the FDA, are neither legally binding nor legally enforceable - to not follow could lead to FDA investigation

Commercial Container Label

This is the container the manufacturer sends to the pharmacy and must have the following prominently displayed: - name and address of manufacturer, packer, and distributor - established name of drug product - active ingredients, including quantity and proportion of each - inactive Ingredient Name(s) (w/ some exception) if not oral - statement of identity (generic and proprietary names) - statement of recommended or usual dosage or reference to package insert - quantity- Weight and Measure (e.g. 75mg) - quantity- Container (e.g. #100 capsules) - route of administration (except if oral) - lot or control # - expiration date (unless exempted) - "Rx" only or Caution: "Federal law prohibits dispensing without a prescription" - direction to RPh regarding container type for dispensing (e.g. "light resistance bottle")

Class 3

Type or recall in which the product is not likely to cause adverse health consequences

Class 2

Type or recall in which the product may cause temporary or medically reversible adverse health consequences, but the probability of serious adverse events is remote

Class 1

Type or recall in which there is a reasonable probability that the product will cause serious adverse health consequences or death

2

Under cGMP, the number of years in which a manufacturer registered with the FDA is inspected

USP-NF

United States Pharmacopeia/National Formulary - independent private organization founded by physicians and pharmacists in 1820 - independent of the FDA - contains monographs of active and inactive ingredients

2

What is the order of the acts/laws (look at pic)? (answer 2)