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Sept. 5, 2012

Chapter 2 a.

Federal Regulation of Medications: Development, Production, and Marketing

Pages 39-68

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History of Major Legislation(Not Including Controlled Substance Laws)

• Pure Food & Drug Act 1906• Food, Drug, and Cosmetic Act 1938 – Sulfanilamide; Safe, Misbranding/Adulteration; • Durham-Humphrey Amendment 1951- Rx/Otc; Oral Rxs; Refills• Food Additives Amendment 1958• Color Additive Amendments 1960• Kefauver-Harris Amendment 1962 – Thalidomide; Safe AND effective• Medical Device Amendments 1976 –Dalkon Shield• Orphan Drug Act 1983• Drug Price Competition Act 1984• Prescription Drug Marketing Act 1987• Safe Medical Devices Act 1990• Generic Drug Enforcement Act 1992• Prescription Drug User Fee Act 1992• Nutrition Labeling & Education Act 1990• Dietary Supplement Health & Education Act 1994; Reduced FDA authoride (food vs. drug)• Food & Drug Administration Modernization Act 1997• Food & Drug Administration Amendments Act 2007• Food & Drug Administration Safety and Innovation Act of 2012

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Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012

• The Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on July 9, 2012, gives FDA the authority to collect user fees from industry to fund reviews of innovator drugs, medical devices, generic drugs and biosimilar biologics. It also reauthorizes two programs that encourage pediatric drug development.

• "Support for FDA user fees is a testament to the important role FDA plays in America’s healthcare continuum. FDA’s medical product decisions sit at the intersection of public health, innovation, and commerce and touch the lives of nearly every American every day," said FDA Commissioner Margaret A. Hamburg, M.D.

• This is the fifth reauthorization of the Prescription Drug User Fee Act or PDUFA, first enacted in 1992, and the third reauthorization of the Medical Device User Fee Act, or MDUFA, first enacted in 2002. Both programs have provided steady and reliable funding to maintain and support a staff of trained reviewers who must determine whether a proposed new product is safe and effective for patients and do so within a certain time period. The new user fee programs for generic drugs and biosimilar biologics build on the successes of these two established user fee programs

• ALSO: REQUIRES INQUIRY INTO WHETHER TO MAKE HYDROCODONE COMBOS Cii

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FDASIA (HYDROCODONE PROVISION)

• SEC. 1139. SCHEDULING OF HYDROCODONE.• (a) IN GENERAL.—Not later than 60 days after the date of• enactment of this Act [October 1, 2012], if practicable, the Secretary of Health and• Human Services (referred to in this section as the ‘‘Secretary’’)• shall hold a public meeting to solicit advice and recommendations• to assist in conducting a scientific and medical evaluation in connection• with a scheduling recommendation to the Drug Enforcement• Administration regarding drug products containing hydrocodone,• combined with other analgesics or as an antitussive.• (b) STAKEHOLDER INPUT.—In conducting the evaluation under• subsection (a), the Secretary shall solicit input from a variety of• stakeholders including patients, health care providers, harm prevention• experts, the National Institute on Drug Abuse, the Centers• for Disease Control and Prevention, and the Drug Enforcement• Administration regarding the health benefits and risks, including• the potential for abuse and the impact of up-scheduling of these• products.• (c) TRANSCRIPT.—The transcript of any public meeting conducted• pursuant to this section shall be published on the Internet• Web site of the Food and Drug Administration

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Regulation of DrugsHow and When (Cont’d)

-MAJOR LEGISLATION -CORE OF TODAYS LEGISLATON

FOOD, DRUG AND COSMETIC ACT OF 1938

(21 U.S.C. §301 et seq.)

Several amendments to the core act

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FOOD, DRUG AND COSMETIC ACT OF 1938

No “new drug” could be introduced into interstate commerce unless first proven ‘safe’ for labeled indication. (Pre-1938 drugs on market exempt from proving safe).– Established New Drug Application/Approval Process (NDA)– Required ‘adequate directions for use’ and other labeling

requirements …• Unless dispensed pursuant to prescription from state-authorized

prescriber – Required labeling for habit-forming drugs (no longer because of

FDAMA of 1997)

Applied to cosmetics as well as food and drugs, but not to devices until 1976 (Dalkon Shield, IUD).

Creates two major offenses: adulteration and misbranding

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FOOD, DRUG AND COSMETIC ACT OF 1938

Did NOT establish prescription-only/OTC status of drugs. Drug manufactured determined status of drug by its label (if sold OTC, had to have “adequate directions for safe use by consumer”).

Exemption from labeling with “adequate directions” if drug dispensed on written a prescription, but didn’t create prescription only category of drugs

Regs issued in 1938 shortly after passage of act allowed for prescription only category of drugs if not necessary for public safety (i.e., if had prescription-only warning, shipped for prescription sale only, and had labeling not easily understood by layperson)

So, manufacturer could create prescription-only class by simply labeling it as such Did not required drugs to be ‘effective’ for intended purposes Recognized “Official Compendia,” privately published, that standardized drug quality

– USP/NF Monographs• Chemical characteristics and quality standards of listed drugs• USP/NF merged

– Homeopathic Pharmacopoeia of the United States Anything published in official compendia is a drug

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Prohibitions

Its is unlawful to introduce into interstate commerce and article that is– Adulterated or– Misbranded

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AdulterationAdulterated drugs and devices. A drug or device shall be deemed to be adulterated:501(a) (1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or (2)(A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice, or (3) [container composed of poisonous or dangerous substance]; or (4) … [unsafe coloring additive if for coloring only]…

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Adulteration

• …(b) If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium… No drug defined in an official compendium shall be deemed to be adulterated under this paragraph because it differs from the standard of strength, quality, or purity therefore set forth in such compendium, if its difference in strength, quality, or purity from such standards is plainly stated on its label.

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Adulteration

• Whenever a drug is recognized in both the United States Pharmacopeia and the Homeopathic Pharmacopeia of the United States it shall be subject to the requirements of the United States Pharmacopeia unless it is labeled and offered for sale as a homeopathic drug, in which case it shall be subject to the provisions of the Homeopathic Pharmacopeia of the United States and not to those of the United States Pharmacopeia.

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Adulteration

(c) If it is not subject to the provisions of paragraph (b) of this section and its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess.

(d) If it is a drug and any substance has been (1) mixed or packed therewith so as to reduce its quality or strength or (2) substituted wholly or in part therefor.

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Misbranding

Labeling must not be false or misleading, including healthcare economic information

Labeling must include a listing of active ingredients and quantity and listing of inactive ingredients in alpha order

Labeling must contain “adequate directions for use” and “adequate warnings against use” by children and others for whom use might be dangerous

If drug cannot be labeled with “adequate directions for use”, it must contain “adequate information for use”

It is misbranding if a drug imitates another drug

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Misbranding P. 64

Where adulteration deals with strength, purity and quality, misbranding focuses on representations made by manufacturer on label or labeling. FDA must approve labeling/label. Can’t be false or misleading.

Before 1997 FDAMA “Habit-forming” on label. List active ingredient and quantity (unless for non-human) and

inactive ingredient alphabetically (unless for non-human or if an OTC cosmetic).

Adequate directions for use and warnings against use. Adequate “information” for use if drug can not be labeled to protect

consumer (i.e., rx drugs, see Durham-Humphrey) It is misbranding if a drug imitates another drug (otc’s looking like

controlled substances)

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Federal Food And Drug Administration (FDA)

P. 45

• Housed under the Department of Health & Human Services (DHHS)

• Authority for administering the FDCA• FDA secretary appointed by President

with confirmation of Senate

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Functions of FDA

• Rulemaking• Issue guidance documents• Incorporate advice from standing

advisory committees of outside experts

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What is a Drug?

• Articles recognized in the USP or Homeopathic Pharmacopeia

• Articles intended for use in diagnosis, cure, mitigation, treatment or prevention of disease (Part B)

• Articles other than food intended to affect the structure or function of the body (Part C)

• Definition is intentionally broad to include almost anything with an intended therapeutic purpose or purpose of altering the structure or function of the body

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Evidence A Product is a Drug

• Labeling• Advertising• Nature of product

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Food or Drug?P.46

• Generally depends upon intended use• Food definition not very helpful in itself• Congress likely intended the meaning of food

in the exclusion from part C of drug definition to apply to food used for its ordinary purpose and in an ordinary manner.

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SEC. 201. [21 U.S.C. 321] CHAPTER II—DEFINITIONS 1 SEC. 201. [21 U.S.C. 321] Definitions; generallyFor the purposes of this Act— 2

(e) The term "person" includes individual, partnership, corporation, and association. (f) 1 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. (g)(1) The term "drug" means (A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic 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 disease 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 article specified in clause (A), (B), or (C). A food or dietary supplement for which a claim, subject to sections 403(r)(1)(B) and 403(r)(3) or sections 403(r)(1)(B) and 403(r)(5)(D), is made in accordance with the requirements of section 403(r) is not a drug solely because the label or the labeling contains such a claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 403(r)(6) is not a drug under clause (C) solely because the label or the labeling contains such a statement.

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Is it a drug?

• Do Cats Make Terrible Pets• Diagnose, cure, mitigate, treat or prevent disease

• D – Diagnose• C – Cure• M – Mitigate• T – Treat• P – Prevent

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Health or Disease Claims for Foods

• A health claim for a food made by a manufacturer could result in the product being considered a drug

• The Nutrition Labeling & Education Act of 1990 and subsequently FDAMA allows foods to contain health claims if approved by the FDA by regulation or by the “significant scientific agreement” test

• Manufacturer must submit considerable evidence to support the claim to obtain FDA approval

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P. 50

What is DSHEA?The Dietary Supplement Health and Education Act of 1994, which spells out regulations regarding the manufacture and sale of dietary supplements, defines a dietary supplement as “a product (other than tobacco) intended to supplement the diet that bears or contains one of 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 a concentrate, metabolite, constituent, extract, or (F) concentrate, metabolite, constituent, extract or combination of any ingredient noted in clause (A), (B), (C), (D), or (E).”

The act defines permissible labeling claims and places the burden of proof on the Food and Drug Administration to show that a product is unsafe. It also outlines safety requirements for new dietary ingredients.

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Are Dietary Supplements Unregulated?No. DSHEA grants the FDA the authority to regulate dietary supplements in two important respects.

First, the FDA regulates product labeling. Whenever a marketer wants to make a claim about a supplement, it must submit the proposed claim to the FDA within 30 days after its first use. Claims are limited to “general structure function” and as a rule may not assert that a product prevents or treats disease. The FDA may stop the manufacturer from advertising the claim if it is deemed impermissible.

Second, DSHEA holds supplement manufacturers to what are known as “good manufacturing practices” (i.e., industry standards for maintaining product quality). In addition, the Federal Trade Commission maintains authority over supplement advertising: Manufacturers must report truthfully what their products contain and must have proof backing up any claims they make.

Additionally, the Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2006 requires what’s known as “adverse event reporting,” the FDA’s way of informing the public about any incidents related to a product once it is on the market. This is the same system of reporting used for FDA-approved drugs and biologics.

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Nutritional or Structure/ Function Claims

• DSHEA permits 4 types of nutritional support claims:– Benefiting a classical nutrient deficiency disease– Describing to role of the DS in affecting the structure/function of

the body [this is an exemption to the definition of “Drug” under the FDCA 21 USC Sec. 321(g)(1)(C). ]

– Characterizing the mechanism by which a DS act to maintain the structure or function

– Statements of general well-being

• Claims must be substantiated as truthful and not misleading

• Label must contain disclaimer

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Health or Disease Claims

• DSHEA only permits DS manufacturers to make health claims if either the FDA approves the claim by regulation or by the significant scientific agreement test.

• Pearson v. Shalala, however, held that DS manufacturers could make health claims not approved by the FDA provided they are not false or misleading and accompanied by a disclaimer

• FDA now allows qualified and unqualified health claims

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Dietary Supplements Containing Drugs

• DSHEA excludes an article as a DS if it was approved as a drug prior to it being marketed as a DS

• Pharmanex case (Cholestin®, had lovastatin in it (made

from a fungus), same drug as Mevacor) establishes that DSs cannot be specially manufactured to concentrate the natural drug ingredient

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Safety Issues

• FDA can only remove a DS on the basis the product is adulterated, defined as presenting “significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labeling”

• Ephedrine Alkaloid DS example • Dietary Supplement & Nonprescription Drug Consumer

Protection Act requires manufacturers to report serious adverse events

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Implications of DSHEA for Pharmacists

• Product selection• Education of patients as opposed to

promotion of products• Restrictions regarding the display of DS

publications

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Drug and/or Device?Medical Device Amendment (MDA) of 1976

• Historical approach of the FDA prior to the Medical Device Amendment was to declare devices as drugs when necessary

• Definition of device excludes articles that achieve their purpose through chemical action and metabolism.

• Whether a device containing drugs is a drug or device is dependent on various factors

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Drug and/or Cosmetic?P. 55

• Definition of cosmetic generally includes topical articles intended for cleansing, beautifying or altering appearance

• A cosmetic can become a drug if the seller makes a health or structure/function claim

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Labels and Labeling PAGE 56

• The term “label” means a display of written, printed or graphic matter upon immediate container….

• The term “labeling” includes labels and other written, printed or graphic matter upon any article or any of its containers or wrappers OR ACCOMPANYING SUCH ARTICLE.

• Labeling is defined as written or printed or graphic matter “accompanying” the article.

• Courts have defined accompanying (p. 56) (is it an “integrated distribution program”)

• If the written, printed or graphic matter is not labeling, it is advertising

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Official Compendia• USP– Published by the USPC– Sets uniform standards– USPC works closely with the FDA but is private

• HPUS– Publishes standards for homeopathy products by the

HPCUS, a private organization– Role and legal authority of HPUS

• Pursuant to FDCA, if a drug is recognized in USP or HPUS the drug product must meet all standards of the compendia

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Prohibited Acts• Most prohibited acts involve misbranding or

adulteration• Violation of FDCA is subject to strict liability

– Good faith excuse applicable (SEE 21 USC 303(c) )• Applicable to pharmacies

– The mere receipt and subsequent delivery of an adulterated or misbranded drug (§301(c))

– The doing of any act which causes a drug to be counterfeit (§301(i)(3))

– The alteration, mutilation, etc. of the labeling (§301(k))– (what about filling an otc drug as a prescription???)

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FDA Enforcement Authority

• Injunction• Criminal action• Seizure of products• Warning letters

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Product Recalls

• FDAAA established FDA authority to order drug recalls

• Three classes of recalls• Manufacturers responsible for notifying seller

and seller for notifying consumers if necessary

• Pharmacists responsible for knowing of product recalls

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Nonprescription Drug Labeling• User friendly format including pharmacological category or

principal intended use, cautions and warnings, adequate directions for use, and a “Drug Facts” panel

• Pharmacies that relabel or repackage must conform to the same labeling requirements as manufacturers

• Professional OTC labeling may be published by manufacturers for indications not appropriate for lay diagnosis or treatment.

• Drugs that are both OTC and prescription exist when some indications can be labeled with adequate directions for use and some cannot. (i.e., Zantac, Prilosec)

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Review Question

• A manufacturer of catsup advertised that its particular brand of catsup would effectively treat gouty arthritis. Which of the following would be correct:

• • a. The catsup is likely a food• b. The catsup is likely a drug• c. The catsup is likely both a food and a drug• d. The catsup is likely neither a food nor a

drug

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Review Question

• A manufacturer of catsup advertised that its particular brand of catsup would effectively treat gouty arthritis. Which of the following would be correct:

• • a. The catsup is likely a food• b. The catsup is likely a drug• c. The catsup is likely both a food and a drug• d. The catsup is likely neither a food nor a drug

• ANSWER: C.

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Review Question

• Which of the following can make structure/function claims without being considered a drug.

• • a. Vitamin D• b. Lipstick• c. Breakfast cereals• d. A & B• e. A & C

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Review Question

• Which of the following can make structure/function claims without being considered a drug.

• • a. Vitamin D• b. Lipstick• c. Breakfast cereals• d. A & B• e. A & C• ANSWER: A