Pharm Law - FDCA and Accompanying Laws

Drug Defined 321 (g) (1)

(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 (B) *articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals* (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals (D) articles intended for use as a component of any article specified in clause (A), (B), or (C). *Important note: Intended use establishes a drug*

Additive Amendments

*Food Additive Amendments of 1958* *Color Additive Amendments of 1960* • Established the regulation and conditions for use of color additives in food, drugs, and cosmetics • Ensure safety of color additives

Non-Prescription Labeling Requirements

-Drug Facts Label • Instituted 1999, required by 2002 Principle display panel • Statement of identity • Required size (percentage of package) • Net quantity -Pregnancy and breast-feeding warning -Calcium, Sodium, Magnesium, Potassium content -Domestic contact information to receive ADR report Note: Non-Prescription Labeling must include *adequate directions for use*

New Dietary Ingredient Definition

Manufacturer must notify FDA if it intends to market supplement containing "new dietary ingredient" • New Dietary Ingredient is defined as: A dietary ingredient not sold in US in a dietary supplement prior to 10/15/94 • New Dietary Ingredient must demonstrate to FDA why ingredient is "reasonably expected to be safe for use" --• Safety data must be presented • Manufacturer & distributor is responsible for determining if it is a new dietary ingredient

Family Smoking Prevention and Tobacco Control Act

granted the FDA the authority to regulate the manufacture, distribution sale, labeling, advertising and promotion of tobacco products to protect public health *Family Smoking Prevention and Tobacco Control Act* is passed into law June 22, 2009 • Created FDA Center for Tobacco Products • Bans flavored cigarettes • Prohibits tobacco companies from using terms such as "low tar," "light" or "mild" • Requires larger warning labels on packages • Stops youth-focused marketing • Requires tobacco companies to reduce levels of nicotine in cigarettes • Requires full disclosure of ingredients and additives

Narcotics Boom and Burst

*1914 Harrison Narcotics Tax Act* • Gained regulatory authority on opiates and cocaine *1937 Marijuana Tax Act* • Taxed marijuana possession and use to the brink of prohibition • Especially non-medical use • Repealed in 1970 with the Controlled Substance Act

Specific Label Requirements 21 CFR 201 (A)

"Contains FD&C Yellow No. 5 (tartrazine) as a color additive" • Further warning statement required in precautions section of package insert "Contains FD&C Yellow No. 6 as a color additive" • "Phenylketonurics: Contains Phenlalanine ___mg -->• Aspartame containing drugs • "Contains sulfite..." • Systemic antibiotics, "to reduce the development of resistance, use only in proven or strongly suspected

FDCA Definition of "Drug"

*Drug*: articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals by affecting the structure or any function of the *Drug vs.Device*: instrument, apparatus, implant, in vitro reagent, or other similar or related article, which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or intended to affect the structure or any function of the body and which does not achieve any of its primary intended purposes through chemical action within or on the body. *Drug vs. Cosmetic* articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body...for cleansing, beautifying, promoting attractiveness, or altering the appearance *Drug vs. Food*: raw, cooked, or processed edible substance, ice, BEVERAGE, or ingredient used or intended for use or for sale in whole or in part for human consumption, or chewing gum

Drugs vs Dietary Supplements

*Drugs* • /Premarket review of safety and efficacy/ • Regulated by *CDER* • Products and manufacturers registered • *FDA/FTC regulates advertising* • cGMP standards • Various formulations • Disease Claims *Dietary Supplements* • *No* premarket review • Regulated by *CFSAN* (Center for Food Safety and Applied Nutrition) • Products and manufacturers *not* registered • FTC regulates advertising (Federal Trade Commission) • cGMP standards (current Good Manufacturing Practice) • Oral formulation only • No Disease Claims

Label vs. Labeling

*Label*: (sticker attach on the bottle) display of written, printed, or graphic matter upon the immediate container of any article [21 USC 321 (k)] *Labeling*: All labels and other written, printed or graphic matters either: Upon any container or any of its wrappers or accompanying such article [21 USC 321 (m)]

Prescription Drug Marketing Act of 1987

*Prevents re-importation of a drug into US. Prohibited hospital and healthcare entities from reselling their pharmaceuticals* Prescription Drug Marketing Act of 1987 is concerned with the "diversion market" of drugs. The PDMA: • Banned reimportation *except by manufacturer* • Required state licensing of drug wholesalers • Banned sale/trade/purchase of drug samples --• Provided record keeping restrictions • Prohibited hospitals and other healthcare entities from reselling drugs to other businesses • Prohibited the sale, purchase, trade, or counterfeiting of any coupon • Permitted hospitals to return drug products, to manufacturer/wholesale

Dietary Supplement and Nonprescription Drug Consumer Protection Act 2006

*Required serious reporting serious adverse events for nonprescription drugs and dietary supplements* • Parallel systems: --15 day manufacturer reporting requirement --*6 year record keeping requirement* Limited importation of certain nonprescription drugs and dietary supplements FDA evaluates these reports and may take action if necessary

FDASIA

- Expands the scope of products that qualify for accelerated approval, creates a new "breakthrough therapy" program (esp. antibiotic) - drugs that treats a serious or life-threatening condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies gives Fast Track review benefits - Creates incentives to encourage the development of products for antibiotic-resistant infections - Improves FDA's inspection authority and the drug supply by expediting inspections

DS can make three distinct claims on their label / labeling

1. *Health claims* -Link between substance and disease or health-related condition (calcium reduces risk of osteoporosis) 2. *Nutrient content claims* -Amount of substance in a product (High in Oat Bran) 3. *Structure/function claims* -Intended benefits of using product (bitter orange promotes healthy weight) --• Must include Disclaimer: "This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease." -Can NOT make any disease claims

Prescription Drugs 21 USC 353 (b)

1. Drugs which cannot be properly labeled for self-use -• *No 'adequate _directions_ for use'* 2 Drugs which require a physician's supervision because of its toxicity 3. Habit-forming forming drugs -• Original language stricken from the statute Prescription Drugs *must be labeled with adequate _information_ for use* (ie. package insert) All other drugs, by default, are nonprescription

Timeline Review of Drug Acts

1906----1938 (No drugs proof of safety or effectiveness) -->adulteration & misbranded 1938----1962 (Drugs Proof of safety only) 1962----Today (Drugs Proof of safety & efficacy)

Package Insert Revised

2006 Package Insert format revised for first time in 25 years that has: • Highlights section • Recent major changes (last year) • Table of Contents • Date of initial product approval • Toll-free number and Internet reporting information for ADRs • Patient counseling section Designed, in part, to try and reduce medication errors Applies to all new drugs and those approved in preceding 5 years to the final rule

Alcohol and OTC internal analgesics/antipyretics

21 CFR 201 (G) Specific labeling: Advises consumers with a history of heavy alcohol use to consult a physician when use APA and NSAID: --• 3 or more drinks per day • APA w/ alcohol - Liver damage • NSAIDs w/ alcohol- Internal bleeding • Combination APA & NSAID w/ alcohol - Liver damage and Stomach bleeding • Thus, Required labeling or else misbranded • Issued April 29, 2009

PP Packaging Case Study

30 year old woman enters the pharmacy to pick-up her alprazolam prescription. Upon receipt of the bag, she immediately opens and quips at the cashier, "I told you I don't want these stupid caps on my prescriptions." • What actions, if any, should the pharmacist do? • What concerns exist? -Apology ..will not do it again

Current Good Manufacturing Practices 501(a)(2)(B), 21 CFR 211

Abbreviated cGMP's • Not actually defined in the FDCA --• *Intended to maintain consistent strength, quality, purity, and identification of finished product* • Considered a minimum standard • Facilities must register and are inspected once every two years 21 USC 360 (h) --• Changes must be reported to the FDA • Violations subject to action --• administrative (withdrawal of approval) --• judicial action (injunctions and seizures) *Premise: can't test every finished product for adulterants*

Structure functions claims

Acceptable: • Promotes relaxation • increases sexual desire and improves sexual performance • helps maintain cardiovascular function • Supports healthy immune system Unacceptable: • reduces the pain and stiffness associated inflammatory disease • relief of bronchospasm • shrinks tumors of the lungs • builds resistance to colds and flu • Supports long lasting, hard and firm erections

Manufacturer Labels 21 CFR 201

All requirements must be prominent and conspicuous • Rx: require to have adequate information for use (package insert) • OTC: require to have adequate directions for use (drug facts label) • Name and address of manufacturer • Brand name, if applicable • Established drug name --• Must be at least half as big as brand name • Dosage and Quantity --• Non oral drugs must include inactive ingredients • Lot number to determine manufacturing history • Expiration date • Barcodes • NDC requested, but not required Note: Drugs distributed solely in Puerto Rico or in a Territory where the predominant language is non- English, the predominant language may be substituted on the label

Durham-Humphrey Amendment of 1951

Also referred to as Prescription Drug Amendments -is named after two pharmacists • C. Durham (Congressman NC) • H. Humphrey (Former Senator MN and US Vice President) Divided drugs into two distinct classes given: • *Rx (legend) and OTC (non-prescription)* • Authorized oral prescriptions and refills of prescriptions • Established standards for information required on prescription labels and labeling

"New Drug" Defined 321 (p)(1)

Any drug the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the *safety and effectiveness of drugs*, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof • Any article intended to be used as a drug that does not have an approved application is deemed a new drug subject to enforcement

REMS Example: Aranesp

Aranesp, was used for cancer, increase WBCs. However, it increase risk of cardiac problems and increased cancer growth (with decreased survival REMS came in and issued: • *Communication plans* by launching *website and mail* Dear Healthcare letters • Elements to assure safe use --• ESA APPRISE Program established-Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs (Erythropoiesis-Stimulating Agent) --• & Physicians in this program must be certified • Implementation systems --• Amgen (manufacture) will monitor compliance and conduct random audits • Make sure each patient have medication guides explainabout the risk --• Required distribution with every dispensing

Compounding Quality Act (2014) - 503B of the FDCA

Compounding Quality Act issued in 2014 *as a result of New England Compounding Center incident.* • *Sterile Compounders* may register as *"Outsourcing Facility"* and are exempted from FDA approval requirements: --MUST comply with CGMP requirements; will be inspected by FDA according to a risk-based schedule; and must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound --• MUST NOT compound drugs on FDA ban list or essentially copy approved drugs • Simple repackagers and non-sterile compounding not included -Outsourcing Facility Fee for small and big business.

Drug Efficacy Study Implementation (DESI)

DESI is Required under the Kefauver-Harris Amendment • All drugs approved between 1938 and 1962 required evidence of effectiveness --• Permitted to remain on the market during evaluation --• Drugs found to be safe and effective could be marketed after evaluation • 581 reviews covering 18,400 drugs • Established if drugs were effective, non-effective, or required further study • *IRS: drugs grouped if Identical, Related, Similar*

Medical Foods Definition

Defined by the Orphan Drug Act, 21 U.S.C. 360ee (b) (3): Food formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation To be labeled as food

Diet Supplement Claims

Dietary Supplements (DS) may make Structure Function Claim: -• Disclaimer FDA has not evaluated the claim. *Dietary Supplement product is not intended to "diagnose, treat, cure or prevent any disease* • Qualified Health Claim • Nutrient Claim Dietary Supplements may NOT make: Disease or Drug Claims

Drug Supply Chain Security Act (Track and Trace) 2013

Dispensers must: • confirm that trading partners (manufacturers, repackagers, wholesale distributors, dispensers, and third-party logistics providers) are authorized • provide lot-level product tracing information— namely, transaction information, history, and statements—for 6 years • establish systems for verification and handling of suspect or illegitimate products

Kefauver-Harris Amendments of 1962

Drug Efficacy Amendment • Intended to further improve and strengthen the drug approval process --• Closed many of the loopholes in drug safety and clinical investigation • Imposed pre-marketing requirement for proof of efficacy (NDA / sNDA) --• "substantial evidence" standard --• retroactive to 1938 • Established GMP requirements • Brought prescription drug advertising within jurisdiction of FDA (from FTC) • "Full Disclosure" in labeling • Required drug labels to contain both brand and generic name • Expanded FDA inspection authority • Manufacturers to register/list with FDA for inspection • Mandated informed consent in testing • Required reporting of clinical ADRs

Poison Proof Exemptions

Drugs exempt to be packaged in poison proof containers *PAINS-E* • *P*rednisone, Potassium (unit dose), Pancrealipase • *A*nhydrous cholestyramine • *I*sosorbide and sublingual nitrates • *N*itroglycerine • *S*ex hormones (conjugated estrogens, BC) • *E*ffervescent aspirins, Erythromycin Note: Should know this for MPJE

Specific Drug Requirements 21 CFR 201 (G)

Drugs must have following info. on the labeling: • Glandular preparations -->No scientific evidence • Isoproterenol -->Severe paradoxical bronchoconstriction • OTC sore throat lozenges/troches --> If severe or persistent call physician, may be severe • Ipecac -->Call for professional advice before using • Nonoxynol 9 -->Does not protect against HIV • Phenindione -->Causes agranulocytosis and hepatitis

National Academy of Sciences Rating of Review

FDA contracted with the National Academy of Sciences (NAS) / National Research Council. NAS includes: 30 panels of experts reviewed the efficacy of drugs • Effective (19%) • Effective, but...[better alternative exists] (24%) • Probably Effective (7%) • Possibly Effective (35%) • Ineffective (15%) • Ineffective as a fixed combination (15%)

Dietary Supplement

FYI-DS -Can not claim products can cure diseases -Can not claim products have pharmacological uses - becomes a drug (needs FDA approval) -May include health, nutrient content, or structure/function claims on label Examples: These are not allow supplement make claim: - Folic Acid Supplement: Healthful diets with adequate folate may *reduce a* women's risk of having a child with a brain or spinal defect - Calcium Supplement: Regular exercise and healthy diet with enough calcium help teens and young adults white and Asian women *maintain good bone health* and *may reduce* their high risk of osteoporosis later in life. - Whey Protein: Builds muscle mass, *reduces* muscle fatigue, enhances strength. The Food and Drug Administration have not evaluated this statement. This product is not intended to diagnose, treat, cure, or prevent disease Nutrient content claims - "Good source of calcium - must have at least 10-20% of DV for calcium"

Dietary Supplement Health and Education Act of 1994

Facilitated the marketing of dietary supplements • DSHEA Broadly defined dietary supplement that provided very lenient regulation / CFSAN oversight • No premarket approval requirement for safety or efficacy • *Prohibits regulation by FDA unless proof that the product is unsafe --•Eg. Ephedra banned due to safety concerns* • Provides guidelines for displaying published product information --• Must be separate from product, reprinted in entirety, not promote a certain product and not be misleading

Diet Supplement Compared to Food

Foods are not intended to affect structure function of the body DS is only intended to supplement the diet • Not a conventional food • No serve as a basis for the diet • Not intended as a sole item of a meal • *Drugs* (not DS)* intend to diagnose, treat, cure or prevent any disease* • *DS intend to affect/maintain normal structure or function of the body* • Drugs can be topical / oral / IV / otic / ocular / nasal • *DS are oral use only*

Drug Price Competition and Patent-Term Restoration Act

Hatch Waxman Amendment 1984 • Balances patent protection for brand drugs with increasing availability of generic drugs --• Granted greater patent protection for Brand Drugs --• Generic drugs did not have to show proof of efficacy 1988 Generic Animal Drug and Patent Term Restoration Act Insight: The Hatch-Waxman bill, known officially as the Drug Price Competition and Patent Term Restoration Act (Public Law 98-417), brought about the following changes: Generic drugs no longer need to prove their safety and efficacy. Under the bill, generic drug manufacturers need only submit an Abbreviated New Drug Application (ANDA) to prove their product's bioequivalence to the original branded drug. This is a cheaper process for manufacturers, as the cost of conducting clinical and non-clinical studies or risking liability for patent infringement damages are not a part of the equation for the generic drug manufacturers. Generic drugs are granted a 180-day period of exclusivity. Either the first drug to file an ANDA, or the first group of drugs, is granted this period. Manufacturers filing ANDAs can only do so for drugs that have not been patented. *ANDAs can only be filed when a branded drug's patent has expired.* Generic drugs cannot go on to the market until the branded patent has expired. Branded drug patents must not have been infringed or proven invalid. (If a patent is shown to be invalid, the FDA must wait 30 months until it approves a generic.) Because branded drugs lose so much of their revenue when generic drugs are introduced, the Act provides them with patent extensions options, which now average about three years.

Federal Anti-Tampering Act of 1982

INCIDENT: The Chicago Tylenol murders were a series of poisoning deaths resulting from drug tampering in the Chicago metropolitan area in 1982. The victims had all taken Tylenol-branded acetaminophen capsules that had been laced with potassium cyanide. A total of seven people died in the original poisonings, with several more deaths in subsequent copycat crimes. These incidents led to reforms in the packaging of over-the-counter substances and to federal anti-tampering act/laws Federal Anti-Tampering Act of 1982: Requires tamper evident packaging for nonprescription drugs (giả mạo) This act in response to 1982 Tylenol/Cyanide incident • Illegal to tamper with consumer products --• Were they Reckless disregard? or intended to cause serious injury? --• knowingly communicates false information that a consumer product has been tainted --• Knowingly threatens in which the threat may reasonably be expected to be believed • Subject to fine and imprisonment

Two Classes Emerging

If manufacturer *cannot provide adequate directions for use, the drug requires the manufacturer to provide adequate information for use* and the drug becomes *prescription* only requiring a prescription by the physician • Package Insert requirement • Physician serves as the Learned Intermediary

Importation of Active Pharmaceutical Ingredients (API)

Importation of Active Pharmaceutical Ingredients (bulk substances) legal only if: -• Intended for compounding and meets the requirements of 503A FDCA or -• Has an approved drug application (NDA/ANDA/NADA/ANADA/IND) or -• Used in an approved OTC monograph drug • FDA maintains a list of products to be detained without physical examination (Import Alert #66- 66) • Must be labeled with adequate directions for use

FDA Importation for Personal Use

Importation of drugs is illegal under FDCA • Reimportation only allowed by manufacturer • FDA inspectors exercise enforcement discretion for personal use: -• *the product must be for personal use (a 90-day supply or less, and not for resale)*; -• intended for a serious condition for which effective treatment may not be available domestically -• no commercialization or promotion to U.S. residents -• *drug poses no unreasonable risk*; and -• patient affirms in writing it is for the patient's own use and provides doctor's contact information -• FDA should not routinely search personal baggage

Is tobacco a drug?

In 1996 FDA attempted to regulate Tobacco as a drug with rule • Nicotine = drug • Cigarette = device --> Promulgated regulations to reduce tobacco usage among children and adolescents Debate: 2000 Supreme Court rules 5-4 FDA does not have authority to regulate tobacco as a drug. Within weeks of this ruling, FDA revokes its final rule • Court rules Congress did not intend tobacco to be overseen by FDA

1914 Harrison Narcotics Tax Act

In response to growing addiction to opiates and cocaine-containing medicines, the Harrison Tax Act established that manufacturers, pharmacists, importers, and physicians prescribing narcotics should be licensed and required to pay a tax. This is still legal today

Must a pharmacy that compounds drugs follow cGMPS?

It depends...if they compound in bulk and are considered manufacturers, then yes. However, if they are simply compounding for a single patient, then no...sort of. It then becomes a state law matter

Warning letter case for violate New Drug law

Mr. Thomas R. Fuhnnan Florida Bottling, Inc The FDA inspected your facility located at 1035 NW 21st Terrace, Miami, FL 33127 and reviewed your website at www.lakewoodjuices.com. The FDA has determined that your Fresh Pressed Blueberry Blend, Pure Aloe, Pure Pomegranate (organic), and Tart Cherry juice products are in violation of the FDCA Unapproved New Drug Your product labels and your website promote your juice beverage products for conditions that cause them to be drugs under section 321(g)(1). Your products are not generally recognized as safe and effective; therefore, the products are "new drugs" under section 321(P). New drugs may not be legally marketed in the US. without prior approval from the FDA. Examples of violation include: • Fresh Pressed Blueberry Blend label and webpage: • "[R]educes infections" • Tart Cherry label and webpage: • "Reduce the Pain of Arthritis, Gout ..." Please respond to this Warning Letter within fifteen (15) days and include documentation necessary to show that correction has been achieved

Dietary Supplements Labeling

Must include: • Descriptive name of product--> States that it is a "supplement" • Name and place of business of manufacturer, packer, or distributor • Complete list of ingredients and source. Eg. Rose hips as source of vitamin C • Net contents of products • Nutrition labeling --• "Supplement Facts" panel

FDA Amendments Act (FDAAA) 2007

Myriad of provisions to update FDA's authority, with emphasis on drug safety • *Reauthorized user fees (IV)* • *Pediatric exclusivity further secured* • Established program to collect fees for pre-review of DCTA (*Direct-to-consumer advertising*- do not need to get a pre-approval by FDA. However, if there is a problem the FDA come in and tell DCTA to take down advertising, there is no good. So, make sure the ad is properly, they can pay money to FDA for pre-view) • Authorized certain post-marketing investigations • Clinical trial registry expanded --• "applicable trial" "basic results" required to be listed • Hefty civil money penalties authorized • *REMS authorized* (Risk Evaluation and Mitigation Strategy)

Tamper-Evident Requirements 21 CFR 211.132

Now, *OTC Products* must be packaged in a tamper-resistant packages • "Having one or more indicators/barriers to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred." • Use of distinctive design or identifying characteristic • Label must identify tamper-resistant features • Required two-piece, hard gelatin caps be sealed using an acceptable technology • *Exemptions include dermatological, dentifrice, insulin, and lozenge products*

Prescription Drug User Fee Act of 1992 (PDUFA)

PDUFA is passed in attempt to expedite and facilitate the drug approval process • *Contribute ~50% to the CDER budget* • *Sunset provision --• Must be reauthorized every five years* • Successful by most accounts • Concerns of conflicts-of-interest • Performance Goals on FDA

FDA Export Reform and Enhancement Act of 1996

Passed in response to growing industry concerns • Allowed exports of approved drugs to countries with different labeling requirements • Authorized exports of unapproved drugs for clinical investigation • Authorized the export of certain unapproved products in anticipation of marketing approval • Import for Export

FDA Modernization Act of 1997 (FDAMA)

Passed to 'modernize' some of FDA operations Extremely industry "friendly" • Allowed for a fast-track approval of drugs esp.--• Serious or life-threatening disease • Reauthorized PDUFA (II) • Established databank of clinical trials • Granted additional patent protection for *pediatric investigation*-6months exclusive study • Eliminated 'batch certification' of insulin and antibiotics

Case Study 1

Patient with Meniere's Disease orders Serc (betahistine) which is an unapproved drug in the US from an online licensed Canadian Pharmacy. The drug is an antihistamine used to treat Meniere's associated vertigo. The drug had an approved NDA in the US until the FDA identified 'unsubstantiated efficacy information' in the application and withdrew its approval. At the US Border, customs' agent identify the product as an unapproved drug.

Package insert requirements

Prescription drugs must include 'adequate information for use' -• Intended primarily for physician • Intended to provide physicians complete information on the product • Must not be promotional, false, or misleading • FDA reviewed and approved • Labeling intended to provide healthcare providers the necessary information to understand, prescribe, and counsel

Drug Diversion prior to Prescription Drug Marketing Act (PDMA) of 1987

Prior to PDMA, drugs were diverted in 3 ways: 1. Drug samples given to physicians which ended up being traded 2. Hospitals or other health care entities got special pricing and were then selling for profit 3. Wholesalers were selling and shipping drugs to foreign companies in foreign countries, who were then reimporting the drugs back into the U.S. via smuggling or substituting, then reselling here illegally (gray market)

What is The Great American Fraud book about?

Samuel Hopkins Adams's series articles on magazine in 1905 that exposed many of the false and even ridiculous claims made by patent medicine manufacturers and showed that these medicines frequently harmed rather than helped those who took them. The series had a huge impact and was published as a book in 1906.

1937 Elixir Sulfanilamide Incident

Sulfanilamide was a newly discovered and highly effective antibiotic • Available originally in powder form • Massengill salesman reported a demand for liquid formulation • Company chemists discovered diethylene glycol as a solvent It taste of Raspberries,--> Taste of Death. • Formulation never tested beyond flavor and fragrance • 107 people killed, some of which were children • *Dramatized the need for 'safe' drug laws* • The drug was not misbranded or adulterate. Drug said it has sulfonamide in it.--> it did not violate Pure Food & Drug Act. • Compound misbranded only as to elixir (contain alcohol in it)

Warning letter 2

The FDA inspected your facility located at 1035 NW 21st Terrace, Miami, FL 33127 and reviewed your website at www.lakewoodjuices.com. The FDA has determined that your Fresh Pressed Blueberry Blend, Pure Aloe, Pure Pomegranate (organic), and Tart Cherry juice products are in violation of the FDCA *Unapproved New Drug* Your product labels and your website promote your juice beverage products for conditions that cause them to be drugs under section 321(g)(1). Your products are not generally recognized as safe and effective; therefore, the products are "new drugs" under section 321(P). New drugs may not be legally marketed in the US. without prior approval from the FDA. Examples of violation include: • Fresh Pressed Blueberry Blend label and webpage: • "[R]educes infections" • Tart Cherry label and webpage: • "Reduce the Pain of Arthritis, Gout ..." Please respond to this *Warning Letter within fifteen (15) days* and include documentation necessary to show that correction has been achieved

WARNING LETTER 1

The Food and Drug Administration (FDA) has reviewed the label and labeling of your Cheerios® Toasted Whole Grain Oat Cereal. FDA's review found serious violations of the Federal Food, Drug, and Cosmetic Act (the Act) and the applicable regulations in Title 21, Code of Federal Regulations (21 CFR). *Unapproved New Drug* Based on claims made on your product's label, we have determined that your Cheerios® Toasted Whole Grain Oat Cereal is promoted for conditions that cause it to be a drug because the product is intended for use in the prevention, mitigation, and treatment of disease. Specifically, your Cheerios® product bears the following claims ort its label: • "you can Lower Your Cholesterol 4% in 6 weeks" " • Did you know that in just 6 weeks Cheerios can reduce bad cholesterol by an average of 4 percent? Cheerios is ... clinically proven to lower cholesterol. A clinical study showed that eating two 1 1/2 cup servings daily of Cheerios cereal reduced bad cholesterol when eaten as part of a diet low in saturated fat and cholesterol."

Thalidomide Tragedy

This event involved the occurrence of very serious birth defects in children of pregnant women who had been given Thalidomide as a sedative. The drug side effects should have been known and available to doctors and patients, but were not until much harm had been done. Thalidomide • Coined "Germany's best babysitter" used for morning sickness and to sedate children • Marketed throughout the world in the 1950s without a prescription • 1960 marketed in 46 countries with sales approaching aspirin • 1961 reports of phocomelia in the literature • Pending US approval withheld despite political pressure • Drug subsequently approved in 1998 in US

FDCA Prohibitions

Three major offenses outlined by the FDA 1. Placing an unapproved new drug into the stream of commerce --• Approved drug applications 2• Adulteration of a drug --• cGMP's 3• Misbranding of a drug -• USP/NF Standards Further Prohibitions • Tampering with a drug label • Refusing to permit access to or copying of any record • Falsification of records • Refusal to permit entry or inspection • Doing of any act which causes a drug to be a counterfeit • Certain drug importation

What isThe Jungle story about?

Upton Sinclair's The Jungle: Muckraking the Meat-Packing Industry. Upton Sinclair wrote The Jungle (novel 1904) to expose the appalling working conditions in the meat-packing industry. His description of diseased, rotten, and contaminated meat shocked the public and led to new federal food safety laws.

Risk Evaluation and Mitigation Strategies (REMS)

a plan to minimize drug-induced harm • *Communication plans* • Elements to assure safe use • Implementation systems • Medication guides *Required for about 200 drugs* Insight: REMS are designed to help reduce the occurrence and/or severity of certain serious risks, by informing and/or supporting the execution of the safe use conditions described in the medication's FDA-approved prescribing information. REMS are not designed to mitigate all the adverse events of a medication, *these are communicated to health care providers in the medication's prescribing information*. Rather, REMS focus on preventing, monitoring and/or managing a specific serious risk by informing, educating and/or reinforcing actions to reduce the frequency and/or severity of the event

New England Compounding Center

is a bigger pharmacy that caused: • Fungal meningitis outbreak from three contaminated lots of medicines • Methylprednisolone for epidural use -->53 deaths, 733 harmed, spread 23 states ~ 14,000 patients were involves

Pure Food and Drug Act of 1906

is also called Wiley Act lawful stated that any food or drug *adulterated* or *misbranded* is prohibited. However: • No general requirement to disclose ingredients: --Must disclose ONLY alcohol, morphine, opium, cocaine, heroin, alpha or beta eucaine, chloroform, cannabis indica, chloral hydrate, or acetanilid • No requirement to substantiate claims --• Only Efficacy claims permitted

1937 Marijuana Tax Act

penalties for the untaxed possession of marijuana. • Taxed marijuana possession and use to the brink of prohibition. Especially non-medical use • Repealed in 1970 with the Controlled Substance Act So Marijuana was legal since 1937-1970

Orphan Drug Act

provides incentives to develop new drugs for rare conditions *Orphan Drug Act of 1982* (21 CFR 316) is passed to stimulate drug development for uncommon diseases • Orphan Drug is a drug used to treat a rare disease or condition --• defined as less than 200,000 people in the US or no reasonable expectation to recover development • Incentives (khích lệ) include: tax benefits, protocol assistance, grants and contracts, and extended marketing exclusivity • Approval still follow conventional rigors • Large number of drugs approved are Orphan Drugs

Poison Prevention Packaging Act of 1970

requires all medications to be packaged in childproof containers to "prevent accidental child poisoning". - However, patients who sign a waiver or make a blank request are exempted from this regulation. -Physician may request a non child-resistant container for one bottle/prescription but not for the patient - Certain emergency medications such as nitroglycerin sub-lingual are dispensed in non-childproof packaging,

Pre-1938 Drugs 'Grandfathered'

• After 1962, drugs marketed before 1938 were allowed to remain on the market without further regulatory action --• Labeled for same indications of use, no change in formulation, dosage, strength • Have never been technically, approved by the FDA --• Do not appear in the orange book --• Historical usage substituted for clinical data

Dietary supplements definition

• *Dietary supplement is product taken by mouth containing a "dietary ingredient" intended to supplement to diet* • Dietary ingredients include: Vitamins, minerals, herbs or other botanicals, amino acids, enzymes, organ tissues, glandulars, and metabolites • Can also be extracts or concentrates • Oral formulations: Tablets, capsules, softgels, liquids, powders, bars Eg. Diet supplement is FOOD. Ear drop supplement is NOT food. It is a drug.

Center for Food Safety and Applied Nutrition (CFSAN-FDA)

• *Monitor marketplace for potential illegal products* --• Unsafe products or those that make false/misleading claims • Obtain information from : Inspections, Internet, Consumer and trade complaints, Lab analyses of selected products, & Adverse events reported to the agency

Comprehensive Addiction and Recovery Act (CARA-2016)

• *Permits pharmacist to partially fill Schedule II controlled substance prescriptions* based on the request of the prescriber or patient • Authorizes nurse practitioners and physician's assistants to administer, prescribe, and dispense narcotics in office-based opioid treatment programs --• increases the patient limit for office-based treatment from 30 to 100 (first year) and 275 thereafter

Horse named Jim incident

• 1901 - Fourteen children died from tetanus from a horse named Jim -a retired milk wagon horse in St. Louis • 30 quarts of diphtheria antitoxin serum before contracting tetanus taken out from the horse which develop antitoxin. • The same time in Camden NJ, 9 children died from tetanus after receiving small pox vaccine • 1902 Passage of the Biologics Control Act ---• First Virus-Toxin Law • *1944 Public Health Service Act (PHSA)* --• Principle law that currently governs biologics (BLA) --• *Rigorous standards for safety, purity and potency*

Manufacturer Responsible

• A firm is responsible for determining that the supplements it manufactures are safe and that any claims made are not false or misleading --• Prohibited from selling products that are adulterated or misbranded • *Firm does not have to provide the FDA with the evidence they gathered to support their claims* • But must report serious adverse drug events within 15 days

Restricted Access Programs

• Accutane • Clozaril• Exjade • Fosamax • Increlex • Iressa • Letairis • Lotronex • Nexavar • Nplate • Nexavar • Onsolis • Plan B • Revlimid • Thalidomid • Tikosyn • Tracleer • Tykerb • Tysabri • Xyrem --> These are drugs have potential side effects.

Poison Prevention Packaging Act of 1970 15 USC 1471

• Also known as the PPPA • Designed to reduce the risk of children ingesting dangerous substances. • Required locking caps on most prescriptions In 1970, PPPA is passed to protect children from accidental poisonings with "household substances" • Enforced by the Consumer Product Safety Commission (CPSC) --• Initially enforced by FDA • Pharmacist must dispense most drugs using child- resistant containers • Manufactured such that 80% of the children less than 5 years old of age cannot open them within 10 minutes, and at least 90% of adults can

Biosimilar (351k) Approvals 2009

• Analytical studies demonstrating that the biological product is "highly similar" to the reference product (brand drug) notwithstanding minor differences in clinically inactive components; • Animal studies • A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD) sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product. • FDA may determine, in its discretion, that an element described above is unnecessary in a 351(k) BLA • *Approved drugs (CBER/CDER) listed in Purple Book*

Homeopathic Drugs

• Based on *extreme dilution* and the premise, 'like cures like' • *Regulated as drugs under the FDCA* --• Rx and OTC products available --• *States license prescribers* • Approved products must meet the standards of the HPUS • Same adulteration and misbranding provisions as other drugs • Exempt from expiration date requirements

PPP Act - Pharmacies

• Cannot reuse containers (compromise integrity) --• Glass or plastic-threaded container may be reused with a new safety cap • Use of reversible caps permissible, although discouraged • Patient may make a blanket request for non-child resistant containers (oral or written) • Physician may require a non-child resistant container for a particular prescription (oral or written, may 'check the box') • All drugs must comply (with exemption)

Non-prescription drugs

• Default drug class • Must include *adequate directions for use and adequate warnings* • Treat conditions which can be self-diagnosed • Must be non-toxic • (Must be non-habit forming)

Unit-Dose Label Rx Drugs CPG 7132b.10

• Drugs may be packaged / repackaged into unit-doses --• Intended for institutional use --• Challenges for small size • NDC recommended • Expiration date --• Established by state --• Typically earlier of manufacturer's expiration date or 1 year -----• USP Guidelines

Federal Food, Drug, and Cosmetic Act (FDCA)

• Enacted in 1938 • The basis for our current drug law • Regulates all drugs introduced into interstate commerce • Provides the basic legal framework for the regulation of food, dietary supplements, drugs, cosmetics, and medical devices • Has been amended more than 100 times since its original passage Provided essential definitions: • Drug / New Drug • Adulteration and Misbranding Products must be safe (non-toxic) before marketing -•Eliminating requirement to prove intent to defraud in drug misbranding Provided express authority for factory inspections and enforcement Must disclose all active ingredients Labels now had to contain adequate directions for use with warnings

Unit Dose Label Requirements

• Established (generic) name; Brand name, if applicable, • Strength and dosage form • Quantity of active ingredient in each dosage unit • Expiration date (look to state and USP guidance) • Lot or control number • Name or place of business of man/packer/distributor • Any special statements required by compendia --• Multi-dose quantity requirement, if applicable • "Warning: may be habit forming" if applicable • Directions may be located on outer packaging or stored on premises in lieu of directions on label

Drug Specific Labeling

• Estrogenic compounds / Estradiol / Thyroid hormone activity • Mineral oil / Wintergreen oil • Tannic Acid and Barium Enema preps • Potassium salts / Sodium phosphates / Magnesium Sulfate Products / Aluminum in parenterals • Acetophenetidin (phenacetin products) • Salicylates • Digitalis and Cardiotonics • Water soluble gums (alginic acid, guar) • Chloroflorocarbons / Ozone depleting agents

FDAMA

• Expanded rights of manufacturers to disseminate off- label drug information • Permitted manufacturers to provide economic information to formulary managers • Ensured the availability of compounded drugs by pharmacists by exempting from approval and manufacturing requirements (503A) --• To be discussed with Trade Regulation later in the semester

FDA Reauthorization Act of 2017 (FDARA)

• Extends user fees for brand drugs, generics, biosimilars, and medical devices • Reauthorized orphan drug program • Incorporates patient experience data in drug development • Develops risk based approach to medical device inspections • *"Calls for a lowering of cost of prescription drugs"*

CARA- 2016

• HHS Establishes Pain Management Best Practices Inter-Agency Task Force • Removes a financial disincentive that discourages abuse-deterrent formulations (line-item extensions) --• No longer included in the Medicaid Rebate Statute • Expand the reporting requirements and access to state prescription drug monitoring programs by practitioners as well as law enforcement • Expand the availability of naloxone to law enforcement agencies and other first responders • Expand disposal sites for pharmaceuticals • Launch an evidence-based opioid and heroin treatment and intervention program to expand best practices

Package Insert Sections

• Highlights • Product name • Boxed Warning • Recent Major Changes • Indications and Usage • Dosage and Administration • Dosage Forms and Strength • Contraindications • Warnings and Precautions • Adverse Reaction • Drug Interactions • Use in Specific Populations • Drug Abuse and Dependence • Overdosage • Description • Clinical Pharmacology • Nonclinical Toxicology • Clinical Studies • References • How supplied / Storage and Handling • Patient Counseling

21st Century Cures Act 2016

• Innovation Projects • Advancing precision medicine • Supporting young emerging scientists • Patient Focused Drug Development • Advancing New Drug Therapies • Patient Access to Therapies and Information • Vaccine access certainty and innovation • Mental Health • Electronic Health Information

Hospital/Nursing Homes, Manufacturer Exemptions

• Institutional employees may dispense to institutionalized patients using noncompliant packaging --• Pharmacy may dispense with non-compliant packaging • Manufacturers may market one size for elderly or handicapped people in noncompliant packaging --• Must be labeled "This Package for Households without Young Children" or "Package Not Child Resistant

GMPs of dietary supplements

• June 25, 2007 FDA issued Final Rule establishing industry wide cGMPS: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements 1• *Manufacturers must conduct appropriate tests to verify the identity of the product* --• 100% identity testing of ingredients --• May petition for exemption 2• *Manufacturers required to maintain quality and consist controls* • Record keeping provisions

Less than Effective List (LTE)

• List of drugs less than fully effective • These drugs is still "Ongoing" agency evaluation • Medicare Part D fails to cover these drugs • Published in Federal Register, with opportunity for hearing • FDA exercises enforcement discretion to remove from marketing • Examples: Donnatal, Extardol cream, Granulex spray

Most new drugs are approved as: Prescription Drugs or Nonprescription Drugs? Why? Specifically, what factors should be considered in determining which class?

• Most new drugs are approved as: *Prescription Drugs* - have higher side effects, toxicity, patient cannot self diagnosis, that needed an adequate direction from the manufacture, -->must need prescription from physician

Pharmacy Label Requirements [21 USC 353 (b)(2)]

• Name and address of the dispenser • Prescription (serial) number • Date of the prescription or of its filling • Name of the prescriber, • Name of patient, if state on Rx • Directions for use if state on Rx • Cautionary statements, if any *These are Federal Pharmacy Label requirement* What's missing? Note: state law imposes additional requirements.

FDA Safety and Innovation Act (FDASIA) 2012

• PDUFA Reauthorized (V): First time includes generic drugs, medical devices, biosimilars • Renews and strengthens three essential laws to improve the safety and effectiveness of pediatric drugs, biological products, and medical devices used in children • Provides FDA with new authorities to combat shortages of drug products in the United States and imposed new requirements on manufacturers regarding early notification • Increases patient participation in product regulation

Drug Samples 21 CFR 203 (D), FR Dec 3, 1999

• Physicians may posses and use drug samples (eg. in doctor office) • Manufacturer must have detail written polices and procedures including: -• Annual inventory requirement -• Standing requests by physician not permitted--> Written request required -• Drugs may be delivered via mail or by person ---• Required receipt upon delivery • Licensed prescriber must have proper storage and handling conditions • *Retail pharmacies should not possess drug samples* • Product must be labeled as a sample • Physicians may donate drug sample to charitable institution

Burden of Proof on FDA

• Presents a significant or unreasonable risk of illness or injury • FDA must prove this to be true in order to remove supplement from market --• Can only occur AFTER drug in on the market • Under original DSHEA, FDA plays no role in approving a supplement for release into the market • Each case de novo (a new look) determination

Adequate Information for Use Examples

• Product name • Boxed Warning • Contraindications • Warnings and Precautions • Adverse Reaction • Drug Interactions • Use in Specific Populations • Drug Abuse and Dependence • Overdosage

The Medicare Prescription Drug Improvement and Modernization Act 2003

• Provides prescription drug (coverage) benefits to Medicare patients (> 65 years old, Disabled, ESRD) --• Medicare Part D (pay for drugs) • Coverage is voluntary • Available through insurance companies • Deductible $310 and "Donut Hole" from >$2,830 to <$4,550 (2010) • Excludes weight loss or gain, fertility, cosmetic or hair growth, cough or cold relief, vitamins and minerals, non-prescription drugs, barbiturates, and benzodiazepines

Side Effects Statement

• Required under FDAAA • "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088" • Options: • (1) Sticker attached to bottle • (2) Preprinted prescription vial cap; • (3) Separate sheet of paper; • (4) Consumer medication information or • (5) FDA-approved Medication Guide

Retail Pharmacies & Samples

• Retail Pharmacies may not have drug samples • Samples do not include: -• "starter packs" -• drugs that are provided free of charge -• drugs at a reduced price, pursuant to an indigent patient program

Biologics Price Competition and Innovation Act 2009

• Title VII of the Patient Protection and *Affordable Care Act* • Authorizes the approval of "generic biologic drugs" ---• *"351(k)"* • First Biosimilar Approved March, 2015 -->• Filgrastim-sndz (Zarxio, Sandoz)

Bifurcated Drug Class Framework

• Two class distinction based on misbranding • Non-prescription drugs must be labeled with adequate directions for use (default class) • Drugs that can not be labeled with adequate directions for use may be sold if: --• Prescribed (written/oral/refill authorized) by practitioner licensed by law --• Dispensed by a licensed pharmacist meeting certain requirements --• Sold as prescription w/ Adequate information for use • *Prescribers and dispensers are authorized by state law* *Consequences* • Non-prescription drugs are used to treat minor illnesses which don't require medical intervention and patients can understand the health risks involved and how to use the drug • All other illnesses and drugs require a physician - to control the amount of medication patients received through prescriptions and refills • Pharmacists repackage prescription drugs for sale to a patient in a pharmacy vial --• Exempt from labeling requirements of manufacturers --• Must follow, minimal legal requirements on prescription container

Biologics Price Competition and Innovation Act

• User fee supported abbreviated pathway for generic biologics • Brand drug has 12 year exclusivity • 1 year first generic exclusivity for interchangeable product • *Six month pediatric exclusivity* • No 30 month stay provision • Complex patent dispute process