1.  The Federal Government

• Congress
• Administrative Agencies (FDA, DEA, etc.)
• Courts/Judicial Process

2.  The State Government

• Legislature
• Administrative Agencies (Board of Pharmacy)
• Courts/Judicial Process

1.  Legislative Branch (Congress)

• Feds and states can regulate same area
• Criminal, Civil, and/or Administrative actions
• Administrative Agency Enforcement

2.  Executive Branch (Regulatory Agencies)

• Enabling legislation (express or tacit)
• Administrative rule-making (policy making)
• Administrative decision-making (adjudication authority)

3.  Judicial Branch (Court of Interpretations)

• Review constitutionality of legislation
• Interpet meaning/intent of legislation
• Review administrative enforcement efforts

• Balance risks vs. benefits
• Promote health, safety, and welfare
• Ensure individual patient safety
• Standardization/consistency for professionals and consumers
• Societal demand (Rx-to-OTC switch/Advertising Rx drugs)

• Required federal government to grant premarket approval for every biological drug and for the process and the facility producing such biological drugs
• This act when made when contaminated smallpox vaccines and diptheria antitoxins led to tetanus outbreaks and death in children

• Goal: accurate labeling of food and drugs (did not apply equally to advertising)

Two definitional bases for enforcement:

1. Adulteration
2. Misbranding

• Recognizes USP-NF as official standard
• Did nothing to address safety or efficacy of the underlying drugs
• Did set the stage for today's laws

A drug listed in the USP, but which did not meet USP specifications (unless variations from the USP were clearly labeled)

• Addressed "false and fraudulent" claims
• FDA had to prove knowledge and intent
• Amendment did not help all that much

• Taxed the production, sale, and use of opium
• Required prescriptions for products exceeding the allowable limit of narcotics
• Mandated increased record keeping for doctors and pharmacists dispensing narcotics
• Predecessor of the Controlled Substances Act

• Discovery of Sulfanilamide won chemists the 1932 and 1936 Nobel Prizes
• 1st "miracle" drug
• Labeled as an elixir
• Liquid was made with diethyl glycol (antifreeze)
• 107 died as a result
• FDA could only sieze under a misbranding theory (it contained no alcohol)
• Manufacturer was sued and the chemist that used diethyl glycol as the vehicle was fired

Drafted in 1933 -- Not enacted until 1938

• New drugs must be proven safe for the use under labeled conditions prior to marketing
• Labeling to contain adequate directions for use
• Approval by FDA required prior to marketing
• Main authority still revolves around misbranding and adulteration -- new definitions for both
• Warnings must be included for habit-forming drugs
• Pre-1938 drugs not subject to FDCA

• Thyroxine
• Digoxin
• Nitroglycerin
• Phenobarbital

• Fails to conform to USP/NF standards for purity, quality, strength, and appropriate assays
• Not stored under USP standards

• Incomplete labeling
• Misleading labeling
• FDA largely defines and enforces "incomplete" and "misleading"
• FDA now approves ALL labeling (Rx and OTC)

1. Drugs NOT requiring medical supervision for their safe use:

• Referred to as OTC
• OTC's must give "adequate directions for use"
• The amendment also provides for oral Rx's and refill Rx's

2. Drugs REQUIRING medical supervision for their safe use:

• Must have a "legend" stating "Caution: Federal law prohibits dispensing without a prescription"
• Must appear on the manufacturers label, but then DO NOT need to give "adequate directions for use"
• Drug MUST then be dispensed with prescriber's direction for use

AKA Drug Efficacy Act

• Does not apply to pre-1938 drugs
• Adds efficacy to safety as a prerequisite for FDA new drug approval process
• Shifted from pre-market notification to FDA pre-market approval by FDA
• Established good manufacturing practices
• Adds clinical study oversight safeguards and important patient protections
• Greatly slowed drug approval process -- safety easier to establish than efficacy
• This amendment forever changed the FDA drug review and approval process

1. Proven safe and effective for intended use
2. Adequate labeling (approved by FDA)
3. Meets good manufacturing practices
4. Produced by a registered manufacturer

• Does not apply to pre-1938 devices
• Expands FDA authority over medical devices
• Establishes device classes and device GMPs
• Some "Generally Recognized as Safe" devices have yet to be approved (grandfathered)

Low Risk

• Tongue depressors, gauze, manual stethoscopes, etc.
• Subject to Good Manufacturing Practices (GMPs), etc.

Medium Risk

• Infusion pumps, X-Ray machines, Powered wheelchairs
• Subject to same controls as Class I devices (GMPs), AND:
• Product-specific controls or performance standards

High Risk

• Artificial hearts, pacemakers, stent and catheters, etc.
• Subject to FDA approval process like new drugs
• Have to be proven safe and effective in clinical trials and pass an FDA premarket approval process

• Designed to promote development of drugs for rare diseases, but which are prohibitively expensive/un-profitable to develop
• Defined as diseases affecting fewer than 200,000 people in the US
• Companies rewarded with tax deductions and marketing exclusivity for an extended time (7 years post FDA approval)

AKA Drug Price and Patent Term Act

• "Abbreviated New Drug Application" -- demonstration of bio-equivalency = sufficient now
• "Patent Term Extensions" to brand name drugs -- extension capped at 5 extra years
• Applies equally to US drugs and imports
• Requires FDA to publish the "Orange Book" -- Bioequivalency of "brand" to "generics"

• Record-keeping and re-sale limits on "samples"
• Prohibits re-sale of drugs bought by non-profits except for its patients, employees, and related entities
• Requires state licensure of wholesalers and other secondary distributors, repackagers, etc.

• Created the current uniform label format
• Standardized "serving size"

Standardizes "descriptor" use:

• "low" calorie
• sugar "free"
• "light"
• "high" fiber

Regulates nutrient/disease relationships

• calcium/osteoporosis
• fiber/cancer
• Na/HBP
• Fats/ASHD and cancer

• Supplements treated more like foods than drugs
• "Overstating" can result in regulation as a drug
• "Intended to treat, prevent, cure" = prohibited
• Disclaimer required: "statement not evaluated by FDA"
• Botanicals and "natural source" items covered too

• Main intent was to get FDA additional non-government source of revenue so it could hire more personnel to assist in the drug review process
• Enacted only a 5 year "pilot" term
• Manufacturers pay fees for FDA review

• Enacted to overhaul the FDA and its regulatory process
• Main purpose was to expedite the drug review process
• Fast track approval for drugs for "life threatening" diseases
• Permits manufacturers to provide info about off-label uses
• Limits prescriptions compounding w/o manufacturers license -- aimed at bulk-compounding pharmacies

• Pre-Clinical Testing
• File IND (Investigational New Drug)
• Clinical Trials
• File NDA (New Drug Application)

• The 1st application that a sponsor/manufacturer must submit to FDA
• FDA has 30 days to decide if drug is suitable for testing
• Sponsor submits pre-clinical (animal) studies
• Sponsor provides descriptions of proposed clinical protocols

Phase 1

• Small group of healthy individuals
• Purpose is to evaluate toxicity, pharmacokinetics, and safety

Phase 2

• Larger groups (100+)
• To patients who have disease or symptoms
• Purpose is to preliminarily evaluate effectiveness and dosage

Phase 3

• Very large groups (1000+)
• In controlled studies to compare effectiveness versus standard therapy

Phase 4

• Post-Marketing studies

• Submitted after clinical trials (1, 2, and 3)
• Manufacturer may market drug once approved
• After a drug is marketed, Phase 4 studies may be conducted for post-marketing surveillance purposes
• "Fast Track" status may be requested for drugs intended for serious or life-threatening conditions

• For generic drugs
• Requires less data (pharmacokinetic and bioavailability)

• After marketing, manufacturers may desire to make changes in the drug's synthesis, production procedures, packaging, labeling, etc.

Type P = Priority because of major therapeutic gain

Type S = Similar drug

• All Rx and OTC drugs marketed in the US have an NDC number
• Is assigned by the FDA
• Does NOT have to be placed on packaging
• Does NOT have to be placed on dosage units
• Identifies manufacturer, drug, and package size

1st five digits identify manufacturer

2nd five digits identify drug and package size

• Name, address of manufacturer, package, or distributor
• Name of drug
• Net quantity
• Weight of active ingredient
• The Federal Legend
• Appropriate Warnings as necessary
• Adequate Directions for use
• Route of administration
• Any special dosage directions
• Manufacturer's control (lot) number
• Expiration date established by the manufacterur

• Name, address of manufacturer, package, or distributor
• Name of Product
• Net quantity
• Weight of active ingredients
• Name of any habit forming drug
• Cautions and warnings
• Adequate directions for use

• Requires child-resistant containers (CRCs) on certain "household substances"
• Requires CRCs on all Rx drugs, except for certain listed products
• Requires CRCs on specifically listed OTCs
• Authorizes Consumer Products Safety Commission to set standards for child-resistant packaging, or "special packaging" as its called in the Act

• the prescriber specifies that one is NOT to be used
• the patient indicates NOT to use such a closure
• the container will be used in an institutional setting and the drug administered by a health care professional
• refills must use a new vial and cap
• the CPSC discourages the use of reversible caps
• there is a list of exempt Rx products

• Indicator or barrier to entry
• If breached or missing, there is a visible evidence of tampering
• Label statement describing barrier or indicator
• Required for certain OTCs, devices, and cosmetics
• Dermatologicals, lozenges, and insulin are excluded

• Doesn't cover drugs without NDA
• Generics listed must have approved ANDA
• Pre-1938 not required to be in the Orange Book

• A = products considered therapeutically equivalent to "reference" product
• B = products NOT considered therapeutic equals
• AB = products with actual or potential equivalency problems

• Used when two or more "reference" drugs are available which are not bioequivalent to each other

Adalat CC = AB1

Procardia XL = AB2

A nifedipine generic rated AB1 can be exchanged for Adalat CC

Those that are AB2 can be substituted for Procardia XL

BC = extended-release formulations

BE = delayed-release formulations

BD = active ingredients with documented problems

BP = active ingredients with potential problems

BN = aerosols or nebulized formulations

BR = rectal formulations

BT = topical products

BS = drug standard difficulties

BX = insufficient data

B* = questions remain to be resolved

• A list of drugs that CANNOT be generically substituted
• Usually "narrow therapeutic index" drugs
• Missouri is a negative formulary state

• A list of drugs that may be generically substituted
• Based on bioavailability data
• Illinois is a positive formulary state

• A physician CAN prescribe an approved drug for an unapproved use
• A pharmacist CAN advise a physician in regard to use of a drug for an unapproved use
• A sales representative CANNOT promote the use of their company's drug for an unapproved use

Class I

• Likelihood of injury or death from use of product
• May include public warning

Class II

• Temporary or reversible health problems from use of a product

Class III

• Use of product NOT likely to cause health problems

Market Withdrawal

• Minor health risk or minor FDA violation

For Non-Aqueous Liquids and Solids

• Not more than 25% of the time remaining on the commercial product or a maximum of 6 months -- whichever is less

For Aqueous Solutions Obtained From Manufactured Products

• 14 days when stored at cold temperature

For All Others

• The duration of therapy, but no more than > 30 days

• The responsibility for the proper prescribing of legend drugs is upon the prescribing practitioner, but a corresponding responsibility rests with the pharmacist who dispenses the prescription

1.  First Letter

Before 1985 = A

After 1985 = B

Mid-Level Practitioner = M

(nurse practitioners, nurse midwifes, nurse anesthetists, clinical nurse specialists, physician assistants, optometrists)

2.  Second Letter

First letter of last name

Followed by 7 numbers that can be verified by the following calculation

(1st + 3rd + 5th) + 2(2nd + 4th + 6th) = the last digit of the final sum should be the same as the 7th digit

A hospital employee may use the hospital's DEA number provided that the hospital issues the prescriber an internal code that is to be added to the end of the DEA number

Federal Program, Federal Funding

• Brings minimum healthcare to elderly > 65 yo, certain disabled persons of any age

4 Components:

Part A = Hospital services

Part B = Physician services

Part C = Part B via Managed Care Co.

Part D = Rx Drug Benefit

• Benzodiazepines
• Weight loss/gain drugs
• Fertility drugs
• Cosmetic and Hair Growth drugs
• Cough and Cold Preps for symptom tx
• Outpatient drugs that the manufacturer requires testing

• Brings minimum health care to:

-Medically indigent persons (blind, disabled, aged), -Financially indigent (no or low income and asset base)

• Medicaid covers:

Hospital services (Inpt, Outpt)

Physician services

Diagnostics (lab, x-ray, etc.)

Skilled nursing facilities and home health

Dental and Optometric services

Outpt Rx drugs

"Condition of Participation" in the Federal Medicaid Funds Matching Program

• federal requirement of states
• if state wants federal money, it will adopt OBRA rules

Requires states to participate in various OBRA initiatives, such as:

• Mandatory rebates
• Demostration projects
• Drug utilization review

• Manufacturers must provide pharmaceuticals to Medicaid at their "best price"
• Manufacturers pays the state the difference b/w the lowest price and the "average" manufacturer's price

• Determine whether the patient outcomes improve and costs decrease as a result of pharmacist DUR, services, etc.
• Part of a continuous quality improvement (CQI) cycle

1. Retrospective Review

• did therapy conform to the "ideal"

2. Educational Programs

• physician or pharmacist symposia to improve use of medications

3. Prospective Review

• new data concerning the dispensing of medication

1. Duty to maintain patient profiles
2. Duty to screen therapy
3. Duty to counsel patients about their drug therapy (duty to warn)

• Prohibits knowingly making a false statement of fact in applying for benefits or requesting payment for services
• Prohibits willfully soliciting, receiving, offering or paying any remuneration in exchange for referrals or the provision of Medicare/Medicaid paid goods/services
• Violations are a felony!

• Employment Arrangements
• Personal Service Arrangements
• Space/Equipment Leases
• Fair Market Value Transactions
• Certain Investment Interests

Restraint of Trade = Unlawful (Sec 1)

Monopolies = Unlawful (Sec 2)

Market Power vs Monopoly

Per se Violations

• Price fixing
• Boycotting
• Tying Amendments
• Some exclusive contracts

Price discrimination among similarily situated purchasers = generally unlawful, if it tends to injure/limit competition

• Robinson-Patman exception
• Better pricing to nonprofits = okay if limits apply

Permitted by Durham-Humphrey Act

Can happen in 3 ways

• Manufacturers request the switch via SNDA
• Manufacturer can petition the FDA
• FDA can recommend the switch

• FDA regulates Rx drugs via FDCA
• Federal Trade Commission regulates OCTs via FTC act
• Lanham Act (Trademark) prohibits false and misleading advertising