2.

Pharmacy Laws and Regulations (Q:3%)

THE FOOD AND DRUG ADMINISTRATION
The Drug approval process
- FDA is responsible for protecting the public health by assuring the safety, efficacy and security of
human and veterinary drugs, biological products, medical devices, our nation’s food supply,
cosmetics and product that emit radiation
- The Food and Drug Administration (FDA) split up the responsibilities among six centers
o Center for Drug Evaluation and Research (CDER)
Phase Subject Purpose
Pre- Animals (e.g., rodents) Relative safety, therapeutic potential,
Clinical Manufacture will file investigational new drug (IND) application w/ the FDA
IND permit to initiate phase 1
Phase I Healthy subjects (-20-80) Safety: side effects, adverse effects, PK & PD
Phase II Patients (-35-100) Safety & efficacy: Dosing range studied (optimal dose)
Phase III Patients (-300-3000) Determine if drug is better (safer or more effective)
Efficacy for treating the condition compared to placebo or gold-standard Tx
505(b) NDA Once show the result, the new drug application (NDA) is used for drug and biologics
505(j) aNDA license application (BLA is used for biologics); these will include all the collected data
CDER will review 90% of applications for w/in 10 month (6 months for priority drugs)
Phase IV Patients Post-marketing surveillance; after drug approved, it study to examine the risk and
benefits of the new drug in a different population or in high-risk population, also long-
term effects of drug exposure
- New label, add new indication, dosage or strength, any other changes, a company must submit
supplemental new drug application (sNDA)
Prescribing Information approval
- When drug is approved, the package insert is approved concurrently
o Indications and usage
o Dosage and administration
o Dosage form and strength
o BBW is present
o Contraindication
o Warnings and Precaution
o Adverse Reactions
o DDI
o Use in Specific Population (including pregnancy, nursing, pediatrics and geriatrics)
o Description
o Clinical pharmacology
o Clinical Studies
o References
o How supplied/ storage and handling
o Patient Counseling Information
The over the counter drug (OTC) approval process
- Either with the same NDA process used for Rx drugs or can be approved though the simpler
OTC drug monograph process
- OTC drug monograph process in 3 steps (three-phase public rulemaking process)
o Each phase requires a publication in the Federal Register, the federal government’s daily
newspaper
o The final version is the drug monograph
o First phase of the process, the FDA forms adversary review panels to review the active
ingredients and determine whether they are “generally recognized as safe and effective” for use
in self-Tx.
o The conclusion are published in the Federal Register in the form of an advanced notice of
proposed rulemaking (ANPR)
 o Second phase is the agency’s review of active ingredients; FDA publishes its conclusions in the
Federal Register in the form of tentative final monograph (TFM)
o Third phase is Final OTC drug monograph, which establish the conditions under which the OTC
drug has been recognized as sage and effective
Generic drug approval and the abbreviated new drug application
- Generic drug approval requires an Abbreviated New Drug Application (ANDA)
- ANDA reviews the generic product’s chemistry, the manufacturing controls and the labeling
- Does not require pre-clinical and clinical studies
- The Bioavailability data required with an NDA is replace with a simpler bioequivalency analysis
FDA adverse event reporting system and Medwatch
- All drug causes some adverse event should be reported to the FDA’s MedWatch Program
- Pt cannot report to MedWatch directly; pt and healthcare professionals can report to the drug
manufacture who required to collect data for the first 3 years (part of phase IV)
- If the ADR are serious enough, the FDA may mandate REMS or removed from the market
Unapproved drugs remain on the market
- Drug established before 1938 is not unapproved by FDA; some drugs required to submit NDA (e.g.,
levothyroxine)
- Unapproved drug will have an NDC # but will not be listed in the FDA’s approved drug product with
Therapeutic Equivalence Evaluations (Orange book)
Direct-To-Consumer advertising for drugs
- Rx drug advertising is regulated by the FDA
- ORX drug advertising is regulated by the Federal Trade Commission (FTC)
- Does not need FDA approved but the FDA will get involved is the information is false (misleading
statement, misbranding)
- FDA minimum requirement for what an advertisement must contain
o Name of the drug (brand & generic)
o At least one FDA approved use for the drug
o The most significant risks of the drug
Drug recalls
- Drug recalls are made for a variety of reasons
Market withdrawal
- Manufactures may withdraw a drug for many resons such as, safety issue, or decreased market
demand
Counterfeit drugs (fake, illegal drug)
- Misbranded and adulterated, manufacture does not follow Current Good Manufacturing Practice
(CGMPs)
- FDA is responsible for investigating reports of counterfeit drug
- E.g., Avastin, Adderal, Plan B One-Step

PURE FOOD & DRUG ACT (1906) (The WILEY ACT) before 1905, we can buy anything
- First legislation that offered protection consumers from drug misuse
- Establish Meat inspection law and comprehensive food and drug law
- Drug was to mandate accurate product labeling and to require that the ingredients used in drugs met
the standards of strength, quality, and purity in USP and National Formulary (NF)
- The law required that food or drug label could not be false or misleading
- No adulterated or misbranded drug

FOOD, DRUG AND COSMETIC ACT (1938) FDCA

- 107 deaths from diethylene glycol used as antifreeze
- Manufacture required to prove safety of a drug before it can be marketed
- The product claims must be accurate, and all ingredients must be listed on the label
- Drug could not be adulterated or misbranded
- FDA was given authority to inspect manufactures and distributors
- Definitions: food, drug, dietary supplement, device for human & animal, but cosmetic is human only
 o Food: items used for food or drink, the components in the food or drink and chewing gum
o Drug:
 Items recognized as drugs by the USP, NF and the official Homoeopathic
Pharmacopoeia, and their supplements
 Item used to diagnosis, cure, mitigate, treat or prevent disease
 Item intended to affect the structure or any function of the body
o Dietary Supplements: are defined as food (b/c cannot do health claim; e,g., cure, prevent
 Product (other than tobacco) intended to supplement the diet that bears or contains one
or more of the following ingredients: a vitamin, mineral, herb or other botanical, or amino
acid, and their concentrates and extracts. These can be in combination
 Dietary substance meant to supplement the diet by increasing the dietary intake and
which is not used as the conventional food or as the sole item of a meal or the diet
o Devices:
 Instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or
similar that recognized by USP
 An item intended to be used in the diagnosis of disease or other conditions, or in the
cure, mitigation, treatment, or prevention of disease
 Item intended to affect the structure or any function of the body, and which does not
achieve its primary intended purposes through chemical action, and which is not
dependent upon being metabolized
o Cosmetics: Items that are intended to be rubbed, poured, sprinkled, sprayed on, introduced
into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness,
or altering the appearance, and the components of cosmetics, except soap
- Causes of Drug Adulteration:
o It is filthy, putrid, or decomposed
o it has been prepared, packed, or stored under unsanitary condition where it may have
become contaminated with filth, or where it can become dangerous to person's health
o It contains a drug recognized in official compendia, but its strength is different from official
standard, or the purity or quality is lower than the official standard
o It contains a drug not recognized in official compendia, but its strength is different from that listed
on the label, or the purity or quality is lower than that listed on the label
o The official monographs of the USP are used to make sure that the drug meet the requirements
for the compound's identity strength, quality and purity is lower than that listed on the label
- Causes of Drug Misbranding: involved labeling (outside of bottle)
o Lack of required information on package (weight, count, warnings, use in specific groups,
unsafe dosages, methods of use, Tx duration)
o If there are any false or misleading product information (e.g., imitating another drug)
o Lack of special precaution such as “Keep original container”
o If the information is illegible (cannot read)
o If the packaging does not contain the proprietary (branded) or established common name
recognized by USP monograph
o Not contain the manufacture and business location and packer or distributor
o If there is improper packaging or incomplete labeling of additives
o If there is a deficient in packaging according to the requirements of the Poison Prevention
Packaging Act
DURHAM-HUMPHREY AMENDMENT (1951)
- Clear distinction was made b/w OTC and prescription drug
- Three condition that would make a drug available only by Rx
 Habitat-forming
 Consider unsafe for use except under the supervision d/t toxicity
 Drugs limited to Rx use only under a manufacturer's new drug application
- Another term used for prescription drugs: Legend drugs (now simplified to Rx Only)
- OTC drugs were required to contain adequate direction for use in the “drug facts label”
 o The labeling must include safety in pregnancy and breast feeding, the Ca, Na, Mg and K content
and the product’s US contact information to report adverse events

KEFAUVER-HARRIS AMENDMENT OF 1962 (also known as the Drug Efficacy amendment)

- Thalidomide was used as sleeping pill and nausea in pregnancy, but the approval in the U.S. was
blocked by a pharmacologist, Dr. Frances Oldham Kelsey
- Kefauver-Harris Amendment which implemented the following changes:
o Manufactures must prove both safe and effective before it can be FDA-approved
o Post-market, Manufactures must continue to report serious side effects to the FDA
o Individuals must give their informed consent when they are study subjects
 the individual has a right to know what to expect, including all the risks & benefits
o FDA had to conduct retrospective evaluation of the effectiveness of drugs approved b/w
(1938 – 1962)
o Allowed the FDA to establish Current Good Manufacturing Practices (CGMPs) for drug
manufacturing and to perform inspections
 CGMP prevent contamination, mix-ups, deviations, failures, and eeors
o The FDA was given oversight to regulate the advertising of prescription drugs
o The Federal Trade Commission continues to regulate advertising of OTC drugs

CONTROLLED SUBSTANCES ACT (1970) (Comprehensive Drug Abuse Prevention & Control Act)
- Controlled substances are drugs that have the potential for addiction & abuse
 require stricter regulation & control
- Established closed system of the manufacturing, distribution, dispensing to reducing drug diversion

POISON PREVENTION AND PACKAGING ACT (1970) (PPPA) FOR Rx drugs!!!

- PPPA is enforced by the Consumer Product Safety Commission to prevent accidental poisoning in
children less than 5 y/o
- Requires some household substances and drug to be packaged in child-resistant (C-R) packaging
which must be difficult for children under 5 y/o to open within a reasonable time, and not difficult for
normal adults to use properly (physician or patient can make request)

DRUG LISTING ACT (1972)

- Required to have a unique national drug code (NDC) number on OTC & Rx package & insert
- NDC is 10- or 11-digit code with three segments e.g., NDC 0015-3479-11
o Labeler code (4 or 5 digits) assigned by FDA who sell the product??
 A labeler is any firm that manufactures, repacks or distributes a drug product
o Product code, identifies the strength, dosage, formulation (3 or 4 digit), assigned by labeler
o Package code, identified the package size and type (1 or 2 digits), determined by labeler

FEDERAL ANTI-TAMPERING ACT (1982)

- In 1982, 5 people died after taking Tylenol capsules filled with cyanide in Chicago (adulterated drug)
- Required tamper-resistant features on OTC medications
- Exceptions: skin products, insulin, lozenges, tooth cle2aning powder (dentifrice)

ORPHAN DRUG ACT (1983)

- Providing incentives to manufactures to develop orphan drugs, including a tax credit for 50% of the
clinical testing costs; Drugs are also given a 7 years period of exclusivity
- Orphan drugs are developed under the FDA's Office of Orphan Products Development (OOPD)
- Drugs eligible for inclusion in this program include products that will treat disease that affect less
than 200,000 people in the U.S., or for products with no reasonable expectation that the cost of
research and development will be recovered by the sales revenue

HATCH-WAXMAN ACT (DRUG PRICE COMPETITION & PATENT TERM RESTORATION ACT) 1984
- To streamline generic drug approvals and grant patent protection to drug innovators (the manufacture
that made the brand name drug)
- The purpose is to increase the availability of generics and cut costs
- Application for generic drug to approval is one of two abbreviated applications:
o Abbreviated New Drug Application (ANDA) OR
o 505 (b)(2) application, which referred to as a paper NDA
- Under the ANDA, the company must provide study data to establish that the generic drug has the
same active ingredient, route of administration, dosage form, and strength as the branded drug, and
bioequivalent to the branded drug
- Inactive ingredient can be different
o Inactive ingredient are also called inert or excipient
o Such as fillers, extenders, diluents, wetting agent, solvents, emulsifiers, preservatives, flavors and
sweeteners, absorption enhancers, SR matrices and coloring agents
o Inactive ingredients are not always inert. E.g., phenylalanine, lipid emulsion
o Inactive ingredient are listed in the CDER ingredient dictionary, which is part of the Orange book
- No longer had to conduct clinical trials to establish safety and efficacy
- NDA allows the generic drug manufactures to submit evidence of previously published report of
investigations of safety and effectiveness
- Provided patent protection to the company that create the brand name drug by granting up to 5 yrs of
patent exclusivity

PRESCRIPTION DRUG MARKETING ACT (1987) PDMA

- Purpose is to reduce public health risks from adulterated, misbranded, counterfeit or expired drugs
- Prohibits reimportation: Rx drug products manufactured in the US and subsequently exported to a
foreign country cannot be reimported back into the US except by the product’s manufacture
- Sale of drug samples & coupons was prohibited
- Drug coupons are either given to prescribers to provide to pts at no cost, or are given to consumers
by the manufacture in some type of product promotion
- Pt cannot buy drugs in other countries and bring them into the US except;
o The quantity is for ≤ 90 days supply, and is for the pt (cannot resold)
o Effective Tx is not available in the US, the condition is serious, the drug is no unreasonable risk
- PDMA requires wholesalers to be state-licensed and meet uniform standard to blocked hospitals from
reselling drug as a normal part of business by placing strict limits on the percentage of drugs that
hospital pharmacies can resell
- Selling to drug to another hospital is only permitted in order to help other hospital d/t drug shortage

*OMNIBUS BUDGET RECONCILIATION ACT (1990) (OBRA)

- Purpose is to reduce improper medication use and inefficient use of federal dollars spend
- Requires the pharmacists to perform a prospective drug utilization review & counseling
for all Medicaid beneficiaries before dispensing the Rx to the pt
- State were also required to perform a retrospective drug utilization review

DIETARY SUPPLEMENT HEALTH AND EDUCATION ACT (DSHEA) 1994

- Defined as food product (before of this act, supplement were regulated in the same manner as drug)
- Adulteration and misbranding remain prohibited
- FDA will require a pre-market review for safety data (only onetime)
- Not required safety, efficacy date or FDA approval
- The product must include a disclaimer that the FDA has not evaluated
- The difference b/w drug and supplement is the health claim of the product
- Supplement cannot say “cure, prevent, correct or treat a disease or condition”
- Permitted to claim that a supplement addresses a nutrient deficiency, supports health or is linked to
body function; e.g., “Supports intestinal health” or “Relax and sleep”
- Information that must be on a dietary supplement label includes
o a descriptive name of the product such as “supplement or dietary supplement”
 o the name and address of the manufacture, packer or distributor
o complete list of ingredients and the net content which is the amount in the container
o each dietary supplement must include the “supplement Facts” box on the label

FDA MODERNIZATION ACT (FDAMA) 1997

- it required the establishment of a registry for clinical trails, approved labeling changes for a food &
drugs, enabled the manufacture to discuss off-label drug use, extended amendment passed in 1992
(PDUFA) that permits the FDA to charge a manufacture fees to expedite the drug review process
- FDAMA made special exemption for compounding pharmacists to continue preparation of
individualized drug products not otherwise available
- w/o accurate labeling, a drug is misbranded
- Under the Durham-Humphrey Amendment, all Rx required a label that included the statement
“Caution: Federal law prohibits dispensing w/o Rx”
- But under the FDAMA: can simplified to “Rx only”
- FDAMA permitting fast-track approval updated
- Regulation were developed to accelerate approval for high-priority medication
- FDA has four programs to help speed the development and review of new drugs
o Fast track designation
o Breakthrough therapy designation
o Accelerated approval
o Priority review designation

THE DRUG ADDICTION TREATMENT ACT (DATA) 2000

- Prior to the DATA 2000, the primary Rx was methadone, which was available only through a DEA-
registered OTP, and These are not widely available and can stigmatize those seeking care
- DATA 2000 permits physicians to prescribe & dispense CS in office-based setting to treat
- In 2016, the Comprehensive Addiction and Recovery Act (CARA) allowed nurse practitioners and
physician assistants to treat pts for opioid dependence as well

FDA AMANDMENTS ACT (FDAAA) 2007

- Give new authority to the FDA to enhance drug safety
- The Risk Evaluation and Mitigation Strategy (REMS) program is the part of this legislation
- The drugs will require more involvement from the manufacture, distributor, prescriber, pharmacist
and/or pt to ensure that the benefits of the drug outweigh the risk

AFFORDABLE CARE ACT (2010) ACA also known as “Obamacare”

- AphA has identified several areas that have a large impact on the pharmacy
o CMS innovation Centers (CMSIC), Essential Health Benefits, Medical Loss Ratio, Integrated
Care Models, Transitional Care Models
o Improvements to Medicare Part D Medication Therapy Management (MTM)

THE BIOLOGICS PRICE COMPETITION AND INNOVATION ACT (2010) BPCI

- Biologics are derived from living organisms such as vaccine, insulin, human growth hormone,
erythropoietin, interferons and others
- Use “biosimilars” instead of “generics”
- Biosimilar is cost saving about 20-35%; (conventional drugs is -75% saving)
- BPCI created an abbreviated licensure pathway for biological products that are demonstrated to be
biosimilar to or interchangeable with an FDA approved biological product
- Biosimilar must have the same mechanism of action, route of administration, dosage form and
strength as the reference product, and will only be approved for the indications of the reference
biologic
- In 2015, filgrastim-sndz (Zarxio), a leukocyte growth factor become first biosimilar approved in the US
- These drugs are listed in the FDA’s Lists of Licensed Biological Product with Reference Product
Exclusivity and Biosimilarity or Interchangeability Evaluations (Purple book)
DRUG QUALITY AND SECURITY ACT (2013) DQSA
- DQSA is consist of the Compounding Quality Act and the Drug Quality and Security Act
- The tragedy at the New England Compounding Center
- The Compounding Quality Act, give the FDA increased authority to regulate compounding
- The law marks a distinction b/w traditional compounder and “outsourcing facilities”
- If facility compounds sterile drugs for human, they can register as an outsourcing facility under 503B
- To prevent counterfeit drugs from entering the market, the Drug Supply Chain Security Act
established requirement to document the transactions of Rx drugs through the pharmaceutical supply
distribution chain
- Documentation must include transaction information, transaction Hx, and transaction statements

PREGNANCY AND NURSING LAVELING FINAL RULE 2014

- Previously Pregnancy Categories (A,B,C,D and X) will no longer be used
- The new requirements will be in package inserts by 2020
- Drug approved since June 30, 2001 will be required to use the new labeling requirement
- If the drug was approved prior to this date, the only change required in the labeling is to remove the
letter category, and keep the previous information
- The new information is placed into 3 categories
o Pregnancy: previously labor and delivery guideline
o Lactation: previously labeled “Nursing Mother”
o Females and Male of Reproductive Potential

THE COMPREHENSIVE ADDICTION AND RECOVERY ACT (2016) CARA

- CARA is an amendment to the Controlled Substances Act
- CARA authorized funding and regulatory help in response to the opioid epidemic
- The opioids find their way into the hands of others, including younger family members
- CARA permits pharmacist to partially fill schedule II drugs at the request of the pt or prescriber
- Any remaining opioids must be filled w/in 30 days from the date the prescription was issued
- Previous law regarding Schedule III-V still apply (partial fills are permitted for schedule III-V for up to 6
months from the issue date)