PHP308 Federal Regulations Part 3

NCSL website: legislation highlights -In bills enacted in 2013-2014, the language usually required that the prescriber "must be notified" of any allowable substitution made at a pharmacy. In 2015 bills the language commonly has been adjusted to say "communicate with," allowing a notation in an electronic medical record (EMR), PBM records or "pharmacy record that can be electronically accessible by the prescriber." (This would allow a physician to assess and compare the patient experience, but not delay the transaction.)

"Notification" vs "Communication:"

Under the poison prevention packaging act, what two components allow a container to be reused?

**Is glass or threaded plastic AND **A new safety closure is used.

5 general steps in getting a biologic approved by the FDA with a BLA?

1. Laboratory testing 2. Animal trials 3. Clinical trials under an IND 4. Product safe and effective submit a BLA 5. FDA approval biologics license with a US license # Note FDA approval to market a biologic is granted by insurance of a biologics license. The US license number must appear on the product labeling (misbranding if the product does not have the number on it)

Naming convention for biologics? (3)

1. Name (shared between innovator and related biologics 2. Suffix - random 4 letters submitted with IND or BLA Proper name 3. Proper name that contains both (FDA may add a prefix if it decides it is necessary to prevent errors but all will have a suffix)

FDA required MedGuides for products that: (3) 1. ? 2. ? 3. ?

1. Patient labeling could help prevent serious Adverse Events 2. Product has serious risks that could affect patient's decision to use or continue to use 3. Patient adherence to directions is crucial to effectiveness: "Medication Guide" program

What are the four exemptions that allow to dispense non-safety caps?

1. Prescriber request: may request on an individual prescription and its refills 2. Patient request: may have a blanket request for all prescriptions. • Request may be oral - but written statement better to prove defense later down the line 3. Institutionalized patients - if medication is administered by institutional personnel. 4. For manufacturer: • May market one size in noncompliant package to assist elderly or handicapped individuals. Must contain the language "This Package for Households Without Young Children" or "Package Not Child Resistant" (see PPPA guide posted in Brightspace) For example: 1. Sublingual nitroglycerin tablets; 2. Sublingual and chewable isosorbide dinitrate tablets in doses of 10 mg or less 3. Effervescent aspirin or acetaminophen tablets 4. Oral contraceptives packaged in "dialpacks" 5. Unit dose potassium supplements 6. Cholestyramine and colestipol powder 7. Aerosol inhalation products

Importation for personal use: -Controlled Substance Act (CSA) allows for a personal use exemption of • What amount? (units) • How can they be brought into the country?

50 units; Have to come in by person (cannot be mailed)

If the wrong generic is chosen, what violation is this considered?

A misfill/misbranding

What do the following drugs all have in common: -Digoxin, warfarin, phenytoin, levothyroxine

All are considered Narrow Therapeutic Index (NTI) Drugs

Defines an appropriate period of time during which a prescription drug may be retained by a patient after it is dispensed and takes into account such factors as the conditions under which the medication may be stored in the patient's home, the type of packaging, the nature of the drug being dispensed, and the frequency with which the package may be opened. -Date that we say (usually a year from day we dispense, or lower depending on expiration)

Beyond Use Date

"virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, ... applicable to the prevention, treatment, or cure of a disease or condition of human beings." -Large complex molecules dependent on living systems so their manufacturing processes are hard to replicate -Because of the complexity of manufacturing and characterizing it, the PHS Act emphasizes the importance of appropriate manufacturing control for products. • Environment - light, temperature, moisture • Manufacturing systems -Because, in many cases, there is limited ability to identify the identity of the clinically active component(s) of a complex _____________ product, such products are often defined by their manufacturing processes. •Changes in the manufacturing process, equipment or facilities could result in changes in the biological product itself and sometimes require additional clinical studies to demonstrate the product's safety, identity, purity and potency.

Biologics

This act (42 USC 262(k)) was part of Affordable Care Act. -Intent was to reduce the cost of specialty products. -Created abbreviated licensure pathway for biologics shown to be "biosimilar" (interchangeable) - Section 351(k) of Public Health Service Act -BPCIA establishes an abbreviated pathway for approval for products that are "highly similar" or interchangeable

Biologics Price Competition and Innovation Act of 2009 (BCPIA)

A biological product that is highly similar to and has no clinically meaningful differences from an existing FDA- approved reference product.

Biosimilar (biosimilarity)

Demonstrates that its product is highly similar to the reference product by extensively analyzing the structure and function of both the reference product and the proposed biosimilar. •demonstrate that its proposed biosimilar product has no clinically meaningful differences from the reference product in terms of safety, purity, and potency (safety and effectiveness).

Biosimilar Biologic Product

Who regulates the following biologics? -cellular products, gene therapy, vaccines, allergenic extracts, antitoxins, antivenins, venoms, blood, blood components, and plasma derived products.

CBER

Which of the following have no prescriptive authority? • Medical Doctor (MD) • Dentist • Podiatrist • Chiropractic physician • Veterinarian • Pharmacist - changing • Physician's Assistant - changing • Midwives • Doctor of Osteopathic Medicine

Chiropractic physician

Type of Rx--> OTC switch Entity can petition fda to switch Rx to OTC (happened with antihistamine) -ins companies did not want to cover -surprised has not happened with naloxone

Citizen petition

NCSL website: legislation highlights -Some legislation requires the pharmacist to explain the cost or price of the biologic and the interchangeable biosimilar. The enacted laws in Colorado, Georgia, Illinois, North Carolina and Texas require that any authorized or allowable substitution must have the lowest cost.

Cost or Pricing

If you do not comply with patient package inserts (PPI), what is this considered apart of? I. Adulteration II. Misbranding III. Label IV. Labeling A. I,II,III B. I, II, IV C. II, III D. II, IV E. I, II, III, IV

D. II, IV

You are a pharmacist working a shift during a rainy day. You recieve a script for a benzo 30 days, 5 refills from a dentist. What do you do?

Do not fill it. It is out of their scope to prescribe this medication for this duration with refills (does not make sense) -Could fill one for 2 days and no refills (makes sense for a procedure) -Need to think about each script we fill

PRESCRIPTION DRUG MARKETING ACT -Establishes restrictions to limit misbranding and adulteration situations -defined as a unit of drug not intended to be sold and intended to promote the sale of the drug -Establishes requirements for distribution to prescribers -prohibits community pharmacies from receiving samples -Should only be in physician offices, not in community pharmacies

Drug Samples

Exempts the pharmacy label on dispensed drugs from §502 except for certain provisions -Specifies the minimum information that a dispensed Rx label must contain. Federal required elements: -The name and address of the dispenser, -Serial number and date of the prescription or its filling -The name of the prescriber -And if stated on the prescription: the name of the patient, and the direction for use, and cautionary statements if contained on prescription • State standardized prescription labels and requirements

Durham Humphrey

Establishes criteria for distinguishing prescription drugs from OTC drugs • Legally establishes oral prescriptions and refills • Although the amendment did not contemplate electronic prescriptions, other federal and state laws permit them. Prescription (legend) medications: -Unsafe except under the supervision of a practitioner -Toxicity and method of use requires a practitioner's supervision -Collateral measures necessary to use the drug require supervision -Subject to an NDA approval process

Durham-Humphrey Amendment

Identifies the time during which the prescription drug may be expected to meet the requirements of the Pharmacopeial monograph, provided it is kept under the prescribed storage conditions. -Date manufacturer has on bottle -Some states allow expiration states on bottle instead of BUD

Expiration date

NCSL website: legislation highlights -Any biological product under consideration for substitution must first be approved as "interchangeable" by the U.S. Food and Drug Administration or FDA. (Three products have gained full FDA approval as a biosimilar (but not yet interchangeable) in the United States, as of November 2016)

FDA approval

Can a board of pharmacy inspect a store w/o notice? Do they need a warrent?

FDA can inspect a pharmacy to determine if the pharmacy is compounding or manufacturing and can extend the search if probable cause exists that the pharmacy is manufacturing -Yes, because of licensure, we agreed to terms for them to look -No do not need a warrent

True or false: The FDA has authority over generic substitution regulation

False: Generic substitution is part of the Pharmacy Practice Act in the states. The FDA does not have authority over substitution regulation.

1.The generic drug's labeling must be basically the same as that of the approved brand-name drug. 2. The drug company must: -Fully document the generic drug's chemistry, manufacturing steps, and quality control measures -Detail each step of the production process -Comply with regulations for current good manufacturing practices(cGMPs) -Give a full description of the facilities it uses to manufacture, process, test, package, label, and control the drug 3. Inspection at the proposed manufacturing site to determine that the company: -Is capable of meeting commitments of the application -Can manufacture the product consistently -Is in compliance with US FDA GMPs

Generic Drug Requirements

-Labeling must accurately differentiate generic product from brand - -Remember therapeutic equivalence is not therapeutic substitution.

Generic substitution

Which amendment gave birth to the orange book?

Hatch-Waxman

PRESCRIPTION DRUG MARKETING ACT -Enacted to prevent ______________ and similar entities from reselling, purchasing, trading, or offering to do any of these activities, differentially priced drugs to community pharmacies and others so as to prevent adulteration and misbranding opportunities and cost • Contract pricing • 340B pricing • Important exceptions exist, most notably selling or dispensing Rx drugs pursuant to prescription

Hospitals

NCSL website: legislation highlights -Some state legislation provides immunity for pharmacists who make a substitution in compliance with biologics state law.

Immunity

Which of the following does not have to be the same for an FDA-approved generic drug to be pharmaceutically equivalent? •active ingredient(s) •labeled strength •dosage form •administration •inactive ingredients

Inactive ingredients may differ

Biosimilar that meets additional requirements: • is expected to produce the same clinical result as the reference product in any given patient. • products administered to a patient more than once, the risk in terms of safety and reduced efficacy of switching back and forth between an interchangeable product and a reference product will have been evaluated.

Interchangeable or interchangeability

Types of regulations: (mandatory or permissive?) -Must substitute a less expensive generic unless Dispense as Written Some states mandate consumer consent Some states require that the cost saving be passed on to the consumer

Mandatory

-Manufacturers of innovator biologics are granted ____ years of exclusivity: additional ___ months if studies were performed in pediatric patients -Biosimilar product applications may not be submitted for ___ years after approval of the innovator -The first interchangeable biosimilar is granted ___ year of exclusivity

Manufacturers of innovator biologics are granted 12 years of exclusivity: additional 6 months if studies were performed in pediatric patients Biosimilar product applications may not be submitted for 4 years after approval of the innovator The first interchangeable biosimilar is granted 1 year of exclusivity

Manufacturers set criteria and receive FDA approval to distribute ______________. -Manufacturer must distribute to dispensers for new and refills -Must be distributed by practitioner or pharmacies to patients unless it meets the exemption - very individualized exemptions: *practitioner administered *inpatient setting Example Drugs: Accutane, Avonex, Advair Diskus, Lariam, Lindane, Nolvadex, Serevent Diskus, Strattera, Ziagen

MedGuides

Paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Medication Guides (MedGuides)

FDA's voluntary safety information and adverse event reporting program -Drugs, devices, biologics, dietary supplements, foods and food additives -Goals 1. report problems 2. get safety information out to patients -FDA enters information into a database and broadcasts new safety information as "MedWatch Alerts" -Official form (FDA 3500) can be found at www.accessdata.fda.gov/scripts/medwatch/index.cfm?actio n=reporting.home

Medwatch reporting (moral obligation)

Does the pharmacist have the right not to fill a prescription based on their moral and/or religious beliefs? What is the pharmacist's obligation if they do not fill the prescription? (ex: contraceptives, hormone replacement TransG, C2) Vermont had death with dignity--> pharmacist would have to dispense

Most states allow us to not fill (language usually says (do not hinder)- cannot take script and not give it back--> can fill somewhere else -Do not ever have to fill something that we think is clinically incorrect -Generally will have to let employer know if religious belief

Drugs with less than a two-fold difference between median lethal dose and median effective dose or two- fold difference between minimum toxic concentrations and minimum effectiveconcentrations. • Controversy exists as to whether FDA's statistical parameters for bioequivalence are accurate enough for certain NTI drugs; FDA drafting new guidelines • Pharmacists should exercise particular professional judgment when called upon to substitute B rated NTI drugs

Narrow Therapeutic Index (NTI) Drugs

Medication: may utilize all pharmaceutical agents in the treatment of conditions of the human eye and its appendages, including anterior uveitis and glaucoma, without surgery or other invasive techniques and Scheduled Medications including -oral steroids -narcotic and non-narcotic analgesics, within the scope of the optometrist's practice, and in accordance with the following: -A prescription for oral nonsteroidal anti-inflammatories shall not exceed one seven-day supply; -A prescription for oral steroids shall not exceed one seven-day supply; -A prescription for any controlled substance listed in schedules III—V of R.I. Gen. Laws Chapter 21-28, shall not exceed one seventy-two (72)- hour supply. (DEA registration required) -May prescribe schedule II hydrocodone-containing medications provided that the prescription does not exceed one seventy-two (72) hour supply. (DEA registration required) -No optometrist shall deliver any medication by injection.

Optometrists With Amplified Therapeutic Privileges

Medications which may be used by certified optometrists qualified to administer and prescribe topical therapeutic pharmaceutical agents in the treatment of conditions of the human eye and its appendages but not holding amplified privileges in accordance with § 20.4.2(B)(1) of this Part, include -topical medication (mast cell inhibitors or stabilizers), -lubricants, decongestants, -mucolytics, -antibiotics, -steroids with a clinical potency not exceeding 1/4% methyl-prednisolone or equivalent.

Optometrists Without Amplified Therapeutic Privileges

List with approved drug products with therapeutic equivalence evaluations? -uses 2 letter rating system and for some products 2 letters and a number Pharmacists must comply with state law when substituting and exercise professional judgment substituting B rated products -Requirements *Some states mandate consumer consent *Some states require that the cost saving be passed on to the consumer

Orange book

Intent of Act to protect children from accidental poisonings due to "household substances" from OTCs and prescription drugs -Manufactured such that 80% of children less than 5 years of age cannot open them, whereas 90% of adults can. -Administered by the Consumer Product Safety Commission -The law establishes the standards for child resistant containers -Container may not be reused unless: **Is glass or threaded plastic AND **A new safety closure is used. Some Exemptions: • Pharmacies • Manufacturers If dont follow--> adulteration/misbranding

POISON PREVENTION PACKAGING ACT

Act which states required to license wholesale distributors of prescription drugs • Bans reimportation of Rx drugs except by manufacturer or emergency use Prescription Samples: • Bans sale, trade, or purchase of Rx drug samples • Mandates requirements for Rx drug samples • Prohibits resale of Rx drugs purchased by hospitals or health care facilities, with certain exceptions • Bans the trafficking in or counterfeit of drug coupons -Gov'ts first attempt at addressing counterfeit products

PRESCRIPTION DRUG MARKETING ACT

NCSL website: legislation highlights -The individual patient must be notified that a substitute or switch has been made; this provision is included in at least 12 states. In some cases, state law would require patient consent before any such switch is made. (Some consumer experts note that proving notification or consent may discourage use of an approved biosimilar.)

Patient Notified?

Title 21 CFR Sec. 310.515 -Potentially dangerous drugs must be dispensed with it -Manufacturer is required to provide it in drug pkg. Information must be approved by the FDA for informational use only -Required for estrogens and progesterone products Sec. 310.515 -Applies to community pharmacists, physicians and hospital pharmacists that dispense these drugs -Must be dispensed with new and refills

Patient Package Inserts - PPI

Importation for personal use: -FDA "compassionate use" policy- what is allowed?

Patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.

Statement of origin that identifies each prior sale, purchase, or trade of a drug, including the date of those transactions and the names and addresses of all parties to them

Pedigree

Types of regulations (mandatory or permissive?): -A pharmacist may choose to substitute if the prescriber issues Rx allowing substitution Some states mandate consumer consent Some states require that the cost saving be passed on to the consumer

Permissive

Pharmacies required to provide number to patients for reporting with new and refills -Must provide patients with statement: "Call your doctor for medical advice about side effects You may report side effects to the FDA at 1-800-FDA-1088" In these ways: 1. Sticker attached to container or package 2. Preprinted vial cap 3. Separate sheet 4. In information materials distributed 5. In a MedGuide

Pharmacy Requirement:

NCSL website: legislation highlights -The prescriber (such as a physician, oncologist, physician assistant, etc.) would be able to prevent substitution by stating "dispense as written" or "brand medically necessary."

Prescriber Decides

What is the difference between the proper name and core name of biologics?

Proper Name means the nonproprietary name designated by FDA in the license for a biological product licensed under the PHS Act. (ex: replicamab-cznm) Core Name means the component shared among an originator biological product and any related biological product, biosimilar product, or interchangeable product as part of the proper names of those products. Two examples of a core name are filgrastim and epoetin alfa. (Ex: replicamab) Notice how no suffix with core name

Lists biological products, including any biosimilar and interchangeable biological products, licensed by FDA under the Public Health Service Act (the PHS Act). -includes the date a biological product was licensed under 351(a) of the PHS Act and whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act. -includes whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already-licensed FDA biological product). -351(K) - abbreviated pathway www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm

Purple book

What color is the biologics book?

Purple!

For this to happen, must be able to be labeled: • Patient can self diagnosis • Self treat • Self manage • Supervision of a practitioner is not warranted • Low potential for abuse or misuse • Risk/benefit 3 Methods • Manufacturer requests • Citizen Petition • FDA amends or add to an OTC monograph

RX to OTC switch

NCSL website: legislation highlights -The pharmacist and the physician must retain records of substituted biologic medications.

Records

The single biological product, already approved by FDA, against which a proposed biosimilar product is compared.

Reference product

-Prescription Drug Marketing Act generally prohibits reimportation of Rx drugs in attempt to prevent counterfeiting -Some patients, organizations and political entities wish to obtain prescription drugs from Canada and other countries because of lower costs -FDA has instituted a "compassionate use policy" and CSA Act also allows for limited personal importation -Medicare Modernization Act would allow wholesale importation of Rx medications from Canada provided Secretary of HHS would approve -Homeland Securities Act permits limited personal importation from Canada -FDA will enforce the no importation law against businesses (RxDepot case)

Reimportation and Counterfeiting

Necessity of Prescription Label. In accordance with §5-19.1-18 of the Act, to every box, bottle, jar, tube or other container of a prescription which is dispensed, a label shall be attached, the contents of which shall include: § The name of the prescriber; § The full name of the patient; § The name and address of the pharmacy; § The name of the drug dispensed in accordance with RIGL Chapter 21-31; § Quantity and strength of the drug dispensed; § The date of dispensing; § The prescription number; § The expiration date of the prescription in accordance with §13.21 of these Regulations; A full instruction on the use of the product in plain language. **Cannot handwrite a label unless emergency- RI specific**

Rhode Island regulations

What does scope mean? Who determines scope? How does it change?

Scope: What exactly that individual is allowed to write RX for -Our responsibility to know whether that practitioner has right to write that script where would you go to see what optometrists can write? -go to each and every practitioner and find there practice regs -Go to RI regulations for physicians to see -Need to know law for each state (tough to float in NE) -Changes through regulations

Requires pharmaceutical manufacturers participating in Medicaid to sell outpatient drugs at discounted prices to health care organizations that care for many uninsured and low-income patients

Section 340B of the Public Health Service Act

Suffix of biologic name (should or should not?).... -Be unique -Be devoid of meaning -Be four lowercase letters of which at least three are distinct -Be nonproprietary -Be attached to the core name with a hyphen -Be free of legal barriers that would restrict its usage

Should

Suffix of biologic name (should or should not?).... X Be false or misleading, such as by making misrepresentations with respect to safety or efficacy X Include numerals and other symbols aside from the hyphen attaching the suffix to the core name X Include abbreviations commonly used in clinical practice in a manner that may lead the suffix to be misinterpreted as another element on the prescription or order X Contain or suggest any drug substance name or core name X Look similar to or be capable of being mistaken for the name of a currently marketed product (e.g., should not increase the risk of confusion or medical errors with the product and/or other products in the clinical setting) X Look similar to or otherwise connote the name of the license holder X Be too similar to any other FDA-designated nonproprietary name suffix

Should not

Why is FDA winning battle counterfeiting between states?

Supremacy clause

Available to hospitals for medicinal, mechanical and scientific purposes and in treatment of inpatients. -Some specific uses which fall under these general categories are: sterilizing solutions, antiseptics, compounding prescriptions, and preparation of specimens. -Charity clinics may use for medicinal for out-patients if they do not charge -Community pharmacies can not obtain this type -Prohibited sale to community pharmacies or practitioners -Stored in securely locked storeroom with labels and markings on containers

Tax free alcohol (190 proof ethyl alcohol) - Title 27

Used in compounding in community pharmacies -Obtainable from outlets that sell liquor at retail

Tax paid alcohol

Importation for personal use: -Department of Homeland Security Appropriation Act of 2007 individual patients may import an FDA approved medication -From where? -How? -How much? (day supply limit) -Any exceptions?

The Homeland Security Act allows a 90 day limit and it must be carried in (on person). It can not be mailed. -from canada -by person -90 day limit -exception is biologics

Who regulates the following biologics? -Monoclonal antibodies for in vivo use. -Most proteins intended for therapeutic use, including cytokines (e.g., interferons), enzymes (e.g. thrombolytics), and other novel proteins, except for those assigned to the other branch (e.g., vaccines and blood products) -This category includes therapeutic proteins derived from plants, animals, humans, or microorganisms, and recombinant versions of these products. Exceptions to this rule are coagulation factors (both recombinant and human- plasma derived). -Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or down-regulating a pre-existing, pathological immune response). -Growth factors, cytokines, and monoclonal antibodies intended to mobilize, stimulate, decrease or otherwise alter the production of hematopoietic cells in vivo.

The categories of therapeutic biological products regulated by CDER (under the FDC Act and/or the Public Health Service Act, as appropriate)

Concept that a biosimilar product may be approved for an indication without direct studies of the biosimilar in that indication. -If the total evidence in the biosimilar application supports administration of biosimilarity for at least one of the reference product's indications, then it is possible for the biosimilar manufacturer to use data and information to scientifically justify approval for other indications that were not directly studied by the biosimilar manufacturer.

This concept is called "extrapolation" and is critical to the goals of an abbreviated pathway—improving access and options at a potentially lower cost.

Do adalat and procardia have the same generic substitution?

Two brand names: that's why ab1 +ab2 -Must be careful with extended release (must sub product that is bioequivalent to (ex: for procardia, not adalat if Rx is written for procardia CC ER)

NCSL website: legislation highlights -The state must maintain a public or web-based list of permissible interchangeable products.

Web Lists

Can a psychiatrist write for oral contraceptive?

Yes, they went to med school (still a physician) -could be for patient who was abused in a sexual manner

Can you sub brand for generic?

You can (if patient want brand can get brand) -its with other way around that must sub if not written (dispense as written)

If you have prescriptive authority in CT, can you fill in RI?

depends if that kind of scope of practice can prescribe in our state

Which of the following have limited prescriber capability? • Medical Doctor (MD) • Dentist • Podiatrist • Chiropractic physician • Veterinarian • Pharmacist - changing • Physician's Assistant - changing • Midwives • Doctor of Osteopathic Medicine

• Dentist • Podiatrist • Veterinarian • Pharmacist - changing • Physician's Assistant - changing • Midwives

3 ways of RX to OTC switch? Why is it important to know for pharmacists?

• Manufacturer requests • Citizen Petition • FDA amends or add to an OTC monograph -Important to know because, for example, if through manufacturer request only that product can be OTC

Which of the following have full prescriber capability? • Medical Doctor (MD) • Dentist • Podiatrist • Chiropractic physician • Veterinarian • Pharmacist - changing • Physician's Assistant - changing • Midwives • Doctor of Osteopathic Medicine

• Medical Doctor (MD) • Doctor of Osteopathic Medicine

What two components must be true for a generic drug to be bioequivalent?

• Pharmaceutically equivalent AND • Therapeutically Equivalent: clinically safety and efficacy (produce intended results) BE= PE + TE