Learning Objectives- Exam 1

Historical figures who contributed to the advancement of science and pharmacy:

Hippocrates

father of medicine

“pharmakon”

scientific systemized medical knowledge

Historical figures who contributed to the advancement of science and pharmacy:

Dioscordes

De Materia Medica

physician and botanist

naturally occurring medicinal materials

Historical figures who contributed to the advancement of science and pharmacy:

Galen

Galenic pharmacy

Galenicals

pharmacist-physician

naturally occurring vegetable drugs and formulations

Historical figures who contributed to the advancement of science and pharmacy:

Paracelsus

specific drug to specific disease

changed pharmacy from botanical science to chemical science

Historical figures who contributed to the advancement of science and pharmacy:

Karl Wilhem

lactic acid, citric acid, oxalic acid, tartairc acid, arsenci acid, glycerin, calomel, benzoic acid, oxygen

Historical figures who contributed to the advancement of science and pharmacy:

Friedrich Serturner

morphine from opium

Historical figures who contributed to the advancement of science and pharmacy:

Joseph Pelletier and Joseph Caventou

quinine, cinchonine, brucine

Historical figures who contributed to the advancement of science and pharmacy:

Joseph Pelletier and Peirre Robiquet

caffeine

Historical figures who contributed to the advancement of science and pharmacy:

Pierre Robiquet

Codeine from opium

Historical figures who contributed to the advancement of science and pharmacy:

Jonathan Roberts

1st hospital pharmacist

Development and purpose of USP and NF:

When was USP created and why?

in 1820 to establish drug standards

Development and purpose of USP and NF:

Pharmakon =

drug

Development and purpose of USP and NF:

poiein =

make

Development and purpose of USP and NF:

What led to the evolution of the USP?

influences of synthetic organic chemistry

Development and purpose of USP and NF:

Pharmacopeia

any recipe/formula/other standards required to make drugs

Development and purpose of USP and NF:

What happened in Mass in 1808?

MA published its own pharmacopeia used by apothecaries to properly fill prescriptions from physicians since it defined the identity of drugs and prep

Development and purpose of USP and NF:

What happened in 1820?

the US pharmacopeial convention was founded in DC by a group of physicians; all states were invited to participate but only 11 came

Development and purpose of USP and NF:

How many drugs were in the first USP? Why?

200

they were deemed “most fully established and best understood”

Development and purpose of USP and NF:

Father of USP?

Dr. Lyman Spalding

Development and purpose of USP and NF:

When was the NF made? by who?

in 1888 by APhA

Development and purpose of USP and NF:

What did the NF include when it was first made?

drugs that were left out of the USP

Development and purpose of USP and NF:

In 1906, the USP and NF standards for _____, _____, and ______ were officially recognized

strength, quality, and purity

Development and purpose of USP and NF:

What happens in 1975?

the USP buys NF and they drop their first combined compendium in 1980

Components of the USP-NF and Central features of a typical drug monograph:

3 components

monograph

general chapters

general notices

Components of the USP-NF and Central features of a typical drug monograph:

monograph

Standards for all drug substances, dosage forms, and compounded preparations (USP). Standards for all excipients (NF).

Components of the USP-NF and Central features of a typical drug monograph:

general chapters

Tests/procedures referred to in multiple monographs are described in detail

Components of the USP-NF and Central features of a typical drug monograph:

General notice

provides definitions of terms used in the monograph

Components of the USP-NF and Central features of a typical drug monograph:

general chapters examples

797, 795, 800

Components of the USP-NF and Central features of a typical drug monograph:

USP 797

sterile compounding

Components of the USP-NF and Central features of a typical drug monograph:

USP 795

nonsterile compounding

• 3 classifications: simple, moderate, complex

• complex: requires special training

• USP-NF is preferred source for compounding but if it is not available the next highest grade should be used

• defective product log must be kept by the pharmacy and reported to MA board of pharmacy

Components of the USP-NF and Central features of a typical drug monograph:

USP 800

hazardous drugs (sterile and nonsterile compounding)

Compare and Contrast significant drug regulation and control federal laws and their impact:

food and drug act of 1906

required that drugs marketed interstate comply with claimed standards for strength purity and quality

Compare and Contrast significant drug regulation and control federal laws and their impact:

Sherley amendement 1912

Addressed manufacturer’s claims of therapeutic benefit

• no more false or misleading claims (would result in seize)

• prosecution

Compare and Contrast significant drug regulation and control federal laws and their impact:

Federal Food, Drug, and Cosmetic Act 1938

• there is a need for safe administration of drugs after tragedy caused by sulfanilamide

• required SAFETY testing before marketing

• required product labeling with directions

• no drug could be distributed without filing NDA and FDA approval

• injunctions

Compare and Contrast significant drug regulation and control federal laws and their impact:

per the food drug and cosmetic act of 1938, what 5 things did the new dug approval process depend on?

• ingredients

• methods used to evaluate products

• standards used to evaluate formulations

• preclinical studies

• clinical trials

Compare and Contrast significant drug regulation and control federal laws and their impact:

what did the federal food, drug and cometic act of 1938 establish but not require?

established guidelines for safe use of drugs

did NOT require EFFICACY

Compare and Contrast significant drug regulation and control federal laws and their impact:

Durham Humphrey amendment of 1952

no refills without valid prescription

Compare and Contrast significant drug regulation and control federal laws and their impact:

the Durham Humphery amendment clarified dispensing obligations of _____

pharmacists

Compare and Contrast significant drug regulation and control federal laws and their impact:

What did the Durham-Humphrey amendment define?

drugs that cannot be used safely without proper medical supervision and determined what drugs are OTC

Compare and Contrast significant drug regulation and control federal laws and their impact:

the Durham-Humphrey amendment was further supported by which two acts/ amendments?

drug abuse control amendments of 1965 and comprehensive drug abuse prevention act and control act of 1970

Historical events that prompted change in drug regulation:

Thalidomide babies

women used to take thalidomide for morning sickness and then it messed with their babies

led to Kefauver- Harris amendment of 1962

Compare and Contrast significant drug regulation and control federal laws and their impact:

Kefauver-Harris Amendment of 1962

amendment made to the FDC act of 1938

required IND to be filed with FDA

Compare and Contrast significant drug regulation and control federal laws and their impact:

under Kefauver-Harris amendment of 1962 how many days is the FDA given to review for approval of NDA?

180

Compare and Contrast significant drug regulation and control federal laws and their impact:

Kefauver-Harris amendment required that drugs be proven

safe and efficacious (exempted grandfathered drugs which had entered the market between 1906 and 1938)

Compare and Contrast significant drug regulation and control federal laws and their impact:

KH required manufacturers to…

record and report adverse events

Compare and Contrast significant drug regulation and control federal laws and their impact:

KH gave FDA control over

RX drug advertising

Compare and Contrast significant drug regulation and control federal laws and their impact:

KH established

good manufacturing practices

Compare and Contrast significant drug regulation and control federal laws and their impact:

comprehensive drug abuse prevention and control act of 1970

established 5 schedules for drugs subject to abuse

Compare and Contrast significant drug regulation and control federal laws and their impact:

FDAs strongest labeling requirements for high risk medications associated with serious adverse reactions

black box warning

Compare and Contrast significant drug regulation and control federal laws and their impact:

Pregnancy and Lactation Labeling Rule

“use in specific populations”

Compare and Contrast significant drug regulation and control federal laws and their impact:

Drug Listing Act of 1972

NDC

10 digits

Compare and Contrast significant drug regulation and control federal laws and their impact:

Orphan Drug Act of 1983

enabled FDA to promote research and marketing of drugs needed for treating rare diseases

Compare and Contrast significant drug regulation and control federal laws and their impact:

Drug Price Competition and Patent Term Restoration Act of 1984

• extension of patent life

• Speed of FDA approval of generic drugs

• introduced abbreviated New Drug Application

Compare and Contrast significant drug regulation and control federal laws and their impact:

Prescription Drug Marketing Act of 1987

• “the Dingell Bell”; drug diversion act

• prohibits drug reimportation

• sales restrictions

• sample distribution

• wholesale distributors

Compare and Contrast significant drug regulation and control federal laws and their impact:

Prescription Drug User Fee Act of 1992

allows the fda to accept user fees from drug and biologic companies in return for committing to review new drug applications within certain time frames

Compare and Contrast significant drug regulation and control federal laws and their impact:

The prescription drug user fee act is credited with a more….

rapid application review process and the speedier approval of new drugs

Compare and Contrast significant drug regulation and control federal laws and their impact:

prescription drug user fee act included designated and resources for…

post marketing studies to monitor the continuing safety and efficacy of new drug products

Compare and Contrast significant drug regulation and control federal laws and their impact:

DSHEA of 1994

• regulates labeling claims for herbs and dietary supplements such as vitamins, mineral, amino acids, and botanicals

Compare and Contrast significant drug regulation and control federal laws and their impact:

DSHEA legally does NOT…

consider supplements drugs

Compare and Contrast significant drug regulation and control federal laws and their impact:

under DSHEA companies can choose to become…

USP verified meaning they adhere to USP-NF Standards

Compare and Contrast significant drug regulation and control federal laws and their impact:

FDA Modernization act of 1997 was the first…

major overhaul of the FDC Act of 1938

Compare and Contrast significant drug regulation and control federal laws and their impact:

FDA Modernization Act of 1997

 Streamlined FDA policies
 Codify FDA regulations (next slide)
 Expand patient access to investigational treatment for
life-threatening disease
 Accelerated approval of new drugs
 Center for Drug Evaluation and Research (CDER)
 Center for Biologics Evaluation and Research (CBER)
 Guidelines and Regulations
29

Branches of the FDA:

Code of Federal Regulations (CFR) and the Federal Register (FR)

 Title 21 CFR
 Volumes 1-8
 Volume 9 = DEA
 Updated annually
 Federal Register (FR) issued each day
 Final regulations
 Legal notices

FDA:

Drug Product Recall

Manufacturers/Practitioners legally bound to report adverse
reactions to FDA MedWatch Program

class 1 recall

serious/ irreversible harm/ death

class 2 recall

temporary consequences

class 3 recall

not likely to cause adverse health consequences

Branches of the FDA:

CDER

CBER

Center for Drug Evaluation and Research

Center for Biologics Evaluation and Research

Branches of FDA:

CDER - Watch dog

evaluates new drugs for safety and effectiveness before they can be sold

watch for drug problems

monitor drug advertising

protects drug quality

Branches of FDA:

CDER - The review Team

 CDER’s Offices of Drug Evaluation
 Pharmacologists
 Physicians
 Pharmacokineticists
 Statisticians
 Microbiologists
 and more

Branches of FDA

CDER- Benefit vs Risk

can determine what are high priority drugs

• drugs that offer a significant medical advantage over current therapies

• approval of these drugs can be accelerated

Drug Discovery Summary

basically the path a drug travels from lab to cabinet is long and unique. It requires research, molecular modifications, and mechanism based drug design. Drugs can be isolated from nature (plants and animals-vax) or synthesized in a lab

Prodrugs

Levodopa is bioactivated by dopa decarboxylase to the active dopamine

Discovery begins with

the identification of a target disease and potential therapeutic compound

the discovery aspect of drug discovery is the most ____ and _______ ________

most variable and least successful

Nonclinical development-

translates discovery science into therapeutic candidates

it involves modifications, scale-up, purification, test methods and production

studies in animals

clinical development

studied performed in humans

phase 1, 2, 3, and 4

many drugs work by interacting with…

specific cell macromolecules like receptors or enzymes that play a critical role in a physiological or disease process

cellular macromolecules=

small molecules like traditional pharmaceuticals or they can be other proteins =

lock or target

key

key/lock fit can be optimized for

specificity and interaction strength

Nonclinical studies are performed to demonstrate the compounds:

• ability to bind with the desired affinity and specificity

• has an acceptable safety profile based on tolerability in animals

• has a reasonable chance of showing efficacy in humans based on animal findings

• used to estimate the starting dose and dose range for clinical trials

single dose toxicology

genotoxicity

reproductive toxicity

cns safety

respiratory safety

bioavailability

pharmacokinetics

efficacy

drug-drug interaction

repeat-dose toxicology

cardiovascular safety

phototoxicity

carcinogenicity

primary pharmacology

secondary pharmacology

primary pharmacology

main point of the drug

studies on the mode of action/ effects in relation to the desired therapeutic effect

secondary pharmacology

endpoints, side effects

studies on the mode of action/ effects NOT in relation to its desired target (general)

purpose of IND

initiate clinical study

negates federal law

documents safety

Defining New in IND:

required anytime a sponsor wishes to conduct a…

clinical trial of an unapproved drug in the US, regardless of whether the drug will be commercially developed

Defining New in IND

an approved drug can also be considered a…

new drug and may therefore require an IND to conduct a clincal trial

Defining New in IND

An IND is required to intiate a clinical trial in the US if the drug is

• A new chemical entity

• Not approved for the indication under investigation

• In a new dosage form

• Being given at a new dosage level

• In combination with an unapproved drug

primary goal during preclinical development is to

determine if the investigation product is reasonably safe for initial use in humans and if it exhibits activity that justifies further development

the sponsor is focused on collecting information to establish…

the product will NOT expose humans to unreasonable risk in clinical studies

An IND is a series of docs submitted to the FDA when a…

sponsor hopes to test its drug by conducting clinical trials

AN IND is not approved, however, unless FDA says otherwise, 30 days after an IND is submitted…

the company may begin clincial trails in the US

Following intial submisssion…

many additional documents may be submitted to and IND such as IND amendments

IND Contents

• administrative

• CMC

• nonclinical

• clinical

IND Review - Pharmacology

Focuses on results of pharmacology and toxicology
testing and attempts to relate test results to human pharmacology

IND Review - Chemistry

Evaluates manufacturing and processing procedures to
ensure the compound is adequately reproducible and stable in its
pure form

IND Review- Clinical

Evaluates the clinical trial protocol to determine if:
1. the subject will be protected from unnecessary risks, and
2. the study design will provide data relevant to safety and effectiveness of the
drug.

sponsor may commence clincal trials after how many days after FDA received FDA submission?

30 days, unless the FDA says otherwise