Exam 1 Mehta SG Part 2 Flashcards
( Drug History, History of the FDA and Modern FDA)
What are the differences in pharmacoepidemiology
The differences in pharmacoepidemiology are….
-True randomization does not occur
- The intervening decision-making and
behavior of doctors and patients can
alter the drugs’ effect - Outcomes are measured in terms of
probabilities (or rates) of events - The magnitude of drug experience in the
analysis is much larger than that of
conventional pharmacology, ranging to
millions of patients and millions of
person-years of exposure
What is the margin of safety?
*Margin of safety
- The difference between the usual effective dose and the dose that causes severe or life-threatening (lethal) side effects
- The margin of safety is LD50 ÷ ED50 (lethal dose divided by effective dose)
If LD50 is 10 mg and ED50 is 2 mg then the margin of safety is only 5
*10 ÷ 2 = 5o This means that the lethal dose is only 5x the effective dose, which may be predictive of a low margin of safety in humans - Acceptable margin of drug safety in humans is > 2000
Define Margin of safety
*Margin of safety
- The difference between the usual effective dose and the dose that causes severe or life-threatening (lethal) side effects
- How safe it is
What is the acceptable Margin of drug safety in humans?
> 2,000
- Acceptable margin of drug safety in humans is > 2000
Margin of safety equation
LD50 ÷ ED50
LD50= Letha dose
ED50= effectiveness dose
- The margin of safety is LD50 ÷ ED50 (lethal dose divided by effective dose)
- If LD50 is 10 mg and ED50 is 2 mg then the margin of safety is only 5
*10 ÷ 2 = 5
Factors affecting drug cost and drug development
What Influences Drug Costs?
- Research & development costs including
the FDA approval process
- Complicated manufacturing process
-Extent of coverage and reimbursement
for the drug by third-party payers
(insurers)
- Desired profit margin of the
manufacturer
- Maximizing profits prior to patent
expiration
- Export to foreign countries
- Cost is dictated by the foreign
government or negotiated between
the manufacturer and that
government
- Typically drug costs overseas are
lower than cost in the U. S.
How long until you can submit an NDA?
- NDA is submitted after the successful
conclusion of clinical trials - After ~8 to 9 years of animal and
human testing
What is NDA?
New Drug Application (NDA) Process
- NDA is submitted after the successful conclusion of clinical trials
-After ~8 to 9 years of animal and
human testing - If FDA approves, the drug manufacturer can sell the new product as an exclusive proprietary drug
- Patent on drugs lasts ~ 20 years after applying for the patent prior to Phase 1 of clinical testing
Clinical Phases of Drug Development
(short version)
Clinical Phases of Drug Development (FDA Approval)
- Phase 1
o Involves 20 – 100 people in the clinical
trial
o Tested for safety in healthy volunteers - Phase 2
o Up to several hundred people in the
clinical trial with the disease
o Tested for short-term safety and
effectiveness - Phase 3
o Several hundred to several thousand
people involved in the trial
o Tested for safety, dosage,
effectiveness, adverse events - Phase 4
o Post-marketing surveillance for
adverse event monitoring forever - The entire process can take 8 to 15 years and cost ~$1 to 2 billion
How long can the entire process of Clinical Phases of Drug Development Take?
- The entire process can take 8 to 15 years and cost ~$1 to 2 billion
Clinical Phases of Drug Development
Phase 1
- Phase 1
o Involves 20 – 100 people in the clinical
trial
o Tested for safety in healthy volunteers
Clinical Phases of Drug Development
Phase 2
- Phase 2
o Up to several hundred people in the
clinical trial with the disease
o Tested for short-term safety and
effectiveness
Clinical Phases of Drug Development
Phase 3
- Phase 3
o Several hundred to several thousand
people involved in the trial
o Tested for safety, dosage,
effectiveness, adverse events
Clinical Phases of Drug Development
Phase 4
- Phase 4
o Post-marketing surveillance for
adverse event monitoring forever
Conventional Pharmacology compared to to Pharmacoepidemiology
Define Pharmacoepidemiology
- Pharmacoepidemiology is the study of drug outcomes as documented in observations of clinical data from large populations of typical patients receiving routine care
What is the importance of pharmacoepidemiology?
The importance of pharmacoepidemiology is highlighted by a
- number of prominent drug withdrawals in recent years, such as Vioxx (anti-inflammatory drug) resulting in heart attack & stroke
-Each of these withdrawals was
preceded by severe or fatal adverse
effects unrecognized or
underappreciated at the time of
approval
What is the original source of Quinine and what was it used to treat?
- Bark of some trees contained quinine
- Quinine is still used today as a drug of choice against MALARIA
- The first specific drug used to treat an infectious disease
What is the original source of Synthesis of arsenicals and what was it used to treat?
- synthesized arsenicals by attaching an arsenic atom to a carbon atom
- It led to the use of arsphenamine (Salvarsan-first chemotherapeutic agent) to treat syphilis
What is the original source of Digitalis and what was it used to treat
- Purple foxglove lead to isolation of digits
OLD: made tea to treat edema of cardiac
NOW: drug of choice for congestive heart failure
What is the original source of alkaloid morphine and what was it used to treat?
alkaloid morphine from opium & opium source is poppy plant
- pain control
What is the original source of Caffeine and what was it used to treat?
Caffeine is extracted from the
- coffee plant, Coffea arabica
What comes from Atropa belladonna (Devil’s cherries) and what was it used to treat?
Two alkaloid substances isolated from plant
Atropine
- Dilates the pupils (medicinal use)
Scopolamine
Used for motion sickness
What is the original source of Atropine and what was it used to treat?
- from atropa belladonna plant
- Dilates the pupils (medicinal use)
What is the original source of Scopolamine and what was it used to treat
- from Atropa belladonna plant
- Used for motion sickness
What is the original source of and what Salicylic acid was it used to treat
- Willow bark is a source of salicin, which is metabolized to salicylic acid in the body
- Salicin and salicylic acid are chemical precursors to aspirin
- Acetylsalicylic acid, also known as aspirin
What is Epinephrine and where is it produced?
Epinephrine, also known as adrenaline
- It is a hormone and a Neurotransmitter
- Produced in
- Some neurons of the CNS
- The Chromaffin cells of the adrenal medulla
from the amino acids, Phenylalanine and
tyrosine
What is produced by
- Some neurons of the CNS
- The Chromaffin cells of the adrenal medulla
from the amino acids, Phenylalanine and
tyrosine
Epinephrine, also known as adrenaline
What is Acetylcholine (Act)
- one of many neurotransmitters in the
autonomic nervous system (ANS) - acts in both PNS & CNS
- only neurotransmitter used in the motor
division of the somatic nervous - in Cardiac tissue, acetylcholine neurotransmitters have an inhibitory effect which lowers heart rate
- at neuromuscular junction in skeletal muscle it acts as an excitatory neurotransmitter
in ____________ , acetylcholine neurotransmitters have an inhibitory effect which _____________
- in Cardiac tissue, acetylcholine neurotransmitters have an inhibitory effect which lowers heart rate
at _________________ in _________________ acetylcholine acts as an excitatory neurotransmitter
at neuromuscular junction in skeletal muscle it acts as an excitatory neurotransmitter
What is Sulfa and where is it produced?
- Sulfa is the active antibacterial portion of the red dye
- Prontosil (red dye)- had no antibacterial
properties.
- chemical changes to Prontosil and became
sulfanilamide - Sulfas are used today to treat infections of the urinary tract
Origin of Penicillin
-discovered in mold known as penicillium notatum inhibited growth of staphylococcus aureus (a bacteria)
- named and name the active ingredient in SA penicillin
- Penicillin was used during WWII in 1941, and saved many lives
Durham - Humphery Act of 1952
Granted the FDA authority to determine which drugs may be sold without a prescription (OTC)
- OTC are sold w/ lower dosage
How does the FDA regulates drugs sold without a prescription.
FDA regulates drugs sold without a prescription
- FDA reviews OTC drugs for misbranding and
adulteration - FDA sets guidelines to which OTC drugs are safe
and effective - FDA has authority to prevent sales and to
withdraw OTC drugs from the market
-FDA reviews OTC drugs for ___________ and
____________
FDA reviews OTC drugs for misbranding and
adulteration
FDA sets __________ to which OTC drugs are _____
and ________
- FDA sets guidelines to which OTC drugs are safe
and effective
FDA has authority to _________ ________ and to
___________ OTC drugs from the market
FDA has authority to prevent sales and to
withdraw OTC drugs from the market
How does the FDA regulate supplemental product manufacturers
- To test products for purity
- To assure that products do not contain
contaminants - To verify that contents within package matched
labeling information
What does the FDA do?
The FDA is responsible for…
1)protecting the public health
- by assuring the safety, efficacy and security of drugs, medical devices, food supply, cosmetics & products that emit radiation
2) advancing the public health
- by helping to speed innovations that make medicine more effective, safer and more affordable. get the public accurate science based info
3) Regulating
- Manufactures , Marketing and distribution of tobacco to protect the public heath & reduce use by minors
4) Significant role in Nation’s counterterrorism capabilities
- by ensuring the security of food supply and fostering Development of medical products to responds to public heath threats
The FDA is responsible for…
Name first responsibility
1) protecting the public health
- by assuring the safety, efficacy and security of drugs, medical devices, food supply, cosmetics & products that emit radiation
The FDA is responsible for…
Name Second responsibility
2) advancing the public health
- by helping to speed innovations that make medicine more effective, safer and more affordable. get the public accurate science based info
The FDA is responsible for…
Name third responsibility
3) Regulating
- Manufactures , Marketing and distribution of tobacco to protect the public heath & reduce use by minors
The FDA is responsible for…
Name fourth responsibility
4) Significant role in Nation’s counterterrorism capabilities
- by ensuring the security of food supply and fostering Development of medical products to responds to public heath threats
What is ANDA
Abbreviated New Drug Application
- ANDA is an application for a U.S. generic drug approval for an EXISTING LICENSED medication or approved drug
- not required to include trial data to establish safety and effectiveness
- Instead demonstrate their products is bioequivalent
Bioequivent = Same effectiveness
T/F. for an ANDA the applications require preclinical (animal and in vitro) and clinical (human) trial data to establish safety and effectiveness?
FALSE
ANDA they are
- not required to include trial data to establish safety and effectiveness
- Instead demonstrate their products is bioequivalent
Bioequivent = Same effectiveness
what application is for a U.S. generic drug approval for an EXISTING LICENSED medication or approved drug
ABBREVIATED NEW DRUG APPLICATION (ANDA):
general phases of drug development
- Synthesis or discovery of new chemicals from the test tube or plant(s)
- Safety evaluation in animals and humans
- Effectiveness evaluation in humans
- Review of new drug application
- Post-marketing surveillance to report all adverse effects
why should we study pharmacology as audiologists
There are ~2,000 drugs and > 400 side effects that could impact the audiologic/vestibular system, it’s evaluation/management, i.e.,
Obtaining an accurate case history and/or test results, which might lead to a misdiagnosis of auditory-vestibular problems
Short-term toxicity testing
- Testing in animals
- General profile screen in mice
- Determination of the lethal dose = LD50
- Dose of a drug that kills 50% of the total
number of mice that receive it - Determination of effectiveness dose = ED50
- Dose of a drug that causes an effect in
50% of the total numbers of mice that
received it
Long-term toxicity
AKA Chronic Toxicity Studies
- Daily dosing to rats and dogs from 3 months to 2 years
- Observe for toxicities, evaluate blood chemistries
- Sacrifice the animal, then evaluate histopathology
- Many toxic effects appear only after repeated dosing over many months or years
-That is the reason why post approval
regulation is required
Investigational New Drug Application (IND)
- Submitted if the drug has an impressive margin of safety in mice
- Submitted if a drug lacks long-term toxicities
- Submitted if a drug does not cause cancer, reproductive effects, or birth defects
- A 30-day approval by the FDA (usually takes longer)
Clinical Phases of Drug Development (FDA Approval)
Phase 1 (longer version)
- Begins immediately after IND approval
- 20-100 healthy volunteers
- evaluates safety of the drug in humans
- Determine what the does does w/drug
- Establishes the dose of toxicity
- Trial lasts for several months
- Non-blinded trials
- Participant and investigator are both aware of what is being administered
Clinical Phases of Drug Development (FDA Approval)
Phase 2 (longer version)
- Given to patients having the condition for which the drug is intended
- several hundreds of patients
- Short term - effectiveness and safety
- several months to two years
- Single- blind trial
- drug evaluated against placebo
- Participants are unaware what they are receiving
Clinical Phases of Drug Development (FDA Approval)
Phase 3 (longer version)
- Several hundred to several thousand
- Confirms drug safety, dosage & effectiveness
- 1- 2 years
- Randomized, Double blind
- Participant nor investigator knows which groups is the subject - NDA is submitted after the successful conclusion of clinical trials
Clinical Phases of Drug Development (FDA Approval)
Phase 4 (longer version)
Post - Marketing Surveillance
- After FDA approval
- Drugs is monitored for the reminder of its life span
- A drug can be pulled off market if new toxins are uncovered.
Treatment use of investigational drugs occurs when?
Treatment use of investigational drugs
Occurs during review of the NDA
Expanded access (compassionate use protocol)
- A drug can be used under certain conditions prior to FDA approval for patients who are not in the drug’s clinical trial, such as
- Desperately ill patients
- When the side effects are not an issue
- No comparable alternative drug is available
Right - to - Try law
- Drugs used after phase 1 clinical trails but before FDA approval
- used for desperately ill patients with no other alternative
What study Pharmacology?
- There are ~2,000 drugs and > 400 side effects that could impact the audiologic/vestibular system, it’s evaluation/management, i.e.,
- Adverse drug reactions that can affect auditory-vestibular systems
- Audiologists need to have the knowledge base to recognize and prevent an ototoxic effect of a chemical
- Audiologists also need to have the knowledge base to recognize and manage an ototoxic effect once it has occurred
Transmembrane Receptors
The ligand has to match the cell receptor to be able to enter. lock & key
Life Cycle of Drug Approval
- Drug Discovery phase:
o This phase produces a new molecule
o First patents are filed at this stage and
granted several years later - Drug Development phase
o The process requires that biological
characterization and toxicology animal
studies be conducted prior to filing an
Investigational New Drug (IND) application
o An IND is required at the start of clinical
(human) trials (Phase I to III)
o At the conclusion of successful clinical trials,
the drug company files a New Drug
Application (NDA), which is reviewed by the
FDA - Post Approval Regulation
o Once approved, a drug must be monitored
for the remainder of its life span (Phase IV)
o The first of the drug’s patents expires 20
years after its application
o Abbreviated New Drug Application (ANDA)
can be filed before expiration of original
patent
o Once the patent expires, generic versions
can become available
Life Cycle of Drug Approval
Post Approval Regulation
- Post Approval Regulation
o Once approved, a drug must be monitored
for the remainder of its life span (Phase IV)
o The first of the drug’s patents expires 20
years after its application
o Abbreviated New Drug Application (ANDA)
can be filed before expiration of original
patent
o Once the patent expires, generic versions
can become available
Life Cycle of Drug Approval
Drug Development phase
- Drug Development phase
o The process requires that biological
characterization and toxicology animal
studies be conducted prior to filing an
Investigational New Drug (IND) application
o An IND is required at the start of clinical
(human) trials (Phase I to III)
o At the conclusion of successful clinical trials,
the drug company files a New Drug
Application (NDA), which is reviewed by the
FDA
Life Cycle of Drug Approval
Drug Discovery phase:
- Drug Discovery phase:
o This phase produces a new molecule
o First patents are filed at this stage and
granted several years later
Drug Patents
When patents expires other companies can market the generic drug under a trade name of their choose
ex: coke
Pepsi both trade name
