CHAPTER 2
FDA
Protecting and promoting public health through regulation of
o Food Safety, Tobacco products, RX and OTC drugs/medications, Vaccines,
Biopharmaceuticals, Blood Transfusions, Cosmetics, Electromagnetic imaging devices,
Animal food/feeds, Veterinary Products
o Collect medications and monitor the safety of drugs using Post-marketing surveillance by
med watch programs
o Determines the official labeling for all RX and OTC medication
o No regulation over herbal supplements
Off-Label
Off Label use is the prescription of drugs for unapproved indications, age groups, dose, route
of administration
Both Prescription and OTC drugs can be used in off-label ways
Off-label is legal unless it violates ethical or safety guidelines
There can be health risks or differences in legal liability
(Cytotec being used for labor, but off label used for peptic ulcer disease)
Schedules
WHO
Who prescribing process
o 1. Define the problem/diagnosis (Define the patient’s problem) (physical exam)
o 2. Specify therapeutic objective
o 3. Choose the treatment (Choose which drug or treatment is needed)
o 4. Start the treatment
o 5. Educate the patient
o 6. Monitor the effectiveness (monitor treatment)
,Drug development
Phase 1- The drug is tested on healthy volunteers
o Evaluate safety, tolerance, pharmacodynamic effects (effects of drug on the body,
heart, blood pressure, ECG), absorption, distribution, metabolism, and excretion
o Must complete Investigation New Drug Application
Summarizes the established preclinical and manufacturing information along
with the investigator's guidance
o Trials will be stopped if the half-life is too short or too long or poor bioavailability
o Stopped with significant ECG changes and severe adverse effects
o Start with sub-pharmacological doses that are escalated following multiple doses
o Cost- 500,000-1.5M
Phase 2- Trials with people who have the disease for which the drug is thought to be
effective
o Efficacy and Safety on the target population
o Single maximal tolerated dose/several dose levels are tested on the target
population
o Progress to stage 3 depends on- drug efficacy relative to competitors, safety profile,
probability of technical and regulatory success, remaining patent life of the drug,
cost of goods to produce the drug, market share, price, reimbursement
Phase 3- Large number of patients in medical research centers receive the drug in phase 3.
This larger sampling provides information about infrequent or rare adverse effects. The FDA
will approve a new drug application if phase 3 studies are satisfactory.
o Minimum of two trials
o Several Thousand Patients
o Confirms clinical doses, frequency, and timing of administration for approval
o Designed to test the hypothesis of efficacy
o Adverse effects are collected to assess benefit-risk potential
Phase 4- This phase is voluntary and involves postmarket surveillance of the drug’s
therapeutic effects at the completion of phase 3. The pharmaceutical company receives
reports from doctors and other healthcare professionals about the therapeutic results and
adverse effects of the drug. Some medications, for example, have been found toxic and have
been removed from market after their initial release.
Infants/Children
Issues in pediatric prescribing
o Drug formulated and packaged primarily for adults (not tested on pediatric
population)
o Less physiologically tolerate medication error due to developing renal, immune, and
hepatic functions
, o There is a lack of safety and efficacy studies in the patient population most
medications are studied in adult populations – age-related differences and
medication metabolism and mechanisms of action don’t necessarily apply to
pediatric populations
o Kids do not have fully mature liver and renal function and are at high risk for toxicity
and adverse drug effects
Doses based on weight (mg/kg)
Physiological differences
o Infants have more water, less fat
o Immature liver makes fewer serum proteins, is less able to metabolize drugs
o Blood-Brain barrier less well-developed in infants
o Renal function not fully developed until 30 months
Pediatric Absorption
o Gastric pH does not reach adult level until age 1 year
Acidic environment is needed to absorb the medication less medication will
be absorbed by the infant
o Children have a greater body surface area and will have greater absorption of topical
medication
Infant skin more permeable leading to greater absorption of topical
medications (increased hydration and thinner stratum corneum)
Immature peripheral circulation will prevent the absorption of IM or SQ
medications
Pediatric Distribution
o Differences in Body Water and Fat
o Immature Liver function
Age 0-6 months less albumin and fewer plasms proteins
Fever binding sites in pediatric patients result in higher blood concentrations
of two or more drugs or less affinity for one of the drugs
o Immature Blood-Brain Barrier
o Birth: the blood-brain barrier is not developed leading to greater risk of CNS toxicity;
drug enters the CNS (Increased risk of drugs entering CNS)
Phase 1 Metabolism
o Cytochrome P-450 (CYP) 3A enzymes play a major role in drug metabolism
The 3A system, 3A4 is low in neonates and does not reach adult levels until
about 6-12months
o CYP3A7 earliest isozyme to show activity and present in utero (declines rapidly after
birth)
o CYP3A7 decreases throughout the first 6 months with an increase in CYP3A4 and
CYP3A5
FDA
Protecting and promoting public health through regulation of
o Food Safety, Tobacco products, RX and OTC drugs/medications, Vaccines,
Biopharmaceuticals, Blood Transfusions, Cosmetics, Electromagnetic imaging devices,
Animal food/feeds, Veterinary Products
o Collect medications and monitor the safety of drugs using Post-marketing surveillance by
med watch programs
o Determines the official labeling for all RX and OTC medication
o No regulation over herbal supplements
Off-Label
Off Label use is the prescription of drugs for unapproved indications, age groups, dose, route
of administration
Both Prescription and OTC drugs can be used in off-label ways
Off-label is legal unless it violates ethical or safety guidelines
There can be health risks or differences in legal liability
(Cytotec being used for labor, but off label used for peptic ulcer disease)
Schedules
WHO
Who prescribing process
o 1. Define the problem/diagnosis (Define the patient’s problem) (physical exam)
o 2. Specify therapeutic objective
o 3. Choose the treatment (Choose which drug or treatment is needed)
o 4. Start the treatment
o 5. Educate the patient
o 6. Monitor the effectiveness (monitor treatment)
,Drug development
Phase 1- The drug is tested on healthy volunteers
o Evaluate safety, tolerance, pharmacodynamic effects (effects of drug on the body,
heart, blood pressure, ECG), absorption, distribution, metabolism, and excretion
o Must complete Investigation New Drug Application
Summarizes the established preclinical and manufacturing information along
with the investigator's guidance
o Trials will be stopped if the half-life is too short or too long or poor bioavailability
o Stopped with significant ECG changes and severe adverse effects
o Start with sub-pharmacological doses that are escalated following multiple doses
o Cost- 500,000-1.5M
Phase 2- Trials with people who have the disease for which the drug is thought to be
effective
o Efficacy and Safety on the target population
o Single maximal tolerated dose/several dose levels are tested on the target
population
o Progress to stage 3 depends on- drug efficacy relative to competitors, safety profile,
probability of technical and regulatory success, remaining patent life of the drug,
cost of goods to produce the drug, market share, price, reimbursement
Phase 3- Large number of patients in medical research centers receive the drug in phase 3.
This larger sampling provides information about infrequent or rare adverse effects. The FDA
will approve a new drug application if phase 3 studies are satisfactory.
o Minimum of two trials
o Several Thousand Patients
o Confirms clinical doses, frequency, and timing of administration for approval
o Designed to test the hypothesis of efficacy
o Adverse effects are collected to assess benefit-risk potential
Phase 4- This phase is voluntary and involves postmarket surveillance of the drug’s
therapeutic effects at the completion of phase 3. The pharmaceutical company receives
reports from doctors and other healthcare professionals about the therapeutic results and
adverse effects of the drug. Some medications, for example, have been found toxic and have
been removed from market after their initial release.
Infants/Children
Issues in pediatric prescribing
o Drug formulated and packaged primarily for adults (not tested on pediatric
population)
o Less physiologically tolerate medication error due to developing renal, immune, and
hepatic functions
, o There is a lack of safety and efficacy studies in the patient population most
medications are studied in adult populations – age-related differences and
medication metabolism and mechanisms of action don’t necessarily apply to
pediatric populations
o Kids do not have fully mature liver and renal function and are at high risk for toxicity
and adverse drug effects
Doses based on weight (mg/kg)
Physiological differences
o Infants have more water, less fat
o Immature liver makes fewer serum proteins, is less able to metabolize drugs
o Blood-Brain barrier less well-developed in infants
o Renal function not fully developed until 30 months
Pediatric Absorption
o Gastric pH does not reach adult level until age 1 year
Acidic environment is needed to absorb the medication less medication will
be absorbed by the infant
o Children have a greater body surface area and will have greater absorption of topical
medication
Infant skin more permeable leading to greater absorption of topical
medications (increased hydration and thinner stratum corneum)
Immature peripheral circulation will prevent the absorption of IM or SQ
medications
Pediatric Distribution
o Differences in Body Water and Fat
o Immature Liver function
Age 0-6 months less albumin and fewer plasms proteins
Fever binding sites in pediatric patients result in higher blood concentrations
of two or more drugs or less affinity for one of the drugs
o Immature Blood-Brain Barrier
o Birth: the blood-brain barrier is not developed leading to greater risk of CNS toxicity;
drug enters the CNS (Increased risk of drugs entering CNS)
Phase 1 Metabolism
o Cytochrome P-450 (CYP) 3A enzymes play a major role in drug metabolism
The 3A system, 3A4 is low in neonates and does not reach adult levels until
about 6-12months
o CYP3A7 earliest isozyme to show activity and present in utero (declines rapidly after
birth)
o CYP3A7 decreases throughout the first 6 months with an increase in CYP3A4 and
CYP3A5
