Ch2- Lec 2- Drug Regulation and Control Flashcards
Brief History of Drug Discovery & Development
- 1800 to 1820: Organic plant acids were extracted from plants by pharmacists in Germany, France, and Sweden
- 1883: Synthesis of antipyrine. Important because done in a test tube and this changed the way drugs were discovered from this point forward
- 1925 to 1945: Rapid advances in pharmacy research.
- Alexander Flemming discovered Penicillin
- James-Watson Crick solved the structure of DNA
Plant poisons: Life before drugs could be synthesized
Morphine: from opium poppy
Quinine: from cinchona bark
Digitalis: from foxglove
Belladonna: from deadly night shade
The alkaloids are not present in plants to supply us with medicines but are probably present to discourage predators
Problem is with purity and producing enough for our needs
Not all plants of same species are grown under same conditions so potency will vary
Drug Discovery
- Purpose: To find active ingredients and/or modify the chemical structures of existing active ingredients of drugs to form the basis of a new agent.
- It takes the services of many
- Chemists
- Pharmacologists
- Toxicologists
- Formulation developers (i.e. pharmaceutics)
Drug Development
- Purpose: To provide superior dosage forms and a way of delivering effective drugs throughout the body
- Mostly done by scientists usually with a PhD
- At a pharmaceutical company
- At a school of Pharmacy
Early Formulation Studies
What properties are investigated?
- Drug solubility:
- Less than 10 mg/ml is considered poorly soluble
- Partition coefficient:
- Preference for lipid verses preference for aqueous phase
- Dissolution Rate:
- Speed at which a drug substance dissolves in a medium
- Physical Form:
- Crystal verses amorphous verses powder etc.. Will alter the rate and extent of absorption
- Stability:
- Retention of drug substances within dosage forms
The “Goal Drug”
- Ideally this group seeks to develop a compound with the following characteristics
- Can produce a desired effect
- Can be administered at the most desirable route (orally)
- Can be administered at a minimal dosage and frequency
- After exerting a necessary effect should be eliminated from the body efficiently, and without negative side effects
A “Lead Compound”
This compound is the closest agent to the “goal drug” possessing the fundamental desired biologic or pharmacologic activity
It may NOT contain all of the properties of the desired compound, and so medicinal chemists often modify the lead compound.
Drug Researcher
Pharmacology: Determines biologic activity and mechanism of drug action in vitro & In vivo
Drug Metabolism: Determines the absorption, distribution, metabolism and elimination (ADME)
What is the extent of drug absorption and distribution in the body?
What is the mechanism of the drug metabolized by the body?
Toxicology: Deals with adverse and undesirable effects of the drug. Consider: What is the maximum tolerated dose?
_______________________________________________
See Textbook for detailed descriptions and be able to distinguish one discipline from another
Other examples of issues addressed by researchers in vivo
Make sure that the appropriate dosage form is being used to deliver therapeutics to the intended site of drug action
Non-specific delivery to intended targets is the main reason for drug-related side-effects
CDER
Assess benefit to risk relationship
Is a particular drug safe and effective enough ?
AZT (azidothymidine) toxic but highly effective
Make drugs available to the public sooner
Provide clear standards for drug evaluation
High priority drugs
These are defined as drugs that offer a significant medical advantage over current therapies
Cancer drugs Division of Oncology
Contraceptive drugs Division of reproductive & Urologic drug products
Generic drugs Division of Generic drugs
Investigational New Drug Application
Once a drug has been developed, before it can be administered to humans it must be filed with the FDA. This is an IND Application.
This protects the rights & safety of subjects and makes certain that the research objectives stated can be achieved with the investigational plan
Main purpose of this application is to provide the FDA with sufficient information to make a meaningful evaluation of a new drug
IND is then assigned to a CDER official,
Can place hold on trial due to inadequate information, inadequate qualifications of investigators or significant risk of harm to patients
IND Application
Preclinical studies demonstrate adequate safety. This is to be determined by phase I clinical trials.
Phase I Clinical Trials
Drug should show promise as a useful drug
Phase I: What is the safe dose in 20 to100 patients)?
Usually brief study (less than 1 year).
Purpose is to determine toxicology, metabolism, and pharmacologic actions
Application contains:
The plan for the study
Chemical Structure
Animal testing results
Manufacturing information
What about clinical trial material (CTM) for Phase I studies?
Biopharmaceutical properties clinical study
Practical considerations
Actual supply of bulk
Time allowed for preparing bulk stock
Advantages of extemporaneous formulations
Short development time
Minimal drug substance requirements (few hundred grams)
Minimal formulation development
Minimal analytical work
Disadvantages of extemporaneous formulations
Unpleasant taste
Patient compliance issue
Dosing inconvenience for multiple dose studies
Phase II clinical trials
If drug shows adequate safety in phase I it then enters phase II clinical testing
Purpose: To determine compound’s effectiveness
Phase II:
Drug is tested in hundreds of patients (~100 to 300 people).
Patients have the disease that the drug is intended to treat
Extensive pharmacologic, toxicological and pharmacological testing
Many clinical agents do not make it to this point
What about clinical trial material (CTM) for Phase II studies?
“powder in a bottle”- not very good approach
Capsules or tablets are typically necessary
Generally, same dosage form as phase I can be used here. Except,
When required dosage strength is not supported
When medium-to-large scale is not feasible
Alternatively, a new formulation closer to desired commercial dosage form can be introduced during phase II
What about (CTM) for Phase II studies?-Continued-
Other Critical factors:
Phase II covers a large dose range so # of dose strengths may be large
This is determined by,
Team of scientists (pharmaceutical scientists, pharmacokineticists, & clinical study and clinical supply coordinators)
Limitations with high dose strengths:
Dissolution and processability
Limitations with low dose strengths:
Content uniformity and stability issues
Phase III clinical trials
Purpose: To demonstrate long-term safety & efficacy of drug product; to discover drug’s efficacy standards
Several thousands of patients in many centers (~1000-3000 people)
Carried out over several years
HOW good is the drug in treating the disease or condition?
What are the short-term side effects and risks associated with drug use in patients whose health is impaired?
Investigational drug will be used in several randomized, controlled studies in various clinical research facilities including,
Clinical research facilities
Veterans administration
University teaching hospitals
What about clinical trial material (CTM) for Phase III studies?
Data from stability should be performed on at least 3 primary batches of drug products
Stability testing must cover minimum period of12 months typically at 25 ºC
Changes in dosage strengths and manufacturability of CTM may be necessary to achieve specific goals of Phase III
However, the same formulation, processing and packaging procedures as with commercial product is recommended
Drug Approval Process
Timeline for development of new drug
The development process may take upto15 years.
Some high-priority drugs may get approved faster based on urgency.
Most of the time is spent in clinical trials
___________________
See page 28 of dosage form textbook
Drug Dosage and Terminology
Usual adult dose: Starting dose for a patient
Usual dosage range: Safety dose range for administering drug product
Dosage Regimen: Schedule of dosage
Maintenance doses: Maintain clinically relevant drug levels in blood
Prophylactic dose: Administered to prevent patients from contracting the disease
Therapeutic dose: Administered once disease has been contracted
Drug Dosage and Terminology 2
Minimum effective concentration (MEC):
The minimum dose required to get a desired effect
Minimum toxic concentration (MTC):
Administering drugs above this level will produce dose related toxicities
Median effective dose (MED):
This dose will produce a desired intensity of a drug effect in 50% of the individuals tested
Time-blood level curve
Ideally, the drug serum levels should be maintained above the MEC and below the MTC.
Concentrations above the MTC will cause toxic side effects
Drug Dosage & Terminology
Determination of drug dosage form
Age: Neonatal, Pediatric & Geriatric Patients
Body Weight: Milligrams (of drug)/ per kilogram of body weight
Body Surface Area: 1 mg/M2 BSA- NOMOGRAM
Sex: Men and Women have different responses to certain drugs due to biochemical & Physiologic factors
Pathologic State: Disease State
Times of administration: Before or after meals
Tolerance: Ability to endure influence of a drug
BSA
is used to determine drug dose in humans
Due to the correlation that exists between physiological processes and body surface area (BSA), some drug doses are determined based on this relationship
- 1800 to 1820: Organic plant acids were extracted from plants by pharmacists in Germany, France, and Sweden
- 1883: Synthesis of antipyrine. Important because done in a test tube and this changed the way drugs were discovered from this point forward
- 1925 to 1945: Rapid advances in pharmacy research.
- Alexander Flemming discovered Penicillin
- James-Watson Crick solved the structure of DNA
Brief History of Drug Discovery & Development
Morphine: from opium poppy
Quinine: from cinchona bark
Digitalis: from foxglove
Belladonna: from deadly night shade
The alkaloids are not present in plants to supply us with medicines but are probably present to discourage predators
Problem is with purity and producing enough for our needs
Not all plants of same species are grown under same conditions so potency will vary
Plant poisons: Life before drugs could be synthesized
- Purpose: To find active ingredients and/or modify the chemical structures of existing active ingredients of drugs to form the basis of a new agent.
- It takes the services of many
- Chemists
- Pharmacologists
- Toxicologists
- Formulation developers (i.e. pharmaceutics)
Drug Discovery
- Purpose: To provide superior dosage forms and a way of delivering effective drugs throughout the body
- Mostly done by scientists usually with a PhD
- At a pharmaceutical company
- At a school of Pharmacy
Drug Development
- Drug solubility:
- Less than 10 mg/ml is considered poorly soluble
- Partition coefficient:
- Preference for lipid verses preference for aqueous phase
- Dissolution Rate:
- Speed at which a drug substance dissolves in a medium
- Physical Form:
- Crystal verses amorphous verses powder etc.. Will alter the rate and extent of absorption
- Stability:
- Retention of drug substances within dosage forms
Early Formulation Studies
What properties are investigated?
- Ideally this group seeks to develop a compound with the following characteristics
- Can produce a desired effect
- Can be administered at the most desirable route (orally)
- Can be administered at a minimal dosage and frequency
- After exerting a necessary effect should be eliminated from the body efficiently, and without negative side effects
The “Goal Drug”
This compound is the closest agent to the “goal drug” possessing the fundamental desired biologic or pharmacologic activity
It may NOT contain all of the properties of the desired compound, and so medicinal chemists often modify the lead compound.
A “Lead Compound”
Pharmacology: Determines biologic activity and mechanism of drug action in vitro & In vivo
Drug Metabolism: Determines the absorption, distribution, metabolism and elimination (ADME)
What is the extent of drug absorption and distribution in the body?
What is the mechanism of the drug metabolized by the body?
Toxicology: Deals with adverse and undesirable effects of the drug. Consider: What is the maximum tolerated dose?
_______________________________________________
See Textbook for detailed descriptions and be able to distinguish one discipline from another
Drug Researcher
Make sure that the appropriate dosage form is being used to deliver therapeutics to the intended site of drug action
Non-specific delivery to intended targets is the main reason for drug-related side-effects
Other examples of issues addressed by researchers in vivo
Assess benefit to risk relationship
Is a particular drug safe and effective enough ?
AZT (azidothymidine) toxic but highly effective
Make drugs available to the public sooner
Provide clear standards for drug evaluation
High priority drugs
These are defined as drugs that offer a significant medical advantage over current therapies
Cancer drugs Division of Oncology
Contraceptive drugs Division of reproductive & Urologic drug products
Generic drugs Division of Generic drugs
CDER
Once a drug has been developed, before it can be administered to humans it must be filed with the FDA. This is an IND Application.
This protects the rights & safety of subjects and makes certain that the research objectives stated can be achieved with the investigational plan
Main purpose of this application is to provide the FDA with sufficient information to make a meaningful evaluation of a new drug
IND is then assigned to a CDER official,
Can place hold on trial due to inadequate information, inadequate qualifications of investigators or significant risk of harm to patients
Investigational New Drug Application
Preclinical studies demonstrate adequate safety. This is to be determined by phase I clinical trials.
Phase I Clinical Trials
Drug should show promise as a useful drug
Phase I: What is the safe dose in 20 to100 patients)?
Usually brief study (less than 1 year).
Purpose is to determine toxicology, metabolism, and pharmacologic actions
Application contains:
The plan for the study
Chemical Structure
Animal testing results
Manufacturing information
IND Application
Biopharmaceutical properties clinical study
Practical considerations
Actual supply of bulk
Time allowed for preparing bulk stock
Advantages of extemporaneous formulations
Short development time
Minimal drug substance requirements (few hundred grams)
Minimal formulation development
Minimal analytical work
Disadvantages of extemporaneous formulations
Unpleasant taste
Patient compliance issue
Dosing inconvenience for multiple dose studies
What about clinical trial material (CTM) for Phase I studies?
If drug shows adequate safety in phase I it then enters phase II clinical testing
Purpose: To determine compound’s effectiveness
Phase II:
Drug is tested in hundreds of patients (~100 to 300 people).
Patients have the disease that the drug is intended to treat
Extensive pharmacologic, toxicological and pharmacological testing
Many clinical agents do not make it to this point
Phase II clinical trials
“powder in a bottle”- not very good approach
Capsules or tablets are typically necessary
Generally, same dosage form as phase I can be used here. Except,
When required dosage strength is not supported
When medium-to-large scale is not feasible
Alternatively, a new formulation closer to desired commercial dosage form can be introduced during phase II
What about clinical trial material (CTM) for Phase II studies?
Phase II covers a large dose range so # of dose strengths may be large
This is determined by,
Team of scientists (pharmaceutical scientists, pharmacokineticists, & clinical study and clinical supply coordinators)
Limitations with high dose strengths:
Dissolution and processability
Limitations with low dose strengths:
Content uniformity and stability issues
What about (CTM) for Phase II studies?-Continued-
Other Critical factors:
Purpose: To demonstrate long-term safety & efficacy of drug product; to discover drug’s efficacy standards
Several thousands of patients in many centers (~1000-3000 people)
Carried out over several years
HOW good is the drug in treating the disease or condition?
What are the short-term side effects and risks associated with drug use in patients whose health is impaired?
Investigational drug will be used in several randomized, controlled studies in various clinical research facilities including,
Clinical research facilities
Veterans administration
University teaching hospitals
Phase III clinical trials
Data from stability should be performed on at least 3 primary batches of drug products
Stability testing must cover minimum period of12 months typically at 25 ºC
Changes in dosage strengths and manufacturability of CTM may be necessary to achieve specific goals of Phase III
However, the same formulation, processing and packaging procedures as with commercial product is recommended
What about clinical trial material (CTM) for Phase III studies?
Drug Approval Process
The development process may take upto15 years.
Some high-priority drugs may get approved faster based on urgency.
Most of the time is spent in clinical trials
___________________
See page 28 of dosage form textbook
Timeline for development of new drug
Usual adult dose: Starting dose for a patient
Usual dosage range: Safety dose range for administering drug product
Dosage Regimen: Schedule of dosage
Maintenance doses: Maintain clinically relevant drug levels in blood
Prophylactic dose: Administered to prevent patients from contracting the disease
Therapeutic dose: Administered once disease has been contracted
Drug Dosage and Terminology
Minimum effective concentration (MEC):
The minimum dose required to get a desired effect
Minimum toxic concentration (MTC):
Administering drugs above this level will produce dose related toxicities
Median effective dose (MED):
This dose will produce a desired intensity of a drug effect in 50% of the individuals tested
Drug Dosage and Terminology 2
Ideally, the drug serum levels should be maintained above the MEC and below the MTC.
Concentrations above the MTC will cause toxic side effects
Time-blood level curve
Age: Neonatal, Pediatric & Geriatric Patients
Body Weight: Milligrams (of drug)/ per kilogram of body weight
Body Surface Area: 1 mg/M2 BSA- NOMOGRAM
Sex: Men and Women have different responses to certain drugs due to biochemical & Physiologic factors
Pathologic State: Disease State
Times of administration: Before or after meals
Tolerance: Ability to endure influence of a drug
Drug Dosage & Terminology
Determination of drug dosage form
is used to determine drug dose in humans
Due to the correlation that exists between physiological processes and body surface area (BSA), some drug doses are determined based on this relationship
BSA
