Drug Discovery and Clinical Trials Flashcards
Drug Discovery
- Disease characterization
- Target selection & identification of “drug hits”
- Lead optimization
- Pharmacological profiling
Pre-Clinical Development
In vitro and in vivo Animal models
- Pharmacokinetics & Toxicology
- Formulation & Synthesis scale up
Clinical Development
Drug tested in human volunteers & patients
- Safety & Efficacy
- Pharmacokinetics & Toxicity
Compound-centered approach to Drug Discovery
Compound with interesting activity and/or chemistry
Screen biological systems for interesting biological functional effects
Target-centered approach to Drug Discovery
Identify protein target with known disease association/activity
Screen large chemical libraries to Identify drug hits that interact with target and modify activity
Lead Optimization
Identified new drug lead may not have best properties for a drug. Develop chemically modified drug variants.
Screen for improved pharmacological profile.
What is the goal of pre-clinical development?
To provide evidence that a drug is safe for future testing in humans
What is safety pharmacology?
Evaluate drug using in vivo animal testing for the presence of any obvious acute systemic toxic effects
- two different species and two routes of administration
No-effect dose
The maximum dose at which toxic effects are not seen
LD50
The dose that kills 50% of animals
What are the major steps in preclinical development?
A. Safety Pharmacology
B. Toxicology
C. Pharmacokinetic testing
- fully characterize pharmacokinetic parameters: ADME
D. Drug Interaction studies
- determine metabolism by CYP450 family members - identify any possible inhibitors of CYP450
- determine specificity for Drug Transporter proteins
E. Chemical & Pharmaceutical Development
Investigational New Drug Application (IND)
Vehicle for providing evidence to the FDA that a new drug drug is a viable candidate for further development and appropriate for initial limited use in humans (i.e. “reasonably safe”)
What are the components of the IND?
- Animal Pharmacology and Toxicology data
- Manufacturing information
- Clinical Protocols and Investigator information
Investigator IND
Request to study an unapproved drug
Emergency use IND
Allows authorization of an experimental drug in an emergency situation for use in a single patient that has a serious or immediately life-threatening condition
Treatment IND
Allows promising experimental drugs that have not yet been approved to be used in patients with serious or immediately life-threatening conditions where no other therapy is available and death is likely
Institutional Review Board
Minimize potential risk to human subjects
Determine whether potential risk is reasonable relative to anticipated benefit
Superiority Trial
Trial designed to demonstrate that one treatment is clinically superior to either placebo or another drug
Non-inferiority Trial
A trial designed to demonstrate that one drug is not appreciably less effective than the standard
Phase I Clinical Trial
20- 100 Healthy Volunteers
Is it safe? Tolerability PK
Phase II Clinical Trial
100-200 Patients
Does it work in patients?
Dosing
Phase III Clinical Trial
1,000-6,000 Patients
Does it work in large patient populations
Phase IV Clinical Trial
Post- marketing Surveillance
Adverse effects
Interactions Compliance
New Drug Application
NDA contains all pre-clinical and clinical data collected during a drug’s research & development and must be FDA approved to enter market
What information must appear on the label?
Approved indications Clinical Pharmacology - Dosage - Adverse Reactions - Contraindications - Special warnings and precautions e.g. not for pregnancy/specific condition
What are the 3 classes of drug recalls and their meanings?
Class I: Reasonable probability that use of drug will cause serious adverse health consequences or death e.g. microbial contamination
Class II: Use of drug will cause temporary adverse health consequences, although probability of serious health consequences is remote
Class III: Use of drug is unlikely to cause adverse health consequences e.g. quantity packaging error
How does marketing of a generic drug work once the patent is expired?
Once a patent has expired any company may submit an Abbreviated New Drug Application (ANDA) to allow marketing of a GENERIC VERSION of the drug with NO need to provide evidence of efficacy & safety
