Drug Discovery and Clinical Trials Flashcards
Describe the stages and roles in the drug development process.
- DRUG DISCOVERY
- disease characterization
- target selection
- lead optimization
- pharmacological profiling - PRE-CLINICAL DEVELOPMENT (shortest)
- in vitro and in vivo animal studies
- PK and toxicology trials
- formulation and synthesis - CLINICAL DEVELOPMENT (longest)
- human trials
- safety and efficacy
- PK and toxicity trials
Describe the essential elements of compound-centered and target-centered drug discovery.
COMPOUND-CENTERED
- compound has interesting activity or chemistry
- biological screen to test for unique functional effects
TARGET-CENTERED
- identify protein target with known association with disease
- screen drug library to see if anything hits it
Define the role of lead drug optimization in the context of the drug development process.
- lead may not exhibit ideal properties
- develop chemically modified drug variants
- screen for improved drug profile
LEAD COMPOUND - NEW CHEMICAL ENTITY (NCE)
Describe the principal goal of pre-clinical drug development, the major steps involved in this process and their primary function.
- goal: prove drug is safe for human trials
SAFETY - in vivo animal testing done to assess for any adverse effects
- determine no-effect dose: maximum dose without toxic effects
- determine median lethal dose (LD50): dose that kills 50% of the animals
TOXICOLOGY
- Ames test for genotoxicity
- carcinogenicity
- teratogenicity
- anti-target testing to make sure drug doesn’t interact with known drug-induced adverse effect targets (ex: hERG)
PK TESTING
- ADME
DRUG INTERACTION STUDIES
- metabolism with CYPs
- any possible inhibitors of CYPs
- specificity for drug transporter proteins
DEVELOPMENT
- chemical stability
- large scale synthesis
- formulations suitable for studies
Describe the process by which a new drug candidate becomes an approved new drug.
- new drug candidate
- investigational new drug application
- FDA IND and IRB reviews
- clinical trial phase I, II, III
- new drug application (NDA)
- FDA NDA review
- new drug
Describe the functions of the FDA in the drug approval process.
CDER - center for drug evaluation and research
- safety, efficacy
- reviews all applications for new and generic drugs
- monitors pharmaceutical compliance with current good methods of practice (cGMP) (quality control)
Describe the composition, primary functions and role of IRB in the drug approval process.
role - review, approve, monitor all clinical trials
composition - >5 people (scientists, nurses, statisticians, lay people)
purpose - ensure rights of participants, informed consent, , able to stop trial if concerned
Describe the primary purpose of the INDA and list the major required components of the application.
PURPOSE - determine if drug is reasonably safe enough to continue studies
COMPONENTS
- animal pharmacological and toxicological data
- manufacturing information (composition, stability, able to be manufactured)
- clinical protocols and investigator information
Describe the 3 types of INDA and their uses.
INVESTIGATOR
- request to study an unapproved drug
- request to study an approved drug for a new indication, change in administration route, change in approved patient population
- submitted by person/company who will be studying it
EMERGENCY USE
- use of experimental drug in emergent situations
- single patient with life-threatening condition
- no other therapy or not enough time for IRB approval
TREATMENT
- allows experimental drug to be used in patients with life-threatening conditions
Describe the following for Phase I clinical trials:
- typical # of participants
- setting
- typical trial design
- primary objective
- 20-100 healthy volunteers
- inpatient setting
- open label (no blind) with increased incremental dosing
- objective: safe, tolerable, maximum tolerated dose
Define the purpose and contents of the NDA.
- all preclinical and clinical data
- done after phase III completed
- outcomes: approved, approvable, not approved
stages: - application reviewed
- priority review
- standard review
List the FDA approved data that must be included on the approved drug packaging labels.
- approved indications
- clinical pharmacology
=> dosage
=> adverse reactions
=> contraindications
=> warnings/precautions (black box)
Define the 3 classes of drug recall.
CLASS I
- probability drug will cause adverse effects or death
CLASS II
- probability drug will cause temporary adverse effects, not serious
CLASS III
- unlikely to cause health consequences (packaging error)
Describe the process by which generic drugs are approved including what critical pharmacological information needs to be provided to support the application.
- must establish bioequivalence
- drug formulation must contain equal amounts of active ingredient
- comparative PK and PD
- similar absorption rate
- cGMP compliance
Describe the following for Phase II clinical trials:
- typical # of participants
- typical trial design
- endpoints
- primary objective
- 100-200 patients with target condition
- single- or double-blinded randomized controlled trial
=> evaluated against placebo or standard of care
=> parallel or crossover - definitive end point (achieve actual goal of therapy) or surrogate end point (achieve goal associated with disease) =======> meet with FDA to determine if safe enough for Phase III
- objective: efficacy, safety
