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Flashcards in Drug Discovery and Clinical Trials Deck (17):
1

Describe the stages and roles in the drug development process.

1. DRUG DISCOVERY
- disease characterization
- target selection
- lead optimization
- pharmacological profiling

2. PRE-CLINICAL DEVELOPMENT (shortest)
- in vitro and in vivo animal studies
- PK and toxicology trials
- formulation and synthesis

3. CLINICAL DEVELOPMENT (longest)
- human trials
- safety and efficacy
- PK and toxicity trials

2

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

3

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)

4

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

5

Describe the process by which a new drug candidate becomes an approved new drug.

1. new drug candidate
2. investigational new drug application
3. FDA IND and IRB reviews
4. clinical trial phase I, II, III
5. new drug application (NDA)
6. FDA NDA review
7. new drug

6

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)

7

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

8

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
1. animal pharmacological and toxicological data
2. manufacturing information (composition, stability, able to be manufactured)
3. clinical protocols and investigator information

9

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

10

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

11

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

12

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)

13

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)

14

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

15

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

16

Describe the following for Phase III clinical trials:
- typical # of participants
- typical trial design
- endpoints
- primary objective

- 1000-6000 patients with target condition in target population; distributed across ethnic groups and gender
- double blind randomized controlled trial
=> against placebo or standard of care
- definitive or surrogate ========> NDA application
- objective: population efficacy, safety

17

Describe the following for Phase IV clinical trials:
- typical # of participants
- setting
- typical trial design
- endpoints
- primary objective

- post-market surveillance, adverse effects, interactions, compliance
- physicians report adverse effects
- large populations allow for discovery of unusual side effects