Drug discovery and clinical trials

Question 1

Give an overview of the drug development process

Answer 1

drug discovery
investigation of what the drug does
is the drug safe?
clinical evaluation

Question 2

Describe pre-clinical development

Answer 2

Wide range of non-human studies
toxicity
pharmacokinetic analyisis

Question 3

Describe clinical development

Answer 3

tested for efficacy, side effects, potential dangers

in volunteers and patients

Question 4

What are some drug discovery routes?

Answer 4

development of traditional remedies - aspirin
some serendipity - cyclosporin
chemistry - beta blockers
metabolites of existing drugs - paracetamol
extensive screening
molecular design

Question 5

Describe target selection

Answer 5

to identify the molecular targets involved in disease

Knowledge of biological processes and mechanisms of disease and signalling pathways

Question 6

Give examples of cellular targets

Answer 6

receptors
enzymes
transporters
ion channels

Question 7

Give examples of proteomic targets

Answer 7

protein interactions
protein-protein
protein-nucleic acid
protein - ligand

Question 8

Describe pharamcogenomics

Answer 8

new drug targets may be identified through the use of next generation sequencing 
- whole genome 
whole exam
detection of SNPs
RNA sequencing

Question 9

Describe the stages of pre-clinical development

Answer 9

pharmacological testing - safety, etc
Preliminary toxicology testing - determine max non toxic dose
pharmacokinetic testing in animals (ADME)
Chemical and pharmaceutical development to assess feasibility of synthesis and compound stability

Question 10

What is ADME?

Answer 10

Absorption
Distribution
Metabolism
Elimination qualities

Question 11

Describe good clinical practise in clinical trials

Answer 11

international ethical and scientific quality standard
protection of human rights
assurance of efficacy and safety

Question 12

Describe phase 1 clinical trials

Answer 12

initial administration of new drug in humans
estimation of initial safety and tolerability of expected dose range
single ascending dose studies
multiple asdcending dose studies
pharmacokinetics
some pharmacodynamics
Drug dose
20-50 participants
usually health volunteers (apart from in early cancer trials)

Question 13

What is NOAEL?

Answer 13

No observed adverse effect level

Question 14

What is MABEL

Answer 14

minimal anticipated biological effect level

Question 15

describe proof of concept trials

Answer 15

linking phase 1 and phase II

aims to estimate whether a compound may have a clinically significant effect in other diseases / conditions

Question 16

Describe phase 2A clinical trials

Answer 16

assessments carried out in phase I are repeated on a larger group of participants (50-500)
protocol assesses efficacy 
therapeutic drug tested on patients 
vaccines tested in healthy patients 
continuation of safety evaluation
continuing to assess dosing intervals 
may assess in various target populations

Question 17

Describe phase 2B clinical trials

Answer 17

appropriate dosing and intervals
how well the drug works at that dose
Sometimes referred to as pivotal trials

Question 18

Describe pivotal trials

Answer 18

provide evidence for drug marketing approval

must be proven effective before can be approved

Question 19

Describe phase 3 clinical trials

Answer 19

therapeutic confirmation studies
RCTS
comprehensive assessment of efficacy and safety

Question 20

Describe phase 3A trials

Answer 20

conducted before submission of new drug application
intended patient population
information needed for packaging or labelling

Question 21

Describe 3B trials

Answer 21

After regulatory submission but before approval

supplements earlier trials

Question 22

Describe phase 4 trials

Answer 22

after listening / registration
therapeutic use studies 
long term
may compare to established drugs
real life studies 
pharmacy-economic evaluation

Question 23

Describe a parallel group trial

Answer 23

new treatment vs standard treatment

patients followed up to determine effect

Question 24

Describe cross-over trials

Answer 24

randomise patients into treatments in different order

patient acts as their own control

Question 25

Describe factorial trials

Answer 25

assign patients to more than 1 treatment comparison group

Question 26

Describe superiority trials

Answer 26

aims to show that the new intervention is more effective than the comparative treatment - placebo or current best treatment

Question 27

Describe equivalence trials

Answer 27

designed to prove that two drugs have the same clinical benefit
should demonstrate that the difference between the two is clinically negligible

Question 28

Describe non-inferiority trials

Answer 28

aims to show that the effect of a new treatment cannot be said to be significantly weaker than the current treatment

Question 29

What are the advantages of RCTS

Answer 29

randomisation tends to produce comparible groups

provides valid statistical tests

Question 30

What are the disadvantages of RCTs?

Answer 30

may not be generalisable
recruitment may be difficult
acceptability of randomisation process
administrative complexity of trial