Drug discovery and clinical trials Flashcards
Give an overview of the drug development process
drug discovery
investigation of what the drug does
is the drug safe?
clinical evaluation
Describe pre-clinical development
Wide range of non-human studies
toxicity
pharmacokinetic analyisis
Describe clinical development
tested for efficacy, side effects, potential dangers
in volunteers and patients
What are some drug discovery routes?
development of traditional remedies - aspirin
some serendipity - cyclosporin
chemistry - beta blockers
metabolites of existing drugs - paracetamol
extensive screening
molecular design
Describe target selection
to identify the molecular targets involved in disease
Knowledge of biological processes and mechanisms of disease and signalling pathways
Give examples of cellular targets
receptors
enzymes
transporters
ion channels
Give examples of proteomic targets
protein interactions
protein-protein
protein-nucleic acid
protein - ligand
Describe pharamcogenomics
new drug targets may be identified through the use of next generation sequencing - whole genome whole exam detection of SNPs RNA sequencing
Describe the stages of pre-clinical development
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
What is ADME?
Absorption
Distribution
Metabolism
Elimination qualities
Describe good clinical practise in clinical trials
international ethical and scientific quality standard
protection of human rights
assurance of efficacy and safety
Describe phase 1 clinical trials
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)
What is NOAEL?
No observed adverse effect level
What is MABEL
minimal anticipated biological effect level
describe proof of concept trials
linking phase 1 and phase II
aims to estimate whether a compound may have a clinically significant effect in other diseases / conditions
Describe phase 2A clinical trials
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
Describe phase 2B clinical trials
appropriate dosing and intervals
how well the drug works at that dose
Sometimes referred to as pivotal trials
Describe pivotal trials
provide evidence for drug marketing approval
must be proven effective before can be approved
Describe phase 3 clinical trials
therapeutic confirmation studies
RCTS
comprehensive assessment of efficacy and safety
Describe phase 3A trials
conducted before submission of new drug application
intended patient population
information needed for packaging or labelling
Describe 3B trials
After regulatory submission but before approval
supplements earlier trials
Describe phase 4 trials
after listening / registration therapeutic use studies long term may compare to established drugs real life studies pharmacy-economic evaluation
Describe a parallel group trial
new treatment vs standard treatment
patients followed up to determine effect
Describe cross-over trials
randomise patients into treatments in different order
patient acts as their own control
Describe factorial trials
assign patients to more than 1 treatment comparison group
Describe superiority trials
aims to show that the new intervention is more effective than the comparative treatment - placebo or current best treatment
Describe equivalence trials
designed to prove that two drugs have the same clinical benefit
should demonstrate that the difference between the two is clinically negligible
Describe non-inferiority trials
aims to show that the effect of a new treatment cannot be said to be significantly weaker than the current treatment
What are the advantages of RCTS
randomisation tends to produce comparible groups
provides valid statistical tests
What are the disadvantages of RCTs?
may not be generalisable
recruitment may be difficult
acceptability of randomisation process
administrative complexity of trial
