2 - CML and Imatinib Flashcards
cml
chronic myelogenous lukemia
cause of cml
uncontrolled proliferation of myeloid cells
chronic phase
3-5 years
proliferation occurs but diseases controlled
acute/blast phase
extreme proliferation
treatment for cml
imatinib
3 steps of translational pipeline
- discovery
- development
- delivery
delivery
regulatory approval
imatinib pre clinical trials
- test on pure protein (kinase assay)
- test if it inhibits proliferation of BCA-Abl +ve cell lines
- test in primates
phase 1 trials
- interested in toxicity, tolerated dose and pharmokinetics of drug
- either on healthy people or cml patients
- dose is slowly increased
- no. of people trialled slowly increased
phase 2 trial
- test patients with disease
- small study
- interested in finding biological response
- finding optimum dose
- sometimes randomised control trial
biological response to imatinib
found in phase 2 trials
haematological and cryogenic response
- no more Philadelphia chromosome
phase 3 trial
we know drug is safe and how it is processed by the body
full scale RCT
e.g. 1000 cml patients
cost effectiveness tested by NICE
rct
randomised control trial
how do observational studies generate hypothesis
they identify patterns and trends in populations
rational drug design
designing small molecules that are complementary to biomolecular target
better than trial and error
requires knowledge of disease mechanism
which phase of trials tests to find the optimum dose fo drug
phase2
advantages of randomisation
eliminates bias in treatment assignment
facilitates blinding/masking
maximises statistical power
3 types of randomisation
simple - use random no. generator
blocked
stratified
which types of randomisation do you use if you have a small smaple size
blocked or stratified
advantages of blinding/masking
prevents patients/care-givers knowing which intervention was recieved
3 types of blinding
open-label
single-blind
double-blind
define bias
unintentional adjustment in design/conduct of a trial
how do you avoid bias
blinding/randomisation
allocation concealment
standardised procedure
standardised equipment
problems with bias
may cause unreliable results
what is ‘intention to treat’ (ITT) analysis
‘once randomised, always analysed’
all patients allocated to original groups are included accordingly in analysis
even if they drop out
advantages of ITT analysis
provides unbiased comparisons
avoid effects of cross-over and drop-out
what is NICE
a rationing body to reduce variation in access to new interventions
what does NICE stand for
national institute for health and care excellence
how does NICE evaluate economic considerations for new drugs
NHS cost savings
HTA - health technology assessment
CEA - cost effective analysis
how is HTA for
to calcute if the money for the drug production is really worht it
how do you calucate HTA
life expectancy in years x HR-QoL
how is QoL measured
EQ-5D questionnaire
what are the 5 domains of health
mobility self-care usual activities pain/discomfort anxiety/depression
what does QUALY stand for
quality adjusted life years
‘currency’ of health
QUALYs
QUALYs
length of life combined with quality of life
life expectancy x HR-QoL = QUALYs
ICER - incremental cost effectiveness ratio
what is it and what is it used for
statistic used in CEA to summarise cost effectiveness of a health care intervention
how do you calculate ICER
cost of new intervention - cost of old intervention
divided by
QUALYs of new intervention - QUALYs of old intervention
how does ICER tell you how cost-effective a treatment is
if the ICER is less than £20,000 per QUALY gained, then the NHS deem it cost effective
what is CEA
cost effective analysis
the comparative analysis of alternative courses of action in terms of both cost and consequences for health
describe the CEA graph
HR-QoL on y-axis
time on x-axis
area between curves for treatment A and B = QUALYs gained
transgenes
introduction of genes from a different source into a cell
techniques used to create transgenes
transfection
transduction
uses of transgenes
researching function of gene/protein
gene editing
gene therapy
what kind of sequences are introduced into cells
cDNA
CRISPR constructs
promoters
steps for creating transgenes
1 - purify mRNA from target cell
2 - convert mRNA –> cDNA using RT
3 - selectively amplify gene of interest (PCR)
4 - add restriction enzyme sequence
5 - use plasmid –> promoter sequence drives transcription of cDNA
6- GFP used to show localisation of gene in cell
7- transfection/injection/infection into nucleus
3 ways to transfect cDNA into nucleus
electroporation
lipid-mediated transfer
CaPO4 transfer
