2 - CML and Imatinib

Question 1

cml

Answer 1

chronic myelogenous lukemia

Question 2

cause of cml

Answer 2

uncontrolled proliferation of myeloid cells

Question 3

chronic phase

Answer 3

3-5 years

proliferation occurs but diseases controlled

Question 4

acute/blast phase

Answer 4

extreme proliferation

Question 5

treatment for cml

Answer 5

imatinib

Question 6

3 steps of translational pipeline

Answer 6

1. discovery
2. development
3. delivery

Question 7

delivery

Answer 7

regulatory approval

Question 8

imatinib pre clinical trials

Answer 8

1. test on pure protein (kinase assay)
2. test if it inhibits proliferation of BCA-Abl +ve cell lines
3. test in primates

Question 9

phase 1 trials

Answer 9

• 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

Question 10

phase 2 trial

Answer 10

• test patients with disease
• small study
• interested in finding biological response
• finding optimum dose
• sometimes randomised control trial

Question 11

biological response to imatinib

Answer 11

found in phase 2 trials

haematological and cryogenic response
- no more Philadelphia chromosome

Question 12

phase 3 trial

Answer 12

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

Question 13

rct

Answer 13

randomised control trial

Question 14

how do observational studies generate hypothesis

Answer 14

they identify patterns and trends in populations

Question 15

rational drug design

Answer 15

designing small molecules that are complementary to biomolecular target
better than trial and error
requires knowledge of disease mechanism

Question 16

which phase of trials tests to find the optimum dose fo drug

Answer 16

phase2

Question 17

advantages of randomisation

Answer 17

eliminates bias in treatment assignment
facilitates blinding/masking
maximises statistical power

Question 18

3 types of randomisation

Answer 18

simple - use random no. generator
blocked
stratified

Question 19

which types of randomisation do you use if you have a small smaple size

Answer 19

blocked or stratified

Question 20

advantages of blinding/masking

Answer 20

prevents patients/care-givers knowing which intervention was recieved

Question 21

3 types of blinding

Answer 21

open-label
single-blind
double-blind

Question 22

define bias

Answer 22

unintentional adjustment in design/conduct of a trial

Question 23

how do you avoid bias

Answer 23

blinding/randomisation
allocation concealment
standardised procedure
standardised equipment

Question 24

problems with bias

Answer 24

may cause unreliable results

Question 25

what is ‘intention to treat’ (ITT) analysis

Answer 25

‘once randomised, always analysed’
all patients allocated to original groups are included accordingly in analysis

even if they drop out

Question 26

advantages of ITT analysis

Answer 26

provides unbiased comparisons

avoid effects of cross-over and drop-out

Question 27

what is NICE

Answer 27

a rationing body to reduce variation in access to new interventions

Question 28

what does NICE stand for

Answer 28

national institute for health and care excellence

Question 29

how does NICE evaluate economic considerations for new drugs

Answer 29

NHS cost savings
HTA - health technology assessment
CEA - cost effective analysis

Question 30

how is HTA for

Answer 30

to calcute if the money for the drug production is really worht it

Question 31

how do you calucate HTA

Answer 31

life expectancy in years x HR-QoL

Question 32

how is QoL measured

Answer 32

EQ-5D questionnaire

Question 33

what are the 5 domains of health

Answer 33

mobility
self-care
usual activities
pain/discomfort
anxiety/depression

Question 34

what does QUALY stand for

Answer 34

quality adjusted life years

Question 35

‘currency’ of health

Answer 35

QUALYs

Question 36

QUALYs

Answer 36

length of life combined with quality of life

life expectancy x HR-QoL = QUALYs

Question 37

ICER - incremental cost effectiveness ratio

what is it and what is it used for

Answer 37

statistic used in CEA to summarise cost effectiveness of a health care intervention

Question 38

how do you calculate ICER

Answer 38

cost of new intervention - cost of old intervention
divided by
QUALYs of new intervention - QUALYs of old intervention

Question 39

how does ICER tell you how cost-effective a treatment is

Answer 39

if the ICER is less than £20,000 per QUALY gained, then the NHS deem it cost effective

Question 40

what is CEA

Answer 40

cost effective analysis

the comparative analysis of alternative courses of action in terms of both cost and consequences for health

Question 41

describe the CEA graph

Answer 41

HR-QoL on y-axis
time on x-axis

area between curves for treatment A and B = QUALYs gained

Question 42

transgenes

Answer 42

introduction of genes from a different source into a cell

Question 43

techniques used to create transgenes

Answer 43

transfection

transduction

Question 44

uses of transgenes

Answer 44

researching function of gene/protein
gene editing
gene therapy

Question 45

what kind of sequences are introduced into cells

Answer 45

cDNA
CRISPR constructs
promoters

Question 46

steps for creating transgenes

Answer 46

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

Question 47

3 ways to transfect cDNA into nucleus

Answer 47

electroporation
lipid-mediated transfer
CaPO4 transfer