drug discovery and clinical trials

Question 1

drug discovery initial identification

Answer 1

published research 
disease knowledge
pharmaceutical analysis generating hypotheses
traditional or herbal 
luck
metabolites of existing drugs

Question 2

cellular drug targets

g protein coupled receptor

Answer 2

drugs as selective ligand

Question 3

cellular drug targets

ion channels

Answer 3

challenging due to pore forming homology

Question 4

cellular drug targets

transport proteins and enzymes

Answer 4

protein kinases, targets for oncology

Question 5

genetic associations

Answer 5

GWAS sequencing of whole genomes allows for identification of subgroups requirements for new personalised medicines

Question 6

high throughput screening target validation

Answer 6

large no. modulators against drug candidate to rapidly exclude those with poor response

Question 7

bioinformatics

Answer 7

analyse data sets to show targets and understand disease processes to identify drug targets

Question 8

Pre

pharmacodynamics PD

Answer 8

what drug does to the body

Question 9

Pre

pharmacokinetics PK

Answer 9

what body does to the drug

Question 10

Pre

basics of PRECLINICAL study

Answer 10

animal models no humans 
PK
PD
safety and toxicological investigations
pharmaceutical development-large scale feasibility

Question 11

Pre

pharmacodynamics research

Answer 11

site/mechanism of action
influence of age sex and other factors
dose-response

Question 12

Pre

pharmacokinetics research

Answer 12

absorption- rate and bioavailability
distribution in tissues
metabolisms - accumulation and interactions
excretion- clearance and organ

Question 13

Pre

safety and toxicological

Answer 13

adverse effects
non toxic dose
therapeutic range
post mortem for tissue damage
intra and inter species variability

Question 14

Pre

pharmaceutical development

Answer 14

formation and administration
large scale synthesis/purification feasibility
compound stability under different conditions

Question 15

when can Pre go to clinical

Answer 15

once thorough and comprehensive preclinical satisfied a regulatory body for safety and efficacy can move on to human testing

Question 16

basics CLINICAL TRIALS

Answer 16

human volunteers
expose more people collect more data
needs authorising by medicines and healthcare produce regulatory agency MHRA
good clinical practice

Question 17

phase 1 clinical trials

Answer 17

initial human administration
estimate safety and dose range
small n of health volunteers
use exhaustive pre clinical data to minimise risk
specialist units and trained investigators for consequences

Question 18

phase 1 clinical trial administration

Answer 18

slow infusion
SAD-single ascending dose, if no adverse effects increase dose in a new group until side effects or PK safety
MAD

Question 19

phase 1 clinical trial Pharmacokinetics PK

Answer 19

measure at freq. intervals for conc vs time
absorption, distribution, metabolism, excretion
monitor any variance from pre clinical animal models

Question 20

phase 1 clinical trial pharmacodynamics PD

Answer 20

consider mechanism of action, specificity and immune targets
body system disturbances
high potency

Question 21

phase 1 clinical trials drug dose

Answer 21

MABEL- minimum anticipated biological effect level(minimum dose to cause biological effect in human)
NOAEL- no observed adverse effect level(highest does no adverse effect)

Question 22

p1 clinical trial volunteers and objectives

Answer 22

small number less than 20 or 30 of healthy volunteers with no other medication with valid informed consent (or cancer patients)
determine MTD (max tolerated dose) and MEC (minimum effective conc)

Question 23

p1 ADME

Answer 23

absorption into systemic circulation
distribution of drug into tissues
metabolism and or metabolites
excretion of drug from body

Question 24

p2a basics

Answer 24

same as p1 but larger n 50-500
can look at differences in age
appropriate dosage in patients

Question 25

p2b basics

Answer 25

therapeutic range assessed for efficacy
pivotal trials-evidence for drug marketing approval
once shown effective against disease or condition can go to p3

Question 26

p3 basics

Answer 26

therapeutic confirmation using large n and RCT

large and long term assessment on safety

Question 27

p3a

Answer 27

before drug application submission
use on patient pop
info on labelling
modelling for drug drug interactions and differences in subgroups

Question 28

p3b

Answer 28

after application but before approval/marketing
supplements earlier trials
increased patient exposure

Question 29

p4

Answer 29

post registration and licensing
2000-10000
comparison against other drugs
continued pharmaco-economic evaluation

Question 30

RCT gold standard basics

Answer 30

intervention vs control
follow up and measure outcomes at time points
single or double blinded
randomisation

Question 31

PICO

Answer 31

population
intervention
control
outcome

Question 32

RCT problems

Answer 32

noncompliance
missing outcomes(loss follow up)

Question 33

NNT-number needed to treat

Answer 33

average no. patients receive treatment before ones positive outcome - ideally close to 1

Question 34

NNH-number needed to harm

Answer 34

chance of experiencing harm because of intervention

should be large

Question 35

types of RCT design

Answer 35

superiority- show more effective
equivalence - show same benefit, clinically unimportant difference
non inferiority - effect not weaker than current

Question 36

RCT advantages

Answer 36

comparable groups
valid stat tests
closely matched groups
gold standard

Question 37

RCT disadvantaged

Answer 37

cost and time
generalisability issues
recruitment
complex administration