Clinical trials

Question 1

clinical trial gone wrong

Answer 1

cannabinoid drug that caused death/brain damage
FAAH - stops natural cannabinoids being broken down
didn’t wait long enough between increasing doses
doses higher than animal tests therapeutic dose

Question 2

preclinical development

Answer 2

tissue models, cell cultures, brain slices, animals

MOA, pharmacokinetics, toxicology, formulation, synthesis scale up

Question 3

drug discovery

Answer 3

preclinical development, characterisation, ED50, ADME, LD50, phase 1, 2, 3, approval, phase 4

Question 4

phase one trials

Answer 4

first in human trials - healthy volunteers (males), small sample
test safety and tolerability, pharmacokinetics, best practice
base on info from animal studies
tolerance - MTD, MABEL
ascending doses - SAD and MAD
adverse side effects

Question 5

MTD

Answer 5

maximum tolerable dose

Question 6

MABEL

Answer 6

minimal anticipated biological effect level

used to determine first dose in human

Question 7

SAD

Answer 7

single ascending doses

Question 8

MAD

Answer 8

multiple ascending doses

Question 9

phase two trials

Answer 9

small-scale in patients with disorder of interest
efficacy and dosage, long term toxicology, safety
best practice parameters, side effect profile in patient population
placebo or comparative

Question 10

phase three trials

Answer 10

large scale controlled clinical trials - worldwide
test efficacy
better side effect profile
comparisons

Question 11

regulatory approval

Answer 11

submission of full data and review by agencies
MoH -> NEAC (national ethics advisory committee) -> ethics committee + medsafe
health research council -> SCOTT (standing committee on therapeutic trials)
also needed before clinical trials

Question 12

phase four trials

Answer 12

post release surveillance
market expansion, life-cycle management, new indications, formulations, combinations, regimens
only now are women, elderly, children introduced

Question 13

clinical trial

Answer 13

an experiment or set to establish safety, efficacy, practicality of new drug/medical proceedure

Question 14

example of phase 1 trial with bad results

Answer 14

MK-801 NMDA receptor non comp antagonist
effective in vivo and in vitro
hallucinations and behavioural disorders in humans

Question 15

ethic committees review…

Answer 15

qualifications of investigators, locality assessment (crash carts, comfortable, emergency number), experiment protocol (what is done by who, statistical analysis)

Question 16

the human factor

Answer 16

don’t give doses near LD50, not too many X-rays, blood tests

is a placebo ethical?

Question 17

design attributes

Answer 17

control groups - confounders
random allocation - avoid bias/balance extraneous factors
blind measurements - subject and experimenter
replication - controls for random fluctuations, calculate sample size

Question 18

side effects

Answer 18

SAE (serious adverse event = death)
minor or serious (allergic response)
larger sample = more reported
report even if unrelated
discontinue?

Question 19

participants

Answer 19

hospitals, GPs, advertising
informed consent - benefit, failure, danger, requirements, criteria
can give consent for unconscious adult
16 +

Question 20

cultural issues

Answer 20

maori consultation, tissue storage, disposal, shipping of tissues, stored tissue/genetic analysis

Question 21

end of trial

Answer 21

is it ethical to withdraw? alternative?

continued responsibility, arrange at beginning

Question 22

access to info

Answer 22

results must be published online in full

Question 23

audits

Answer 23

inspect clinic and laboratory

FDA, client-company

Question 24

declaration of helsinki

Answer 24

protect peoples health and rights
do no harm
knowledge cannot override rights

Question 25

ethics committee

Answer 25

look at advertising, information, consent, payment (baseline), dose, samples taken, population, facilities

Question 26

medsafe

Answer 26

safety vs efficacy | adverse effects vs pharmacodynamics

Question 27

first dose in human

Answer 27

life threatening acute events, haematological/biochemical toxicity, rashes, ECG changes

Question 28

cancer drug trial benefit to patient

Answer 28

has protocol, contributing to science, treatment plan, clinical contact

Question 29

decision

Answer 29

conclusion or resolution reached after consideration choice from several possibilities -> commitment of resources, specification of criteria

Question 30

decision points

Answer 30

lead identification, entry to development, first in human, proof of mechanism, proof of concept, phase 2/3 transition, submission, approval, risk management, pricing, post-marketing

Question 31

NCE

Answer 31

new chemical entity

Question 32

better than competitor?

Answer 32

effectiveness, safety, patient factors (easy/adherence)

Question 33

ketamine

Answer 33

anaesthetic -> treatment resistant depression and anxiety R and S racemic mixture injections S enantiomer only? more potent, less side effects, expensive to separate

Question 34

ketamine animal studies

Answer 34

investigate route of administration | IV = high Cmax and AUC, IM = R and S different

Question 35

ketamine human studies

Answer 35

oral + tamper resistant tablets, slow release rate = less potential for abuse chiral vs non chiral = no difference adverse effects = dissociation, headache, dizziness depression scale rating MADRS = 72% response

Question 36

pharmacovigilance

Answer 36

monitoring medication safety | reduce risk and harm (can't eliminate)

Question 37

types of adverse effects

Answer 37

A - augmented (predictable from MoA or dose) B - bizarre (rare, individual characteristics) C - continuing D - delayed (exposure vs outcome) E - end of use

Question 38

ADRs

Answer 38

3-6 % of hospital admissions, increase admission time b 7.8 days, twice as expensive as medicine costs, 12% associated with disability or death

Question 39

generic medicines

Answer 39

when innovator goes off patient cheaper same molecule, different manufacturing, colour, formulation

Question 40

adverse events in trials

Answer 40

temporal relation, dose, nature exclude confounders compare with other studies

Question 41

clinical toxicology

Answer 41

diagnosis and management of poisoning | adverse health from taking something

Question 42

case definition

Answer 42

signs and symptoms of all involved time and location - common exposures who is and who isn't a case

Question 43

pombe poisoning

Answer 43

interview and review records and patients and biological specimens nausea and vomiting and seizures and death non targeted screening found answer LC-MS = fatty acid bongkrekic acid produced by bacterium

Question 44

investigating toxicity

Answer 44

look for further cases list possible toxins review literate and evaluate confirmatory testing for source and clinical specimens