Drug development and clinical trials

Question 1

what is the animal (sci proc) act of 1986?

Answer 1

legal requirement- preclinical trials have to take place in 2 different species before clinical trials can take place

Question 2

what is the medicine for human use (clinical trials) regulations 2004?

Answer 2

timely and cost effective clinical trials

they are extremely expensive and also there is a potential risk of putting humans at risk

Question 3

what are the 2 sets of guidance for clinical trials ?

Answer 3

OECD and the ICH
ICH= international conference on harmonisation of technical requirements for registratios of pharmaceuticals for human use (EU, japan and USA)

Question 4

what is involved in exploratory (non-GLP) toxicology ?

Answer 4

in vitro screens

• in silico screens
• mutagenicity
• cytotoxicity
• immunocytoxicity
• hepatoxicity
• embryotoxicity

single and repeat dose range finding studies in 2 species

Question 5

what is involved in regulatory (GLP) toxicology ?

Answer 5

safety pharmacology
genotoxicity - in vitro and in vivo
28 day repeat dose toxicity and recovery in 2 species
- these are part of preclinical development

3-12 month chronic toxicity in 2 species
reproductive toxicityy in 1 species covering fertility and implantation, fetal development an pre and post natal effects
- these are part of clinical phase 1/2

24 month carcinogenicity in 2 species - this is part of clincal phase 4

Question 6

what are the mutiple protocols which each drug has to go through by the ICH requirements ?

Answer 6

pharmacology studies (s7a-s7b)
toxicity testing (s4)
toxicokinetics and pharmacokinetics (s3a-s3b)
reproductive toxicology (s5)
genotoxicity studies (s2)
carcinogenicity studies (s1a-s1c)

Question 7

what are the other protocols which certain drugs may have to go through due to the ICH requirements ?

Answer 7

photosafety evaluation- s10
immunotoxicity - s8
juvenile animal toxicity- m3
non-clinical abuse liability - m3

Question 8

what protocol do life threatening or serious diseases have to go through ?|

Answer 8

m3 protocol

Question 9

what are the different categories of adverse effects and give examples ?

Answer 9

mechanism-related= eg. diabetes using insulin can cause levels to go back to normal however it could also cause glucose levels to be too low
off-target= e.g beta blockers acting at different receptors and causing a bad effect
dose-related toxic= e.g toxic effect on a different organ such as hepatoxicity
idiosycratic reactions= where it does something completely different such as rays syndrome with aspirin or anaphylatic shock with penicillin

Question 10

what are the outcomes of looking at adverse effects /

Answer 10

target organs
dose dependence- adverse effects vs therapeutic dose
exposure
reversibility

Question 11

what is the safety pharmacology protocol ?

Answer 11

objectives include using a single dose and observe the undersirable or adverse effects on the body at around the therapeutic dose
helps to determine the mechanisms of the adverse effects
also used to determine pharmacodynamic vs adverse dose and time course

Question 12

what is the core battery part of the safety pharmacology protocol ?

Answer 12

it is used to look at the effects on the CNS, cardiovascular system and respiratory system

• this is normally carried out in rodents
• for CNS test- rodent may be put on a rotating wheel to see how long it can stay on the wheel
• for the cardiovascular tests- the rodent is anaesthetised and then you look at changes in HR and BP
• for the respiratory tests- rodents are placed in a chamber and it can measure changes in pressure in the chamber to determine tidal volumes

Question 13

what are the follow-ups and supplementary tests involved in the safety pharmacology protocol ?

Answer 13

follow up tests- may look at cns behaviour or look at contractility of the heart
supplementary tests are used to look at the different effects on different body systems e.g look at GIT to look at acid secretion

Question 14

what is involved in the 28 day toxicology studies ?

Answer 14

use a dose that has been used in other studies
carried out in 2 species, a rodent and a non rodent
the steady state effects are looked at in 5 different groups ( control, therapeutic dose, 5-10x therapeutic dose, toxic dose and toxic + recovery )
at day 28 the animals are culled and histological studies are carried out to determine what the toxic effects were

Question 15

what is measured from the 28 day toxicology studies /?

Answer 15

no observable effect level - no pharmacologcal effect in the most sensitive species
maximum tolerated dose - dose before you see any adverse effects
no observable adverse effects level
no toxic effect level

Question 16

what does the 28 day toxicology study enable the calculation of ?

Answer 16

enables the calculation of the first in man dose

Question 17

what is involved in the reproductive toxicity protocol ?

Answer 17

this came in after the thalomide disaster
all aspects of reprodcution are looked at
toxicological species and a non rodent for embryo toxicity(rabbit) - rabbit is used because it has similar gestation processes to us
the dose and route used should be as close to what would be used in humans and its route should be the same

Question 18

what are the outcomes of the reproductive toxicity protocol ?

Answer 18

maturation of gametes
mating behaviour 
implantation 
developing foetuses > mid pregnancy 
post natal growth and function

Question 19

what is the purpose and confounding factors associated with clinical trials in man ?

Answer 19

other factors that will influence the use of the drug need to be determined e.g drug to drug interactions

Question 20

what are the key feature of clinical trials in man ?

Answer 20

for a clinical trial it requires

• informed consent
• assess to health of individuals - measurable outcomes
• controls
• randomisation
• blinded- single= participant doesnt know and double= participant ans researcher doesnt know

Question 21

what are the regulatory requirements of clinical trials in man ?

Answer 21

gone through an ethical commity
key one is to reduce clinical trials- so people doing similar cliniccal trials know what to look for- therefore results have to be made public

Question 22

what are the ethical issues associated with clinical trials in man ?

Answer 22

finanical inducements
liability and appropriate care
benefits outway the risks
have to ensure that sufficient work has been done to out way the risks

Question 23

what are the different designs of studies ?

Answer 23

parallel- control and test are run at the same time
- benefit is that it is done more quickly and so people are less likely to drop out but it is not as well controlled

cross-over= 1 takes a placebo and 1 takes the drug and then they stop and they swap around
- advantage is that everyone is their own control but more/people drop out of this because it takes longer

Question 24

what are phase 1 clinical trials ?

Answer 24

these are the first in man studies
healthy individuals are used
aims = find out basic pk, safety and maybe a little about pharmacodynamics
this only occurs in a few individuals
also wants to deterine the optimum dose and route of administration

Question 25

what are the stages of assessing phase 1 trials ?

Answer 25

dose is given to 3 peeople

• if no subjects show dose limtiing toxicity then go to a higher dose
• if 1 subject shows dose limiting toxicity then try it in another 3 patients
• if 2 or 3 show dose limiting toxicity then that is the maximum toleratted dose
• if 1 shows dose limtiing effects in all 6 then go to higher dose but if 2 or 3 show these effects then it is the maximum toleraed dose

Question 26

what are the aims of phase 2 clincical trials ?

Answer 26

investigate clinical efficacy
assess short term safety
dose finding- altering doses to determine therapeutic dose

this is the decision point as to whether to continue

Question 27

what happens in phase 3 clincial trials ?

Answer 27

clinical efficacy- decide on dose
safety
- particpiants used have to match the population it is going to be used in
multicentre and mutlinational- trials needs to occur in different countries to provide mixed populatio

Question 28

what is involved in phase 4 clinical trials ?

Answer 28

post marketing surveillance- this carries on for the life time of the drug

Question 29

what are the main stages in drug discovery and how long does its take and cost ?

Answer 29

1- exploratory development 
2- discovery 
3- EMA registration 
4- full development 
5- new medicine 

process takes about 15-20 years and costs about 1 billion dollars