clinical drug development Flashcards
GLP
good labratory practice
ICH
international conference on Harmonization
NME
new molecular entities
FIH or FIM
FIRST IN HUMAN/MAN
SAD
Single Ascending dose
ATD
anticipated therapeutic dose
MAD
multiple ascending dose
IMP
investigational medicinal product
CTA
clinical trial application
CIB
clinical investigator brochure
ICF
informed consent form
Belgium competent authorities
department of Research and devlopment of the federal agency for medicine and health product FAMHP
IND
investigational new drug
IB
investigator brochure
MRSD
maximal recommended starting dose
MABEL
minimal anticipated biological effect
HED
human equivalent dose
PAD
pharmacologically active dose
pivotal trial
phase 2 also called like that because it represents the most rigorous demonstration of a medicine efficacy
MED
minimal effective dose
Phase 3 clinical trial
is a trial conducted in the patient population for which the medicine is intended, after efficacy has been demonstrated and generating additional data on efficacy and safety in relatively large number of patients
NDA
new drug application
Superiority trial
during phase 3, is done to detect difference between treatment they want to prove that the new treatment is better Thant the existing one. One sided analysis cause you just prove that drug A is better than B
Equivalence trial
phase 3 and is done to confirm the absence of difference. It is more popular at the moment
you show that drug A is as good as drug B no difference no better no worse. Statistically it is really complex cause it is a two side kind go testing statistically so not popular anymore
non inferiority trial
phase 3 and you show that the new treatment is at least as effective as. It should not be worse, it might even be better but you don’t check that. One sided testing then and easier to rpove
non inferiority trial
phase 3 and you show that the new treatment is at least as effective as. It should not be worse, it might even be better but you don’t check that. One sided testing then and easier to rpove
Bonafide phase 4 stsudies
investigate the effectiveness of drug in real life and the safety too in the context of pharmacovigilance. I trie to get the best real possible complete picture of benefit and risk of the drug
seeding trial
a pseudo clinical trial designed by the company that is put in place to promote the use of a product that was recently approved. They try too appear like they want to answer a scientific question but it is really more of a marketing strategy to get the physician to prescribe the drug
hard endpoints
objective and measurable endpoint such as death or survival or decreased morbidity
surrogate endpoints
they are parameters more something that have to be measured such as a biomarker. Something related to a clinical endpoint with a sort of predictive parameter that can replace the clinical endpoints
when you try to show your drug is better than the existing one, ou take surrogate endpoint to how it. Advantage too cause it is quicker to get these information than morbidity
clinical endpoints
describe how patient feel function survive such as quality of life survival morbidity mortality etc. depending upon what you think the most important are for this drug, you can refer to certain endpoints as being primary or secondary
SoC
standard of care
RCT
randomized controlled trial
it is prospective and analytical and experimental studies
it is the most convincing one
advantages is that they can be controlled for the unknown and unmeasurable cofounder, very powerful in terms of statistics. however you a some limitation such as the number of participant, the exposure and the follow up
there are some inclusion nd exclusion criteria (limit external validity) artificial expensive ethical etc so don’t forget these
IVRS
Interactive voice response system
nocebo
negative expectation resulting in undesirable effect
therapeutic advantage
difference of effect between the real compound and placebo
ECTA
EXPLORATory clinical trial application
part of the early development before/part of phase 1
limited non-clinical toxicology so very limited human exposure
no therapeutic intend
no intention to loof at MTD
MRSDA divided by 50
allow earlier differentiation of promising compounds
expose human earlier
reduced cost of closed medicine
fewer studies and animals
microdosing 500 ug less
you can use it to look at the biodistribution and receptor occupancy using PET
PK grounds carbon 14 plasma concentration
tissue distribution and R occupancy
umbrella/platform trial
one disease but we look for different possible therapy (breast cancer or covid)
basket/bucket trails
here it is one therapy that is tested in different disease (cancer too). Eg tissue/tumor agnostic treatment
so they ignore the type of tissue where the tumor is occurring and just focus on the type of mutation.
adaptive design
umbrella and kucket approach together.
you think about all the different combination possible and therefore taste more combination more efficiently and quicker
PoP studies
proof of principle
DART
developmental and reproductive toxicity
parallel group design
is randomization of people in two groups that are given another treatment for the whole duration of the trial
the advantages are that this can be long lasting, easy to perform and anlyse
however, you introduce a large variability because the two groups are technically not identical so you really need a big number of participant to get over this.
cross over design
you divide in two groups and give them a certain treatment. After x amount of time you stop the treatment, allow for a washout time and exchange the treatment or no treatment between the group. This reduces the number of participants and variability, as every subject has its own control.
However, there are different problem such as the period effect of disease which is when the disease itself is not sufficiently stable and does not allow to perform a cross over design
some subject could die during the first part, so you need people that will be ok over the two parts of the treatment
you also have the carry over effect of R - it is when participant in the first group that get the drug get better or cured you cannot really switch them to the other treatment
the washout period can also be very comp^licated (for example not done with AB) as people need to get back to the baseline
very complicated analyse
eIND
exploratory investigational new drug
Master protocol
are a last alternative approach to increase the efficiency of drug development
at the beginning, it was really one treatment one disease one protocol. The new approach tries to maximise the number of questions answered in a shorter time
they design overarching protocol to answer multiples question at the same time such as for precision medicine, in antibiotic research or oncology
it can be really complicated and expensive to make a new protocol every time for each different mutation responsible for a certain type of breast cancer so we try to bring everything in one protocol
it includes the umbrella/platform trial, the basket. bucket trial and adaptive design
the advantages are that it uses a common screening platform
there is 1 overlooking organisation, it uses a network of experiences clinical centres, you can use the same controls group
however it does cost a lot of time and money, it requires a complex organisation and the start up time can be long
Case report
it is about 1 signle case/observation that is unusual and rare. You can then challenge dechallenge rechallenge to observe the relationship between exposure and consequence
advantages is that is it cheap and hypothesis generating, as well as easy
however it give little evidence on causalityn you can’t test these hypothesis
pbservational and descriptive
case serie
when you are pooling diffferent cases reports with a comparable history - you try to get a description of a characteristic and outcome among a group:
its great as it can estimate the number of incidences (rule of three) and hypothesis generating.
However you again have little evidence on causality, you have no control population to compare with and no hypothesis testing
it is again observational and descriptive
case control
observational and analytical
you compare cases with control and you look at the differences in preceding exposure - so retrospective
you know who has the disease and who not and you look at how is the exposure different
you then have the risk in odds ratio
adv are that you can investigate rare and lates response, can check for multiple exposure at the tiam and is easy quick cheap
however it is sensitive to bias in terms of selection, information, recall and you also can get some confounding effect
cohort studies
are observational and analytical. However, this one involves a cohort that will be followed over time from exposure to a consequence. it can be prospective, follow up over time
it can be retrospective and ambidirectional too.
adv is that multiple responses can be investigated like smoking can give COPD/Lung cancer,
you can check for rare exposure and
you get information on incidence
selection bias is less likely
neg is that you need a very large group, it is also sensitive to bias on outcome data and it is very long experiment
MRSD advantage and inconvenitent
it is simple to use and has historical evidence based
however the approach is typically done on small molecule such as NCE
ignore step 5 and too simple allomertric calling
MED
minimal effective dose
biomarker
also allows to predict PD
does the binding predict a good response
