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Clinical research - Coggle Diagram
Clinical research
diff features of research method involving human subject
medical research
clinical trial, epidemiological studies
social science research
survey questionaire interview
Intervention
physical procedures to gather data/manipulate subject
Interaction
communication between investigator and subject
Quantitative vs Mixed vs Qualitative
Qualitative
case study
allows detailed understanding of the case
unable to generate research findings beyong similar cases
participant observations/interviews
used to collect qualitative data
simple to perform, cost effective and able to generate detailed info
collaborative enquiry
active engagement of participants, develop awareness of research findings and increase acceptance of research findings
common experimental designs
before and after design
population observed twice, once before and once after intervention, change due to intervention is measured
comparative design
compare effectiveness of diff treatment modalities
control group design
Cross-sectional design
study population only sampled once
simple and cost effective but change cannot be measured
Longitudinal design
data collected more than twice, over a period, studying of pattern change over time, trend can be observed
Reference period
Prospective
compare present observation with future data
Retrospective-prospective
study population current observation to be compared with past data and future data
Retrospective
compared current observation with recall of past data
roles in clinical trials
monitor
investigator
conduct trial in accordance with protocol, regulatory conditions, the regulations and principles of GCP, have adequate facilities and resources
have sufficient oversight of trial and time to conduct trial
provide adequate medical care to subjects
consent and provision of info
keep adequate trial-related documents
communicate with IRB
report serious adverse events to sponsor and IRB if required within sitpulated timeline
sponsor
impose restrictions on research, use info arising from research, compensate subjects and investigators
ensures trial is conducted under supervision of qualified PI
ensure trial is conducted at specific place
put and keep in place arrangements to ensure compliance with GCP
notify HSA of trial suspension, termination or conclusion and submit final report within stipulated timelines
notify HSA of serious breach of GCP/protocol and urgent immediate hazard within stipulated timelines
report unexpected serious adverse drug reactions to HSA within stipulated timelines
IRB
research subject
should have informed consent before collecting data and performing procedures, risk of harm should be minimised,
purpose of clinical trial, duration of study, frequency of visits, procedure, risk and benefits, alternatives, confidentiality, compensiation for injury, who to contact, right to refuse or withraw, voluntary participation
CRO
acts as a bridge between sponsor and rest of stakeholders involved in clinical trial, ensure safe, ethical clinical trials
moniitoring: controlling compliance with protocol and procedures
generation of clinical study report for submission to regulatory authorities for drug approval, control and storage of documentation
IRB: a group of individuals who review and monitor studies with human subjects, to help protect their rights and welfare. they approve or disapprove or modify research studies, conduct continuing reviews, suspend or terminate approval
Design of clinical trials and Basic principles of good clinical practise
Pilot
small scale, open design but could imply uncertainty about safety or efficacy of medicine
Controlled
adhered to tightly designed protocol, aims to reduce variability of factors and biases that might influence outcome
Open vs blind
open
all parties aware of treatment groups
situations
lifestyle changes
for case studies with life threatening situations
when ethical considerations do not permit blinding
surgical procedures
blind
one or more parties are kept unaware of the treatment assignment
prevent bias in the design and execution of clinical trial
source of bias: selection of patient, clinical staff administering treatment, doctor assessing treatment, team interpreting trial results
type of blinding
single blind
only participant unaware>provides some control but prone to bias(investigator)
double blind
participant and cliinician/data collectors are unaware of treatment
best controlled trial design, expectation of parties do not affect outcome, decrease chance of observational bias and should be used whenever possible
unblinded
all parties involved are aware of the treatment
placebo vs active comparrator
placebo: inert medication or procedure, used with single/double blind to reduce bias
active comparator: act as benchmark or gold standard in which new drug is to be compared
Parallel vs cross over
parallel: patients randomly allocated to one of the two treatments and remain on it till the end
Crossover: each subject receives treatment allocated in random order, changing over halfway
susceptivle to carry-over effects if treatment effect from first preiod has not worn off when conducting second period
wash out period needed to ensure drug effect is removed
13 principles of GCP
informed consent
trial staff
clinical trial data
medical decision
confidentiality
compliance with study protocol
good manufacturing practise
good quality trial
quality assurance
info on medicinal product
ethics
trial participants
stages of clinical trials
II
conduct on small number of patients, <200, to test drug effectiveness in treating condition, establish dose level and regimen
later stage: larger scale in patients to formally assess dosage response and continue to expand efficacy and safety database, single blind design often used with placebo and active comparator
III
conduct on larger number of patients(1000s), carried out with placebo and comparison standards
investigators are usually specialists in the disease, useful to obtain safety and efficacy data to satisfy product licensing authorities
I
usually conduct small group of healthy volunteers(25 to 80)
volunteers undergo exhaustive medical exmaination before tests and are strictly moitored during trial
dose administered to volunteers is a small fraction of that administered by same route to animals
Code of ethics:GCP
belmont report
beneficence
human subjects should not be harmed deliberately, risk of harm should be minimised
justice
risk and benefits of research must be distributed fairly
selection of research subjects: randomisation to remove bias
respect for persons
individual have autonomy to make decision for themselves
INFORMED CONSENT
voluntariness
comprehension
adequate info
key steps in drug discovery and development
Drug discovery>clinical testing>approval for production
identify target>lead discovery> lead optimisation>preclinical testing>clinical trials(phase I, II, III)>review and approval by FDA/EMA>post approval
target identification: identify suitable disease and understand it, select a promising approach and identify targets that fit the approach
need to assemble a multi-disciplinary team and obtain satisfactory budget
hypothesis driven
Lead discovery: how to identify potential new drug?
High throughput screening: biological screening of vast libraries of chemical compounds/natural products to find a 'hit'
drug candidates evaluated for ability to block activity
labour intensive and expensive
Rational drug design
identify cause of disease
Structure activity relationship
require extensive knowledge of target-
understanding of bioassay systems which can measure desired drug activity
Testing
4 types of classical assay
Enzyme/substrate
Antibody/antigen
receptor/ligand
Cell based
Lead optimisatiom
to improve properties of lead compounds
can efficacy, potency, adverse effects/toxicity profile be improved
is suitability of intended route of administration confirmed?
can onset and duration of action be improved
Preclinical Testing
how to minimise risk of giving lead drug to humans?
Standard toxicology study design
Mutagenicity testing
optimised analytical method development-crucial to demonstrate exposure levels in toxicology studies
Carcinogenicity testing
Safety pharmacology on core battery
data management and statistics in clinical trials