lecture 12 - introduction to clinical trials Flashcards
What are the clinical trial phases?
Phase 1
first in man
Phase 2
first in patients
Phase 3
randomised controlled trial
Phase 4
post-marketing surveillance
what are retrospective vs prospective studies ?
both study how a ‘behaviour’ affects an ‘outcome’
the behaviours may be an action taken as part of the study - interventional or may be an existing characteristic - observational.
outcome is the occurrence of the disease, clinical effectiveness of treatment and incidence of drug side effects
Retrospective
- select two or more groups with different outcomes and look into their past for different behaviours
- always observational (examining past behaviours only)
Prospective
- set-up two or more groups with different behaviours and monitor into the future to look for specific outcomes
- groups can be chosen for the behaviour (observational, cohort study)
- behaviour can be imposed on a specific group (interventional, RCT)
describe the clinical trial study design
Case studies
retrospective and observational study of individual patients, phase 1 – 2
Case control studies
retrospective and observational study of groups of patients, phase 1 – 4
Cohort study
prospective and observational study of groups of patients, phase 3 – 4
Randomised clinical trials
prospective and interventional study of groups of patients assigned, phase 3 – 4
Practice guideline/systematic review
review of published literature, phase 1 - 4
Meta-analysis
numerical combination of data from multiple phase 3 and 4 studies
descried scalalr continuous data
Indication of effect / side effect in each patientbased on a numerical measurement
Can be objective (assessed quantitatively)
physiological measures
weight, BMI, blood pressure, blood glucose
no conscious component
Can be subjective (assessed qualitatively)
can use rating-scale scores
pain index, depression index
high conscious component (susceptible to placebo effect)-
Group data presented as mean (with confidence interval
Binary (dichotomous) data
For ease of comparison many clinical trials measure outcomes in terms of a binary (yes/no) response in each participant
- a “responder” meets a predefine measure of outcome
Is a therapeutic effect (or side effect) seen?
- of at least a predefined magnitude (who determines this?)
Gives a simple measure of intervention outcome
- the Responder Rate
describe the concept of responder rate
Commonest starting point
the proportion (0 – 1) of members of the group responding
Responder Rate for intervention P
probability of response = p, no response = 1 - p
Responder Rate for intervention Q
probability of response = q, no response = 1 – q
An RR = 0.7 means that 70% of participants met the condition for being classed as a “responder”
what are the participants in phase 1 ?
Small number
typically 20 – 100
Healthy
do not suffer from condition drug is intended to treat
Young adult
Male
worries regarding unknown effective on female fertility(what about male fertility!)
Paid
how much is the risk worth?
what are ethical concerns in phase 1
Giving potentially dangerous drugs to healthy people
limits phase 1 studies for highly toxic medicines such as some cancer therapies (straight to phase 2)
Use terminal/hopeless patients instead or in addition?
Can participants accurately assess risk?
what are other phase 1 problems ?
small so will not detect rare issues, not randomised so will be vulnerable to selection bias and not representative - effects in a specific group of individuals only
what are the participants of phase 2 ?
Medium numbers (typically 50 – 300)
Participants have condition the new drug is designed to treat
but no other comorbidity
Larger phase 2 trails can be randomised comparative trials
sharing the characteristics of a small phase 3 trial
what are problems with phase 2 trials ?
Difficult to assess therapeutic effects of drug because participants condition may improve spontaneously
Difficult to assess therapeutic effects of drug because of placebo effects
Difficult to assess side effects of drug because of nocebo effects
describe placebo/ nocebo
Placebo effect
- psychological (you expect the drug to work, so it does)
- behavioural (you unconsciously and unintentionally modify your behaviour and this is therapeutically beneficial)
Nocebo effect
- psychological (you expect the drug to have an unpleasant effect, so it does)
- behavioural (you modify your behaviour and this produces an unpleasant effect)
Placebo treatment
- inactive treatment used as a comparator in blinded studies
- allows study to identify and account for any placebo/nocebo effect
what are biases from placebo effect
Patient bias
participant’s beliefs and/or behaviours affects outcome
Investigator bias
investigator’s beliefs influences their behaviour towards participants
investigator’s behaviour towards participants alters the participant’s beliefs and/or behaviours affecting outcome
Solution - blinding
either the participant, the investigator, or both do not know what treatment the participant is receiving
what are Participants in a phase 3 trial
Large number (typically 300 – 3,000)
Multi-centre
All study participants are selected to:
have specific selected criteria (inclusion conditions)
not have specific selected criteria (exclusion conditions)
Study (trial) population is divided into two or more treatment (intervention) populations
how can bias be avoided ?
Must be matched as closely as possible for:-
age
gender
disease severity
smokers
socio-economic group
this is achieved by randomisation and stratification.
