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semester 4 - CPT & Prescribing > 1. clinical trials > Flashcards

1. clinical trials Flashcards

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1
Q

Definition of a Clinical Trial

A

Any form of planned experiment which involves patients and is designed to elucidate the most appropriate method of treatment for future patients with a given medical condition

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2
Q

Purpose of a Clinical Trial

A

To provide reliable evidence of treatment efficacy

and safety

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3
Q

define efficacy

A

the ability of a health care intervention to improve the health of a defined group under specific conditions

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4
Q

define safety

A

the ability of a health care intervention not to harm a defined group under specific conditions

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5
Q

what are the 5 Stages in Drug Development & Monitoring, who are the stages tested on and how many people?

A

Pre-Clinical Phase - Laboratory studies
• Pharmacology, Animal toxicology
• Cell cultures, Animals

Phase I- Volunteer studies
• Pharmacodynamics, Pharmacokinetics, Major side-effects
• <100 healthy volunteers

Phase II - Treatment studies
• Effects and dosages, Common side-effects
• <1,000 patients

Phase III- Clinical trials
• Comparison with standard treatments
• <10,000 patients

Phase IV- Post-marketing surveillance
• Monitoring for adverse reactions, Potential new uses
• Whole population

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6
Q

what needs to be considered in clinical trials?

A
  • Inclusion criteria

* Exclusion criteria

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7
Q

Reasons for Pre-Defining Outcomes

A

Need to define what, when and how outcomes are to be measured before start of the clinical trial:
– prevent ‘data dredging’, ‘repeated analyses’
– have a clear protocol for data collection
– agreed criteria for measurement and assessment of
outcomes

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8
Q

Primary outcome

A

– preferably only one primary outcome

– used in the sample size calculation

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9
Q

Secondary outcomes

A

– other outcomes of interest

– often includes occurrence of side-effects

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10
Q

Types of Outcomes

A
  • Patho-physiological
  • Clinically defined
  • Patient-focused
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11
Q

examples of Patho-physiological outcomes

A

– tumour size
– thyroxine level
– other biomarkers

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12
Q

examples of Clinically defined outcomes

A

– death (mortality)
– disease (morbidity)
– disability

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13
Q

examples of Patient-focused outcomes

A

. – quality of life
– psychological well-being
– social well-being
– satisfaction

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14
Q

Features of an Ideal Outcome

A

• Appropriate and Relevant – to patient, clinician, society, etc.
• Valid and Attributable – any observed effect can be
reasonably linked to the treatments being compared
• Sensitive and Specific – chosen method of measurement can detect changes accurately
• Reliable and Robust – outcome measurable by different people in various settings → similar result
• Simple and Sustainable – method of measurement is easily carried out repeatedly
• Cheap and Timely – not excessively expensive to measure nor has a long lag time

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15
Q

How do we show comparability between groups?

A

• We need to try to ensure groups compared are
as equivalent as possible.
• One way of demonstrating ‘comparability’ between groups is by collecting baseline data on characteristics that we think may relate to both the condition and the outcomes we are investigating

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16
Q

Suggested baseline data

A
  • Age

* Gender

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17
Q

What are the most important ethical considerations

for any trial to go ahead

A
  • Trials of new drugs may do harm
  • So…you should only conduct a trial if you are genuinely in ‘clinical equipoise’ and don’t know what is best treatment for patients.
  • Patients/participants must understand what participation involves (including known and unknown risks)
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18
Q

In order to be able to give a fair comparison of effect

and safety, a clinical trial needs to be?

A
  • Reproducible – in experimental conditions
  • Controlled – comparison of interventions
  • Fair – unbiased without confounding
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19
Q

Explain the disadvantages of non-randomised

clinical trials

A

• Non-randomised clinical trials involve the allocation
of patients receiving a new treatment to compare with a group of patients receiving the standard treatment
BUT
• Allocation bias – by patient, clinician or investigator
• Confounding – known and unknown

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20
Q

Non-Random Allocation

A

Allocation of participants to treatments by a person, historical basis, geographical location, convenience, numerical order, etc. leads to the potential for allocation [aka. selection] bias and confounding factors to unwittingly cause unidentified differences between the treatment groups being compared

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21
Q

Comparison with Historical Controls?

A

Comparison with historical controls involves the comparison of a group of patients who had the standard treatment with a group of patients receiving a new treatment

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22
Q

Explain the disadvantages of historical controls

A

selection often less well defined, less rigorous
• treated differently from ‘new treatment’ group
• there may be less information about potential
bias/confounders
• unable to control for confounders

23
Q

Randomisation?

A

Allocate participants to the treatments fairly

24
Q

advantages of randomisation?

A
  • Minimal allocation bias – randomisation gives each participant an equal chance of being allocated to each of the treatments in the trial
  • Minimal confounding – in the long run, randomisation leads to treatment groups that are likely to be similar in size and characteristics by chance
25
Q

how do we do ‘Randomisation’?

A

• Toss a coin (best as an explanation)
• Random number tables
Most trials now use:
3rd party, computer generated random allocation, accessed by phone/internet

26
Q

what is the effect of randomisation in large and small groups

A

better in large groups

27
Q

How might Knowledge of which participant is receiving
which treatment bias the results of a clinical
trial?

A

– Patient may alter their behaviour, other treatment, or
even expectation of outcome (behaviour effect)
– Clinician may alter their treatment, care and interest
in the patient (non-treatment effect)
– Investigator may alter their approach when making
measurements and assessing outcomes
(measurement bias)

28
Q

Blinding (or Masking)?

A

Allocate participants to the treatments fairly

29
Q

advantages of blinding?

A

Remove allocation bias – by ensuring that randomisation gives each participant an equal chance of being allocated to each of the treatments in the trial

30
Q

types of blinding

A

• Single blind – one of patient, clinician, assessor
does not know the treatment allocation (usually patient)
• Double blind – two of patient, clinician, assessor
does not know the treatment allocation (usually patient + clinician/assessor)
• Triple blind (term rarely used as ‘double blind’ usually implies all do not know the allocation)

31
Q

Example of Blinding

A

• Aim to make the treatments appear identical in
every way, e.g. appearance, taste, texture, dosage regimen, warnings
• Use a designated pharmacy to label identical containers for the treatments with code numbers, and to have a code sheet detailing which code number corresponds to which treatment

32
Q

Examples where Blinding is difficult

A 
• Surgical procedures
• Psychotherapy vs. anti-depressant
• Alternative medicine, e.g. acupuncture, vs.
Western medicine, e.g. drug
• Lifestyle interventions
• Prevention programmes
33
Q

define Confounding

A

a factor that is associated with the disease AND the outcome of interest, and this association is separate to the relationship between the risk factor (or intervention) being investigated.

34
Q

define Bias and what are the types

A

systematic distortion in allocation/measurement etc.
– May effect selection (then essentially is a confounder)
– May effect outcome measurement by:
• Patient
• Doctor / researcher etc.
– Other forms of bias exist, including:
• Publication bias

35
Q

define confounder

A

A confounder is a factor associated with the exposure and is independently a risk factor for the disease

36
Q

what prevents confounding?

A

randomisation

37
Q

what prevents selection bias?

A

randomisation

38
Q

what reduce outcome measurement bias

A

Blinding

39
Q

Placebo Effect

A

“Even if the therapy is irrelevant to the patient’s
condition, the patient’s attitude to his or her illness,
and indeed the illness itself, may be improved by a
feeling that something is being done about it”

40
Q

Placebo

A

A placebo is an inert substance made to appear
identical in every way to the active formulation
with which it is to be compared, e.g. appearance,
taste, texture, dosage regimen, warnings, etc.

41
Q

aim of placebo?

A

to cancel out any ‘placebo effect’ that may exist in the active treatment

42
Q

Ethical Implications of Placebo

A
  • A placebo should only be used when no standard treatment is available
  • Use of a placebo is a form of deception
  • Therefore, it is essential that participants in a placebo-controlled trial are informed that they may receive a placebo
43
Q

Losses to Follow-Up?

A

Not every participant remains in the trial:
– their clinical condition may necessitate their removal
from the trial (appropriate)
– they may choose to withdraw from the trial
(unfortunate)

44
Q

how to prevent ‘losses to follow-up?

A
  • Make the follow-up practical and minimise inconvenience
  • Be honest about the commitment required from participants
  • Avoid coercion or inducements
  • Maintain contact with participants
45
Q

what might cause Non-Compliance with Treatments?

A

– they may have mis-understood the instructions
– they may not like taking their treatment
– they may think their treatment is not working
– they may prefer to take another treatment
– they can’t be bothered to take their treatment

46
Q

how to prevent Non-Compliance with Treatments ?

A

• Simplify the instructions
• Ask about adherence
• Ask about effects and side-effects
• Monitor adherence, e.g. tablet count, urine level,
blood level
• Understand it is never possible to achieve 100%
adherence

47
Q

Explanatory Trial: ‘As-Treated’ Analysis?

A

• Analyses only those who completed follow-up
and complied with treatments
• Compares the physiological effects of the
treatments

48
Q

disadvantage of Explanatory Trial

A

loses effects of randomisation

• Non-compliers are likely to be systematically different from compliers ⇒ selection bias and confounding

49
Q

Pragmatic Trial:

‘Intention-to-Treat’ Analysis

A

• Analyses according to the original allocation
to treatment groups (regardless of whether
they completed follow-up or adhered to
treatment)
• Compares the likely effects of using the
treatments in routine clinical practice

50
Q

advantage of Pragmatic Trial?

A

ALSO preserves effects of randomisation →

minimal selection bias and confounding

51
Q

‘As-Treated’ vs. ‘Intention-to-Treat

A

• ‘As-Treated’ analyses tend to give larger sizes
of effect
• ‘Intention-to-Treat’ analyses tend to give smaller and more realistic sizes of effect

Clinical trials should normally be analysed
on an ‘Intention-to-Treat’ basis

52
Q

what should be considered in an RCT?

A 
– The disease of interest
– The treatments to be compared
– The outcomes to be measured
– Possible bias and confounders
– The patients eligible for the trial
– The patients to be excluded from the trial
53
Q

Steps Involved in a RCT:

Conduct of the Trial

A

Identify a source of eligible patients
• Invite eligible patients to be in the trial
• Consent patients willing to be in the trial
• Allocate participants to the treatments fairly, i.e.
without bias or confounding
• Follow-up participants in identical ways
• Minimise losses to follow-up
• Maximise compliance with treatments

54
Q

Steps Involved in a RCT:

Comparison of Outcomes

A

• Compare the outcomes fairly to see:
– Is there an observed difference in outcome between
the treatment groups?
– Could the observed difference have arisen by chance,
i.e. is it statistically significant?
– How big is the observed difference between the
treatment groups,
i.e. is it clinically important?
– Is the observed difference attributable to the
treatments compared in the trial?

semester 4 - CPT & Prescribing (25 decks)

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