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CTP > Lecture 1: Clinical trials > Flashcards

Lecture 1: Clinical trials Flashcards

1
Q

What does a good clinical trial involve?

A

Comparison

new treatment vs standard treatment over time

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2
Q

What is the definition of a clinical trial?

A

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

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3
Q

What are 2 asepcts a clinical trial must provide?

A

Efficacy: the ability of a health care intervention to improve the health of a defined group under specific conditions
Safety: the ability of a health care intervention not to harm a defined group under specific conditions

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4
Q

What are the different phases of a clinical trial?

A

Phase 1: volunteer studies, <100 volunteers (looking at pharmacodynamics/pharmacokinetics/major side effects)

Phase 2: treatment studies, <1000 patients (looking at dosage and common side effects)

Phase 3: clinical trials, <10,000 patients (comparison with standard treatments)

Phase 4: post-marketing surveillance, whole population (monitoring for adverse reactions- yellow card reporting, potential new uses)

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5
Q

How do you get a fair comparison?

A

-ensure the 2 groups don’t know whether they are receiving the placebo/old drug or the new drug

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6
Q

How do you determine who should/shouldn’t take part in a clinical trial?

A
  • inclusion criteria

- exclusion criteria

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7
Q

What was the inclusion criteria for the AstraZeneca vaccine clinical trial?

A
  • ages 18-130
  • all sexes
  • healthy volunteers
  • those at increased risk of SARS-CoV2 infection
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8
Q

What was the exclusion criteria for the AstraZeneca vaccine clinical trial?

A
  • confirmed or susepcted immunosuppressive or immunodeficient state
  • significant disease, disorder or finding
  • prior or concomitant vaccine therapy for Covid-19
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9
Q

What are the reasons for pre-defining outcomes?

A

Need to define what, when and how outcomes are to be measured before the start of the clinical trial

  • have a clear protocol for data collection
  • agreed criteria for measurement and assessment of outcomes
  • prevent ‘data-dredging’/’repeated analyses’
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10
Q

What are primary and secondary outcomes?

A

Primary

  • preferably one primary outcome
  • used in sample size calculation

Secondary

  • other outcomes of interest
  • often includes occurrence of side effects
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11
Q

What are the different types of outcome?

A

Patho-physiological e.g. tumour size/thyroxine levels/biomarkers

Clinically defined e.g. death (mortality), disease (morbidity), disability

Patient focused e.g. QoL, psychological well-being, social well-being, satisfaction

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12
Q

What are some features of an ideal outcome?

A
  • appropriate and relevant
  • valid and attritbutable
  • sensitive and specific
  • reiable and robust
  • simple and sustainable
  • cheap and timely
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13
Q

What are some timings of measurement?

A
  • baseline measurement of relevant factors (monitor for inadvertent differences in groups)
  • monitoring outcomes during the trial
  • final measurement of outcomes (comparing final effect of treatments in trial)
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14
Q

How do we show comparability between groups?

A
  • we need to try an ensure groups are compared equivalent as possible
  • one was of demonstrating ‘comparability’ 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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15
Q

What are some suggested baseline data for the covid vaccine?

A

-age
-gender
-ethnicity
-occupation exposure
-social class
-comorbidities
-BMI
To ensure the 2 groups are equivalent

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16
Q

What are the most important ethical considerations for any trial to go ahead?

A
  • trials of new drugs may do harm

- patients/participants must understand what participation involves (including known and unknown risks)

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17
Q

What must clinical trials be to be able to give a fair comparison of effect and safety?

A

Reproducible- in experiemental conditions (record exactly how you did your experiment)
Controlled- comparison of interventions
Fair- unbiased without confounding (confounders are things that are related to the disease and the outcome e.g. alcohol/smoking in heart disease, so important that study has equal numbers of heavy drinkers/smokers in both arms of study)

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18
Q

What is the disadvantage of a non-randomised clinical trial and use of historical controls?

A

Comparison with historical control: e.g. looking at leic patients now with the drug compared to 2 years ago without the drug
-many other aspects that have changed in that period of time, not just the drug

Non-randomised: e.g. comparing leic patients who have access to the drug to norfolk patients who don’t have access to the drug
-differences within population e.g. ethnicities
-

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19
Q

What are non-randomised clinical trials and its problems?

A

Involve the allocation of patients receiving a new treatment to compare with a group of patients receiving the standard treatment

  • confounding (known and unknown)
  • allocation bias (allocating groups unfairly)
20
Q

What is non-random allocation?

A

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

21
Q

What is comparison with historical controls and its problems?

A

Involves the comparison of a group of patients who had the standard treatment with a group of patients receiving the new treatment
-but for the standard treatment group: selection is often less well defined/less rigorous, unable to control for cofounders, less information about potential bias/cofounders, treated differently from the ‘new treatment’ group

22
Q

Why is random allocation (randomisation) a good thing?

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 long run, randomisation leads to treatment groups that are likley to be similar in size and characteristics by chance

23
Q

How do we do randomisation?

A

-toss a coin
-random number tables (even vs odd)
Most trials now use:
3rd party, computer generated random allocation

-randomisation of larger groups leads to less confounding

24
Q

What is stratified randomisation?

A

When randomisation of a small group doesn’t work very well you can use this (you could just sample a larger group)
-stratifies the study into subgroups, with the same attributes, then followed by simple random sampling of the subgroups

25
Q

What is the problem with knowing the treatment allocation (open label)?

A

Knowledge of which participant is receiving which treatment may bias the results of a clinical trial

e. g.
- patient may alter their behaviour, other treatment, or even expectation outcome (behaviour effect)
- clinician may alter their treatment, care and interest in the patient (non-treatment effect: not due to treatment)
- investigator may alter their approach when makng measurements and assessing outcomes (measurement bias)

(sometimes it has to be an open label trial)

26
Q

Why do we blind clinical trials?

A

-remove allocation bias

27
Q

What are the different 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 don’t know the allocation)

28
Q

How do you establish blinding?

A
  • aim to make treatments appear identical in every way (appearance, taste, texture, dosage regimen, warnings)
  • use a designated pharmacy to label identical containers for the treatments with code numbers and have a code sheet detailing which code number responds to which treatment
29
Q

What are some examples when blinding is difficult?

A
  • surgical procedures
  • psychotherapy vs anti-depressants
  • alternative medicine e.g. acupuncture vs western medicine
  • lifestyle interventions
  • prevention programmes
30
Q

What is 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 being investigated

31
Q

What is bias?

A

Systematic distortion in allocation/measurement

  • may affect selection
  • may effect outcome measurement by patient/dr
  • publication bias
32
Q

How do we remove confounding and bias?

A

Confounding: randomisation (should use a concealed allocation so no possibility of predicting next allocation of patient)
Bias: blinding (and randomisation)

33
Q

What is the placebo effect?

A

Even if the therapy is irrelevant to the patients condition, the patients attitude to his/her illness may be improved by a feeling that something is being done about it

34
Q

What is a placebo?

A

An inert substance made to appear indentical in every way to the active formulation with which it is being compared e.g. appearance, taste, texture, dosage regimen, warnings

35
Q

Compare the active treatment and the placebo:

A
  • the active treatment has the placebo effect PLUS the active treatment effect
  • whereas the placebo only hasthe placebo effect
36
Q

What are the ethical implications of placebo?

A

Use of a placebo is a form of deception

  • a placebo should only be used when no standard treatment is available
  • therefore it is essential that participants in a placebo-controlled trial are informed that they may receive a placebo
37
Q

Why do you get losses to follow up?

A

Not every patient remains in the trial

  • their clinical condition may necessitate their removal from the trial (appropriate)
  • they may choose to withdraw from the trial (unfortunate)
38
Q

How do you minimise losses to follow up?

A
  • make the follow up practical and minimise inconvenience
  • be honest about the commitment required from the participants
  • maintain contact with the participants
  • avoid coercion or inducements (payments for questionnaires etc, should be voluntary)
39
Q

Why does non-compliance occur?

A
  • they may have mis-understood the instructions
  • may not like taking their treatment
  • may think their treatment isn’t working
  • may prefer to take another treatment
  • they can’t be bothered to take their treatment
40
Q

How do you maximise adherence with treatment?

A

-simplify the instructions
-ask about adherence
-ask about effects or side effects
-monitor adherence (tablet count/urine level/blood level)
(understand it is never possible to achieve 100% adherence)

41
Q

What is an explanatory trial?

A

A study where you are looking for the best possible effect under the most perfect conditions

  • efficacy study (produce a desired result under ideal conditions)
  • do an ‘as treated’ analysis (exclude people who haven’t taken the treatment )= this affects randomisation
  • non-compliers are likely to be systematically different from compliers= selection bias and confounding
42
Q

What is a pragmatic/effectiveness study?

A

Looking for real world results
-intention to treat analysis
-take into account non-compliance
=compares the likely effects of using the treatments in routine clinical practice
-preserves the effects of randomisation and minimises selection bias and confounding

43
Q

How does ‘as-treated’ differ from ‘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 be run on an intention to treat analysis

44
Q

Example illustrating the two types of analysis:

A 
New treatment 
Compliers: 70%, -40 mmHg
Non-compliers: 30%, +5 mmHg
Standard treatment
Compliers: 100%, -30 mmHg

If you just look at compliers (as-treated), the new treatment appears better, but if you consider the non-compliers, the standard treatment appears better (intention to treat)

45
Q

What are some considerations in an RCT (randomised controlled trial)?

A
  • disease of interest
  • treatments to be compared
  • outcomes to be measured
  • possible bias and confounders
  • patients eligible for the trial
  • patients to be excluded from the trial
46
Q

How would you conduct the trial in an RCT?

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
  • follow up participants in identical ways
  • minimise losses to follow-up
  • maximise compliance with treatments
47
Q

How do you compare outcomes in an RCT?

A
  • is there an observed difference between the treatments groups
  • could the observed difference have arisen by chance? (is it statistically significant)
  • how big is the observed difference between the two groups? (is it clinically important?)
  • is the observed difference attributable to the treatments compared in the trial?

CTP (4 decks)

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