8 Clinical Trials

Question 1

Q: Define bias.

Answer 1

A: A systematic error in design, conduct or analysis of a study which produces a mistaken estimate of treatment effect

Question 2

Q: Define confounding.

Answer 2

A: When a variable (or factor) is related to both the study variable and the outcome so the effect of the study variable on the outcome is distorted

Question 3

Q: What is a clinical trial and what is it designed to do? Provide examples. (4)

Answer 3

A: a planned experiment in humans, designed to measure the effectiveness of an intervention

The intervention is usually a new drug, but the method can equally be applied to the assessment of a surgical procedure, a vaccine, complementary therapy

Question 4

Q: How do experimental studies like clinical trials differ from most epidemiological studies (surveys, cross sectional, cohort, case control, ecological) which are observational?

Answer 4

A: In observational studies the investigator measures what happens but does not control it.

E.g. an investigator may record whether people smoke, and relates this to whether or not they develop lung cancer

In contrast, in a clinical trial, the investigator would allocate one group to smoking and the others to not smoking, and then see who got ill

(this example this would not be done as it is both unethical and impractical since people do not smoke or not just because someone tells them to)

Question 5

Q: What type of study is a clinical trial? Must contain? Method? Ideally- known as?

Answer 5

A:  Experimental study
 Must contain a control group
 Prospective: participants are followed through time
 Patients are enrolled, treated and followed over same period of time
 Participants should be randomised to control or intervention groups
 Ideally the participants and the researcher are unaware if a participant has been assigned to the treatment or control group. This is known as blinding

Question 6

Q: What must you define in a clinical trial? (4, 2-3)

Answer 6

A: 	Define your intervention 
	Define your comparator 
–	Placebo
–	Alternative treatment
–	Standard of care 
	Define your inclusion criteria 
	Define your exclusion criteria

Question 7

Q: What is the clinical trial overall design?

Answer 7

A: Defined population
                  |
                 \ /
         Randomised
         |                  |
        \ /                \/ 
Intervention        Control

both
|
\ /
cured // not cured

Question 8

Q: What is a control group in a clinical trial? Why are they included? Eligible for? What may they be given?

Answer 8

A:  The control group is those study participants who do not receive the intervention under assessment.
 A control group must be included otherwise you cannot be sure why the outcome happened; it may be due to the new treatment or it may have happened anyway.
 Eligible for intervention but receive comparator(placebo/alternative/standard care)
 Control groups may be given a placebo (an inactive substance such as a sugar pill, or water injection), or a standard treatment.

Question 9

Q: Why is randomisation used in clinical trials? Ensures? How? Without?

Answer 9

A:  Ensures balance + avoid/remove treatment allocation bias
 People who are eligible for the trial (i.e. have the condition you are interested in) are recruited, consent is obtained and then they are randomly allocated to the intervention or control groups
 Without randomisation, it is possible (indeed likely) that the investigator will choose different patients for each group

Question 10

Q: What are the 3 times of randomisation?

Answer 10

A:  Block randomisation.
 Stratification
 Minimisation

Question 11

Q: What is a single blind?

Answer 11

A: do not know whether they are getting the new treatment or not

Question 12

Q: What is a double blind trial?

Answer 12

A: neither the patient nor the doctor knows which treatment they are getting

Question 13

Q: What does blinding prevent? Elaborate for participants and doctors.

Answer 13

A: prevent bias in reporting or measurement of the outcome, measurement bias

People who are getting a new treatment (or treatment compared with no treatment) often report improvement in subjective symptoms because they are enthusiastic and hopeful

Similarly if a doctor knows that a patient is on the new or active drug they may look for more improvements

Question 14

Q: What is a triple blind?

Answer 14

A: Statistician does not know

Question 15

Q: Why are clinical trials are strictly regulated? What do all clinical trials have to be (4)?

Answer 15

A: ensure that patients are protected

 Registered,
 Reviewed by an independent scientific committee
 Approved by a Research Ethics Committee
 Adhere to government and international guidelines.

Question 16

Q: What must all participants in a trial provide and be able to do?

Answer 16

A: informed consent, and be free to withdraw at any time without affecting their care

Question 17

Q: What do trials have that have the power to un-blind the results? Elaborate.

Answer 17

A:  Trials will have an independent data monitoring committee – a group of independent researchers who can check progress during the trial
 They will usually un-blind the results to see if there is any major difference in outcome (improvement or side effects) between the intervention and control groups
 If there is a large difference, they have the power to stop the trial

Question 18

Q: At the end of a trial the results will be analysed. How these are presented will depend on? in terms of?

Answer 18

A: the particular design of the study

The outcomes are presented in terms of efficacy (the true biological effect of a treatment) or effectiveness (effect of a treatment when actually used in “normal” practice)

Question 19

Q: What are 5 trial outputs?

Answer 19

A: – The experimental event rate (EER) = incidence in the intervention arm
– Control event rate (CER) = incidence in the control arm
Relative risk = EER/CER

– Relative reduction = (CER- EER)/ CER
– Absolute risk reduction (ARR) = CER- EER
– Number needed to treat (NNT) = 1/ARR

Question 20

Q: Clinical trials are now expected to be reported according to? This ensures?

Answer 20

A: he CONSORT (Consolidated Standards of Reporting Trials) guidelines

that papers about trials include all the relevant information for readers to critically appraise the paper

Question 21

Q: Why, in short, must the phases of the clinical trial be followed? How many phases are there?

Answer 21

A: Several stages must be followed in the development and evaluation of a new drug to ensure it is safe and effective

4

Question 22

Q: Describe phase I trials. Aim? Will include? Size?

Answer 22

A:  Aim to test the safety of a new treatment
 This will include looking at side effects of a treatment e.g. does it make people sick, raise their blood pressure etc?
 Involve only a small number of people, usually healthy volunteers

Question 23

Q: Describe phase II trials. Aim (2)? Size?

Answer 23

A:  Test the new treatment in a larger group of people who have the disease for which the treatment is to be used, to see whether the treatment is promising, i.e. effective at least in the short term and look at safety
 Usually a few hundred people are involved at this stage

Question 24

Q: Describe phase III trials. Size? Aim? Patient background? More people needed when?

Answer 24

A:  Compare the new treatment with the treatment currently in use, or with a placebo -These trials look at how well the new treatment works, and at any side effects it may cause
 Often several thousand patients will be involved
 Patients will be recruited from multiple locations and this might include several different countries
 The smaller the expected advantage of a treatment, the more people will be needed to take part in a trial

Question 25

Q: Describe phase IV trials. When? Aim?

Answer 25

A: Done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use

Question 26

Q: Describe the ACCOMPLISH hypertension treatment trial.

Answer 26

A:  An RCT was carried out on patients with hypertension, comparing benazepril plus amlodipine (the intervention) to benazepril plus hydrochlorthiazide (the control).
 The primary endpoint was a vascular event (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke etc)

Question 27

Q: Describe the number needed to treat (NNT) eg 45.

Answer 27

A: You would need to treat 45 people with the new treatment for an average of three years to avoid one additional vascular event