Study Design: Clinical Trials

Question 1

What is a confounding variable?

Answer 1

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 2

What is a clinical trial?

Answer 2

A planned experiment in humans, designed to measure the effectiveness of an intervention (usually a new drug).

Question 3

Why are clinical trials unique to other epidemiological studies?

Answer 3

Experimental studies (e.g. trials) are different from most epidemiological studies (surveys, cross sectional, cohort, case control, ecological) which are observational.

Question 4

What are the features of a clinical trial?

Answer 4

• Experimental study
• Contain a control group and random allocation
• Blinding

Question 5

What must be defined in a clinical trial?

Answer 5

• The intervention
• The comparison (placebo, alternative treatment, standard of care)
• Inclusion criteria
• Exclusion criteria

Question 6

Why do clinical trials use a control group?

Answer 6

To be sure why the outcome happened; it may be due to the new treatment or it may have happened anyway.

Question 7

Why randomise clinical trials?

Answer 7

• Ensures balance

- To avoid/remove treatment allocation bias

Question 8

How are clinical trials randomised?

Answer 8

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.

Question 9

What are the three types of randomisation?

Answer 9

Block randomisation.
Stratification
Minimisation

Question 10

What is blinding and double-blind trials?

Answer 10

Blinding means that the patient does not know whether they are getting the new treatment or not.

In a double-blind trial neither the patient nor the doctor knows which treatment they are getting.

Question 11

Why use blinding/double-blind trials?

Answer 11

• To prevent bias in reporting or measurement of the outcome -
  measurement bias.
• Avoid placebo effect
• If a doctor knows that a patient is on the new or active drug they may look for more improvements

Question 12

How are clinical trials made ethical?

Answer 12

Strict regulation
All clinical trials have to be:
- Registered
- Reviewed by an independent scientific committee
- Approved by a research ethics committee
- Adhere to government and international guidelines.

Trials have an independent data monitoring committee –check progress during the trial.

All participants in a trial must provide informed consent, and be free to withdraw at any time without affecting their care.

Question 13

What do the independent data monitoring committee do?

Answer 13

They will usually un-blind the results to see if there is any major difference in outcome between the intervention and control groups.
If there is a large difference, they have the power to stop the trial.

Question 14

How are the results analysed?

Answer 14

The presentation of results depends on the 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 15

What are the outputs of a clinical trial?

Answer 15

Experimental event rate (EER) = incidence in the intervention arm
Control event rate (CER) = incidence in the control arm
Relative risk = EER/CER
Relative risk reduction = (CER- EER)/ CER
Absolute risk reduction (ARR) = CER- EER
Number needed to treat (NNT) = 1/ARR

Question 16

Why are trials reported according to CONSORT guidelines??

Answer 16

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

Question 17

Phase I trials:

• Aims
• How many people are involved?

Answer 17

• Aim to test the safety of a new treatment, includes 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.

E.g. The disastrous trial of the anti-inflammatory drug TGN1412 at Northwick Park Hospital in 2006 was a phase I study.

Question 18

Phase II trials:

• Aims
• How many people are involved?

Answer 18

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 effective (at least in the short term) - Also look at safety.

Usually a few hundred people are involved at this stage.

Question 19

Phase III trials:

• Aims
• How many people are involved?

Answer 19

Test the new treatment in a larger group of people (often several thousand patients will be involved)

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.

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 20

Phase IV trials:

- Aims

Answer 20

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 21

What are the potential sources of bias in clinical trials?

Answer 21

• Allocation Bias
• Measurement Bias: deal with blinding
• Reporting bias: selective reporting e.g. positive trials most likely to be published