In the context of a clinical trial, define and explain the significance of the following terms:

a) Intention to treat analysis.

b) Randomization.

## College Answer

ITT is the process by which the patients are analysed in the group to which they are randomised.

There are four major lines of justification for intention-to-treat analysis.

1. Intention-to-treat simplifies the task of dealing with suspicious outcomes, that is, it guards against conscious or unconscious attempts to influence the results of the study by excluding odd outcomes.

2. Intention-to-treat guards against bias introduced when dropping out is related to the outcome.

3. Intention-to-treat preserves the baseline comparability between treatment groups achieved by randomization.

4. Intention-to-treat reflects the way treatments will perform in the population by ignoring adherence when the data are analyzed.

RANDOMISATION is the process of assigning clinical trial participants to treatment groups. Randomisation gives each participant a known (usually equal) chance of being assigned to any of the groups. Successful randomisation requires that group assignment cannot be predicted in advance.

Randomisation aims to obviate the possibility that there is a systematic difference (or bias) between the groups due to factors other than the intervention. Allocation of participants to specific treatment groups in a random fashion ensures that each group is, on average, as alike as possible to the other group(s). The process of randomisation aims to ensure similar levels of all risk factors in each group; not only known, but also unknown, characteristics are rendered comparable, resulting in similar numbers or levels of outcomes in each group, except for either the play of chance or a real effect of the intervention(s). Concealment of randomisation is vital.

## Discussion

A brief answer to these questions is possible. However, by asking that the candidate *"explain the significance"* of these concepts, the college has authorised a torrent of gibberish. One could really get carried away with this.

a)

**Definition of intention to treat analysis**: This is the practice of grouping patient data according to the randomised allocation of the patient, rather than according to the treatment which they received.

According to Fischer et al,

*"ITT analysis includes all randomized patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocol."*

**Significance of intention to treat analysis:**

- All enrolled patients have to be a part of the final analysis
- Maintains prognostic balance generated from the original random treatment allocation (preserving the bias- reducing effects of randomisation)
- Avoids overoptimistic estimates of the treatment's efficacy
- Accurately models the effect of noncompliance and protocol deviations in clinical practice
- Prevents bias introduced due to outcome-associated dropouts
- Prevents bias by resisting the post-hoc manipulation of data to eliminate inconvenient outcomes
- Preserves the sample size, thus preserving the statistical power
- Minimises Type 1 error
- Allows for the greatest external validity
- Supported by the CONSORT statement
- Essential for a superiority trial

However:

- Heterogeneity may be introduced if dropouts and compliant subjects are mixed together in the final analysis
- Patients who never received the treatment are analysed together with those wo did, which dilutes the treatment effect
- A large number of dropouts and non-compliant subjects may cause a massive variation in outcome data and could make an effective treatment appear ineffective.

b)

**Definition of randomisation:** This is the practice of deliberately haphazard allocation of patients to study groups, in order to simulate the effect of chance. Randomisation gives each participant an equal chance of being assigned to any of the groups. Successful randmisation involves a process of allocation which cannot be predicted or "gamed" prior to allocation.

**Significance of randomisation:**

- Minimises selection bias
- Minimises group heterogeneity
- Controls unknown confounders, which should be randomly and evenly distributed among the groups
- Allows probability theory to be used to express the likelihood that chance is responsible for the diffences in outcome among groups.
- Failure to use random allocation and concealment of allocation were associated with relative increases in estimates of effects of 150% or more.

### References

Montori, Victor M., and Gordon H. Guyatt. "Intention-to-treat principle."*Canadian Medical Association Journal* 165.10 (2001): 1339-1341.

Gupta, Sandeep K. "Intention-to-treat concept: A review." *Perspectives in clinical research* 2.3 (2011): 109.

Fisher LD, Dixon DO, Herson J, Frankowski RK, Hearron MS, Peace KE. *Intention to treat in clinical trials*. In: Peace KE, editor. Statistical issues in drug research and development. New York: Marcel Dekker; 1990. pp. 331–50. (*not even a sample exists online! I was forced to quote from Gupta et.al.) *

Beller, Elaine M., Val Gebski, and Anthony C. Keech. "Randomisation in clinical trials." *Medical Journal of Australia* 177.10 (2002): 565-567.

Moher, David, Kenneth F. Schulz, and Douglas G. Altman. "The CONSORT statement: revised recommendations for improving the quality of reports of parallel group randomized trials." *BMC Medical Research Methodology* 1.1 (2001): 2.

Herbert, Robert D. "Randomisation in clinical trials." *Australian Journal of Physiotherapy* 51.1 (2005): 58-60.

Kunz, Regina, and Andrew D. Oxman. "The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials." *Bmj*317.7167 (1998): 1185-1190.

Altman, D. G., and C. J. Dore. "Randomisation and baseline comparisons in clinical trials." *The Lancet* 335.8682 (1990): 149-153.

Zelen, Marvin. "The randomization and stratification of patients to clinical trials."*Journal of chronic diseases* 27.7 (1974): 365-375.