Therapeutic trials:

Are conducted among individuals with a particular disease to assess the effectiveness of an agent or procedure to diminish symptoms, prevent recurrence, or reduce mortality from the disease.

Preventative trials:

Are conducted to evaluate whether an agent or procedure reduces the risk of developing a particular disease among individuals free from that disease at the beginning of the trial, for example, vaccine trials. Preventative trials may be conducted among individuals or among entire communities.

A distinguishing characteristic of an intervention study is that the intervention (the preventative or therapeutic measure) being tested is allocated by the investigator to a group of two or more study subjects (individuals, households, communities).
Subjects are followed prospectively to compare the intervention vs. the control (standard treatment, no treatment or placebo). 

The main intervention study design is the randomized controlled trial (RCT).

The randomized controlled trial is considered as the most rigorous method of determining whether a cause-effect relationship exists between an intervention and outcome. The strength of the RCT lies in the process of randomization that is unique to this type of epidemiological study design.

The aim of randomization is to ensure that any observed differences between the treatment groups are due to differences in the treatment alone and not because of confounding (known or unknown) or bias. That is, that the groups are similar in all respects apart from the intervention under investigation.

• A sample of patients with the condition, and who meet other selection criteria, is randomly allocated to receive either the experimental treatment, or the control treatment.

• Occasionally, a placebo will be used in the control group, but where there is already an accepted treatment, it is unlikely to be ethical to use a placebo. 

• The experimental and control groups are then followed for a set time, and relevant measurements are taken to indicate the results (or 'outcomes') in each group.

• Methods of randomization:

  • Simple randomization: For example, computer generated random number tables. Simple randomization is rarely used.

  • Block randomization: is a method used to ensure that the numbers of participants assigned to each group is equally distributed and is commonly used in smaller trials.

  • Stratified randomization: used to ensure that important baseline variables (potential confounding factors) are more evenly distributed between groups than chance alone may assure. However, there are a limited number of baseline variables that can be balanced by stratification because of the potential for small numbers of subjects within each stratum.

  • Minimized randomization: This method may be used when the study is sufficiently small and simple randomization will not result in balanced groups.

• Blinding in randomized controlled trials

  Blinding is a process where the critical information on allocation of treatment is hidden either from the patients, or from observer or the evaluator in the study. The method of blinding in RCT is used to ensure that there are no differences in the way in which each group is assessed or managed, and therefore minimize bias. Bias may be introduced, for example, if the investigator is aware of which treatment a subject is receiving, as this may influence (intentionally or unintentionally) the way in which outcome data is measured or interpreted. Similarly, a subject's knowledge of treatment assignment may influence their response to a specific treatment. Blinding also involves ensuring that the intervention and standard or placebo treatment appears the same.

  • Double blinding is when neither the investigator nor the study participant is aware of treatment assignments. However, this design is not always possible.

  • A single blind RCT is when the investigator but not the study participants know which treatment has been allocated.

  • Triple blinding imposes blinding to the patients, investigators, and statisticians, who in turn might introduce bias to the results of the study based on their knowledge of the allocated agent. Blinding the statistician is the least important in the conduct of a clinical trial.

Strength: 

• A well designed RCT provides the strongest evidence of any epidemiological study design that a given intervention has a postulated effectiveness and is safe.

• Randomization provides a powerful tool for controlling for confounding, even by factors that may be unknown or difficult to measure. Therefore, if well designed and conducted, a RCT minimizes the possibility that any observed association is due to confounding.

• Clear temporal sequence - exposure clearly precedes outcome.

• Provides a strong basis for statistical inference.

• Enables blinding and therefore minimizes bias.

• Can measure disease incidence and multiple outcomes. 

Weaknesses:

• Expensive and time consuming.

• Ethical constraints - for example, it is not always possible or ethical to manipulate exposure at random.

• Requires complex design and analysis if unit of allocation is not the individual.

• Inefficient for rare diseases or diseases with a delayed outcome.

• Generalizability - subjects in a RCT may be more willing to comply with the treatment regimen and therefore may not be representative of all individuals who might be given the treatment.