Figure 1: Choosing the Concurrent Control for Demonstrating Efficacy

This figure shows the basic logic for choosing the control group; the decision may depend on the available drugs or medical practices in the specific region.

Is there proven effective treatment?
No
Options

• Placebo control (see 2.1), with design modifications¹, if appropriate
• Dose-response control (see 2.3)
• Active control seeking to show superiority of test drug to active control (see 2.4)
• No-treatment control (see 2.2), with design modifications¹, if appropriate

Any combination of above controls (see 1.3.6)

Is there proven effective treatment?
Yes
Is the proven effective treatment life-saving or known to prevent irreversible morbidity?
Yes
Options

• Active control; superiority, or non-inferiority if there is historical evidence of sensitivity to drug effect (see 1.5)
• Placebo control with appropriate design modifications¹ (e.g., add-on study)

Dose-response control (limited cases)

Is the proven effective treatment life-saving or known to prevent irreversible morbidity?
No
Is there historical evidence of sensitivity to drug effects for an appropriately designed and conducted trial (see section 1.5)
Yes
Options

• Placebo control (see 2.1), with design modifications, if appropriate
• Dose-response control
• Active control showing superiority to control
• Active and placebo controls (3-arm study; see 2.1.5.1.1)

Active control non-inferiority (see 1.5)

¹ Add-on, replacement, early escape, brief placebo period, and randomized withdrawal (see section 2.1.5.2).