Table 1.

Approaches to the Design of Phase II Trials

Approach	Method	Advantages	Disadvantages
Intuitive	Provide drug to select group of investigators who observe effects in open-label, unblinded studies and make recommendations	Rapid, cheap and ease to conduct	Investigators cannot reliably discern clinical benefit Purely subjective
Mechanistic	Administer drug in multiple doses and select dose that has optimal biologic effect thought to best reflect mechanism of action of drug	Often quantitative Testable hypothesis Rational	Limited ability of pre-clinical research to reliably identify relationship of importance of mechanism in animals to human Biologic effect of drug may be impossible to measure in patients Drug may have multiple effects that may supercede its intended actions Difficult to determine the degree of the biologic effect required to demonstrate efficacy Short-term biologic effects may not be maintained long-term No clear relation between mechanistic efficacy and effect on clinical outcomes
Efficacy-Pilot	Administer drug in multiple doses and select dose that has optimal effect on an arrary of clinical end points	Clinical relevance	Usually no single end point selected, so determines if “things are generally going in the right direction” Differences are typically small and trends are often conflicting Does not give benefit: risk information
Safety-Pilot	Administer drug in multiple doses and select dose that has optimal safety profile	Clinical relevance	Assumes that mechanism of action and clinical efficacy is established Difficult to determine the correct dose of a new drug based on its safety profile Unlikely that safety can effectively be assessed in intermediate sized trial (<500 patients) Does not give benefit: risk information

(Adapted with permission from Packer M, Current perspectives on the design of phase II trials of new drugs for the treatment of heart failure. Am Heart J 2000; 139: S202–S206)