The Burden of the “False-Negatives” in Clinical Development:Analyses of Current and Alternative Scenarios and Corrective Measures

The ‘false-negatives’ of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to ‘false-negatives’ are larger than those leading to ‘false-positives’ especially in typically under-powered early-phase trials. In addition, ‘false-negatives’ are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in 3 developmental scenarios. Scenario 1, representing the current status-quo, assumed 50% statistical power at Phase-2 and 90% at Phase-3. Scenario 2 assumed increased power (80%), and Scenario 3, increased stringency of alpha (1%) at Phase-2. Scenario 2 led, on average, to 60.4% increase in productivity and 52.4% increase in profit. Scenario 3 had no meaningful advantages. Our results suggest that additional costs incurred by increasing the power of Phase-2 studies are offset by the increase in productivity. We discuss the implications of our results and propose corrective measures.