The use of phase 2 interim analysis to expedite drug development decisions.
OBJECTIVE
To expedite drug development, we propose a two-step decision-making process that utilizes interim efficacy results from a comparative phase 2 trial to determine whether to accelerate subsequent phase 3 preparations, and final analysis to ultimately determine whether to conduct phase 3 testing.


METHODS
The operational characteristics of this process were evaluated by modeling simulated data of oncology trials and retrospectively analyzing data from historical comparative phase 2 trials. Progression-free survival (PFS) was used as the primary endpoint; the estimated PFS hazard ratios (HRs) of ≤0.60 at interim and of ≤0.65 at final analysis favoring the experimental arm were defined as positive results. The conditional probability of achieving a target PFS HR at final analysis, based on observed interim results, was also estimated by imputing post-interim data with and without the proportional hazard assumption.


RESULTS
Simulations of phase 2 trials showed that estimated interim PFS HRs correlated with estimated final PFS HRs, with reasonably low false-positive rates for supporting phase 3 "go" decisions at interim. Using observed historical data, decisions based on interim PFS analyses also matched final phase 3 "go" and "no-go" decisions with a false-positive rate of 16.7% (2 of 12 trials) and a false-negative rate of 9.4% (3 of 32 trials). Analytical modeling accurately predicted final PFS HRs from observed interim data when accounting for appropriate underlying assumptions.


CONCLUSIONS
The results support the usefulness of a two-step decision-making process that utilizes interim phase 2 results to reduce the interval between phase 2 completion and phase 3 initiation.
Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United States. Electronic address: huang.jenny@gene.com.
Jie
J
Huang
Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United States.
Asha
A
Das
F. Hoffmann-La Roche, Ltd., Grenzacherstrasse 124, CH-4070, Basel, Switzerland.
Hans Ulrich
HU
Burger
Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United States.
Wei
W
Zhong
Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United States.
Wenwen
W
Zhang
Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United States.
Grazyna
G
Lieberman
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003198:Computer Simulation; D003657:Decision Making; D018572:Disease-Free Survival; D023381:Endpoint Determination; D006801:Humans; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design
D000970:Antineoplastic Agents
Hazard ratio; Modelling and simulations; Phase 2 interim analysis; Phase 3 decision-making; Prediction