Getting the right dose(s) for Phase 3 program and market authorization is considered as one of the most difficult tasks in new drug development. A large percentage of drug development failures were attributed to an inappropriate dose selection at Phase 2. Often, a selected dose was later discovered with either a less favorable benefit-risk profile or less efficacy compared to competitors. In January 2014, EMA issued a qualification opinion paper recommending a MCP-mod approach (Multiple Comparison Procedure – Modelling) for a dose-response model-based design and analysis for Phase 2 dose ranging study (DRI). The paper highly promotes the exploration of the dose response curve in the early stage of the development to facilitate a better understanding of potential dose options for reaching a more informative decision. It advocates the importance of identifying the minimal effective dose (MED) under the current safety-centric drug development environment. We extended the MCP-mod approach to incorporate PK/Response modeling and potential even earlier dose-response exploration starting from the proof of concept study (POC). We used simulations under different assumed true underline dose-response profiles to compare different POC-to-DRI design and analysis scenarios including: a simple 2-arm (high dose vs. placebo) POC followed by a DRI analyzed by pair-wise between-treatment comparisons, a 2-arm POC followed by a DRI analyzed by MCP-mod, a 2-arm POC followed by a DRI analyzed by MCP-mod through PK/Response modeling. In addition, we compared scenarios of including multiple doses in a POC to obtain information and enhance DRI design potentially with reduced doses or better dose spacing. Based on the simulation results, PK/PD modeling can greatly increase the chance of identifying the MED. The benefit of early exploration of dose-response relationship with multiple doses in a POC study turns out to be scenario-dependent due to relatively high variability of small POC studies. Therefore, a program-wise trial simulation is recommended to evaluate different POC-to-DRI designs under different compound specific assumptions.