1. Successful Concepts Study Rationale Literature Review Study Design Rationale for Intervention Eligibility Criteria Endpoint Measurement Tools

2. Successful Concepts Study Rationale –Condition to be studied is common and of great enough severity in the proposed study population to justify an intervention –Focus background rationale on mechanism(s) likely to be relevant –Is Intervention likely to be adopted by patients? (Size of benefit vs. convenience/ side effects)

3. Successful Concepts Literature Review –Up-to-date –Relevant to proposed intervention in proposed population –Do not misinterpret results from previous studies –Do not ignore data that do not support the intervention –Make sure that numbers match correct references

4. Successful Concepts Study Design –Clear and consistent focus Background, primary objective, measurements, length of intervention, statistical design, title –Evidence supports anticipated incidence of events - necessary for sample size –If noncompliance was an issue in related studies, propose plan to address –Account for other treatments patients might be taking that will affect endpoint –Blinding is important - especially when subjective endpoint –Historic controls problematic

5. Successful Concepts Study Design –Power study to detect minimally clinically important difference - provide details (estimate of standard deviation; absolute size of effect in the measurement instrument) –Realistic effect size –Include plans to handle missing data (acknowledge if high mortality will be a problem)

6. Successful Concepts Study Design –Phase I Studies Endpoints –Toxicity –Feasibility –Dose Finding; Time to Effect; Duration –Evaluate Potential Endpoints and Instruments –Phase II Studies Endpoints –Evaluate Potential Endpoints and Instruments –Toxicity –Signals of Efficacy Statistical design Plans for phase III

7. Successful Concepts Rationale for Intervention –Previous studies suggest pathophysiologic mechanism(s) –Rationale for dose and duration of intervention –Proposed dose/intensity of intervention likely to have an effect on the proposed outcomes –Side effect profile –Is intervention likely to be beneficial only in a subset of patients?

8. Successful Concepts Eligibility Criteria –Heterogeneous population has possibility of missing clinically meaningful effect –Criteria should reflect target population If treating condition, population should have condition If preventing condition, population should not have condition Limit to part of population likely to benefit

9. Successful Concepts Endpoint –Choose the endpoint that is most important to patient’s well- being (e.g. anorexia/weight/function; sexual function vs. vaginal length) –Clearly define primary endpoint and how it will be measured –Choose best instrument for measuring endpoint Are all questions relevant to population and condition being studied? Can measurements be standardized across sites? –Choose best time for measuring endpoint consider time needed to see effect natural history of condition and mechanism of action of intervention potential for loss to follow-up

10. Successful Concepts Endpoint –Make sure study time points are clear Baseline in relation to diagnosis/treatment Timing of assessments in relation to fixed point –Patient reported outcomes not always the best or the only relevant outcomes –Problems with CTCAE as primary endpoint Not sensitive enough to detect all clinically relevant changes Multibarreled Not validated –Explain uses for all data collection at all time points

11. Successful Concepts Measurement Tools –Explain why proposed tools are the appropriate measures to use in this study –Validated in similar populations - provide details