Successful Concepts for Study Design and Intervention in Common and Severe Conditions

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