Principles and approaches for research methods to Design, Analyze, Communicate (DAC) clinical studies.
The purpose of this tool is to enable a rigorous and standardized review and subsequent discussion by study teams to enhance the probability of carrying out an informative study. Consider the DAC Best Practices when discussing your answers.
Best Practices
1. Prioritize disease burden/ target epidemiology as criteria for trial site selection
2. Use accepted and validated endpoints whenever possible
3. Map study outcome to immediate or ultimate policy impact
4. Justify effect estimates and prevalence assumptions
5. Simulate trial to ensure right sample size and optimal design
6. When feasible and relevant, apply adaptive, pragmatic, platform, or other innovative clinical trial designs
Design aspects
10. Summarize your study design inclusive of objectives, assessments and endpoints.
11. Describe how the proposed eligibility criteria relate to the population suffering from/at risk of the disease/condition. What steps will you take to ensure as diverse and representative a population as possible and appropriate will be included in this study? Will any restrictions in eligibility affect generalizability? Conversely, are you planning on restricting eligibility and enriching the population to maximize the chance of demonstrating efficacy? If so, please expand on the reasons. Are the chosen geographies able to identify sufficient patients meeting the eligibility criteria? If this is a cluster randomized trial, what eligibility criteria will apply to clusters?
12. Will this study enroll special populations including elderly/children/pregnant women/nursing mothers? If so, have appropriate safety considerations been given to these populations? Is the target population for clinical use likely to include these groups? , If these special populations are excluded from the study, yet experience the disease, discuss how this gap will be addressed, and how this will affect the product label or policy considerations on the use of the intervention in this population.
13. How do the primary and secondary endpoints address the scientific questions and purpose(s) of the trial? Are the endpoints appropriately validated and accepted? If so, how (e.g., reference regulatory guidelines that specify the proposed endpoints or provide peer-reviewed publications of similar or precedent studies that use the same endpoints)? Please also describe the rationale for the selection of the time period for measuring the endpoints. If no validated/accepted endpoints exist, please detail the input and alignment on your endpoints that you have received from key disease area stakeholders (e.g., disease area researchers, policy makers) and any limitations this poses to the potential subsequent value of this study.
14. Endpoint methodology, variability and timing: Describe the methodology for assessing the primary and key secondary endpoints. Is this methodology generally accepted? Describe what is known about variability of the primary and secondary endpoints (where appropriate). Consider diurnal variability, seasonal and geographic variability, measurement variability, spatial variability (if cluster randomized) and intra-person variability over time. What are the strengths and limitations of these endpoints regarding the consistency with which they may be ascertained in study subjects? For endpoints that are based on lab data that are non-routine (e.g., antibody titers and other biologic assays) and if the sample analysis is not done in a single central lab, are the methods validated across the labs?
15. Is a run-in time period required, and if so for how long and why? Will you use it to correct for/ improve inputs on actual site-specific burden of disease, recruitment rates, and other potential inputs?
16. Describe how the duration of the study is adequate to answer the scientific question, considering the anticipated clinical efficacy effect, as well as expected duration of effect and risk of treatment failure/relapse. Please include consideration of any unique characteristics that your target population or investigational agent may have. [For Vector Control interventions, are there plans to monitor durability and efficacy over the life of the product?]
17. What is the basis for the effect size estimate used to power your study? Describe the current data (noting when generated) in a relevant setting that justifies the response rates and explain if/how it varies depending on the severity of the disease. What efforts have been made to ensure the estimate is not inflated? Have assumptions on effect size been considered, including likely severity of disease to be enrolled into the study, based on inclusion/exclusion criteria? What is the minimally clinically relevant effect size and is the study powered to detect it?
18. What is the basis for the sample size calculation? Does the protocol allow for adjustment of sample size based on review of event rates at baseline, during a run-in period, or during the study?
19. Describe the randomization method, including type of randomization, stratification factors and other features of the randomization scheme and any restrictions and methods used to implement.
20. Provide a detailed description of the simulations that were conducted as a part of developing your proposed study design and include the associated code if applicable. Explain how the simulations support your design as the best one to implement (e.g., adaptive and/or factorial allows testing of multiple doses/interventions). Have simulations been run on the likely response rates/disease prevalence/incidence/likely variability of the data/ability to follow up patients etc.? If so, please describe. If simulations were not conducted, please explain the decision not to do so.
21. Describe how you have considered the design and outcomes of previous studies and/or real-world evidence in the design of this study (please include references to those studies and/or the sources of real-world evidence data that was used). If any of these studies were of poor design or had other weaknesses, explain how you plan to address these aspects in your design.
22. If the study will test a drug, vaccine, or therapeutic intervention (including trials of disease prevention), describe the dose selection criteria. Please provide background documentation into the pharmacokinetic/pharmacodynamic (PK/PD) assessments or other dose/regimen ranging that support the dose and regimen selection or other references supporting the proposed dose(s). Is it currently licensed and being used in accordance with the license/standard of care? If not, do you envisage any changes before further studies?
23. Describe the mechanism of action of the investigational agent or intervention and how that is relevant for the proposed use.
24. Describe how the study plan accounts for gender in determining target population, eligibility criteria, effect size estimate and dosage/dosing regimen. If you are not considering gender as a variable, please explain why. Is this study testing for gender differentiation or covariate gender effects? If yes, please explain your plans for sample size and randomization techniques. If no, please provide a rationale.
25. Provide detail about the proposed study location(s) and describe how the disease burden and epidemiology at the proposed study location(s) is appropriate to enable the trial to address the study question and is consistent with the operational timelines.
26. Describe your plans for PK sampling during this study relating results to what is already known about the PK of the test medicinal product. How will this be linked with PD effect/efficacy measures/adverse reactions?
27. If using an active comparator as control, is it being used consistent with its approved authorization from a stringent regulatory agency and/or WHO prequalification?
28. Explain how the potential for interactions (e.g., drug-drug or between agents in the study/or food effects or other substances recipients may receive) have been considered and addressed in your design.
29. Detail the main potential sources of bias during the study and how these will be minimized.
30. What provisions have been made for patients failing treatment and any who may require long term treatment?
31. Please describe your plans for blinding the study. Please describe who will and will not be blinded to study treatment
32. Describe your safety monitoring plan including any safety aspects that require specific monitoring and/or mitigation action and/or
Please note: Implementors of studies should also always refer to relevant regulatory standards and guidelines (e.g. FDA, EMA) to assist with study/protocol design.
