Are there additional requirements LOIs/Applications requesting over $5 million in direct costs?

If requesting a budget with direct costs over $5 million, up to a maximum of $10 million, applicants must highlight and justify the need for the requested material and personnel resources to support the scale and scope of the proposed study. Applicants should not recapitulate the Budget Justification document or its budgetary line items; instead, applicants should describe and justify study needs to address the research question to be studied in a rigorous and patient-centered fashion. Potential examples include scale and scope requirements to achieve the following: inclusive, diverse, and representative participation by patients, study sites, care-delivery environments, disadvantaged patients, communities, and geographic areas; planned subgroup analyses to provide meaningful information to inform clinical practice; or planned analyses accounting for adaptations associated with pragmatic study design and conduct. Applications must:

• Examine large and diverse populations, as appropriate, with an overall sample size that allows precision in the estimation of the hypothesized effect sizes. The application must also have planned subgroup analyses aimed at generating meaningful information to inform clinical practice. 
• Make use of multiple study sites offering care reflective of the diversity of US health care. Applicants proposing studies with more than $5 million in direct costs will be considered nonresponsive if only a single study site is proposed.

Please refer to the Additional Review Considerations section in the PFA that will be applied to submissions requesting over $5 million in direct costs.