Under the Big Grants policy, any unsolicited application with a budget of $500,000 or more in direct costs in any year requires that you submit documentation with your application stating you have discussed it with an NIH (e.g., NIAID) program officer and the institute (i.e., NIAID) has agreed to accept it.
As an example, the policy would apply to an investigator-initiated R01 application with direct costs of $300,000 in year one, $300,000 in year two, $300,000 in year three, $700,000 in year four, and $700,000 in year five.