; and (B) there is relevant early evidence based on adequate and well-controlled investigations, including early-stage clinical investigations, to establish that— (i) the drug provides a positive therapeutic outcome; and (ii) the outcome of the drug is consistent with or greater than currently marketed on-label therapies, with equal or fewer side effects, if there are currently marketed on-label therapies. (2) Protocols The Secretary shall promulgate rules that establish the appropriate protocols to enable rolling, real-time, mid-trial submission while preserving the integrity of the ongoing trial and without penalizing the sponsor for seeking provisional approval under this section. (3) Real world evidence The Secretary shall allow the use of real world evidence (as defined in section 505F(b)), including real world data used to generate real world evidence, to support an application for provisional approval under this section, and to fulfill the follow-up requirements and support applications for approval under section 505 or section 351 of the Public Health Service Act, as applicable. (4) Use of scientifically substantiated surrogates (A) In general The sponsor of an application for provisional approval under this section may use scientifically substantiated surrogates to support such application. (B) Definition In subparagraph (A), the term scientifically substantiated surrogates means surrogate endpoints to predict clinical benefit other than such endpoints previously validated by the Secretary, based on— (i) epidemiologic, therapeutic, pathophysiologic, or other evidence