Requirement to study the drug post-approval to “verify and describe its clinical benefit”. Case 6:14-cv-06640-FPG-JWF Document 47-4 Filed 09/22/16 Page 30 of 52 30 Priority Review • • 1992 PDUFA FDA agreed to goals for drug review times - - Standard review = 10 month clock Priority review = 6 month clock Criteria: - - - - Increased effectiveness in treatment, prevention, diagnosis, elimination or reduction of treatment-limiting drug reaction, documented enhancement of patients willingness or ability to take the drug according to required schedule and dose safety & effectiveness in new subpopulation, ex children Case 6:14-cv-06640-FPG-JWF Document 47-4 Filed 09/22/16 Page 31 of 52 31 Subpart H Accelerated Approval • • • • 1992 (21 CFR 314.500) regulation “Reasonable likely to predict” vs “survives, feels or functions” Surrogate vs direct clinical benefit; studies need to be AWC, needs confirmatory studies If confirmatory studies demonstrate direct clinical benefit, , traditional approval is granted, could lead to removal Case 6:14-cv-06640-FPG-JWF Document 47-4 Filed 09/22/16 Page 32 of 52 32 Requirements 21 CFR 314 Subpart I • • - - • (1) (2) Postmarketing studies. Approval with restrictions to ensure safe use.

520 applies only to drugs “treating serious or life-threatening illnesses.” 21 C.F.R. § 314.500. The FDA amended 21 C.F.R. § 314, in part, to permit approval of such drugs “at the earliest possible point at which safety and efficacy can reasonably be established under existing law.”