FDA Safety and Innovation Act FDASIA

1. FDA Safety and Innovation ActFDASIA

2. FDASIA • Enacted into law – July 9, 2012 • 11 Titles - Many new provisions to FD&C and PHS Acts • Reauthorizations (e.g., PDUFA, MDUFA, BPCA, PREA) • New provisions • New user fee programs for generics and biosimilars • Drug shortages • Expediting drug development • And more

3. 3 -Tiered Regulatory System • Statutes (Laws) • Passed by Congress and signed by the President • Food, Drug & Cosmetic Act (FD&C Act) • Public Health Service Act (PHS Act) • Regulations (details/implementation of the law) • Written by FDA and approved by the Executive Branch • 21 CFR (Code of Federal Regulations) • Guidance (FDA’s interpretation of the Regulations) • Written and approved within FDA • Advice non-binding on FDA or sponsor 3

4. FDASIA TItles

5. TITLE IX: DRUG APPROVAL AND PATIENT ACCESS • 8 Sections • Sec. 901 Enhancement of accelerated patient access to new medical treatments • Sec. 902 Breakthrough therapies

6. Accelerated Approvals Sec. 901. Enhancement of Accelerated Patient Access To New Medical Treatments Accelerated Approvals Clarifies provisions and encourages expanded use and scope Lists types of evidence that FDA can rely upon Sec. 902. Breakthrough Therapies Breakthrough Therapies New pathway Goal is to expedite development for drug that offer substantial improvement over existing therapies 6

7. Accelerated Approvals Fast Track Product “intended, whether alone or in combination with one 1 or more other drugs, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medicalneeds for such a disease or condition.” Accelerated Approval “for a serious or life-threatening disease or condition…. has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint….. taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments……” “epidemiological, pathophysiological, therapeutic, pharmacologic, or other evidence developed using biomarkers, for example…” “postapproval studies to verify and describe the predicted effect on irreversible morbidity or mortality or other clinical benefit.” 7

8. Breakthrough Therapies • Breakthrough Therapies • “intended, alone or in combination with 1 or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”

9. Request for Breakthrough Therapy Designation • A concise summary of information that supports breakthrough therapy designation request for the indication being studied, including: • The basis for considering the drug to be one intended to treat a serious condition • The preliminary clinical evidence that the drug may demonstrate substantial improvement over available therapies. A sponsor should describe the preliminary clinical evidence, including, for example, justification for the clinical study endpoint used and a brief description of statistical analyses • If applicable, include a list of documents previously submitted to the IND considered relevant to the designation request, with reference to submission dates. 

10. TITLE X—DRUG SHORTAGES • 8 Sections • Requires reporting of both permanent market exits and temporary interruptions • Enables FDA to include biological products by regulation • Applies to all manufacturers (not just “sole” manufacturers) • Coordination:Task force and strategic plan

11. Title I: PDUFA PDUFA V commitments include • Review program- New Molecular Entities (NMEs) and Original BLAs • Enhancing regulatory science • PROs, drugs for rare diseases, biomarkers • Benefit-risk implementation plan • Enhance drug safety system • Standardize REMS, evaluation of Sentinel • Electronic submissions

12. PDUFA V Original BLA Review Standard Timeline FILING & PLANNING ADVISORY COMMITTEE POST – ACTION ACTION REVIEW Months Review Time 9 0 1 2 3 4 5 6 7 8 10 11 12 9 10 7 8 5 6 0 1 2 3 4 PDUFA Time Application Receipt Late Components Receipt Final Inspection Completed Conduct Filing Review DAY 60 -Inform applicant of review designation, filing determination DAY 74 - Communicate filling review issues Conduct Review Issue Information Requests Issue Discipline Review Letters Labeling Review Mid-Cycle Meeting Issue Discipline Review Letter Applicant MC Communication (14 days after MC meeting) Applicant MC Communication (14 days after MC meeting) Agency briefing Package(<20 days b/F AC) Depends upon Advisory Committeee meeting date Late Cycle Meeting (<12 days b/F AC) AC held generally <3 mo before Goal Date/ (Note: if no AC held Late Cycle Meeting held < 3mo before Goal Date) • EXISTING PDUFA TASK/ GOAL/ MILESTONE • NEW PDUFA V TASK/ GOAL/ MILESTONE Goal Date

13. Title II: MDUFA MDUFA III commitments include • Performance goal enhancements • Process Improvements • Emphasis on communications with sponsors • Submission acceptance criteria (“RTA”) • Shared Outcome Goals • A new type of commitment - reduce the average Total Time to Decision

14. Title III: GDUFA Title IV: BsUFA • GDUFA • Application fees • Facility fees • Backlog fee • BsUFA • Application fee • Annual product fees • Annual establishment fees • Biosimilar biological product development fee

15. Title V: Pediatric Drugs and Devices • Reauthorization of PREA and BPCA – provisions made permanent • Best Pharmaceuticals for Children Act (BPCA) • Written request – if neonate studies not included, give explanation • Pediatric Research Equity Act (PREA) • Pediatric Plans - Sponsors required to submit earlier • after End of Phase 2 (or such other time as agreed upon) • requires meetings and/or correspondence and internal PeRC review • Allows for deferral extensions for delayed pediatric studies • Authority to issue and post non-compliance letters for overdue PREA post-marketing requirements

16. Title VI – Medical Device Regulatory Improvements • 20 sections • Premarket Sec 601, 606, 607 • Postmarket Sec 605, 615, 616

17. Device Improvements: Premarket Sec. 601 Precludes FDA from disapproving an IDE only because the study will not support a marketing application Sec. 606 New ‘Clinical Hold’ authority, authorizing CDRH to suspend a device trial rather than withdraw the IDE Sec. 607 New de novo classification provision - an abridged pathway for moderate-to-low risk devices 17

18. Device Improvements: Postmarket Sec. 605 Directs FDA to proactively identify strategies for using recall information to improve device safety Sec. 614 Unique Device Identifier Sec. 615 Mandates Sentinel system for devices Sec. 616 Postmarket surveillance orders – authority to order at approval or after, manufacturer must commence surveillance within 15 months of an order

19. TITLE VII: DRUG SUPPLY CHAIN Section 701 Registration of domestic drug establishments. Section 702 Registration of foreign establishments. Section 703 Identification of drug excipient information with product listing. Section 704 Electronic system for registration and listing. Section 705 Risk-based inspection frequency. Section 706 Records for inspection. Section 707 Prohibition against delaying, denying, limiting, or refusing inspection. Section 708 Destruction of adulterated, misbranded, or counterfeit drugs offered for import.

20. TITLE VII Continued Section 709 Administrative detention. Section 710 Exchange of information. Section 711 Enhancing the safety and quality of the drug supply. Section 712 Recognition of foreign government inspections. Section 713 Standards for admission of imported drugs. Section 714 Registration of commercial importers. Section 715 Notification. Section 716 Protection against intentional adulteration. Section 717 Penalties for counterfeiting drugs. Section 718 Extraterritorial jurisdiction.

21. TITLE VIII—GENERATING ANTIBIOTIC INCENTIVES NOW • 18 Sections • Provides for 5-year exclusivity extension at time of approval for antibacterial and antifungal drugs that have been designated as “Qualified Infectious Disease Products” • QIDP is an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections

22. TITLE XI—OTHER PROVISIONS(some highlights) • Section 1121 Guidance document regarding product promotion using the Internet • Section 1123 Optimizing global clinical trials • Section 1124 Advancing regulatory science to promote public health innovation • Section 1131 Strategic integrated management plan • Section 1132 Assessment and modification of REMS • Section 1136 Electronic submission of applications (drugs/biologics); e-copy for devices • Section 1137 Patient participation in medical product discussions • Section 1140 Study on electronic drug patient labeling • Section 1142 Conflicts of Interest – advisory committees • Section 1143 Notification of FDA intent to regulate laboratory-developed tests

23. Resources • Food and Drug Administration Safety and Innovation Act (FDASIA) http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm20027187.htm

24. FDASIA Acronyms • BPCA- Best Pharmaceuticals for Children • BsUFA- Biosimilars User Fee Act • FD&C Act- Food Drug and Cosmetic Act • GDUFA- Generic Drug User Fee Act • IDE – Investigational Device Exemptions study • MDUFA- Medical Device User Fee Act • PDUFA- Pharmaceutical Drug User Fee Act • PHS Act- Public Health Service Act • PREA- Pediatric Research Equity Act • PROs- Patient Reported Outcome • REMS- Risk Evaluation Mitigation Strategy • RTA – Refuse to Accept • QIDP- Qualified Infectious Disease Product • QMS- Quality Management System