Introductions to recent updates to the regulations and the impact of FDAAA and FDASIA on the review process?

1. Introductions to recent updates to the regulations and the impact of FDAAA and FDASIA on the review process? Partha Roy, Ph.D. | April 23, 2013

2. Outline • Evolution of PDUFA • FDASIA Implementation • User Fees: PDUFA, GDUFA, BSUFA • Impact of 3 UFAs on Review • Pediatric Drug Development • Breakthrough Therapies • GAIN Act • Increased Patient Participation in Medical Product • Revisiting FDAAA • Sentinel Initiative

3. A Tale of Three UFAs……………. • Prescription Drug User Fee Act (PDUFA) • Generic Drug User Fee Amendments (GDUFA) • BioSimilarUser Fee Act (BSUFA) • Each with specific programmatic details • Aim to keep review work on sound financial footing • Focus on public health mission • Focus on public transparency

4. Evolution of Prescription Drug User Fee Act (PDUFA) • PDUFA 1 (1992): US Congress gave FDA the authority to collect fees to support the process for the review of human drug applications, specifically to diminish the backlog of new drug applications at FDA and shorten review time • PDUFA II (1997): expanded the scope to include activities related to the IND period and to increase FDA communications with industry and consumer groups. • PDUFA III (2002): expanded the scope to include both preclinical development and a 3-year post-approval period. • PDUFA IV (2007) authorized under FDA Amendments Act (FDAAA): concentrated on new measures concerning post-market drug safety • ………And now in 2012, PDUFA V reauthorized under Food Drug Administration Safety Innovation Act (FDASIA) through September 30, 2017.

5. Evolution of PDUFA: Positive Impact on Review Outcome

6. Evolution of PDUFA: Positive Impact on Review Outcome

7. Direct Impact of PDUFA on Review Time Source: FDA CDER Data as of November 30, 2011, from John Jenkins, OND Director: “CDER New Drug Review: 2011 Update,” at FDA/CMS Summit, Dec 8, 2011

8. PDUFA V Impact on Review

9. Review Goals PDUFA V

10. Review Goals PDUFA V

11. Review Timelines Previous NDA/BLA Review Timelines for all NDAs New PDUFA V Review Timelines for NME NDAs and original BLAs Approval Filing Review Process 6-10 Months Total NDA Submission Complete Response Letter Withdrawal by Applicant • 6 Months (priority) • 10 Months (standard) Approval Filing Review Process 8-12 Months Total NDA Submission Complete Response Letter Withdrawal by Applicant • 6 Months (priority) • 10 Months (standard) 60 Days (all NMEs/BLAs)

12. Review Model – “the Program” • Applies to all NME NDA/BLAs • To promote greater transparency and improve communication between FDA’s review teams and applicants • To improve the efficiency and effectiveness of the first cycle review process • Decrease the number of review cycles needed for approval • Will be evaluated by an independent contractor with expertise in assessing the quality and efficiency of biopharmaceutical development and regulatory review programs

13. FDA Interactions during review Sponsor - FDA meeting ≥ 2 months prior to submission Internal to FDA Sponsor - FDA meeting ≥ 3 months (standard review) and ≥ 2 months (priority review) of PDUFA goal date Phone call to Sponsor ≤ 2 weeks following meeting

14. Review Model • Pre-submission meetings • Not less than 2 months prior to submission • May reach agreement to submit limited number of components not later than 30 days after the original NDA • Such components would not be expected to materially impact ability to begin the review • Examples: • Updated stability, Final audited nonclinical report

15. Day 74 Letter • Communicate review issues • Planned review timeline, includes target date for feedback regarding proposed labeling, post-marketing requirements/commitments • Include the date for an internal mid-cycle review meeting (internal FDA meeting) • Preliminary plans re Advisory Committee

16. Mid-Cycle communication • Cross Discipline Team Leader (CDTL) will call applicant , generally within 2 weeks of meeting, to provide update on status of review • Significant issues • Information requests • Major safety concerns (thoughts re Risk Management) • Advisory Committee • Date for late cycle review meeting

17. Discipline Review (DR) Letters • FDA intends to complete primary and secondary reviews and issue letters in advance of the planned late-cycle meeting • If DR letters not issued, issues will be communicated in brief memo as part of the Agency briefing package for the late cycle review meeting

18. Late-Cycle Meeting - Topics Meeting held with the sponsor • Major deficiencies • Advisory Committee topics • REMS or Risk Management • Information Requests • Data or analyses sponsor may wish to submit, and whether such data would be reviewed in current review cycle

19. Late-Cycle Meeting • Occurs > 3 months (standard review) and > 2 months (priority review) prior to the PDUFA goal date • Agency briefing package -Sent to applicant > 12 days before the meeting -Contents • DR letters • Assessment of Risk Management • Brief memorandum of substantive application issues

20. Late-Cycle Meeting with Advisory Committee • Occurs > 12 days before the AC • AC to occur >3 months (standard review) and > 2 months (priority review) prior to the PDUFA goal date • Agency briefing package -Sent to applicant > 20 days before the AC -Contents • AC Briefing package • DR letters, Risk Mgt, memo of substantive issues • Potential questions/topics for AC

21. Meeting Management Goals Revised draft Guidance end FY2013 • Type A meetings scheduled within 14 days; To occur within 30 days • Type B or C meetings scheduled within 21 days; Type B to occur within 60 days, Type C 75 days • Meetings re REMS or postmarketing requirements shall be Type B meetings • Post-Action meetings (requested within 3 months of action) shall be classified Type A meetings

22. Enhancing Regulatory Science and Expediting Drug Development • Communication and Training staff (end FY2013) • Dedicated liaison staff -Point of contact for general questions or clarification on which Division to contact for questions -Secondary point of contact for sponsors who are encountering problems in communication with the review teams on INDs • Draft Guidance 2Q2015

23. GDUFA Impact on Generic Drug Development and FDA Review

24. GDUFA Overview and Impact on Generic Industry • Generic Industry is large and fragmented • Made‐up of manufacturers of final dosage form (FDF) and active pharmaceutical ingredient (API) (approximately 95% of the ANDAs reference a DMF for the API) • Thousands of firms spread world‐wide • Generic firms usually work on a smaller budget than the innovators • Being first to file (Paragraph IV) and receiving a 180 day exclusivity is very important for generics

25. Increase in Foreign Inspection with Respect to Active Pharmaceutical Ingredient (API) and Final Dosage Form (FDF) Source: Generic Drug User Fee Amendments of 2012 , Russell Wesdyk, FDA, OPS, (http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/default.htm)

26. Does GDUFA capable of addressing the unprecedented regulatory challenges? • $299MM per year is less than 1.5% of Generic Drug sales • Expected to reduce costs considering the improvement in the submissions proposed and reduced regulatory timelines • Doubling in OGD staff over the life of the program • Efficiency enhancement is a critical component of GDUFA • GDUFA is Modest Size Despite 10 X Plus the application volume of Brands

27. Outlines of the Agreement • Funding level = inflation adjusted $299M/year • Application Fees • Applications in the backlog (year 1 only) of $50M • Drug master file fee (and availability for reference list) • ANDA and prior approval supplement (PAS) filing fee • Facility Fees • Involved in manufacture of generic drugs, whether API or FDF, domestic or foreign • Individual fees calculated/published • Fees not linked to types of services; rather overall goals

28. Type of Fees • For fiscal year 2013, $50M will be derived from backlog and $249M will be charged for ANDAs, DMFs and Establishments. • For fiscal year 2014-2017, $299M will be charged for ANDAs, DMFs and Establishment • Division of fees • 6% from DMF reviews • 24% for ANDA original and prior approval supplement (PAS) • 56% for inspection of facility related to FDF manufacturing • 14% for API facilities

29. Some Significant Changes Due to GDUFA to ANDA and DMF Review Process • Complete Response letters rather than discipline specific letters to the ANDA holders and DMF holders • Telephone information requests to address easily correctable deficiencies in ANDAs and DMFs during the review process before and after issuance of complete response letters • When requested by the ANDA sponsor or DMF holder within 10 business days of FDA issuing a first cycle complete response letter, FDA will grant a 30 minute teleconference to clarify issues and answer questions. Priority for such teleconferences will be given to expedited and first major amendment applications.

30. Some Significant Changes Due to GDUFA to the ANDA and DMF Review Process (continued) • DMFs, which pay a one time fee, will undergo a completeness assessment (draft guidance published) • The DMFs that pay the GDUFA fee and are deemed “complete” will be placed in a publicly available database at the FDA website, http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/default.htm • During the approval of the ANDA, FDA will issue the DMF holder API, a letter to indicate that the DMF does not have any further open matters as part of the review associated with the referencing ANDA (not an approval or even “adequacy” letter. The status of DMF can change with any amendment)

31. Some Significant Changes Due to GDUFA to the ANDA and DMF Review Process (continued) Firms will self identify following facilities: • Facilities that manufacture, or intend to manufacture, human generic drug APIs or FDFs, or both* • Sites and organizations that package the FDF primary container/ closure system and label the primary container/closure system. • Sites that are identified for repackaging from one primary container to another. • Bioequivalence (BE)/bioavailability (BA) sites that are identified in a generic drug submission * Only these sites will pay the annual facility fees, except for the sites and organizations involved in manufacturing of PET products

32. Some Significant Changes Due to GDUFA to the ANDA and DMF Review Process (continued) • Failure to self identify a facility and pay fees will lead to the FDF and/or API being considered misbranded and be in an arrears list. • FDA will employ a risk-adjusted biennial CGMP surveillance inspection model for inspection of generic API and FDF manufacturers • FDA will make inspection classification results and date of the last facility inspection available to the public and industry on FDA’s website on timely basis. • During the five years of the program, FDA will undertake a study of foreign government regulator inspections(CGMP and bioequivalence), report findings publicly, and develop a program to utilize foreign inspection classifications when and where appropriate.

33. Goals and Metrics based on GDUFA of ANDA (original) and PAS Original (complete) ANDA Review and PAS reviews (this implies first complete response and may not be an approval) • 60% of submissions within 15 months for FY 2015 receipts • 75% of submissions within 15 months for FY 2016 receipts • 90% of submissions within 10 months for FY 2017 receipts

34. Goals and Metrics based on GDUFA of ANDA (original) and PAS (continued) PAS (No Inspection Required) • 60% of submissions within 6 months for FY 2015 receipts • 75% of submissions within 6 months for FY 2016 receipts • 90% of submissions within 6 months for FY 2017 receipts PAS (Inspection Required) • 60% of submissions within 10 months for FY 2015 receipts • 75% of submissions within 10 months for FY 2016 receipts • 90% of submissions within 10 months for FY 2017 receipts

35. Goals and Metrics based on GDUFA for Inspection and Backlog Inspection Metrics Risk-adjusted surveillance inspection • Achieving biennial inspection rate and parity of foreign and domestic frequency in FY2017 • Pre-approval inspections (PAIs) continue Backlog Metrics Review and act on 90% of backlog applications pending on Oct. 1, 2012, by end of FY 2017 (current backlog is ~2700 applications, original and supplements)

36. Changes in OGD based on introduction of GDUFA Significant changes: • OGD is on the way to becoming a super office directly under CDER • The CMC discipline is going to be separate under a new office, the Office of Pharmaceutical Quality (OPQ) with the ONDQA • This will assure a higher consistency of the review of the CMC sections of new chemical entities as well as generics

37. Changes in OGD based on introduction of GDUFA • A new DMF Review Division dedicated to review of Type II DMFs for APIs • A new team to review CBE-0 and CBE-30 supplements • Introduction of QbD for the final dosage form (FDF) • Improving the quality of DMF submissions through introduction of non-mandatory QbR for Type II DMFs for APIs in near future (Type II DMFs only referenced by NDAs do not need to submit this) • Increased communication with industry through publications, presentations

38. BSUFA Impact on Biosimilar Drug Development and FDA Review

39. BSUFA: Fees to support FDA’s Biosimilar Product Development(BPD) and Review Program activities • The Biosimilar User Fee Act of 2012 (BSUFA) authorizes FDA to assess and collect fees for biosimilar biological products from October 2012 through September 2017 • Fees support FDA’s biosimilar review program activities • BsUFAfee rates are set equal to PDUFA fee rates for applications, supplements, establishments, and products • BSUFA also includes biosimilar biological product development (BPD) fees for products in the development phase. • When a sponsor submits a biosimilar biological product application for a product, the fee for the application is reduced by the cumulative amount of previously paid BPD fees for the product • FDA committed to review performance goals under BsUFA • BsUFAgoal types are similar to the PDUFA goal types, with some differences in timeframes • Under the BSUFA program, there are five types of formal meetings that can occur between sponsors and FDA staff to discuss biosimilar development programs

40. BPD fees intended for products in development • BPD fees include the initial BPD fee, the annual BPD fee, and the reactivation fee • The BPD fee is an annual per-product fee, not a per-meeting or per-review activity fee • A sponsor must pay an initial BPD fee for a product to participate in FDA’s BPD Program for that product • Once a sponsor has paid the initial BPD fee for a product, beginning in the next fiscal year, FDA will assess an annual BPD fee for the product until the sponsor submits a biosimilar biological product application for that product that is accepted for filing, or discontinues participation in the BPD Program for that product • If a sponsor has discontinued participation in the BPD Program for a product and wants to again engage with FDA on development of the product as a biosimilar product, the sponsor must pay a reactivation fee to resume participation in the BPD Program for that product • BPD fees are not assessed for a product after the biosimilar biological product application is filed

41. BsUFA established five meeting types specific for biosimilar development programs

42. Meetings provide key opportunities to keep biosimilar development programs on track Christl, 2012

43. FDASIA Pediatric Drug Development

44. Pediatric Drug Development: New provisions under FDASIA 2012 • New requirements for Pediatric Study Plans • Provision for extension for deferred studies • Neonates and the Written Request • Pediatric Priority Review Voucher

45. Pediatric Regulatory History in US Source: Adopted from Melissa S. Tassinari, Pediatric and Maternal Health Staff, OND, CDER, Dec 4, 2012

46. Changes under FDASIA • Pediatric Study Plans – PSPs • Sponsors required to submit plans at End of Phase 2 • Must include: • Outline of the pediatric study or studies that the applicant plans to conduct (including, to the extent practicable study objectives and design, age groups, relevant endpoints, and statistical approach) • Any request for a deferral, partial waiver or waiver, along with supporting information

47. Pediatric Plan within Overall Drug Development WR issued (BPCA) PSP Agreed PREA requirements EOP2 PSP modifications Approval Source: Adopted from Melissa S. Tassinari, Pediatric and Maternal Health Staff, OND, CDER, Dec 4, 2012

48. Pediatric Study Plan should include…… • Overview of the disease in the pediatric population for the product under development • Potential plans and justification for use of extrapolation • Plans and justification for full or partial waiver • Plans for pediatric specific formulation development • Nonclinical data, complete or planned, to support studies in children • Synopsis/summary of all clinical studies planned • Timeline for the Pediatric Study Plan • Provide any agreements with other Health Authorities (e.g., PIP for EMA)

49. Review Timeline • Submit initial PSP within 60 days of EOP2 meeting • Review Division and PeRC must review this PSP within 90 days • Review Division must discuss the initial PSP with Sponsor by day 90 (meeting or written comments) • Sponsor must incorporate recommendations and submit “Agreed Initial PSP” within 90 days from the meeting • PeRCmust review “Agreed Initial PSP” within 30 days of submission of Agreed Initial PSP • Letter to confirm agreement with “Agreed Initial PSP” must be sent to sponsor within 30 days of submission of Agreed Initial PSP

50. New Provision for PREA under FDASIA • To allow extension for deferred studies under PREA • General criteria for acceptance of extension requests • Provide general consistency with reasons for delayed FDAAA Post Marketing Requirements [PMRs] • Delay in development could not have been prevented or could not have been foreseen • Sponsor will still be able to complete the studies