FDA Hot Topics

1. FDA Hot Topics Alan E. Williams, Ph.D. Office of Blood Research and Review, CBER, FDA Pharma Conference January 27-29, 2010

2. FDA Hot topics The Office of Blood Research and Review (OBRR), CBER • Current organization and activities • Quality Program

3. FDA Hot Topics (cont.) FDA’s response to emergencies? • Blood Safety Team • Incident Management Teams • Blood Supply emergency response considerations Selected updates • Concurrent Plasma • Malaria Deferral • Cerus INTERCEPT • BP and Pulse (Won’t cover: Biovigilance; Statistical Process Control; Emerging Infectious Diseases)

4. New staff in OBRR - 2009 IOD • Ginette Michaud MD, Deputy Director for Science and Medicine • Joseph Giglio – Associate Deputy Director for Quality Assurance Division of Blood Applications • Richard Davey, MD Director • Orieji Illoh MD, Medical Officer • Verdell Nelson, Consumer Safety Officer, BPB • Aaron Josephson, Regulatory Information Specialist • Mary Surratt, Consumer Safety Officer • Joyce Rockwell, Consumer Safety Officer • Annette Ragosta, Consumer Safety officer • (Two open Consumer Safety Officer positions)

5. Regulatory Accomplishments FY’09 • 882 BLA and BLA supplements • 9 PMAs and PMA supplements • 26 510(K)s - all types • 27 510(K) add-to file and post market commitments • 49 Original INDs • 2 Original IDEs • 53 in-person meetings with sponsors/applicants • 780 telecons/other sponsor interactions

6. Other Accomplishments FY’09 • One TSEAC three BPAC meetings • Four public workshops (A1PI Trials, Blood Component Licensure, BECS 510(k)s, Emerging Arboviruses) • Four final and two draft guidance documents • Multiple liaison meetings (e.g. AABB, PPTA, Alliance of Blood Operators) • Multiple CBER and international reference panels for blood borne pathogens and plasma derivatives • Multiple Laboratory Site Visits • 25 scientific publications

7. OBRR Quality Program • CBER Quality initiative started by Dr. Goodman • OBRR is first CBER Office to begin a formal Office-wide Quality Program • Joe Giglio hired as Associate Deputy Director for Quality Assurance • Quality Plan and Quality Assurance Manual completed • SOPs being developed on prioritized basis • Performance metrics and oversight interactions established (daily T-x report, mid-cycle checklist and tracking, monthly Regulatory Forum and application status review meeting).

8. Managed Research: Overview Program: • Geared towards facilitating the safety, efficacy and availability of blood and blood products • 26 Principal Investigator (PI) initiated programs located in 7 laboratories represent the 6 office priorities (12 PIs in 3 DETTD labs; 14 PIs in 4 DH labs) Budget process: • Individual programs in each Division are evaluated annually for public health impact, mission relevance, feasibility and productivity • Based on a formula, each program receives a score that is used to determine the operating budget for that program • Funds are distributed to each PI after review by the Office Director

9. The Regulatory Site Visit Training Program (RSVP) • CBER-specific program. • Intended to provide training for CBER staff in on=site aspects of manufacturing, laboratory testing, quality control, and regulatory affairs • Promotes mutual understanding, open dialogue • By law, must be formally arranged by sponsor response to Federal Register Notice • http://www.fda.gov/BiologicsBloodVaccines (then search SOP 8115 in biologics search field)

10. New Developments in FDA Emergency Response? Initiation • Sentinel data – CDC or DHHS • “Friday afternoon telephone call” • Anticipated emergencies (e.g. pandemic) • Emergency IND “Sunday night telephone call”

11. The CBER Blood Safety Team • Chaired by Basil Golding, M.D. • Experts from OBRR, OBE, OCBQ, OCOD, OD, OCTGT, OVRR meet to: • Discuss importance of reported blood product events • Respond rapidly to events that potentially threaten the safety and availability of blood products (Rapid Response Team) • Plan, coordinate and institute an in-depth investigation if warranted • Evaluate the importance of the outcome of the investigation

12. The CBER Blood Safety Team (Cont.) Make recommendations to upper management regarding actions that should be taken, e.g. • Communications of risk • Mitigations • Withdrawal of a product • Identify any additional data and policy needs to ensure safety and availability of blood products

13. Old Model New Model Blood Safety Team: New Model Emergency OPs Emergency OPs Office Director BST Office Director and FDA Upper Management as appropriate BST

14. Incident Management Teams • Under direction of Office of Emergency Operations/Office of the Commissioner • e.g. for H1N1 pandemic – 12 Team Leads met in Incident Command Center (or telcon) 2x daily to discuss all aspects of FDA responsibility. (respirators, blood supply vaccines, web ads, etc)

15. Preparedness of the Blood System for Pandemic Influenza A/H1N1 - II • FDA issued draft guidance on donor and unit management. Recommendations include: • No deferral for contact exposure • Defer for 7 days post disease onset or 24 hours post symptoms • Train back-up personnel • Discretion to retrieve products if donor becomes ill within 48 hours of donation • FDA has developed current considerations for blood supply support in the event of serious disruptions. • Absence of serious supply disruptions has led FDA to keep seeking formalization of a response plan for broader emergency use.

16. Key Characteristics of the US Blood Supply – Existing Response Network • AABB Interorganizational Disaster Task Force (TF) • Emergency blood supply coordination responsibilities under ESF-8 of NRP • Level 1 members convene by telephone conference within one hour of an event (including representatives from affected blood establishments) • Level 1 includes all major blood organizations, HHS, FDA, CDC, DOD • TF has been active in TOPOFF exercises, as well as proactive planning for large events (political conventions, superbowl, etc) • AABB Pandemic Influenza Task Force • Proactive pandemic planning over past two years • Task Force has proposed FDA regulatory flexibility during pandemic-related shortages (Wide range of regulatory flexibilities proposed to FDA) • AABB has urged FDA to be transparent regarding its intentions so as to allow planning by the blood community • June 26 meeting with FDA liaisons

17. Emergency Response Strategies Discussed with the blood community (in context of H1N1) Blood Establishments Preparations • The best preparation is for Blood Establishments to anticipate crisis-related disruptions and prepare back-up plans for key manufacturing steps (staff training, regulatory approvals, supply management, BECS override options, recordkeeping in an adverse environment) • Blood establishments should also increase communications with hospital customers to keep close track of supply status and modulate collection volumes appropriately

18. Emergency Response Strategies Discussed with the blood community (in context of H1N1) cont. Modification of Standards • Adherence to standards is a critical foundation of the current blood collection system. Any relaxation of standards will be dependent upon supporting data that assesses risk: benefit to the greatest extent possible. • At the same time, FDA is actively seeking mechanisms that will help to preserve critical blood supplies in a pandemic or other disaster. • Standards for triage of blood components used electively in times of emergency would greatly facilitate the optimal use of available blood supplies

19. Planning a Regulatory Response Step I. Define candidate interventions – including risk/benefit Step II. Define appropriate triggers Step III. Define FDA Response Pathways • Strongly encourage proactive contingency planning by regulated manufacturers • Modify Regulations • 640.120 Variances • Issue new guidance • Enforcement Discretion • Emergency Use Provisions • IND and EUA

20. Specific Pandemic-Related Interventions Discussed at 6/26/2007 Meeting with AABB 1.Reduction of 56 day RBC interdonation interval based upon pre-donation Hb determination - projected large increase in RBC supply with minimal to no safety impact 2. Reduce weight requirements for double RBC apheresis by five pounds. 3. Relaxation of malaria and BSE-related travel deferrals (1-3% increase in accepted donors - establishments would not recruit deferred donors) 4. Relaxation of internal QC frequency and FDA reporting timelines Important: Discussion of useful intervention triggers was not conclusive (transfusion services measures deemed unreliable)

21. FDA positions conveyed to the blood community - Points to consider The AABB-proposed regulatory “flexibilities” are a conceptual start, but are in need of more sophisticated assessment • 1. What would be the gain in donors/donations? • 2. What would be the impact on safety (donor and product)? • 3. What situations would trigger the intervention? • 4. What organizational entity (community or government) would declare the need (and accept responsibility for) an intervention • 4. From the blood establishment perspective, what mechanisms would produce the most efficient pathways for FDA to provide flexibility?

22. Modifications to Regulations • Broad implementation of Exceptions/ Alternative Procedures • There may be a need for revised regulations that provide the CBER Director with authority to grant exceptions/alternatives to current blood regulations based upon unanticipated immediate need for products. This mechanism currently exists for tissues ( 21 CFR 1271.155(g)). • Proposed for blood components as 21 CFR 640.120(b)

23. 640.120 One Time Exceptions and Alternate Procedures “Variances” • SOP modifications and donor eligibility are submitted as prior approval supplements (PAS) per 601.12 Guidance. • All Biologics License Supplements (PAS, CBE-30, CBE) require CBER FDA Compliance Check which may require up to 21 days. This impacts value of 640.120 for emergency situations

24. Guidance • Well-established regulatory pathway • FDA recommendations promote retention of a uniform national standard • Can be retracted with follow-up guidance • Can be issued quickly when extreme situation warrants (e.g. 9/11; anthrax) • However, there are disadvantages to including urgent guidance development as a long-range plan

25. Guidance (cont.) • Formulation and clearance of guidance is generally time-consuming. Urgent publication may not permit optimal scientific/regulatory input-particularly if subject matter experts are otherwise engaged. • Guidance generally applies broadly, so regulatory interventions may or may not be appropriate for all blood establishments in all situations, at all times. • Published guidance cannot anticipate new developments during a crisis.

26. Targeted Enforcement Discretion • It may be possible to link targeted enforcement discretion by FDA to emergency “triggers” as defined through advance published guidance • Enforcement discretion has been proactively used in the past as a tool for regulatory flexibility • Targeted enforcement discretion places the burden for documenting “triggers” at the blood establishment level. • There would be an advantage to not receiving individual requests for variances for each blood establishment.

27. Use of non-Standard Blood products in Medical Emergencies • 606.151(e) - … life-threatening emergencies. .. complete documentation justifying the emergency action…signed by the physician. • 606.160(b)(3)(v) - Records shall be maintained that include … signature of requesting physician • 610.40(g)(1) …. Blood may be released or shipped prior to completion of testing in following circumstances ….properly label the blood…… complete the tests as soon as possible and provide results to consignee • Compliance Policy Guidance section 220.100 (CPG 7134.11) Interstate Shipment of Biological Products for Use in Medical Emergencies:

28. Emergency Use Authorization • 2004 Bioshield legislation • Pre-EUA review would allow emergency planning • Requires HHS Secretary Declaration of Emergency • Feasibility for blood components has not been formally evaluated

29. Current FDA Policy Issues

30. Concurrent Plasma • FDA seeks to establish standards for a licensed plasma product that would replace recovered plasma for further manufacturing of injectable products • Bring all plasma used for manufacturing of injectable products under the regulatory umbrella of FDA-licensure • Product standards intended to be compatible with current manufacturing practices (as defined in short supply agreements), but specificwith respect to conditions of collection, freezing, and storage

31. Concurrent Plasma - (cont.) • Ease current restrictions on re-labeling of FFP and WB-derived FP24 to plasma for further manufacturing use. • Increased overall size and flexibility of plasma inventories • Increased availability of AB plasma and male plasma for TRALI reduction • Increased plasma volumes for derivative production • Reduce discard of unused plasma • Recovered plasma (unlicensed) would remain an option for further manufacture of non-injectable products (e.g. reagents)

32. Current Considerations - Concurrent Plasma • Plasma collected concurrently with a licensed cellular product, either by whole blood collection or by apheresis • May be labeled immediately at the time of collection • May also be labeled initially as licensed FFP (or other licensed plasma for transfusion) and re-labeled as Concurrent Plasma at any time. (Note apheresis FP24 is not currently a licensed product)

33. Current Considerations: Concurrent and Plasma Labeling • Labeling for Concurrent Plasma should include conditions of collection, freezing and storage that may impact final product • FDA position is that source material for biological products must meet defined quality standards. • Expected to be compatible with current practice as defined in short supply agreements) • Labeling should be designed to preserve flexibility as new scientific information becomes available

34. Blood Donor Deferral for Malaria Risk Associated with Travel to Mexico Issue: FDA sought advice from the Blood Products Advisory Committee on whether it is acceptable to allow blood collections without any deferral from individuals who have traveled to certain Mexican states that have a low malaria transmission rate.

35. Discussion Issues Models suggests exemption of Mexican State of Quintana Roo from travel deferral would risk one PTM case in 36 years vs 45,000 donors retained annually Why not all of Mexico? Can a line of risk acceptance be pre-defined for future donor eligibility decisions?

36. Presented data: No record of a TTM case from donor travel to Mexico Advantage to unburdening DHQ from travel question that is major source of post-donation information and resulting operational burden Quintana Roo has experienced Dengue outbreaks recently

37. INTERCEPT Blood System for Pathogen Inactivation Issue: The Cerus SPRINT study of pathogen inactivated (S59) platelets identified potential safety and efficacy concerns. FDA and Cerus have discussed the design of future studies aimed at addressing these issues. FDA seeks the advice of the Committee regarding the design of a new Phase 3 study and the adequacy of the proposed product development program which includes a Phase 4 study and staged rollout of the product.

38. Background A safe and effective pathogen reduction system would have the potential to reduce current blood component risks from known and unknown transfusion-transmitted agents. 1/277,000 viral (cumulative) 1/86,000 bacterial (platelets) 1/1,000,000 (protozoa) ??? Future EID No protection for some agents with non-lipid envelope (e.g. HAV)

39. Data INTERCEPT approved by France, Germany, Switzerland, >350,000 INTERCEPT platelet products used to date Hemovigilance systems in EU countries are used to monitor adverse effects. Reports show much lower AE rates than US SPRINT Phase III trial may reflect differences in: recipient populations platelet preparations lower sensitivity of hemovigilance approach

40. BPAC Discussion Proposed path forward→→ New randomized controlled Phase III study with careful pulmonary monitoring to assess efficacy, and adverse effects (ALI as primary; ARDS as secondary endpoints) Phase IV post-market study (with phased rollout)

41. BPAC Discussion (cont.) Benefit : risk ratio currently more challenging in US where NAT testing is routine apheresis platelets are cultured. Ratio would change in face of an EID threat. Public comments – Pathogen reduction technology needed, don’t set bar so high as to eliminate product development “have been chasing transfusion-transmitted agents for decades, chance to change the paradigm of how we manage infectious diseases”

42. BPAC Recommendation A Committee member proposed that the phase 3 study should be powered to rule out a 50% increase in ALI rate and an 80% increase in ARDS similar to trials of Celebrex required by CDER. This would require a study of about 3,000 subjects. The Committee supported this approach.

43. Blood Pressure and Pulse as Blood Donor Eligibility Criteria Issue: FDA sought the advice of the Blood Products Advisory Committee on using blood pressure and pulse as part of the donor physical assessment to determine donor eligibility.

44. Discussion Donor reactions are primarily a function of central blood volume and cardiac output (young age, female gender, FT donor status are co-factors) Blood pressure not predictive of reactions among existing donors (but BP extremes not taken as donors) Pulse is weak predictor of donor reaction

45. Discussion Psycholological factors at work in immediate reactions Monitors…. “Want info and want to watch needle go in” Blunters… “tell me when its over” …Distraction works) ARC and BSI – Limiting donation to >3500 ml volume (15%) in 16 and 17 year old females reduced reactions 25% Immediate re-positioning interventions can counter fainting (contract legs and butt, if standing, squat down)