FDA Hot Topics. Alan E. Williams, Ph.D. Office of Blood Research and Review, CBER, FDA Pharma Conference January 27-29, 2010. FDA Hot topics. The Office of Blood Research and Review (OBRR), CBER Current organization and activities Quality Program. FDA Hot Topics (cont.).
Alan E. Williams, Ph.D.
Office of Blood Research and Review, CBER, FDA
January 27-29, 2010
The Office of Blood Research and Review (OBRR), CBER
FDA’s response to emergencies?
(Won’t cover: Biovigilance; Statistical Process Control;
Emerging Infectious Diseases)
Division of Blood Applications
(daily T-x report, mid-cycle checklist and tracking, monthly Regulatory Forum and application status review meeting).
(then search SOP 8115 in biologics search field)
Make recommendations to upper management regarding actions that should be taken, e.g.
Blood Establishments Preparations
Modification of Standards
Step I. Define candidate interventions – including risk/benefit
Step II. Define appropriate triggers
Step III. Define FDA Response Pathways
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)
The AABB-proposed regulatory “flexibilities” are a conceptual start, but are in need of more sophisticated assessment
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.
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?
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
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.
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)
??? Future EID
No protection for some agents with non-lipid envelope (e.g. HAV)
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:
lower sensitivity of hemovigilance approach
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)
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”
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.
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.
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
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)