FDA Workshop on “Emerging Infectious Diseases: Evaluation to Implementation for Transfusion and Transplantation Safet

1. FDA Workshop on “Emerging Infectious Diseases: Evaluation to Implementation for Transfusion and Transplantation Safety” Day 1: “Evaluating Emerging Infectious Diseases (EIDs) for Transfusion Safety” May 11, 2010 Paul A. Mied, Ph.D. Update for the Blood Products Advisory Committee July 26, 2010

2. Goal of the EID Workshop To explore strategies for EID threat detection, intervention, and the prioritization of effort

3. Key Questions 1. How do we and should we characterize the risk to blood safety from an EID? 2.What are the criteria to prioritize EIDs that pose a threat to blood safety? 3.How should regulators, blood organizations, manufacturers, and other stakeholders develop a response to the threat from EIDs?

4. Emerging Infectious Diseases • New infections • Re-emerging infections • Drug-resistant infections whose incidence in humans has increased within the past 20 years or whose incidence threatens to increase in the near future.

5. Factors that Contribute to the Emergence and Spread of Infectious Diseases • Physical Environmental Factors • Genetic and Biological Factors • Ecological Factors • Social, Political, and Economic Factors - human demographics, behavior, and sanitation - closer human contact with wildlife and its habitat - failure of control measures - international travel and commerce - microbial adaptation and change - human susceptibility to infection - climate and weather

6. Surveillance • the ongoing systematic collection, analysis, and interpretation of outcome-specific data ↓ needs to be disseminated in a timely fashion

7. Some Thoughts about EIDs • About 70% of our 68 or so EIDs have been zoonotic • New threats will emerge; many will be zoonotic • Key will be: - “to unite human and veterinary medicine - to anticipate potential threats to blood safety - to be vigilant for early detection ↓ Improve predictive capability, coordination and communication through strong national and international partnerships”

8. Horizon Scanning • the systematic examination of potential threats, opportunities, and likely developments • the ability to detect novel and unexpected issues, persistent problems, or trends

9. Repositories of Specimens • Specific purpose for each • TTVS, RADAR, and TRIPS linked donor-recipient Repositories • Contributions of each Repository - evaluation of transfusion-transmission of known agents - may be very useful for that purpose for new and future EID agents

10. Critical Information about an EID • Is the agent blood-borne? • Is there an asymptomatic blood-borne phase? • Have transfusion transmissions been observed? • Does the agent survive component mfg and storage? • Does the agent cause disease? What is the disease attack rate, severity, mortality, treatability of the disease? • What is the prevalence and incidence in donors? Is it significant? • Is there professional, regulatory, and public concern? • Are interventions available? • What would be the impact of those interventions on resources?

11. AABB TTD EID 4-Year Project Goals: 1. To describe known and potential EID agents for which transfusion transmission is documented or its potential exists, and no effective intervention exists; 2. To create fact sheets for the agents; 3. To prioritize agents as to their blood safety threat.

12. Perspectives on Prioritization • “Prioritization is not the main function. We get a feel for which ones have significant risk that requires us to take action.” • “If you can develop a multi-pathogen (detection) chip or pathogen reduction, the question of prioritization becomes moot” • “It’s more difficult to factor in public perception and the societal concerns” • “We acted because a test was available; but the paradigm has changed for test manufacturers” • “We acted in the face of a disease: SFV: No TTD XMRV: No TTD?”

13. Key Questions on Prioritization • “What is acceptable risk?” • “When do we act with an intervention? And, when an intervention is introduced, can it be removed if it is no longer needed?” • “How do we know when a trigger for action is reached?”

14. Two EID Case Studies • 1. Babesia - expanding geographically - regional testing is conceivable • 2. XMRV - no transfusion transmission observed - no known causative relationship to disease - donor prevalence is unknown - test methods have not been standardized - literature is controversial: inconsistent findings for viral markers

15. The Precautionary Principle “ Action should be taken even if its value cannot be proven; that is, even if there is only a theoretical risk of harm. If risk is possible, then we must err on the side of caution.”

16. How do we Prioritize Our Response to an EID Threat? • “We could develop a scoring system or a formula for prioritizing” • We could develop an “EID Agent Priority Matrix”

17. high vCJD Plasmodia moderate Leishmania T. cruzi Influenza virus subtype H5N1 SLE virus HIV variants Chikungunya virus Dengue viruses Babesia CWD B. burgdorferi low Public Perception B19 virus HAV HHV-8 very low SFV absent theoretical very low low moderate high Science/Epidemiology EID Agent Priority Matrix Stramer et. al. 2009 Transfusion 49: Suppl.

18. “ XMRV is an excellent model” • Deliberate action plan • Does it cause disease? • Is it transfusion transmitted? • A model for the future

19. “WNV was a very good model” • Developed a Model: Likely to be transfusion transmitted • Infection; disease; epidemiology; a test in place

20. “What’s the appropriate action now?” • Babesia: “Implementing blood donor testing is an option that could be considered” • XMRV: “Continue research and perhaps consider implementing an interim blood safety intervention”

21. Decision-making Framework of Health Canada 3 phases: 1. Issue Identification: identify a possible risk to blood safety; • Risk Assessment by surveillance and hemovigilance; Benefit Assessment; 3. Risk Management: identify and analyze options, select and implement strategy, monitor results; surveillance

22. Risk Assessment • Hazard Identification • Dose Response Assessment for the infectious agent • Exposure Assessment: distributions, not point estimates • Risk Characterization • Risk Management: Risks vs Benefits, compare “what-ifs”

23. What do we Need to Manage EID Risks? • “Stronger links with other governments, regulatory authorities and public health.” • “Increased networking of researchers; global coordination of responses to EIDs.” • “Collaboration and communication with our domestic and international stakeholders.” • “A forum to describe how the decisions that were made were made.” Question: “What is the appropriate vehicle or process to put this forum into action?”

24. Tools to Address EIDs • TessArae High Multiplicity Resequencing Pathogen Microarrays (RPM) • Technologies for prion protein assays and blood filters that are under development • Pathogen Reduction Technology (PRT) • Expectations vs realities • Perceived costs vs potential benefits of lower infection rates and eliminating some current tests. • “Combining methods may offer advantages: Orthogonal process approach was suggested – combines NAT and PRT to cover the Window Period. Could Testing + Inactivation or Removal = Reduced Deferrals?”

25. Final Questions • What do we do about lack of interest and participation from the manufacturers due to the small market and margins? • Where will the funding come from as threats emerge or current technology becomes antiquated?