Meeting Transcript of the Advisory Committee on Blood & Tissue Safety & Availability

Thursday, September 13, 2018
Crystal City Marriott
1999 Jefferson Davis Highway,
Arlington, VA 22202

Appearances

By ACBTSA Members

Jacquelyn Frederick, MT(ASCP)SBB, MBA, HON DB/DPH; Chair, Retired CEO Versiti, Inc.

Emily A. Blumberg, MD, FACPM.D., FACP, Vice-Chair, Director, Transplant Infectious Diseases, University of Pennsylvania; Professor of Medicine, Division of Infectious Diseases, Perelman School of Medicine, University of  Pennsylvania

James J. Berger, MS, MT (ACSP) SBB, Designated Federal Official, Senior Advisory for Blood & Tissue Policy, Office of HIV/AIDS and Infectious Disease Policy Office of the Assistant Secretary for Health, US Department of Health and Human

Alex J. London, PhD, Director, Center for Ethics and Policy, Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Carnegie Mellon University

Brian S. Custer, PhD., MPH, Director of Epidemiology and Health Policy Science Vice-President Research and Scientific Programs Blood Systems Research Institute

Cassandra D. Josephson, MD, Professor, Pathology, Laboratory Medicine & Pediatrics, Emory University School of Medicine Medical Director, Transfusion, Tissue and Apheresis Services, Children's Healthcare of Atlanta (Via Telephone)

Camille N. Kotton, MD, FIDSA, Clinical Director, Transplant and Immunocompromised Host Infectious Disease, Massachusetts General Hospital

Mark W. Skinner, JD, President & CEO Institute for Policy Advancement Ltd

Marian Macsai, MD, Eye Bank Association of America North Shore University Health System Glenbrook Hospital

Louis M. Katz, MD, Chief Medical Officer, Biomedical Services, America's Blood Centers

Mary Gustafson, Vice President, Global Regulatory Policy, Plasma Protein Therapeutic Association

Sridhar Basavaraju, MD, FACEP, CDR USPHS, Centers for Disease Control and Prevention Office of Blood, Organ, and Other Tissue Safety Division of Healthcare Quality Promotion (Via Telephone)

Scott A. Brubaker, CTBS, Director, Division of Human Tissues, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration

Nicole, Verdun, MD, Director, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration

Marilyn E. Levi, MD, Director, Division of Transplant, Health Resources and Services Administration

Nora Ratcliffe, MD, Chief, Pathology and Laboratory Medicine White River Junction VA Medical Center, Department of Veterans Affair

By Non-ACBTSA Members

Steven Sloan, MD; Emily Storch, MD; Jay E. Menitove, MD; Michael P. Busch, MD, PhD; Roger Dodd, PhD; Martin Ruta, PhD, JD; Richard Forshee, PhD; Dana Devine, PhD; David Wendler, PhD; Zbigniew Szczepiorkowski, MD, Ralph Vassallo, Jr., MD; Aaron Tobian, MD, PhD; Gwendolyn Poles, DO, Juanita Jones, MPH

Proceedings

The Chairperson: Good morning, everyone. I'll give everyone ten seconds to get settled.

Good morning and welcome, everyone, to our advisory committee for Blood & Tissue Safety & Availability.

Let me start by thanking all of you for, in a short timeframe, being able to participate in this meeting and for all the work and good guidance you're going to give us on critical issues for tissue and blood that our country needs going forward.

I am Jackie Fredrick. I am your new chairperson on the committee. I tried to get around to meet most of you, and I apologize if I missed you. I, for sure, will get around to introduce myself.

You can read my official bio, I'm sure, somewhere, but I have about 40 years of experience in transfusion medicine.

Leading an organization most recently that provides blood, bone marrow stem cells, organs, and tissue, is involved in basic blood disease research, clinical care of patients with blood disorders and advanced diagnostics.

And most recently, in the last decade, also was involved in bringing on an OPO into our organization and a tissue bank.

It is my privilege to serve with all of you on this committee and very honored to have this position at this point in my career. So welcome.

First order, I would like to thank Jay Menitove for his four years of service as your chairperson. Jay did an excellent job on leading the committee through some important issues. The good news is Jay's not off the hook. Jay will continue to chair the Subcommittee on Sustainability of the Blood System.

I've known Jay for many decades and find him a truly committed physician, dedicated to the care of patients and donors. And so, thank you, Jay, for your four years of service of service, chairing this committee.

So I want to start the meeting by reviewing why we exist. I know there are at least some of us to this committee that are new, and certainly our guest might be here for the first time.

So just I think a reminder that we are part of a group of advisory committees under the Assistant Secretary for Health who reports to the Secretary of HHS. And we are part of the Office of AIDS and HIV Detection and Prevention, so it's -- we are in HHS.

But most importantly is why we exist, is we deliberate today and into the next year that we are here to really advise our Secretary of HHS and make recommendations. Specifically, we report up through the Assistant Secretary of Health.

And all issues can be discussed here as it relates to regulations concerning blood, tissue, and/organs, issuing the regulations, transmissible and communicable diseases, and carrying out health research.

So as we begin our discussion today, we are here to assist, and guide, and consult with that office so that they can make better policy for the patients and the public in our country.

One provison is when it comes to organs and bone marrow, our responsibility really is to the infectious disease threat with those. There are other committees that cover the broader issues of solid organs and stem cells.

So important for us to keep in mind why we are here and the good work we do in advising the Assistant Secretary of Health.

So with that, we are going to move on to do a roll call. Jim and I discussed it, and we thought we might do it a little bit differently and have you introduce yourself.  Seeing as I'm new do, I can get a better feel for how we do that.

Do you want me to start?

Mr. Berger: Yes, please.

The Chairperson: So maybe, Alex, if we can start with you and just go around the table? And then we'll end with the people on the phone.

Dr. London: Good morning. I'm Alex John London. I'm a professor of philosophy at Carnegie Mellon University, where I interact the Center for Ethics and Policy, and my work is in bioethics and research ethics.

Mr. Brubaker: Hi. I'm Scott Brubaker. I'm from FDA CBER, Office of Tissues and Advanced Therapies. I'm the director of the Division of Human Tissues.

Dr. Macsai: Hello. I'm Dr. Marian Macsai. I work in Chicago as a practicing ophthalmologist, and I'm here representing the Eye Bank Association of America.

Mr. Skinner: Good morning. I'm Mark Skinner. I'm an attorney by profession. I -- I live with severe hemophilia. I come from the patient community, previously had served as president of the National Hemophilia Foundation, The World Federation of Hemophilia, a long, long involvement. I think this is about year seven on this committee.

Dr. Ratcliffe: Hi, I'm Dr. Nora Ratcliffe, and I'm here representing the VA.

Ms. Gustafson: Hi, I'm Mary Gustafson. I'm the vice-president of Global Regulatory Policy for Plasma Protein Therapeutics Association. I'm representing the Plasma Protein Therapy Community.

Dr. Kotton: Camille Kotton. I'm a transplant infectious disease specialist at Massachusetts General Hospital and Harvard Medical School. And I have a special interest in organ and blood- transmitted infectious disease.

Dr. Custer: I'm Brian Custer from Blood Systems Research Institute in University of California, San Francisco, trained as an epidemiologist and health economist.

Dr. Katz: Louis Katz. I'm the chief medical officer of America's Blood Centers, infectious diseases clinician. That's it.

Dr. Levi: Hi, I'm Dr. Marilyn Levi, Transplant Infectious Disease, joined HRSA one year ago as a medical officer in the Division of Transplantation.

Dr. Sloan: Steven Sloan, blood bank medical director at Boston Children's Hospital. I'm here representing AABB.

Dr. Blumberg: Hi, I'm Emily Blumberg. I'm a transplant infectious disease doctor at the University of Pennsylvania and vice-chair of this committee.

The Chairperson: Thank you. Oh, and the people on the phone?

Dr. Josephson: Yes. This is Cassandra Josephson. I'm a professor of Pathology and Pediatrics at Emory University and the medical director of the Blood, Tissue, and Apheresis Services at Children's Healthcare of Atlanta, and I'm a Pediatric hematologist and oncologist.

Dr. Basavaraju: This is Sridhar, Sridhar Basavaraju, director of the CDC Office of Blood, Organ, and Other Tissue Safety.

The Chairperson: Anybody else on the phone? Thank you.

Mr. Berger: We do have a quorum.

The Chairperson: Thank you. I should also say all of you, committee members have a pack in front of you with the short bios, and names of all the committee members, the agenda, the advance notice of this committee meeting in the Federal Register, and the charter for this committee for your review also.

So with that, the beginning of our meeting is going to include two reports. The first from BPAC and held on July, and the second from the Subcommittee for Sustainability.

Our first presenter will be Emily Storch. Dr. Storch is with the FDA and will update us on the July BPAC. Welcome, Dr. Storch.

Dr. Storch: Thank you.

FDA/BPAC Update

Dr. Storch: Good morning. My name is Emily Storch, and I am a medical officer in the Division of Blood Components and Devices in the Office of Blood Research and Review at the FDA.

And today, I will be providing an update of the recent FDA BPAC held this past July on strategies to control the risk of bacterial contamination in platelets.

So the issue for discussion is that bacterial contamination of platelets remains a concern. FDA has held several BPAC meetings to discuss various aspects of this issue.

Most recently, a BPAC was held this past July, as mentioned, in which the committee had the opportunity to discuss all available strategies in one session. These strategies include culture- based methods, rapid testing methods, and pathogen reduction technology.

And FDA intends to issue a revised draft guidance this calendar year on strategies to control the risk of bacterial contamination in platelet products.

The regulation on control of bacterial contamination in platelets is found in 21 CFR 606.145(a), which states that blood establishments and transfusion services must assure that the risk of bacterial contamination of platelets is adequately controlled using FDA-approved or cleared devices or other adequate and appropriate methods found acceptable for this purpose by FDA.

FDA states in the preamble to this regulation that this requirement can be met by testing for bacterial contamination or pathogen reduction.

Current platelet dating is a maximum of five to seven days based on the preparation method, the storage container used, and the bacterial testing.

For five-day storage, primary culture is performed no earlier than 24 hours after collection, or the platelets are treated with an FDA-approved pathogen reduction device within 24 hours of collection.

For seven-day storage, primary culture is performed, as well as additional secondary testing, using a test labeled as a safety measure when collected into an appropriately labeled container.

Looking at bacterial contamination of platelets through fatalities reported to the FDA of septic reactions from apheresis platelets, you can see that existing strategies have reduced the number of fatalities but risk remains.

This reduction in risk coincides with AABB standard 5.1.5.1 which became effective in 2004, calling upon blood establishments and transfusion services to limit and detect bacterial contamination of platelets.

And since that time, primary bacterial culture, mainly aerobic, has been performed by blood centers on nearly all apheresis platelet in the United States.

And as you can see from the graph, before full implementation of this standard, there were approximately six to eight fatalities per year, whereas after full implementation around 2005, that number decreased to zero to four fatalities per year.

Data show that with current bacteria culture practice, bacteria are detected in approximately 1 in 5000 donations at the time of sampling.

And current data show that reported septic transfusion reaction rates, by passive surveillance, are approximately 1 out of 100,000 and by active surveillance, 1 out of 10,000.

There are, however, some limitations of current primary culture practices, in that there is a residual risk of septic transfusion reaction at the time of transfusion.

As you can see from the top diagram, when you have low numbers of bacteria early in shelf life, you are less likely to transfer the bacteria to your sample and be able to detect contamination, leading to a high likelihood of false negatives.

There is also a lag time between inoculation and growth, as shown in the bottom diagram. This lag time is variable, but for all species, detection is most likely in exponential phase where its false negatives are more likely in the lag phase.

And as a correlate of this is clinical sensitivity of day 1 culture for contamination on days 5 to 7 has been shown to be less than 40 percent.

The following slides will give an overview of the strategies that were discussed at the July BPAC meeting, as shown in the table. At the meeting, invited strategies described studies related to these strategies. It was followed in the afternoon by an open public hearing and an open committee discussion that we'll discuss.

So starting with the strategies to control the risk of bacterial contamination in five-day platelet products. The first discussed was primary culture, followed by secondary culture on day 3. And this strategy was presented by Dr. Evan Bloch, from Johns Hopkins University, where this strategy has been implemented.

In this strategy, primary culture is performed at least 24 hours after collection, using an 8 mL sampling volume, and collected into aerobic media. Secondary culture, in contrast, is performed on day 3 using only 5 mL sampling volume, but also collected into aerobic media.

The next strategy discussed minimal proportional sampling volume. And the strategy comprises a single culture, with no secondary testing; whereby the sampling volume is increased proportionally to the collection volume.

In this strategy, the sampling volume is at least 3.8 percent of the collection taken in 24 to 36 hours approximately after the donation and drawn into 1 to 3 culture bottles and aerobic media. And Dr. Ralph Vassallo, from Blood Systems, Inc., presented his experience with this strategy.

The following strategy discussed for five-day platelets was primary culture, followed by secondary rapid testing on the day of transfusion. In this strategy, primary culture is performed using the standard methodology as -- as discussed.

And in contrast, the secondary rapid testing is performed within 24 hours of transfusion, using a

0.5 mL sampling volume. And the strategy of bacterial rapid testing was presented by Dr. Michael Jacobs, on behalf of Verax Biomedical and Immunetics, Inc.

And then the next strategy discussed for five-day platelets was pathogen reduction technology. There is currently only one pathogen reduction technology device approved by the FDA.

This device is based on amotosalen/UVA technology, which as you can see in the diagram, involves treatment with amotosalen, which targets the nucleic acids, causing intercalation. And following UVA illumination, there is crosslinking, and subsequent replication is blocked.

The intended use of a pathogen reduction technology is to reduce the risk of transfusion- transmitted infection, including sepsis, and is performed within 24 hours of collection.

Also discussed were strategies to control the risk of bacterial contamination in seven-day platelet products as follows.

The first method discussed for seven-day storage was primary culture, followed by secondary culture performed on day 4. In this strategy, primary culture is performed 12 to 24 hours after collection for apheresis platelets, and 36 to 48 hours after collection for platelet pools.

The size of the sample is 16 mL, divided evenly into aerobic and anaerobic medium. And there is no hold period after the testing or loading of the bottles, meaning that the units are immediately released after sampling.

Then the secondary culture is performed on day 4. And here, the products sample are each apheresis unit and each pooled platelet in contrast to the primary culture, which are taken from the main collection. And again, the sampling volume is 16 mL, divided evenly between aerobic and anaerobic media.

And the next strategy discussed for seven-day platelets was large volume delayed sampling, entails a single culture to extend storage up to seven days. The sample is taken 36 to 48 hours after collection, using 16 mL from each component.

The sample is inoculated into aerobic and anaerobic culture media, and held for approximately six hours after sampling. And Dr. Carl McDonald from the National Health Service Blood and Transplant in England presented his experience with this strategy.

And then following the last strategy discussed for seven-day platelets was primary culture, followed by secondary rapid testing to extend beyond day 5 up to day 7.

And this is the same strategy as was discussed for five-day platelets, with the exception that for seven-day platelets, secondary rapid testing is performed with a test labeled as a safety measure.

And as mentioned, bacterial rapid testing was presented by Dr. Michael Jacobs on behalf of Verax and Immunetics.

So following the presentation then opened the committee public discussion. The specific question asked of the committee was to please comment on the advantages and disadvantages of each of the various strategies to control the risk of bacterial contamination in platelets, including the scientific evidence and the operational considerations involved.

The committee was reminded, however, that there are challenges in strategy comparison, and the committee was not asked to make direct comparisons. Specifically, it was mentioned that the studies on the strategies are not directly comparable because many variables affect bacterial contamination and/or detection rates.

For example, the apheresis technology used, the timing of sample collection, the sample volume, whether aerobic or anaerobic culture are used, and techniques of skin preparation and diversion.

Further, there are changes in standards and practices over time, definitions and reporting of septic transfusion reactions vary, different outcomes are evaluated, and importantly, different strategies have not been evaluated in parallel.

Then following the presentations by the invited speakers, an open public hearing was held at which various speakers presented topics of concern, including implementation of pathogen reduction technology and secondary rapid testing; the importance of operational considerations, among them, the potential difficulty of dual inventories; advantages and disadvantages of anaerobic bottles; questions regarding the safety and efficacy of older platelets as well as particular clinician preference, whether they would prefer younger platelets; and limitations of passive surveillance, and the fact that there is no defined threshold of safety.

So to highlight some of the summary points of the committee discussion, it was clear there was a general consensus that multiple strategies appear to improve safety.

However, it was noted frequently that the sparse data creates challenges in strategy evaluation and comparison, which leads to a continued need for surveillance data and future research.

However, it's also very much emphasized, the operational considerations are important. And as a correlate of this, different strategies may serve different regions and populations, which leads to the conclusion, among other points, that multiple options should be provided. And while existing data are incomplete, this should not preclude timely action.

And overall, there was a consensus that FDA guidance providing enhanced safety measures is needed.

So in summary, bacterial contamination of platelets remains a leading cause of septic transfusion reactions and related fatalities.

The recent BPAC provided an opportunity for a discussion of the advantages and disadvantages of each of the available strategies to control the risk of bacterial contamination in platelets, including the scientific evidence and operational considerations involved.

And FDA intends this calendar year to issue a revised draft guidance on strategies to control the risk of bacterial contamination in platelets and will take into consideration the BPAC discussion. Thank you.

The Chairperson: Thank you, Dr. Storch. Are there any questions for Dr. Storch? (No response.) Hearing none. Thank you very much. And we're perfectly back on time. Thank you.

Next, we're going to hear a report by Dr. Jay Menitove for the Subcommittee on Sustainability of the Blood System.

ACBTSA Sustainability Update

Dr. Menitove: Thank you, Jackie, and thank you to members of the committee.

This is going to be somewhat of a review for those who have been on the committee and an update for those who are new to the committee. And I'll do my best to keep you on track.

Okay. So if we go back four years, one of the -- or the discussions at that time concern the sustainability of the blood system. And at that time, it was clear that there was one committee and only one committee really that was appropriate for addressing the big issue of sustainability, and that was -- that was this committee.

The approach taken was eventually for the Department of Health and Human Services to contract with the consultant and a subcommittee was formed that would provide some guidance for the report that eventually would be delivered.

And that was delivered in the fall of 2016, a study conducted by the RAND Corporation. RAND looked at -- or took several thoughts in approaching the subject of sustainability, status quo, without policy intervention, a targeted policy intervention and a fundamental shift in the blood system structure and management. And they settled on the middle where they would take a targeted policy intervention step.

And their thinking about this was that some or most of the pressures on blood centers stemmed from aspects of the blood system other than their interaction with the hospitals.

There was an expectation for surge capacity among blood centers and a sense among blood centers that there was a need to address public health emergencies and testing.

RAND thought that fixing or removing fixed costs from blood centers to do this, but there might be a short-term undesirable consequence of blood center exit, and they proposed seven recommendations.

Collect more data because they had insufficient data. Develop and disseminate the vision for appropriate levels of surge capacity. Pay blood centers for maintaining surge capacity. Build relationships with brokers. Build and implement a value framework for new technology. Pay directly for new technologies where there's no business case for adoption, and implement emergency youth authorization and contingency planning for key supplies and inputs.

The subcommittee met, presented its report to the full committee at the meeting two years ago, and the committee report, which several of you have seen obviously before, differed somewhat from the RAND report.

The committee felt that blood is a public good, built on the altruism of non-remunerated donors. Simple supply and demand in the economic principles do not fully address the societal value of this critical national resource.

Recommendations came out from this committee to conduct additional data collection and for the Secretary to -- or Assistant Secretary to convene a panel of stakeholders to suggest appropriate data elements, that there should be an exploration of direct payment to blood centers to cover the costs of the infrastructure required to maintain adequate supplies for the public good, to examine models of risk-based decision-making to inform future public policy to include all stakeholders in the vein-to-vein process, and to reduce regulatory uncertainty.

So to sort of summarize, I think a sense of several of us as we left the meeting two years ago, RAND took the viewpoint from an economist point of view, suggested tweaks to the system.

I think the committee felt there was a more crisis-oriented -- had a more crisis-oriented viewpoint and stressed the approach to the public good.

So what happens next? We put together a series of phone calls, subcommittee conference calls, to confirm and document the sustainability risk. And a suggestion that we followed was to follow a stress test format similar to that that the banking industry underwent in 2008, 2009.

We felt that there was -- it was more than a financial crisis. There was a shrinking of the donor pool, a lack of supplies, lack of innovation support, and possibility a problem with system elasticity. We also noted that there was a lack of central decision-making in terms of where policy was formulated.

So we put together three working groups: hospital, blood center, and industry suppliers. The names of the people who participated are on the slide. The hospital working group, this was about -- so nothing really has progressed in terms of these working groups over the last year, probably year and a half.

The concerns expressed were on the reliability of the blood supply, that shortages did exist periodically, that there were issues with the safety of blood for patients in terms of lack of adoption of signification safety measures.

And there was a concern about the availability of specialized products from referenced laboratories, HLA matched platelets and such.

The blood center working group mentioned some -- several issues that they were concerned about: The change in hemoglobin requirements with the loss of donors, reliance on high school donors with concern about iron testing, preparedness in the case of unprecedented events.

FDA mandates that really were, in fact, unfunded mandates for which CMS funding was not compensated in a timely manner and the insurance value of blood not compensated.

The industry suppliers work group weighed in, stating that the industry consolidation into large diversified companies with result in less investment in transfusion medicine, and made an interesting comment that investor return on investment was important for sustainability similar to that of blood donor generosity for sustaining the supply of blood.

They also stated that revenues generated by whole blood and apheresis collections were eroding some of the -- the blood centers were increasing their efficiency by splitting apheresis platelet products, and that was eroding the number of kits that were being sold and impacting, further impacting, manufacturers of blood supplies in a negative way, and that innovation was at risk.

So for a while we had joint conference call with BOTSEC, the Blood, Organ and Tissue Senior Executive Committee. And the sense of that was that we were going to have a meeting of minds between the public and government sectors, and private transfusion medicine sector.

But we had a few calls, but they're really introductory in nature, and they were suspended because we're waiting additional data collection and analysis. And we've been doing this now for over a year, actually. With the sense being that if blood centers had negative margins, we had to prove it, and that was coming out of the analysis of the RAND report.

And in the interim, we've seen publications of The New England Journal of Medicine. Chris Hrouda was a member of this committee, Harvey Klein, he still is, Jay Epstein likewise, and very much I think reflected the outcomes of some of our discussions.

In The New England Journal article that came out a year ago, and I think that you'll remember, we stated that the nation's blood supply with a public trust, a strategic resource, that the pipeline is now in danger of disruption and that the medical community treats blood as a commodity, and that hospital consolidation shifted the bargaining power to hospitals. Fewer customers for blood centers, more power to hospitals in terms of the negotiation.

That there was no direct link between hospital reimbursement to blood centers and hospitalized patients, and that some type of significant public or private intervention will probably be required to maintain an adequate blood system infrastructure.

And they concluded that a constructive intervention to stabilize the blood system, although urgently needed, is yet to be envisioned. I think we are still there.

There were multiple letters I know that were sent to The New England Journal in response to the editorial. One was published that expressed the fact that blood centers were doing better, that 37 percent of the members of Blood Centers of America, in fact, had improved their financial position, and that 43 percent had increased their net income between 2017 and 2016.

On subsequent analysis, I think it became apparent that some of these improvements were based on investment income rather than operational income. And that's still being considered.

I attended the ABC annual meeting in March of this year. ABC members reminded me that the blood supply is adequate and sustainable to-date from an adequacy point of view, but there are questions about resiliency, and they were fairly adamant about that.

And then I think in the last couple of weeks you have seen an open letter from Chris Hrouda at the American Red Cross. And Chris, in his letter, stated that the industry professionals and transfusion medicine experts have warned of the perils that befall a weakened blood system, that these thought leaders have expressed concern that the vitality of the blood system is severely threatened. And unfortunately, their efforts have merely served to sound the alarm, but failed to ignite action or reform.

Chris went on -- if I don't mess up my papers here -- to say that despite credible efforts by blood centers to control costs, these have not sufficed. Most blood products distributed in the United States are supplied at a cost lower than that to produce them.

He said that improved cost recovery for blood centers can be achieved through two primary channels: innovation and pricing, that they have modernized, and been innovative, and reduced cost. And the second is to raise prices for products and services, which they are in the process of doing.

So -- and additional comments are that the FDA has put out guidance for Babesia, and there is a licensed test for Zika.

And so in terms of Babesia, cost recovery, potentially, could be an issue going forward. 14 states may be involved in testing and not the rest. And there could be geographic price differences, shifting production possibly to non-endemic regions or importing from non- endemic regions to, or non-endemic regions, from non-endemic to, or away from endemic. You know what I'm trying to say.

So where are we? Actually, we're in abeyance, pending the completion of data collection and analysis to prove that there are negative margins. Study is being conducted by BARDA.

They are looking at various spirals, as they term them, for red cells, and also looking at collection processing, and shipping data, and financial analysis. The Red Cross and ABC have provided, and they are, in fact, being analysed.

I was asked to put a spotlight on the current level of concern for the committee and I got various opinions. The sense is it's probably yellow, a possibly yellow to red, in terms of financial margins for blood centers, but unclear.

It's unclear what the reactions of the price adjustments for core activities will be. It's unclear what the reaction to cost recovery for Zika and testing will, but clearly, it'll run into the tens of millions, if not more, dollars.

So at this point, where are we? We're encouraging completion of the data analysis that's in progress. That would be reviewed primarily or initially by BOTSEC, and we would then like to get the subcommittee together again to review the data and to resume the joint conference calls.

And then we expect to have a full report from the subcommittee and completion of our activities by the next advisory committee meeting. With that, Jackie, thank you.

The Chairperson: Thank you, Jay.

Is there anyone on the call from BARDA?

Oh, sorry. Do you know if you could speak to the progress on the data analysis and when we might have that analysis available to us?

Ms. Jones: Yes. Hi. This is Juanita Jones with BARDA. Our hope is to have the blood data or analysis to you by December.

The Chairperson: That's terrific. Thank you. Thank you very much for your work. And sorry to put you on the spot. I think, Jay, one of our plans is to put that on the agenda, I hope, for our April meeting, also. Are there questions for Jay? Mr. Skinner?

Mr. Skinner: Hi, Jay. Thank you for the report. So for some of us that had been on the committee a long time, I mean this is sort of a bit uncharacteristic of the way the committee has operated.

In the past, the committee has prepared recommendations. They send them to the Secretary, we receive the timely response in terms of what the Secretary would do with the recommendations.

We're sort of two years on from the last committee, and this is the first time we've received a report, which is an oral report. So not to doubt what you're saying in terms of the plan, but I'm still not clear that this is sort of at administration response in terms of the committee or sort of where we fit.

Any thoughts in terms of whether, you know, this is part of an official plan or response from the Secretary for our work or whether we're going to receive confirmation, sort of clarity on the path forward of how this fits in the administration's plans.

I guess it sort of all goes to the relevance of this committee and sort of its priority with the overall structure. So maybe it's not a question for you, maybe it's a question for Jim.

But I just sort of would be curious because quite a bit of time has gone by. We had a sense of urgency, and it doesn't seem we're moving at an urgent pace. Others can feel free to disagree with me.

Mr. Berger: Mark, thank you for you input on that. What has happened is that this is part of the process where the recommendations have gone forward to the Assistant Secretary for

Health. And part of that piece, that we're still waiting for that information, is the blood sustainability modelling that was tasked from the Assistant Secretary for Health to us by BARDA.

And that's the part that we're looking forward to. Once BARDA has their information completed in December, it's scheduled to be briefed to the Blood, Organ and Tissue Senior Executive Counsel, which is the HHS basically, Executive Counsel that's made up with the different agencies.

And with those results that once they go forward to their briefing, their recommendation will be made as to what HHS can do with that information. And then that will be brought back to the Advisory Committee on Blood and Tissue Safety and Availability.

So basically, it's a part of the process that we initiated a couple years ago, which has just taken time for American Red Cross, America's Blood Centers to provide their data because there's a lot of financial data that was required. There's a lot of significant collection data impacts on testing that BARDA's reviewing.

So it just probably has taken longer because they want to do a thorough analysis, and it's such an important question.

Dr. Menitove: But, Mark, I think you asked the right question, and a sense of continued pressure to get this done, it's obviously appreciated.

The Chairperson: And other questions for Jay? (No response.)

The Chairperson: Jay, I have one. There were two other important recommendations. One was with regards to reimbursement and the other with providing a platform for the industry to be able to discuss rationalizing the structure.

Do you know the intent of how those would move forward?

Dr. Menitove: Jackie, it really comes down to, I think, what Jim just said. We're -- we're in abeyance pending analysis of the data. I mean at the last meeting, and it was quite some time ago, the sense was that blood -- the committee was concerned, the economists were going to let market forces play out.

And so is there a prove of negative margins? And I think until the data are analyzed and there is a third party looking at the results, we really are just in abeyance.

And if margins are negative, there is an issue that's real. Then I think we have to prove that we can move forward. If the proof isn't there, then that's where it is.

I wish I could give you a more definitive answer.

The Chairperson: Thank you. And thank you for your continued work.

Dr. Menitove: Thank you very much.

The Chairperson: Are there questions from the phone participants.

Dr. Josephson: No, we have no question on the phone.

Unidentified Speaker: No questions here.

The Chairperson: Okay. Thank you. Thank you, Jay.

I would just ask the committee, this afternoon I think we have two hours for discussion, if there is any further discussion the committee would like to have on the direction of the Subcommittee on Sustainability or further guidance, we might want to give them -- we can discuss it at 3:30.

I'm going to have to go up and get -- thank you -- my slides. So the purpose -- moving on to the purpose of this meeting, and all the subsequent speakers we'll hear this morning and this afternoon, I'd like to review now.

Purpose of the Meeting

The Chairperson: Just background, similar to what Jay gave is the purpose of this meeting, how this come about and why are we talking about risk tolerability today.

And again, a reminded that this committee, one of the recommendations you made was to examine models of risk-based decision-making to inform policy with all stakeholders. And I'll have a few more introductory comments about all stakeholders in the vein-to-vein process. So this takes one of the other recommendations made by this committee to move forward.

I also, in preparing for this appointment, re-reviewed several times the RAND report, and they mentioned this in -- in two ways I think. They are under their opportunities to improve sustainability. They talked about stakeholders -- stakeholders want support in making technology adoption decisions. And I agreed into that a framework by which we could make new technology adoptions.

And then recommendation 5 to them talked about a value framework for new technology. And in many respects, that gets to innovation and that gets to as their decision-making process we can have to both retrospectively, which we often do in this industry, and prospectively make risk-based decision to guide policy, even in the development of innovations.

So that's how we got here through the recommendation of the -- sorry. Now, I have to get the --

So we're going to begin dealing with a complex issue. Certainly, other industries have dealt with this and other transfusion medicine communities around the world also.

But today, we want to start the process to define a tolerable infectious disease risk in blood safety from a patient's perspective. And I think this gets back to the recommendation around ensuring that all stakeholders participate.

We have a short meeting today, but we have tried to have an agenda which at least touches on many of the important stakeholders. By no means do we think this agenda is a comprehensive inclusion or review as we go forward.

Today's agenda really is to educate the committee, so we can begin the discussion and set the direction for the future as we go forward. And so you'll see the agenda is in multiple parts, to hear from stakeholders, to hear a historical perspective, because obviously, we have a lot of experience with this issue and want to learn from the past, and education around risk and ethics, et cetera.

And then stakeholders certainly from the transfusion medicine industry, the healthcare industry and the very important patient constituency that we all serve.

In the agenda, we laid out some potential charges we might consider later on today. Keep those in mind as you listen to the speakers. By no means are these the only charges or even the eventual charges we will end up with as we go forward.

So the first part of the agenda will really set the landscape for transfusion medicine and infectious disease. We have three esteemed, long-time experts, who had lived this journey over at least the last three decades. And so we'll all hear from Drs. Busch, Dodd, and Ruta.

First, I would introduce Dr. Mike Busch. Welcome, Mike. Thank you for travelling from the West Coast.

Keynote: Historical Perspective Infectious Disease Risks

Dr. Busch: Great. Thanks to be hear. I still feel young, so it seems odd to be required as to talk about history here.

Anyway, it was interesting to get this request. It was only in three or four weeks ago. And so I looked back at actually earlier stuff and actually, in several publications back in 2006 and 2010, I kind of reviewed the history of blood safety.

And in those documents, I kind of framed up what I'll share with you now in terms of historical perspective. But then I've also included some more recent work around response to emerging threats.

So in one of those earlier papers, we kind of looked at the historical perspective from the context of time and approaches that were possible to assess risk.

So in the early '80s, we -- and into the '90s, we really used retrospective cohorts, that is where samples had been saved and donor-recipient samples were available.

Risks were high enough that we could actually measure those risks through analysis of testing of samples from donors and/or transfusion recipients. And I'll show you some examples of that.

So these retrospective cohorts were useful, but they became less useful as we implemented sensitive screening test. And for a period of about five years, we were attempting to and did try to directly measure risk by either assessing the frequency of missed infections in donors or the rates of transmission into recipients.

And I'll review a few of those studies. But we quickly came to realize that the risks were so low that we could not measure them even with quite large prospective studies.

So this led to the current era, which continues to evolve, where we really estimate the risk for the major agents through modelling strategies and as emerging threats come along, again, combined modelling strategies with sometimes large prospective studies.

So again, in this era of retrospective cohorts for both HIV, hepatitis C and B, there were large studies of repository specimens that allowed testing of those samples.

They had been stored prior to the availability of test, and then later were able to be tested to assess the rates of infection in donors and the risk of -- directly the risk of transfusion- transmission prior to the availability and, in fact, the discovery of several of these agents.

So the classic work really by Harvey Alter's group and there was a parallel study led by James Mosley called The Transfusion-Transmitted Viruses study.

But in Harvey's work, it illustrated here and the review he wrote with Harvey Klein -- you can see that prior to screening, we had actually 35 percent of recipients getting infected with hepatitis, and most of that was non-A, non-B hepatitis.

The introduction of surface antigen testing and progressive improvements in HBV testing now had not have essentially eliminated HBV risk, but we had a large non-A, non-B hepatitis that was later determined to be hepatitis C, reduced by using surrogate testing, ALT anti-core, but then really dramatically reduced with HCV antibody testing and then now NAT testing.

So really, in the prospective ongoing work of Harvey continues to lead in NIH, there had been no transmissions of hepatitis or HIV for the past two decades.

So we did a study in San Francisco, as I mentioned, the transfusion safety study, again led by James Mosley, saved 200,000 donations before the HIV antibody test was available in San Francisco and in three other high risk cities.

And those samples were later tested, and the rates of HIV were determined, the recipients traced. 90 percent of these HIV antibody-positive units transmitted HIV to recipients. So a large number of recipients became infected.

Over the subsequent several years, as we implemented testing in early 1985, the rate of infected donations here in San Francisco dropped dramatically.

In addition, the characteristics of the infected donors, since we'd excluded high-risk gay men, changed from predominantly MSM to a mixture of MSM and heterosexuals in the infected donors we detected.

But what we did was combine that rate of infection in the TSS cohort with data on infections in donors going back. So when we picked up positive donors or donors who had been identified with AIDS, we could look back at their prior donation record over the prior decade or so and determine that by the time we actually executed the TSS, the rate of donations by infected donors had dropped dramatically.

And as we looked back, and particularly, you know, the gay population in San Francisco, they were actually very active donors prior to the knowledge of transfusion AIDS and deferral.

And we combined that data then with the increasing rate of HIV in the San Francisco community through the San Francisco Men's Health Study. And compiling that data, we ended up with this figure, which is the risk of HIV in transfusions by transfusions in San Francisco prior to antibody screenings.

So again, antibody testing was implemented in the early '85. The TSS allowed us to fix, get a fix on the rate of infection just before screening. But then by combining those data on the rates of donations by gay men and the HIV expansion in the population, we could show that the risk had increased really dramatically to over 1 percent in 1982 before we realized this risk was serious.

And then you can also see the dramatic positive impact of high-risk donor deferral following the definition of the first transfusion AIDS case that came from San Francisco.

So the other approaches that were used then, the prospective risk measurement study. So once we had screening in place, we did have breakthrough cases, and I'll show a few slides on those. And early on, they were fairly frequent because the first-generation tests weren't that good.

We also did studies, large studies, of infections in donors who tested negative, and I'll show you results of that study.

And then the fact study led by Ken Nelson enrolled a fairly large number of recipients, I think in the range of 50,000 in several high-risk cities and collected samples pre and post-transfusion, and was able to document the rate of seroconversion of donors to HIV, HCV and HBV. And then we also faced a request to consider p24 antigen testing that I'll share.

So this was a study that I was involved with with Girish Vyas in San Francisco where we actually tested 75,000 donations from zero negative donors, isolating the PBMCs and doing pooled culture and pooled PCR. So in a sense, this was the first mini pool testing which we still do for NAT testing.

So what this ended up doing was identifying through the culture and PCR one infected donor that had been missed by the early serologic testing. So this was a huge study. I don't know how much it cost. A lot of work and -- and yet it only detected one case. So your precision of

that -- and this was when we were still running early generation assays.

So these points here represent the measured risk in that study, and then as I mentioned, Ken Nelson, in the fact study measured the risk of seroconversion in Houston and the Baltimore region.

So these were really the last direct measures of risk-based on actual testing of either large numbers of negative donors or seroconversion rates in recipients.

I want to mention is p24 antigen controversy, because it actually evolved into this committee. So actually, interestingly, Susan Stramer, who was an avid at that time, reported with JPLN (phonetic) the first analysis of seroconversion panels that led to the identification of p24 antigen, preceding the detectability of HIV antibody.

And Roger Dodd, who's here speaking, with Lou Barker (phonetic), wrote an editorial that accompanied that early paper.

So this led to a strong interest on the part of FDA and the industry to assess the utility of p24 antigen testing. And two large studies were executed. One was, again, led by Harvey Alter and Jay Epstein. And that looked at the frequency of p24 antigen in half a million antibody-negative US blood donations and no antigen positive units were identified.

In parallel, the NHLBI funded a study using the TSS repository to identify donations in that earlier repository from young men living in high-risk zip codes.

And we tested them for p24 antigen, and I'm not going to going into the details on this slide, but the bottom line here was we were able to focus the testing on a subset of repository samples, about 9,000 that were, again, negative for HIV antibody but -- but were from high-risk or higher risk zip codes and young men.

And we found zero positive antigen positive units, resulting in an estimate from that extrapolated estimate of less than one in 2 million donations would be antigen positive, antibody-negative.

So this is, you know, the kind of large studies that you have to do to try to estimate risk, but then you get zero yield. And is that enough to say, we don't need to do this?

At that time, the FDA BPAC committee voted to not recommend antigen testing that was overridden by the FDA, was a strong pressure from Congress. And that actually led to the decision to not have any blood bankers on BPAC. And that led eventually to the decision to establish this committee. So an interesting story.

So when we got to this point, we began to think about, okay, we can't measure risks, so how do we estimate it? And we realized -- and again Roger will go into some of these as well.

We realized that the risks really fall into four different potential sources. Window period, meaning that period before the markers become positive, where people can be infectious and donate.

So-called immunosilent carriers, which are people who are infected but never formed the markers that we test for.

Testing errors and viral variance, that these viruses can evolve in diverse HIV strains or hepatitis, et cetera could be missed by current tests.

And we don't have time to go into detail, but the bottom line is that extensive studies really have disproven the existence of immunosilent carriers for the major virus testing errors are extremely rare, especially with current automation.

And viral variance, although they are occurring and they can be missed by tests, the companies are really aggressive, and we're all involved in monitoring for viral variance. And when they are detected, the assays are fixed. So this is really a very small contribution.

So the major risk is really the window period infectious risks. And again, Roger will talk more about incidence and current and recent risks, and present the latest data.

But the general premise is that if we can measure the incidents of infection in donors and we know the window period that precedes the detectable markers, we can estimate residual risk by mathematical formulas.

We can also project the yield of a new test by multiplying the incidents rate times the window period closures that that new test achieves.

So again, I'm not going to go into any detail here, but a lot of work was done in the early '90s to really develop and refine these models, both by the Red's (phonetic) program and by the Red Cross. And for all three viruses, these had been extensively utilized to estimate residual risk through that incidents window period modelling.

In addition, there've been look-back studies and extensive work to characterize the infectious window period. And I'll give you a taste of that in a minute.

This is a slide that, again, Roger will show later, but I'll just mention because it was really a seminal study led by Lyle Petersen at CDC, now the head of the arbovirus division, where he compiled data on seroconverting donors.

And there were 179 donors who seroconverted where the prior donations were transfused to patients, and those patients were tested. And 36 of these became infected. And we'll look at that distribution in a minute.

But the analysis showed that if you were donating at short intervals, so if your prior negative donation was given within three months, 76 percent of the time, that unit transmitted HIV. Whereas as you go out in time, the rate of transmission drops.

And through a statistical analysis, Glen Saton (phonetic), Lyle Petersen developed an estimate that the infectious window period with that first-generation test was 56 days, and with the second-generation test, 42 days.

Now, a lot of work was done by multiple groups to then evaluate how good were newer assays at reducing that window period. And you can see here that the transition from the early antibody test to the second-generation antibody test reduced the window period pretty substantially by about 20 days. And the antigen and nucleic acid-based testing would further reduce that window period.

So this led to the principle that we could reduce the infectious window period by moving from the first to second, to third generation serologic test, potentially adding antigen although we'd shown that that yielded virtually nothing.

And then the ultimate goal was to really introduce nucleic acid testing, eventually hopefully closing the window.

So a lot of work was done. A colleague of mine, Ivy Fiebig (phonetic), led an extensive analysis of seroconversion panels that led to the definition of the ramp-up doubling time and the stages of early acute HIV infection. The so-called Fiebig staging system is actually used worldwide to characterize infected persons and timing of infection.

And we also developed around that time a test we call the detuned or less sensitive antibody test; we call these incidence assays which can detect recent seroconverter.

So all of the detection of very early infection is clustered here over that first month. And we really needed a tool to be able to measure recent seroconverters that can then be used to estimate incidence with greater power.

And this is now being used extensively in the US and internationally, in donor, and other populations to get a better estimate of incidents, including in first-time donors.

So unlike -- as Roger will talk about measuring incidents in repeat donors, with the incidence assay you can estimate incidents in first-time donors.

So measuring the rate of infected donations is part of the puzzle, but the other part is to get infectivity and understanding of what's the minimal infectious dose by transfusion that could infect people.

So Steve Klayman (phonetic), and Nico Layle (phonetic) and I, and a number of groups have thought about that and worked on that, and there's various approaches that can be used. You can have in vitro culture assays, but we now know that those are really insensitive and not reflective of infectivity in vivo.

There's been extensive animal model studies where donor samples have been titered down into macaques or chimps, or animal models like humanized mice to estimate the minimal infectious dose in different stages of infection.

Human case investigation, really this is doing look-back, and I'll show you data on that, and it's quite informative to try to understand what the minimal infectious dose is by compiling the recipient outcome data similar to that Lyle Petersen work but now with more contemporary transfusion.

And so these are the approaches that we used. One other characteristic that we realized is that it's not as simple as just every unit from every donor is the same or every recipient is the same. There's a lot of variables within the donor unit, the viral load, the genotype, all possible mutations, again whether there's antibodies already present in the sample.

There are transfusion factors like, did you leuk-reduce the blood, was the blood stored? All of those influence the infectivity of the unit.

And then there are recipient factors. If recipients already have antibodies and are immune, they are less susceptible, maybe protected. There may be immunosuppression and other factors such as fundamental resistance due to mutations in recipients.

So again, a slide from that that I'm not going to talk about in any detail, Roger will come back to this, but it led to the concept of trying to understand what is that minimal infectious dose, particularly, the infectious period prior to detectability of virus by either individual donation or mini pool NAT.

So a lot of the focus has been on characterizing the window phase infection, and then using that estimate of that duration times the incidents rate to estimate risk.

I wanted to share a few slides though on look-back in positive recipients. Because as I mentioned, in the first year or so after we started screening, a fairly large number of recipients got infected with HIV.

And these were found through look-back, through donors testing positive, and then recipients who were required and appropriately notified recipients of prior negative donations.

So there were, you know, about 40 or 50 infections in that first year or so. And then a smaller number, as we move to second-generation antibody test, but since NAT you can see that that number has been very small in the US. And Roger will present a slide with the latest data from the US Red Cross system.

This slide, you obviously can't see, but I just want to comment Nico Layle, a close colleague, has over the course of the last, you know, 15 years compiled and monitored data from all of the transmissions of HIV identified worldwide from NAT screen blood.

And I just want to make three points here. One is that there were several testing errors were the donors were highly-viremic but the test failed. These were detected in Europe, and they were fixed.

So there were examples of transmissions due to testing errors, due to sequence in single genome targeted which later required -- led to the requirement for dual-target NAT test. They target multiple regions of the genome.

A second point is one of these was a breakthrough case from a pathogen-reduced product. So this was a methylene blue treated FFP that transmitted. So although pathogen reduction is great, and I'm a strong advocate, we shouldn't be convinced that it's an absolute safe method and, clearly, testing will continue to be needed.

All of the other cases here, with the exception of this one here, will do the mini pool NAT. So they were low viral load units that were missed because we used -- probably missed because we used mini pools of six to 16 donations to do the testing rather than individual donation NAT.

Most of the world, to be honest, is converted to ID-NAT. In South Africa, and I'll show you data from that, has extraordinary rates of infection and NAT yield. They reported and have a paper coming out now, the first case of transfusion-transmitted HIV that was missed by individual donation NAT.

This is data from South Africa. We worked closely with Marian Ramilian (phonetic) and her team, and you can see that they get very high rates of HIV. There's actually a paper in press on ten years of yield. But you can see here in over six million donations tested, they picked up, you know, over 11,000 infected donors.

The large majority of those were antibody and RNA-positive, but they did pick up about -- you know, 3 percent of the infections were window-phased. They were viremic antibody-negative donations.

They also picked up small numbers of what they called elite controllers or people who are antibody-positive but RNA-negative. And of note, no detail, but they've actually seen a dramatic increase in this rate of antibody-positive, RNA-negative donations over the last five years.

And as we've studied that, it turns out that donors are giving blood but are on anti-retroviral therapy. They know they're infected. They're taking anti-retroviral, and they're donating anyway.

And so they are RNA-negative and antibody-positive because they're supressed. And we're seeing the same thing in other countries around the world and beginning to look at it, and unfortunately seeing it in the US.

So a new concern over people presenting to donate blood who are denying the risk and on anti- retroviral, or potentially taking PREP, Pre-exposure Prophylaxis and donating, an area of strong focus of the TTIMS group.

But I want to focus then on this viremic antibody-negative units because what Marian and the team have done, they've done viral load and understand the distribution of viral load during the pre-seroconversion window phase.

Many of these were very low viral loads, so the only way to quantify them was with replicate testing and plus one (phonetic) analysis. These units here that are antibody-negative and RNA- positive are almost certainly all infectious.

In contrast, once you've got antibody and there's elite controllers that are antibody-positive and RNA-negative, and probably the RAT-suppressed patients, the viral loads are so low and the antibodies neutralize the infectivity. So we believe that very few of these are infectious.

Now, in Marian's paper and relevant to the point I want to make to this committee, we still do mini pool NAT in the US. We do pools to 16 on the Grifols platform and 6 on the Roche platform.

So Marian took the subset of the samples that were detected by the South African National Blood Service as window phase infectious and performed multiple replicate testing on both the Grifols ultrio system and the Roche tag (phonetic) screen system.

And you can see that overall the pool testing, when performed on these samples, missed about 8 percent, 8 to 10 percent of the units that were picked up their window phase, when tested by diluted pools, mini pools, were missed. And if you focus then on the antigen negatives, it's even a higher percent.

So this is telling us that we're missing infections that could have been picked up. They could have been picked up, but we picked up so few, and again Roger will get into this that we're tolerating that risk.

So with respect to tolerable risk considerations, the discussion today, I think we have a model here. We're saying we're accepting a very low residual HIV risk because it's -- we can't afford and logistically execute ID-NAT testing here and the risk is so low. But I think that's an object for discussion.

We did develop an international study group which compile data from 20 regional blood centers in 15 countries that were doing ID-NAT and antibody testing, and I want to show a little bit of data focusing on HIV. The same work's been done on the other viruses.

But this compiled data from 12 million donations, over 7,000 HIV infected donations that had been tested for HIV, RNA and antibody in parallel. And what we did was to carefully model the infectious window periods detectable by antigen, by mini pool NAT, by ID-NAT, understand the elite controllers, and we incorporated an estimate of infectivity into that.

I'm not going to show the formulas, but the major point is that we developed the concept we call efficacy. What proportion of total infections that are being given in the blood supply in these different locations are detected or interdicted by different testing strategies, and what's the impact of residual risk depending on which testing strategy you used.

So we developed these models, and assuming that 100 percent of window phase infections concord in RNA and antibody-positive would transmit in a low rate of elite controller transmissions, we were able to express the efficacy of screening, the proportion of total risk interdicted by different testing strategies.

And in first-time donors, you can see that the vast majority of risk -- this ranges only from a 100 to 95 percent. So, you know, 99.9 percent of risk is being interdicted if you do ID-NAT plus antibodies. If you do mini pool NAT, you're only missing less than 1 percent of donations.

So otherwise, I showed you earlier that if you test window phase donations by mini pools, you miss, you know, 10 or 15 percent. Off the overall risk, the vast majority are being detected because the vast majority of infections are the positives by antibody and RNA that are infectious.

So I'm going to skip this, but just to point that actually there's some data supporting here the possibility that you could do ID-NAT and drop antibody testing, especially as we move into

pathogen reduction. And certainly, as we move into pathogen -- I'm sorry. You could keep ID- NAT alone and drop antibody testing.

So these are considerations that we're still weighing, and certainly FDA would need to buy in. Not only for HIV but hepatitis, we have similar work there. And certainly, there's a strong sense in a number of countries are considering dropping HCV antibody testing and focusing on HCV RNA testing.

So just to transition to the end here, toward the end here, we've dealt with HIV, HBV, and HCV. And up till now I've been focused on the residual risk as we've implemented new tests and try to understand the utility of those new tests, the residual risk.

But what's challenged us over the last, you know, 20 years now has been just that annual concern over emerging infectious threats.

It started out, from my perspective, with a phenomenon called idiopathic CD4 lymphocytopenia. This was the concept that people might gave AIDS but test negative.

We did very large studies that disprove that. There's other things like bacteria that hit the radar screen back in the mid-90s, it had been discussed earlier. But it's still a big concern, still a problem even though we've tried to test.

Variant CJD, other things like T. cruzi, West Nile, et cetera. I'm not going to talk about it, Roger will. But those things have been dealt with through implementation of rational screening strategies, all the way to the most recent concern over Zika.

Now when we look at these emerging agents, they're very different than the classic pathogens. So when we talk about HBV, HIV, HCV, these are chronic infections in asymptomatic donors.

And they are transmitted by blood transfusion, we know that, and we implement test, then we can prevent not only transmission but prevent disease. These are disease-causing agents.

In contrast, these new agents we're responding to, many of them create very transient infections and infections like bacteria, hepatitis A, West Nile virus, Zika. These are very transient infections.

There are also mostly zoonotic agents. They are not things that were spreading to each other. They are infections that are spread from animals to humans, for example West Nile coming via mosquitoes from birds.

And many of these have unclear transfusion-transmission risks, so it's hard to do the studies. I'll show you some examples of some efforts to measure transfusion-transmission risk.

But they require large studies and often in locations not in the US because these are not primarily US agents.

And then others don't cause disease. So things like GBV, the TTVs, human endogenous retroviruses, influenza, these can be maybe transmitted but there's no disease consequence when they are by blood transfusion.

So this has led to a conceptual sort of strategy that when we look at a new emerging risk, we can kind of do a variety of studies to understand those risks. We can do screening studies of the donors. We can enrol infected donors.

Most important, we can look at transfusion-transmission to recipients, or do animal model studies to look at infectivity of these new agents in different animal model systems.

And this is work that fortunately National Heart, Lung and Blood Institute has been part of and helping frame out these strategies.

So we now have a kind of a model for how to approach a new emerging risk. I want to just touch on three examples to illustrate the approaches and the findings.

One of them is so-called XMRV, xenotropic murine leukemia-related virus, which was reported in Science as being associated with chronic fatigue syndrome. And in this first Science paper, they had a control group of blood donors and ten percent of the blood donors were positive.

So this led a huge concern, oh, my god, we're transmitting this retrovirus to humans via blood transfusions. So that led to a working group, the Blood XMRV working group, which was funded by NHLBI but consisted of FDA, HSS, et cetera.

And no detail here, but it took years and probably millions of dollars to extensively study the concern over XMRV. Eventually, this was proven to be a contaminant of prostate cancer cell lines that were sent around the world and contaminated this laboratory.

And it was eventually, through a study again conducted by the working group, proven to be false positive, and this was all determined to be contamination-related and this is not a transfusion pathogen.

Not only XMRV but many of these other agents I referenced, the ICL, the PTLVs, et cetera, now are fake news. They are not real, but it takes a lot of work to disprove these agents as real.

I want to touch on dengue. This is after the West Nile experience. Obviously, we started screening, again Roger will present on that huge success interdicted thousands of infected donations, prevented lots of transmission every year in the US.

But dengue we knew has been spread in many regions of the world. There were transfusion- transmitted cases being reported, Hong-Kong, Singapore, later a case reported from Puerto Rico by the Red Cross.

And we knew from studies of donors that there were fairly high rates of dengue viremia in donors that were being observed during epidemics, including in Puerto Rico.

And so that led to concern about the need to screen the blood supply, and indeed screening was implemented under IND in Puerto Rico by the Red Cross for several years.

But a large study was conducted that I want to share from the Registry Brazil program. And this study, actually led by Brian Custer who's here and Ester Sabino, enrolled 50,000 donors in two regions in Brazil, Rio de Janeiro and Recife, coastal regions during a very large dengue 4 epidemic, and enrolled about a thousand recipients who got blood from those donors in these hospitals.

And putting all these together, we ended up with a number of recipients, I'll show in the next slide, who had dengue and those units were transfused into patients, and we ended up with 21 RNA-positive recipients.

Of those 21 RNA-positive recipients who became infected by dengue around the time of transfusion, seven of them were unequivocal transfusion-transmission cases.

So this more than doubled the world's reported cases of transfusion-transmitted dengue. But 15 of these units were transfused into -- I'm sorry, 15 recipients got infected with dengue, but they didn't get it from the supply. They got it from the mosquitos around the time of transfusion.

So two out of three infections that occurred in recipients were not transfusion-transmitted. They were background transmissions via mosquitos. And this just sorts these cases. Again a number of the recipients were antibody positive, so less informative. But really again, we had six probable and one likely case.

But the important finding from the study was, one, there is transfusion-transmission. About a third of positive units transmitted. But when you look at the outcome of the recipients who got infected from transfusion, either from transfusion or coincidentally from mosquitos, there was no difference in the clinical course of those patients compared to background control recipients.

So no disease. Transfusion of dengue by -- dengue transmission by transfusion goes in the immunosuppressed patients. The disease is an immunologic response syndrome.

So although dengue is being transmitted during epidemics, it's not causing any disease based on this study. So the decision was made to stop testing, and still to this day, dengue screening is not performed in any region of the world.

Then Zika hit, and of course, Zika had a huge outbreak in Latin America, particularly South America, Central America, and the Caribbean. And it was a massive explosive outbreak in 2016, and then it disappeared in 2017 and has not come back.

So we don't understand why. I think it will come back. This is the data from Puerto Rico. So when we started screening in April, as required by FDA, the very first day, we picked up five viremic donations.

Doing serologic testing by this point in time using the donor population, about 4 percent of the donor pool in Puerto Rico was already seropositive to Zika. So they had already been infected and we didn't know it.

But you can see a very high peak that almost two percent of donations, and then as the epidemic waned it dropped off by the end of the year and there had been no Zika NAT yield cases in Puerto Rico for the last almost two years.

So an amazing outbreak, like about 23 percent of the Puerto Rican population got infected during this one outbreak. So a huge outbreak, but the question was, were these unit transmitting?

There were no proven transfusion-transmission cases from Puerto Rico. There are only a couple reported from Brazil.  And that led to the need to understand those infected donations and work from Philip Williams and in collaboration with Roche and our team has sorted them into whether they were detected in the window phase, prior to antibody versus the later phase where the antibody is positive and the viral load is suppressed.

And these red dots are actually continental US yield cases which tend to be travel-acquired and late.

So a key question became, what's the infectivity of these donations as you go through the acute viremia pre and post-seroconversion? And again, this is data from Susan Stramer, just looking at the US cases and Roger will come back to that later.

But to look at these infectivity questions, again, NIH stepped up and we had funding to execute a very large natural history study of viremic donors where we enrol donors and track the rates and kinetics of viremia and persistence of virus in different blood compartments, and most importantly looked at the infectivity question.

And we've infected a large number of macaques, exposed them to blood from infected donors in different stages of infection, characterized the dynamics of replication of the virus in these macaques, and then now how have executed studies to estimate the minimal infectious dose, both during the ramp-up phase prior to seroconversion and now looking at post-seroconversion viremia, and then also looking at the efficacy of pathogen reduction.

So taking high, very high, titer units that have pre-seroconversion virus, subjecting them to pathogen reduction and then infecting chimps or inoculating chimps just to confirm that the pathogen reduction could deal with the very high titer peak viremic units.

So this study is still in progress, but basically to finalize, the finding is that you will actually require a fairly high dose of virus to transmit into macaques, in the range of close to 3,000 titer of virus in the inoculum to infect macaques.

So this is not that infectious a virus if you get it from a transfusion. If you get it with a mosquito bite, the mosquito saliva increases the infectivity and the replication of the virus.

So transfusions though from human to human, actually you require a fairly high dose of virus to transmit.

In contrast, if you take a mouse and you immunosuppress the mouse to knocking out immune response genes, the mice can be infected with quite low doses.

So this is, you know the kind of work that we need to do to answer the question of, is screening effective, do we need ID-NAT, is mini pool sufficient, which is what we're moving to, et cetera.

So just to close, with two final slides, you know, this kind of concept of a pyramid of understanding, we need good test data, we need to measure the prevalence and incidents in donor populations.

Sometimes these studies are done here. Sometimes the best place to do the studies is where the outbreaks are happening, where the viruses are.

We need to understand the performance of our test, the analytic sensitivity of both molecular and serologic test. We need to understand infectivity. We need to understand transmission risks. So actual transfusion-transmission risk.

And then finally, we need to understand the efficacy of the technologies, both screening assays and pathogen reduction, and this concept of percent risk avoided but different testing strategies.

Then finally, you know, we really do need to ask the fundamental question of, can we afford zero risk? What is the cost-effectiveness of different testing technologies?

So my last data slide is from Brian Custer who's here, who's been analysing this question of cost- effectiveness or cost utility for decades. And this is a compiled data, looking back to data from very early studies estimating the cost utility of antibody testing, which confirmed that actually HCV antibody testing was cost-saving.

It costs as less money to screen than we were preventing infections and disease in recipients. A no-brainer.

Early HIV antibody testing in bacterial culture is essentially very cost-effective. But as we go down this list, even things like West Nile testing relatively cost-effective, less than a million per quality but not great. T. cruzi testing pathogen reduction -- but then as we get down to things like Zika testing, $300 million per quality-adjusted life year.

So we really have to use the health economic process and the risk-based decision-making process to inform our decisions. And I think this retrospective review of what have we learned and historical, both lab data, infectivity data, et cetera, but also cost-effectiveness data I hope is useful to the committee in its deliberations today.

So thank you for your attention.

The Chairperson: Thank you, Mike, for a very informative discussion and thank you also for all the work you've done over these many decades along with your partners at HHS and around the world. Questions for Mike?

Dr. Josephson:  This is Cassandra on the phone.

The Chairperson: Yeah, we can hear you, Cassandra.

Dr. Josephson: Okay. You can hear me? Okay.

Mike, I wanted to ask with the quality-adjusted life year, and I know Brian's in the room, whether you could comment on paediatric cases specifically and how an analysis could be done to kind of look at their quality of life years as opposed to adult's life. I don't know how this analysis was done.

Dr. Busch: I'll give that one to Brian.

Dr. Custer: All right. Thank you, Cassandra, for the question.

So most of the analyses that we do, we do attempt to try to look at different blood recipient population age groups. And so while there's a summary measure that's been on the slide right now, we have looked at the differences, and of course, as you would expect because there's many more life years to be gained in a paediatric population, screening for infections to prevent transfusion-transmission tends to be more cost-effective.

But for example, with Zika, it's not going to ever be cost-effective in that patient population as compared to an older transfused population. So we are cognizant of that, and there are some methods we can use to try to get estimates for paediatrics.

Dr. Josephson: Okay. So I just wanted to make sure that when we are talking about risk tolerance, in all infected phases that we remember that that is different, and (indiscernible) obviously is different or -- or infection if it's transient. I just want to make sure that we keep that point in mind.

Dr. Busch: Yeah, I would just add that in the most recent analysis that Brian, and Sue (phonetic) and colleagues have done, the other consideration that's unique to Zika is, of course, if a pregnant woman gets infected there's a risk of maternal/fetal transmission and that, you know, terrible neurologic outcome.

So that was factored in. So I think, Cassandra, again Brian's work and others have looked at age- specific cost-effectiveness and the unique characteristics of certain agents like Zika.

Dr. Josephson: Thank you very much.

Dr. Custer: So if I could thank you again, Mike, for the great talk.

I wanted to turn to the data that you presented suggesting for the South Africa context that 8 percent of -- if they were doing mini pool testing, they might be missing 8 percent of infections.

I think that that may be true for South Africa, but I think we have to be very cautious about implying that that might be the situation in the US for those reasons that the donor base is quite different. The burden of infection in South Africa is also quite a bit a different.

But in particular, we are cognizant of some pretty strong difference in inter-donation intervals that are evident in the population in South Africa compared to the US.

And so we may not have quite such a profound effect of missing that high number of infections in the US context.

Mr. Busch: Yeah, great -- great point. And just to expand a little bit, in South Africa, we've looked very carefully at the inter-donation interval distributions of the seroconverting donors and their NAT yield donors. And there are people give very consistently through the course of acute infection.

And over time, again, the seroconversion intervals of the infected donors are very consistent, and the viremia rates and the window phase are just perfectly distributed.

So they don't take temperatures of donors there. And because it's a heterosexual epidemic, they don't ask questions that would cause people to self-defer.

So there are factors that may be the basis for the difference that Brian is referencing, which is when we look at US donors who seroconvert, they're not coming in right after they become infected.

There's a delay in donation. First reported in a paper George Schreiber led, you know, 15 years ago, but now corroborated by the TTIMS program with the particular bounce of people coming in who are seroconverting about a year after their first -- their prior negative, and that's because we collect people through drives (phonetic) on an annual basis. So you're absolutely right.

On the other hand, I think the NAT yield rate data is a reflection, and if you would plot the viremia of the NAT yield donors, my bet is those are fairly evenly distributed. So that NAT yield rate would be able to be used to impute what the ID misses.

Dr. Custer: So sorry. Just to follow up on that. The transfusion-transmissible infections monitoring program is going to have this viral load data available. And so we'll have some information to provide some insights around that topic.

The Chairperson: Dr. -- Mr. Skinner.

Mr. Skinner: Mike, great talk. I didn't want to just sort of either -- either push back or query one comment that you made, and maybe I misinterpreted it.

There isn't an established acceptable quality for blood safety to my knowledge, and you made a comment that sort of like the million-dollar threshold maybe was acceptable. I mean in general health, it's around $100,000.

And so I'm not sure that we should assume that blood safety ever is going to be measured on par with what are sort of typical cost per quality thresholds in health.

And maybe that's part of the topic of this discussion, but equating safety and risk, it seemed like you had made a judgment of what the threshold was, and I'm not sure that has been defined and accepted. But maybe -- certainly you --

Mr. Busch: I agree with that. There are other countries. Italy has considered this in a pretty formal way and have kind of come away with that million-dollar.

So there are countries that are, if you will, ahead of us in terms of facing the challenge of tolerable risk and trying to incorporate health economics, and you know, risk assessment into that.

But that's really part of the risk-based decision-making process.

Mr. Skinner: I'm not saying I disagree with you, just we haven't gotten there in the United States yet.

Dr. Custer: Sorry, Mark. I guess I'd like to just follow up on that comment. You're right that we haven't explicitly gotten there, but through revealed preferences we have gotten there.

The choices that we make tells where our society is placing the value. And so as long as we make decisions to adopt technologies that are $100,000 for quality-adjusted life, that says one thing.

But we make decisions to be well over a million dollars for quality-adjusted life here. And so it is revealed preference, but it's not an explicit one.

Dr. Katz: Well, I always try to bring back the title to a chapter Alan Williams from FDA wrote. Maybe it was still there, you'll see it then. And the title was, There's Something About Blood.

It's very clear that thresholds that we use for breast cancer screening, or prostate screening, or what not are here, but blood safety decisions, expressed as Brian exhibited, are almost over a magnitude different.

Question is, is that the right way to look at it?

The Chairperson: And further questions? Dr.Verdun?

Dr. Verdun: So just a point. I think that from an FDA perspective, we're often met with emerging infectious agents. And so I think it's -- you know, it's quite convenient and, you know, it's helpful in some ways to go back and do a post-hoc analysis about cost and cost-benefit.

But I just want to make the point that -- that often, we're faced with emerging threats, and having to make decisions about testing in the face of quite honestly a crisis at that time. And so I just wanted to make that point in terms of the discussion here.

Dr. Busch: Yeah, I want to totally endorse that, and you know, certainly proactive risk response by FDA in the industry is good, but it needs to be done in the context of studies that are evaluating the appropriateness of that response and a willingness to reverse it. And certainly, the recent decision to allow mini pool Zika is good.

You know, if we don't -- so there's that process of not getting stuck with –

Dr. Verdun: Absolutely.

Dr. Busch: -- and antigen. You know, but we should be getting rid of surface antigen testing, etcetera. So the cost --

Dr. Verdun: It definitely needs to be fluid in terms of our decision-making and not fixed. But I just wanted to make that point that we really often, you know, at FDA we are faced with making the blood supplies safe.

And if we have this emerging threat, we often have to make those decisions at that time. And I just wanted to make sure that we appreciated that point as well.

The Chairperson: Thank you. Dr. Sloan?

Dr. Sloan: Yeah, likewise we heard from you, Mike, that there's an emerging change in the populations donating blood in terms of HIV and that some people on anti-retroviral therapy are donating blood with very low -- low viral titers.

Given that, does that call into question a strategy in which one drops the antibody test?

Dr. Busch: Yeah, I know, for HIV in light of that, no, you cannot drop antibody testing.

Because, you know, again careful studies are going on on the infectivity of these -- these, you know, denied ART and prep breakthrough infections because the molecular and serologic test will not perform the same if you supress viremia quickly or if you get infected on prep.

So a lot of work needs to be done. But no question, I agree with you, not dropping HIV antibody.

The Chairperson: Okay. Good discussion. Thank you so much, Mike.

And obviously, we got very quickly to the point and purpose of this meeting as we go forward.

Dr. Dodd is going to further this discussion with the current landscape of infectious disease testing. Roger, welcome.

Landscape of Infectious Disease Risks

Dr. Dodd: Well, thank you very much, Jackie. I was sitting there, getting more and more depressed because by contrast to Mike's talk, I feel I'm giving the sort kindergarten version.

And I hope that the committee and the audience think I've underestimated their capacity. I just sort of took a different line, I guess, and I apologize for stepping back a little bit.

So my title, which I was asked to talk to, is Landscape of Infectious Disease Risks. And there are many different sorts of landscapes. Perhaps you'll think my talk's like this, but these are intended to illustrate where we might or might not be with transfusion risk.

So there's this, and there's this. And I hope to convince you by the end of my talk that the current landscape for transfusion risk is more like this.

But we're vividly reminded particularly today that this particular landscape can be seriously disrupted by, for example, a hurricane. And we've had a few hurricanes to face in our time working in blood and blood safety.

So some disclosures, and I want to point out that at this point, my opinion is not necessarily those of the Red Cross. They're primarily mine.

So the focus is on transfusion-transmissible infections, and I'm going to talk about TTIs. I'm going to talk about the interventions that are in use, the sources of risk, the assessment of residual risk, and I'll go into a little bit more detail as Mike pointed out.

And I'm going to give you some current estimates that I think are pretty much where we stand today, spend a little time on emerging threats because I think this is what we've got to look to for the future, the decision-making process, if any, and a brief commentary.

And as Mike pointed out, there's really two different groups of TTIs, Transfusion Transmissible Infections. They are, what I would call for the purpose of this talk, the traditional TTIs which rather conveniently seem to me to predate the year 2000. So they were the last millennium threats.

They generally were chronic infections, generally parentally transmitted. And the key villains I guess were hepatitis B, hepatitis C, HIV, HTLV, syphilis, and malaria.

And then there are the emerging TTIs, which are current, again post the year 2000, and perhaps unexpectedly have turned out to be mostly acute, self-limiting infections.

Usually, they've been arthropod-borne or zoonosis. And the examples that we've had to deal with have been Variant CJD, West Nile, dengue, T. cruzi another Chagas disease, Babesia and Zika.

Bacteria, I'm not discussing here, but other than to point out that the current observed risk of sepsis from bacterial contamination of platelets is about 1 in 100,000 products transfused.

But if you'll look much more carefully, this is a gross underestimate. And you might want to keep that in mind as we talk about other risks along the way.

And we really don't know what's happening for the future. There's only a very limited capability of predicting an emerging infection.

The interventions, I think this is the kindergarten part are quite clear selection of donor populations and assessment of donor suitability.

And it's important to note that at least in the US perspective, if you take a look at the frequency of infectious disease markers among first-time donors, that is people who've not given blood before or have not been tested before, they are markedly lower than the most estimates of the community frequency of such infections.

So by going to the right places for donors and asking the right questions, we've already sorted out the majority of the potentially infectious donors.

Donor suitability questions have some efficacy, medical questions and of course, as Mike pointed out, body temperature and other brief physical inspection, questions about travel, questions about behaviors, again, lead to the deferral of inappropriate, many inappropriate donations.

And deferral records, indeed, thought to be important although that's somewhat controversial. There have been studies suggesting that it's not particularly effective in preventing further transmission of disease.

But for some cases, once you're out, you're out forever and it obviously makes, at least, philosophical sense.

Donation testing, we tend to think of as the most important and effective intervention both sensitive and specific. And this is the area that we're going to focus on.

Lookback has some value even if it's only to alert individuals who might not otherwise be aware that they have been infected by the transfusion.

And of course, quality systems and automation have essentially eliminated some of the worst errors in the arena of accidental release of unsuitable products. And we can rely on those.

And just as a reminder, the nature of donation testing right now is there are really three types of test -- we test for or of markers that we test for antibodies, antigens, and nucleic acids.

HPV is essentially unique in as much as we currently explicitly test for three markers, the antigen, and antibody, and nucleic acid.

HCV, antibody, and nucleic acid, and there are some tests that incorporate tests for antigen which is really not necessary in the face of nucleic acid testing, similarly for HIV.

But so-called fourth generation tests are becoming the only tests to be available in the US and we will inadvertently, if you like, be testing for antigen as well. But they are really superseded by nucleic acid testing.

HTLV, only for antibody.

T. cruzi, Chagas disease, only for antibody.

West Nile, Zika, and Babesia, effectively detected by nucleic acid tests.

Babesia, as licensed by the FDA, was a combination of antibody and nucleic acid testing. But that particular approach is really not now available for, basically, for reasons outside of science. And we believe that effective testing will be achieved via a new level of nucleic acid tests.

The sources of risk of infection in this context include an inaccurate donor history, the wrong question, or the wrong answer, the absence of a test, the failure of a test, and test inability to detect some infectious donations, the window period. And this is the only thing that really is critically important at this time, and clerical, and quarantine error have been minimized.

So I'm really going to talk only about the window period from this point on. So the definition of the window period in the context of transfusion is the time period during which the infectious agent is present in the blood and can infect the recipient but cannot be detected by the available tests.

It's usually initiated shortly after exposure at the time when symptoms are absent in the donor and the length of the window period is inversely related to the sensitivity of the testing system. So for NAT testing, we have the shortest window period. Antigen, slightly longer and antibody, longer still.

And Mike had already put up and discussed this particular finding of the Petersen and others and these are actual lookback data. The lighter line represents the data that we observed.

And it's the frequency of infection among recipients of donations by time from the positive donation back to the prior donation which was the one that was associated with the look back and the infection.

And the smooth line is the model for the window period at that time, was of the order of 40, 45 days. And since that time, the window period has been -- the reduction in the window period has been assessed through the sensitivity of the tests applied.

And again, Mike showed this and the point really is that the nature of the nucleic acid positive -- does this thing work, yes, it does -- the nucleic acid positive component of the evolution of infection varies very much.

And it's very long for HCV, a very long period when nucleic acid is the only detectable component before antibody and a very slow increase for HBV. So the window period differs and the impact of different sensitivities clearly will differ also.

So residual risk, as we think of it in this context, is the likelihood of infection from a fully-tested blood component. And it can be looked at, as Mike pointed out, by direct observation. And this has been done in the context of hepatitis, West Nile Virus, and Babesia.

By lookback, in terms of looking at the infectivity of prior donations, this has been done for T. cruzi, HIV, HTLV, and hepatitis B, the latter from sample libraries and from window period estimation. And as Mike points out, it's pretty hard to do anything about window period estimation these days.

So how do we estimate the residual risk from the window period, I commented on what the residual risk is. And what we are really looking for is the donation will be given during the window period that has a potential for a virus or a pathogen to be present.

It doesn't actually consider the issue of infectivity. So it is a worse case estimate. It's a potential infectivity. And again, Mike pointed out that we don't know that much about infectivity per se.

And risk is the incidents, that is the frequency of new infection in the donor population, times window period.

An incident is derived from donor testing observations, new infections per person-year, and the window period as we've discussed. So this requires pretty good knowledge of the dynamics of early infection and test sensitivity. And it assumes that all post-window period infectious donations are detected through testing.

And I'm going to show some Red Cross data which is based on confirmed positive tests. It represents about 40 percent of the US blood supply or about 5 million donations per year.

This is the incidents of new infections per 100,000 person-years among repeat donors to the Red Cross during periods 2007 through 2016.

And a couple of points in general, all markers have been declining in incidents. HCV not as a statistically significant decline because of this bump here. And these data are always bumpy, so we shouldn't read too much into this.

But HIV and particularly HBV have been statistically significantly declining over the years. And the current figures are, for HIV, 1.27 cases per 100,000 person-years of observation; HBV, 0.66; and HCV, 1.42.

These data were put together by Lauren Crowder in the (Indiscernible) who's sitting here in the room. Thank you, Lauren.

And if you look at these in the context of residual risk, and frankly, I'm a little surprised how much it has gone down.

But the current data that Lauren produced indicate that the residual risk by this method for HIV is 1 in 3 million products, for hepatitis B is also 1 in 3 million, and 1 in 3 and a half million for HCV. This is a long way from where we started when, as Mike pointed out, 20 percent or 30 percent of recipients would show signs of hepatitis post-transfusion.

HTLV has also been an issue of retrovirus. And there is a published window period-based estimate of the risk of HTLV, 2007, 2008, 1 per 3.4 million and more recently learnt, let's take another look with Red Cross data, and it's still 1 to 3.3 million. We do see incident cases of HTLV in the US population.

Transmission has been identified by lookback and clinical disease is infrequent among test- positive individuals. And more importantly, current thinking is that leukoreduction may, in fact, eliminate transmission risk because this is a cell-associated virus and doesn't seem to be effective if free in the plasma.

So these estimates don't consider leukoreduction. And in the UK, they have made changes and policy on HTLV testing on the grounds of the elimination of infectivity or assumed elimination of infectivity by leukoreduction.

I put this up, as did Mike, as an example, first of all, if you will, of the successive older measures we've put in place since 1969. This is Harvey Alter's data.

But to point out that these studies were observational looking for hepatitis in patients. These are patients with NIH, but now, this is no longer possible because the frequency of infection is essentially zero, at least, in this study.

What about observational studies for HIV? Well, this represents I think four published and one unpublished data of point representing all cases, all recognized cases of transfusion- transmission of HIV in the United States since the implementation of nucleic acid testing in 1999.

So there were five events. And it's very interesting talking about sensitivity of testing to point out that in two cases, two products were transfused, but only one of them caused infection.

So this is the red cells and the fresh-frozen plasma from one donor. Only the recipient of the fresh-frozen plasma was infected. The same for another case in Georgia and one case back here were both were infected.

So it suggests that even with the current level of testing in mini pools, we are getting close to the detection limit, at least, for infection from red cell product.

So let's move on to merging infections. I think that we all know that AIDS was a dread disease, and it set the zero-risk standard that seems to be what we anticipated these days.

And subsequently, consideration was given to other transfusion-transmitted infections, but I think we really don't know if there was a clear and explicit decision policy in this context.

Do we really believe in zero-risk, or perhaps more realistically, as low as reasonably achievable? Do we think about risk-benefit? Do we think about cost-benefit?

And is there room to move towards risk-based decision-making? I'll talk about a little bit about this towards the end. But examples that we've had to deal with, I've already listed.

I put dengue and chikungunya here because they were considered as potential threats. But in actual fact, no organized effort was put into either of these. No decisions were made about continued testing.

And it is interesting, I and my colleagues spent quite a lot of time talking, talking to industry and talking to others about dengue. And we talk to people and areas of high prevalence of Dengue.

And their perspective was relative to the problems of a dengue outbreak. A couple of cases in blood recipients were basically totally irrelevant in the context of broad public health decision- making. So for example, Brazil sort of poo-pooed the whole idea and said, no, we don't need to do this.

So it's interesting to think about broad public health in the context of comparison with transfusion, medicine safety.

So variant CJD, of course, a uniformly fatal dread disease. It was perceived as a potential threat of transfusion transmissibility. And preventative measures were initiated prior to any evidence of transfusion-transmission.

I think this is probably the only case I know where this really happened. And I think the situation is understandable because the pathology of the disease was not well-understood. Certainly, it was recognized that it was far more involved in lymphoid tissue than it was classic CJD.

And of course, there was and still is no test available. And the United States regulators established donor deferral criteria based on putative exposure to the agent which really boiled down to time living in the United Kingdom and other parts of Europe.

There was a careful effort to balance the risk control with the impact on blood availability. And eventually, it was considered that maybe about a 3 percent donor loss will be tolerated against the potential benefit of removing exposed individuals from the donor pool.

But as of yet, and perhaps as of ever, only four transfusion-transmitted infections have been definitively identified globally. Three of those had disease but all these cases occurred in the UK, nowhere else in the world. We'll return to that a little bit later.

West Nile Virus made an unexpected appearance in the United States in 1999. And there was an extraordinary rapid spread throughout the North American Continent and now through both North and South America.

It was, of course, an acute infection, mostly, asymptomatic, but potentially fatal. And there were over 2,000 severe neurologic disease cases within the year 2002.

And this probably represented several hundred thousand infections overall in the U.S. But the important issue from our perspective, because we really didn't think too much about this, although the CDC, Petersen, and his colleagues did make an estimate of the potential risk.

And that was published just a few days before the first transfusion-transmission was reported. But in 2002, 23 cases of transfusion-transmitted infection were reported. So we reacted to a finding of transfusion transmissibility, not the presence of the infection.

And mini pool-NAT was implemented in 2003. It took eight to nine months, generally considered to be a great success, although not by all. And since that time, there have only been 14 breakthrough cases of transfusion-transmission.

And the infection, it was infection that was not detected by mini pool-NAT. And as a result, individual donation-NAT is implemented in areas in times of high incidents. And this has required quite a lot of work and a lot of interface between blood centers and rapid reporting.

And this, I think, yes, this is a Mike Busch slide. I think this is here just to make a point that this turns out to be the sequence of events in early infection with West Nile Virus and other viruses of this type.

And RNA and infectivity are present for about a week before the antibodies start to appear. Once antibodies have clearly established, there seems to be essentially no evidence of transmissibility by transfusion somewhere around this point and later. So the impact of individual donation testing is really around this part of the curve.

The agent of Chagas disease in the United States was a different story. It was known that Chagas disease was present in the United States. And there had been a small number of reported cases, seven overall in the US and Canada.

And after a lot work, a lot of assessment of the prevalence of this infection in the United States, testing was initiated in 2007. We started out with universal testing, but almost all positive donors had been infected many years previously, generally, in their home country.

Specific studies after the implementation of testing revealed no incident cases in about 4 million person-years of observation. And we and the FTA agreed to step back to one-time testing. So each donor was tested only once and that lasts for the rest of their donation history.

And subsequent to 2007, no transfusion-transmissions have been reported in the United States. As it turns out, at the time of the initiation of testing, lookback on 242 prior donations from seropositive donors revealed only one infectious donation which did infect two recipients. So even though we did a lot testing, the actual infectivity that we were preventing was pretty infrequent.

Babesia is an interesting case study. It's an emerging test situation. Babesia microti is currently the most frequently reported transfusion-transmitted infection.

It's been under investigation for many years. And also, for quite a few years, formal studies of testing have been undergoing -- been undergone under investigation on new drug procedures.

And there is now a licensed testing for antibodies and/or DNA. But as I mentioned earlier, this particular test is not available for non-scientific reasons.

And in the future, likely, RNA only testing by most sensitive procedures may, indeed, be all that's necessary. And studies have actually demonstrated the efficacy of this effect.

And these were a couple of general studies, this was a report from Barbara Herwaldt (phonetic) from CDC about transfusion-transmitted Babesia up through, I can't read it, 2006, I think. There were 164 cases.

And subsequently, these reported cases and the great number of percentage of these were in seven states which we probably know about.

And these are some data actually from New York which indicate the increase in community- acquired cases of Babesia and also transfusion-transmitted Babesia, most of which occurred in the late summer.

So this is an effect that's quite significant. These are some data that were published from the Red Cross, Susan Stramer's work in the New England Journal and this represents, sorry, the pattern of testing with DNA only, DNA plus antibody, and antibody only, and again, showing this seasonal peak.

And the important thing about this testing was it enabled Susan to figure out what was actually going on as the result of testing.

And in specific areas in New England, she was able to follow 386 -- 390,000 donations which were associated with zero transmissions of Babesia whereas in exactly the same areas for a variety of reasons a blood was not screened for quite a long a time and there were 23 cases in

1.16 million.

This turned out to be highly statistically significant. And the odds ratios was about 15, that is if you didn't get tested blood, it was 15 or 16 times more likely to get Babesia than if you had tested blood.

So I think this is a demonstrated success. The interesting thing is, and we will come back to this in a moment, that the structure for testing at the moment is that it's done at the request of hospitals. It's the hospital that decides whether or not to take a tested blood.

Guidance has recently come out from the FDA, at least draft guidance. And they have suggestions for testing or donations in 14 states and DC. And I think there will be some discussion about that are coming up.

Zika virus, Mike talked about at great length. It's a dengue-like virus. It's associated with explosive outbreaks. And what's the particular concern here in the United States is that it appeared in Brazil, and Caribbean, including Puerto Rico.

There were some imported cases in the US and a very few locally transmitted cases. There was recognition of the threat to the fetus with a very serious fetal disease syndrome, including microcephaly.

And the US Public Health Service committed to protect pregnant females from infection. And this resulted in the requirement for nationwide individual nucleic acid testing for donations.

This was a monstrous effort to get this implemented. By my account, it resulted in about a nine- fold increase in the amount of nucleic acid testing that had to be done.

And the estimated cost of this effort was about $139 million per year. Mike gave an even a higher cost. But there has been a subsequent decline in cases in the Americas, and we are not seeing any cases right now.

The Red Cross also published its findings here and I would actually, in the end, just draw your attention to this figure which was that the finding of cases cost about $5.3 million per infected donor, assuming that all donations are infectious.

And as I pointed out earlier for West Nile Virus, this is not necessarily the case because a number of these were antibody positive. So the conclusions were low yield and high cost. And as Mike pointed out, we're in the process of moving back to a triggered mini pool testing policy.

And in fact, this was discussed at a BPAC or a fairly recent BPAC where BPAC rejected the idea that all Zika safeguard should be eliminated. But it also rejected the idea that we should continue doing single-donation testing.

So basically, we ended up with a use of mini pool-NAT in all states with an ID-NAT trigger and that got 10 yes votes and 1 no vote.

So how do we make decisions in this area? We think about the size of the risk, the severity of the disease among infected recipients, the dynamics of the outbreak, the risk-benefit ratio, including whether or not blood availability is affected, competing priorities, public and political pressure, support from manufacturers.

This is a difficult area because manufacturers have to figure that they are going to get a profit from what they do -- the availability of resources, including funding, consideration of alternate approaches, and we want to consider tolerable risk.

And this is what the rest of this meeting is going to be about. And we need to think about monitoring and the TTIMS program has been mentioned already.

Most of the data I've shown you have been developed from actual experience. The FDA is in a more difficult position because they have to make estimates from knowing information. And you will be hearing from Dr. Forshee a little bit later how they go about this. We need to think about whether this is an appropriate decision-making situation.

So this is the fantasy, I guess. This is my interpretation of what I've been talking about, that magnitude of risk for the agents that I've discussed now in the US, it appears that HBV, HCV, and HIV, by window period estimation, offer a risk of around 1 in 3 million.  That's, I think, pretty low. And looking for post-transfusion cases reveals almost nothing.

HTLV, we've had no known cases. I'm estimating about zero syphilis, no known case since 1960, so we'll call that about zero.

VCJD, four known cases globally, but none in the United States.

West Nile Virus, the data looked like about 1 in 10 million, 14 reports in 15 years.

T. cruzi, nothing in 11 years.

B. microti, zero in 390,000 with testing. And the IND studies around 1 in 50,000 absent testing.

Zika, I would say likely zero now. And the pattern of Zika has been basically one big epidemic and disappearance elsewhere.

So my commentary at this point is residual risk for currently managed TTIs is extremely low, as judged by window period estimates and/or observation. There has been no -- in my opinion, there's been no explicit guiding policy driving management of new threats, other than zero risk and/or as low as reasonably achievable.

In general, as Mike pointed out -- and Mark, forgive me for saying this. But the cost per QALY of blood safety measures greatly exceeds current accepted norms per QALY in other fields.

The nexus for decision-making about these issues is unclear. And Jay made this point in his presentation. Although requirements are ultimately set by the FDA, but the in the interim, other players and the decision game at the moment include CDC, HHS, accrediting organizations, blood providers, and now, to some extent, hospitals.

And finally, there will be more emerging infections with TTI potential and maybe it's time to come to grips with all this. Thank you.

The Chairperson: Thank you, Roger. And thank you for all the work you've done over the decades at the American Red Cross in this field.

Dr. Dodd: Thank you. Thank you.

The Chairperson: Questions for -- Emily?

Dr. Blumberg: I think the concept of risk is really interesting, and I liked the way that you've framed it a lot.

One of the things that in working as an infectious disease physician in times of sort of epidemics like Zika is dealing with the fact that the public perception and the potential for risk can be, you know, significantly impactful on sort of screening.

But then you wind up in situations where you try to rapidly bring out tests, as with Zika, where you don't really know the performance characteristics of the test, and there is no real vetting of the test. And I think it just brings up this very difficult area.

How do you serve all masters in this and like try to improve or at least, improve the perception of safety and yet not impact in a negative way on the blood supply?

You know it's just really -- I've been sort of intrigued by this and I think Zika, in particular, was so difficult. And I like the comment that you made, Dr. Verdun, about just we're driven a little bit by these epidemics and emerging threats. And I think it is -- what will happen when Zika's going to happen with something else in the not too distant future. So I'm just curious about what both of you think about that issue.

Dr. Dodd: Well, I really think it's a core issue. And I think that one of the concerns that I think many of us had in the blood provision side was not so much about the quality of the test because these had actually been worked out pretty well.

And they were made by manufacturers with whom we are familiar and who understand the issues. That's not always the case.

So that wasn't perhaps quite so much of a problem. But what was the problem was that the whole field of blood collection distribution has been shrinking.

And deliberately, we've been removing excess capabilities. And suddenly to have this huge increase in activity in terms of testing put on to us with relatively short timeline was really quite difficult.

And I think that everybody is to be congratulated. I think we understand the rationale behind the concern and the very rapid turn out. But one of the things we did say is, okay, guys, but we're not going to able to this again, at least, not as long as we're still doing that, you know, the current test.

So it's whether the capacities there and whether the capacity can be maintained in these sorts of problem areas.

I'm sure it was a very difficult decision for HHS to make, and I don't think we can criticize it. But we have to recognize the difficulties.

And I don't know the real answer to your question. I hope that this committee can get their arms around it, though.

The Chairperson: Lou?

Dr. Katz: Well, I want to -- I want you to speculate looking backwards a little bit about what Nicole said about the precaution for example that might have driven Zika.

To what degree are we continuing to pay 30 and 40 years later for the perceived shortcomings of responses in the early 80s with HIV and post-transfusion hepatitis? And is there anything we can do about that?

Dr. Verdun: You know, I think he was making a statement though.

Dr. Katz: No, I --

Dr. Verdun: Oh, you weren't? Oh, okay. I'm sorry.

Dr. Dodd: You want -- you want my speculation?

Dr. Katz: Yes.

Dr. Dodd: I think that -- I think that it goes back to what I believe this meeting is intended to stimulate which is the thought of what is a reasonable and rational target for action. And it's always difficult to make decisions in a hurry.

I'm not sure that we -- I think we perceive ourselves as still putting right the errors of the early 1980s. But I think that this was a classic silver lining in as much as this is what drove us into a very high level of consciousness.

I think that setting a target, and it's not necessarily a definitive single target, but if you look at the way the Canadians look at tolerable risk, they sort of have a little block that, if I remember rightly, is basically a size of the epidemic and severity of disease. And they have green, yellow, and red blobs in the block. So it gives you a sort of a sliding scale.

And I think that nobody ever likes to say how many deaths can we put up with. But at the same time, how much can we spend to completely avoid it?

So I think that thinking of a target might be reasonable, and I think it's hard. I'm sure that (indiscernible) will have some thoughts about this.

But I mean generally, public health operates with an epidemiologic rather than an individual level. And it was always very interesting to me early in the days of decision-making around things like HIV and so on that a lot of the blood bankers were really (indiscernible).

They weren't epidemiologists. And time and time again, you'd hear them make sentences, they would make comments like, I wouldn't give these to my mother, and yet the question really is, how many of 100 million mothers should we be concerned about?

So it's very difficult. I think most people think personally and they don't think population-wise. And it's a tough conflict.

Dr. Verdun: I just wanted to make a couple of quick comments.

So one thing that you said is -- I'm not quite clear of what you meant on vetting of testing. I mean we certainly, at FDA, vetted the testing and the things were done under IND and --

Dr. Blumberg: I guess what I meant was that -- so in organ transplantation, for example, we always talk about thing being FDA-approved for that indication.

And just in terms of the -- one of the downstream effects of the mandate for blood testing with Zika was that it didn't spill over into the organ transplant world where clearly, it had not been fully evaluated because let's face, that's a whole different set of circumstances. So vetted might be the wrong term but license for -- you know, enough of whatever procedures had to be gone through to license it.

So I probably spoke imprecisely about that. But you know just the difficulty -- so I think what happens in blood donation does have repercussions beyond blood donation.

Dr. Verdun: Sure. Yeah.

Dr. Blumberg: And so the Zika was a specially confusing as those of us in infectious disease were asked about, what does this mean for screening organ donors? And most of us we're in situations where there was no possible way to get that testing done in organ donation.

So sorry, I probably should need to be more specific.

Mr. Brubaker: Yeah. Hi, this is Scott. The test kit approval process like the labeling claim is there also for tissue donation. But it's not recommended for testing ACTP donors because this virus can be found in different ACTPs after the test is negative.

So you have to take all of it into account. For organ donation, it's voluntary. So you would decide what to do in that case for an organ donor.

The Chairperson: Thank you. Any other questions? Or those of you who are on the phone, do you any questions?

Dr. Basavaraju: Hi, this is Sridhar from CDC. So one thing I just wanted people to keep in mind, going forward, as we think about magnitude of risk, so Roger had a slide that demonstrated magnitude of risk particularly for HIV, and hepatitis B, and C.

And one thing I think we should keep in mind is that when you identify transfusion-transmitted HIV, or hepatitis C, or something like that, one thing is that, you know, you have to keep in mind that there are -- you had to look for it, right?

So you could have potentially unrecognized transmission neither because you know the disease is detected much later. People actual have to ask about transfusion history, and I would think that that might be the case for some of the other disease too.

So I think -- what I'm trying to say is that it's not necessarily easy or straight forward to quantify magnitude of risk particularly when surveillance methods and surveillance systems don't necessarily always ask completely for transfusion history.

Dr. Dodd: Yes, definitely, I agree with that that looking for cases in the transfused population which is generally a passive activity is not a good way of assessing risk.

But on the other hand, I think that the methods that Mike and I explained in the current situation where we look at the window period and the likelihood of having a pathogen -- and defining risk is the likelihood of having a pathogen-containing blood product probably over estimates the risk.

So the truth, I think, probably lies somewhere between, for HIV, the two sets of numbers that I put up, the actual cases since 1999 and the potential risk of getting an HIV-containing blood product. So -- and both are pragmatic, but I think that that's the way I look at it, at least.

The Chairperson: Thank you, Roger.

Dr. Dodd: Thank you.

The Chairperson: Our last speaker in this series will be Dr. Ruta, who will talk about the FDA's experience during this timeframe. Dr. Ruta?

Evolution of the HHS and FDA Response to Infectious Disease Threats to Blood Safety

Dr. Ruta: Okay. Good morning, everyone.

So I actually envisioned this as a two-part talk. I was going to give part of it, and I was going to ask for Rich Forshee to come up and talk a little bit about risk assessments. And I'm going to talk about evolution --

The Chairperson: Can you speak into the microphone, please?

Dr. Ruta: Should I start over?

All right. Good morning, everyone. So I envisioned this as a two-part talk where I'm going to talk a little bit about some of the history of evolution of HHS and FDA response to infectious diseases and ask Rich to go through some specific examples where we dealt with risk assessments that we used in our decision-making.

I'm going to leave this up here for a while and, you know, let you look at it. So I generally would start a talk like this by saying that blood in this country is collected by an industry, not government officials. And it is regulated by FDA under two statutes, FTC Act and the PHS Act.

So this is a statement from the Secretary of HHS back in '95 and it sort of states kind of the obvious that blood will always be capable of transmitting disease, and it's very difficult to make it completely free of risk, but that the federal government will do everything in its power to reduce risk. And that's the sort of the framework that existed since '95, and I think it exists today.

All right. So I'm going to briefly go over the events that got us here. So I'm going to talk about the 1970s and the transition from paid to volunteer donors.

I'm going to talk about the AIDS crisis and how the impact of the HIV transmissions influenced decision-making within FDA and HHS. And then we'll come to a few slides on our current thinking about decision-making principles for blood safety, and then we'll have a few examples presented from Rich.

Okay. So this was kind of touched on a bit. And coming last, I get to talk a little about the other speakers have talked. So I just remind everyone that --

Just to remind everyone, back in the '70s, blood was collected from both paid and volunteer donors. And the discovery of the hepatitis B virus and its association with post-transfusion hepatitis led to a requirement for testing for hepatitis surface antigen in 1971.

And together, they showed that there's a very high prevalence of hepatitis in paid donors, and that led the effort to move the country from paid donors to volunteer donors.

So this was a major effort. And about half the blood supply was collected from paid donors at that time. And the effort was articulated in a HHS policy called the National Blood Policy.

And that policy actually had several objectives, one of which was to try and transition the blood supply from paid to volunteer donors and was left largely to the industry, to the America's Blood Commission to try and carry out this change.

But what really affected the change was the FDA, starting to write good manufacturing practices for blood establishments. And one of those requirements was blood from paid donors had to be labeled as paid. And that pretty much helped to eliminate commercialism for transfusion components and which reduced the hepatitis risk.

And so together, with the introduction of the surface antigen test and the transition to volunteer donors, it really did have a major impact on blood safety.

And we kind of take this for granted in our country, but many countries around the world are so dependent on paid donors and on family replacement donors, and we are not. And our donors, as Roger said, are much safer than actually even the general population.

And we generally attribute the questions that we ask to donors, the deferral questions, together with the fact that the volunteer donors, that both those together effectively reduce the marker rate in first-time donors about 85 percent for HIV, HBV, and HCV. So we're starting with a much lower risk population, at least, for HIV, HBV, and HCV.

All right. So I'm going to quickly go through the events of the AIDS crisis to explain how we got to where we are.

So in 1981, there was a report of immunodeficiency in gay men. By '82, it was found in hemophiliacs, and then in a child in December of '82. And there's a lot of controversy here about how quickly the government or industry reacted.

And a few years ago, Mike, Dr. Busch, had a themed issue of transfusion in which many of the participants wrote about their experiences during this time.

But by March of 1983, both the PHS and FDA were recommending that blood establishments take certain steps, and that, including to defer members of groups at increased risk for AIDS and they should refrain from donating.

And they include sexually active homosexual and bisexual men, past and present IV drug users, Haitian immigrants, and sexual partners of these persons.

So as the committee knows, these are really controversial deferrals. And this committee has dealt with revisiting some of these deferrals over time, as have FDA.

And many of those who collect blood or those who are from FDA have taken lots of angry phone calls from people who couldn't donate because they fell into one of these groups.

So the people in these groups felt that they were being stigmatized and discriminated against. By 1985, the HIV antibody test was approved and later mandated.

So what was the impact of the AIDS, of the HIV virus before testing went into effect? So the CDC estimates that about 9500 hemophiliacs had been infected with HIV. And they also estimated that about 30,000 transfusion recipients were infected prior to testing.

So some key events had happened that I think started to interdict the HIV transmissions. And I want to focus on this one a bit, because in 1984, we saw the first introductions of pathogen inactivation for the clotting factors.

And the use of the inactivation procedures, whether it was the heating method or the solvent- detergent method, not only interdicted hepatitis B and HIV but also would prevent transmission of hepatitis C.

So since 1987, the Armor (phonetic) incident, we haven't had documentary reports of HIV, HBV, and HCV transmission from clotting factors.

And this methodology had four breaching effects.  So the inactivation procedures are very robust at eliminating lipid envelope viruses. So because of these procedures that were in place and with demonstration by the manufacturers, we didn't require West Nile testing 20 years later when West Nile entered the country, or Zika testing for source plasma for plasma derivatives because of demonstration that the Zika virus can also be inactivated.

So the pathogen reduction was really one way to inactivate a class of viruses, lipid envelope viruses.

And of course, there still is a remaining issue with the non-lipid enveloped viruses where there not as readily inactivated and additional measures must be taken.

And of course, by 1990, FDA had begun to approve recombinant clotting factors which eliminated the concern about human viruses.

Okay. So there are number of safety measures that were put in place as result of the HIV infections. And as I mentioned earlier, there was deferral, people who were at risk.

And this led to FDA's five layers of safety which included providing education material, asking people to self-defer, asking history questions, followed by testing, deferral list, quarantine, and correcting manufacturing issues.

And the same pattern was repeated many times as new agents came along.  So before there was a test, what the FDA could do was to identify the risk factors associated with that new agent or the geographic factors associated with that agent and put in deferral criteria for those individuals.

By 1990, hepatitis C testing came into place which also helped improve blood safety. And then in -- I think one of the important events occurred in 1994.

And this was sort of a serendipitous event where one morning, the FDA commissioner was having his breakfast and reading the Washington Post and read an article about HIV being detected by PCR.

And so he got the idea that led to the use of PCR to prevent HIV transmissions through blood, and that led to the FDA Conference on the Feasibility of Genetic Technology to close the window period in donor screening.

And this conference brought everyone together, the blood establishments, the device manufacturers, and the commissioner challenged them and he said, come up with a PCR technology or genetic technology that will help close the antibody window period and prevent HIV transmissions.

And that was the effort that went forward. And the NIH helped fund part of the development of the NAT test.

So these tests came about, first, for source plasma, and by '97, FDA was allowing universal NAT testing for HIV and HCV under IND for source plasma, and then in 1999 for whole blood. And this mini pool NAT testing was used as a novel strategy.

And so this technology that came out this conference in '94, we then go on provide the platforms that were used to rapidly introduce some test which I'm going to come to. And one of the emphases I have to say we have on '90s was on GMPs.

Okay. Well, also, as result of the infections in the hemophilia community and the patient community, there's a lot of anger by the recipients of blood and blood products because they felt that the government had been slow and the industry has been slow to warn or take action.

And they asked for a Congressional investigation. And Senator Kennedy, Senator Graham (phonetic), and Congressman Gus (phonetic), asked HHS to investigate the events that occurred around the HIV transmissions.

And as result, the HHS commissioned the Institute of Medicine to conduct a report on HIV which issued in '95 called HIV and the Blood Supply: an Analysis of Crises Decision-Making.

Okay. And so I'm going to go through some of the recommendations, but that's why this committee is here. This committee is here because one of the recommendations came out that report was to have a committee like this, and I'll come to that in a minute.

And also, I want to say, one of the ways to bridge the anger that occurred among the patient groups was to include them in the -- at the table when decisions were made.

And so the FDA invited one of the hemophilia patients to be a voting member of the Blood Products Advisory Committee. And that was the first time that a consumer representative was on the FDA committees. And inclusion into the process, I think a greater insight and a feeling of participation by the community.

All right. So what were the findings of the IOM report, and there were actual 14 recommendations, but I'm only going to go through a couple of them. And they found that there were missed opportunities by no wrong doings, and they actually said that there was a failure in leadership within HHS to coordinate the ability to take action in the face of uncertainty, and that there was inherent bureaucratic inertia.

They also said that we are over-dependent on industry as a source of data. And specific recommendations, and these have been talked about, but these are the actual recommendations here.

And of them is, where uncertainties or countervailing public health concerns preclude eliminating potential risks, the FDA should encourage, and where necessary, the blood industry to implement partial solutions that have little risk of causing harm.

And this is a principle act when you think that there's a problem, and there's not that much information.

And a second one which I followed it, which I put together in this slide is that go back and review the decisions that you made when it was uncertain about the value of key decisions. So as you get more information, go back and review the decisions you put in place and revisit them.

All right. So what were the responses of HHS? Well, first of all, they designated the Assistant Secretary for Health as the Blood Safety Director. So the Assistant Secretary for Health is responsible for blood safety.

Then they set up a Blood, Organ and Tissue Senior Executive Council which consist of the heads of NIH, FDA, CDC, HRSA, DVA, with participation by DOT. And they are meant to coordinate government actions on blood safety.

And finally, one of the recommendations was the creation of this Advisory Committee on Blood Safety and Availability. And it's established as an expert panel to intentionally include patients, industry, and the government sitting at the same table, so they all can be participants in the discussion. And this committee reports to the BOTSEC and the Assistant Secretary.

And as the result of the structural changes that were put in place by the department, there's been a closer interaction between CDC, NIH, FDA, and the other PHS agencies because we all go to report to the boss at the top.

So this slide, I called the Shadow of AIDS and I think it was what Lou was referring to, earlier. And it is that the approach to blood safety management for new and emerging agents was really deeply influenced by the loss of public trust experienced with AIDS and by the IOM report.

And subsequent decision-making has been characterized by more timely actions including safety warnings, willingness to act in the face of scientific uncertainty, low risk tolerance, proactive engagement with patient groups, greater transparency of decision-making processes, regulatory focus on cGMPs across the industry.

And there was a lot Congressional oversight in the '90s going on into the early 2000s. In fact, at some point, we are up there every three months with different Congressional hearings on blood safety.

And these are the various reports that Congress issued related to blood safety. And they -- really, a lot of them deal with infectious disease risk.

So I just want to go quickly go through the 2000s. So as been alluded to before, in the late 1990s and early 2000, the VCJ risk became apparent and we started -- we issued the donor deferral criteria prior to evidence of transfusion-transmission.

And we did so in a risk-based manner in which we tried to take into account the decrease in the risk to the donor versus the loss -- I'm sorry, decrease of risk to the patient versus the loss in the donor pools.

In the early 2000, there was national use in investigational HIV and HCV mini pool NAT for transfusion.

By 2002, with the introduction of West Nile into this country, there was very rapid development of investigation of West Nile test and that was because of the platforms that already existed for NAT testing for HIV and HCV.

And so the manufacturers already had the hardware ready to go and needed to come up with new probes and primers. As Roger alluded to, there was introduction of Chagas serological testing for all donations based on a presumed-benefit, but we later changed that to first-time donations based on new approval -- based on new information.

Then in 2014, there was the first approval of pathogen inactivation technology for plasma and for apheresis platelets. So this is something that this committee had recommended some years earlier.

And it holds the potential of changing the paradigm of chasing infectious diseases. If we can get robust pathogen inactivation procedures in place, then we can think based on each -- for the characteristics of each virus about the need for testing and about the need for continued testing and donor deferral criteria.

And when the -- in 2016, when the investigation and later use of the licensed NAT testing for Zika virus were mandated, we were told by the establishments that if you were using the pathogen inactivation technology that you didn't have to test for Zika.

And somewhere late in 2018, NAT and serological Babesia tests were approved and draft guidance for implementation were issued.

So I want to go over some of the decision-making principles for blood safety and availability. So we do risk-benefit analysis when we approve products at FDA.

We do risk-benefit analysis taking account availability when we make decisions regarding

test -- regarding safety issues. So what you need here is a risk-making process that includes risk assessment, risk management, and risk communication. And the output is depending on the scientific input. And we take into account risk and benefits.

And we try to be transparent in our decision-making. And the way we do that is by going to our advisory committees, like this one, or by getting comments to draft guidance on proposed changes.

And this decisions that are made in this country are looked at by other countries just as decision made in other countries. Then people come back to us and say -- but they do it in a different way in England/or in Italy as we've mentioned, why do you do it your way?

So there are often very complex issues in decision-making. So when a new agent enters a country, there may not be -- there usually is no test available, or there is no test available.

So what we have available to us are donor screening and deferral criteria. And we have to balance the risk of loss of donation versus benefit for keeping the at-risk donation of the donor -- out of the blood supply.

We then go back and look at that based on emerging data, and we tried to use quantitative risk assessments since the 1990s to inform decision-making. And these generally account for donor loss versus risk reduction.

So our decision are made on both the science and the statues that we operate under. We tried to have public dialogue with public meetings, including scientific workshops, advisory committees in which experts in many different areas and patient representatives participate. And we try to have open public hearings where public participation is encouraged.

We get external scientific advice from two advisory committees, one is the FDA Blood Products Advisory Committee, and then from this committee, too, most recently, with the deferral criteria for MSM back in 2010 and 2015.

And we worked very closely with CDC and NIH and report to the Blood, Organ and Tissue Senior Executive Council that's chaired by the Assistant Secretary.

And we go back and look at prior decisions based on new scientific information. And Rich Forshee will give you a couple of examples where we made decisions when there wasn't as much information as we would have liked and then revisited those decisions when more information became available.

But there's always a concern that if we eliminate a deferral criteria, if we eliminate a test, will this reduction and stringency lead to new transmission?

So as Roger and Mike discussed, there are ongoing threats of blood safety which include the Arboviruses, and they continue to be, and emerging agents or constant threat. We've had rapid test development for West Nile Virus and Zika based on existing NAT platforms.

The tick-borne agents are an area that's of growing concern with Babesiosis highlighted the need to address geographic differences in the country. And there are several known tick-borne infections that pose emerging threats.

And finally, as Emily mentioned at the beginning, we still have bacterial contamination of platelets under discussion.

So to summarize, in the 1970s, emerging infectious diseases have posed novel threats to blood safety and there were novel interventions. We had deferrals based on behavior, and geographic exposure.

And we had a requirement for new test, mini pool NAT, and the beginnings of development of pathogen reduction technologies.

So the HHS and FDA response to EIDs has evolved significantly then since the AIDS era. Our current decision-making is proactive and highly focused on risk reduction.

There's greater attention to public input and communication. There is an increased used of quantitative risk assessments. Policy-making practices reflect lessons learned and institutional changes. And we try to engage with stakeholders to get comments.

So that ends my part of the presentation. I was going to suggest that maybe we'll let Rich come up, and then we can take questions.

Use of Risk Assessments

Dr. Forshee: Good morning, everyone. I'm Rich Forshee. I'm with the Office of Biostatistics and Epidemiology in FDA.

I'm going to talk today a little bit about some of the quantitative benefit of risk approaches that we've used.

In the time that I have, I'm not going to be able to go into great detail on any of them, but I want to give you a flavor of some of the things that we consider.

So most of the risk management decisions that we make at CBER are benefit-risk decisions. The statutory basis for much of what we do is to consider benefits and risks.

And the acceptable level of risk that we would consider is going to depend very much on the context that we are talking about.

And in particular, some of the CBER-regulated products can have very different benefit-risk considerations. Last year, we approved the first chimeric antigen receptor t-cell therapy for people with cancer that wasn't treatable by other treatments.

This had a good deal of risk associated with it, but because of the risks from the diseases that people were facing, the higher risk of the treatment was considered warranted.

Contrast this with vaccines, which are usually given to healthy individuals to reduce some future risk, we have very little risk tolerance when we are looking at vaccines.

And as Dr. Ruta described in his presentation, given some of the history that we've had with blood products, we have traditional had a low risk tolerance for blood products as well.

I'm going to talk about the couple of recent examples where we've done quantitative benefit- risk assessment for blood safety related issues. I want to be sure to acknowledge my colleague, Hong Yang, who contributed a great deal to the slides I'm about to share.

So the two examples that I'm going to be discussing are work that was done to look at Transfusion-Transmitted Variant Creutzfeldt-Jakob Disease.

In particular, we're going to be looking at the risk assessment that we did to reevaluate the travel deferrals that we had in place. And I'm going to be talking about some of the work that we did related to transfusion-transmitted Zika virus.

So for transfusion-transmitted infectious diseases, CBER and the Office of Blood Research and Review shares responsibility for the management of TTIDs.

There are few major risk mitigations that we consider when we're looking at emerging infectious disease. There is donor deferral that's going to be based on risk questionnaire.

This is going to look at risk behaviors. This is going to look at travel exposure or in some cases they can look at exposure to infectious agents for which we don't have testing available.

We also can do blood testing for infectious agents, and we also have technologies to inactivate or remove infectivity.

We try to build comprehensive benefit-risk assessment models when we were considering policy options. And I should emphasize that we always do this in the context of few options that we're considering including the status quo as the baseline option.

So we're going to look at options that might include things involving risk behavior, travel exposure, or exposure to infectious agents. One area that we evaluate are the donor risks.

So we're interested in prevalence and incidents among blood donors in particular. We then try to model the number of infectious units that may be donated under different policies.

There were some talk earlier this morning about the risk of transmission of units after they have been transfused. That is something that we consider in these models, but I do need to emphasize that often times, we don't have good data on what that risk of transmission is.

So we have a place for it. We tried to consider it, but better data would always be helpful in that area.

Based on all of this, we tried to estimate what the recipient risk is under the different policy options that we're considering. And simultaneously, we consider the donor loss that we may have either as a result of additional restrictions from the donor questionnaire or false positives that may come from testing all of the units of blood that are collected.

And again, some of the areas of intervention that we can consider are donor deferral, blood testing, and pathogen reduction, or some combination of these as a possible policy option.

We actually think there is a lot of advantages to the kind of quantitative modeling that we do to assess benefits and risks. We've listed some of them here.

One of the earliest is that the process of setting up a quantitative benefit-risk assessment helps to clearly identify what the questions are and to determine what the scope of the benefit risk assessment is going to be.

It's also a way to integrate data from many different sources in order to understand the complex systems that we're looking at.

We put a lot of emphasis on incorporating the uncertainty that we have from all of the sources. We want to be as transparent as we can about what we don't know, as well as what the science can tell us.

It helps us evaluate multiple options and look at the relative strengths and weaknesses. We found out that it really helps discussion and helps to focus discussion on some of the important point. And it's a good way to inform decision-makers and improve our communication.

So let me talk a little bit about the recent work on the transfusion-transmitted vCJD. As I think, everyone here knows vCJD is a fatal disease with a long incubation period.

As was mentioned earlier today, we don't have any donor testing that could be done to identify someone who might have vCJD.

The concern that we have in the US is donors who may have been exposed during travel and residence in risk countries, there is the concern that this could be transmitted through blood transfusions.

The original FDA guidance on this was to indefinitely defer donors who had a history of time spent in the UK that was more than three months during the years of epidemic, and other countries in Europe where people had spent more than five years from 1980 to the present.

And our risk assessment did indicate that with these criteria in place, the transfusion- transmitted vCJD risk would be very low on the order of less than 1 in 100 million.

More recently, we've revisited this question as we've learned more about the trends in vCJD and BSE. These cases have been decreasing worldwide. And we did want to consider a revision of the policy to reduce donor loss, so we developed a new model to rank the geographic vCJD risk worldwide based on the vCJD case rate and the number of travelers.

Based on this risk assessment, we were able to identify that the UK, Ireland, and France were the top three countries, by far, and that those three countries alone accounted for 95 percent of the total risk.

The risk assessment evaluated in the option to lift deferral for European countries other than the UK, Ireland, and France. The result of this would be a very similar risk reduction to what we have in the current policy.

And it will allow 100,000 currently-deferred donors to donate. And it would simplify the donor questionnaire. And the results of this risk assessment supported the December 2017 draft guidance to move towards these recommendations.

The other thing that I would add here is that we also incorporated new data on how leukoreduced blood products reduce the risk of transfusion-transmitted vCJD and that helped to assure us that there wouldn't be an increase in the risk with moving to this kind of a change. So that's an example of where we revisited the policy and incorporated new data and relapsed some of the earlier policies.

There've been a lot of talk this morning about the risk of transfusion-transmitted Zika virus in particular in Puerto Rico. As probably everyone here knows, the original response was to stop blood collection in Puerto Rico. That was not a sustainable response.

At that time, we did a risk assessment, and we were able to show that using ID-NAT in Puerto Rico would reduce the transfusion-transmitted Zika virus risk by about 86 percent.

More recently, we have considered whether we could move towards mini pool testing. This is based in part because the epidemic has been waning as was discussed earlier.

So in this model, we used information based on the Zika virus doubling time in human blood and the limits of detection as we move from ID-NAT to mini pool NAT testing.

And we were able to show there is a measurable increase in risk in moving this area, but it's small. And the probability that MP NAT would still detect the first case that an ID-NAT would detect was reasonably high. And so we determined that this probably supported moving to the MP16. Mini-pool testing in general, MP16 and MP6 are both used depending on the platform.

So in summary, the benefit-risk assessment has been used extensively at CBER. We use it to inform regulatory decision-making, evaluate benefits and risks of policy options, it helps to facilitate internal discussion to improve communication among all stakeholders.

We believe that benefit-risk assessment helps to advance regulatory science and that it enhances the FDA's capability to protect public health.

Based on some of the comments I heard this morning, I'd also like to mention that one of the things that benefit-risk assessment can help with is identifying where new data could be helpful.

And the exchange of data amongst stakeholders to help inform some of the key steps in the benefit-risk assessment can help all of us better understand the consequences of the different policies that we're considering.

And with that, I want to thank everyone who has contributed to this work. Hong Yang, in particular, helped with these slides. We have a whole team that works on risk-assessment.

And I should definitely mention Steven Anderson has really been a proponent of benefit-

risk -- quantitative benefit-risk assessment for 20 years. And he has really led the development in this area.

So thank you very much.

The Chairperson: Thank you Drs. Ruta and Forshee. We will open up for questions. People on the phone, do you have questions for either Martin or Richard?

Dr. Josephson: No. No questions, here. Thank you.

The Chairperson: Okay. Thank you, both, very much for all the work you've done.

Dr. Ruta: Thank you.

The Chairperson: We are going to take a break now. And so I think we're scheduled for a 15- minute break. Let's be back at 11:25, and we will start with Dr. Devine and the risk-based decision-making model she's been working at.

Pardon?

Unidentified Speaker: It's already 11:24 right now.

The Chairperson: Oh, okay. Yeah. I actually did mean 11:35 but 11:40, it is. And we'll make up to 15 minutes in lunch. So instead of lunch being an hour, it will be 45 minutes. Thanks.

(Whereupon, at 11:23 a.m., the meeting was adjourned.)

The Chairperson: Okay, if we could reconvene? Our next speaker is calling in from Canada. So if you could take your seats. Okay, thank you -- thank you very, very much.

We're going to move into the -- part of the agenda with our next two speakers speaking to risk management and risk-based decision-making.

So our next speaker, Dr. Dana Devine, who I think many of you in the transfusion medicine world know, has been very active and instrumental in the Canadian Blood Services, leading an effort to define a risk-based model back in 2010.

And now, that has gone on to be used through the ABO also. So we're very pleased to have someone with Dana's background review with us their risk management approach for blood products.

So she's going to be on the phone and her slides however will be up on the screen. Dr. Devine?

Dr. Devine: Hi, there. Can you hear me?

The Chairperson: We can, perfectly.

Dr. Devine: Okay, great.

The Chairperson: Thank you.

Dr. Devine: So, just trying to sync the slides. I just want to make sure you're looking at my title side?

The Chairperson: Yes.

Dr. Devine: Okay, terrific. So I'm assuming someone there will change them as I ask for that?

The Chairperson: Yes.

Dr. Devine: So --

The Chairperson: We have that –

Dr. Devine: Okay, great.

The Chairperson: -- all arranged.

International Perspective Blood Products Risk Management

Dr. Devine: So first of all, I'd like to just say thank you for the invitation to speak with you today.

I am going to talk about the risk-based decision-making framework that was developed by the Alliance of Blood Operators.

If you could go to the second slide? Which essentially outlines the steps that have been identified in the decision-making process for the framework. And I'm going to go through each of them, and I'm going to do that in the context of a problem that was presented before Canadian Blood Services.

So I would give the preface to just say that while this framework is designed to be used by anyone, where Canadian Blood Services got to in the question that I'd used the framework for, may not necessarily be where every other organization would get to.

So I would say that, while I was ask to provide an international perspective, I'm really bringing you a very specific Canadian example. I didn't want to speak for all other nations.

So within the decision framework that has been developed by the Alliance of Blood Operators, there are important policy foundations that need to be considered, and these are indicated in the gray boxes on the slide.

So these are, risk management principles: risk communication, stakeholder participation, the principles one uses for the assessment of the risk, and then risk tolerability.

I would say that this framework was developed with a lot of input. And I have heard a number of voices in the room this morning from individuals who were involved in developing this framework.

So I think that you have a lot of expertise breathing the same air that you are right now who know a lot about this framework and how to stand it up and operate it.

Could you go to the next slide, please? I just made a list here of a few studies that we're aware of that have been using the RBDM framework. And they, as you can see from the countries listed, are really in a number of different locations.

Some countries obviously have embraced this methodology very readily. There's -- there's three -- there's three examples listed here from Australia. Canada -- and for Canadians, we've done this for both Babesia and CMV testing.

And it is that example of CMV testing that we'll just take you through, so that you can see how we apply the different parts of the process and where that takes us.

Next slide, please. So the first thing one has to do is get prepared to do a RBDM exercise. And so before actually getting into it, it's very important to review the foundational elements of risk management.

And you need to do that so that each step of the way, you can do this as efficiently and as effectively as possible because the process is actually quite laborious.

Takes a lot of focus and energy to do this, and so you want to make sure that you're as best prepared as you can be.

Next slide, please. The way one generally does that is by starting out with a review of all of the pertinent literature related to the question that you have in front of you and any existing expert advisory committee recommendations that are available. So you're pulling together all of the existing thinking around the topic.

Then, one must assemble the team that's going to do this piece of work. And it's really important to have a good range of expertise that you think you will need to really explore the question in depth.

And for the typical kinds of questions that we struggle with in blood safety, this would be represented by the kinds of expertise that are listed on this slide.

So med micro (phonetic), and epi (phonetic), people with transfusion medicine expertise, health economics, very importantly, people who have expertise in stakeholder engagement and communications. And then, of course, you need to have people who have risk management expertise.

And we also have found it very important to have people who have good expertise in statistics and modeling because often, we're a little bit short of date. And so one then has to really understand how to assess the data that one does have at hand.

One then needs to review the policy foundations and the decision-making process of the framework so that you can really understand what it is you're asking this group of people to do. And then one starts to go through the process.

Next slide, please. So stage 2 is all about formulating the problem. What's very important is to be able to define and characterize the problem so that you can then drill in and identify what is the overall assessment question, what are the decision drivers, and what are your risk management options that you want to evaluate in your process?

Next slide, please. So I'm going to use the example of CMV testing in Canada. We recently changed the policy of availability of CMV testing, and I thought I would use that as an example of how we use the RBDM framework to try to get a better understanding of the decision that we wanted to make and the kinds of inputs that we were going through as we considered this policy change.

So I know that this is a bit of a mixed audience, but I think, probably, everyone in the room is well aware CMV is a common herpes infection which is usually systematic, or may cause mild fatigue, sore throat, and general malaise. This virus importantly replicates in mononuclear white blood cells, and they're precursors after which the virus becomes latent.

So this a virus that's contained in white blood cells. It therefore can be transmitted by transfusion. But the vast majority of blood products from CMV positive donors will actually not transmit an infection.

The risk of transfusion transmission CMV arises primarily when the donor is in the window period, and so the virus is maybe high titer. It's not gone latent in white blood cells at that point.

We worry about this because inspection through transfusion of CMV can pose a risk in immunocompromised patients and to some patients in other high-risk groups.

When CBS undertook this RBDM exercise, we were operating in a world in which we had two strategies in place to reduce the risk of CMV transmission through transfusion.

One of which was we have full prestorage leukoreduction for all components that are prepared. And we also had CMV antibody-negative inventory available upon request.

And so we were interested in understanding whether this was the right policy or we should be looking at doing something different.

Can I have the next slide, please? So we then formulated the problem. And so we actually had the questions that you see before you on this slide as our problem formulation.

And we were asking ourselves, is the strategy of CMV risk mitigation that we are undertaking, meaning both leukoreduction and testing, is that proportional to the risk associated with transfusion transmission of CMV?

And if that question came up to the answer, no, then we would say, well, okay, what is an alternative strategy for CMV testing that could be implemented that takes into account the appropriate safety, and also operational impacts, of that testing?

The next slide, please. As we went through this problem formulation exercise, we essentially came up with -- with six -- although, it looks like five here, but I'll explain it. There's actually six possible risk management options.

The first one, of course, is always to not change anything, to meet all our orders through CMV- negative products using antibody testing, and that we would potentially continue down our path of trying to educate our physician users of our blood products in Canada about CMV use -- CMV- negative request in an effort to reduce the amount of volume that was being ordered.

Our second option was that we would stop providing CMV-negative products entirely and rely on leukoreduction alone to reduce transmission risk.

Our third option, which actually has sort of two different choices here, the first was to provide CMV antibody-negative product or intrauterine transfusion for neonates under 28 days of age, and in the elective transfusion of CMV zero negative pregnant women, or, another variation on that would be to provide CMV antibody-negative product for intrauterine transfusion only.

Our next option that we considered was the option around using NAT testing to identify CMV- negative product for target risk groups that would were listed in option C. So this was sort

of -- this was a subset of work that was done as we were considering the options in C.

And then lastly, the other option that we considered was the introduction of pathogen reduction technology or pathogen inactivation technology.

Go to the next slide, please? We then move on to consideration of the participation strategy. And at this stage of the ABO RBDM framework, the intent is to define the need for risk communication and stakeholder involvement.

At least from Canadian Blood Services' perspective, we believe there's always a need for stakeholder involvement, but we also need to ensure that we've identified the appropriate stakeholders. And then we go from there to develop a participation plan.

The next slide, please. And so for the CMV issue, we developed a risk communications strategy, and we also went out and started the conversations with various stakeholder groups.

We have a group that's called the National Liaison Committee. That is a committee of our board of directors at Canadian Blood Services, and it represents and has members on it of different patient advocacy groups, professional associations, also some blood donors.

And we often take things we're thinking about and want feedback on to this group for stakeholder discussion. And we set this up in a fairly formal stakeholder feedback process.

And so we did that with our National Liaison Committee. In addition to the groups in the National Liaison Committee, we also identified two additional stakeholder groups that had high interest in this issue and influence on what was actually done subsequently.

The first of these were the treating physicians who use our products, and we also have transfusion service directors and members of a group that's called the National Advisory Committee on Blood and Blood Productions, which is a Canadian group that represents all of the provinces and territories in Canada.  So this includes the blood operators of both Canadian Blood Services and also Héma-Québec.

And so this is essentially the users of all of products that are provided by either of the blood operators, and they provide opinion for us.

And then the other important stakeholder group in our system are the provinces and territories because they -- in the Canadian model, as you will all know, they are the funders and operators of the health care system in which this product is made available and therefore, impacts of policy change are born in part by them.

And the next slide, please. For stage 4, we -- we go on to accumulate all of the data that we need to analyze the risk management options effectively.

And that's done by a series of quantitative and qualitative assessments. And this is where a lot of the data issues that have been talked about this morning will come into play.

Next slide, please. So for this particular example, we looked at a series of assessments. We did a blood safety risk assessment, which essentially showed us that the residual risk CMV in our leukoreduced products in Canada is very low.

And all of our products are leukoreduced which is important. And that is actually a regulatory directive that is place in Canada since 1998.

We also did an assessment of budget impact because it was important to -- it's always important to understand what the financial implications are of these kinds of policy decisions.

And we knew that at the time that we were testing about just under half of our donations for CMV, and that if we implement the selective inventory approach, the cost of testing would obviously be quite a bit lower.

We undertook an operational impact assessment that essentially was trying to ask the question, so if you make the policy change, can your organization -- how is your organization going to manage that?

There'll have to be a new algorithm in place for understanding how testing works, for the identification of what would potentially be a boutique product distribution.

And then what would be the actual risks of leukoreduction filter failure, or the wrong unit being sent to the hospital through pick and pack error, or labeling errors. And so all of that had to be assessed.

And then lastly, we did a contextual assessment where we really looked at the recommendations that were happening from other groups. And that might include Canadian groups, like the National Advisory Committee, but also organizations outside of Canada, such as the UK's SaBTO.

And the next slide, please. In the 5th stage, one undertakes the actual evaluation. And so in this stage, all of these assessment results that I just described, the stakeholder feedback that you've obtained, the risk tolerability analyses, are all put together to look at how they feed information into your risk management options.

And one takes all of that information -- go to the next slide, please -- and actually attempts to do a quantitative or a ranking order of your different options.

And so one takes the information that's there for each option, and through these different categories of safety risk, the infrastructure and resources required, and other concerns that may have been identified through your process -- ethics, trust, your stakeholder tolerability of the risk -- and one puts a risk ranking on it of 1, 2, 3; low, medium, or high. And then uses those to actually provide a numerical ranking depending on the total level of risk.

And so -- well, you're driving for lowest risk, and so one looks at the distribution of the different option rankings that you've come up with. And you can see in this particular one that for us, through this process, we identified that option C was actually our best option. That came up with the number 1 ranking.

And so you can see there's also tied rankings, and so that's a possible outcome of the process as well.

Once you've gone through this -- can you move to the next slide, please -- you're at stage 6. So here's where the rubber hits the road, and you need to now make the decision.

And so this is where once all of the work that you have undertaken, and all of the factors have been considered, you actually will choose one of the options that you put forward at the beginning of the process.

And once that option is selected, you have to put in play an implementation and monitoring plan so that you will understand what the impact of your policy change is going to be.

And very importantly, the communication of the decision to the stakeholders for whom you have solicited input, and any other stakeholders that you have identified in the process, that communication needs to be made. And that step is really critical.

Next slide, please. So in this particular example that I've brought forward, the risk assessment for these questions suggested that what was in play at Canadian Blood Services of the belt and suspenders approach of doing both leukoreduction and testing, was not clinically required to provide a CMV safe product, and that a more restricted inventory of CMV-negative products was a reasonable policy to implement.

We then went on to basically determine that both the options of C1 and C2, which simply related to who could actually get the product, would be acceptable strategy. So either one was acceptable.

And then the next slide. As we dug into that deeper, where we elected to go was to consider that the antibody testing approach would be limited, and that we would align that with the advice we were receiving from the National Advisory Committee.

And that advice basically said that CMV safe blood was perfectly okay to use. The one time when they recommended that CMV-negative product would be used was for intrauterine transfusion, primarily because there's a paucity of data that would allow us to include that group in the leukoreduced only.

So what we then did was adopt that as our recommendation and our decision, and get our communication plans lined up.

We put together a number of physician education packages, little YouTube clips that were made by key opinion leaders in Canada, and other opportunities for people to go really have a way to look at how did this RBDM framework arrive at that decision, and what are the data that support this, so that the policy decision around safety, people would have comfort that this had been made with a thorough investigation of where things stood at the time. We also looked of course at cost effectiveness. This was always an important piece of it.

And we have in play -- right now, it's not yet completed -- looking at the cost effectiveness of the possibility of implementing NAT CMV for this small number of units that we are distributing for intrauterine transfusion.

Next slide, please. So that's sort of very briefly an example of how the framework was actually applied in a specific, real world example.

A lot of the things you've talked about so far this morning, I personally believe could actually benefit from using this kind of a framework.

In any jurisdiction, you may get to a different answer, but I think that having a concrete set of processes that are followed by all who are involved in the decision-making may actually

get -- number 1, you get to a decision faster. And number 2, you have much less disagreement along the way.

So I hope that that's of use to you. There are a lot of people in the room who have been involved in developing this framework. So I'm sure that you will have a very interesting discussion.

Now, I'm happy to answer any questions.

The Chairperson: All right. Thank you, Dr. Devine. We will open it up for questions for Dana. Alex?

Dr. London: Thanks for that presentation. It was really informative and interesting.

I have a question about the assessment stage and the transition from quantified assessments of risk to whether those matter or not.

So we didn't -- in what you presented, we didn't see the numbers that were underlying the assessments that people gave. But maybe you can say something about how the group should determine whether 1 in 100,000, or 1 in 200,000, or 1 in 500,000 are treated the same or treated differently than -- the magnitude of --

Like, at what point does the magnitude of a small difference make a difference? And how do you make the comparisons between those magnitudes of small differences and some of the other variables on the burden side?

Dr. Devine: Yeah.  So I guess I would start by saying that that certainly, in the Canadian context, we long ago recognized that there's no such thing as zero risk. And so we are prepared to accept some risk.

In terms of an actual cut off, there really isn't one. It's very much dependent upon the actual risk you're seeking to mitigate, and what -- if something goes wrong, what are the sequalae for the recipient?

And so that kind of discussion is very important in doing these assessments, is that that's really part of the blood safety risk, is what -- you know, what happens if it doesn't go the way it's supposed to.

Dr. London: But did you mean -- I have two follow up questions. Did you mean individual recipient when you said that?

Dr. Devine: Yes, yes.

Dr. London: I forgot my second question.

Dr. Josephson: Can I ask a question? It's Cassandra on the phone.

The Chairperson: Yes. Go ahead, Cassandra.

Dr. Josephson: I have a question about was there consideration -- you said there was costs consideration. I kind of was wondering how you had set that cost consideration?

And did you consider how many patients would be receiving both the CMV-negative, and leukoreduced products, versus how many wouldn't, depending upon the group that got chosen to be given the product who had the least amount of data representing whether they should use that strategy?

So what I mean is, how many people are getting intrauterine transfusions versus how many premature infants would be getting this request?

And how would that change the actual cost of the -- so that's what I was wondering. How did you all weigh all that in?

Dr. Devine: So we did have the -- we do have the data around how many intrauterine transfusions are done per year in the hospitals that we provide products to.

Dr. Josephson: Mm-hmm.

Dr. Devine: The actual number of transfusions that are given to neonates is a more elusive number in system because --

Dr. Josephson: Mm-hmm.

Dr. Devine: -- data are not quantified in that way. So we have some ballpark data we're able to extrapolate from, but it's not a hard and fast number by any means.

Dr. Josephson: Well, I just wondered -- I just wondered in the factoring of it. Because premature infants, the more premature they are, have run a similar risk to the intrauterine transfusions, in the sense of their immune system.

And so then I wondered how finely tuned that decision was made, based on finances? Or, how many people would be asking for this product?

You know, the two strategies versus the one, and did -- did that even go into this analysis, I guess? Or does it not go into the analysis?

Dr. Devine: It only went into the analysis from the perspective that it's part of the information and input that we solicited from treating physicians.

Dr. Josephson: Okay, okay. Not in the sense of how many patients would be reduced. How many times you reduce this request? And how many, you know -- so how would it impact the blood supplier side that you wouldn't be testing as many units because you'd have much less requests? That would

Dr. Devine: Yeah. No, we -- we knew that. Because as part of the consideration, we looked at what -- at what we --

What should we be standing up, as a blood operator, for ensuring that there was product available for hospitals that do IUT?

And so we know how many units we need to test per week in that model. So that was all part of the actual calculation. That's part of the operational impact assessment.

Dr. Josephson: But you -- but you couldn't calculate that for the (indiscernible)?

Dr. Devine: No.

Dr. Josephson: Because you don't have those numbers? Okay –

Dr. Devine: That's right.

Dr. Josephson: That was my question. Okay, thank you.

Dr. London: So --

Dr. Basavaraju: Hi, this is Sridhar, from CDC. I had a question about the cost effectiveness evaluation that you do. Do you guys do a cost benefit analysis where you look -- calculate QALYs and things like that?

Dr. Devine: It depends on what the subject is. So we will at times do that. What we recognize -- it's the same thing that someone else brought up earlier this morning -- is the calculation of QALYs in the blood transfusion space is so many orders of magnitude different from anything else in medicine that we don't put as much emphasis on that.

Dr. Basavaraju: But in the situations where you do, how do you decide like, the dollar amount?

Dr. Devine: Yeah, we don't. We actually do what we can to calculate a QALY, but it -- I would say that it -- it rarely becomes the thing that decides whether or not you're going to take action.

The Chairperson: Brian Custer, and then Alex London.

Dr. Custer: Hello, Dana. I wanted to have a question that's really kind of a two-part question related to --

Evaluations, it seems, so far have been done for the first time. And as you either get better quality data, so you have less uncertainty, or you do a reevaluation, have there been examples? Or is there --

I know the process is designed to allow for that, but trying to think about how you would revisit a decision? And if there's sort of thoughts within Canadian Blood Services for your approach or your timelines for doing that right?

So one of the main questions that I think we're grappling with is, how do we make changes, potentially, to policy over time?

Dr. Devine: Sure. I mean, the only example that I could give you where we have done that for, we went through an RBDM for Babesia within Canadian Blood Services.

And what we are now doing is, we're doing another Babesia zero prevalence study, because we want to make sure that our decision not to implement Babesia testing was -- is still the correct one. And so we're going back and pressure testing that.

Dr. London: Sorry, yeah. I remembered my second question. So the QALY question is really about consistency of judgements across the whole range of medical interventions.

I'm wondering whether just in the kind of blood supply-related decisions that you would be making, whether you do anything to look at the consistency of the judgements that you make across different cases?

It doesn't have to be with -- with QALY. QALYs, it could be some other metrics, but I'm guessing it might -- the question is really, if you're willing to accept some marginal increase in risk, do you then look at whether that's in line or out of line with the other marginal increases in risk that you take in other blood-borne pathogens?

Dr. Devine: Not in the way that you're -- that you're looking for, no. Not in a Canadian context.

Dr. Katz: For people who are coming to the RBDM framework kind of new, as someone who's been involved for a number of years, the format that it's presented has changed a little.

The original diagram was a cycle, and in the framework, it is an expressly iterative process. It's there in the work. It doesn't show up in the graphics as nicely anymore, but it's deeply embedded that this is an iterative process. And I think that's important to understand.

Dr. Devine: Thank you. You're right.

The Chairperson: Dana, this is Jackie Fredrick. I have a question about how you determine particularly patient stakeholders, and how ensure you have enough stakeholder involvement that is valuable?

Dr. Devine: So that's always a -- that's always a concern. I mean and -- and we have -- I think we may be blessed in Canada that we have quite a large number of patient advocacy groups who are users of blood and blood products. And we have an ongoing contact with all of those groups.

So we have a very actively stakeholder engagement activity in the organization. And so we know well who to be in contact with.

This is a -- you know, this is really an outcome of the tainted blood tragedy in our country, which at least up until the opioid crisis, was our largest public health disaster ever.

And so there's still a lot of attention paid to blood and blood safety on the part of people who are receiving blood and blood products.

Our Canadian Hemophilia Society, although they're primarily -- is certainly for their clotting factors, they're -- they're dominantly recombinant. They still have a very large role to play, and there's a -- an actual -- and a whole organization that's a national rare blood disorders organization that we can interactive with.

So we have about -- I think there must be about ten different patient advocacy groups that we have regular contact with. And so we have individuals who are part of those groups.

We also reach out to the Cancer Society, the kidney folks, the Heart Foundation; looking for patient advocates who can speak for those patients who may not necessarily be chronic users of blood and blood product.

So we just have a -- we just have really tried to keep the tent as big as we can, and get as many voices into that process as possible.

The Chairperson: Thank you. Any further questions for Dr. Devine?

(No response.)

The Chairperson: Thank you very much, Dana, for sharing that with us.

Dr. Devine: You're very welcome.

The Chairperson: We're going to move on to our second speaker concerning risk, and that is Dr. David Wendler.

Dr. Wendler, welcome.

Risk Perception and Ethics

Dr. Wendler: I was going to say, good late morning, good -- hopefully not too long prelude to lunch for everybody.

So what I'm going to talk about is risk perception and ethics around risk perception. So I take it that a primary challenge for this group is to figure out what levels of risk are acceptable in different contexts and how determinations of what level of risk is acceptable should be consistent across different contexts. So I'm not going to address that question directly.

What I'm going to try to think about is, how should perception of risk be included in those decisions and making those decisions?

And when you face a challenge and you ask somebody who does ethics to help you, it's a bit like having a challenge and asking a psychiatrist for help. You can get two sorts of answers.

One answer you can get is you can get -- you've got a challenge, and here's this idea you never thought about, or this approach you never thought about. Do that and things are going to be better.

Sometimes I try to give talks like that. Sometimes I give talks like that. Sometimes psychiatrists give feedback like that.

Another kind of feedback is, yup. You've got a challenge, and what you're doing seems like a reasonable way to try to address it. It's not going to make it easy, but it seems like you're taking the right approach.

And for the by and large, I'm assuming that my talk is going to be more of the latter type for this group. I'll be very interested if people think that it's not, but I'm assuming it's going to be largely consistent. It's at least consistent with a lot of what I've been hearing this morning.

Just to say, I work for the NIH, but I don't speak for the NIH. I don't speak for DHHS. I just speak -- these are just my own views.

So just some basic background that everybody already knows about risks. And so this will be important in a minute when we talk about perception, because I think how you take perception into account is going to depend upon which aspect of risk you're talking about.

So risk involves chance of experiencing some harm as a result of an activity or an intervention, like getting a blood transfusion. Philosophers think of harms in terms of experiences or events that are bad for the individual who experiences it.

The term the philosophers often use is, setting back a person's interest, or setting back a person's interest in having a flourishing or a valuable life.

So obviously, one risk of receiving a blood transfusion is the chance of getting an infection. That's the challenge. And standardly, people think of the two components of risk.

There's the magnitude; if it happens, how bad is it for the person who's affected? And that includes both the severity at any given time and the duration across time.

And then there's a likelihood; what are the chances of that harm actually being realized? So what are the chances of a particular infection, for example, as a result of having a transfusion?

So the reason why I was just distinguishing those two is because I take it that people's perception of risk can involve either the magnitude of the risk, or it can involve the likelihood, the chances that a particular risk is going to happen.

So people might wonder, how bad would it be for me to get a CMV infection, for instance? And they also might wonder, what are the chances that I'll get infected with CMV if I undergo a blood transfusion?

So I think that the ethical response to these different perceptions is different because I think the significance they have for the kind of work you guys do is different.

So with respect to perceptions of magnitude, how we perceive magnitude, how we think about harms, is relevant to how bad the harm actually is for us. And the reason is because how bad things for us depends, to a large extent, on how we experience them.

And how we experience things in our lives depends to a large extent on our perceptions of those things and how we think about them.

So just to give a specific example, how bad is it to have a particular infection is going to depend on how people react to having that infection, how they live with having that infection.

So if having a particular kind of infection -- if finding out that you're infected with CMV tends to lead people to deep clinical depression, then that infection could be very bad for those individuals, even though the symptoms might be relatively mild and the treatment might be relatively straight forward.

So knowing people's perception of the magnitude of the harms can be important in deciding to what extent you should address them because they're important for figuring out how bad that harm is for people in the first place.

So this is what I was saying, is so the perception of the magnitude, it's ethically important because it's relevant to determining how bad a particular harm is for the people who experience.

So to make public policy decisions and to make treatment decisions, it's important for us to know how people view the magnitude of particular harms.

So I don't know if people know this literature. There's a lot of work now in clinical care trying to get stakeholder input, rather than just to assume that doctors and nurses know how bad it is to have a particular condition, and which conditions patients think are better and worse for them, and which they -- how they relatively rank the bad ones.

We're trying to get input actually from patients themselves. What is it like to live with and experience a condition, and how bad is that for you? And use that as a way of prioritizing things like, what the NIH does research on.

And then similarly, in terms of public policy, when we don't know, we shouldn't assume that we know what the public thinks about the experience, what it's like to live with a particular infection, say. It's important to find out, to get input. So that's perception of magnitude. So think perceptions of magnitude are important, hopefully in the way I tried to describe.

How about perceptions of likelihood? And the difference here, obviously I think, is while the way we think about the way we experience harms, how we think about that can affect how bad the harm for us is. I think it's very different when we talk about perceptions of likelihood.

The fact that I think, say, the chance of me getting CMV from a transfusion, if I think that's high, that doesn't affect the chances that I'll actually get CMV infection from a transfusion.

So here, our perceptions of likelihood, our perception of the chances that a harm is going to be experienced aren't relevant to actually how that harm is, how high it is or how low it is, in fact.

Now, when people have accurate perceptions in cases where, with respect to the chances of harm, people's perceptions are basically tracking the objective facts about the chances, then typically at least, there aren't any ethical considerations.

We can base treatment decisions, we can base public policy decisions on the perception, or the actual harm, since they're tracking one another.

And moreover, decisions, whether they're treatment decision or public policy decisions that get made on either of these bases, will be regarded as appropriate by both patients and the public, because their perception of those risks are tracking the actual risks.

So the challenge then, and the ethical issues I think typically get raised when people have inaccurate perceptions of the chances of particular harms.

And these are the cases in which I think important ethical issues arise, that the challenge is for a committee like this is to figure out how to address perceptions in these cases.

And the obvious challenge is that, to the extent the perceptions don't track the actual chances of a harm, if you base treatment decisions or public policy on those perceptions, you might end up with problematic policy and problematic treatment decisions.

So obviously, there's two ways that perceptions might significantly not track the actual chances of harm. One, is that perception might underestimate the risks.

We might think that a risk is very low when it's actually relatively high. This happens, for instance, people get used to things. You have experience with something, it's never hurt you in the past, you may then assume that thing is safe, when actually what's happened in the past is that you've gotten lucky.

I ride a motorcycle on the weekends, and I have a debate with my boss all the time about which of these things is going on, whether I've just learned that riding a motorcycle is safe, or in his view, I'm just stupid and I've gotten lucky so far, and that's going to end at some point. So here's just familiarity might influence and make -- maybe I'm -- I'm underestimating the risks that I face.

In other cases, you overestimate the risk that's going to particularly happen with things that we haven't had experience with. I'll talk about some of the other influences in a minute. So there's underestimating, obviously, and there's overestimating.

So problems of underestimating, people who are patients might ask for a treatment when it's excessively risky and inappropriate for them. Public safeguards that we might try to put in place might be seen as unnecessary and wasteful.

My guess is that underestimating of risks, from a perception point of view is a problem that you guys might like to have. My guess is that more often, in this context, the worry is about cases in which there's overestimating of risk. So I'll talk and focus a little bit more on this.

And here, the worry, obviously, is in a treatment context, patients might resist something, like a transfusion that they need, if they think the risks are a lot higher than they really are.

And from a public perception of policy, people might worry that the policies we have are inadequate, they're insufficient, and maybe people don't care about the affected individuals.

And so I take it, the big ethical challenge that's relevant to this context is figuring out how to respond to overestimates of perceptions of risks in the transfusion and the blood context.

So here's the challenge that I see, is to try to figure out how we can take seriously people's perceptions of risks in this context, how we can respect the people who have those overestimates, but try to address them, and try to insulate, to the extent we can, our treatment decisions, and our public policies, from overestimates of risks.

So how do we do that? The obvious thing is, in part, knowing what the influences are. There's lots of people in this room know this literature. There's a lot of literature on various influences on our risk perception, and particularly, factors that influence us when we tend to overestimate risk.

Things like, agency, whether or not there's somebody else involved or not. Whether we have a sense of control over the context. Whether we're familiar with the context or not. We talked about that one a minute ago. And also, there's interesting literature in the transfusion realm with respect to gender and the influence gender might have on people's perception of risks.

One of the other problems here on why I think the respect part of this is so important is that overestimates of risks tend to be associated in context with people who have less power, and either feel that they have less standing, or actually have less standing, and less say.

So then there's a concern that not taking these overestimates seriously may end up ignoring people who are relatively or absolutely powerless in the context.

So in figuring how to respond, my first lesson is always, this isn't a problem that affects some people. This is a problem that affects absolutely all of us. And part of this is our endowment from our evolutionary history.

The reason why we're all here right now is because our ancestors were pretty good and pretty quick at responding to risks. And the way you get really quick and fast at responding to risks is you rely on certain heuristics, like whether or not the sound you hear in the dark is a familiar one or an unfamiliar one.

And the people who took unfamiliar sounds as innocuous got killed too often. They didn't leave any ancestors. The ones who were afraid of unfamiliar things, they left ancestors and they are us.

And so we end up with certain biases, which in a lot of contexts, are valuable. That's the reason why we're here, but they can get us into trouble in some cases too. So I think one thing is to remember just that, this is all of us. It's not just particular people.

I had this experience, I don't know how many hundreds of flights that I've taken, but every time I get on a plane, and there's a little bump, my initial reaction is, that's it, it's over.

Now, here's a case where you would think familiarity would get met to the point, how many times have you had a bump like that, Dave? Hmm, maybe 15,000 times in my life. But it's the control, right? I don't have any control, and so I'm terrified for about the ten seconds that that's going on. It's a reaction that a lot of us have.

And so I think one of the things in figuring out how to deal with these overestimates is just keeping in mind that, to a certain extent, they're built into us, and it's something that all of us have. I think that's for us to know, and for the people that are overestimating to try to realize as well.

So we're talking about this, some of the worries here are a legacy of things, like the AIDS crisis in the '80s. And so part of it I think is, to the extent that we can do so, is to control the appearances that influence people's perception of risk.

So one of them, obviously, is developing trust. And we estimate risks to be lower when we're dealing with people whom we trust. And so one of the things, obviously, is working hard to make sure that not only it is, but it appears, and is clear that it's a trustworthy context.

Another one is control. We all need control, and we all overestimate risks when we're not in control. And so the idea is people -- and we talked about earlier, of having stakeholders at the table actively, proactively soliciting input and giving people control over policies can make a difference.

Another one is at least some of these influences aren't fully hard wired. We can change some of them, we can educate people. I'll give you one example from the bottom.

We do a lot of work with research in clinical care in Africa, and we were at a conference a couple of years ago. And we were talking about researchers who were collecting blood and storing blood samples. And there had been a lot of resistance in the community.

And people were saying, well, this is Northern Ghana. In northern Ghana, people have views about witchcraft, and blood is very associated with witchcraft, and there's really nothing you'll be able to do. And if you try to do research in this area, it's just not going to go anywhere.

People aren't going to give you their blood.

So we had a conference on this, sent some researchers to Northern Ghana. They went into these villages and they brought some people, the village elders, into their lab.

They show them the process of phlebotomy, of taking the blood. They show them what they do with the blood, they show them how they store the blood. And by and large, the worries just went away.

So it wasn't the case that these people had some background worries. What was going on instead was these people didn't understand what was going on. And when we don't understand, we fill in the details, sometimes in nefarious ways. And so education is one of the ways of trying to correct some of these overestimates in some contexts.

Of course, education isn't always going to succeed. And when it doesn't, there's going to be a mismatch. People may continue to overestimate risks, and there may be a big gap between the estimates of risks and the actual chances of harm.

And one thing to realize in this case is then that lowering the actual risks may not have any impact at all on the perception, because the perception may not be tracking the actual risks. It may be tracking some perception that the person has or that the public has.

And so in this context, I think it's really critical to make sure that there's disentangling between the educational efforts, the attempts to clarify people's perceptions, and the decision that get made in terms of both treatment and public policy.

Another one I think -- and this, I think, can work particular when you have -- actually have people involved. One thing we can realize is, okay, this is something that all of us have -- all of us have hardwired in us.

And certain cases, we can say, okay, yeah, I know you guys are worried about this, but what we need to realize is that's not tracking the actual chances.

And so what we need to deal with is deal with your reactions, rather than attempting to change the actual risk.

So I have snakes here, because for reasons I don't understand, my older brother loves snakes, and I'm absolutely terrified of them. And we were mucking out his barn this summer, and there was a snake.

And he picked it up, and I thought that was an absolutely ridiculous thing for him to do. He knows snakes; this is a harmless snake.

He knows I'm a philosopher, so he asked me -- he said, look, what if snake charmers were right and this thing were a way to cure you of some illness that you have. What would you want me to do?

And I take it the answer is, I'd want you to try to put the snake on me, and implement the treatment, even though I'm going to be scared to death the entire time, and I'm going to feel terrible about it.

So I think there are these contexts in which we can get people to recognize that maybe they shouldn't be making decisions. And maybe the standards they use for the decisions that we make shouldn't be based on the reactions that they have and the perceptions that they have of the risks.

So I think one of the things that's really critical here is, as people have been saying throughout the morning, getting stakeholder input early and proactively, and getting people involved in making the decisions can be really critical.

And what this suggests to me is to the extent that these influences are affecting people, and in particularly to the extent that they're leading people to overestimate risks, I think what it requires then is thinking carefully about what's the best way to solicit that input so that the overestimates can be addressed to the extent that they can be addressed. And to the extent that they can't be addressed, that the decisions get insulated from those overestimates.

I can tell you this, we do consults with patients at the NIH Clinical Center who are deciding whether or not to get intubated at the end of life.

And one of my routine questions for the nurse is, how's the patient doing right now? What's a good time of day for the patient? And let's not have this patient decide a life or death decision when they're not in a good place to be making decisions.

So it's trying to figure out different ways to optimize the decision-making that people have, the input that they give you, and minimizing the biases and how they affect the input that they might give you. I don't know how to do this with respect to community consultation and stakeholders.

One thing I was thinking, we do empirical research, and we do two kinds of empirical research. We just do quantitative empirical research where we just ask a thousand people a number of questions.

And another one is, we do focus groups, where we bring people in, we explain the context to them, and then we try to get their input after things have been explained to them.

And it seems to me, doing that in this context, might be a much better way of trying to address people's overestimates, rather than just asking them, off the top of their head, what's your sense of what the risks are, and what acceptable risks are?

To actually get them involved in the entire process so they see the complexities and can reflect on their own concerns to the extent that they have them.

All right. So that's my suggestions. As I've mentioned, it seems to me, most of them are things that people are doing. So my summary would just be, to that extent, this seems like ethically the right way to go. Taking into account risk perception, I think, is really important.

I think, as I mentioned, it's important to distinguish when the perceptions are concerning the magnitude of the harm versus the likelihood, or the chances, of the harm.

In the latter case, I take it, our perception of the chances of harm isn't relevant to what the actual risks are. And to the extent possible, we should be deciding how to treat patients.

And we'd be -- should be deciding how to safeguard and monitor the blood supply based on the actual chances of harm, not on the perception of harm.

And so what we need is to find some way to respect those overestimates but to the extent that we can address them and also insulate them from the decision-making process.

Okay. Thank you.

The Chairperson: Thank you very much. Questions?

Dr. Josephson: I have -- I have a question. Sorry. Cassandra, I don't know --

The Chairperson: Yeah, go ahead Cassandra.

Dr. Josephson:  Okay.  That was an excellent talk.  I was curious if you can comment on our -- our healthcare system and (indiscernible) of having a more litigious system than some other countries.

I know it's a hard thing to comment on, but as we're talking perceptions, and as we're talking about not just patients, but the positions at (indiscernible) and what some of the driving thoughts are around when people are worried about risks.

Dr. Wendler: Right.

Dr. Josephson: What are some advice that you give -- I mean, I think the focus groups are a great idea, but I -- I think they need to be with physicians too, not just with --

Dr. Wendler: Yeah.

Dr. Josephson: -- patients, but what -- just a take on the different approaches between let's say Canada and the United States with regard to the ethics around topical-made (phonetic) decisions with risk.

Dr. Wendler: Right. Yeah, I think it's a -- I think it's a great question and I agree with you. I think the -- I'm assuming you were talking about, our, you were talking from the US perspective and the litigious nature of the ---

The Chairperson: Yeah. I was --

Dr. Wendler: -- US context.

The Chairperson: -- I was just specifically thinking about that and what positions when they're doing blood --

Dr. Wendler: Yeah.

The Chairperson: -- and -- and all of that.

Dr. Wendler: Right.

The Chairperson: Where's that ethics part and what their fears are as well.

Dr. Wendler: Yeah. I think that's a great question, and I -- I agree with you.

I think at least one of the implications is, that getting the perceptions of patients and the public isn't going to be enough, to the extent that these are worries on the part of clinicians, and that those worries are driving what clinicians do, the kinds of things they're willing to order or not, for instance, then I think we need to address the clinicians as well. I think that's absolutely right.

When I -- so I'm -- I'm trained as a philosopher. I hadn't done any medicine at all. Until about 23 years ago, I landed at the hospital at the NIH, and I've been there ever since.

And I tell people that one of the most important lessons I've ever learned about medicine from working at a hospital for 23 years is that doctors are afraid of lawyers.

And we all need to realize that, and we all need to take it into account. And I can tell you, I think it's just another example of overestimating risks.

It's true at the NIH Clinical Center that the physicians have these concerns to. The chances that they could get sued, given that they work as a federal employee, is almost zero. It's really, really close to zero, but it still drives decision-making nonetheless.

So I think you're right. We need to take into account that physicians have these concerns too and see how we can address them.

Dr. Josephson: Thank you.

Dr. Katz: Yeah. So, so much of your perspective during your talk has been at the individual patient or clinician level. And for example, the risk-based decision-making framework that we just --

Dr. Wendler: Mm-hmm.

Dr. Katz: -- heard about, specifically asks us to think at a societal level.

Dr. Wendler: Mm-hmm.

Dr. Katz: And so there's -- talk about that disconnect and how –

Dr. Wendler: Yeah.

Dr. Katz: -- we bridge it.

Dr. Wendler: Yeah. So I think that we need to do both of them, obviously. And you guys need to do a lot at the societal level.

And I think, for me, I take it that one of the biggest challenges is when you're doing that, and you're getting stakeholder input, it's having the stakeholders who, to the extent possible, can adopt that perspective, right?

Rather than -- and, obviously, it's going to can be helpful to have individual patients in getting their perspective too. But what you're going to want is you want people who can give you, in a sense, not a patient's perspective, but -- and this is hard -- the public's perspective, right?

Because when you're doing this at an epidemiological level, it's not a question of what this person wants or values. It's trying to get a sense for what we do at a more societal level.

And the things that people -- Alex and other people -- were talking about before is, that's especially important when you start realizing the necessity of trying to be consistent and fair across these different contexts.

And trying to say that the amount of resources we put into risk reduction, with respect to one infection, should be reasonable, given what we've done with respect to other

infections -- blood, with respect to other kinds of devices, for instance. Yeah.

Dr. London: I -- I have a couple of questions, but one is about the -- whether we should take people's perceptions of the probability of risk into account.

I mean, does it matter whether you die in the plane crash, or die in the car crash, if people are misestimating the probability of dying in an airplane crash, and that leads them to drive more?

Dr. Wendler: Mm-hmm.

Dr. London: We're worse off from a public health standpoint.

Dr. Wendler: Right.

Dr. London: So at some point –

Dr. Wendler: Yeah.

Dr. London: -- don't we have to condition on people's misunderstandings or bad perceptions of probabilities?

Dr. Wendler: Yeah. I think at least in two ways, we definitely do.

So the first one is, as you're saying, we want to know what people's perception of the risks are, independent of what the actual risks are. We need to know the actual risks, and as we talked about before, that's really hard to get the data.

But even independent of that, we want to know people's perception of those risks for exactly the reasons you're talking about.

Even though planes travel is dramatically safer than driving in a car, people don't think that. So what they're going to do is, they're going to drive sometimes rather than flying a plane. And that might be bad for -- it's bad for road congestion maybe. It's also bad for public health.

So one, I think we do need to know their perceptions, A, so we can anticipate these reactions. Two, hopefully then, once we identify them, we can try to do some of the steps I was talking of, trying to educate them, and get them to see them in the right way.

But the -- what I was also saying, is this is what I was talking about disentangling our decision- making from our education process.

What I don't think we should be doing in that case is saying, okay, look, people are still scared about planes, we need to be putting a lot more money into making planes safer, one, because it's probably not justified given the benefits you're going to get from it.

But two, the perceptions are tracking the actual risks. And so even if you were table to lower the risks even further, you're not going to affect the phenomenon that you're worried about.

What you really need to do is take seriously the perceptions as an independent concern that you need to tack with and realize they're not always going to track the actual risks. Yeah.

Dr. London: So -- so if -- if novel infectious diseases were like airplanes, where we don't know their prevalence but they're super salient in the media --

Dr. Wendler: Yeah.

Dr. London: -- and it became known that someone contracted a novel infectious disease from a transfusion --

Dr. Wendler: Right.

Dr. London: -- they could misestimate -- I mean, if you're dead, you're dead. So it may not be misestimating the magnitude.

Dr. Wendler:  Right. Right.

Dr. London: So should we then -- is that a reason to treat novel infectious diseases differently from things that are equally likely to cause morbidity or mortality, but that have kind of faded in to the normal background --

Dr. Wendler: Yeah.

Dr. London: -- set of risks?

Dr. Wendler: Yeah. So my first thought would be it is a reason to treat them differently, but it's not, at least at the first pass, a reason to treat them differently at the level of what safeguards you're going to put in place, exactly what sort of lab tests you're going to do.

Instead, I was saying, I think initially at least, it should be a reason to treat them differently in terms of the education, and the extent to which you're going to, as I mentioned, emphasize the trustworthiness of the system and try to educate people.

And so maybe if -- once -- we're going to get new infections, right? We're going to get nasty new infections. When we get them, I think part of the challenge then is going to be, stay out in front in terms of explaining to people the extent to which there are safeguards in place.

So if there's pathogen testing that's already in place, explaining that, and the extent to which that's going to catch this infection, that pathogen testing doesn't care whether it's an old or new -- whether it's a new infection.

Now, I guess there might be -- I don't know if you want to -- so -- no, actually wants to do the philosophy too.

So you might think in the end, look, but how about if there's a case where you just do all that and it just completely fails and there's still mass hysteria about a novel infection in a way that's really undermining trust in the system, or in -- in blood transfusions in general, or across the country?

I think if that happens, again, my first thing is, don't start there. It's try to start with addressing the perceptions themselves. But I think, if they end up being intransigent and they really are having dramatic effects, then I think you might have to make acceptations and not treat them consistently as you would and say, look, we're just going to have to treat this one differently.

And put more measures in place that, from a purely risk benefit estimate, in this case, aren't justified. But then, of course, they are justified if there really is this potential. But my goal is to try to keep from getting there, to the extent that it's possible.

The Chairperson: Any other questions? (No response.)

The Chairperson: Thank you, Dr. Wendler.

Dr. Wendler: Thank you.

The Chairperson: We are going to take a luncheon break now, and we're going to try to get you all back here at 1:30. It's okay if you want to bring your food with you or your lunch with you.

But we'll break, and at 1:30, we're going to go on to our stakeholder groups. Thank you. (Whereupon, at 12:51 p.m., the meeting was adjourned.)

Afternoon Session

The Chairperson: Thank you all. And I'm sure others will come back. I know we had a tight timeframe for where the restaurants were to get food.

So the rest of our session is devoted to hearing from stakeholders. In your agenda, you have the stakeholders that are part of the agenda.  And then, I believe we have additional people who will give comments in our public comments session. And then the committee will begin to discuss what we heard.

So first of all, we're going to start with Dr. Zigi. I've known Zigi for a long time. And I'm half Polish, and I still haven't learned to pronounce his last name. So welcome Zigi, and we look forward to your comments.

Dr. Szczepiorkowski: Good afternoon.

The Chairperson: I tried.

AABB

Dr. Szczepiorkowski: I'm Zigi Szczepiorkowski, and I will be presenting a statement of ABC, ARC, and AABB.

So first, it is a perspective of all those three organizations. Collectively, our organizations represented the nation's blood collection establishment's transfusion services, and transfusion medicine professionals.

We commend the Advisory Committee on Blood and Tissue Safety and Availability, ACBTSA, for convening the meeting to explore the definition of a tolerable risk for infectious diseases from a patient's perspective. We are pleased to present our joint perspective on the tolerable level of risk in blood safety, with an emphasis on infectious diseases.

Our joint perspective focuses on the following six principles related to risk tolerability in blood safety.

First, validated risk-based models enable decision-makers to evaluate a blood safety in the context of a range of emerging risks and other societal priorities that must compete for limited resources, balance demands for safe blood with a need to ensure the blood is available to patient, and are useful tools to drive policy-making and evaluate blood safety.

The second, a comprehensive approach to blood safety that is inclusive of donor safety, the safety of blood products, the safety of transfusion medicine, and the safety of the patient.

Three, support the research related to new threats to the safety of the blood supply.

Four, recognition that biovigilance and hemovigilance are critical to advancing the safety of blood supply.

Five, voluntary standards and guidance contributed to blood safety.

And six, risk tolerability may vary significantly between different constituencies, as well as between organizations and individuals within a single group.

As more ACBTSA members are aware, the United States blood system is comprised of a complex web of private and public stakeholders. Blood and blood components originate from altruistic volunteer donors.

Blood collection establishments collect, test, process, and distribute blood components to hospitals and other settings of care where blood is transfused to patients.

Other key private stakeholders include device manufacturers, testing laboratories, clinicians, private standard setting, and recreational organizations and payers.

Public stakeholders central to the US blood system include the Food and Drug Administration, the Center for Disease Control and Prevention, the National Institute of Health, the Office of Assistant Secretary for Health, and Office of the Assistant Secretary for Preparedness and Response, as well as other federal, state, and local government agencies.

And this slide depicts that, with understanding that AABB essential here, basically has -- comes from people from all those different areas.

The committee which is considering risk tolerability for infectious diseases in the context of this diverse system at a critical time for the blood community.

The blood sector faces mounting economy pressures from existing and emerging voluntary and mandatory safety measures which are intended to protect the health of patients and donors, but are costly to implement. Current reimbursement mechanisms are not aligned with the blood community's role in protecting the public health.

Additional challenges include changing medical practices, reduced blood utilization, and a limited donor pool, and consolidated -- consolidation throughout the healthcare system.

Together, these challenges limit the ability of the blood system to invest in research and development, and adopt innovative technologies.

The following perspective on the risk tolerability reflects feedback received through a process that AABB piloted to assess the viewpoints of its diverse membership, which includes both the institution and individuals involved in transfusion medicine, and serotherapy.

AABB surveyed a subsequent volunteer leadership and members, including members of certain committees -- blood center, chief executive officers, medical directors, and transfusion services and hospital-based blood banks of the AABB board of directors -- to guage whether there is consensus among its diverse membership on the positions being presented today.

The survey was delivered to 313 participants, and 81, 26 percent (phonetic) responses were completed. It is important to mention that the results are interestingly consistent across all the segments we surveyed.

The results of the survey illustrated there is a widespread agreement on general principles related to the risk tolerability. Some alternative viewpoints were shared with AABB, and we have included those responses in an addendum we will provide to the committee.

As the ACBTSA Committee, to explore tolerable levels of risk in blood safety, we urged the committee to work with the stakeholders to explicitly and clearly define all terms.

All stakeholders in the US blood system must have a common understanding of key terms, such as, safe, blood safety, risk, and the risk-based model, prior to defining a tolerable level of infectious disease risk in blood safety.

AABB, America's Blood Centers, and American Red Cross, support the use of validated risk-based models to drive policy-making, and arrive at decisions related to blood safety interventions and new technologies.

Importantly, risk-based models do not consider a particular risk, such as a specific infectious disease, in a vacuum.

Rather, models enable decision makers to evaluate blood safety in a context of the range of emerging risks and other societal priorities that must compete for limited resources.

They also balance demands for safe blood, of the need to ensure the blood is available for patients. As you can see on the slide, the agreement level here is pointed out. So that's what we see.

The risk-based models are useful tools to evaluate blood safety since the terms, safe, and, safety, are continually evolving, and are not uniformly defined for the US blood supply.

The blood community has revolutionized blood safety over the past 30 years, implementing new processes and tests that have substantially reduced the risk of transmitting infection via transfusion. Despite its tremendous stride, and similar to all biologics, blood will always have inherent risks.

As an example of the definition of the risk listed here, and we realize that safety is also considered different depending which population we're discussing, which population we address.

Second, the AABBs, America's Blood Centers, and the American Red Cross take a vein-to-vein approach to blood safety and believe that blood safety includes donor safety, the safety of blood products, the safety of transfusion medicine, and the safety of the patient.

Critically, blood safety is inaccessibly intertwined with the availability of blood and blood products. Patient safety is jeopardized when a new safety requirement or the implementation of new technology limits the availability of blood.

As we consider terrible levels of transfusion-transmitted risks, we must remember that the patient's safety is much more vulnerable to non-infectious complications, including transfusion associated circulatory overload, TACO, the transfusion of an incompatible unit of blood, and transfusion-related acute lung injury, TRALI.

Imagine infectious diseases -- sorry. Okay. Imagine infectious diseases will continue to pose new threats to the safety of the blood safety. Therefore, the nation must continue to support research related to these potential threats.

Ongoing public and private investments in research is critically -- critical to identifying new threats, as well as developing and evaluating new safety processes and technologies.

In addition to investment in research, we encourage ACBTSA and policy makers to consider, one, programs and reimbursement mechanisms related to blood safety mandates and FDA recommendation and guidances. As well as, two, ways to support the implementation of safety measures and innovation when market incentives do not otherwise exist.

Novel blood safety technologies and interventions cannot be affective, and will not contribute to improved safety, unless they're accessible, affordable, and implemented by the blood community.

Although by medical advanced research and development authority, BARDA, has provided critical financial support for developing new technologies to protect the blood supply, there have not been similar investments to support the implementation of these safety technologies.

For instance, in 2016, the Food and Drug Administration required all US blood collection establishments to implement additional safety measures within four to 12 weeks using either testing for Zika of an investigational nucleic acid test or pathogen reduction technology.

HHS estimated in a June 2017 study that this requirement for universal adoption of an individual donor testing for the Zika virus would cost the blood system approximately $137 million annually.

A recent study published in New England Journal of Medicine concluded that testing individual blood donations for Zika not only had a high cost, but it also had a high low yield. Out of 4 million blood donations screened, only nine were confirmed positive for Zika.

Importantly, current reimbursement mechanisms are not aligned with the blood community's role in protecting the public health. We believe that public policies need to support and finance the implementation of new technologies that are required for blood safety initiatives.

Point four, we believe that real time data, including biovigilance and hemovigilance, are important in advancing the safety of the blood supply.

AABB specifically surveyed its members on the need for robust, well-funded biovigilance program in the United States to track the risks and benefits of transfusion, as well as effectiveness of safety interventions, both proposed an existing to reduce risk.

As this committee has discussed in the past, comprehensive surveillance data will enable entire blood community to engage in more thorough risk assessments and make more informed

decisions regarding strategies to protect patient and donor safety. They will not adversely impact the availability of blood products.

At present, biovigilance efforts are limited and inconsistent throughout United States. For example, in 2001, Babesiosis -- it was '11. So 2011, Babesiosis was classified as nationally identifiable conditioned, and the Centers for Disease Control and Prevention, CDC, began conducting surveillance for the disease.

Despite its classification, as of 2015, Babesiosis was only reported in 33 states. Cases are reported by state and county of residence, which may differ from where exposure occurred. Thus, it is difficult to fully understand the incidents and prevalence of Babesiosis.

Similarly, bio hemovigilance is necessary to monitor donor safety, transfusion safety, and patient safety. Since 2006, AABB has worked with the federal government to establish a US national hemovigilance program.

We believe that increasing the resources available for national hemovigilance efforts will contribute to improve assessment of risk, stronger evidence-based policy-making, and continued quality and safety improvements in transfusion medicine.

We believe that the public and private sectors should work together to ensure that new biovigilance and hemovigilance efforts do not create burdensome, unfunded mandates for blood centers, transfusion services, or other private stakeholders.

Volunteer standards and guidance will continue to play an important role in blood safety. AABB examines the current science and aims to assist its members, blood collection establishments, as well as hospital transfusion services, in improving patient care.

AABB's quality-based standards and systems assessment help mitigate risk for AABB accurate organizations. These organizations set quality goals, and use processes within their individual frameworks, to reduce specific risks.

As an example, AABB adopted standards and issued guidance aimed at reducing the incidence of bacterial contamination, as well as TRALI. Following AABB's November 2016 recommendation that blood collection and transfusion facilities begin to implement TRALI risk reduction measures for higher plasma volume components, FDA fatality reports indicated that a death due to TRALI fell significantly; from 34 in 2007, to 16 in 2008, and 8 fatalities in 2016.

We appreciate the different constituencies, and organizations, and individuals within a single constituency may have different risk tolerances. Risk tolerability may vary significantly from one patient to another, and that risk tolerability from a societal perspective would be quite different from individual patient's perspective.

We commend ASBTSA for its initial focus on the patient's perspective. We believe the advisory committee should continue engaging with a wide variety of patients, prospective patients, and the public through activities that promote widespread discussion on the risk tolerability and the prioritization of healthcare resources, such as in person and virtual town hall meetings.

We believe that a multidisciplinary approach to is needed to understand risk tolerability related to blood safety. Today's agenda scratches the surface of the complex topic, (indiscernible) of physicians, blood centers, and hospitals must continue to be included in these discussions.

In addition, representatives from federal departments, offices and agencies, including the Department of Health and Human Services, the Office of the Assistant Secretary for Heath, the Office of the Secretary for Preparedness and Response, the Office of Assistant Secretary for Planning and Evaluation, the Food and Drug Administration, Center for Disease Control and Prevention, National Institute of Health, Armed Services Blood Programs, and Centers for Medicare and Medicaid Services must continue to be at the table.

We also recommend including representatives of state and local governments for future discussions, since regional, state, and local factors may impact decisions related to blood safety.

Finally, we believe industry provides an important perspective to risk tolerability since their companies bring forth innovative technology that continually advance blood safety.

Thank you for providing AABB, America's Blood Centers, and the American Red Cross with the opportunity to share our joint perspective on risk tolerability related to blood safety. We look forward to working with the ACBTSA, as well as with other private and public shareholders, on this important topic. Thank you so much.

The Chairperson: Thank you very much, Zigi.

And thank you for the survey you all did to provide a sense of the transfusion medicine community.

Questions for Zigi?

(No response.)

The Chairperson: Okay. Thank you.

Dr. Szczepiorkowski: Thank you.

Dr. Verdun: Well, I just have one quick question.

The Chairperson: Oh, sorry.

Dr. Verdun: So there was a lot in this statement about -- I mean, this was a pretty packed statement, but -- we appreciate it. I mean, that -- this is -- this is helpful, and it fosters dialogue. But a little bit more --

I mean, there was a lot of mention about bringing stakeholders to the table to discuss biovigilance and hemovigilance, and ensuring that policies that are put in place, from FDA or others, are sustainable in terms of cost.

Like, how do you envision doing some of these things? I mean --

Dr. Szczepiorkowski: I expected this question, and I think my legal team is waiting there to answer.

The reality is, of course, I think this is the first conversation, the positive conversation. We believe that as this committee picks up this topic, there are so many different ways to work through it. And we all know, being exposed to this area for many years, there are no easy solutions.

So I think we just have to work together in this context, because I think we'll hear more from Ralph and then from Aaron, about the perspectives of blood centers and hospitals.

And I think that it's important to understand that there's no -- I don't think there's a silver bullet. I think we at least believe that this is the start of a conversation.

Those six areas, we believe, are something which we need to work on. Each of them may be approached differently, each of them has a different solution, presumably.

But I think we -- ABC, AABB, and ARC, we all believe that we need to work with everyone involved to make it actually better, and actually working.

And I think as Jay talked this morning about the sustainability of blood supply and our industry, I think urgency is huge. We may not appreciate it as much.

This is like looking at the picture which Roger showed. This is the very quiet, quiet lake. But I think it's not true. I think we just need to work together faster because we all recognize that the risk is very high right now for making a mistake.

But it's a -- yeah, mud in apple pie, I understand, but it's where we start.

The Chairperson: Mark?

Dr. Skinner: So I started -- I started to hold back, but you opened the line of questioning that I sort of wanted to go down. And maybe it's putting you on the spot, but we --

Before lunch, we heard Dana Devine talk and sort of describe the Canadian system, which is a risk framework. And much of what you described as part of a -- sort of a framework for decision-making.

One of the things she did spend quite a bit of time talking about was the stakeholder engagement, and how, specifically, they engage patients. And so sort of picking up on your question, so I mean, you spend time talking about sort of the intergovernmental agency collaboration.

Do you see a scenario like was described in Canada, and as in the ABO framework, as workable to have formal engagement processes with patients in the US to assess risk tolerability and risk acceptance?

Dr. Szczepiorkowski: Sure. I think there is -- there are two answers to your question. I think  I really appreciated bioethicist's presentation today because it put a good frame for me.

So I also work with patients, as I work with donors, and the individual risk versus the societal risk is such a different concept.  Having said that, the RBDM, which Dana talked about, AABB decided to use it for two different areas, and we just published a report on Babesia. It was just last week, I believe.

And again, I think we're learning from that. I think we're learning that in our very fragmented blood system we have in this country, things which may work for Canada, or may work for UK, or it may work for France may not for United States.

So I think the big point is, we need to create a system which will actually allow us to bring all the stakeholders together. And again, identifying stakeholders is critical.

We learned that actual lesson through AABB, that stakeholders are critical. But again, they bring their own personal perspective. This is not a perspective of a large group of people. It's individual perspective, as you've seen in this survey.

So I think it's important for us to recognize that there are mechanisms by which we can get input from focus groups, other larger places, and as well, organizations who represent patients as well.

So I think, absolutely I agree with you, patients have to be part of that. Patient is the consumer in the end. And I think we have to recognize that there is a difference between patients who may have next 20 or 50 -- or 50 years of life ahead of them, and a patient who lack of availability of blood may mean death or life, in terms of the trauma for example.

So the point is, patients have to be there, patients' experiences are different -- there are differences of patients. So I think we need to involve them, and we try to. I think that Canada has a very good system to do that. We are not as great in that.

THE CHAIRPERSON: I think you raise an excellent point that I have as one of the major topics when we get there.

I think the risk-based decision-making model that Dana presented is very good, but the inputs, right, is what you get, and the outputs, and having conversations about that.

I know ASH -- the other ASH, American Society of Hematology, has over the last couple years made a huge effort in what's called their multifaceted sickle cell disease initiatives.

And they have built a whole consortium of people under ASH that we can now, for instance, tap into, because they had the same issues, being the people who treat sickle cell patients.

So I think making an effort to start to try to identify -- I know we have a lot of organ transplant folks around the table, and it's been my impression that you are close to the patients you serve and transplant.

So I think, for the discussion, is really to think about how we bring these groups together and in a viable way.

Okay. Thank you.

I think Ralph is on the phone. Is that right?

Our next stakeholder is a blood center chief medical officer with blood systems, and was intended to present the blood system and medical expertise of our chief medical officers. And that will be given by Dr. Ralph Vassallo.

Ralph?

Dr. Vassallo: Yes. I'm here, Jackie.

The Chairperson: Okay.

Dr. Vassallo: Thank you very much.

The Chairperson: Thank you and -- and welcome. And I'll turn it over to you.

Dr. Vassallo: I appreciate that. How's the audio? Can folks hear me?

The Chairperson: You could maybe get a little closer, and maybe just speak up a little louder.

Blood Center CMO

Dr. Vassallo: Okay. I am getting over viral bronchitis. So I apologize, and perhaps you can boost the audio there a bit.

So starting on the header slide, which I hope you have there. I want to thank you for the opportunity to present the blood center perspective on defining tolerable ID risk from the patient perspective. On the next slide --

This morning, we've discussed the origins of the precautionary principle, but not really the principle itself, because there's not one such thing as, the precautionary principle. There are multiple versions of it, which -- you know, are -- have definitions similar to which tell you -- tell one what to do, and others that tell one what not to do.

But they all involve a preemptive intervention to address a potential harm where knowledge is incomplete or the risk mitigation efforts are being debated and -- for their relative values.

So here, in the precautionary principle, is the need for consistency with prior decisions, and those made in very similar circumstances, and proportionality, not swatting a fly with a sledgehammer, as well as avoidance of counterproductive responses, so that we don't implement a cure that is worse than the disease.

On the next slide, slide 3, there's a really nice article that was published last year from Canada, that's listed on the bottom there, that really describes the present perception of purely precautionary responses, as increasingly risk averse and disproportionate, too hastily implemented, and worse, requiring essentially near certainty before withdrawal of legacy responses.

So it's very difficult for us to remove tests once they come in, as we see with syphilis. So that -- we urgently need a framework to guide A, when to apply the precautionary principle, and B, beas conservative as possible, despite the issues that arise, either economic or convenience-based, but then how to balance risks and benefits of what one implements.

And unfortunately, we've talked a lot about risk and benefit. And that implies that you have a bad solution and a good solution. Unfortunately, more recently, it's between a bad solution and a worse solution. And what we're really talking about is balancing competing risks rather than, in some circumstances, very clear benefits.

That begs the need to transition from a purely precautionary approach, to a risk management approach, particularly as evidence emerges. And how much evidence is the subject of -- or will be the subject of debate.

And lastly, as I mentioned before, when to remove precautionary policies, and how to do that in an expeditious fashion. We need to be able to do that better than we do today.

The next slide is a different one than Roger presented this morning. Looking at infectious disease residual risks that are published in the literature. What one sees is two different orders of magnitude above and below the line, with the majority of the risk coming from bacterial sepsis, predominantly, and platelets, as you can see.

And if you advance the slide once more, a box should appear there suggesting that if one were to take the 2015 data from the AABB survey just published last year, on the number of products transfused, and run them against these literature-based risks, you would come up with somewhere less than 350 affected components per year.

Probably the most contentious one would be Babesia, because in non-endemic areas, the risk is very low, but can be quite high in endemic areas. And that's balanced by the implementation of the three largest blood collectors in the US of Babesia in that testing, which is, as we've heard this morning, is really quite effective in eliminating Babesia transmission by blood transfusion.

So really, we're chasing about 350 affected components, the predominance of which are coming from bacteria detection. And there was a nice presentation this morning by Dr. Storch about what we're doing in that regard to either eliminate, or at least substantially minimize, the impact of bacterial sepsis.

We also recognize that of these 350 components, not all of them are going to cause harm, if you will, due to the inherent resistance, as in quote marks, of patients on antibiotics, people who have been hepatitis B vaccinated, or immune from prior infection.

There's also the impact of the 35 percent one-year mortality from underlying illness that prompted the transfusion, which also blunts the effect of some of these, and this was mentioned earlier, also, blunts our ability to see these and measure them in a passive reporting system.

One the next slide, slide 5, from the really nice sounding board that's been mentioned today, I took one quote with my -- my emphasis there, that the nation's blood supply is both the public trust, but also a strategic resource. And I like the emphasis that it's the availability of safe blood, not just the safety of blood, that is the key component in current medical practice.

So when one looks at the several dimensions of responding to threats to the blood supply, one of which is safety. We are talking today about traditional and emerging infectious diseases, but recognize also there are no recipient-specific adverse transfusion outcomes related to donor factors, processing methods, and matching to avoid alloimmunization.

Blood availability has been declining, and I'll show you some data on that. We know that -- we've spoken this morning about, oh, it's only 2 to 5 percent reduction in the donor base.

Well, we've had multiple 2 to 5 percent reductions in the donor base, and these expanding deferrals are beginning to affect blood availability.

That's coupled with a shift in donor motivation. So the greatest generation that donated because it's the right thing to do are being replaced by younger donors who donate because it feels good and it makes -- and it's a public good. But it's a different focus, if you will, that makes it more difficult to recruit some the newer generation.

We have production-limiting technologies. For example, a pathogen reduction of platelets. It reduces platelet collections by at least 20 percent in the quest to get up to 80 percent pathogen reduction capability, in terms of the guard bands that are set.

And of course, the -- and a lengthy regulatory review can make it difficult once technology is available for a blood center to implement. This all leads to shrinking reserves, and of course, that impacts availability, in a seasonal fashion and during brief local surges.

What we've been ignoring has been blood funding. And we realize that both payers and hospitals are implementing cost containment that affects blood thinners.

Blood thinners are thus in a competitive environment in the US, unlike many national blood services that simply don't see that kind of dimension to the blood supply. And unfunded mandates. A donor mandate perhaps for iron depletion mitigation.

Other recipient safety enhancements lead to increased costs that aren't necessarily equally born by everyone in the system. And that also creates a massive healthcare opportunity cost, that when you're spending $100 or $300 million dollars for a particular intervention, that's $100 to

$300 million dollars that cannot be spent, perhaps on diseases that have more than 350 affected instances, or patients, that are far more morbid and mortal.

And those folks don't have a voice, and that really needs to be considered in the public health discussion.

If you press the events once more, you should see that funding is there for a really important component of availability. And of course, availability has been an ignored part of blood safety, and the assumption that, well, they'll just make it up.

On the next slide, the blood center challenges. We've talked about some of these, but a phrase that I heard some colleagues use has been, destructive competition. The sounding board did use -- did cite a statistic, that approximately 90 percent of the red cells provided in the United

States are subject to sub cost pricing, which is pretty amazing if you think about the sustainability of our supply.

And what we also see are the entry of porado (phonetic) service providers, the ones that do the 80 percent of blood supply that's quite easy, an AABB mix delivered on a routine basis, for the routine needs, which ignore the periodic ebbs and flows of patient need, and leaving that to the providers that are local that are -- it's much harder to produce excesses in group O negative blood, or AB plasma, as well as boutique product safe granulocytes.

We heard that declining utilization has affected the industry significantly by magnifying the effect of fixed cost. And that necessitates increased reimbursement at a time when hospital consolidation has led to stagnation or reduction through competitive pricing to blood center reimbursement.

And of course, blood centers are cost reimbursement entities that as, at least one person said this morning -- I believe Jay said it -- that it has been getting along due to investment income. But what happens when the bare market comes?

Already, it's leading to deferred physical, technical, and computer system maintenance, let alone upgrades. We certainly need modern IT systems and speedier regulatory review to allow us to implement changes to our IT systems.

And as I mentioned with the change in donor demographics, better ways to communicate with them. The house phone that rings during dinner is probably not the way we're going to communicate with the donor of the future.

We also, in the face of increasingly thin inventory reserves, need a robust hospital communication system that allows vein-to-vein tracking of blood to prevent outdating that we see.

Moving on the next slide, number 7. We've talked about the high cost to develop products, barriers to innovation, because of the low margin that are involved in this.

This stagnates the industry, and we've seen at least one major manufacturer announce its intention to pull out of the bag market -- the blood bag market in the US.

Beyond the donor demographic changes, that I believe I've mentioned at least twice, we see that you have young donors right out of college trying to pay enormous student loans, and should they go to the corner blood center and donate blood? Or should they go the paid plasma center and get $35? Increasingly difficult model for blood centers to deal with.

We've seen intrusive regulations, we've seen some countries removing the need to measure blood pressure altogether, for example, whereas we made our requirements more stringent by having the need for an onsite physician at every one of, say, 30 different donation drives in a given day, and the unfunded mandates we've mentioned before.

Cost containment and waning technical talent. The greying of our technicians in the blood bank and technologists is really leading to unsustainable hospital use of universal blood components.

2 percent of the population can donate a safe transfusable -- AB plasma, yet some customers ask for an excess of 30 percent of their plasma to be AB, and in excess of 12 percent of O negative red cells, when 6 to 7 percent of the population are O negative.

What's also been traditionally underappreciated as a challenge has been our need for multidisciplinary input. And we heard the Canadian model, and I believe Zigi just mentioned, we have particular challenges here in reaching wide engagement, not just of ourselves, the operators and donors, and occasionally our hospitals and very rarely our payers. We need to involve patient advocates of all sorts, as well as the public, to make good decisions with a strong decision-making paradigm.

On the next slide, slide 8, you see some evidence of the shrinking strategic reserves. These data come from the AABB surveys, and the NBC US surveys of the past. And you see the difference between the red line, what is collected and distributed each year, and the green line below which is the red cells transfused. And you see that shrinking reserve, along with shrinking prices, that are responsible for shrinking reserve, since it's unclear who needs to bear the burden of a national strategic reserve.

On the next slide, slide 9, you'll see cost of -- well, on the left, non- leukoreduced, and on the right, the leukoreduced red cell. These are ABC data. And what's interesting is from 2003 onward, the cost of a red cell unit has essentially remained exactly the same.

And I believe someone else referred this morning to a very telling statistic from Chris Rota's (phonetic) open letter, that while the urban medical consumer price index has increased by 26 percent from 2010 to last year, Red Cross' average red cell price dropped by 11 percent.

And one can imagine most of the other blood providers have done similarly or at least maintained a 0 percent increase, while hospitals are able to get an increasing share of the annual increase in expenses for human resources, for insurance, and for all sorts of other expenses.

That leads, on the next slide, slide 10. So a slide you've probably seen before. Updated to 2016 with ABC financial ratio data, showing that blood centers, at least in ABC, are fluctuating around a 1 percent margin. But in 2015, dropped dramatically below that non-sustainable loss levels.

As we move on to slide 11, in the realm of appropriately addressing risk, RAND came up with a survey that Jay characterized as an economist's view, which also used 2013 data in 2016.

And I think the conclusion of the effective and efficient operation of US blood system really ignores the situation five years hence from the 2013 data in 2018.

What we see is an untenable zero risk policy, where we essentially publicly endorse a zero-risk goal that makes the inevitable failure appear to be negligent. And in today's litigious environment, that's simply untenable. We really need to move to a risk-based decision model of some sort.

And we've talked about ALARA, as low as reasonable achievable, but I don't -- I think we talk more about it than actually implement such approaches to consider all threats to the supply, in an evidence-based and public health focused manner, not one that weighed down excessively by a single stakeholder opinion.

We need to get all stakeholder's opinions. We need to do it in an ethical fashion. And that was a wonderful talk about the ethics today. And talk about the sustainability much more than we talk about it today.

We've systematically ignored funding in pursuit of a zero-risk policy. And the sounding board mentioned a statistic that since 2009, approximately $1.3 billion dollars has been removed from the fat, if you will, in the blood industry, in terms of collecting, manufacturing, and distributing blood.

But now blood centers, having cut the fat, all that's left to cut is muscle. And in doing so, we risk imminent patient harm, particularly as we implement additional unfunded mandates, potentially Babesia unfunded for some period of time as Zika initially was, and also donor iron mitigation.

We have not really tackled the insurance value of blood. Each and every one of us pays our house insurance, our car insurance, our health insurance very happily -- maybe not so happily but we do it, but no one seems willing to fully bear, or appropriately reimburse costs associated by hospitals and blood centers that outdate blood. It's because you must outdate blood in order to have a strategic reserve.

On the next slide, slide 12, what do we do until we reach Shangri-La? Well, Chris Rota wrote it before ACBTSA in the past had mentioned that commoditization of the free market pressure may not be the best way to shape the safety and adequacy of our blood supply.

We note that anything that's unreimbursed, blood centers are either reducing or eliminating. We've seen surge capacity go down. We've seen blood centers reduce, or get rid of, research programs. Development has stagnated to some degree within the industry.

We're losing physicians who are a source of expert consultation. We don't have blood surveillance, except those surveillance mechanisms that are funded by NIH, but there are many more that need to be funded.

And we're clearly unable to either, enhance service, and in some cases, maintain infrastructure. And that is just particularly important when you talk about turnaround time and product availability locally, because when one consolidates manufacturing to, quote, un quote, cut out the fat, the local presence is lost, and that makes for a very difficult, very difficult environment.

We see increasing blood center competition which decreases sharing. So you have spot shortages in some areas while there's a slight excess in others. And we don't share data and best practices as we should in a competitive environment.

We've talked about the investment gaps, so I'll move on to the next slide 13, to note that that the strategic reserve is just like global warming seems to be worsening our weather events.

This lack of strategic reserve is worsening our holiday and weather event shortages that not only impact elective surgeries, but impact the ability to just simply do non-invasive procedures, like cardiac catheterization of people who have on multiple platelets antagonists and need a platelets available in the unlikely instance that they bleed.

We've talked about vendor exiting. And we've seen that as vendors exist, and there are fewer opportunities, I guess, to buy particular products, critical shortages can occur like occurred with the hurricane in Puerto Rico, with the blood bag production in that territory.

So we're standing by watching potentially irreparable harm to a vital national resource by mandating perfection, if you will, but not accounting for the cost.

So the next slide is one of my favorite quotes about prediction. And despite that, I will, on slide 15, make a prediction about the future. And that is, that eventually, the blood supply will be protected from infectious disease by effective multicomponent pathogen reductions.

We're still going to need to do a limited NAT or antigen testing for traditionally or newly identified pathogens that are at levels that exceed the inactivation threshold, or perhaps even antibody testing, for some period of time, within emerging infectious disease, as we attempt to deal with that that perhaps it's not amenable pathogen reduction, say, a non-lipid envelope virus. That requires continued funding for monitoring and test development.

And in the meantime, we need to have risk-based policies to protect the public by equally promoting availability along with safety and set up mechanisms to appropriately fund this national resource that's so vital.

In the meantime though, we cannot ignore the groups that disproportionately bear risk. And those are the individuals who belong to highly transfused patient subgroups which we'll hear from later today. We really need to consider potentially producing a limited number of safer products for specific indications.

And I'll finish with the next slide, slide 16. Someone did mention this risk-based policy. This is thethe Canadian construct of -- and part of the ABA risk assessment. This one happens to come from Héma-Québec. And you see up top, we discussed today about severity. And people's impression of severity can be quite different.

So not only do we have that discussion, but if we advance one more time, you'll see there on the left, we're going to have -- and we've already had questions today about, what is an acceptable frequency that puts us either in a do nothing, do something but you don't need to be entirely precautionary, or you must be entirely precautionary in red there, because this is a high risk, very common event that we must head off of the path.

So with that, I will thank everyone for their attention. And I'm happy to take questions.

The Chairperson: Thank you, Ralph.

Questions? Yes?

Dr. Macsai: That was a very -- this is Marian Macsai. That was a very interesting presentation. Can you explain why the price has been stagnant for competition?

Dr. Vassallo: Yeah. Certainly, as you attempt to hang onto every -- hospital contracts tend to run in cycles of two to five years. In some cases, every year. You're renegotiating.

So as a hospital consolidates -- or as hospitals consolidate, the next -- the larger hospital that got better pricing will now take a smaller hospital in and require that pricing as part their larger system. Or, that they'll renegotiate and open a request for proposals.

That makes a very competitive environment where hospital -- where, sorry, blood centers compete against each other for hospital -- their right to serve that hospital.

The Chairperson: Other questions for Ralph? Yes.

Dr. Ratcliffe: Hey, Ralph. This is Nora Ratcliffe.

I just have a question about pathogen inactivation, and new technologies being implemented in an environment of competition, where hospitals actually may set that type of innovation by, we're not going to buy this. Is there any thought on -- in the collection industry about how to proceed forward or to make that kind of product available?

Dr. Vassallo: Yeah. It's a very difficult question because, as you've pointed out, it's up to the payer to decide what they would like to pay for, what they feel makes sense.

We've seen large national bodies do risk-based decision-making about pathogen reduction, and decide that the additional benefit -- in the US we're talking, as I said, less than 350 components in all likelihood, is not worth the high cost.

But I think eventually -- the problem is, is without funding more expensive initial technologies, or the initial more expensive funding I should say, we're not going to advance to a point where we have less expensive, easily affordable, and much safer components. That's why I say, it's going to take us at least a decade before pathogen inactivation becomes a technology that's easily doable, affordable.

And we hope that indeed -- since the not only traditional threats, but the emerging threats for many cases headed off at the pass, that indeed that -- that we will find some leaders in the industry that will begin to invest in this technology.

And typically, we see it in places where there's been an event, and the recall bias comes in and the local environment is, never again; we don't want to have a patient suffer a really horrible event.

So we just need to get in the ground level with this, and I think that we have industry partners that are trying to do that.

Dr. Verdun: I just wanted to mention that -- and for pathogen reduction, we have an upcoming workshop at FDA on pathogen reduction, November 29th and 30th. And so I wanted to mention that. It's actually at FDA.

But I think also one of the challenges with pathogen reduction, while we all see it as a promising, you know, technology, there are obviously some advances that still need to take place.  And, you know, what is the ideal technology in that space?

One thing, from our standpoint, which would be wonderful to have, is to have something where you could pathogen-reduce whole blood, and then separate it into its individual components.

But I think that that's obviously part of the -- you know, the conversation in terms of how do we, you know, sustain some of these -- some of the cost, and some of the decision-making that we have do. If we could have a technology that can do that, that would be great.

But I just wanted to mention that workshop. And the goal of that workshop really is to sort of foster innovation and discussion, and foster research in that regard.

The Chairperson: That will be well-received. Marian?

Dr. Mascai: I think this has been brought up in the past, but it seems to me that there's a disconnect.

If the government is mandating testing for protection of the public, and blood and blood products are required for life-sustaining, why aren't they a passthrough? Why are organs a passthrough, cornea's a passthrough. Why isn't blood? And maybe that should be a recommendation that we consider.

Dr. Vassallo: I believe that's been brought up in the past, about a funding mechanism. And you're absolutely correct, because the funding -- when CMS increases funding for Medicare patients, often three years later, that goes to the hospital, and it's not necessarily passed on, or there isn't always a mechanism for some mandated tests, or at least, some mandated processes, to be automatically added to the -- and immediately added to the price that hospitals and payers need to sustain.

So for some period of time, the blood center needs to bear that. So that's a really good statement, but I think that has been raised in the past. Not to be up forward into the future.

The Chairperson: Any other questions for Ralph?

(No response.)

The Chairperson: Thank you, Ralph, very much.

Next, we're going to get the perspective from a hospital-based transfusion physician, Aaron Tobian. Welcome, Dr. Tobian, from Johns Hopkins.

Hospital Transfusion Physician

Dr. Tobian: Thank you very much for the invitation to speak today.

In contrast to Ralph's recent presentation, I'll be giving the hospital perspective. Two disclosures: I am a member of the AABB board of directors, and I'm also the principal investigator of whole blood pathogen reduction technology trial undergoing in Uganda, but which is funded solely by the US government.

So the main objectives that I'll be talking about today are to, first, briefly assess the risks of possible transfusion-transmitted infections, for our patients at the hospital to understand the current economics for healthcare in the United States with a focus on the hospitals, and then evaluate possible alternatives to additional transfusion-transmitted infection testing, specifically, patient blood management, pathogen reduction, hemovigilance, and then reassessing the current model.

So first, on the risks of a transfusion-transmitted infection. We don't need to spend much time on this since it was very well covered by Roger Dodd and Mike Busch, but as we get farther and farther out, our, you know, return on investment for the most recent agents we've been trying to eliminate just are not as fruitful as the huge successes we had initially with HIV, hepatitis B, and hepatitis C.

The real big risks at this point are those possible emerging infections. And there are a number of areas we've seen which possible chikungunya virus, MERS virus, dengue, Ebola, Zika, and yellow fever. And I think it's these types of unknown viruses that could cause the problem that have us most on edge.

But if you look at the overall current risks of blood transfusion, it's incredibly safe with HIV, hepatitis B, hepatitis C. And if anything, as Roger pointed out, it's probably even safer than these initial estimates are. And the other possibilities of CMV, West Nile virus, Chagas, malaria or bacterial sepsis are really in a fairly controlled state.

So there's been a number of discussions of, we need to really put the risk of a transfusion- transmitted infection into the context. And people have talked about airplane fatalities and motor vehicle fatalities this afternoon, but how do we really put this into context? So the risk of HIV, hepatitis B, and hepatitis C is about one in every 1 to 3 million cases. And that is in the same realm as airplane fatalities and lightening fatalities that most of us are not terribly concerned about.

If you look at, what are the real risks associated with transfusion, they are the non-infectious that there's been zero mention of, and those are transfusion associated circulatory overload, or febrile reactions, or transfusion-related acute lung injury.

However, overall, blood safety -- I'm not sure we've ever had such a safe blood component at any other given time. And, you know, if you really look at this compared to a death from a medical air estimated at 1 per 1000 events, you know, HIV, hepatitis B, hepatitis C, is several log- fold different than these other hospital risks.

Now, this chart was initially put together Sonny Zeek (phonetic), and then modified for AABB's red blood cell transfusion guidelines in 2012, where the death from a medical air was estimated at one to one thousand. However, more recent data are showing that the temporal transfer rate of patient harm are continually -- and they are continuing, and there's been no recent decrease of patient harm.

And there's a recent article from the British Medical Journal that is estimating patient harm that causes death at up to 1 percent of all hospital events. So there could be up to about 400,000 people dying every year just based off medical error. And so, if we look -- put that into context of blood safety, we're in two totally different spectrums.

As others have discussed, our approach to the Zika virus has been, you know, quite interesting, and it was estimated out of the Red Cross that it's possibly -- cost $5.3 million dollars just to eliminate one event.

And we actually put together a commentary on, maybe we should be revisiting these approaches to the Zika virus. They actually delayed our commentary for almost a year to get the Red Cross data out at the same time.

But this precautionary principle that maintains that when we're confronted by a public risk, one should act, and of a safeguard against, you know, such a catastrophic event as such the HIV epidemic, is completely understandable. And we are not trying to second guess that.

But it really comes into the decision is how much longer should we continue to practice and initiate blood donor screening for certain viruses such as Zika virus in the United States?

We need to be started to reassess these types of events, think about whether we need to continue, modify, or even possibly stop screening. And there are a number of reasons why, you know, we would want to modify Zika virus screening, just for as an example.

The epidemic is waning, there are very few pregnant women who are actually transfused, which is the greatest risk for transfusion-transmitted infection, and then the clinical symptoms associated with the Zika virus are relatively limited.

So putting this all into context, how do we look at the economics of the current hospital, and look --

(Audio feedback.)

Dr. Tobian: So that sounded wonderful. I'll just stop now and --

If we look at the national healthcare expenditure per the share of the GDP, it's really an amazing trend in the upward direction, and it just continues to grow up.

Current projections estimated to continue to grow at 5.5 percent every single year, reaching

$5.7 trillion dollars per year. We're currently $3.3 trillion dollars right now, so by 2026, healthcare expenditure is expected to be at 5.7 trillion.

The current share of our GDP is 17.9 percent. And by 2026, it's expected to be essentially 20 percent of our GDP for healthcare expenditures.

And this growth is driven by several different factors, such as an increase in medical goods and services, enrollment shifts from private healthcare to Medicare, and other possibilities.

How are the hospitals, you know, settling in to this increased expenditure? And so if you look at the American Hospital Association data for their actual expenses and revenues, every single year, the expenses and revenues for the hospitals are going up.

So this is the percent change every year. So it's on a positive margin for essentially the last 20 years that the expenses and revenues are going up for the hospital.

And it's actually fairly hard to balance. While both expenses and revenues have been going up, it's been hard to overall balance the budgets. And if you look at the number of hospitals operating in a negative margin, it's essentially almost a third of all hospitals in the United States that are operating with a negative budget.

And I was actually speaking to one of our senior administrators, and he was saying that even for the hospitals operating in positive territories, it's becoming tougher and tougher every single year.

So why are we actually discussing hospital economics? Well, blood transfusion is actually a fairly large cost with a large target on its back. So the portion of total hospital costs attributed to blood transfusion usually represents about 1 percent or less of total costs.

However, there are a number of conditions, such as liver transplant, bone marrow transplant patients, where blood transfusion can play up to 5 to 9 percent of total hospital costs for these treatments. And some will be in, you know, 3500, $4000 dollars, just to for the care for these patients.

In addition, that's for some of the bigger hospitals. For the smaller hospitals, it's even more difficult to manage inventories efficiently. Many people are outdating platelets that are at the smaller hospitals, and it just adds to additional costs that is not reimbursed. And this entire environment makes the blood cost a prime target for cost containment efforts.

So while Ralph Vassallo talked about the donor centers are really being hurt by the overall cost structure, the hospitals are not in a current state to all of a sudden absorb large increases in the cost of blood.

So in this type of environment, what are possible alternatives to our current model? And I think that the biggest and probably most successfully areas of patient blood management, and it stole the concept from the five rights of medication reconciliation.

So essentially, you want to be transfusing the right product, in the right dose, to the right patient, at the right time, for the right reason. And so most of the hospitals have created cross- disciplinary strategies for blood conservation, and that is a -- then you would help with anemia management optimization of the red cell mass.

So prior to surgery, making sure that the patient is stable with less likely need for transfusion, you improve hemostasis and optimize coagulation status.

And it's a patient-centered, evidence-based, critical decision-making approach. That's if you can reduce the number of transfusions, not only are you improving patient safety, but the hospitals are pleased because you're also reducing the overall bottom line.

And the former HHS secretary, I think, described the situation quite well when she said that, there's both excessive and inappropriate use of blood in the United States. Improvements in rational blood use have lagged.

And what is really being advocated here is better patient care. It can be a true win-win situation. And the bottom line is, is if a transfusion is not necessary, all you're doing is providing potential harm to these patients without any benefit.

The overall patient blood management programs have been strengthened by numerous randomized clinical trials showing the benefit of restrictive transfusion thresholds and also summarized well in clinical practice guidelines, such as this one, from the AABB that have supported your restrictive transfusion threshold guidelines.

So are we seeing any real benefit from these patient blood management programs?  We recently conducted a study of the nationwide inpatient sample, which is a 20 percent sampling of all patients in the United States, which is considered to be representative of between 95 to 97 percent of the entire US population.

And of all patients who are admitted to the hospital, you see over the years there was a dramatic increase in the number of patients actually receiving a red blood cell transfusion.

However, this peaked in 2011 at 6.8 percent, and has since gone down to 5.8 percent in 2014, and has continued to decline. So there's a almost a 16 percent decline in red blood transfusion use, and we're seeing similar trends in our plasma use.

It's not like we can exactly pinpoint the reason for this, but I personally believe it's multifactorial. There's an increased medical evidence supporting restrictive transfusion threshold.

You've got your patient blood management programs, you have other conservative initiatives, such as cell salvage, pharmacotherapy, improved surgical technics, and then you also have advocacy from federal agencies and medical organizations.

This really, I believe, is the biggest benefit of, you know, what are the best ways to help the patient, and also improve overall costs.

The second area for improving patient care without the current model is pathogen and activation or reduction that has been mentioned several times throughout the day.

And the overall goal is to treat the product globally and through different mechanisms. And this will impact both known or unknown, or emerging infections. And it even can impact such known infections, such as malaria, that we don't have any current testing for.

There's a number of products available in the US and Europe, primarily with plasma and/or platelets. There are a number of developing technologies for red blood cells or whole blood. One of the issues is making sure that the regulatory process to permitting these products is streamlined and permissible.

There are a number of advantages and disadvantages of this technology. The two main technologies are for cellular products are the INTERCEPT and the Mirasol technologies by Cerus and Terumo BCT.

In general, this a broad -- it has brought activity across a large class of pathogens including bacteria and viruses. Pathogen reduction could realistically block merging or unknown infections, and it's comparably safe and efficacious compared to untreated products.

However, it does cost a fair amount of money. It's currently costing about $100 additional per product. As was just briefly mentioned, how do you convince the hospitals that this is of benefit that needs to be evaluated and overcome?

It can cause possible cellular damage in lower increments. So an increased number of transfusions are needed. There is a number of technical complexities, and some question about if there's a regrowth for a low -- if you have a low kill or a fast-growing organism.

Well, another area that we need to need to be thinking about and continuing to support is the hemovigilance networks. And the CDC has supported a hemovigilance for national surveillance of adverse events to improve patient safety, minimize morbidity and mortality, and identify emerging complications and pathogens associated with blood transfusion.

The National Institutes of Health has supported the recipient epidemiology and donor evaluation study. And it's important to both maintain these both nationally but internationally.

As we've seen from some of Mike Busch's data, many of these emerging infections are not occurring immediately in the United States. So it's nice to and good to have early detection programs that can identify emerging threats to the blood system.

Finally, we need to be thinking, should we be having a new paradigm? Should we be accepting additional risks? Or, if we involve pathogen reduction, can certain donor screening be eliminated?

What screening tests could be eliminated? And what type of criteria would be used to determine what tests would be eliminated? Primarily, you'd probably want to, you know, was the infection was treatable, versus not -- untreatable? Was the infection lethal? Or what is the overall risk of the infection?

So, in summary, blood transfusions are incredibly safe when compared to most other hospital procedures, and also compared to transfusions in previous eras.

A zero-risk transfusion policy is noble but likely unsustainable as we continue. Pathogen reduction should be considered, especially if other transfusion-transmitted infection testing could be eliminated.

Programs to monitor blood transfusion, both nationally and internationally, are important to support. And fewer blood transfusions decrease risk and improve patient's safety.

Thank you very much.

The Chairperson: Thank you, Aaron, very much. Questions for Aaron?

Alex?

Dr. London: Thank you. That's really helpful to try to put things into context.

So the $134 million-increase, the number that's been bandied about, looks really tiny in the context of $3.3 trillion that we spend annually on healthcare.

Also, when you had the graph up about the safety of the blood supply relative to things like airline flight and then hospital error, I'm just curious what you want us to take away from that?

Because surely, it's just a scandal that the rate of hospital morbidity and mortality from error is as high it is. And we wouldn't want to imply that that kind of egregious failure of the public trust is something that we should tolerate in areas where we're doing actually a pretty good job of protecting people's health.

Dr. Tobian: I I agree. I'm not proposing that we let HIV infections slip up to 1 percent of all transfusions. That would be an even larger scandal. But I think we do need to make sure we keep this into context, you know.

I believe we're still under the remnant of the 1980s of handling -- how did we handle the HIV epidemic? And, you know, we have a zero-risk policy for blood transfusions, but then when we think about, you know, medication errors or other issues, we're ignoring the issue.

So I think we need to keep that all into context when we move forward.

Dr. Josephson: Can I make a comment?

The Chairperson: Sure, Cassandra.

Dr. Josephson: Cassandra.

THE CHAIRPERSON: Yes.

Dr. Josephson: Okay. Aaron, that was great. This is Cassandra.

I just want to mention about hospitals that have neonatal intensive care units, and usually that have those pediatric patients, that patient blood management is kind of in it's infancy, for lack of better words, because it -- there really isn't the data, like the strong data that was shown for the red cells criteria that, you know, was published.

And I always want to caution that patient blood management, in general in pediatrics, there really aren't great studies. And there is a lot of controversy. And it is more difficult to enforce.

And I just had an international conversation with Australia, England, a bunch of other places, we're trying, from a pediatric standpoint, to understand what to do about patient blood management in the context of neonates and children.

So I just want to say, from the hospital standpoint, that the joint commission, and other places that want us to maybe do more restrictive things, we really don't have the data to do that. We need to be cautious. And Canada was on the phone, we were all kind of struggling with this issue.

So I just wanted to mention that out loud out here because we don't have the data.

Dr. Tobian: I completely agree. If you look at the NIS study that we just showed, there was a decrease in red blood cell transfusion essentially in every single patient category except for pediatrics.

Dr. Katz: There's --

Dr. Josephson: Thank you, Aaron.

Dr. Katz: There's an implicit thing going on in these discussions, that if I sell you a cheaper red cell, the money will be used for something better, that it's a zero-sum game in some way.

Talk about that, Aaron, if you can.

Dr. Tobian: We're a big proponent at the hospital for a cheaper red cell bill.

Dr. Katz: So are you going to spend the five bucks that you saved because I dropped my price on falls or medication errors, or, are you going to spend it on advertising your heart program?

Dr. Tobian: That's really above my pay grade also.

You know, I think the bottom line is that, you know, the hospitals are in a situation where we're prepared, you know, to be adding on hundreds of dollars, you know, to help, you know, the blood donor center.

That, you know, if you've got a third of the hospitals operating in a negative margin currently, and the other -- many others tittering at that level, I don't think you can ask the hospitals to make, you know, the next step.

So I think it really needs to be coming out of more of a national policy than just, oh, well, let's just tell the blood donor centers to up their prices.

Dr. Katz: Yeah. So that gets to two things. One is, the global perspective that I mentioned, societal perspective, in these decisions that is critically important. And the second thing, I can't remember, so --

Dr. Kotton: Dr. Kotton. Thanks for the nice summary.

I'm wondering, so you nicely presented the data as they are at this point. But, you know, there are multiple companies that are doing things like deep sequencing, and multiplexing, and are

primed to give us a lot of answers that we may or may not want about things like viruses that people have. They're talking to me about, do we want to know this about organ donors and whatnot.

And I'm just wondering where you think technology like that will reframe this discussion? I'm almost like scared to ask myself.

Dr. Tobian: I think it depends on your point of the world, right? You know, you could say this could be a huge, you know, benefit that maybe, you know, at a very cheap cost, we can be screening, you know, the blood with one assay, and it would make life much easier, and, you know, could be a possible benefit.

The other alternative is, you know, for the blood donor collection agencies, you could say, well, we've now found 50 percent of all your donors have some, you know, reason to eliminate their blood collection. So they're collecting twice as many units, and then half the blood industry fails.

So bottom line, I don't think we really know. Personally, I'm not convinced that's really going to solve all of our issues.

The Chairperson: Aaron, if we could work together, and you could reduce your costs, and the blood operators could reduce their costs, and we could provide a safer blood product, that would be optimal.

We've been talking about stakeholders. How can we engage you -- not you because I know you're engaged, the -- your clinicians? How do we get the clinicians who transfuse the product to be part of the decision about how long we do Zika testing? Or do we do the next emerging virus?

Because I think that's the part with determining risk tolerability; the patient and the physician who treats are critical to us. So how would you engage them at Hopkins in that discussion?

Dr. Tobian: You know, I think it's key to be reaching out into the community, you know.

So at Hopkins, we recently stopped providing CMV zero negative blood. It was a yearlong adventure into speaking to your OBGYNs, your oncologists, your transplant infectious disease specialists, and really truly going on and engaging with the providers who are on the frontlines.

And so I think a similar approach would need to be taken on a much more global scale.

The Chairperson: Thank you very much.

Dr. Tobian: Thank you.

The Chairperson: We are now scheduled for a 15-minute break. So if we could be back at 3:10?

Thank you.

(Whereupon, at 2:57 p.m., the meeting was adjourned.)

The Chairperson: Okay. To continue on hearing from our patients and patient representatives, our first speaker is Dr. Poles, who is from the Sickle Cell Disease Association of America Organization.

Dr. Poles?

Sickle Cell Disease Association of America (SCDAA)

Dr. Poles: Thank you. Good afternoon, everyone. First, I just want to thank you guys for inviting someone from the Sickle Cell Disease Association of America.

As has already been alluded to by several speakers, there are a lot of stakeholders who need to be at the table. And obviously, this represents one of those critical stakeholders in terms of actually being the recipients of high volume of transfusions.

And I just chose to just do a couple of quick slides on the background of sickle cell disease because I wasn't clear on who my audience was and just to explain why there's such a high demand of red blood cells in sickle cell disease.

So most of you probably already know, it's an inherited recessive genetic disease. The red cells, because of their abnormal shape, create blockage in the vasculature but also, actually, now, we know also cause a lot of damage to the endothelial cells of the vasculature.

There's a lot of intimal proliferation, and all this actually leads to a lot of chronic complications that, in the past, we didn't fully understand the why.

The most common presenting event is the acute painful episodes that most people are familiar with. And although that's the most common presenting event, there are many complications that red cell transfusions are indicated for.

Not all patients but many are, in fact, high utilizers of red blood cells, and it's both for prophylactic reasons, as well as therapeutic indications resulting in anywhere from 15 to 25 units of red cells per year.

And if you're starting this at a very young age, you can imagine with the load is in terms of -- and the possibility in terms of pathogens that are infectious and also transfusion-related complications.

I just chose to put a slide in there. You can easily see the stark difference between -- okay, I'm not doing a good job with this. But on the left-hand side or the normal red cells, and the lifespan for the average cell is 120 days, as opposed to people who are living with the disease, anywhere from 10 to 20 days.

I'm going to -- there is literally no published research in terms of patient perceptions in the sickle cell disease population. So everything that I'm going to share is going to be based partly anecdotally and partly based on reports from the literature, as well as clinicians I've touched base with their experience with infectious agents.

I am actually living with sickle cell disease and began being transfused at the age of nine at Children's Hospital in Philadelphia until I was 17. At that time, it was experimental, to my knowledge. And I've searched the literature. From the time I knew how to search literature, I have not seen any published information.

In medical school, I developed pneumonia, and they wanted to transfuse me because my hemoglobin dropped significantly. But it was in the era of HIV-AIDS scare, and I did choose to refuse receiving red cells. Retrospectively, I'm obviously grateful.

Fortunately, even now, I am hep C, hep B negative, HIV negative, in spite of starting chronic transfusions in the 1960s.

I'm not on hydroxyurea which would ameliorate my need for a transfusion at this point in my life, but I've been intolerant twice, two different trials. So I am being chronically transfused.

So obviously, I have a vested interest both as a clinician and as a patient who receives cells on a regular basis because of renal failure, because of sickle cell disease.

I did have a moderately severe transfusion-related reaction in 2010, etiology unknown. It's not clear whether the institution where I was being transfused was routinely doing leukocyte- reduced cells at that point.

And so my hematologist made a decision to ensure that they were leukocyte-reduced, as well as washed and irradiated.

For me personally, as well as many of my colleagues, not that we are not concerned about infectious disease transmission through transfusions, but we have more concerns about alloimmunization.

Anecdotally, one of my colleagues on the board who is pediatric hematologist in Philadelphia has had several patients who has contracted parvovirus B19 via red cell transfusion. And she's also been concerned about Babesia transmission.

Another colleague who is in Connecticut has actually had more than one occasion of RBC transfusion-transmitted Babesia.

For patients that have been under my care. Over the years, and I'm an internist, not a hematologist -- however, I'm based in Harrisburg, Pennsylvania.

And at the time when I went there, there was literally, and there still is, no sickle cell disease programs in the area. So I actually began a sickle cell clinic at the institution where I was working. So I've been caring for a number of patients, adult patients with sickle cell disease.

And other than doing residency and medical school when HIV was a big concern, I really have not had patients tell me their concerns about infection as much as maybe some pediatric practitioners have.

And it's really because most of the time, by the time patients with sickle cell disease reach adult practitioners, they have been exposed so much to red cell transfusions. And as an illustration was made earlier, when you get used to something, the perception of risk obviously decreases.

And I've had no clinical experience patients I care for who have contracted infectious diseases. But again, a lot of it has to do with taking care of adult patients as opposed to pediatric patient

For colleagues that I've consulted with, clients -- and I'm using the just word "clients" because I'm talking about the community-based organizations under the umbrella of the National Sickle Cell Organization.

Any concerns that they have heard from their clients or the parents of clients with sickle cell disease, they tend to be concerned when they are initially beginning a transfusion program for chronic transfusions or in the acute setting, of one or two-time transfusion, more about the procedure. But they do still have questions about infection and adverse events.

I'm not going to read this slide, but there are multiple indications for red cell transfusion in sickle cell disease. But one comment I will make is that it's been revolutionary in terms of primary and secondary stroke prevention.

Prior to this implementation, prior to the STOPP trial and STOPP2 to trial, up to 25 percent of children suffered from stroke in their early ages.

Once starting the stroke prevention trials and actually implementing it as standard of care, the incidents of stroke has plummeted so that most children do not suffer having a stroke. So that's really been quite remarkable intervention.

Obviously, those children who start getting chronic transfusion at the age, anywhere from as young as two, you know, up to -- they generally stop screening in the adolescent years.

But if they are getting transfusions from a very young age, 15 to 25 units per year, you can imagine how many units they are exposed to, and therefore how many possible episodes of being exposed to any kind of pathogens.

I decided to include a couple of charts. I'm not going to spend time on it because there's been a lot of discussion already about the -- what agents we screen for and then also the number of infections that occur with transfusions. And there just different data that has been shared, so I'm not going to go through that.

But the one thing I will point out on this slide is parvovirus B19, which is a big issue in the pediatric population. And as you can see, it is not fully inactivated and therefore continues to be a concern.

I'm going to talk more about parvovirus, but I did want to share a little bit about alloimmunization because actually, in the sickle cell community, that is more of a concern, not that we are not concerned about infectious diseases because we are.

But alloimmunization is even a bigger concern because the pool of donors versus the recipients that usually have sickle cell disease are very different genetically. And as a result, the risk of alloimmunization is much higher.

And it does lead to difficulty in future cross-matching, as well as eligibility if a patient needs chronic transfusion therapy, not to mention access to compatible blood for acute events, as well as bone marrow tissue donor availability.

It does occur rapidly after initiation of transfusion without, if extended matching is not done. At your facilities that have a robust program for sickle cell, patients with sickle cell disease, there's no question that the full screening is done.

However, in some of your smaller communities where there are no experts in taking care of patients with sickle cell disease, it does become an issue. So in the absence of minor RBC antigen matching, the rate of alloimmunization is 30 percent as opposed to just 5 percent rate in those of other forms of anemia. And obviously, it can lead to typically a delayed hemolytic transfusion reaction.

So the antibiotics that listed there, those are the ones that present the -- against those -- that presents the greatest problem. So extended matching should be initiated on the onset of a transfusion program.

Fortunately, most children who have sickle cell disease, who are placed on a chronic transfusion program, are usually cared for at centers that are adept at caring for patients with sickle cell disease. And so they are ensured to have that extended matching done.

So going back to the parvovirus, as most of you know, it is extremely difficult to inactivate or remove from blood products because of its small size, and it doesn't have a lipid envelope.

In patients with sickle cell disease, the transient aplastic crisis that occurs from the virus, not only is it common in patients with sickle cell disease, but it can be life-threatening.

Patients present with acute severe symptomatic anemia. They would have fever and pain. But the life-threatening complications are acute chest syndrome, splenic sequestration, and complications such as that.

Three of the articles that I'm going to reference, all of which show not only is there a high incidence of parvovirus in patients with sickle cell disease, all of it not being transmitted through transfusions, some of it in community -- a sibling could have parvo B19 et cetera.

And so each article does suggest that a vaccine be developed. Unfortunately, as we all know, vaccines are not necessarily the most profitable thing for pharmaceutical companies to pursue.

It's going to usually depend on the population, how wide of the population is going to utilize it. So that has been a barrier to getting one done.

Although the literature, looking at it over the past few weeks, it looks like there is some activity going on now to see if they can, in face, develop a vaccine that is both safe and effective.

But also in these articles, they demonstrated the -- out of the number of patients that they surveyed, in terms of testing, there was a high percentage, not only who developed parvovirus, whether it was from transfusion are not, but it was a high percentage of those who did develop parvo, significant percentage, that, in fact, did get to red cell transfusion.

And as I shared earlier, a couple of my colleagues mentioned children that they had cared for who contracted it through transfusion therapy. And the article written by Kim Smith-Whitley and her colleagues showed a rate of 11.3 per 100 patient years in this study that she did.

So in 2004, the US FDA regulation governing parvovirus B19 contamination of full plasma or blood products recommended the level be less than 10 to the 4th international units per mL.

And this was based on some observational studies that showed in healthy volunteers, if the product contained greater than 10 to the 7th genome equivalents per mL, then disease transmission, in fact, did happen.

If it was less than 10 to the 6th, no disease has been shown to occur. So the standard right now is 10 to the 4th. However, it appears that that may not be adequate in population, such as those with sickle cell disease because of the immunocompromised state.

CMV, not going to spend a lot of time on it. But in general, patients with sickle cell disease who are transfused, it appears that if the blood is leukocyte-reduced to less than 5 million

units -- less than 5 million per unit of blood is safe in the sickle cell population.

The other option, of course, is using the leukocyte depletion filters to prevent febrile transfusion reactions, which may also serve to protect from CMV.

Emergent infections, which again has been mentioned, one of my colleagues who practices in Connecticut in particular, has had more than one case of babesiosis related to red cell transfusion.

And the other colleague in Philadelphia said it's a concern for her. She did not necessarily say she had a documented case. But it is, depending upon where in the country, it is of a concern and I think that's been alluded to in general already today.

So it can be detected and there was a test that was approved in March by the FDA based on the research that I've done in screening whole blood samples for B. microti.

It appears that guidance, final guidance, is going to be issued sometime this year, if it hasn't already been, to test for babesiosis to prevent transmission of the disease.

There was a study done by Moritz, and it was published in the New England Journal of medicine in 2016. And it did demonstrate the effectiveness of donor testing for babesiosis.

And they found that for those who were screened, there were 75,000 screened, and there were no cases of contraction of babesiosis, whereas the unscreened donations, which is 250,000, the transmission rate was 1 case for 18,074 of unscreened units.

So it does appear that the screening would be effective. Obviously, decisions have to be made based on cost-effectiveness and things like that. And, of course, with malaria, I mean it's very rare in the United States, that may change just because of the immigration patterns.

And so that's really where I'm going to end. The only thing that I will add is just from -- I'm just going to add on from the patient perspective, as well as clinician perspective, that for the sickle cell population in general, not only have there not been studies done to document what kind of concerns they may have about infectious agents and the safety of the blood supply, but not having been at the table and also the --

Generally speaking, there is so many layers that add on to the complexity of the disease that in terms of the infectious nature -- the safety of the blood supply, not that it would not be of concern, but there's so many other layers to the disease and living with the disease. And it tends to affect populations that are not, don't have a great number of resource.

So I would suggest that, as you move forward, to look at how that community can be engaged, not just with ASH which is good, not just with SCDAA which is good, but also folks that would not normally be at the table who do need a voice, and at this point, often times may not ask those questions because not being aware that some of the agents, we are talking about infectious agents, would not even have the possibility of knowing that there is a risk.

I mean babesiosis is a good example. The average patient would not -- probably has not even heard of that particular agent. But HIV on the other hand, because of the crisis, which I'm glad it pushed the community to move forward with better testing.

So that's it.

The Chairperson: Thank you, Dr. Poles. Any follow-up questions for Dr. Poles? Oh, I'm sorry. Mary?

Ms. Gustafson: I just have a comment and perhaps a question. Because you had mentioned parvo B19 and red cell transfusion.

And the FDA recommendation, which was actually adopted by the plasma protein therapy industry as a voluntary standard many years before, is a level to protect the first manufacturing pool and the manufacture of plasma-derived therapies.

So there is not -- I think you were talking about red cell transfusions –

Dr. Poles: Yes.

Ms. Gustafson: -- and community-based infections. I just wanted to clarify that point because I'm not aware of an issue with the plasma-derived therapies.

Dr. Poles: Yes. You're correct. I was referencing red blood cells transfusions.

Ms. Gustafson: Okay, thank you.

Dr. Poles: That was what I was speaking to, specifically because that is the product that is used in the sickle cell community.

Ms. Gustafson: Okay, thank you.

Dr. Poles: Yes. Sorry I wasn't clear.

Dr. Josephson: I wanted to -- it's Cassandra.

The Chairperson: Yeah, is this Cassandra?

Dr. Josephson: Yeah. I was just going to make a comment about malaria. So we just had a patient, and it was published in Transfusion, the story of what happened with a patient who was transfused with sickle cell who had gotten malaria in the United States.

And so it is a concern, and it's not a usual concern, and it was somebody who had a travel history. And we found it was a lookback and -- of who the donor was and how we were able to show that the patient had been traveling.

So I just wanted to add to -- that Babesia and malaria is a concern also in the community, the sickle cell community, as well as other infectious issues. So I thought that Dr. Poles did a great job representing what a lot of the concerns are for clinicians and patients.

Dr. Poles: Thank you.

The Chairperson: Thank you, Cassandra.

Dr. Josephson: You're welcome.

The Chairperson: Any other questions?

Dr. Verdun: I would just make a comment. I also wanted to thank you for you for your presentation. I think that -- this was just a general comment.

We're talking about a lot about risk assessment and risk tolerance that can often be different for different patient populations which also needs to be somehow added into the equation of what we are able to tolerate.

Because it's different for an immunocompromised population, a sickle cell population, in terms of, you know, the tolerance of this sort of risk. So I just wanted to make that comment and also echo thanking you for that comment.

Dr. Poles: Thank you for that comment.

The Chairperson: Thank you. Thank you, Dr. Poles.

Next up is someone familiar to all of you, Mr. Mark Skinner.

Hemophilia Foundation (NHF/Alpha 1)

Mr. Skinner: If you don't mind, I've opted to sit. I'm on the downhill side of my recovery. Anyway, it's a great pleasure to be here and to present today.

So first, the disclosure that you've heard from a number of people, I am not presenting specifically on behalf of any organization. I think it may be listed that it's the Hemophilia Foundation and Alpha 1.

But the views are mine, but they're certainly informed from my experience working with a wide range of organizations, including many others within the plasma user community.

My financial conflicts, mostly research, working in the field of patient outcomes research.

So, you know, there's benefits and curses to being the last of the day, so I'm going to move through some of my slides quickly. But I opted not to just kind of completely delete them because a lot of the information has been put out there.

But certainly, the history of the HIV experience in the hemophiliac community is -- all of us know it. That is the reason this committee actually exists.

So just to put sort of my life in context, I do like with severe hemophilia. According to the recent national registry data, of the estimated 10,000 individuals that acquired HIV, including myself, there's less than 750 of us now still living.

So a dramatic toll on the patient community, and probably something that we can't forget, but it has had a lingering effect, both good and I think today, what we're debating is whether we need to reorient from that time.

So we started this morning actually sort of recounting what happened. And I think it is important. So I'm not going to through each of the steps, but there was a long delay from when we had the first indications and evidence of something going wrong in the hemophiliac community.

From the early identifications in homosexual men to what expanded and, it was at the time referred to as the four H club, not the one we all knew in school and communities, but homosexuals, hemophiliac, Haitians, and heroin users.

And so with that early association beginning in 1982, and that was the picture you saw in the previous screen, was the first CDC meeting. But several meetings actually occurred from then later in July in 1982.

Again, we had more information in the fall of '82. Another CDC meeting in 1983. And it was approaching a year later before we actually took the action that began to change the course.

And so the full data set, this is all published by Bruce Evatt who was the head of the CDC hematologic disease branch at the time.

So I think it's sort of important that we begin to think about when do we have enough evidence to act and when do we put -- take steps?

And so what came out of this was the IOM study which has been referred to earlier. And at least, this is my phrasing of the precautionary principle release. I mean this is direct text out of the report.

But I do think there's a couple of things that the community does recognize, that we do need to implement partial solutions, particularly when there's uncertainty and there's a higher risk of harm.

It's already been said today that there's, in fact, an iterative process. And so it is ongoing. And the piece which is often lost, which we've talked about, is the fact that we do need to reexamine and to responds, and to change our decisions when appropriate.

And maybe this, in fact, is an area where we should focus as much of our attention, that is on whether or not we should act in the first place. But we need to be prepared to respond to new evidence.

But I don't think the challenge should be for us just to wait to act for more information. I think we learned the lessons from what that can do with the community.

I think the second thing that came out of the IOM study report, and so I'm not going to cite all of the recommendations, but really is that it is -- it's a shared responsibility, and it includes patients.

And so that's why you see patients like myself sitting on this committee and other federal advisory committees like BPAC. And although the report specifically mentioned the National Hemophilia Foundation, which I had the privilege to lead a number of years ago, there actually are wide range of patient organizations.

So in addition to NHF, the Hemophilia Federation of America, which I know you'll hear from later today, and others, and our other sister disease groups within the plasma user community actually work together globally.

And a lot of what brings us together, in fact, is this shared burden or the shared concern about the safety of our products and access to those therapies.

So here, you see the range of plasma-dependent patient populations, including the alpha 1, Guillian-Barre, immune deficiency, and the platelet disorders, hereditary angioedema, and there are others that -- in the European Association. And so we actually look at these issues on a global perspective.

So the great thing that happened, and maybe there's a little bit of a lemonade story out of the lemons that we were dealt in the 1980s, but it really did radically transform the process.

The plasma proteins industry, I brought this slide from PPTA, the trade association that Mary represents. But what we've seen over the course in time is a number of steps that have actually brought the safety of the products on which we, as plasma-dependent patient populations, rely to, to a level today where there's not been a viral transmission in recent history.

But the last steps, the virus inactivation removal certainly is the largest of these and has the greatest impact upon the process. And I think that's that broad spectrum of pathogen inactivation that is important to us to consider because it's something that's not yet available for the labile components on a wide spectrum.

This is what I just mentioned, is the Tabor study in the 1990s, but basically reporting that there's been no infections since 1987.

So we've had success at least of the large viruses that we've come to love to hate. But that doesn't mean that we're completely out of the woods.

So one of the things that we do -- I also had the privilege to lead the World Federation of Hemophilia -- is we do annually ask patients, what's important to you?

We have a global forum on blood safety and supply issues. And I think it's interesting. You know, supply is a huge issue. And so the affordability and availability of products, which is driven by a lot of factors, is an important consideration.

If you just look at the blue box, pathogen transmission, looking at the trend and those expressing that is what they thought was the biggest threat to patients today.

You can see, at least, globally -- and I think you've heard that from others that pathogen transmission, at least at it relates to the plasma-dependent patient populations, has decreased as a primary concern. So that's part of the good-news story.

But that doesn't mean that we aren't concerned. So again, looking at data, if you were just looking at a typical patient with primary immune deficiency, alpha 1 antitrypsin or hemophilia A, it takes a lot of donations, a lot of individuals to actually make up the products that would treat us for a year.

So 1200 plasma donations to treat a hemophilia A patient, severe hemophilia like myself, that would be on a plasma therapy, or 900 for alpha 1 antitrypsin, and then all of the others that are dependent upon it.

So we clearly, still, as a plasma-dependent patient population have a concern about the safety of the blood supply and the donors on which we rely.

And it's stories like this in 2009, which said there are 68 emerging infectious diseases, that certainly capture our attention. What do we know about these? What do we know about the trend?

And as we've already seen here, the accelerating pace -- and I put a box around Zika just because the association between Zika and Guillian-Barre, one of our sister diseases in the plasma-derived community, certainly peaked our continuing interest.

So vigilance is high on our list. And although we've been fortunate so far that we have not faced a non-enveloped lipid virus, we don't know what the next one is going to be.

So we do have a sense of constant urgency because the pathogen inactivation techniques are not perfect, and there is always the risk that a pathogen could come through.

By the same token, we've seen a lot of data. So this is 2009 data, sort of parallels what you just saw in the previous screen. Each of these addition safety steps comes with a cost.

And so as we're addressing risks, costs are going up. And I think that sort of nicely frames what the balance is. And I think it's important to recognize that trade-off is not lost to us because somebody has to pay for these products. And if they are unaffordable, they're not available.

And so that, in and of itself, is a challenge.

So I did also have the privilege to serve on the Original Canadian Consensus Conference in 2010 that Dana spoke about. I was one of the patient representatives, where the concept to developing a global risk-based decision-making framework was established.

And so you'll see my name on this paper along with other patient representatives. And starting even in 2010, we recognized that zero is unattainable.

In fact, I talked about zero really is a moving target. As science advances, zero seems like it gets farther and farther away because we realized there's something new that we could accomplish if we could invest.

But we also recognize that the safety of the population is paramount. As the end users, we really bear all, if not the vast majority of the risk. And so really understanding what we, as patients, think, the end users whose veins it's going in, would view as tolerable is important.

So having a framework within which these cost pressures, the chase to zero, and the need to have access can be reconciled really helped us, as a group, think about something different than just zero at all cost, but really we need a framework.

So for the past seven years, I've been on the steering community that's developed this ABO project on risk-based decision-making. And it really is that pink box in the middle, number 3. And I don't need to go back through the process.

But the patient participation, which is really at the core of allowing us as patients to feel comfortable about a framework, that if we can be engaged, and we know we're going to be engaged, and have an opportunity to have structured input in a transparent manner, and to know that our thoughts are being factored into the process, we can work within a framework and can educate that zero at all cost is not the reasonable end goal.

And so it is this collaboration that allows us to begin to balance what the two graphs talked about earlier, sort of balancing fiscal responsibility and the need to achieve zero.

It would be nice if we had infinite resources, but we don't. And so what we really need -- and it was sort of the question that I ask earlier -- there really needs to be an active plan for patient participation and for stakeholder engagement.

Easier said than done. I think even in the test cases that the ABO has had in using the risk-based decision-making framework, while many are including patients, I would say it is far short of robust or consistent.

And I think we're all still learning on how that should occur. But I think the sentiment and the commitment is there. And so some of it really is going to be a matter of execution because I think that we do have buy-in that -- in an era of patientcentric care, that patients need to be involved at all levels, from the early decisions about how their products are made, all the way through to the product that they're using and choose to use in the end.

So although this wasn't published as an official statement, plus, one of the organizations I mentioned before, which is the European platform for the Plasma User Coalition, did send a letter to the ABO in the middle of the risk-based decision-making framework.

We worked with the ABO at two levels. We had two focus groups, one in Europe and one in the US actually to go through the framework. Granted, these were leadership of the various patient organizations.

Of course, many of us are patients ourselves. And really to sort of -- to see if we agreed with what the Canadian Consensus Conference said and whether we thought a risk-based framework was an appropriate step forward.

And so here, you see sort of just excepts from this letter. And so again, we affirmed, as patients, that zero risk is almost always unattainable. It doesn't mean that we don't care about reducing risk.

But we really need to manage that interrelationship between risk tolerance, the supply, and the economic considerations. Because the absent supply in and of itself is a risk and a safety concern for those of us that are dependent upon life-saving medication.

We reiterated our position about the precautionary principle and certainly, that last position that I talked about before, that we really do need to be prepared to consider the entire framework, which is recognizing it's an iterative process.

And we all should be removing, and revising, and reducing, and adapting, or strengthening, and not just putting things in place and leaving them there just to add cost to the system.

So we need to be nimble both in terms of rapid implementation, but also in terms of rapid withdrawal if we're going to be able to continue to advance forward.

So I think the balance really is sort of risk aversion, which is sort of the zero risk to risk tolerability and that balanced risk. It's going to be individual. It's not going to be a global standard.

It's going to vary by disease group. It may vary whether you're immunocompromised, whether you're of maternal age, and in pregnancy. And so hopefully, as we move in to more patient- centered care, we can look at an adaptable level or risk that actually takes each patient populations into consideration.

And we're not even lumped together as whole disease groups. But there will be others that are differently situated than myself in the hemophiliac community that may have different risk needs.

This is my quote. It was published a few years in an article on sort of adapting drug development. But for me, at least, it sort of sums up the case and the balance.

The safest and most efficient drug that no one can afford, is not available, or arrives too late, is of absolutely no benefit to me. I recognize that we need to have a -- that we need to have a conversation. I don't want it handed to me without a conversation.

The last thing I would say, and although we're focused on the drug development -- excuse me. We're focused on the testing, and the blood collection process, and having safe products.

But there is a second step in the conversation. The movement to share decision-making, moving beyond just informed consent of patients I think is fundamentally important.

So the conversation doesn't occur just at the beginning, but it occurs all the way through the continuum from having our input on the donors, in the selection, the criteria, and the risk, all the way down to the treatment setting when I'm making a decision with my clinician between product A and product B that's going into my veins, that my clinicians needs to be informed.

They need to inform me and together, we need to make that decision. So I don't think all of the burden is on the blood system. I think we also have burdens on clinicians, and we need to be prepared for them to be educated about what the challenges are.

So I close with this slide, sort of my four critical elements, is continued vigilance because we don't know what's coming next, that we continue alignment with the stakeholders if we have adequate engagement. And you're going to go in to develop that trust that's needed if there's adequate transparency throughout the process.

And then thinking beyond just the collection of blood, and the safety of the blood itself, but what it means at the point of bedside care and educating patients and clinicians. Thank you.

The Chairperson: Thank you, Mark, very much. Very clear and very well said. Questions for Mark?

(No response.)

The Chairperson: He will remain at the table.

Mr. Skinner: Thanks.

Open Public Comments

The Chairperson: Thank you.  Next, we're going to go to our public comments.  And we believe we have five people who have asked to make comments. I'm just waiting for the slide to come up. Just a minute.

I think three of them are here, and two will be on the phone. Thank you. So these are the requests we've received. And we will take them in order. Nathan Schaeffer, welcome. You can make the comment there is fine.

Mr. Schaeffer: This is okay?

The Chairperson: Yes.

Mr. Schaeffer: Okay, great.

The Chairperson: Thank you.

Mr. Schaeffer: Good afternoon. My name is Nathan Schaeffer, and I'm the senior policy director at the National Hemophilia Foundation.

NHF is the nation's oldest and largest advocacy organization for people with hemophilia, Von Willebrand disease, and other bleeding disorders. Our 52 chapters serve the community in every corner of the country.

First, I want to say thank you to the committee members for your service and your commitment.

As a result of the devastating effect that tainted blood products have had on our community, NHF is acutely interested in policies that ensure safe and reliable blood products.

Blood safety is a dynamic and ever-evolving area that has impact, of course, in the US and aboard. We are always mindful of the potential for new pathogens and unknown risks.

Each new challenge will require a complex and often time-consuming risk assessment. And while multiple stakeholders will be included, patients must be central to these considerations as we ultimately bear the ultimate risk, both in terms of safety and availability.

So consistently hearing directly from patients is the best way to understand risk tolerance and the unique challenges and concerns of patients.

NHF has always strived to ensure that patient focus is at the forefront of these considerations, and we know that the committee shares that commitment.

Finally, I want to reiterate that the community is very keen on the updates from this committee and also that of BPAC. In fact, we'll actually be providing an update about the deliberations of your meeting today at our annual conference in Orland next month.

So please remember that we are here to help you accomplish your current and your future priorities. So thank you again for your service and your attention today. Thank you.

The Chairperson: Thank you, Mr. Schaeffer. Ms. Catherine Anderson?

Ms. Anderson: Good afternoon. My name is Catherine Anderson, and I have Von Willebrand disease, a condition causing prolonged bleeding and extensive bruising.

During childhood, I frequently had nose bleeds that would last hours at a time. In my teens, I missed many days of school due to menstrual periods which lasted for more than a month.

And by the age of 18, I had experienced so many episodes of bleeding into my knees that I had developed arthritis.

At age 22, I was prescribed a life-changing plasma-derived factor replacement therapy that now allows me to live a normal life.

I live independently, have found meaningful full-time employment, and have been able to take up exercise without injuring myself.

I've had the good fortune to have been born after the tainted blood crisis. In my life time, there's been minimal risk of transmission of pathogens through the blood products that I have received.

When I received my first dose of factor replacement therapy at age 14 to treat a gastrointestinal hemorrhage, my mother was required to sign a waiver acknowledging and accepting the risk of pathogen transmission.

She recalled the fear she experienced with her own mother who received numerous transfusions of whole blood in the 1970s and 1980s. For more than a decade, they waited anxiously to receive a diagnosis of human immunodeficiency virus or hepatitis C. Fortunately, that day never came for her, but they watched as our community dwindled all the same.

As an adult, I now have to occasionally sign those same waivers, acknowledging and accepting the risk of transmission of disease. For the most part, I'm confident when I sign those forms because I know the regulatory standards that resulted from that tainted blood crisis offer good protection against HIV and hep C.

There's the additional fact that both of these conditions are now quite treatable. My remaining reluctance stems from the fact that there likely are or will be as yet unidentified pathogens that could be passed on to me.

Given my community's history, I encourage you, as policymakers, to stay vigilant against the threat of new or emerging pathogens. Until such a time that technological advances make it possible to definitely remove all pathogens from blood and blood products, regulatory agencies bear the responsibility to set standards for minimizing the risk of pathogen transmission at every step from the time of donation to the time the medication is administered.

As a consumer, I have the right to make an informed decision about how much risk I am personally willing to tolerate. This should be supported by transparency throughout the chain of supply.

Every effort must be made to put patient interest first. My recommendations are as follows:

First, maintaining, enforcing, and improving clear regulatory standards from minimizing risk on the part of pharmaceutical and biologics companies, including broad scope methods for pathogen removal or destruction.

The second, maintaining, enforcing, and improving clear regulatory standards for minimizing risk on the part of blood and plasma collection centers.

The third, ongoing monitoring for and safety notices issued to blood and plasma collection centers when a possibility for pathogen transmission is identified.

The fourth, standards for transparency at all levels of the relationship between blood and plasma collection centers, pharmaceutical companies, healthcare providers, and consumers.

The fifth and final, a plan of action for future cases of pathogen transmission via blood and plasma products, including product recall, insurance of accountability, and compensation and care for persons affected.

Thank you for your consideration of my comments.

The Chairperson: Thank you, Ms. Anderson.

Dr. Fitzpatrick?

Dr. Fitzpatrick: Good afternoon. I'd like to thank Dr. Fredrick and Jim for the opportunity to speak. I'm a former member of the committee --

The Chairperson: Can you speak up? I don't think the mic is on.

Dr. Fitzpatrick: Dr. Fredrick and Jim, I want to thank you and the committee for the opportunity to speak. I was a former member of the committee, and on the BPAC for six years. I was also the head of the Department of Defense blood program, and military blood banker (phonetic) for 30 years.

I'm currently in a private company, producing freeze-dried platelet product. That's not why I'm here today, and I hope you'll accept that.

I'm here to ask you a few questions. First, thank you for serving because I have sat where you sit, and I know it's not easy. You're being asked to do things that are very difficult.

And that's balance, safety, cost, and protection of the patients that you're hearing from. And the patients are the most important voices to me. And we've seen a lot of risk figures about risk of transfusion and risk of infectious disease.

You're hearing from the chronically transfused, and their risks are different. And I think you should use that perspective in your evaluation of what you're thinking about.

We've heard a lot about zero tolerance and zero risk. We don't know it's zero until we're done looking at it. We didn't know the impact of Zika until we were able to test for Zika and screen the population and know what the risk was. Same thing for babesiosis, and Chagas, and dengue. And those risks change over time.

And if you didn't have the donor population need for testing, would a company develop a test for that disease or that agent? And if you didn't have the test, would you be able to then determine what the actual risk is? And what's the incentive to create the test if we're not screening the donor population?

And what we're missing is an exit strategy. Dr. Verdun very clearly stated FDA is faced with an emerging threat, and they have to do something about that emerging threat, and they have to try to do determine the risk without data.

And so they err on the conservative side, which is what I think we would like them all to do. But there's not an exit strategy. Once we have the data and we know what the risk is, and can we control that risk, how do we exit from that?

How do we either stop testing, restrict testing, do testing when we do know there's a risk? And you'll have to grapple with all that. And that's not an easy thing to do.

If we look back in time, this committee has dealt with AIDS and became -- existed -- out of existence because of that. We didn't know what caused AIDS.

Before that, we had a thing called non-A, non-B hepatitis, which turned into hepatitis C and E, and multiple forms of hepatitis.

And as Roger, and Sue, and Harvey Alter guided us through that maze of testing, the blood supply got safer. And it is, yes, the safest it has ever been in history.

But as my job in the military, and as Jim Berger will tell you, you know, we had the privilege of planning for the first war in Iraq. And then we had the privilege of planning after 9/11.

And the problem is not what you know is in front of you. The problem is what you don't know is going to happen.

We don't know where the next AIDS virus is going to come from. We don't know where the next Zika is going to come from. And there's no confidence it'll disappear after a few months.

So in light of that, if we're going to be proactive, instead of reactive, then this committee, and Dr. Verdun and the FDA have to grapple with the problem of what do we test for, how do we convince industry to develop a test, and then what do we do afterwards?

And I don't know how to put that into quality life years, I don't know how to put that into statistical algorithms that will give you an easy answer because there are lots of permutations that fall around it.

I know that if you look at Malcolm Gladwell's books, we may be at a tipping point. Things here are indicating that there are problems potentially with the sustainability of the blood supply; there are problems with manufacturers of blood materials that are need; there's no incentive for innovation; there's no incentive for research.

And what would happen if we put a fraction of the money being used for some of the tests that some feel are no longer needed into innovative research for blood farming and producing red cells, and platelets, and plasma from something other than a volunteer donor?

Those are recommendations you can make to the Secretary. The Secretary has to act on them, but unless he hears from you, he will have nothing to act on.

So every cloud has a silver lining. In this kind of gray cloud we have, I think we have the confidence that you can react these situations. We have the experience that, over time, the right decisions have been made to protect the safety of the blood supply and the patients that are chronically transfused.

Dr. Katz has been in the same position that many of us have been in the past, which is during the AIDS crisis, I was put in charge of screening all active duty personnel in the Pacific, and then notifying them with the assistance of other doctors that, I'm sorry, you've tested positive, and so is your wife who is pregnant, and so is your six-year-old child.

And at the time, that was a hundred percent fatal disease. So while we shouldn't be constrained by the past, we should learn by the past, and we should be proactive in trying to prevent the past from happening again in the future, or hog-tying us to costs, and requirements, and regulatory burdens that make it difficult to do our job but ultimately protect the safety of the patient.

So I'd ask you to consider that in your deliberations and your discussion. I would ask you to consider that there should be exit strategies for unknown emerging diseases, and that once you have good data, then you can implement an exit strategy.

But in the face of that, I would say that the precautionary principle has held true and worked. And if it's not broken, don't necessarily try to fix it.

The Chairperson: Thank you, Mike.

And we have one last open comment. Deema Tarazi, I believe is on the -- oh, is on the phone? Oh, I'm sorry. Hello.

Ms. Tarazi: Hi, no worries.

Good afternoon, advisory committee members. Thank you for allowing me the opportunity to make public comments during this meeting.

My name is Deema Tarazi, and I'm here today representing Hemophilia Federation of America, which is a community-based grassroots advocacy organization that assists, educates, and advocates people with bleeding disorders.

As you heard today, the hemophiliac community has a painful history with blood-borne transmission of infections. As a result, we have a strong stake in ensuring the safety of the blood supply.

As I outline in our comment letter, I'm here to touch upon our six key principles of blood safety from the patient perspective.

One, patient safety must take the highest priority. Patients bear the ultimate risk in the event of blood-borne infection as they are the end user of these blood products.

We urge policymakers to put patients first and to articulate and implement policies that have as their goal the promotion of quality and safety and the highest possible standards in all aspects of blood transfusion and manufacturing.

Two, blood safety policy must be based on rigorous science. The past four decades have seen a significant advance in knowledge and a corresponding decrease in risk with respect to blood- borne infections.

But regulators and industry need to continue investing and accelerating new safety innovations to address the remaining and emerging threat. It needs to be continued on the base of science and rigorous standards.

Three, the federal government bears responsibility to maintain a strong regulatory framework, investing resource and blood safety, and enforcing safety standards.

It's imperative that government agencies continue to adequately use their regulatory authority and to continue to question the assumptions underpinning their decisions.

Four, the policy-making process must be transparent and inclusive which involves meaningful patient and end user input. As patients bear the ultimate risk of blood-borne infections, they should have a voice in setting priorities, have representation in policy-making process, and be able to express the concerns most important to them.

Five, users of blood and blood products are entitled to clear disclosures that allow them to understand the risk they face and truly give informed consent.

And six, the federal government should consider establishing a no-fault compensation system for individuals who suffer adverse consequences from the use of blood or blood products.

20 years have past since the IOM report made this recommendation, and yet we still lack a system in place for relieving hardship in the event of future transfusion errors.

In conclusion, most patients understand that a blood supply with a zero-risk may not be an attainable goal but nor is it enough to say our existing system does a good job enough at protecting against risk of transmission of known pathogens.

Our nation needs a blood policy that puts patient safety and patient interests at the center, including robust patient involvement in the articulation of standards, recognizing that patients bear the ultimate risk in the event of blood-borne infections.

Thank you for your time and consideration of my comments.

The Chairperson: Thank you, Ms. Tarazi.

And thanks to all of our people who spoke in public session. Committee Discussion

The Chairperson: We are now going to turn to the purpose of our meeting and engage in committee discussions. And Jennifer is going to put up the slides I started with.

While we're putting the slide up, those of you on the committee who have hotel receipts for your room, if you give them to Renee before you leave, it will enable reimbursement, in a timely manner.

Okay. Going back to the purpose of this meeting was to begin to define a tolerable infectious disease risk in blood safety from a patient's perspective.

And I think we've had a thorough review of certainly what has happened with infectious disease in the last three or four decades. We have suggested that we might begin this discussion around these three areas, discussing whether there are key gaps in our understanding around blood safety -- I might say blood safety at-risk and risk. But we can talk about that.

Discussing any studies, we might need to facilitate, and then moving on to -- and what would the committee like to do about that. One of the suggestions might be to form a subcommittee to take this forward.

I would ask committee members, are there other points of discussion we should include in addition to these three? And where would you suggest we insert those topical areas?

Lou?

Dr. Katz: Well, I think that -- there's been a lot of discussion of risk-based decision-making, and we've seen the sequential process, actually cyclic process several times.

It's very, very difficult. RBDM doesn't presuppose outcomes independent of the policy foundations of whoever is making decisions. And I think one of the things -- one of our big gaps is in articulated policy foundation that can be shared across multiple stakeholder groups.

So at some point, as we consider this issue, we need to be able to articulate the policy foundations that will undergird any risk-based approach.

The Chairperson: Thank you. Yes, Dr. Kotton?

Dr. Kotten: Given that the focus is on blood safety from the patient's perspective, I was thinking that the -- discussing key gaps in our understanding of blood safety risk, there's both maybe people sitting at the table but also the patient's perspective and understanding blood safety risk.

Coming more from the organ transplant field, but certainly understanding blood transfusion- transmitted infection, I think that there is very little understanding of the current risk of infection, and then things like the comparative risk of other issues.

You know, when I talk about there's higher likelihood that you would have died driving to my clinic visit in your car than undergoing either a transfusion for an organ transplant, et cetera, I think that I would probably just make bullets, sub-bullets under the key gaps in understanding of blood safety risk, both patient and care providers, family members, et cetera, and then also the medical community.

The Chairperson: Thank you. So that would be under what our key gaps are, right?

Dr. Blumberg: Yeah, and I would add to that. I think the issue of how mitigating risk is going to impact on sustainability.

Dr. Kotton: I think that's a really key point. This is something we deal with a lot in organ transplantation, that every time we turn down an organ donor, it means there's a chance that someone will die because of that decision.

And one thing that we don't talk about -- we talk a lot about screening people who make it in to donate blood. But there's so many people that assume that they're not going to be good blood donors.

And the more barriers we put up, the more people who don't even step foot into the donation center to begin with. And so I think that really affects the plasticity of the system, the ability to have donors, et cetera.

So there's -- the more barriers we put up -- we need to be thoughtful about it so that we don't really reduce the number of available donors.

Dr. Josephson: This is Cassandra. I don't know exactly what thing it sits under, but I was really wanting to focus on the end users, the clinicians in all different areas.

I feel like, you know, in hospitals -- I don't feel like there is a real understanding when people are doing consent with the patient of what the risk are and how to talk about the risk.

And so I don't know whether the focus groups that were being, you know, mentioned before as a strategy or -- coming up with a strategy to talk to clinicians who are the people who are getting consent from the patients.

I think that's a big gap in how to -- how to approach this with the patients themselves.

The Chairperson: I'm just ignorant on this. Do physicians consent or do other care providers consent?

Dr. Josephson: It is supposed to be the physicians that do the consenting.

The Chairperson: Okay.

Dr. Josephson: And I can just tell you from educating new doctors, residents, and educating doctors who have been around for a long time, their understanding of how to talk about the risk is very thin in their understanding in depth.

And I think it starts there a little bit because if there's not a good understanding with the person who is contacting that person and trying to get informed consent, then I'm not really sure how we're going to be doing a good job conveying what the perceptions -- either what people are scared of or what they're being told are the risks. So some kind of campaign to understand that.

The Chairperson: Thanks, Cassandra.

Dr. Josephson: You're welcome.

The Chairperson: Alex?

Dr. London: Yes. So this has been really, you know, a crash course for me. I'm not a blood person. So I'm coming to most of these statistics for the first time, so I really appreciated

Dr. Dodd giving the -- the training-wheels version. That was exactly the level at which I needed things.

So there were certain things that were not clear to me, and so I'll say those. And then I think there are cautions that I have to -- that I want to raise.

One thing is not clear to me is the extent to which some of the risk statistics that we see are conditional on our current practices, such that if we change our current practices, then those risk statistics are going to change.

Because any plan for the future, then that's based on that kind of conditional probability; you just have to make sure that you're not changing the underlying conditions that gave you those -- that degree of safety in the first place.

We saw risk statistics, but it seems to me that they have to be very unequal for different groups blood you have patient populations that are being transfused hundreds of times, individuals being transfused hundreds of times.

And immunocompromised populations where the -- I don't know the average degree of susceptibility isn't going to be adequate, they are much more susceptible at lower titers or concentrations.

And so then I think there are questions about equity, given that we're talking about risk across very diverse populations, some of whom bare greater health burdens and utilize the systems and maybe underserved in different ways.

So I think those are very concrete ways in which risk bundles together in a single statistic a variety of considerations that are often heterogeneous and need to be unpacked and dealt with separately sometimes.

It's not clear to me -- I think I'd like to know more about cases where risk can be reduced on a targeted basis. So we saw the one example of screening blood that would go into a very particular use for a population.

To what degree are those kinds of solutions available? Like what cases, what areas are those kinds of solutions available versus screening the whole population?

And finally, I think we have to be very, very careful about risk comparisons. It's just not -- I think it's extremely controversial to say that we accept the mortality rate on the roads or that we accept the mortality rate from normal medical error. I think, if anything, those are regarded as unacceptable.

The current drive towards, you know, autonomous vehicles represents our own, you know, the current system, driving cars on the road is horrible. And everybody recognizes that. So we can't condition off of unjust or unacceptable conditions when we make risk comparisons.

Finally, I think when we talk about cost-savings, as it come up several times, I think it's very different when there's a system of very well-integrated and closely causally related supply and demand where changes in that system ripple through -- you know, so hospital acquisitions or, you know, some of the other examples versus making comparisons across systems where utilization is going to be completely independent, where there's no guarantee that if you save money in one place that it's going to somehow miraculously be used to reduce medical error or something like that.

So I think those kinds of comparisons have to be dealt with very carefully.

Dr. Basavaraju: Hi, this is Sridhar from CDC. Could I make a comment? Is that all right?

The Chairperson: Yes, absolutely.

Dr. Basavaraju: So I agree with Alex, who just spoke, I think, about how we talk about tolerance of risk. And I just want to agree with him that I don't think we -- I don't think it's fair to compare the rate of injuries or death in car crashes with risk in blood transfusions.

There's something inherently inevitable about having to get on the road the way that society is configured. So I agree with him. I think we don't tolerate risk there as we have seat belts, blood alcohol, laws, and speed limits, and things like that.

The other thing I wanted to talk about is I think the idea of risk-based decision-making is interesting. And I think applying something like that in the United States would be useful.

But I think that if you're going to task a subcommittee with something, I think it would be useful if there was some exhaustive description of how risk-based decision-making in blood safety is done elsewhere and what are the potential models that could be adopted in the United States, given the way the blood industry is configured, the way transfusions are performed, as well as the regulations and laws that might apply to blood safety in the US.

Because I think -- I think that the tolerance of risk would probably be better understood doing that, as well as the decisions that could be made given how health (indiscernible) works here in the US.

The Chairperson: Thank you.

Dr. Custer: So Jackie, if I could make a comment? Because I guess I'm hearing this. Of course, we want to have -- define what we think our tolerable risks.

But at least, to me, to a little bit, that is maybe missing what the larger purpose of risk-based decision-making or something like this which is a prioritization exercise.

So nobody wants intolerable risks, however that's defined. It's that choices may have to be made about which risk is tolerable and which risk is not tolerable.

That's where I think, in particular, for example, the risk-based decision-making framework excels at making sure that we do get stakeholder engagement from voices that we might normally hear in policy debates like patient groups, that a possibility of also expanding that to be maybe clinician groups.

But just making sure that we're hearing voices, that does not change the difficult point of making a decision, whoever is charged with making that decision.

But I guess I'd like to -- when I think about risk, again, it's more about how do we think about -- not competing risk but that there are different risks.

And we want to do everything we can. How do we do the best job of balancing?

Dr. Blumberg: Sort of going on a slightly different direction, I think we also need to think about setting some sort of standardization of how we're going to deal with testing for emerging infections.

And so there has to be, in the face of this, a way to respond to epidemic, potential epidemics, you know, and implementation of testing, and understanding when it's appropriate to do mass testing versus focused testing, you know, in terms safety parameters because I think the thing we learned from Zika is that it's sort of made things very complicated by hitting localized areas where then there was no way to guarantee safe blood supply there.

But being, for the moment, time-limited, so how do you deal with knowing when you can stop testing? West Nile is perhaps a good example of having a more strategized plan for implementing testing that's I think potentially costly and impacts on financial concerns within the industry and that sort of sustainability. So something to consider.

Dr. Custer: So I guess I'd like to make one more point.

This is now about cost and I feel a little bit about danger going into this territory, but I still would like to make the point, which is if we know something is not really achieving a specific safety objective, even if those resources are not going to go to some other alternative use, it is bad policy to continue to do things that are not effective.

So we have to careful about that. So we speak in this industry about the Chagas effect. We knew when we switched from universal testing to one-time testing that there was going to be a price to pay, and indeed, there was.

But many in the industry said, that is a price we're willing to pay in our negotiations vendors because we're setting a precedent for how we think about and deal with risk.

So we don't just ignore cost; we may have to do some things we might not like to do, but we can't actually act like there is an infinite budget, even if we don't reap the benefit. There is only a certain amount of money in society.

The Chairperson: Mark?

Mr. Skinner: So maybe it's the lawyer in me. Sort of challenging the premise of the question, I sort of had a couple of things.

So first of all, the purpose of the meeting, define a tolerable infectious disease risk. And I'm not sure there is a single tolerance level.

So that's sort of why, I think, we've been talking about a framework. It's a process within which a decision can be made, and different levels of tolerance may be decided. So I do sort of challenge the premise and maybe just, you know, striking the A would make me happy. But it's defining tolerable risk and that it may be variable.

The second thing I'm struggling a little bit is, who is our audience for this recommendation? Are we offering guidance to the Secretary that would flow to the FDA so that as they're considering actions that they would understand risk?

Or are we offering guidance that would go out to blood centers where they have discretionary decision-making about whether they're going to implement one system in their blood center and the neighbor state is going to do something different?

Or we are offering guidance, you know, all the way down to the physician level that's making a choice between two products that happen to be on the market, and how they decide which one they offer to the patients?

And it may vary between all those? I think we're closer to the beginning of that process, is trying to guide sort of regulatory decision-making which then would inform the other.

And so maybe just -- if we can be clear on who our audience is that we're wanting to inform, and then we could build out from there. But maybe I'm the only one that was confused, so --

Mr. Berger: I wouldn't say --

The Chairperson: Yeah, I was going to ask you the –

Mr. Berger: I think that's a great point --

The Chairperson: Because of your policy foundation.

Dr. Katz: Well, my policy foundation is if I have to do it, it has to be paid for. I'm just an old doc from flyover country, and things are pretty simple to me.

And that is that FDA appropriately applies the Public Health Service Act and the appropriate enabling legislation, and they deal with safety, pure and potency. That's their job.

And so Zika comes around, and our best judgment, we did what we did. And it doesn't get paid for. It kind of does, but it doesn't really.

So my bottom line is I learned in HIV and HCD (phonetic) that it was paternalistic of me to think that I knew the right answer, and I no longer know the right answer, and that we have to make due diligence to engage the appropriate stakeholders. At which point, a decision will be made.

But it can't be unfunded mandates. So FDA at one of HHS says, thou shalt test for serum (indiscernible). CMS, at the other end, has to be required to pay for it.

I don't think we can wait three to five years for adjustments and reimbursement that are based on crappy data from the hospitals anyway, unvalidated and crummy data.

So at the end of the day, a requirement that there not be unfunded mandates, that CMS has to listen to what FDA is saying, and that the hospitals need to pass it through to the people selling their blood would go a long way to solving the problem.

But at the end of the day, as a blood banker, it ain't my call anymore, and that's probably a good thing. I sit at the table with a much more diverse group than we did in the early '80s, and that's a good thing. Just pay for what we're being told to do.

The Chairperson: Steve, did you have a, okay, question?

My answer, Mark, to your question might be what we want is an integrated risk-based decision- making process that it would involve key stakeholders so that we could make policy.

I might suggest that the audience is BOTSEC. It's really -- BOTSEC is the group that -- where all the key HHS leaders sit to make decisions about an integrated policy foundation.

That's where I thought you were going, Lou, before on the -- in that we would have a decision- making body that within the Secretary's Office that could make those decisions across CDC, CMS, FDA.

Mary, I think you had your hand up first? Then Alex.

Dr. Macsai: Well, I have to totally agree with the cost issue. It cannot be swept under the rug. It's been brought up before; it needs to be brought up again.

Blood is necessary to keep us alive, just like a kidney, just like a cornea. And if we're going to mandate testing, then we have to pay for it, and we, being society, being CMS, not the individual recipient. So that's number one.

And number two is the word "tolerable" because I think it's very -- it's a complicated word because you don't want to tolerate that which you have no treatment for.

Yet I think we know, and we've learned from organ communities, that when you have a limited supply, you will tolerate risk, right?

So if I'm going to die and you're going to give me a kidney from someone with hepatitis C, I don't care; there's a treatment for that. I'll take that kidney because I want to live.

So I think the word "tolerable" is a little complicated because -- we have a treatment for syphilis, but we still test for it. We have treatments for diseases, and we're still testing for them.

Granted, I don't want to give anyone a disease, and so I want all of the patients here to understand I want it to be totally safe. But I think we sort of have to prioritize that which will kill you, we have no treatment for, over that which we can treat.

Like a strep throat, we can treat that. Okay, certain other diseases, we can't treat. So there should be some stratification of the word "tolerable" because we're talking about infectious diseases, many of which we have treatment for and many of which will not kill you.

The Chairperson: Alex?

Dr. London: I just like to try to tease apart four different questions that I've heard, that I wouldn't want to see conflated.

The first is that zero events doesn't mean zero risk. So it's perfectly a reasonable question, what threshold with safety would we like to see for disease transmission events in our blood supply? There's nothing wrong with that question.

The second question, how can we evaluate incremental gains or losses from different transmission mitigation strategies. So this goes to Brian's, you know, at what point is it -- you know, just -- are we doing something that doesn't work or is not effective?

A third question is if the blood supply is in danger, to what degree should screening and safety mandates be adjusted with a goal of promoting solvency?

To me, that's a very different question about how to affect a much large economic system and the degree to which risk considerations should be the lever that we pull in order to achieve that goal.

And the last question is, how should the cost of mitigation strategies be weighed against the cost of trying to influence other factors that influence the sustainability and availability of blood products?

Those are four very different decision problems, and it's not clear to me that the same set of considerations is in play in each of those.

The Chairperson: Thank you.

Dr. Verdun?

Dr. Verdun: I was just going to make a comment about the syphilis conversation because I didn't -- I think that again, we have to sort of appreciate differences in terms of patient populations, in terms of the population that's being transfused.

I bring -- I think syphilis is actually a good example. To say that it doesn't cause death and that it's treatable, in certain populations, it does. And there's, you know, there's tertiary syphilis which, in 30 years, can kill you. It can damage every organ in your body.

So I think that there is -- I mean there are certain -- when we talk about risk, I think we just have to sort of, you know, think through not just -- Alex also said this, and I feel like I'm repeating myself a little bit.

But not just the person that's getting a one-time donation -- one-time transfusion but those that are getting lifetime transfusions. And there are other considerations. It's not so simple.

You know, another thing, I think from an FDA standpoint -- I'll just sort of throw this out here. I mean when we have the next emerging -- I've heard the conversation today, and I understand and I appreciate that we -- that increased stakeholder engagement is good for everyone. And having multiple voices for at the table is good for everyone, with decision-making, with policy- making, with -- you know, with the regulatory oversight.

I think all of those things are important. I would also sort of challenge the committee -- because I've also heard a lot about the Zika experience. I'll put it that way, the experience.

And so you know, I would like to hear from people with the next emerging pathogen that could -- you know, at the point at which we, you know, become aware that there is this

possibility of this -- of something that could potentially cause irreversible harm. Let's just put it that way.

How would this committee want to approach that? You know, like from a prospective standpoint, how would you like to approach that? I think that conversation would be helpful to have.

The Chairperson: Mark?

Mr. Skinner: I think you've raised a really important point. And within the concept of the risk- based decision-making framework project that the ABO did, we actually talked a little bit about sort of when you would apply a framework.

Because you cannot possibly make every decision within a blood center or a hospital using the framework and go through the process. So there has to be a logical triage.

And the precautionary principle really is that which would govern an emergency emergent situation. And at some point, we have to trust the process and the leaders that are making that decision in days, and hours, and weeks.

And then you know, sort of relative to what we think the likely impact is or the cost, then for some of the bigger decisions, like do we implement universal pathogen inactivation sort of across the country?

There is a framework then within which to make that conscious decision, yes or so. And so I think we have to assume that there's a triaging process.

I would be the last one to advocate, because we probably couldn't afford that either, or we'd all be bogged down in meetings, a risk-based decision-making framework process for every single decision, a blood center is going to make.

But I think it does help us on a lot of big policy issues. And there probably is a gray area between the two.

Dr. Verdun: And I agree that we need to continue to -- with each of these, the tests that are implemented, we need to have a continual dialogue and potentially peel back things that don't make sense anymore. I completely agree with that as well. I want to say that.

DR. KATZ: Well, just to use the Zika example, there were other things beside universal individual donations they had on unapproved platforms that could've been done.

And so we had four cases of apparent transfusion in Brazil with no morbidity. We know that in the first two trimesters of pregnancy, transfusion is rare as we say in flyover country as hen's teeth. So the people most at risk, in fact, weren't at much risk because they don't get transfusion.

We know in the United States, within broad bounds, where the vector is, so where the risk of autochthonous transmission occurred, and it's a strip of states across the southern tier.

So there were lots of other things. Now, that said, the decision was made, and we did it, and now, we need to roll back. So it's in the past, and we lived with it, and we did it. It'd be hard to do again.

The Chairperson: Steve --

Dr. Verdun: Have you addressed travel too? Because that was also a huge component of --

Dr. Katz: Well, we had the surveillance in the US that said, yes, there are travel-related cases. But the real risk was going to come from autochthonous epidemic transmission in the southern tier of states.

FDA made a precautionary decision with input from up the food chain in the government as well. We get that, and we did it. Once it was done, we lobbied, we lost, and now, it's time to consider to roll back.

But there were lots of other ways to do it than what was done. And it seemed, to some of us in the blood community, that the approach chosen was zero risk. And we weren't sure that was appropriate.

The Chairperson: Steve had his hand up here.

Dr. Sloan: I just wanted to say I was very impressed by the people from the FDA who spoke and did talk about they were using -- they were weighing risks and benefits of various policies in general, in the general approach. And that was very useful.

What the FDA, however, didn't do was include considerations of economics because the economics, in fact, impacts sustainability of the blood supply. And they didn't include, it sounded like, a stakeholder engaged, transparency, and other mechanisms to ensure trust in the process.

And so I think in that -- for that reason, a risk-based decision-making framework for many decisions would be useful. However, one has to -- I totally agree, one has to carefully consider when to utilize that.

And for a quickly-developing situation like the Zika virus, I think one -- it may not be appropriate to use it right then and there because it takes a while to do RBDM.

But it would be nice to enhance the FDA's current approach so as to include more stakeholder engagement, get more trust, and somehow include the economics of the situation.

Dr. Verdun: Yes, stakeholder engagement, number one. I just want to say something about that. That has to include all stakeholders, right?

So it's not -- and that includes patients, and that includes their families. And so I just want

to -- I'd want to mention that when we talk about stakeholder engagement, what that actually means to us.

And we really do have a mission of protecting public safety. You know, you mentioned that FDA didn't take into consideration costs with some of those early decision-making, with some of the early decision-making with the Zika virus.

I think that, you know, our particular mandate, when we have emerging threats, to the blood supply is to consider public health and to make decisions based upon that.

And so I also wanted to sort of just make sure that that's known.

Mr. Sloan: I totally understand that. I absolutely applaud what the FDA is doing in terms of trying to protect the safety. It's sort of gets to me with that tolerable infectious risk.

A lot of it depends on the -- not just the severity and treatability of the disease, but how much it costs to prevent it. I mean if there was a disease that was treatable, but it costs a million dollars to test every unit, we may say it's not tolerable.

But if it's treatable and it costs 10 cents to test every unit, it's tolerable -- that's something that we don't want to tolerate. I mean it's such a balance there.

So I think economic tests be included. I'm not saying that the FDA is not doing its mission in trying to protect people as much as they can. But in the end, to also protect the sustainability of the blood supply, I think a more in-depth analysis of our RBDM is appropriate in some sense, for some decisions.

Dr. Custer: But just quickly to follow on with that, so that's not going to be in the FDA mandates. So again, going back to what you had said, Jackie, is that something that's a recommendation this committee makes at the BOTSEC level, at some different level? Because we are not changing the rules.

The Chairperson: Emily?

Dr. Blumberg: I think I would look at the Zika thing a little bit differently because I think what it showed us was how difficult it is to ensure safety with an unpredictable epidemic.

You don't know where it's going, and you need to act in real time. And so I note it seems people are being critical. I think it's more that just trying to understand the process.

And maybe what would be the most useful is the understand or have -- you know, for this committee to understand the process, what's the step-by-step way that the FDA recognizes this pot emerging infection that will have potentially tremendous impact on the blood supply, how to act to developing -- putting safeguards in place in rapid time, and assessing the impact of this, all as it's, you know, actively occurring.

And I think maybe the issue is that people felt like they didn't totally understand the process. Or, you know, I think from the organ transplant standpoint, that's the part I can talk about most easily, is that we were told, test the donors, and we didn't really know most OPOs (phonetic) had no access to testing of donors.

And so it becomes complicated. And so it's almost an understanding of process and involving stakeholders, not in the individual epidemic because that's impossible. It's impossible.

But just in sort of the development or the understanding of the process so the people can see and assess. And so that in the development of the process, something that may have impacted on cost, which you're not going to be able to deal with at the time it's ongoing -- but all of these things can just be clear to the individuals who are going to have to be implementing the recommendation.

It's just a little clearer. And, you know, people have a sense how to proceed. I think everybody feels that the FDA is trying to protect people. It's not that. It's just trying to deal with some of the practical implications may be are the harder part.

The Chairperson: So what I'm hearing just a little bit about this -- I don't want to get in too deep into Zika -- is that one of the gaps we need is to really understand how the decision-making processes prospectively work and how this is playing out.

I mean I think we're doing the right thing going back now, after we've looked at the data and we're changing our practices. I would also say, having been through testing for a lot of years, you know, this happened -- Puerto Rico needed blood, what, April 1st; we got them, every drop of blood they needed.

And I believe the test was available in Tampa about the same time, is my recollection. So in one way, there was some process, and a good process, that allowed us to get to there.

So what I'm hearing from everyone is, what do we learn from Zika that we can -- we have a gap in understanding, I think, the process and how, if we came to a risk-based decision-making framework, we could improve upon it.

That's the gap I'm hearing as -- is perhaps a lack of understanding the process, and communication, and engagement.

Dr. Ratcliffe: So I think this is an interesting discussion because I think we think about risk differently when the risk is known like bacterial contamination of platelets.

I mean we've been living with that for many years. We sort of have been taking our time to implement strategies that we think will improve the safety, but we haven't rushed to do that.

Whereas when you have an unknown risk, like the Zika virus, and you don't know what the impact is going to be downstream, you know, we were less tolerant of that particular risk, especially with the population that might've been most at risk even though maybe they don't get transfused as frequently.

It would just have taken one transfusion to a pregnant woman and it's a call like that to just really -- I think public trust in the blood supply again. And I think that's one of the considerations that organizations take into account when they're making public policy like that.

You know, I just want to put a plug-in. I think that as we go forward with this initiative, I think supporting hemovigilance and biovigilance has got to be a critical element of whatever we decide to do as far as assessing risk so that we can at least have some better understanding of what the risks are.

The Chairperson: Thank you. Very good. So I'm hearing pretty consistently the framework and how we use it in different situations, it's not one-size-fits-all; it depends on the context et cetera.

Martin, I think you want to say something?

Dr. Ruta: Yeah, I was going to agree with you, Jackie, and elaborate on it a bit.

So it depends on what the agent is and how immediate the threat is. We generally try to go to the advisory committee to get advice from the advisory committee when there's a threat.

And we did that with Babesia and we actually went back a couple of times to the advisory committee. We tried to have workshops; we did that with Babesia. Then we issue a guidance, and the guidance is open for comment.

So that way, the world, the public can comment and say, we think this is a good idea, we think you should do it differently.

In the case of things like Zika where it was a rapidly emerging disease, the department felt we needed to take action, there's not time to go to an advisory committee and, you know, wait and get that kind of input.

So we acted more immediately. But then what we did is we went back to the advisory committee afterwards and say, this is what we did, what do you think?

And I think we opened up to the committee and to the public a fair range of options, and there was a broad discussion there. And after considering the options, we then went to a revised guidance document.

So FDA has a number of formal ways. So we get an input on policies. And one of those ways is through the advisory committee where the committee can advise us or members of the public can get up and speak.

And the second way we can get input is through guidance documents. And that way, the public gets a chance to comment on the guidance document and make suggestions for change.

And I think the paradigm that we've tried to follow when we can, and most often do, is go to the advisory committee first -- actually, usually have a workshop first, go to the advisory committee, and then write a guidance.

And at each step of those, each of those stages, we're open for public comment.

The Chairperson: Thank you.

Dr. Ruta: So Zika is more of the unusual circumstances where you're trying to respond to an immediate threat that we become aware of. And generally, we become aware of these immediate threats through dialogue with CDC.

The Chairperson: Thank you, Martin. That was very -- oh, I'm sorry. Marilyn?

Dr. Levi: Hi. So two comments. And I apologize to talk about more about Zika because that's the most recent pathogen. Who knows tomorrow what is the new pathogen.

But I actually applauded the FDA's plan and implementation of an emergency IND for two companies, I think, that -- so this was industry, was given these emergency IND.

My question is, my understanding is that they did not get reimbursed for their testing. And so it basically speaks for the importance of industry commitment, and if necessary, financial support for testing if some -- for the next pathogen that comes up because I can just imagine the investment that these companies in testing.

Dr. Verdun: Great point. You know, I can't get into some of the specifics of it, but I think that that also is a point that was brought up earlier today.

But when you have these emerging threats, you need to get test developed quite rapidly. There is some negotiation that has to happen there to get that done.

You have an emerging threat where you know that basically severity of outcome could be pretty bad, you don't completely know the incidents, you don't completely know the prevalence at the time, but you know that it's emerging.

So these are all things that, in terms of decision-making, at the time, you have to do these things quite rapidly.  And I do think that that's an excellent point, that that's another stakeholder in this entire discussion, is how to get these tests developed and, you know, without really knowing how things are going to sort of play out over the course of the next year. That's also a challenge.

Dr. Basavaraju: So this is Sridhar from CDC. I just wanted to -- so I think that -- and I guess maybe, you know, somebody from FDA could maybe clarify this as well.

I think BARDA did actually provide funding for blood through the development of blood screening tests for Zika, at least from what I remember. So I think that they did receive some funding for it.

I think Zika also, to talk about some of the issues from our perspectives at least, on the risks that Zika posed to the blood supply, so there was several.

There's one that Lou mentioned, possible, like mosquito-borne transmission within the United States, so we did see that in some areas.

Then there was return travelers, and we saw hundreds of those in the US. And then there was also the risk of sexual transmission. And there was some sexual transmission cases that were reported.

We didn't know at the time at least to degree to which sexual transmission could propagate the epidemic. So I think that there were multiple sort of moving parts in the epidemiology that I think, you know, warranted pretty quick action.

The Chairperson: Thank you. Not as chairman, as a committee member, some other gaps that I think need to be identified -- are identified that I think need greater understanding is meaningful stakeholder inclusion that does engage people along, what I call, the value chain of the transfusion, so to speak, vein-to-vein.

I think Canada had a nice group that they could go to, but I think offline, a lot of us have talked about, you know, one or two patients at the table don't make inclusion.

And I think Cassandra talked -- I think it was Cassandra -- that we have to get the clinicians and the physicians that transfuse there.

I think the other thing that's missing is -- all the healthcare systems I know about have mechanisms for ethical decision-making and risk-based decision-making.

And I think we need to understand how healthcare treats other activities like this and learn from them. So not just look at what's available throughout the world, but I know particularly academic medical centers have to have robust ethical conversations and risk-based decision- making. How do we learn from that and use that? That was a second observation.

A third was I suspect we still need -- we still have a gap in our understanding about risk and ethics, and risk perception. I mean there's experts in the field in these areas.

Certainly, in the blood community, I'm not sure -- this has been pointed to me several times. We use words and we all don't understand what the words means in terms of risk, and safety, and tolerable risk, and quality life years et cetera.

One is we need to understand more, I think, and have experts at our table around risks, and ethics, and legal, health industry, perhaps risk management people at the table, need to work, I think, towards some common definitions or understanding about the words we use in here so we know what we're about.

And then Lou, I thought this is where you were going before with policy foundation.

But I think Mark, it was a great question, who's the audience, and what is it we want to deliver, and why do we want to deliver?

I have gotten feedback from a lot of people in preparing for this assignment. A decision-making body that can consider cost as well as optimal patient safety, availability, et cetera.

How does that all come together in an integrated and iterative -- iterative process I think is key. So those were just four other gaps I identified.

Jay?

Dr. Menitove: Jackie, just a couple of comments. One is that at least I heard several times with Zika, and so is there a lesson learned opportunity for that?

And that, to me, is a gap. I mean there's obviously lots of opinions about that. And so I think that would be helpful.

The other is I've heard a process for this, a process for that, and a process for something else. And that's, to me, very understandable. If you have an emergency, you have to move, and someone's going to make a decision.

But when you have multiple processes, there needs to be something overarching that, a policy. And I'm not sure that there is a policy. I'm actually not even sure you want a policy. But I do think it's a gap that should be addressed.

The Chairperson: Okay, thank you.

Dr. Verdun: I just wanted to add a separate, completely separate point that I think is just worth mentioning. I think we also have to, just in general, think through individual risk assessment more in terms of donors which this gets a little bit to some of the considerations that we've been discussing with MSM and otherwise.

Not to bring up a completely different topic, but it does get into risk, assessment risk, risk tolerance. But I think that that's something else that we plan on working on and working through in terms of individual risk assessment of donors. I just wanted to mention that.

The Chairperson: Okay. And I think we -- we're probably going to end up having to go there because of the other donor safety issues we're dealing with now and considering. And those are clinician in nature as opposed to infectious in nature.

So I'm getting the sign that we, probably in the next 15 minutes, need to get agreement on how we want to go forward to continue to advance the discussion of tolerable infectious disease risk.

And it sounds to me like we have perhaps a lot more learning and understanding to go through before we are ready to start talking frameworks or anything like that, that there's more learning to do in terms of what we're doing in this country, certainly with FDA's process,

what -- someone mentioned internationally, where's the gaps in our learning, and is there a way to bring this forward at our next meeting and do work in between where we can come back with more information that would move the topic forward.

I think Mark asked some key questions about who's our audience and where are we going with this. What's the committee's feel for what you want us to do next as a committee and where we want to go next?

Dr. Blumberg: Well, I guess a question came up about a subcommittee, and probably that would be a logical step, to just have a group of people talk about a lot of these things that have been outlined to try to figure that out.

Dr. Josephson: How long until our next meeting? I mean what's the timeframe in between?

The Chairperson: So that's a great question. Jim and I were sneaking dates back and forth as we were talking this morning.

And Emily, and Jim, and I, we're looking at, we hope early April?

Mr. Berger: Right.

Dr. Josephson: Okay.

The Chairperson: Early April, and we're actually just checking some other big meetings that would conflict with the committee members around the table.

And then that would allow us to have our second meeting maybe late summer, August-ish.

Dr. Josephson: Okay. Okay.

The Chairperson: So yeah, we have a lot of things we'd like to queue up for the April meeting.

Dr. Josephson: Yeah, so that just helps give a timeframe of what we might accomplish in between, so what kind of -- what kind of strategy do we need to -- you know, what are our goals to accomplish for the next meeting.

The Chairperson: Right. And then I would hope that whatever -- we could put this topic back on the agenda then for the April meeting and continue to have dialogue and learn or bring in other expertise and maybe have more concrete questions that the committee can address.

Brian?

Dr. Custer: So I was just going to maybe I hope not confuse things. But I think that the first purpose of the meeting, the find a tolerable infectious disease risk in blood safety from a patient perspective is one potential subcommittee to think about.

And then there's this broader set of things that we're talking about with the risk-based decision- making framework and what components might work, what might not work.

That's a very different set of considerations that is perhaps speaking to what Jay was talking about, more a context that would set the stage for how information would start to come together in some future vision.

And so there may be multiple different subgroups doing different kind of work is my -- be my recommendation.

The Chairperson: Is there any way you would -- does one need to precede the other? Can they be parallel? Is it better if one precedes?

Dr. Custer: In terms of at least trying to assess things, I think we're in assessment phase. And to me, assessments can be done in parallel. One is not contingent upon the other.

The Chairperson: So would you propose setting up two working groups?

Dr. Custer: Yes, I actually would.

The Chairperson: Thoughts about that?

Dr. Custer: Sorry to interrupt. But just to build on that a little bit more. I mean we've already seen from the risk-based decision-making framework that, example from Héma-Québec in particular, about what their tolerability framework is.

So there's assembling tolerability framework and asking how much of this, a structure, is applicable, are these various levels applicable. I think that that's relatively circumscribe, but still would need to be done.

That's not saying that we're putting forward a recommendation. And then again, there's a separate thing about if we want to use a framework, what are the constituents of that framework? Both need to be done.

And then there's a broader set of considerations about who indeed is our audience for this? It's not just us so --

The Chairperson: Right. Alex?

Dr. London: I guess it -- I have a lingering concern about whether we're being too narrow in what we look at as the benefits of some of the things that we do.

Especially, you know, if there's a new pathogen, we learn about it through screening and developing technologies to assess its prevalence, what are the additional scientific and economic gains that we get from developing these platforms such that, you know, are there scientific benefits that we get from some of the things that we do that don't get quantified by risk reduction to transmission to patients.

So it's not that -- to say that that's not important, but there may be a host of other things that get done in whose benefits are also relevant and that may not be quantified in the bottom line of the stakeholders who are the most -- you know, bear some of the cost most direct.

Dr. Custer: Can I follow on with that –

The Chairperson: And then Mark.

Dr. Custer: The point that you made, Alex, and also that you touched on, Nicole, about this broader, what are the benefits in the system, whether it's infectious disease screening for donors and all of this are very important.

But I -- that my concern -- this work needs to be done anyway. Then there's the broader of how do we think about all of the other externalities and all of the other factors that are really very important that are clearly beyond this.

So again, we either get a very complex agenda that might start to miss this because -- at least in my experience, again, it's been more lip service to the patient's perspective.

So if we really want to bring that in, I think we need to make a diligent effort to do so. But that just begins to look at some things because -- by the same token, and to make the point, you know, the idea perhaps of a world in the future where we just do pathogen reduction technology and we really aren't going to screen donors, there's a whole host of very serious ethical issues that need to be discussed and really work through about asking somebody to donate, having them donate, and then not providing some potential information of high health relevance back to them.

And so I agree completely that this is only one part of the story. I just think that we still need to work this part much more carefully than we have to-date.

Dr. London: I don't disagree with that. I just think there are some delicate issues in how we frame these questions, especially when we're framing them to patients.

Especially if you frame a question as, what are the risk that you're willing to tolerate if the alternative is not available to you, which is what the -- which has come up here multiple times.

And then the whether it's available to you or not isn't necessarily just conditional on the level that we set for our tolerability for this kind of risk. It raises all these other questions.

So I'm happy to try to deal with one thing at a time, as long as the rest of those things aren't brought in the back door subsequent (phonetic) of, right, smuggling under the table.

The Chairperson: Mark?

Mr. Skinner: Well, I don't disagree with Brian's notion of two committees. I'm trying to think through the next steps of how a committee on defining patient tolerability would actually occur.

I could see a process where you could get a wide group of patients to agree that zero is not the absolute goal, which sort of seems to be the theme that we've heard.

But, you know, is -- whether you're getting agreement on 1 percent, 5 percent, 10 percent, I

just -- I'm having trouble thinking what the output of that work product would be absent it being a framework for inclusion and decision-making on a case-by-case basis.

I think it's a useful goal. I'm just trying to figure out how it's -- how it happens. And having been in this RBDM project for six or seven years, we didn't stumble on a path to do that.

We stumbled on a framework to include and do that. And I just don't -- I think it would -- also, I think it'd have to be awfully well-resourced where you would have a pretty significant research project to know that you actually had a representative sample.

I think the framework is an easier first step. But maybe there's value in validating what some of us who have been working in this area for a while who said is, you know, zero is not attainable.

You know, that may be an informed expert opinion, but that may not be representative of the community. And so maybe we do need to go back and have a process to validate that. But I have a hard time figuring how we go beyond it.

The Chairperson: Dr. Kotton?

Dr. Kotton: One of the things I've come to appreciate today is just how heterogeneous the various stakeholders are. And although we have some people here who represent more of the chronic illness component, I take care of patients who may have had trauma and undergo, you know, massive blood transfusion. And I think that's a really a different hat to wear.

And they would have different needs. When I think about them being in one of these rural hospitals that we hear about now where the blood bank may not have that much blood or available to them, I mean they really have a different need.

When I think about the liver transplant patient who comes in and ends up getting 200 units of packed red cells. You know, that's really a different scenario.

So when we think about the level of disease risk that each of those groups are willing to accept, and also whether it's plasma, or red cells, or whatever the blood component is, I think that there's really different levels of tolerability as far as risk acceptance in the same way that there is between blood products and cornea as you've mentioned in organs.

And then many things that we do in medicine, there is a different level of risk acceptance. So there's probably not going to be one tolerable disease risk threshold that we achieve, but probably it will be a fairly heterogeneous answer which is complicated.

I hadn't appreciated that before today.

Dr. Katz: Yeah, I really think the process for decision-making is the critical issue and then you know, I'm a one-trick-pony pay me for what you're going to make me do. I really think those are the two critical things.

And I understand what happened with Zika. I'm not criticizing the agency. It's a good day that they had the pressures they had. They made a decision, we did it, and now, I'm interested to see how fast we can change as circumstances justify.

But I have no idea -- Brian, and Mike Busch, and I participated with the insurance carrier for Canadian Blood Services several years ago in an attempt to model agent, sort of like HIV, and agents sort of like West Nile, and the implications for how much coverage they should have.

And the confidence bounds around every estimate that we made were so wide that it convinced me that you deal with these one at a time. And the important thing is to have something like the RBDM framework that make sure you don't miss a box that needs to be ticked.

And the biggest box that needs to be ticked is clearly funding and engaging the right stakeholders.

Dr. Verdun: I just want to say quick thing because I think it's important to say.

At FDA, we actually do do a lot of engagement. And I just want to say engagement does not always mean agreement. Those are two different things. I just want to say that.

The Chairperson: Yes, absolutely. I believe we are not ready to move forward and make too large of commitments about maybe two subcommittees and what we're doing.

I think maybe what we need -- before we need even a subcommittee, I understand there's another word, working group, that could take the information we learned today and all the dialogue, and perhaps frame it in what's the goal, what are we trying to learn, who do we have to involve, what would be a path forward, both in what's a process and getting to --

I think the tolerability is, to me, the absolute hardest -- hardest thing to do. So what are people -- what are your feelings of putting a work group together to really add more content and structure to this with the purpose of bringing it back and having additional discussion in April?

Maybe the work group could identify additional experts we want or additional topics we've talked about before we ask for charges or commitments.

Dr. Josephson: I think a work group is a great idea.

Mr. Skinner: I like your recommendation. I think maybe there's one other thing though that we could -- did come up that we could ask whoever, whether it was BOTSEC or whoever, to just articulate two things.

What is the process of when they act and then consult, and what is the process where they decide whether to consult and then act. And how do those two processes differ and what's the process for deciding which of those two channels an issue goes through.

I think if we got clarity about that, that would help us understand who our audience is and what problem are we trying to fix.

The Chairperson: Right. That's great. So we will form a working group, outside of this meeting. We'll ask you for volunteers and recommendations for that work group. And then we'll convene it.

Jim says we have money that the work group can meet, in person, not just by phone, one in person.

Right. And by the way, you can recommend -- you can volunteer or you can recommend people. You don't have to be on this committee, right. We can have outside people.

So if you know people you think would be worthwhile and add a lot of content to our work group, so people who might want to volunteer to be on this or recommend others that should be part of this effort.

I think if we have valuable work -- again, in April, then that's maybe where we ask for a charge and form the subcommittees and formalize this more.

So volunteers, recommendations, or if you just want to tell us sources. Sometimes you know of someone and we would have to track them down. Does that -- and then we will also -- Jim will engage with BOSTEC on your two questions, Mark, and we'll have that ready --

Yeah, email any information you want to give to me or Renee, and we'll make sure we share it. We are going to have minutes of this meeting because we have Jennifer and team here. So we will have been able to capture everything here.

The other topic we are going to, I believe, take up in April is the one -- I think Sridhar, we were going to have you comment on that, or Jim?

Mr. Berger: Sridhar, can you talk about the PHS guidelines that we're going to discuss in April?

Dr. Basavaraju: Yeah. So we have received some feedback from the organ transplant community on their thoughts on whether the increased risk designation as part of the 2013 PHS Organ Transplant Guideline for reducing risk of HIV, hepatitis B, and hepatitis C transmission, whether the increased risk criteria should be revised.

And we were proposing to present the issues to the ACBTSA, present the findings of some data, analytic efforts that we've done, and also speak input from the committee on whether there should be revisions to the recommendations in the PHS guideline as they pertain to the designation of increased risk donors.

The Chairperson: Okay, so we'll be depending a lot on our infectious disease experts and transplant people around the table.

So thank you, all, very much for your participation. Look forward to seeing you in April. We will really try to nail down those dates soon and get those out on your calendars.

Please provide me any feedback you want when you get home. I'm glad to receive it. Give your hotel receipts to Renee. If you don't have them, mail them to her.

And with that, I thank you, all, very much for your expert guidance and engagement. And safe travels back.

(Whereupon, at 5:22 p.m., the meeting was concluded.)