ACBTSA September 13, 2018 - Meeting Summary

Committee Business

Welcome and Roll Call

Jacquelyn (Jackie) Fredrick, MT(ASCP)SBB, MBA, retired CEO of Versiti, Inc., chair of the Advisory Committee on Blood and Tissue Safety and Availability (ACBTSA), called the meeting to order and welcomed all the meeting participants. She stated that the purposes of the meeting were to 1) define a tolerable infectious disease risk in blood safety from a patient’s perspective; and 2) identify potential charges by discussing key gaps in the committee’s understanding of blood safety risks and any consultations of studies needed to facilitate further considerations. She said that the committee would also decide if a subcommittee is needed to develop recommendations to move forward.

Ms. Frederick thanked Jay Menitove, MD, immediate past committee chair of ACBTSA, for his leadership during the past four years and for his continued work leading the Subcommittee on Sustainability of the Blood System.

Ms. Fredrick explained that the committee, as a part of the Office of HIV/AIDs and Infectious Disease Policy (OHAIDP) under the Office of the Assistant Secretary for Health (OASH), was established to provide the Secretary of Health and Human Services (HHS) with advice, information, and recommendations on policies and programs related to blood, blood product, organ, and tissue safety and availability. For solid organs and blood stem cells, she reminded the committee to focus on policy issues related to donor-derived infectious disease complications of transplantation because broader issues related to solid organs are covered by other groups.

She then asked the committee members present at the meeting to introduce themselves (see Appendix A for committee members and attendance).

James (Jim) Berger, MS, MT(ASCP)SBB, Designated Federal Officer for ACBTSA, Senior Advisor for Blood and Tissue Policy, Office of the Assistant Secretary for Health, Department of Health and Human Services, stated that the meeting had a quorum.

Strategies to Control the Risk of Bacterial Contamination in Platelets: July 2018 BPAC Update

Emily Storch, MD, Medical Officer, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration

Dr. Storch updated ACBTSA on a recent meeting conducted by FDA’s Blood Products Advisory Committee (BPAC). She said that BPAC met on July 18, 2018 and discussed all available strategies for controlling bacterial contamination in platelets, including culture-based methods, rapid testing methods, and pathogen reduction technology.

Current platelet dating is a maximum of 5-7 days depending on the preparation method, storage container, and bacterial testing. Since AABB’s Standard 5.1.5.1 became effective in 2004, fatalities associated with septic reactions have reduced. The reduction in fatality proved the effectiveness of the existing strategies of limiting and detecting bacterial contamination of platelets. However, the primary bacterial culture currently used by blood centers for apheresis platelet collections has limitations (e.g., residual risk of septic transfusion reactions at the time of transfusion), and bacterial contamination of platelets remains a leading cause of septic transfusion reactions and related fatalities.

At the July BPAC meeting, the committee and invited speakers discussed the following strategies to control the risk of bacterial contamination of platelet products, and the speakers shared their experiences with these strategies.

For 5-day storage:

• Primary culture followed by secondary culture on day 3
• Minimal Proportional Sampling Volume
• Primary culture followed by secondary rapid testing on the day of transfusion
• Pathogen reduction technology (one FDA approved device based on amotosalen/UVA technology)

For 7-day storage:

• Primary culture followed by secondary culture on day 4
• Large Volume Delayed Sampling
• Primary culture followed by secondary rapid testing

At the July BPAC meeting, the committee was asked to comment on the advantages and disadvantages of each of the strategies, including scientific evidence and operational considerations involved with each strategy. Given that the studies on the strategies are not directly comparable, the committee was not asked to make direct comparisons. Additional topics were discussed during the open public hearing session.

The general consensus among the BPAC committee members was that multiple strategies appear to improve safety; limited data, however, create challenges in strategy evaluation and comparison. As a result, there is a continued need for surveillance data and further research. The BPAC committee also emphasized the importance of operational considerations, and pointed out that different strategies may serve different regions or populations. Multiple options, therefore, are needed to maintain the blood supply, given the complex and diverse health system in the U.S. Incomplete data should not preclude timely action. Overall, the committee suggested that guidance providing enhanced safety measures to mitigate the risk of bacterial contamination in platelets is a public-health need.

Dr. Storch said that FDA intends to issue a revised guidance on strategies to control the risk of bacterial contamination in platelet products, and they will take the BPAC discussion into consideration.

ACBTSA Update on the Sustainability of the Blood System

Jay E. Menitove, MD, Chair, ACBTSA Subcommittee on Sustainability of the Blood System

Dr. Menitove provided a brief background of the origin of the ACBTSA Subcommittee on Sustainability of the Blood System, explained the subcommittee’s activities since 2007, and pointed out the differences between the viewpoints of the RAND report (“economist review point”) and those of ACBTSA (“crisis-oriented”).

To address the urgency of the risk associated with the blood system, the Sustainability Subcommittee in 2017 began confirming and documenting the risk of the blood system sustainability in the U.S. The subcommittee formed three Working Groups: the Hospital Working Group, the Blood Center Working Group, and the Industry Suppliers Working Group. Since the formation, each of the three working groups has raised different issues and made recommendations. The Sustainability Subcommittee and the Blood, Organ, and Tissue Executive Council (BOTSEC) also conducted joint monthly conference calls. The conference calls are currently suspended while the subcommittee waits for data collection and analysis.

The subcommittee recently published an article in the New England Journal of Medicine (NEJM) pointing out the crisis in the sustainability of the U.S. blood system. Dr. Menitove himself attended the ABC meeting in March 2018. The general consensus among ABC members, he said, was that the blood supply is adequate today; however, there is also a concern regarding the sustainability. Chris Hrouda, President of Biomedical Services at the American Red Cross, recently wrote an open letter to the U.S. health care community presenting steps to ensure a strong blood supply in the U.S.

Dr. Menitove noted that the current concern level appears to vary. It is unclear what the reactions to price adjustment for core activities and to cost recovery related to Zika and Babesia testing would be.

Dr. Menitove explained that the subcommittee is waiting for data analysis, including financial analysis, to be completed. Results of the analysis will be reviewed first by BOTSEC and then by the Subcommittee on Sustainability. Dr. Menitove anticipated that a full report from the Sustainability Subcommittee will be ready by the next ACBTSA meeting.

A meeting attendee from the Biomedical Advanced Research and Development Authority (BARDA), U.S. Department of Health and Human Services, shared that they plan to complete the analysis by December, 2018.

Following Dr. Menitove’s presentation, the committee briefly discussed the path forward and how to act efficiently given the urgency of the issue. In response to a question from a committee member, Dr. Burger clarified that the recommendations the committee previously made have been submitted to the Assistant Secretary for Health. However, they are still waiting for data to conduct the sustainability modeling. He said that it takes time for the organizations, including the American Red Cross and the American Blood Centers, to provide the data they requested, including financial data. Once BARDA completes the analysis in December, BOTSEC will be briefed, and their comments and recommendations will be provided to HHS and ACBTSA. It is part of the process they initiated a couple of years ago, Dr. Burger explained.

In response to Ms. Fredrick’s question regarding the intent for the committee’s recommendations on reimbursement and a platform for the industry to rationalize the structure, Dr. Menitove said that the subcommittee cannot move forward until the data have been analyzed and a third party has evaluated the analysis.

Purpose of the Meeting

Among ACBTSA’s 2016 recommendations to the Secretary of Health, one was “examining models of risk-based decision making to inform future public policy to include all stakeholders in the vein-to-vein process.” The RAND report also mentioned stakeholders and a value framework for new technology. Ms. Fredrick noted that the agenda of today’s meeting was developed in consideration of the recommendations, and that today the committee starts the process to define a tolerable infectious disease risk in blood safety from a patient’s perspective.

She explained that the purpose is to educate the committee on risks and ethics, learn from the past, listen to stakeholders, set a direction for the future, and discuss potential charges. The agenda consists of three parts, and the first part is to listen to three invited speakers and review the landscape of transfusion medicine and infectious diseases.

Landscape of Theme

Keynote Presentation: Historical Perspective on Infectious Disease Risks

Michael P. Busch, MD, PhD, Director, Blood Systems Research Institute, University of California, San Francisco

Dr. Busch provided an overview of the evolution of approaches used to estimate risks of transfusion-transmitted infections (TTIs), including HIV, HCV, and HBV. Over the years, the approaches have evolved from retrospective cohort studies (1970s to mid 1980s) to prospective risk measurement studies (mid 1980s to early 1990s), and to modeling strategies in recent years. He also reviewed a few studies conducted by his and other groups using different approaches.

During the era of retrospective cohort studies, cohort prevalence data and donor records were used to back estimate the pre-screening HIV risk, and retrospective testing of repositories was conducted to estimate HCV risk and impact of improved antibody screening on HCV as well as HBV risks.

Between 1985 and 1990, prospective studies were conducted to directly measure HIV, HBV, and HCV risks using different testing methods, including hepatitis surrogate testing, p24 antigen testing, and HCV and HIV nucleic acid testing (NAT). The direct measurements of risks required large-scale studies but produced low yield.

The residual risk was traced to four potential sources. Among them, window period is considered the main source of residual risk and accounts for more than 90% of the risk. Studies have shown that other sources of residual risk, including immune-silent carriers, testing errors, and viral variants, are rare.

In the following years, window period models and seroconversion panels were developed, and studies by different groups showed that reductions in HIV seroconversion window periods were achieved using improved diagnostic assays.

In addition to measuring the rate of infected donations, Dr. Busch’s and other groups also investigated the infectivity of HIV, HCV, and HBV to understand the minimum infectious dose. They also compared efficacies of different individual donor-NAT (ID-NAT) options. The studies showed that the infectivity could be influenced by multiple factors, including viral properties, transfusion factors, and recipient factors. The studies also showed that minipool-NAT (MP-NAT), which is still conducted in the U.S. today, failed to detect the infections that could otherwise be detected with ID-NAT. An international study involving 15 countries and six geographic regions further showed that among HIV screening assays evaluated, ID-NAT was associated with the highest efficacy with or without antibody testing; however, elimination of antibody testing could result in failure to detect donations from “elite controllers.”

The past decades have witnessed a changing paradigm of “significant” transfusion pathogens. Different from classic transfusion pathogens (e.g., HBV, HIV, HTLV, and HCV), the emerging pathogens are mostly zoonotic (e.g., T. cruzi and WNV) and can cause transient infections with unknown transfusion transmission (TT) risks. These emerging agents often require large-scale studies to characterize and to understand their threats. Using XMRV (an infectious retrovirus), Dengue, and Zika viruses as examples, Dr. Busch explained how conceptual strategies are used to address threats posed by emerging pathogens. Ongoing studies on Zika virus showed that large doses of the virus are needed for it to infect through transfusion, although mice can be infected with lower doses.

In summary, Dr. Busch said that we need confirmatory testing (NAT and serology) to exclude false positive results; we need to know the prevalence and incidence of infectious disease markers; and we need to understand the performance of the tests, infectivity in each stage of infection, transmission risks, and efficacy of the technologies. However, the fundamental question is, can we afford zero risk? Data on cost per quality-adjusted life year (QALY) suggest that risk-benefit and cost-effectiveness studies are needed to inform decision making.

Discussion

Following the presentation, the committee discussed multiple topics ranging from risk tolerance in different populations to costs and regulatory processes.

QALY and risk tolerance in different populations

Cassandra Josephson, MD, Medical Director of the Children’s Healthcare of Atlanta Transfusion, Tissue, and Apheresis Services, Professor in the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, reminded the committee to take age into consideration when discussing risk tolerance and QALY, and she wanted to know if QALY analysis has been conducted in the pediatric population. Brain S. Custer, PhD, MPH, Director, Epidemiology and Health Policy Science; Vice President of the Research and Scientific Programs at the Blood Systems Research Institute in California, said that they did check QALY in different populations and age groups. There are many life years to be gained in the pediatric population, and they do have metrics that they can use to analyze cost-effectiveness of tests for pediatric population.

Referring to the study conducted in South Africa, specifically the percentage of infections missed by MP-NAT, Dr. Custer commented that the data from South Africa may not reflect the situation in the U.S. due to the differences between donors in South African and the U.S.

Safety, costs, and thresholds

The committee discussed cost-effectiveness thresholds for TTI screening. The magnitude for blood safety is different from other medical conditions, and the cost per QALY for screening emerging pathogens is much higher than screening for traditional infections such as HCV and HIV.

Proactive responses and regulatory processes. Nicole Verdun, MD, Director, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, acknowledged that looking back at the cost is useful. She reminded the committee that when facing emerging threats, FDA, however, must act fast to protect public health. Dr. Busch commented that responses and decisions need to be made on the basis of scientific evidence, and some earlier decisions may need to be revisited based on new evidence.

Antibody testing

In response to a question, Dr. Busch clarified that antibody testing for HIV cannot be dropped.

Landscape of Infectious Disease Risks

Roger Y. Dodd, PhD, Executive Scientific Officer, American Red Cross; Adjunct Associate Professor of Pathology, Johns Hopkins University

Dr. Dodd started his presentation by stating that the current landscape for blood supply and safety in the U.S. is beautiful, but it can be easily disrupted. He then described traditional as well as emerging TTIs, available interventions, assessment and estimate of risks, as well as the decision-making process associated with blood safety.

Traditional TTIs, including HBV, HCV, HIV, HTLV, Syphilis, and malaria, are generally chronic and parenteral; whereas emergent TTIs such as vCJD, WNV, DENV, T. cruzi (Chagas), Babesia, ZIKV are generally acute and usually arthropod-borne or zoonotic.

Current interventions include selection of donor populations, donor suitability, deferral records, donation testing, lookback, and quality systems. Currently there are three types of donation testing: antibody, antigen, and NAT testing.

Sources of risk include inaccurate donor history (e.g., wrong question and wrong answers), lack of test, failure of test, test instability during the window period, clerical errors, and quarantine errors. Dr. Dodd emphasized the significance of the window period, during which an infection agent is present in the blood with the capability of infecting the recipient but cannot be detected by available tests. The duration of the window period varies depending on the sensitivity of the test. The window period of NAT is shorter than the window period of antigen testing, which is again shorter than the window period of antibody testing.

Residual risk refers to the likelihood of infection from a fully-tested blood component. It can be evaluated through direct observation (e.g., hepatitis, WNV, babesia), looking back (e.g., T. cruzi, HIV, HTLV, HBV), and from window period estimation (e.g., HIV, HBV, and HCV).

Data from American Red Cross showed that incidence (per 100,000 person-years) of HIV, HBV, and HCV declined between 2007 and 2016; and the residual risk to U.S. blood supply of repeat donors also dropped. Transmissions of HTLV1/2 had been identified by lookback, and incidence of infection is still detectable in large studies; clinical disease, however, is infrequent among test-positive individuals.

Dr. Dodd noted that the “zero-risk” standard resulted from the AIDS crisis poses challenges to emerging threats, and clear policy guidance is lacking. Take vCJD as an example. The fatal infection is perceived as a potential threat but currently no test is available. The U.S. regulators established donor deferral criteria for vCJD. Only four TTIs, however, have been definitively identified globally, three with disease, and all of which are in the UK.

When making decisions, Dr. Dodd said, multiple factors should be considered, including

• size of risk,
• severity of the disease among infected recipients,
• dynamics of outbreak, risk-benefit ratio,
• competing priorities,
• public and political pressure,
• support from manufacturers,
• availability of resources,
• alternative approaches,
• tolerable risk, and
• monitoring.

Based on window period estimation and known cases, the residual risk for currently managed TTIs, in Dr. Dodd’s view, is extremely low. However, there has been no explicit guiding policy driving management of new threats, other than zero risk and/or as low as reasonably achievable (ALARA).

Discussion

Following the presentation, Dr. Dodd and the committee discussed the challenges associated with dealing with emergent situations (e.g., Zika outbreak), in which the agencies including FDA and CDC need to take immediate actions to protect public health while scientific understanding of the threat and data are lacking.

As Dr. Verdun pointed out, the agencies need to take quick actions (e.g., bringing in tests to detect the emerging pathogens) in emergent situations. Sridhar Basavaraju, MD, Deputy Director of the Office of Blood, Organ, and other Tissue Safety, Centers for Disease Control and Prevention (CDC), added that it is not always easy to quantify the magnitude of risk, and sometimes the public perception of the magnitude of a risk may differ from reality (e.g., Zika).

Dr. Dodd noted that it is difficult to make a sound decision in a hurry. The “moving target,” multiple emerging threats, adds additional challenges. Regarding risk tolerance, Dr. Dodd said that it is very challenging to say how much we can spend to completely avoid the risk and how much risk we can tolerate. Risk tolerance varies from person to person. When it comes to risk and cost, “people tend to think personally but not population wise,” Dr. Dodd noted.

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

Martin Ruta, PhD, JD, Regulatory Council, Office of Blood Research and Review, CBER, FDA

Dr. Ruta started his presentation with a quotation from the Secretary of HHS back in 1995, which, he said, is still relevant today. He then explained the main HHS and FDA responses to infectious disease threats to blood safety in the past decades.

“Blood will always be capable of transmitting disease, … and its use will never be completely free of risk.  But for everyone who relies on blood to sustain life, the Federal government must and will do everything in its power to reduce risk and assure availability.” Secretary of HHS testimony 1995

In the 1970s, blood for transfusion was collected from both paid and unpaid donors. The implications of hepatitis B virus in post-transfusion hepatitis led to volunteer blood donations, which significantly reduced the incidence of transfusion transmitted hepatitis.

In the 1980s, report of AIDS in hemophilia patients raised the question of blood safety and the subsequent report of AIDS in a 20-month-old child linked AIDS to transfusion led to numerous recommendations, including the controversial deferral recommendation, “…members of groups at increased risk for AIDS should refrain from donating.” In 1985 HIV antibody test was approved and later mandated.

In the 1990s, FDA put in place numerous blood safety measures, including the five layers of safety requirement, HCV testing, as well as NAT testing. The HIV/AIDS activism further spurred positive changes. In response to the 1995 IOM Report on HIV and the Blood Supply: An Analysis of Crises Decision Making, the Assistant Secretary for Health was assigned to take responsibility for oversight of the blood system; BOTSEC was established to coordinate government actions on blood safety; and the Advisory Committee for Blood Safety and Availability (ACBSA) was formed as an expert panel to work closely with CDC, National Institutes of Health (NIH), FDA, and other Public Health Services (PHS) agencies.

Dr. Ruta pointed out that the PHS approach to blood safety management for new and emerging disease agents was deeply influence by the loss of public trust and the IOM report. Its subsequent decision making has been characterized as: more timely actions, willingness to act in the face of scientific uncertainty, low risk tolerance, proactive engagement with patient groups, improved transparency of decision making processes, and regulatory focus on cGMP across the blood industry.

In the 2000s, a series of new requirements were established to further reduce the risk for traditional as well as emerging threats, including the 2000 vCJD risk-based donor deferrals; the 2002 national use of investigational WNV, MP and ID-NAT; the 2007 Chagas serological testing; the 2014 approval of pathogen inactivation technology for plasma and apheresis platelets; the 2016 investigational and later mandated use of licensed NAT test for Zika virus; and the 2018 approvals of NAT and serological Babesia tests.

Dr. Ruta pointed out that FDA’s policy making often involves complex issues, and decisions are made based on science and law. For blood safety-related policies, external scientific advice has also been obtained from advisory committees, including BPAC and ACBTSA.

In summary, since the 1970s, emerging infectious disease (EIDs) have posed novel threats to the blood safety and necessitated novel interventions. The HHS and FDA responses to EIDs have evolved significantly since the AIDS epidemic. The current decision making for EIDs is proactive and highly focused on risk reduction. Quantitative risk assessments are increasingly used. Policy making practices reflect lessons learned and institutional changes. The agencies proactively interact with stakeholders, and seek public input.

Benefit-Risk Tradeoffs in Blood Safety

Richard Forshee, PhD, Associate Director for Analytics and Benefit-Risk Assessment, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration

Dr. Forshee noted that most risk management decisions at CBER are benefit-risk based, the acceptable levels of risk may vary depending on the context, and some CBER-regulated products may have different benefit-risk considerations. Using two recent examples (vCJD and Zika), he explained how CBER applies quantitative benefit-risk assessment in regulatory decision making.

CBER risk assessment for vCJD risk via red blood cells (2009-2013)

FDA’S original guidance was to indefinitely defer donors who have spent time in the UK for 3 moths and longer during 1980-1996, or other European countries for 5 years or longer since 1980. However, risk assessment results showed that the risk for transfusion transmission of vCJD is low (1 in 134 million based on estimated of UK vCJD prevalence). In addition, vCJD and bovine spongiform encephalopathy (BSE) cases are decreasing worldwide.

On the basis of the information, the agency recently reassessed the policy. They built a new model to rank geographic vCJD risk worldwide and incorporated new data. The risk assessment results showed that UK, Ireland, and France rank top three countries of risk and account for 95% of the total risk. Based on the assessment, the agency lifted the deferral for European countries other than the UK, Ireland, and France, and allow 100,000 currently deferred donors to donate.

CBER risk assessment for transfusion-transmitted Zika virus in Puerto Rico with ID-NAT blood testing (March 2016)

The initial response to Zika outbreak was to completely stop blood collection in Puerto Rico. The approach, however, was unattainable. CBER risk assessment results showed that ID-NAT could reduce the Zika transfusion transmission risk by 86%. Given that the Zika epidemic appears to be waning, the agency recently considered whether to shift the testing requirement from ID-NAT to MP-NAT testing. Risk assessment showed that the shift could slightly increase the risk but the probability that MP-NAT could detect the first case that ID-NAT would detect was reasonably high. The results support moving to MP-NAT testing in general.

In summary, benefit-risk assessment has been used in CBER to inform regulatory decision making, evaluate benefits and risks of different policy options, facilitate internal discussion, and improve communication. In addition, benefit-risk assessment advances policy making and enhances FDA’s capability to protect public health, Dr. Forshee said.

An International Perspective on a Risk Management Approach for Blood Products

Dana Devine, MD, Chief Scientist, Canadian Blood Services

Dr. Devine explained the risk-based decision-making (RBDM) framework for blood safety using Canadian studies on CMV testing as an example.

The framework involves six stages: preparation, problem formulation, participation strategy, assessments, evaluation, and decision. Each stage has a clearly defined purpose and a step-by-step process.

Stage 1: Preparation

During this stage, a RBDM analysis is launched, and a risk assessment team with different expertise is assembled to review the foundational elements of risk management so that subsequent stages can be carried out efficiently and effectively.

Stage 2: Problem formulation

The purpose of this stage is to define and characterize the problem to identify the overall assessment question, the decision drivers, and the risk management options. Using CMV testing in Canada as an example, she illustrated how they characterized the risk associated with CMV transfusion transmission, formulated the questions, and how they identified all the potential risk management options, including:

• Status quo.
• Stop providing CMV-negative product entirely and rely on leukoreduction to reduce transmission risk.
• C1: Provide CMV antibody-negative product for intrauterine transfusion, neonates under 28 days of age, and in elective transfusion of CMV-seronegative pregnant women; or C2: provide CMV antibody-negative product for intrauterine transfusion.
• Use NAT testing to identify CMV-negative product for target risk groups listed in option C.
• Introduce pathogen reduction technology.

Stage 3: Participation strategy

The purpose of this stage is to define the need for risk communication and stakeholder involvement, identify relevant stakeholders, and develop a participation plan. She stressed the importance of identifying stakeholders and conduct effective communication. In the case of CMV in Canada, in addition to the National Liaison Committee and patients, they identified and engaged two additional stakeholder groups: physicians as well as provinces and territories.

Stage 4: Assessments

The purpose of this stage is to accumulate the data necessary to analyze the risk management options effectively, by performing a series of quantitative and qualitative assessments. For CMV testing in Canada, they conducted a series of assessments, including blood safety risk assessment, budget impact assessment, operational impact assessment, and contextual assessment.

Stage 5: Evaluation

During this stage, assessment results, stakeholder feedback, risk tolerability analysis are used to compare and rank the risk management options. For CMV testing in Canada, they identified option C as their best option.

Stage 6. Decision

After all the factors have been considered, a risk management option is selected, and implementation as well monitoring plans are defined. An important final step is to communicate the decision to stakeholders. For CMV testing in Canada, their final recommendations were:

• Option C2 antibody testing approach should be implemented, in line with recent NAC recommendations.
• Canadian Blood Services develop communication plans and physician education opportunities, in collaboration with NAC and the provinces, on TT-CMV risk and the rationale for this product change.
• Canadian Blood Services study the cost-effectiveness of NAT CMV testing based on outcome and cost data and determine whether to add a NAT testing platform to the existing antibody testing.

Discussion

In response to a question from Alex London, PhD, Director, Center for Ethics and Policy, Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, regarding cost and how to make a burden-related comparison during the assessment stage, Dr. Devine clarified that in Canada, they have long recognized that zero risk does not exist, and they are prepared to accept some risk. The actual cost is dependent on the risk to be mitigated. During this stage, it is important to ask questions like, if something goes wrong, what will be the sequela for the recipient?

In response to a question from Dr. Josephson regarding how the variables were weighed in cost considerations, Dr. Devine clarified that they do have data on how many intrauterine procedures are conducted per year in the hospitals to which they provide products. For transfusions given to neonates, they have a ballpark number to use for extrapolation.

Dr. Basavaraju asked a question about cost-effectiveness evaluation, and he wanted to know if QALYs were analyzed in Canada. Dr. Devine responded that it depends on the subject. Given that QALYs for blood transfusion can be significantly different from other medical conditions, they do what they can about QALY but they rarely look at dollar amounts.

Dr. Custer commented that the framework allows for reevaluation, and he wanted to know if there is any example on how policies are revisited and changed over time. Dr. Devine gave an example of Babesia testing, for which they are doing another seroprevalence study to ensure that the decision on not to implement Babesia testing is still appropriate. Louis Katz, MD, Chief Medical Officer of America’s Blood Center, added that the framework is indeed an iterative process.

In response to Ms. Fredrick’s question regarding stakeholder engagement, Dr. Devine said that in Canada they have very active stakeholder engagement and they know whom to contact. They have about 10 patient advocacy groups that they regularly interact with, and they also reach out to the Canadian cancer society and heart association. Overall, they try to keep their network as large as they can and hear as many voices as possible.

Risk Perception and Ethics

David Wendler, PhD, Department of Bioethics, NIH Clinical Center

Dr. Wendler talked about how risk perception should be included in decision making. A risk, Dr. Wendler said, involves a chance of experiencing some harm as the result of an activity or intervention, and it consists of two components: magnitude and likelihood.

In his view, risk perceptions can involve an individual’s perception of the risk magnitude as well as the risk likelihood, and an individual’s perception of the magnitude of a harm can affect how the individual react to having it. To make treatment and public policy decisions in response to risks, we need to know how people view the harms in question, he said. In contrast to perceptions of magnitude of harm, perceptions of likelihood do not affect the chance that it will occur.

Accurate perception-based treatment decisions and policies will be considered appropriate. On the contrary, inaccurate perception-based policy could lead to problems. For example, when perception underestimates the chances of harm, treatments may be requested that are excessively risky and public safeguards may be considered unnecessary and wasteful; on the other hand, when perception overestimates the chances of harm, appropriate treatments may be resisted and public safeguards may be deemed inadequate and uncaring.

To properly respond, he said, it is important to recognize and respect those who overestimate risks; however, treatment decisions and public policy should be based on the actual chances of harm, not overestimates.

Perceptions of chances of harm are influenced by many factors, and the perception of greater risk is also associated with less power and lower standing. He reminded the committee that the problem of overestimating affects all of us. We can proactively take steps to reduce the potential sources of overestimates by soliciting input early and proactively (e.g., through focus groups), building trust, and through education.

Discussion

In response to Dr. Josephson’s comments, Dr. Wendler agreed that getting patient’s perspective alone is not enough, and that clinicians’ worries and overestimates of risks need to be considered and addressed as well.

In response to Dr. Katz’s question on how to bridge the disconnect between perspectives at the societal level and the individual level, Dr. Wendler said that we need to do both. In his view, it is important to get public input at the epidemiological level but not necessarily at an individual patient level.

Regarding Dr. London’s question whether to take individual’s perception into consideration, Dr. Wendler answered that we do need to know individual perceptions so we can anticipate reactions and try to educate accordingly.

In a following-up question, Dr. London asked if a novel infectious disease should be treated differently from “normal” things that may be equally likely to cause mortality and fatality. In Dr. Wendler view, there is no reason to treat it differently in the beginning in terms of safeguard measures such as lab testing, but there is a reason to treat it differently in terms of education. If the efforts fail and trust might be undermined, he suggested trying to start with addressing the perceptions and decide how to treat on the basis of the nature of the disease.

Stakeholders

AABB

Zbigniew Szczepiorkowski, MD, PhD, FCAP, AABB Immediate Past President

Dr. Szczepiorkowski presented the joint statement on a tolerable level of risk in blood safety, with an emphasis on infectious diseases, from AABB (formerly called American Association of Blood Banks), America’s Blood Centers, and the American Red Cross. The joint perspective focused on the six principles related to risk tolerability in blood safety.

1. The use of validated risk-based models to drive policy making and evaluate blood safety.
2. 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.
3. Support for research related to new threats to the safety of the blood supply.
4. Recognition that biovigilance and hemovigilance are critical to advancing the safety of the blood supply.
5. Voluntary standards and guidance contribute to blood safety.
6. Risk tolerability may vary significantly between different constituencies, as well as between organizations and individuals within a single constituency.

The whole statement is listed in Appendix B.

Discussion

In response to a comment from Dr. Verdun, Dr. Szczepiorkowski acknowledged that there is no easy solution to the issues. He pointed out that we all recognize the risk and we need to start the conversation and work together.

Regarding stakeholder engagement and collaboration, Dr. Szczepiorkowski clarified that AABB did use the framework presented by Dr. Devine for two areas, and they have learned that the U.S. blood system is very fragmented and is different from Canada and other countries. He agreed that patient and stakeholder engagement is important, and he pointed out that patient experiences can be very different.

Ms. Fredrick commented that the risk-based decision model that Dr. Devine described is good, but outputs are dependent on inputs. She reminded the committee to think about how to bring different groups together in a viable way.

Blood Center Perspective

Ralph R. Vassallo, MD, FACP, Executive Vice President, Chief Medical and Scientific Officer, Blood Systems, Inc.; Adjunct Associate Professor of Medicine, University of Pennsylvanian School of Medicine

Dr. Vassallo started his presentation by explaining the origin of the precautionary principle. He pointed out that a framework is urgently needed to guide when to apply the precautionary principle, how to balance risks and benefits, when to transition to risk management with emerging evidence, and when to remove precautionary policies.

He noted that the U.S. blood supply faces many threats, and the blood centers today face many challenges, including destructive competition, needs for modern IT systems and better donor communication systems, costly hospital computer system integration and vein-to-vein electronic inventory control required to safely manage today’s thin inventory reserves, high cost to develop products and low margin, changing donor demographics, intrusive regulations and unfunded mandates, cost containment, and need for multidisciplinary input not traditionally appreciated.

Studies have shown that the blood supply as a strategic reserve is shrinking as the prices for blood components are dropping. From 2010 to 2017, ARC’s average RBC price dropped by 11% while the Medical Consumer Price Index increased by 26%. ABC financial ratio survey revealed that blood centers fluctuate at around 1% margin, and in 2015 the margin dropped to an unsustainable loss level.

He noted that the RAND report ignored the evidence that the blood system is faltering, and that zero-risk policy is untenable. To appropriately address infectious disease risk, he said, we need risk-based decision making that is evidence-based, and considers all stakeholders’ opinions. In addition, “insurance value of blood” must be equally borne by appropriately reimbursed hospitals and blood providers.

He pointed out that commoditization and free market pressure may not be the best way to shape the safety and adequacy of the blood supply. Eventually the blood supply could be protected from infectious disease threats by effective pathogen reduction and limited NAT/Ag testing for traditional and newly identified pathogens. In the meantime, we, however, need risk-based policies to protect the public by equally promoting safety and availability, and appropriately funding a vital national resource.

Discussion

Marian Macsai, MD, Chief of the Division of Ophthalmology for NorthShore University Health System, asked why the price for RBCs has been stagnant. Dr. Vassallo pointed out hospital consolidations and price renegotiation that essentially makes blood centers compete with one another as main reasons.

Nora Ratcliffe, MD, Associated Professor of Pathology and Laboratory Medicine at Dartmouth Geisel School of Medicine, asked a question regarding technologies being implemented. She wanted to know if and how blood centers could proceed forward to make innovative products such as inactivation technology available.

Dr. Vassallo acknowledged that it is difficult. He noted that it is up to payers to decide what they want to pay for, and it may take a decade for pathogen inactivation technology to become affordable.

Dr. Verdun mentioned an upcoming FDA workshop entitled Pathogen Reduction Technologies for Blood Safety, to be held in November 29-30, 2018. The purpose of the workshop is to foster innovation, and it will be open to the public. She commented that pathogen reduction technology is promising, but further advancement is still needed.

Dr. Macsai commented that if the government is mandating testing to protect the public, then the cost of blood should be a pass through. She suggested that the committee perhaps should make a recommendation.

A Hospital Perspective: Designing a Tolerable Risk for Infectious Diseases from a Patient’s Perspective

Aaron A. R. Tobian, MD, PhD, Professor of Pathology, Medicine, and Epidemiology; Director, Transfusion Medicine Division; Deputy Director, Clinical Affairs of Pathology, Johns Hopkins Medical Institutions

The risk of TTIs has reduced during the past decades. Emerging infections, however, pose new threats and challenges. The unknowns, in Dr. Tobian’s view, put us on edge. Compared with other risks such as motor vehicle and airplane fatalities, risk of TTI in the U.S. is small. Using Zika virus, which is rare in U.S. blood donors, as an example, Dr. Tobian pointed out that we need to think and perhaps revise the screening requirements.

The overall U.S. health expenditures is projected to grow 5.5% per year from 2017 to 2026, and reach $5.7 trillion by 2025. Meanwhile hospital expenses and revenues have increased over time. However, about one third of hospitals operate with negative margins. Blood transfusion related costs vary depending on the disease and treatment needed. Challenges of efficiently managing blood-related inventories makes blood costs a prime target for cost containment efforts in hospitals, especially smaller ones. Improving patient management by transfusing “the right product, in the right dose, to the right patient, at the right time, for the right reason” can help reduce cost and improve patient care.

A recent study conducted by Dr. Tobian’s group showed decreasing trends of blood transfusion due to multiple factors, including medical evidence demonstrating the safety of restricting RBC transfusions (e.g., 7 g/dL rather than 10 g/dL threshold in hospitalized hemodynamically stable adult patients), patient blood management programs, and conservative initiatives.

Pathogen inactivation and/or reduction technologies will help address known and unknown risks, but each of the new technologies has its own pros (e.g., broad activity and comparable safety) and cons (e.g., additional cost and technical complexity). Dr. Tobian cautioned that we need to make sure that regulations are streamlined, and he pointed out the importance of supporting hemovigilance programs.

In summary, he said that

• Blood transfusions are incredibly safe when compared with other hospital procedures or transfusion in previous eras;
• Zero-risk transfusion policy is noble, but unsustainable;
• Pathogen reduction should be considered, especially if other TTI testing could be eliminated;
• Programs to monitor blood transfusion both nationally and internationally are important to support; and
• Fewer blood transfusions reduce risks and improve patient safety.

Discussion

In response to a question regarding cost and risk comparison, Dr. Tobian said that we need to keep it in context when we move forward.

Dr. Josephson commented that for hospitals with neonatal intensive care units, patient blood management for pediatric population is still in infancy, there are no data and it is very difficult to enforce.

In response to Dr. Katz’s question regarding blood price, Dr. Tobian suggested that the guidance should come out of national policies.

Camille Kotton, MD, FIDSA, FAST, Director of the Transplant Infectious Disease and Immunocompromised Host Program, Massachusetts General Hospital, commented that technologies such next-generation sequencing could provide more information than we want, and she wondered how the technology would reframe the discussion.

Dr. Tobian responded that it could have pros and cons, but he did not think the technology would solve all the issues.

Dr. Fredrick wanted to know how to engage clinicians and how to have them become part of the decision-making. Dr. Tobian suggested reaching out to and working with practitioners on the frontline globally.

Blood Supply Safety from the Perspective of Patients With Sickle Cell Disease

Gwendolyn Poles, DO, FACP, Retired Internist, Board Member of Sickle Cell Disease Association of America

Dr. Poles shared her experience as a physician and a patient with sickle cell disease (SCD), which is an inherited recessive genetic disease with several genotypes and varying degrees of severity. A patient with SCD may require 15-25 units of red blood cells per year, which increases the risk of transfusion-related complications, she said.

Dr. Poles began receiving transfusion since the 1970s. Despite having experienced adverse effects and transfusion-related reactions associated with transfusion, to her and other patients with SCD, alloimmunization is a bigger concern than TTI. Other threats to patients with SCD include parvovirus, which is common and life threating to sickle patients; cytomegalovirus (CMV), which can cause severe disease in immunocompromised patients; Babesia, for which FDA approved in March 2018 an immunofluorescence-based antibody assay and a nucleic acid test for screening whole blood samples; as well as malaria, which is currently not a common issue in the U.S. but immigration patterns could affect the associated risk.

She pointed out that there are many layers of the disease. Regarding stakeholder engagement, she suggested engaging communities and groups who normally are not at the table and whose voices often are not heard.

Discussion

Dr. Josephson commented that malaria and babesiosis are of concern for patients with sickle cell disease. She said recently there was a case of TT malaria in a sickle cell disease patient.

Dr. Verdun commented that risk assessment and tolerance differ for different populations and should be taken into consideration in decision making.

Patient Perspective on Risk and Blood Safety

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

Dr. Skinner explained how HIV affected the hemophilia community, and how the tragedies propelled patients to engage and organizations to collaborate. He noted that since the HIV crisis, the plasma fractionation industry has developed a multi-layered approach to ensure the safety of plasma-derived products.

He pointed out that “since effective virus-inactivation processes in manufacturing were developed, there has been no transmission of HIV, HCV, and HBV since 1987.” A big threat to patients today, however, is emerging infectious diseases, to which no intervention has been implemented.

Regarding risks vs costs, he noted that the tradeoff is not lost. “The safest and most effective drug that no one can afford, is not available or arrives too late is of no benefit to a patient,” he said. He noted that we need risk-based decision making and we need conversation.

Public Comments

Four public members provided comments at the meeting.

Nathan Schaefer: Mr. Schaefer, Senior Policy Director of the Hemophilia Federation of America (HFA), provided public comment on behalf of the organization. He thanked the committee for their service and dedication, and he encouraged the committee and policy makers to keep patients’ safety as a top priority. “Consistently hearing directly from patients is the best way to understand risk tolerance and concerns of patients,” he said. He noted that the community is keen about the update from the committee and BPAC. He reminded the committee that they are here to help to accomplish the committee’s current and future priorities.

Catherin Anderson: Ms. Anderson, a patient with von Willebrand disease, a condition causing extensive bruising and prolonged bleeding, shared her experience with plasma derived therapies and her mom’s fear of potential transfusion-transmitted infections. Her main concern is about unknown risks. She urged the committee and policy makers to stay vigilant against the threat of new and emerging infections, remain high safety regulatory standards, improve transparency, and develop action plans for future TTIs.

Glen Fitzpatrick: Dr. Fitzpatrick, a former committee member, raised a few questions for the committee to consider. He reminded the committee to remember that risks are different for different populations. Regarding zero tolerance, he said, “we don’t know until we have done the research.” Risks change over time. He said we need to be conservative when dealing with emerging threats but we also need exit strategies. He asked the committee to learn from the past (e.g., the AIDs crisis), proactively prevent the past from happening again, and consider exiting strategies. Meanwhile, primary cautionary principle has worked, if it isn’t broken then do not fix it, he said.

Deema Tarazi: Ms. Tarazi, from HFA, provided her comment and presented HFA’s six key principles from the patient’s perspective.

Patient safety must take the highest priority. “In the final analysis, it is the end user of blood products who shoulders the risk,” she said.

• Blood safety policy must be based on rigorous science. Despite advances made in the past decades, known pathogens continue to present risk and emerging pathogens pose new threats. Policy makers need to address these threats on the basis of rigorous science and evidence-based standards.
• The federal government bears responsibility for maintaining a strong regulatory framework, investing resources in blood safety, and enforcing safety standards. To avoid the pitfalls outlined in the 1995 IOM report, she urged regulators to avoid conflicts of interest and question the assumptions that underpin their decisions.
• The policy-making process must be transparent and inclusive, involving meaningful patient/end-user input. Patients, as end users, bear the ultimate risk of blood-borne infections. Their representation in the policymaking process adds needed perspectives and in the end, can help ensure better community acceptance of the policies developed.
• Users of blood and blood products are entitled to clear disclosures that allow them to understand the risks they face and truly give informed consent.
• 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.

Committee Discussion

Discussion on Key Gaps in Our Understanding of Blood Safety Risk and Any Consultations of Studies Needed to Facilitate Further Consideration

Following the public comment, the subcommittee discussed a wide range of topics and identified additional gaps in the committee’s understanding of blood safety and risk.

Policy Foundations: Risk-based decision making is useful but challenging. In Dr. Katz’s view, one of the gaps in the risk-based decision making framework is articulating the policy foundation. At certain point, he said, we need to be able to articulate the policy foundations that will under-guard any risk-based making approach.

Perspectives: In addition to physicians and other subject matter experts like the committee members, Dr. Kotton pointed out that physicians, patients, caregivers, and family members need to understand TTI risks as well as comparative risks.

Barriers and sustainability: Dr. Kotton reminded the committee to be mindful of barriers that might affect the available donors and the sustainability of the blood supply. Dr. Blumberg added that how we mitigate risk will affect sustainability.

Risk communication strategies: Dr. Josephson pointed out that strategies are needed to help physicians appropriately discuss potential risks with patients when obtaining informed consents.

Risk statistics and comparison: Dr. London commented that current risk statistics seem to be conditional on current practice. When making plans based on those statistics, we need to remember the underline conditions that the statistics were based on. Risk statistics might need to be uneven for different patient populations. Risks bundled together in a single statistic based on a variety of heterogeneous conditions might need to be unpacked and dealt with separately sometimes. He reminded the committee to be careful about risk comparisons. “We cannot condition off unacceptable conditions when we make risk comparisons,” he said.

Risk-based decision making: Dr. Vassallo commented that risk-based decision making can be useful. He suggested forming a subcommittee to describe how risk-based decision making is used elsewhere, and explore if there are models that can be use in the U.S. In doing so, the risk tolerance might be better understood, he said.

Dr. Verdun commented that it would be helpful to prospectively discuss questions such as: when another new threat emerges, how should we react?

Dr. Skinner commented that risk-based discussion making framework can help with bigger policy issues but it might not be practical to apply it to every single decision making.

Risk and risk tolerance: Dr. Custer commented that risk-based decision making involves prioritization. At certain point, choices have to be made on what risks are tolerable and what are not. In terms of stakeholder engagement, it is important to hear the voices that we normally don’t hear.

Dr. Ratcliffe commented that people think of risks differently. When the risk is unknown, we tolerate it less. As we move forward, supporting hemovigilance and biovigilance is critical, which can help us better understand what the risks are.

Tolerable risk level: In reference to the theme of the meeting, Dr. Skinner commented that there is no single tolerable risk level. Marilyn E. Levi, MD, Associate Professor of Medicine, Division of Infectious Disease, University of Colorado, commented that “tolerable” is a complicated word. We cannot tolerate something if there is no treatment for it. She suggested stratifying “tolerable.”

Standardization: Dr. Blumberg noted that in terms of testing for emerging pathogens, a strategized plan for testing and standardization would be helpful.

Target audience and objectives: Dr. Skinner wanted to know who the committee’s target audience is and what the committee’s recommendations would be used for, to provide guidance to the FDA, blood centers, or physicians? In his view, understanding these questions would help the committee move forward.

Ms. Fredrick noted that her vision is developing an integrated risk-based decision making process that would involve key stakeholders to make a policy. The target audience could be BOTSEC, and the goal could be to have a policy making body in the office of OASH that could make decisions across all HHS agencies.

Costs: Dr. Levi said that the cost issue needs to be addressed. If a specific test is mandated, the test should be paid for.

Regulatory processes: The committee discussed how FDA makes its regulation mandates and develops guidelines. It was suggested that economic tests should be considered and stakeholder engagement could be enhanced. Dr. Verdun commented that stakeholder engagement should include all stakeholders. Dr. Blumberg commented that the Zika experience demonstrated the challenges of ensuring safety with unknown epidemiology and reacting in the real time. It would be useful for the committee to understand FDA’s regulatory policy making process step by step.

Scott A. Brubaker, CTBS, Director, Division of Human Tissues, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, added that FDA has numerous ways of soliciting input, from the public as well as advisory committees. In general, they try to conduct workshops and get advice from advisory committees first before developing guidelines, and they try to get public input each step of the way.

Another committee member pointed out that it is not clear if there is an overarching policy for multiple processes, and whether or not we need one.

Funding for technology development: The group discussed the importance of providing funding for technology development, especially when tests need to be developed rapidly when facing emergent situations like the Zika outbreak.

Lessons learned: The committee and the invited speakers frequently referenced Zika during the meeting. It was suggested that lessons learned from Zika would help guide future guidelines.

Ms. Fredrick pointed out four gaps that she identified,

• Meaningful stakeholder inclusion, including but not limited to patients and physicians.
• Ethical decision making and how we can learn from others.
• Better understanding of risks, risk perception, and ethics.
• Audience and deliverables.

Discussion on If a Working Group Is Needed to Develop Recommendations to Move Forward

The committee discussed the potential options of moving forward. The general consensus was there is still a lot to learn and various topics to discuss. After discussing the pros and cons of different approaches, the committee decided to form a working group to discuss and explore a path forward, process and content wise.

To help the committee better understand the audience and problems to solve, Dr. Skinner asked for clarification regarding what is the process of when they decide to act and then consult, what is the process when they decide to consult and then act, how the two processes differ, and what is the process of deciding which of the two processes to use.

Ms. Fredrick asked the committee members to volunteer, or recommend others for the working group. She encouraged the committee members to email her additional feedback.

Closing Remarks and Adjournment

The meeting was adjourned at 5:30pm.

Next Meeting

The next meeting has been tentatively scheduled for April, 2018. Additional topics to be discussed at the next meeting include PHS guidelines pertaining risks to donors.

Appendix A: ACBTSA Members and HHS Support Staff

ACBTSA Members

Chair
Jacquelyn (Jackie) Frederick, MBA, Retired CEO, Versiti, Inc.

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

Public Members

Pam Alesescu, MSW, ASW, Palliative Care Social Worker, Long Beach Memorial Medical Center (absent)

Larry Allen, Consumer Advocate (absent)

Daniel Brennan, MD, Alan A. & Edith L. Wolff Professor of Renal Diseases; Director, Transplant Nephrology, Washington University School of Medicine, Department of Internal Medicine, Renal Division (absent)

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

Cassandra D. Josephson, MD, Professor, Pathology and Pediatrics, Laboratory Medicine and Pediatrics, Emory University School of Medicine; Medical Director, Transfusion, Tissue and Apheresis Services, Children’s Healthcare of Atlanta

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

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

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

Representative Members

Richard J. Benjamin, MBChB, MS(HCM), PhD, FRCPath, Chief Medical Officer, Cerus Corporation (absent)

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

Louis Katz, MD, Chief Medical Officer, Biomedical Services, America’s Blood Centers

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

Stephen Riedel, MD, PhD, D(ABMM), FCAP, Associate Professor, Pathology, Harvard Medical School, Associate Medical Director, Clinical Microbiology laboratories, Beth Israel Deaconess Medical Center; representative of AABB

Lisa Stocks, RN, MSN, FNP, Executive Director, Lifesharing (absent)

Lynne Uhl, MD, Director, Division of Laboratory and Transfusion Medicine, Department of Pathology, Beth Israel Deaconess Medical Center (absent)

Frank S. Wilton, CAE, IOM, President and Chief Executive Officer, American Association of Tissue Banks (absent)

Ex-Officio Members

Mark L. Barr, MD, Co-Director of Cardiothoracic Transplantation; Associate Professor of Surgery, Division of Cardiothoracic Surgery, Keck School of Medicine, University of Southern California; Chair, Advisory Committee on Organ Transplantation (absent)

Sridhar V. Basavaraju, MD, FACEP, CDR, USPHS, Director, Office of Blood, Organ, and Other Tissue Safety, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention

Diane H. Corning, RN, JD, Health Insurance Specialist, Center for Clinical Standards and Quality, Clinical Standards Group, Centers for Medicare and Medicaid Services (absent)

Harvey Klein, MD, Chief, Department of Transfusion Medicine, Clinical Center, National Institutes of Health (absent)

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

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

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

COL Clayton D. Simon, MD, FCAP, Medical Corps, U.S. Army; Director, The Joint Pathology Center (absent)

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

HHS Support Staff in Attendance

James (Jim) Berger, MS, MT(ASCP)SBB, Designated Federal Officer for the ACBTSA, Senior Advisor for Blood and Tissue Policy, Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, Department of Health and Human Services

Chris Bessette, MPH, ORISE Fellow, Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, U.S. Department of Health and Health and Human Services

Richard Henry, ML, MPH, MT(ASCP), Advisor for Blood Policy, Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services

Debbie Seem, RN, MPH, Public Health Policy Advisor, Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services

Appendix B: Joint Statements of AABB, ABC, and ARC

Department of Health and Human Services
Advisory Committee on Blood and Tissue Safety and Availability
September 13, 2018

A Joint Perspective on Tolerable Risk in Blood Safety
Presented by: Zbigniew M. Szczepiorkowski, MD, PhD, FCAP

I am presenting the following perspective on behalf of AABB, America’s Blood Centers and the American Red Cross. Collectively, our organizations represent the nation’s blood collection establishments, transfusion services, and transfusion medicine professionals. We commend the Advisory Committee on Blood and Tissue Safety and Availability (ACBTSA) for convening this 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 a 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:

1. Validated risk-based models enable decisionmakers to evaluate 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 the need to ensure that blood is available for patients; and are useful tools to drive policymaking and evaluate blood safety;
2. 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;
3. Support for research related to new threats to the safety of the blood supply;
4. Recognition that biovigilance and hemovigilance are critical to advancing the safety of the blood supply;
5. Voluntary standards and guidance contribute to blood safety; and
6. Risk tolerability may vary significantly between different constituencies, as well as between organizations and individuals within a single constituency.

Background on the United States Blood System

As most ACBTSA members are aware, the United States blood system is comprised of a complex web of private and public stakeholders. Blood and blood cponents 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 accreditation organizations, and payors. Public stakeholders central to the U.S. blood system include the Food and Drug Administration, the Centers for Disease Control and Prevention, the National Institutes of Health, the Office of the Assistant Secretary for Health and the Office of the Assistant Secretary for Preparedness and Response, as well as other federal, state and local governmental agencies.

The committee 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 economic 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’s health. Additional challenges include changing medical practices, reduced blood utilization, a limited donor pool and consolidation throughout the health care system. Together, these challenges limit the ability of the blood system to invest in research and development and adopt innovative technologies.

Process Used to Develop Perspective on Risk Tolerability

The following perspective on risk tolerability reflects feedback received through a process that AABB piloted to assess the viewpoints of its diverse membership, which includes both institutions and individuals involved in transfusion medicine and cellular therapy. AABB surveyed subsets of its volunteer leadership and members, including members of certain committees, blood center Chief Executive Officers, medical directors of transfusion services and hospital-based blood banks and the AABB board of directors to gauge 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) responses were completed.

The results of this survey illustrate that there is widespread agreement on general principles related to 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 continues to explore tolerable levels of risk in blood safety, we urge the committee to work with stakeholders to explicitly and clearly define all terms. All stakeholder in the U.S. blood system must have a common understanding of key terms, such as “safe,” “blood safety,” “risk,” and “risk-based model” prior to defining a tolerable level of infectious disease risk in blood safety.

Perspective

1. AABB, America’s Blood Centers and the American Red Cross support the use of validated risk-based models to drive policymaking 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 the context of a range of emerging risks and other societal priorities that must compete for limited resources. They also balance demands for safe blood with the need to ensure that blood is available for patients. Strongly Agree (59%, 47); Agree (35%, 28); Disagree (5%, 4); Strongly Disagree (1%, 1)

Risk-based models are useful tools to evaluate blood safety since the terms “safe” and “safety” are continuously evolving and are not uniformly defined for the U.S. 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 these tremendous strides and similar to all biologics, blood will always have inherent risk. Strongly Agree (65%, 53); Agree (31%, 25); Disagree (4%, 3); Strongly Disagree (0%, 0)

2. AABB, 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 inextricably 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. Strongly Agree (58%, 47); Agree (38%, 31); Disagree (4%, 3); Strongly Disagree (0%,0)

As we consider tolerable levels of transfusion-transmitted risks, we must remember that patient 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). Strongly Agree (60%, 49; Agree (36%, 29); Disagree (4%, 3); Strongly Disagree (0%. 0)

3. Emerging infectious diseases will continue to pose new threats to the safety of the blood supply. Therefore, the nation must continue to support research related to these potential threats. Ongoing public and private investment in research is critical to identifying new threats as well as developing and evaluating new safety processes and technologies. Strongly Agree (68%, 55); Agree (31%, 25); Disagree (0%, 0); Strongly Disagree (1%, 1)

In addition to investments in research, we encourage the ACBTSA and policymakers to consider (i) programs and reimbursement mechanisms related to blood safety mandates and FDA recommendations in guidance, as well as (ii) 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 effective and will not contribute to improved safety unless they are accessible, affordable and implemented by the blood community. Strongly Agree (78%, 63); Agree (22%, 18); Disagree (0%, 0); Strongly Disagree (0%, 0)

Although the Biomedical 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 U.S. blood collection establishments to implement additional safety measures within 4 to 12 weeks, using either testing for Zika with an investigational nucleic acid test or pathogen reduction technology. HHS estimated in a June 2017 study that this requirement for universal adoption of individual donor testing for Zika virus would cost the blood system approximately $137 million annually. A recent study published in the New England Journal of Medicine concluded that testing individual blood donations for Zika not only had a high cost, but also had a low yield; out of 4 million blood donations screened, only nine were confirmed positive for Zika. (Saa, P, Proctor M, Foster G, Krysztof D, Winton C, Linnen J, Gao K, Brodsky J, Limberger R, Dodd R, Stramer S. Investigational Testing for Zika Virus among U.S. Blood Donors, N Engl J Med 2018;378:1778-88.) Current reimbursement mechanisms are not aligned with the blood community’s role in protecting the public’s health.

We believe that public policies need to support and finance the implementation of new technologies that are required for blood safety initiatives. Strongly Agree (84%, 67); Agree (15%, 12); Disagree (1%, 1); Strongly Disagree (0%, 0)

4. We believe that real-time data, including biovigilance and hemovigilance, are important to advancing the safety of the blood supply. AABB specifically surveyed its members on the need for a robust, well-funded biovigilance program in the United States to track the risks and benefits of transfusion, as well as the effectiveness of safety interventions, both proposed and existing, to reduce risk. As this committee has discussed in the past, comprehensive surveillance data will enable the entire blood community to engage in more thorough risk assessments and make more informed decisions regarding strategies to protect patient and donor safety that will not adversely impact the availability of blood products. Strongly Agree (64%, 51); Agree (32%, 26); Disagree (4%, 3); Strongly Disagree (1%, 1)

At present, biovigilance efforts are limited and inconsistent throughout the United States. For example, in 2011, babesiosis was classified as a nationally notifiable condition and the Centers for Disease Control and Prevention (CDC) began conducting surveillance for the disease. (Centers for Disease Control and Prevention. Surveillance for Babesiosis – United States, 2014 Annual Summary [monograph on the internet]. 2016. Available from: https://www.cdc.gov/parasites/babesiosis/resources/babesiosis_surveillance_summary_2016.pdf) Despite this classification, as of 2015, babesiosis was only reportable 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 incidence and prevalence of babesiosis. Strongly Agree (58%, 47); Agree (38%, 31); Disagree (4%, 3); Strongly Disagree (0%, 0)

Similarly, hemovigilance is necessary to monitor donor safety, transfusion safety and patient safety. Since 2006, AABB has worked with the federal government to establish a U.S. national hemovigilance program. We believe that increasing the resources available for national hemovigilance efforts will contribute to improved assessments of risk, stronger evidence-based policymaking and continued quality and safety improvements in transfusion medicine. Strongly Agree (52%, 42); Agree (41%, 33); Disagree (6%, 5); Strongly Disagree (1%, 1)

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. Strongly Agree (73%, 59); Agree (27%, 22); Disagree (0%, 0); Strongly Disagree (0%, 0)

5. Voluntary 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 accredited organizations. These organizations set quality goals and use processes within their individual frameworks to reduce specific risks. Strongly Agree (55%, 44); Agree (39%, 31); Disagree (6%, 5); Strongly Disagree (0%, 0)

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 2006 recommendation that blood collection and transfusion facilities begin to implement TRALI risk reduction measures for high plasma-volume components, FDA fatality reports indicated that deaths due to TRALI fell significantly from 34 in FY2007 to 16 by FY2008, with 8 fatalities reported for 2016. (Food and Drug Administration, Fatalities Reported to FDA Following Blood Collection and Transfusion Annual Summary for Fiscal Year 2016, available at https://www.fda.gov/downloads/biologicsbloodvaccines/safetyavailability/reportaproblem/transfusiondonationfatalities/ucm598243.pdf. Last visited August 17, 2018.) Strongly Agree (56%, 45); Agree (39%, 31); Disagree (5%, 4); Strongly Disagree (0%, 0)

6. We appreciate that 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 will be quite different from an individual patient’s perspective. We commend the ACBTSA 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 discussions on risk tolerability and the prioritization of healthcare resources, such as in-person and virtual town hall meetings. Strongly Agree (42%, 34); Agree (48%, 39); Disagree (10%, 8); Strongly Disagree (0%, 0)

We believe that a multi-disciplinary approach is needed to understand risk tolerability related to blood safety. Today’s agenda scratches the surface of this complex topic, and representatives 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 Health, the Office of the Secretary for Preparedness and Response, the Office of the Assistant Secretary for Planning and Evaluation, the Food and Drug Administration, Centers for Disease Control and Prevention, National Institutes of Health, Armed Services Blood Program and Centers for Medicare and Medicaid Services, must continue to be at the table. We also recommend including representatives of state and local governments in future discussions, since regional, state and local factors may impact decisions related to blood safety. Finally, we believe industry provides an important perspective on risk tolerability, since these companies bring forth innovative technology that continually advance blood safety. Strongly Agree (54%, 44); Agree (44%, 36); Disagree (1%, 1); Strongly Disagree (0%, 0)

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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 stakeholders, on this important topic.

AABB is an international, not-for-profit association representing individuals and institutions involved in the fields of transfusion medicine and cellular therapies. The association is committed to improving health through the development and delivery of standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB membership includes physicians, nurses, scientists, researchers, administrators, medical technologists and other health care providers. AABB members are located in more than 80 countries and AABB accredits institutions in over 50 countries.

Founded in 1962, America's Blood Centers is North America's largest network of community- based, independent blood programs. Recognized by the U.S. Congress for its critical work in patient care and disaster preparedness and response, the federation operates more than 600 blood collection sites providing half of the U.S., and a quarter of the Canadian blood supply. These blood centers serve more than 150 million people and provide blood products and services to more than 3,500 hospitals and healthcare facilities across North America.

The American Red Cross shelters, feeds and provides emotional support to victims of disasters; supplies about 40 percent of the nation's blood; teaches skills that save lives; provides international humanitarian aid; and supports military members and their families. The Red Cross is a not-for-profit organization that depends on volunteers and the generosity of the American public to perform its mission. About 5.6 million units of whole blood are collected from roughly 3.3 million Red Cross volunteer donors, separated into 8 million transfusable blood products and supplied to approximately 2,700 hospitals and transfusion centers across the country for patients in need.

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Addendum: Alternative Viewpoints

The perspective on risk tolerability in blood safety presented on behalf of AABB, America’s Blood Centers and the American Red Cross consists of principles approved by AABB’s Board of Directors and agreed to by a substantial majority of AABB members who responded to the survey on the perspective. AABB’s membership is quite diverse, and some of the respondents who disagreed or strongly disagreed with a principle provided AABB with an alternative opinion. AABB committed to noting areas of consensus as well as alternative viewpoints. This addendum provides information on the alternative viewpoints shared with AABB. The feedback included in this addendum does not represent AABB’s position on risk tolerability.

Risk-Based Models: In response to the principle related to using risk-based models evaluate blood safety, AABB received several alternative viewpoints highlighting the need to establish explicit common definitions. For example, one respondent highlighted that “risk” is broad, and suggested that certain risks, such as bacterial contamination, must be fully mitigated over time, while other risks, such as those of reactions and efficacy due to donor differences, cannot be managed. A different respondent was uncertain about the meaning of “risk-based model” and questioned whether existing evidence illustrates that using a risk-based model results in better decision-making.

One person highlighted that decisions related to the adoption of new safety interventions and technologies are not insulated from financial considerations; while safer products, such as platelets, are available, hospitals may be reluctant or unable to pay for these new technologies. One respondent was concerned that a risk-based approach is too relativistic and may result in contradictory policies that could reflect prevailing political opinion.

Blood Safety: One alternative viewpoint highlighted that new safety requirements may prevent adverse events occurring in transfusion recipients, while a different opinion questioned the levels of risk associated with blood transfusions due to a passive hemovigilance system. One person emphasized that blood safety is held to a different standard than other activities with higher levels of risk. One respondent did not believe that patient care is currently impacted by blood availability, while a different respondent highlighted that collaboration among blood centers helps safeguard the availability of blood for patients.

Research Related to New Threats: One respondent opined that public policies should not be equated with government policies and requested that policies support private market innovation.

Biovigilance and Hemovigilance: One respondent cautioned against hemovigilance and biovigilance efforts that create unnecessary new burdens, increase costs or slow down innovation and research. There were four alternative opinions shared related to a national hemovigilance program: one respondent supported a national hemovigilance program, two alternative viewpoints questioned whether hemovigilance should be a priority, and one respondent opined that hemovigilance can be accomplished without a federal mandate.

Role of Voluntary Standards and Guidance in Blood Safety: One person opined that the blood community should agree that safety is important, implement the agreed upon level of safety and suggested that those who use blood components underwrite the costs. Two respondents suggested that previous AABB decisions did not undergo risk-based assessments.

Risk Tolerability Varies Among Constituencies: Several respondents highlighted that decisions related to blood safety and risks to the blood supply should be based on evidence rather than opinion. There was support for engaging with and educating all stakeholders involved in the blood system.