Strengthening Health Systems Through International Blood Product Sharing Agreements

Abstract

Blood products are critical to the success of both routine healthcare delivery and emergency response efforts. Ensuring the safety and availability of blood products presents nations with considerable collection, screening, and distribution challenges that are often exacerbated by public health crises, particularly mass-casualty events involving traumatic injuries. However, recent outbreaks of Ebola and Zika virus disease have also illustrated the importance of securing blood product supplies during ongoing infectious disease emergencies. The United States and other nations should consider enhancing existing mechanisms for sharing medical countermeasures by creating formal agreements for sharing blood products during public health emergencies.

Ensuring the safety and availability of blood products presents nations with considerable collection, screening, and distribution challenges that are often exacerbated by public health crises, particularly mass-casualty events involving traumatic injuries. Recent outbreaks of Ebola and Zika virus disease have also illustrated the importance of securing blood product supplies during ongoing infectious disease emergencies.

Blood and its associated components are medical countermeasures (MCMs) of critical importance during both routine healthcare delivery and emergency medical response. Citing blood shortages as a threat to patient populations worldwide, the World Health Organization's (WHO) Model List of Essential Medicines and the World Health Assembly's resolution WHA63.12 both affirm the need for countries to maintain safe national reserves of voluntarily donated blood.^1,2 Additionally, the US Food and Drug Administration (FDA) identifies blood products as medical countermeasures that may be required during response efforts following a public health emergency.³

Despite blood products' integral role in medical care, nations often wrestle with the considerable challenges of sustaining adequate blood supplies and distributing them efficiently to high-need locations. Blood and its derivatives are also susceptible to contamination by a range of infectious pathogens, thereby presenting critical “hemovigilance” challenges and posing threats to the safety of transfusion recipients. Furthermore, unlike most MCMs, blood products originate exclusively from volunteer donors, undergo extensive screening upon collection, and cannot be stockpiled for more than a few weeks. Though some blood products (such as red blood cells) may be frozen and stored for later use, this practice presents a number of challenges in clinical settings, including maintenance costs as high as $100 per unit stored, the need for adequate storage space and personnel to manage inventories, and thawing times of up to 100 minutes.^4,5

Historically, these limitations have been characterized in the context of health crises involving traumatic injuries. However, recent outbreaks of Ebola and Zika virus disease have raised new questions about blood product management and MCM sharing strategies in the context of infectious disease threats. Such emergencies underscore a need to enhance and extend the protocols and policies that govern both domestic and international blood product collection, testing, and distribution efforts.

This analysis first examines the current state of blood product management during public health emergencies, with particular emphasis on the regulatory systems and policies of the United States. Following is an investigation of blood product needs and management strategies employed during the 2014 West African Ebola epidemic and the ongoing outbreak of Zika virus in Puerto Rico. The analysis concludes with recommendations for US policymakers to prioritize blood product collection, screening, and distribution during infectious disease emergencies; engage with domestic and international partners in both the public and private sector to strengthen blood product management practices; and develop formal protocols that facilitate international sharing of blood products during public health emergencies.

Blood Product Collection and Distribution

Given the risks and challenges associated with blood product management, the United States relies on a complex regulatory framework to ensure the viability of domestically collected blood products. The Department of Health and Human Services (HHS), the FDA, and the Centers for Disease Control and Prevention (CDC) have all implemented policies intended to safeguard the American blood reserve from pathogenic threats. HHS's Advisory Committee on Blood and Tissue Safety and Availability counsels the secretary of HHS on ethical, economic, public health, and policy issues relating to blood product management. CDC conducts extensive surveillance of blood products to detect potential public health risks in the US blood supply. Additionally, per the Public Health Service Act and the Federal Food, Drug and Cosmetic Act, the FDA's Center for Biologics Evaluation and Research (CBER) regulates the collection and therapeutic use of blood and its components, oversees the use of blood collection devices and screening tests, and monitors and enforces safety standards at blood collection establishments.⁶

Several nongovernmental organizations in the United States are responsible for collecting, storing, and distributing blood, including the American Red Cross (ARC), America's Blood Centers (ABC), and the Blood Centers of America (BCA). Additionally, AABB (founded in 1947 as the American Association of Blood Banks) serves as a professional body dedicated to upholding technical and ethical standards in blood banking and transfusion medicine.

Internationally, WHO plays an important role in establishing standards for blood product screening and transfusion. WHO gathers extensive surveillance data on several bloodborne pathogens from its member states, including hepatitis B and C viruses, dengue virus, Ebola virus, Marburg virus, Lassa virus, Crimean-Congo hemorrhagic fever virus, yellow fever virus, and, more recently, Zika virus.⁷ Between 1975 and 2010, WHO released 5 separate resolutions pertaining to blood product acquisition, screening, and transfusion, which recommend that nations make blood safety a national public health priority, promote non-remunerative donation practices, implement national policies to facilitate efficient blood product allocation, improve medical training, and encourage timely reporting of adverse transfusion events, donor deferrals, and best practices.⁸ Additionally, WHO has released guidance for strengthening national blood cold chains, systems for handling and transporting blood products between the point of collection and the point of transfusion that adhere to recommended storage and temperature protocols.⁹ WHO has also published contingency blood product screening guidelines to implement during public health emergencies, suggesting that collection facilities use rapid or single-use assays to test blood products acquired in times of crisis.¹⁰ In addition to WHO, the International Federation of Red Cross and Red Crescent Societies (IFRC) plays an important role in setting standards for transfusion medicine, having developed criteria for building strong and sustainable national blood systems.¹¹

Though the institutions responsible for maintaining blood supply pipelines span both the public and private sectors, they collaborate frequently to ensure the integrity of blood products worldwide. These activities include “hemovigilance,” or screening donors and blood products for dangerous pathogens; monitoring the supply chains used to prepare and deliver blood products; and conducting research in support of developing new methods of securing blood products.

Blood Product Management in Emergencies

HHS's National Blood Collection and Utilization Survey reports that the United States amassed 15,271,000 whole blood and red blood cell units in 2011, of which 93% were collected by blood centers; the remaining units were collected in hospitals.¹² Though many institutions share the responsibility for screening and distributing these units, a lack of interagency coordination could impede efforts to ensure concerted responses to public health emergencies that affect the availability and safety of blood products. Additionally, because the US blood supply depends predominantly on voluntary donations, the availability of blood products fluctuates constantly. Still, despite seasonal shortages during summer and winter months, the US Government Accountability Office (GAO) reported in 2002 that the US blood supply remains generally adequate.^13,14 However, a 2013 assessment of AABB member institutions revealed significant declines in the number of blood products collected.¹⁵ GAO also identified blood product availability as the most important factor in the initial response to a disaster and recommended that blood banks maintain a 7-day supply of blood products at all times.¹³

Public health emergencies—particularly mass-casualty disasters involving traumatic injuries—can exacerbate the challenges associated with maintaining safe blood supplies. Estimated blood product needs during mass-casualty events are often based on data from incidents involving explosives and combat injuries; however, there are few analyses of blood product needs following other types of emergencies involving traumatic injuries, which could also deplete limited inventories.^16-18 For example, medical responders reported that 117 total units of blood products were required to treat injured victims in the 48 hours following the 2013 crash of Asiana Airlines Flight 214 in San Francisco, California.¹⁹

Public health crises not involving traumatic injuries could also affect blood product availability and safety. In 2002, CDC reported an incident in which an organ donor, after receiving several contaminated blood transfusions prior to her death, passed on West Nile virus infections to 4 transplant recipients.²⁰ Additionally, AABB has developed a planning model of a highly pathogenic avian influenza pandemic in which the spread of disease causes major public health challenges and infrastructural failures, including a downsized healthcare workforce, school and hospital closures, and a loss of personnel required to transport goods and services.²¹ AABB notes that such conditions, in turn, could shrink pools of available donors, put blood-system personnel at risk of infection, and result in blood product shortages as the pandemic progresses.²¹

Conversely, surplus donations can also strain blood product pipelines and cause considerable financial losses. In 2003, for example, following a powerful earthquake in Bam, Iran, that resulted in more than 29,000 deaths and 23,000 injuries, the Iranian Blood Transfusion Organization collected 108,985 blood donations; however, only 21,347 units were distributed to hospitals and only 1,231 units arrived in Kerman Province, where the earthquake occurred.²² Later, health authorities reported that the required number of blood products were available prior to the donation surge.²² They also noted that the number of donors testing positive for bloodborne infections typically increases during a disaster, thereby further straining blood product screening mechanisms.²²

Similar challenges emerged in the United States following the events of September 11. After the attacks, HHS, ABC, and ARC issued simultaneous requests for blood donations; as a result, collection facilities amassed 572,000 units of blood in the following weeks, a nearly 40% increase from earlier monthly averages.¹³ However, most survivors of the attacks presented with burns and inhalation injuries and required only 258 units of blood for treatment; two-thirds of the donations collected were stored, and American blood banks ultimately discarded 208,000 expired units.²³ The New York Blood Center incurred between $4 and $5 million in collection and processing costs, and the federal government awarded blood collection agencies over $500,000 as compensation for processing surplus blood donations.^13,23 The surge in donations also presented concomitant public health risks: Many of the individuals who stepped forward to donate blood were first-time donors, and the incidence of hepatitis B and C, HIV, and human T-cell lymphotrophic virus infections is 2.4 times higher among first-time donors than repeat donors.^24,25 The aftermath of September 11 mirrored this phenomenon, with blood banks reporting a nearly 3-fold increase in donations testing positive for hepatitis B and C, as well as HIV.²⁴ The American blood industry subsequently faced considerable public distrust after its mismanagement of donations following September 11.

Blood Product Needs: Zika Virus Outbreak

Beginning in 2015, an outbreak of Zika virus spread rapidly across North, South, and Central America and much of the Caribbean. The emergence of clusters of Guillain-Barré syndrome, microcephaly, and other neurological disorders thought to be associated with the virus prompted WHO to declare the outbreak a public health emergency of international concern (PHEIC) in February 2016.²⁶

Puerto Rico, a US territory, has been struck particularly hard by the Zika outbreak, having reported 259 locally acquired cases of Zika and 2 travel-associated cases as of March 16, 2016.²⁷ CDC predicts that as many as 80% of the island's 3.5 million residents will eventually contract Zika infections.²⁸ Puerto Rico also reports large burdens of dengue virus, which, like Zika, belongs to the flavivirus family and is transmitted by the same mosquito species, Aedes aegypti.²⁹ In fact, in 2009, AABB described an outbreak of Zika on Yap Island, Micronesia, noting that patient sera contained IgM antibodies against dengue and underscoring the transfusion-associated transmission risks posed by emerging flaviviruses.³⁰ Two instances of transfusion-associated dengue transmission have been documented in Hong Kong and Singapore, in addition to cases of transmission resulting from needle-stick exposures, bone marrow transplants, and kidney transplants.³⁰

In light of these risks and the absence of a blood screening test for Zika, FDA issued recommendations in February 2016 to secure the US blood supply from the virus, calling for deferrals of donors at risk of acquiring infections and urging areas of active Zika transmission to obtain blood products from unaffected locations.³¹ Banco de Sangre, a Puerto Rican blood bank, subsequently solicited ABC for blood products to use in delivery wards.³² On March 7, 2016, HHS announced that a shipment of blood donations collected by ARC, ABC, and BCA in the continental United States would be shared with Puerto Rico to ensure the availability of safe blood products for island residents amid ongoing Zika transmission.³³ Currently, American commercial flights and carriers deliver approximately 5,000 units of blood to the island each week.³² Additionally, the FDA, CDC, the Office of the Assistant Secretary for Preparedness and Response (ASPR), and the Biomedical Advanced Research and Development Authority (BARDA) are developing new molecular diagnostic screening tests and pathogen reduction technologies for blood products.³⁴ FDA officials note that while employing additional screening measures for blood products would raise processing costs for blood collection facilities, universal implementation of pathogen reduction technologies could, over time, reduce the need for blood donor screening tests.³⁵

Blood Product Needs: 2014 Ebola Outbreak

In contrast to the protective measures implemented in response to Zika, fewer steps were taken to secure West African blood supplies during the 2014 Ebola epidemic. The epidemic, which began in Guinea, quickly spread to Liberia and Sierra Leone. As with Zika, the scale and severity of the epidemic led WHO to declare a PHEIC in August 2014.³⁶ WHO has reported 28,616 confirmed, probable, and suspected cases and 11,310 deaths in West Africa as of May 19, 2016.³⁷ In addition, 15 deaths and 36 suspected, probable, and confirmed cases were reported in Nigeria, Mali, Senegal, the United States, Italy, the United Kingdom, and Spain.³⁸

Before and during the outbreak, Guinea, Liberia, and Sierra Leone experienced considerable challenges in maintaining adequate national blood product reserves: a lack of blood collection equipment, few willing donors, and public mistrust of healthcare facilities.³⁹ In Liberia, for example, the National Blood Safety Program accounted for only 2.5% of the blood products used at health facilities; the remaining originated from clandestine paid donors.⁴⁰ Similarly, Sierra Leone's National Blood Programme reported that 90% of transfused blood units were donated by clandestine paid donors and family members instead of voluntary donors; healthcare facilities also reported chronic shortages in personnel, test kits and reagents, and blood bags.⁴⁰ As Ebola spread through Guinea in 2014, the country collected only 31,850 units of blood despite an estimated need for 114,700 units.⁴⁰

Amid these shortages, demand for blood products escalated during the outbreak. In September 2014, WHO called for the use of convalescent whole blood and plasma from Ebola survivors as a therapeutic countermeasure, citing the efficacy of blood products in treating a variety of infections, including Ebola.^41,42 The call for donations was echoed by clinicians in Liberia and Sierra Leone, despite reports disputing the effectiveness of convalescent plasma in treating Ebola patients.^43,44 However, the affected countries may have benefited from increased blood donation even in the absence of Ebola. West African nations report high rates of maternal and child deaths from hemorrhage, as well as large caseloads of anemia, malaria, and road traffic injuries—all conditions that require blood transfusions for treatment.^45,46 Existing burdens of other communicable diseases and limited blood screening resources likely posed additional safety threats to West African blood supplies.

Despite the clear need for blood donations to handle routine health concerns as well as treat Ebola patients, neither the United States nor any other country shared blood products with the West African nations shouldering the largest caseloads of Ebola. However, some US agencies and organizations did take further steps to secure the US blood supply. FDA issued nonbinding recommendations in December 2015 for assessing donor eligibility and screening of domestically collected blood products for Ebola.⁴⁷ Additionally, AABB, ABC, and ARC issued a joint statement outlining deferral policies for high-risk donors and encouraging eligible Americans to continue donating blood.⁴⁸

International Blood Product Sharing Agreements

Past public health emergencies—including both mass-casualty events and infectious disease threats—illustrate the importance of access to safe, ample blood supplies. However, these events also underscore the medical, logistical, and financial risks of collecting and screening blood products in the immediate aftermath of a crisis. Given that under current practices, blood products, unlike other MCMs, cannot be stockpiled in advance of an emergency (save for the practice of freezing red blood cells), vulnerable populations might benefit from a new approach to ensuring blood supply availability by encouraging national governments to form agreements for sharing blood products during public health emergencies.

West African governments have already begun exploring the feasibility of such arrangements. For example, Liberia and Sierra Leone have reached an agreement to share convalescent plasma samples for clinical trials; Ebola-affected and unaffected nations across Africa have also considered a formal agreement to facilitate storing and sharing of convalescent plasma in anticipation of future Ebola outbreaks. International public-private partnerships represent another mechanism by which nations can access needed resources and expertise during a public health crisis. ASPR, for example, has established a cooperative agreement with the Pasteur Institute to enhance surveillance and laboratory capacities in 5 African and 3 Southeast Asian countries.⁴⁹ Another partnership between ASPR and the Gorgas Memorial Institute in Honduras supports healthcare training and surveillance efforts in Latin America.⁴⁹

As demonstrated in Puerto Rico as well as West Africa, blood-sharing agreements could help bolster routine healthcare delivery in the midst of a public health crisis. Given the global implications of epidemics and other biological threats, nations, including the United States, could benefit from forming such agreements as a means of enhancing global, national, and regional healthcare delivery capacities. However, adopting this approach would require nations to address several existing challenges in blood product management and international MCM deployment. Following are potential US-focused policy solutions for incorporating blood product sharing agreements into existing MCM-sharing efforts.

Strengthening National Blood Systems

As discussed previously, domestic blood product management remains a challenge even in the absence of an acute health crisis. Given that robust collection and distribution systems are prerequisites for successful international exchanges of blood products, nations should take steps to strengthen existing, in-country gathering, screening, and transportation mechanisms.

According to the WHO Blood Regulators Network's Assessment Criteria for National Blood Regulatory Systems, a central agency at the national level should regulate domestic collection and distribution of blood products.⁵⁰ In the United States, however, blood product management responsibilities are decentralized across multiple agencies in HHS (ie, FDA, CDC), as well as various nongovernment institutions. Consolidating oversight functions into a single, existing governing body (eg, CBER) or creating a new office in FDA, vesting said body with requisite legal powers, identifying strategic objectives for improving blood product management, and establishing metrics for evaluating the success of such efforts could help streamline regulatory activities and expedite formulation and implementation of blood product policies.

Executing these changes might be facilitated by amending the Public Health Service Act, which establishes roles and authorities in HHS and also grants the HHS secretary the power to identify priority MCMs that could mitigate a given health threat.⁵¹ Currently, the act includes numerous provisions for vaccines, including several related to vaccine tracking, availability, development, purchase, and distribution.⁵¹ Including similar provisions for blood products and other biologics could facilitate their acquisition and management during a public health emergency.

International Regulatory and Legal Challenges

Providing international public health and medical assistance—including MCM deployment—remains a critical challenge in responding to global health security threats. Both the Biological and Toxin Weapons Convention (BWC) and the International Health Regulations (IHR) stipulate that state parties should assist members endangered by BWC violations and collaborate in responding to PHEICs, respectively.^52,53

The United States is an important contributor to international efforts aimed at mitigating public health emergencies, and the US government receives frequent requests for MCMs and public health personnel from its global partners, a trend that is likely to continue.⁵⁴ In addition to being a state party to both the BWC and IHR, the United States has enacted laws and policies to facilitate MCM acquisition and sharing during public health emergencies. Besides the Public Health Service Act, which authorizes HHS to stockpile drugs, vaccines, medical devices, and other biological products,⁵⁵ HHS has developed a Policy Framework for Responding to International Requests for Public Health Emergency Medical Countermeasures, as well as an International Emergency Policy and Assistance Framework.⁵⁶ Through its Global Health Security Initiative (GHSI), HHS has also created informal ties with partner nations to strengthen preparedness for a range of chemical, biological, radiological, and nuclear threats; priority activities include stockpiling and deployment of MCMs.^57,58 Finally, the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan identifies blood products for improvised nuclear device explosions as a priority civilian MCM requirement; however, the most recent plan (2015) makes no mention of blood product needs for nuclear disasters or any other type of public health emergencies.⁵⁶

While these policy frameworks have helped to organize the US government's responses to threats such as pandemic influenza, several legal challenges remain in coordinating international exchanges of MCMs, including handling credentialing requirements for healthcare providers administering emergency MCMs, providing liability protection for MCM donors and recipients, and creating compensatory mechanisms for those harmed as a result of receiving an MCM. Therefore, as an initial step, GHSI members and HHS's International Sharing of Medical Countermeasures Working group—which convenes representatives of agencies from across HHS and other departments to review international MCM sharing requests—could formulate criteria under which nations affected by or responding to public health emergencies could share blood products.⁵⁹ Additionally, FDA should collaborate with WHO, Red Cross and Red Crescent societies across the world, ABC, BCA, and AABB to establish legal conditions and safety standards for international exchanges of blood products.

Funding and Logistical Challenges

In forming agreements to share blood products, parties should also consider the logistical challenges associated with transporting them across international borders and within recipient countries. For example, differences in manufacturing standards between countries could present importation obstacles. Per the US's International Assistance System Concept of Operations, foreign firms that produce FDA-regulated products must comply with applicable FDA requirements before, during, and after importation into the United States; in fact, even imported medical products that are already approved for use in the United States may be rejected if they appear to have been manufactured or processed under unsanitary conditions.⁵⁶ In the context of international MCM sharing, breaches at any point in the blood cold chain of a donor nation could render blood products unusable by the United States. Additionally, the US Department of Commerce has the power to restrict MCM deployments to recipient states with embargos or those designated as terrorist states.⁵⁹

Upon acquiring requested MCMs from a donor nation, recipients must also possess mechanisms for deploying them to areas of need. Following Hurricane Katrina, for example, 151 countries and international organizations offered the United States assistance in various forms; however, in many instances, needed resources were hindered by bureaucratic hurdles and the United States lacked a cohesive plan for integrating foreign material assistance into ongoing response efforts.⁶⁰ Furthermore, as seen in West Africa, weak public health and healthcare infrastructure could complicate efforts to deliver donated blood products without compromising the blood cold chain. International partners must therefore work to concurrently strengthen national blood systems as they develop protocols for distributing blood products to potentially resource-poor points of need.

Finally, blood product collection, storage, and distribution efforts are costly endeavors. There are currently no designated mechanisms in the United States for financing bilateral or multilateral MCM exchanges, replenishing depleted MCM stockpiles, or channeling funds to WHO in the midst of a public health crisis.⁵⁹ Although HHS may request supplemental funding from Congress to fund MCM needs during such a crisis, the absence of a dedicated contingency fund can impede rapid responses to progressing threats. Some nations might also lack robust mechanisms for compensating nongovernment partners in public health emergency response. This deficiency could prove especially detrimental for international blood product sharing efforts, given that a significant portion of national blood supplies originate from the private sector.

Strengthening International Collaboration

Though the United States is well-positioned to lead efforts to form international blood product sharing agreements, it is infeasible for any one nation to assume full responsibility for acquiring and sharing MCMs. As an initial step in galvanizing international support for blood product sharing efforts, the United States could first identify potential nations with which to enter into blood sharing agreements. Next, FDA could assess the blood product regulations as well as the legal landscapes of potential partner nations, as a means of ensuring that the regulatory frameworks of both the United States and its partners interface. These discussions should also involve CDC's Division of Global Health Protection and the US Agency for International Development's Office of US Foreign Disaster Assistance to ensure that resultant blood product sharing policies can be feasibly implemented. Finally, WHO and BWC could serve as additional forums for member states to examine the feasibility of bilateral or multilateral arrangements for sharing blood products.

The aforementioned agencies should also coordinate with blood collection authorities in both donor and recipient nations to strengthen systems for monitoring existing blood product inventories as a means of preventing surges and deficits in national blood supplies. Taking these steps would not only strengthen interagency and public-private sector ties, but also enable health authorities to begin considering policies and frameworks for sharing valuable resources required for both emergency and routine healthcare delivery during global public health crises.

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