In the United States, access to investigational products during the EVD epidemic occurred via uncontrolled single-patient-use Emergency Investigational New Drug (EIND) authorization from the FDA.¹⁴ Many of these investigational products did not have existing clinical protocols for humans and had limited data available on pharmacokinetics, optimal dosing, and safety in humans. Thus, in many cases, investigational protocols had to be developed by local clinical investigators or the product sponsors in parallel with the EIND process for individual local institutional review board (IRB) approval.

Development of protocols was influenced by uncertainties in the international research community regarding the ethical acceptability of withholding treatments with inadequate prior testing in humans, the ethics of conducting research on a disease with a high case fatality proportion during an emergency, and the optimal study design for assessing countermeasures in a setting in which randomized, placebo-controlled trials (the gold standard of medical research) were not always feasible.¹⁵ The few facilities in the United States with established biocontainment units had to quickly implement new protocols in coordination with their clinical research infrastructure and biocontainment unit clinical staff in the midst of patient care.¹⁶ Furthermore, optimal supportive clinical management of EVD patients was not well-defined prior to the 2013–2016 epidemic. The case fatality proportion of 18.5% for the 27 patients with EVD managed in biocontainment units in the United States and Europe was substantially lower than that for patients managed in West African Ebola treatment units, suggesting that intensive care management of patients with other etiologies of critical illness may be beneficial for patients with EVD. However, many unanswered questions remain about the optimal supportive clinical management of patients with EVD, and ensuring access to investigational MCMs across multiple clinical sites remains a challenge.¹⁷

Despite a lack of preparation for the conduct of clinical research specific to biocontainment units and preexisting coordination of research efforts, organizations and individuals obtained and administered investigational products on an emergency basis for the 11 EVD patients cared for at medical centers in the United States. Although patients did not receive similar MCMs under a common protocol, clinical data were shared in weekly international clinical calls to help inform care of new EVD patients and were subsequently published in the medical literature.² This was made possible through both federal and local efforts, as well as private industry participation. Federal agencies, including the Centers for Disease Control and Prevention (CDC), the FDA, the Biomedical Advanced Research and Development Authority (BARDA), the Department of Defense (DOD), and NIAID, coordinated information sharing regarding medical countermeasures and compassionate use, while the FDA provided timely review of EINDs and connected institutions to pharmaceutical companies.

At each institution, emergent implementation of the clinical research occurred: local IRBs met ad hoc to accommodate needs, sponsored programs offices rapidly executed confidentiality disclosure agreements and contracts, research pharmacists developed protocols and procedures for product preparation, staff were trained in product administration and safety monitoring, and case report forms were developed. These efforts were replicated for each MCM at each institution. Biotechnology and pharmaceutical companies shared available data on current investigational MCMs, most of which were not publicly available at the time, and worked closely with federal and local partners to expedite the process.¹⁸

As the epidemic continued, attempts to increase coordination across the biocontainment units grew, leading to multiple federal, academic, and industry partners coming together to discuss potential investigational therapies, clinical care options, and collaborative approaches. Despite these efforts, opportunities for improvement in both process efficiency and research outcomes were evident. The epidemic, however, was on the decline well before controlled trials were launched, limiting the ability to conduct effective and robust clinical trials in the already challenging context of an international infectious disease emergency (Figure 1).

In an effort to better prepare the United States to respond efficiently and effectively to future epidemics, NETEC was created to increase the capability of US public health and healthcare systems to safely and effectively manage individuals infected with suspected and confirmed special pathogens¹³ (Table 1). When launched in 2015, NETEC was charged with several core responsibilities, including readiness assessment and metric development, education, training, and provision of technical assistance to increase the competency of healthcare and public health workers and the capability of healthcare facilities to deliver safe, efficient, and effective care to patients infected with EVD or other special pathogens. In 2016, NETEC’s charge was expanded to include developing infrastructure to support clinical research readiness for future epidemics; the SPRN is composed of the 10 RESPTCs (Figure 2), which are also the institutions that are responsible for providing clinical care in their HHS region.

The SPRN is developing infrastructure through which research can be incorporated into the care of patients at the RESPTCs, with a focus on network engagement, infrastructure readiness, and training readiness. With resources and expertise distributed regionally through these 10 centers, the goal of the network is to markedly improve clinical research readiness for EVD and other special pathogens in the United States.

The SPRN has maintained a close collaboration with federal and other external partners as an extension of the relationships developed during the 2013–2016 EVD epidemic. To facilitate this, the SPRN formed a partner working group with the goal of continuing those collaborations to support better coordination of investigational MCMs. The partner working group, in addition to NETEC membership, includes BARDA, CDC, the FDA, NIAID, the DOD’s Infectious Disease Clinical Research Program (IDCRP), and the US Army Medical Research Institute of Infectious Diseases (USAMRIID). CDC, the FDA, BARDA, the Department of Defense, and NIAID provide expertise for the selection of appropriate MCMs, as well as for the progression of MCMs through the research and regulatory pipelines.

Given that individuals admitted to biocontainment units may be infected with Ebola virus or other special pathogens for which there are no licensed treatments, standards of care, or prophylactic options for close contacts or exposed individuals, the MCM working group has focused on assessing the evolving landscape of investigational counter-measures. The goal of the MCM working group is to develop guidance on pathogen-specific therapeutics or prophylaxis measures based on the available supporting scientific evidence and to catalogue the supporting scientific evidence. To acquire this supporting scientific evidence, the MCM working group is assessing existing literature and unpublished findings from federal, academic, and industry partners while organizing the results in reviews that will be designed to provide operational guidance to clinicians during epidemics in any global setting. These include EVD as well as other special pathogens that would utilize investigational MCMs as the primary therapeutic. During the 2013–2016 EVD epidemic, there was a paucity of resources available about potential therapeutics. By contrast, specifically for the current 2018 outbreaks in the Democratic Republic of the Congo, the MCM working group has compiled a status report of investigational MCMs for EVD that were distributed to the NETEC leaders (Table 2). These documents can serve as a template for future MCM summaries for other special pathogens and will be updated routinely as new therapeutics emerge.

The primary deliverable is to document potential MCMs for priority pathogens to inform SPRN research goals; the documents will be available on the main NETEC website.²⁵ To avoid duplication of effort, the group will liaise with existing groups conducting similar reviews. Public access to these documents will serve 2 purposes: first, they will be a rapidly accessible resource for clinicians involved in the care of people known or suspected to be infected with special pathogens, whether associated with an established RESPTC or not; second, they will be available for researchers to review, which may stimulate ideas for novel or complimentary MCMs.

Nine deliverables were created in the SPRN contract in order to benchmark progress in the creation of a network that can support special pathogen research (Table 3). These activities also meet several of the goals and objectives outlined in the 2018 National Biodefense Strategy.²⁶ They are described below under 3 broad headings of network engagement, infrastructure readiness, and training readiness.

The 2013–2016 EVD epidemic provided the first collective experience of managing and using investigational therapeutics for patients with EVD in biocontainment units in the United States. Beyond advancing knowledge and practice in the safe delivery of effective care, the biocontainment units that cared for patients with EVD and the many partners engaged in enabling delivery of investigational products to patients learned valuable lessons. The SPRN is leveraging those lessons and partnerships formed to expand and sustain engagement across the 10 RESPTCs and external partners, to develop research infrastructure for biocontainment units and to establish training readiness to optimize opportunities for clinical research in biocontainment units in the future for national infectious disease priorities.