2

Conducting Clinical Research During an Epidemic

With the Ebola epidemic rapidly spiraling upward in the summer of 2014 and the international community searching for a way to quell the tide, attention turned to the possibility of using experimental medicinal products to treat Ebola patients. There were no therapeutic treatments or vaccines for Ebola that were proven safe or effective, and the Ebola-specific agents that were furthest along in development had only reached the stage of preclinical studies in nonhuman primates. The lack of agents with demonstrated efficacy meant that there were no treatment options outside of supportive care for Ebola, and even supportive care was frequently difficult to obtain, particularly at the beginning of the outbreak. The available Ebola treatment units (ETUs) were filled to capacity and beyond, and health care workers had little to offer patients beyond a “bed, three meals, [oral] fluids, tablets, anti-malarials, [and] painkillers”—and sometimes even these were unavailable (MSF, 2015). More advanced supportive care, such as monitoring electrolytes and blood chemistry or respiratory and renal support, was often not possible, as it required nonexistent equipment and technical and laboratory support. Little information was available about the factors that allowed some patients to recover and others to succumb to the illness; mortality was high (MSF, 2015). As one frontline doctor with Médecins Sans Frontières (MSF) in Sierra Leone, Javid Abdelmoneim, stated, “I can only say you have around 50 percent chance of dying, and I can do very little about it for you” (MSF, 2015, p. 17).

Initially the World Health Organization (WHO) and some nongovernmental organizations providing care on the ground were opposed to using untested medical products due to the level of mistrust, conspiracy allega-

tions, and violence toward international health workers (McCoy, 2014). As a representative from MSF noted in Science, “There are rumors that we are spreading disease, harvesting organs, and other horrible things. Bringing in unlicensed things to experiment on people could be very counterproductive” (Enserink, 2014a, p. 364). However, in July 2014 two infected American aid workers—Kent Brantly and Nancy Writebol—were treated with an experimental agent and the perceptions of the international community and the responders in-country changed (Enserink, 2014b). Brantly and Writebol received doses of the experimental agent ZMapp, an engineered monoclonal antibody cocktail that had been shown to be effective in rhesus macaque monkeys but had not previously been administered to humans (Qiu et al., 2014). ZMapp was shipped to Monrovia for the aid workers before they were separately evacuated for further management at Emory University Hospital in Atlanta, Georgia (Seay, 2014). Although critically ill with Ebola, both Brantly and Writebol recovered and were Ebola-free when discharged in late August 2014. Their recovery brought global attention to investigational agents, and ZMapp was soon “dubbed ‘secret or magic serum’ by the media,” and “generated hope, suspicion, accusations of inequity, and requests for additional product” (Goodman, 2014, p. 1086). Foreigners who had been infected with Ebola were treated with other experimental therapies in addition to ZMapp, including convalescent plasma, convalescent whole blood, and the experimental antiviral drug TKM-Ebola. Despite the global publicity, however, it was unknown what effect, if any, the untested products had on the patients’ recovery. As Bruce Ribner, the lead physician at Emory University Hospital, where the patients were treated, and the director of Emory’s infectious disease unit, said, “Frankly we do not know if [ZMapp] helped them, made any difference, or even delayed their recovery” (Moisse, 2014).

Some of the perceptions around the effectiveness of investigational agents were influenced by the disparate clinical care international workers received. Foreigners infected with Ebola were evacuated from the region to the United States or Europe and were provided state-of-the-art supportive care. In fact, 22 out of 27 patients treated in the United States or Europe between August 2014 and December 2015 survived—a case-fatality rate far lower than in West Africa at the beginning of the epidemic (McWhirter et al., 2014; Uyeki et al., 2016). Even in the face of minimal evidence that these experimental therapies were safe or effective, the media and public focused their attention on the untested products rather than on the role of supportive care, and there were urgent calls to make the products more widely available (Singh, 2015; Wahl, 2014). Shortly after Brantly and Writebol received ZMapp, African health authorities questioned why two Americans had received the drug while no treatment was made available for the thousands of Africans infected with Ebola. The Liberian assistant

health minister, Tolbert Nyenswah, said, “This is something that has made our job most difficult. The population here is asking: ‘You said there was no cure for Ebola, but the Americans are curing it?’” (McWhirter et al., 2014).

EARLY DEBATES ABOUT USE OF PRODUCTS

With global attention focused on experimental therapies for Ebola—and calls to make them more widely available—it forced the question of how these agents could best be utilized in the fight against Ebola. Since early mortality rates were high and the agents offered at least the possibility of benefit some argued that experimental therapies should be given to as many patients as possible. Others argued that because so little was known about the agents, it was necessary to conduct formal clinical trials in order to quickly and efficiently identify beneficial therapies or vaccines. This tension—between those responding to the massive humanitarian crisis who desired medicinal products to treat individuals, and those who supported the use of medicinal interventions only after products had been evaluated for safety and efficacy in clinical trials—complicated the early discussions about the appropriate international response to the epidemic. Frontline humanitarian agencies, such as MSF, were overwhelmed with carrying out basic patient care and public health measures, and they considered the international community’s initial response to be dangerously inadequate to meet the needs of the affected communities (MSF, 2014a). Due to the time and resource constraints of taking care of Ebola patients, some frontline providers appeared convinced that it was impossible to both provide effective clinical care and conduct useful clinical research.

Research Versus Care

This tension between research and care is ever present in public health emergencies. The urgent desire to help current patients with whatever is available may appear to be in conflict with the need to learn as much as possible about potential interventions in order to help current and future patients. During the Ebola epidemic, some caregivers may have felt that providing clinical care and conducting clinical research were mutually exclusive and that one could not be done without harming the other effort. Clinical research and clinical care are sometimes at odds because care focuses on the individual, current needs of a specific patient (Sacristán, 2015), while clinical research benefits future patients and not necessarily the specific patient enrolled in the research; however, patients who enroll in clinical trials often benefit from receiving better medical care than patients not enrolled in trials. Furthermore, in a research setting health care decisions are not based only on the interaction of one health professional and

one patient, but are often controlled through the process of randomization, and adherence to a standard protocol is required. This lack of autonomy on the part of both clinician and patient can add to the tension.

Despite tensions between research and clinical care, they can also be seen as two sides of the same coin, ideally conducted in tandem (Sacristán, 2015). The Declaration of Helsinki addresses this in its guidelines for physicians; it states that research and medical care may be combined “only to the extent that the research is justified by its potential preventive, diagnostic, or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects” (WMA, 2013). In the initial stages of an outbreak or epidemic, when care centers and workers are inundated with patients, it may be appropriate to focus the limited resources available on clinical care so as not to detract from the clinical response and incorporate research later when staff is not spread as thin. However, it is critical that the possibility of integrating research into clinical care is part of the discussions and planning from the outset, because it can take considerable time to obtain necessary approvals for research and to fully train the study team, while the opportunity to initiate a trial is continually reassessed as conditions on the ground change. If the planning does not occur early in the epidemic, the epidemic may be waning—or over—by the time a study is designed, approved, and ready to be implemented. This aptly describes the Ebola outbreak in the first 6 months of 2014.

An initial question was whether it was ethical to conduct research at all, given the extreme demands already placed on frontline care providers during the epidemic. Because there were no drugs or vaccines approved to treat or prevent Ebola or ready to enter into clinical trials at the outset of the epidemic, many felt that there was an ethical imperative to conduct such research as quickly and safely as possible. Providers needed to learn how best to treat patients or prevent new Ebola infections and to assess how health systems could be configured and equipped to meet these health needs. The WHO Ethics Working Group report from October 2014 stated that there was an ethical obligation to do research during the epidemic and that research should be part of the public health response (WHO, 2014b). Only by increasing the knowledge base about Ebola and about the merits of various treatment or prevention strategies could clinicians be sure that their efforts improved patient outcomes and communities be reassured that their scarce resources were used wisely and efficiently (UNESCO, 2006).

Expanded Access

Although providing experimental therapies in the context of a clinical trial is the ideal way to monitor and minimize risks of unproven agents

while maximizing the scientific information gained, in some circumstances it is appropriate to administer unproven agents outside of an approved clinical trial. This is called an expanded access exemption or “compassionate use.” In the United States, a number of conditions must be met in order for a patient to be granted access to a drug under expanded access: (1) there is no comparable or satisfactory therapy available, (2) the probable risk from the investigational product is not greater than the probable risk from the disease, and (3) providing the investigational product will not interfere with the conduct of clinical trials (FDA, 2016).

The foreign aid workers, like Brantley and Writebol, received experimental therapies under an expanded access framework. In October 2014, the WHO working group report referred to compassionate use of investigational products as justifiable as long as data are collected and shared (WHO, 2015). However, most of the examples of expanded access provided were cases of foreign health workers who were evacuated from West Africa to the United States or Europe in order to ensure that they received optimal supportive care, and who, in desperation, were also offered whatever experimental intervention was available—and more than one if available (Enserink, 2014b). In this context, it would have been extremely difficult to attribute either beneficial or detrimental outcomes to any one of these investigational agents. The use of investigational agents under expanded access in these situations did not contribute to the knowledge base, but they did serve to initiate rumors that there was a cure for the foreigners that was not being made available to Africans. The belief that investigational agents in the very early stages of development were likely to be highly effective furthered the view that randomized controlled trials were unethical. For example, Caplan et al. concluded that because “all available agents have been variously deployed against infected persons treated in the United States and Europe, the case for randomization to placebo in West Africa is morally suspect” (Caplan et al., 2015, p. 6).

The assertion of a right to access an intervention without established efficacy in these circumstances is controversial at best. Any such right must be grounded in a concern for individual health, and there is no evidence that investigational products in the early stage of development will promote the health of humans treated with the agent. In fact, most agents in the early stages of development are eventually proven to be ineffective or even potentially harmful (Dresser, 2009). Additionally, a right to access interventions approved for treating another condition, but without established efficacy for another particular condition might be unbounded in its scope since there are potentially a great many interventions that have no evidence of efficacy for a particular condition but whose use might be supported on theoretical or even speculative grounds. Moreover, rights such as this do not exist in a vacuum. They can only be honored through the expenditure

of time and resources for research. When limited resources have to be used to address the health needs of many individuals, proof of efficacy is a reasonable requirement for the use of resources. Absence of evidence of efficacy thus reduces the strength of the claim that scarce resources should be directed to the provision of novel interventions of unknown value.

Others argued that expanded access should be avoided because its “use exposes many patients to investigational interventions, often undermines fair access to experimental agents, compromises the collection of robust data to determine the safety and efficacy of interventions, and consumes scarce resources for uncertain clinical benefits” (Rid and Emanuel, 2014, p. 1844). Additionally, given the limited supply of experimental Ebola treatments and vaccines at the time, randomized trials may actually have been the most equitable way to distribute these products (Largent, 2016; Rettner, 2014). The strongest argument for providing expanded access to unproven therapies during the Ebola epidemic is that the high lethality of the disease tipped the ethical scales in favor of providing interventions that could be helpful, however remote that prospect of benefit may have been and even given the potential for harm. This argument springs from the principle of beneficence—the notion that medical care providers should seek to help patients. Yet even under such conditions, the social costs of providing expanded access merit consideration. Specifically, under circumstances like the Ebola epidemic, the principle of beneficence supports providing products under an expanded access exception when the following conditions are met (Darrow et al., 2015; FDA, 2016):

• A sufficient amount of the product is available after supplying the needs of clinical trials.
• Providing expanded access would not preclude or delay the initiation of more conclusive investigations of the intervention in properly designed studies. This could occur, for example, if the availability of investigational products off protocol depleted the supply of individuals willing to enroll in studies that could yield generalizable knowledge about the product’s safety and efficacy.
• Existing evidence does not suggest such an unfavorable risk–benefit balance that the product would not even “make the cut” for inclusion in clinical trials.

PLANNING CLINICAL TRIALS

Given the urgency of the situation, the August 2014 WHO ethics panel concluded that there was an “ethical imperative to offer the available experimental interventions that have shown promising results,” noting that the “only way of obtaining evidence on the safety and efficacy of any intervention in Ebola virus disease is during an outbreak” (WHO, 2014a, p. 4). The panel stated that compassionate use is “justified as an exceptional emergency measure” but said that it should not “preclude or delay the initiation of more conclusive investigations of the intervention(s) in properly designed clinical studies” (WHO, 2014a, pp. 5–6). The panel identified a number of conditions for the use of investigational interventions (WHO, 2014a):

• The investigations should not divert attention or resources from public health measures.
• Ethical criteria should guide the use of such interventions.
• The use of the interventions should be based on the best possible assessment of risk and benefit.
• The interventions should have been demonstrated to be safe and effective in animal models, in particular in nonhuman primates.
• Expanded access for individual use should be employed only with a shared understanding of the criteria for such exceptions, and it should not preclude or delay high-quality clinical investigations.
• The uncertainty about the safety and efficacy of the interventions should be acknowledged and communicated to all stakeholders to avoid unfounded expectations.
• Investigational therapies should be administered in concert with necessary supportive treatment, management of side effects, and monitoring the progress of treatment.
• The data generated from the use of investigational therapies should be systematically collected and shared.
• The decision to use investigational therapies should take into consideration the available standard of care and feasibility in the setting.

Not all stakeholders were in agreement with the WHO’s conclusions or the focus on clinical research. Criticism was aimed at the makeup of the August WHO ethics advisory panel, as only a few of the panelists

had a background in bioethics or medical ethics, women were underrepresented, and the panel included no representatives from the countries actually affected by Ebola (Schuklenk, 2014). Some public health advocates questioned the choice to focus on the treatment of individuals rather than on broad public health measures; other critics argued that the WHO’s individualistic medical ethics approach “frames the issues incorrectly, imposes the wrong priorities, and uses the wrong set of values” (Dawson, 2015, p. 107). A medical advisor at Queensland Health in Australia worried that the “inappropriate focus on experimental treatments for individuals diverted attention away from infection control and other measures that would benefit everyone,” and asserted that “thousands died while we argued over the wrong questions” (Gericke, 2015).

Despite these criticisms, attention soon turned toward planning clinical trials in order to identify safe and effective therapeutic(s) or vaccine(s). Discussions—and sometimes heated debates—ensued about which candidates should be tested and how the trials should be designed. These discussions were heavily influenced by stakeholders’ perspectives and experiences with the early days of the epidemic. The overwhelming numbers of desperately ill patients, combined with the limited number of caregivers and the resource constraints they faced, likely contributed to the perception among frontline personnel that resource-intensive research designs would not be feasible or else would compromise patient care and therefore would be inherently unethical. Similarly, the belief that the fatality rate was very high and that the outbreak was out of control, supported by a Centers for Diseases Control and Prevention (CDC) projection that the numbers could reach over a million people in a few months (Meltzer et al., 2014), likely influenced the way stakeholders framed the response strategy to focus on expanding numbers of treatment beds rather than conducting ongoing research and evaluation. Pertaining to clinical trials in particular, this belief created a context in which some stakeholders prioritized research strategies designed to detect only highly efficacious medicinal products (i.e., a magic bullet) that could potentially be used during the epidemic at hand, while others believed that looking for something even moderately effective was equally worthy of research. Rather than considering both approaches as complementary, the desire to quickly identify an intervention that might be a game changer led some stakeholders to deprioritize efforts to conduct studies that might make real but incremental improvements to the understanding and treatment of Ebola (Branswell, 2014).

In order to implement clinical trials, researchers and stakeholders needed to answer two initial questions: Which potential therapeutic agents or vaccines should be tested? And how should the clinical trials be designed?

Identifying Candidates to Research

To identify candidates for trials, researchers looked to the few Ebola-specific agents that were in early stages of development, and also explored the possibility of repurposing approved drugs for the new indication of Ebola. Although already approved for another indication, repurposed drugs would still require clinical investigation in order to determine the efficacy and safety of the drug for the new indication and patient population. Researchers sought to investigate numerous agents with limited evidence of potential value in the search for a highly efficacious medicinal product to treat Ebola. This pursuit resulted in a glut of proposals that “flooded the in-boxes of staff at the WHO and research funding agencies. Silver nanoparticles. Cholesterol-controlling statins. A breast cancer drug. Intravenous ozone. Vulture gastric fluids. An influenza antiviral. Interferon. Almost anything you can think of [was] being advocated as a potential Ebola curative, often with few or no data to support the case” (Branswell, 2014). In order to prioritize and select compounds to study in clinical trials for the treatment of Ebola, the WHO convened the Scientific and Technical Advisory Committee on Emergency Ebola Interventions (STAC-EE) in November 2014 in Geneva. Here the committee noted their inundation with an ever-increasing number of potential agents for proposed trials: “WHO and partners receive daily proposals for potential products against [Ebola] from the scientific community” (WHO, 2014d).

In order to winnow these down, the STAC-EE committee developed a set of criteria regarding the minimum levels of evidence required for an agent to be considered for clinical trials. The summary of this meeting makes clear that there was disagreement about the relative importance of the availability of an agent and the efficacy of that agent. Some participants believed that products that were readily available or easy to produce, such as brincidofovir and favipiravir, should be prioritized despite a lack of evidence that they would be effective in Ebola patients. Others thought that “availability was not a reason to study drugs with weak supporting data” and favored prioritizing drugs that had shown strong preclinical evidence of efficacy, such as monoclonal antibodies and small inhibitory RNA, even if they were less readily available (WHO, 2014d). Ultimately, the STAC-EE committee published a list of around 20 potential agents, acknowledging that “many of these have already been tested and shown to have no activity against the virus” (WHO, 2014d). Participants said that scientists and developers should “assess themselves whether further investigation is warranted” (WHO, 2014d); others later said that the list was not helpful, as it showed products “that barely worked in a mouse . . . in the same column as something that was shown in a non-human primate to be very

effective.”¹ This lack of prioritization of the agents to be tested may have reduced the likelihood that clinical trials would identify beneficial agents. If fewer agents were proposed it is possible that more comprehensive data would have been available on the more promising agents.

It is difficult to estimate how long an emergent epidemic will last or how many people will be affected, and therefore difficult to determine the number of people who could enroll in a trial. By limiting the number of agents studied and the number of trials allowed to proceed, the trials that do proceed will be more likely to enroll enough participants to reach conclusive results, and the likelihood of identifying effective interventions will be maximized. In order to achieve this prioritization and limiting of trials, a rapid response body that offers access to broad expertise and mechanisms to avoid conflicts of interest in decision making is needed. Such a body should have the ability to convene the expert members at short notice, and have the authority to determine which studies will actually proceed (see Chapter 7 for further discussion).

Choosing Appropriate Trial Designs

Trial design was one of the most contentious areas of debate among those participating in discussions about Ebola clinical trials. Stakeholders disagreed about the proper approach to ethical, scientific, and practical issues, and they disagreed about how these issues should inform design decisions. (A synopsis of some study designs is presented in a table in Appendix B.) The clash between humanitarian medicine and research science was also evident in these discussions. As one representative present at the meetings later offered, “The fundamental tension is between the obligation to treat patients with whatever intervention offers the best hope of success and the obligation to gather objective evidence in a scientifically rigorous manner. The stakes are high in a crisis in which time is short and consequences of treatment failure are deadly” (Dawson, 2015, p. 45). Stakeholders struggled with issues such as using randomized trials versus nonrandomized alternative designs, the use of a standard-of-care control

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¹ Testimony of Anthony Fauci, Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Committee Meeting #1, Washington, DC, February 2016.

arm, and the fair distribution of limited product. Though stakeholders disagreed on all these topics, they later were in agreement on one issue: Too much time was spent debating trial design, rather than quickly implementing trials and discovering safe and effective products in time to fight the epidemic² (Cohen and Kupferschmidt, 2014).

Randomized Controlled Trials

The gold standard for a clinical trial continues to be the randomized controlled trial (RCT). An RCT is considered the best tool for assessing the efficacy of a treatment and is used for several reasons: it avoids selection bias, improves comparability between the experimental and control arms, and allows for valid statistical testing that permits a reliable assessment of the likelihood that observed differences in outcomes between arms could be due to chance (Suresh, 2011). In an RCT, patients are allocated by chance to an arm of the study. There are several types of arms, including (NIH, 2016)

• Experimental: A group of participants who receive the intervention that is the focus of the study, that is, the investigational treatment or vaccine.
• Control: A group of participants who do not receive the investigational treatment or vaccine.
  • Active: A group of participants who receive an intervention that is considered to be effective but that is not the investigational treatment (e.g., a vaccine for hepatitis rather than the product under investigation).
  • Placebo: A substance that does not contain active ingredients and is made to be physically indistinguishable from (i.e., it looks and tastes identical to) the investigational treatment or vaccine.
  • Sham: A procedure or device that is made to be indistinguishable from the actual procedure or device being studied but that does not contain active processes or components.
• Standard of care: A group of participants who receive standard medical care for the condition being studied. Standard of care is sometimes but not always provided in conjunction with the experimental treatment, a placebo, or sham.

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² Testimony of Edward Cox, director, Office of Microbial Products, U.S. Food and Drug Administration. Public Webinar with International Regulators of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak, WebEx, May 2016.

While most trials employ randomization through the comparison of two treatment approaches (e.g., the investigational therapy versus a control), others may compare multiple approaches, with or without a control group. For example, a factorial design randomizes each individual to two or more treatments over the course of a single trial so that multiple questions can be addressed in a single trial (Montgomery et al., 2003). When two or more known effective treatments are available, a head-to-head comparison of treatments (without a control) can be an appropriate design to compare their relative effectiveness and safety. Multiarm, multistage designs and Bayesian adaptive platform designs have also been proposed for situations in which multiple experimental agents are simultaneously available (Gurrin et al., 2000; MRC CTU, 2014). “Adaptive clinical trials are designed to take advantage of accumulating information, by allowing modification to key trial parameters in response to accumulating information and according to predefined rules” (Lewis, 2012, screen 5). (See Box 2-1 for more information on adaptive trial design.) Each of these trial designs involves randomization. There are many procedures for the random assignment of participants to treatment groups in clinical trials. Simple randomization (i.e., the investigational therapy versus a control) is just one form of randomization—some others include block, stratified, and covariate

adaptive randomization—each type has its advantages and disadvantages for a given situation (large versus small trials, known prognostic factors, etc.). Clinical trial teams will need to assess the context surrounding the trial before determining which type of randomization to use; however, the benefits of randomization (as discussed above) contribute to it being an essential part of clinical trials to establish efficacy.

It should also be noted that the analysis of trial results depends in part on the design chosen for the trial. Because patient enrollment for a clinical trial is typically staggered, the regular interim analysis of trial results allows rapid identification of highly effective (or harmful) treatments, enabling researchers to terminate a study early if a treatment appears particularly beneficial (or harmful). Several statistical approaches to interim monitoring, constructed to avoid increasing the false positive rate, are widely used, as discussed in Proschan et al. (2006) (see Box 2-2 for additional information on statistical guidelines for early termination of a trial).

Alternatives to Randomization

During discussions about trial design for Ebola research, a wide variety of arguments were voiced in favor of and opposed to RCTs, with stakeholders concerned about scientific validity, safety of participants, the feasibility of conducting RCTs in the context of an epidemic, and ethical issues. Proponents of RCTs said that this design was the “most efficient and reliable way to evaluate the safety and effectiveness of candidate products” (Cox et al., 2014, p. 2350). Proponents also argued that conducting a trial without a randomized concurrent control group would be unethical because it would not be possible to determine the efficacy of the investigational treatment, with one scientist stating that such a trial “would be scientifically invalid, and a scientifically invalid study by definition cannot be ethical” (Davis, 2015). In addition, proponents of RCTs maintained that it would be unethical to give patients an unproven, potentially unsafe medication outside the controlled environment of an RCT (Dunning et al., 2016b). Clifford Lane, deputy director for clinical research and special projects at the U.S. National Institute of Allergy and Infectious Diseases, reinforced this viewpoint, saying, “The idea that there’s no need for randomized, controlled trials presupposes that the drugs have zero side effects, that they are efficacious, and that there’s no substantial variability from patient to patient. I don’t think any of that is true” (Hayden, 2014, p. 178).

Some of the arguments against randomized trials were based on ideas about how the affected communities would perceive randomization or on the logistics of carrying out such a trial. Peter Horby, an epidemiologist at the University of Oxford, reasoned that “[t]hese trials will be conducted in a context of fear, distrust, a lack of effective care options, the admission

of multiple family members to the same center, and sometimes violence against health-care workers. Scientific arguments cannot tell us what will work in these conditions” (Hayden, 2014, p. 178). Further, the objectors noted that the controlled conditions of a randomized trial may not have been logistically possible, given the state of the health care systems in the affected countries (Adebamowo et al., 2014). MSF was clear in its belief that randomization “might not be feasible for therapeutic trials in the context of a very deadly disease with no other therapeutic options.”³ At an October 2014 meeting, the WHO Ethics Working Group heard from

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³ Personal communication, Annick Antierens, Médecins Sans Frontières, March 25, 2015. Trial designs in epidemic emergencies: The perspective of caretakers and aid workers, based on the experience in the 2014–2015 Ebola outbreak.

participants from Guinea and Liberia that in their view, communities would not accept a randomized controlled trial because it would “deny a new experimental treatment to some participants” (WHO, 2014b). Proponents of RCTs acknowledged that carrying out controlled trials in the region would be challenging but said they believed that RCTs would be acceptable to the community if public health leaders were “to articulate the rationale for conducting scientifically valid trials, to work closely with local health authorities, and to engage community leaders” (Cox et al., 2014, p. 2351).

Given the hesitations of some stakeholders about conducting RCTs, many alternative trial designs to avoid randomization were proposed at the WHO ethics advisory panel meeting on August 11, 2014. Some argued that those who pushed for RCTs were “doggedly insisting on gold standards that were developed for different settings and purposes” (Adebamowo et al., 2014, p. 1424). Participants at the meeting noted that further discussions were needed in order to determine “the trial designs that are the most appropriate for accommodating the current constraints of the international outbreak response, including use of pragmatic trial designs and exploration of innovative methods for rapid assessment of efficacy and safety” (WHO, 2014a). The proposed alternative designs used a variety of approaches to avoid randomization or to avoid a concurrent control group, including designs that would implement a control group only if a shortage of experimental treatments arose.

Several trial teams proposed using a single-arm trial design, in which study participants are given an experimental agent and their outcomes are compared to expected outcomes based on previous experiences with Ebola, i.e., historical controls. Such designs would remove the requirement for a concurrent control group while obtaining evidence about whether outcomes were better than historical controls. Detractors of this type of study design argued that comparing outcomes of study participants to previous outcomes was not meaningful, because mortality rates for Ebola varied widely and because some study participants might receive better supportive care than others, making it impossible to know if the investigational treatment was responsible for any improvement in observed mortality rates (Cox et al., 2014). This argument is particularly pertinent in an evolving epidemic where patient characteristics may be different at different times in the epidemic. For example, how early an individual seeks care and the quality of the general supportive care available at the time of presentation may change over time. According to a presentation by the U.S. Food and Drug Administration (FDA), “it is far safer to use a concurrently controlled trial than to rely on a historical control unless the effect is very large. If the effect is large, stopping rules can limit the duration and study size so that little time will be wasted” (Temple, 2013). The FDA presentation continued that there was “little reason not to make the first patient trial an RCT, with

rare exception” (Temple, 2013). For Ebola, the use of historical controls to assess treatment efficacy may have been ill advised, as varying infection rates and mortality rates were observed over the course of the epidemic and by location, adding considerable risks to the use of historical controls (Nason, 2016).

ETHICAL PERSPECTIVES

While some of the debate over trial design was focused on logistical or scientific considerations, much of the conflict stemmed from disagreements over ethical issues. Planning and conducting scientifically and ethically sound research in the midst of the Ebola epidemic was a complicated task. The early stages of the Ebola epidemic were characterized by widespread uncertainty, anxiety, and mistrust among all health care and public health workers, researchers, and especially the general public and community leaders (Fairhead, 2015). Attacks on treatment facilities and aid workers enhanced the perception of social risk and instability surrounding Ebola treatment (McCoy, 2014). Reports that foreigners who were infected while working in the epidemic response were being cured by Western experimental drugs further complicated the process of engaging communities in an honest discussion of just how little was known about many of the investigational interventions being proposed for study, of why research was needed, and about the relative merits of different trial designs.

In this context, stakeholders disagreed on how to resolve a number of ethical dilemmas. However, while researchers certainly can and should take context into account when planning clinical trials, research conducted during an epidemic is still subject to the same ethical principles that guide all human subjects research. There is now broad consensus about the core requirements for ethical research with human participants and a recognition that in order to conduct research in an emerging crisis, certain standard requirements may require expedited processing or increased flexibility, or both (CIOMS, 2016; COE, 1997; HHS, 2009; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979; Nuremberg Code [1947], 1996; UNESCO, 2006; WMA, 2013). For example, in a rapidly moving epidemic where time is of the essence, ethical review may need to be accelerated so as not to unduly delay the start of a valuable study while cases are still appearing.

However, even in such circumstances, the substantive ethical requirements governing research with humans do not change (CIOMS, 2016; Curry et al., 2014). This conclusion is not new. For example, Guideline 20 of the recently revised CIOMS International Ethical Guidelines for Health-Related Research Involving Humans specifically addresses “research in disasters and disease outbreaks” and states: “In the conduct of research

in disasters and disease outbreaks, it is essential to uphold the ethical principles embodied in these guidelines. Conducting research in these situations raises important challenges, such as the need to generate knowledge quickly, maintain public trust, and overcome practical obstacles to implementing research. These challenges need to be carefully balanced with the need to ensure the scientific validity of the research and uphold ethical principles in its conduct” (CIOMS, 2016). A similar position was stated in a 2009 WHO technical consultation, “Research Ethics in International Epidemic Response” (WHO, 2009). That report states that “even in an infectious disease emergency or other crisis situation, the principles and values embodied in international and national ethics guidelines must be upheld” (WHO, 2009).⁴

Ethics in Human Subjects Research

Since the promulgation of the Nuremburg Code in 1947, numerous efforts have been made by different organizations to codify the basic ethical principles that should govern research with human subjects (CIOMS, 2016; COE, 1997; HHS, 2009; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979; Nuremberg Code [1947], 1996; UNESCO, 2006; WMA, 2013). A vast scholarly literature has emerged over time on the central ethical questions, as new situations have been identified and thinking has evolved. The committee has identified seven moral requirements that are widely recognized in authoritative guidance documents and the scholarly literature that are of particular importance for evaluating trials conducted during the Ebola epidemic and other similar circumstances in the future, these requirements are (1) scientific and social value, (2) respect for persons, (3) community engagement, (4) concern for participant welfare and interests, (5) favorable risk–benefit balance, (6) justice in the distribution of benefits and burdens, and (7) post-trial access (see Box 2-3 and Appendix C).

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⁴ Additional background documents addressing relevant issues are reviewed by Research for Health in Humanitarian Crises (R2HC), a program launched in 2013 through a strategic partnership between the nongovernmental organization Enhancing Learning and Research for Humanitarian Assistance, based at Save the Children (UK), and the Wellcome Trust and the Department for International Development (UK). The aim of the program is to “increase the level and quality of collaborative research on recognised public health challenges in humanitarian crises occurring in low- and middle-income countries” in order “to improve health outcomes by strengthening the evidence base for public health interventions in humanitarian crises.” R2HC has been promoting an ethical framework for the development and review of health research proposals to be conducted in the context of an international humanitarian response (R2HC, 2016; Wellcome Trust, 2013).

1. Scientific and Social Value

The value of a study depends on the scientific quality of the information that the study is designed to produce, and the relevance and significance of the information to address an important clinical or public health problem (CIOMS, 2016). In addition, the information that a trial is designed to produce must be of sufficient value to justify the various risks, burdens, and costs associated with the research, including the risks and burdens to the study participants (CIOMS, 2016; COE, 1997; Nuremberg Code (1947), 1996). In the context of a public health emergency, the value of the research conducted should also be sufficient to justify allocating scarce resources—including money, time and energy of caregivers, the use of institutional spaces, and opportunity costs—to research rather than to activities that could impact the emergency more immediately and directly. Ultimately, the value of research depends on whether the information is of sufficient quality to be used to make decisions about care and the allocation of resources. Many stakeholders rely on research data to make decisions that affect the rights and welfare of large numbers of people and that will alter the ways scarce resources are allocated; for example, regulators use data to decide whether to approve a new intervention; third-party payers rely on data to decide which interventions to use, pay for, recommend, or disseminate; and clinicians use research data to make treatment decisions (CIOMS, 2016). Together, these considerations provide strong justification for the default expectation that trials that are conducted during a public

health emergency should be designed to produce data that are sufficiently reliable to guide the practice of experts in the medical and public health communities and to meet applicable regulatory standards for the approval and registration of interventions that are demonstrated to be safe and effective (CIOMS, 2016).

2. Respect for Persons

In order to be ethical, research with human subjects must always be conducted in ways that demonstrate respect for the individuals and communities that participate in and host the research. Showing respect includes honoring people’s fundamental rights, showing genuine concern for their welfare and interests, and allowing them to make momentous decisions about their body or decisions that will affect their welfare or other life prospects. In order to facilitate informed decision making, researchers must provide prospective study participants with relevant, reliable, and understandable information about the choices that are available to them, what risks and possible benefits are associated with each option, why the research is needed, and what will happen if they choose or decline to participate (CIOMS, 2016; COE, 1997; HHS, 2009; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979; Nuremberg Code [1947], 1996; UNESCO, 2006; WMA, 2013). Individuals can only be included in a study if they (or a proxy when appropriate, for example research involving children) have voluntarily consented to participate after having understood the associated risks and benefits; if this consent is unconstrained by deception, coercion, or other forms of manipulation; and if they understand that they have the right to withdraw at any time (CIOMS, 2016; COE, 1997; HHS, 2009; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979; Nuremberg Code [1947], 1996; UNESCO, 2006; WMA, 2013). In addition to being a moral requirement of research, showing respect for people is critical for building a relationship of trust between researchers and communities; this relationship has major implications not only for the research at hand, but for future interactions between researchers and communities, including patients and their advocates.

3. Community Engagement

Emergency situations are often fraught with uncertainty and increased stress and strain on underlying social divisions. This context can exacerbate preexisting mistrust and complicate the process of communicating important information to communities and to prospective study participants, particularly when the circumstances involve life and death decisions and when

there is a great deal of uncertainty about potential interventions. It can be challenging to communicate the potential risks and benefits of participating in research, the details of a clinical trial design, and relevant concepts such as randomization, standard of care, control arms, and individual versus societal benefits. Despite the challenges, engaging communities in dialogue about these issues and facilitating an informed decision-making process is critical to showing respect for communities (CIOMS, 2016). (See Chapter 6 for further discussion about community engagement.)

4. Concern for Participant Welfare and Interests

Although the goal of clinical research is to answer scientific questions and to generate new information, studies require the participation of individuals whose health and welfare are at stake. As a result, concern for study participants requires that the risks to participants be limited to those that are necessary in order to conduct sound scientific inquiry; gratuitous or unnecessary risks are never justified (CIOMS, 2016; WMA, 2013). The potential risks to participants are not just related to the intervention itself, but also include harms resulting from breaches of confidentiality, violations of privacy, or discrimination or stigma as a consequence of participation (HHS, 2009). In addition to minimizing risks, researchers should also make efforts to increase benefits to the participants (CIOMS, 2016; UNESCO, 2006). In an emergency situation, where participants are particularly vulnerable, it is paramount that research be conducted in ways that advance participant health. Many ethics documents that consider research in humanitarian crisis situations place great emphasis on ensuring benefits to participants (R2HC, 2016). However, this is not always possible, and many of the ethical disagreements about various trial designs during the Ebola epidemic reflect differing views on how to reconcile concern for the welfare of individual participants with concern for scientific and future social value.

5. Favorable Risk–Benefit Balance

In the conduct of research, the requirements of sound science and the requirements to respect the health and welfare of study participants may appear to conflict. To be ethically acceptable, research must be designed in a way that maximizes the benefits while minimizing the potential harms (CIOMS, 2016; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979; UNESCO, 2006). At one extreme, studies that do not generate reliable scientific information are ethically objectionable because their value does not justify the costs and burdens associated with their conduct. At the other extreme, the knowing

neglect or abuse of study participants cannot be justified by advancements to the social good. The challenge for research ethics is reconciling this tension. Some ethicists argue that since people are free to accept personal risks for many different purposes (e.g., recreation), informed individuals should be permitted to voluntarily accept the risks of studies that offer the prospect of generating benefit, as long as the risks have been minimized and are not out of proportion with the value of the information likely to be generated from the trial (Veatch, 2007). However, the dominant approach to this problem holds that this tension can be reconciled when research begins in—and is designed to disturb—a state of “equipoise.” Equipoise refers to a state of disagreement or uncertainty in the expert medical community about the relative therapeutic, diagnostic, or prophylactic merits of a set of interventions for a particular health problem (Freedman, 1987). The rationale behind this approach is that because there is no agreement that one of the interventions is superior to the others, then it is ethical to allow participants to be allocated at random to receive one or more of these interventions and then to observe, measure, and document the outcome. “An interpretation of equipoise that requires uncertainty on the part of the individual clinician is not ethically justifiable because it prevents studies that are likely to improve the quality of patient care without the credible expectation that this restriction will improve outcomes” (London, 2017, p. 526). Additionally, if randomized studies increase the prospect of obtaining information that will help to resolve this uncertainty or disagreement, such studies are arguably much more likely to have significant scientific and social value.

6. Justice in the Distribution of Benefits and Burdens

To be ethically permissible, the benefits and burdens of research must be fairly distributed. Research should not focus disproportionately on the health needs of some groups while neglecting the health needs of others, and the burdens of research participation should not be borne solely by groups of people who are unlikely to benefit from the knowledge generated. (See Box 2-4 for a discussion on the inclusion of pregnant women and children in clinical trials.) Some groups are particularly vulnerable to neglect or exploitation because of deprivation, disease, marginalization, or oppression. Thus, fairness requires that these groups not be excluded from research nor should they bear a disproportionate share of the burdens of research participation (CIOMS, 2016). Victims of public health emergencies are placed at increased risk and heightened vulnerability in many ways, but also may have unique health needs that cannot be studied outside of the emergency situation. Failing to conduct research in such situations under the guise of protecting the vulnerable would have the adverse effect of perpetuating the knowledge gap about the health condition. Conducting

research in emergency situations is an important component of our ability to safely and effectively address the health needs of current and future victims of the emergency situation.

7. Post-Trial Access

When communities host and participate in clinical research on an investigational product that is shown to be effective and safe, there is an ethical obligation to provide post-trial access to the product. Post-trial access is supported by Guideline 2 of the newly released CIOMS 2016 International Ethical Guidelines for Health-Related Research Involving Humans, Article 15 of the UNESCO Universal Declaration on Bioethics and Human Rights, and elsewhere (CIOMS, 2016; UNESCO, 2006). While broadly accepted, the concept of post-trial access has been controversial with regard to who bears the costs of the access—the research sponsor, the manufacturer of the product, individual participants in the trial, the host nation, or some other entity. While the principles and practice guiding this aspect of the ethics of clinical trials have not been clearly defined, Nicole Lurie, Assistant Secretary for Preparedness and Response at the Department of Health and Human Services has provided an important perspective in the context of the Ebola epidemic of 2014–2015: “There was a very clear commitment that if we found anything that worked, we are making it available. I just want to be super clear about that. That was never a question.”⁵

The Effect of Mortality Rate on Equipoise

During the Ebola epidemic the mortality rate was frequently discussed in deliberations about selecting appropriate trial design. Some stakeholders argued that it would be unethical to randomize patients to a standard-of-care arm, when the current standard of care “does not much affect clinical outcomes and the mortality is as high as 70 percent” (Adebamowo et al., 2014, p. 1423). They argued that in such an environment, “it is problematic to insist on randomizing patients when the intervention arm holds out at least the possibility of benefit,” and they maintained that “ethical arguments are not the same for all levels of risk” (Adebamowo et al., 2014, p. 1423). In contrast, proponents of RCTs countered that there were no data to support the assumption that patients with a life-threatening dis-

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⁵ Testimony of Nicole Lurie, at the time the Assistant Secretary of Preparedness and Response, U.S. Department of Health and Human Services. Public Workshop of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak, February 23, 2015, Washington, DC.

ease would always choose to use a first-in-human experimental product of unknown safety and efficacy (Nelson et al., 2015).

A basic tenet of clinical research is the concept of equipoise, defined as “genuine uncertainty about whether an untested treatment has benefits or risks that exceed those of conventional care” (Adebamowo et al., 2014). The underlying rationale behind this approach is that because there is no agreement that one of the interventions is superior to the others, it is permissible to allow participants to be allocated at random to receive one or more of these interventions and then to observe, measure, and document the outcome. For some, equipoise breaks down or is not applicable in contexts of extremely high mortality and where available options for care offer little benefit (Adebamowo et al., 2014). Because at the time trial designs were being considered it was estimated that Ebola had a mortality rate of 70 percent or more and it was thought that supportive care offered little benefit, the conclusion was reached by some that it was unethical to randomize participants to an investigational agent or to an arm that provided only standard-of-care treatment measures (Caplan et al., 2015; WHO Ebola Response Team, 2014).

There are several problems with this argument. First, it rests on an assumption about the benefits and risks of investigational agents and the consequences of receiving an appropriate standard of care alone that was not supported by sufficient evidence. Notably, for the investigational therapeutic interventions tested during the Ebola epidemic, the available preclinical data were insufficient to determine that a product was more likely to provide a therapeutic advantage to recipients than to worsen their already fragile condition. Given that most of these products were novel and that failure rates for novel interventions in general are in the range of 90 percent, it seems unreasonable to expect that interventions in the early stages of development would have an appreciable therapeutic advantage, let alone have sufficient efficacy to constitute the desired magic bullet (Dawson, 2015; Hay et al., 2014; Thomas et al., 2015). Additionally, in the early stages of the epidemic, some ETUs were unable to provide patients with basic support, including intravenous (IV) fluids and electrolyte management, and offered only oral fluids (MSF, 2016). It was reasonable to expect that mortality rates in patients who did not receive such supportive care would be higher than in patients who did receive necessary physiological support. This calls into question the stark perception that existed, that Ebola had a uniformly high mortality rate and, therefore, that it was futile to try to improve outcomes with the use of standard supportive treatment.

Second, this view seems to presuppose that desperately ill patients cannot be made clinically worse by the adverse effects of potent therapeutic

agents or other modalities. However, this is a morally suspect assumption. Even if we assume that Ebola has a 70 percent mortality rate, being given an investigational agent in the early stages of development might lower this risk, but perhaps as likely it might increase it, thereby reducing the survival rate below 30 percent. Third, this position assumes a greater degree of certainty about relevant factors than is warranted. Overall estimates of mortality from emerging infectious diseases are often uncertain and influenced by many factors. Since subclinical cases are often missed or confused for other conditions, mortality estimates can be biased by the fact that only the sickest patients are properly diagnosed (Lipsitch et al., 2015). In retrospect it is clear that initial assumptions about mortality rates and the shape of the epidemic were incorrect. As the response to Ebola improved, the overall mortality rate in the three high-impact countries progressively dropped over the course of the epidemic, from 61.5 percent in July 2014 to 40.7 percent in July 2015; the mortality rate also differed among the three countries, from a high of 66.6 percent in Guinea to 45.1 percent in Liberia and 30.0 percent in Sierra Leone (Johnston, 2015).

Fourth, the position articulated above treats Ebola as an exceptional case. Sound and socially valuable research often takes place among gravely ill participants involving study designs in which novel agents are compared against standard therapies. Preventing such studies on the grounds that they deny sick patients the chance of receiving a potentially beneficial intervention would create or exacerbate gaps in our knowledge about how best to treat the patients with such conditions. Preventing these studies would reduce our ability to efficiently form an accurate picture of the relative merits and hazards of novel interventions. At the height of the AIDS crisis, before there were any proven treatments, the mortality rate of untreated AIDS was essentially 100 percent. While AIDS differs from Ebola in many ways (e.g., incubation period), similar arguments were made against placebo-controlled randomized trials from AIDS activists such as AIDS Coalition to Unleash Power (ACT UP) (Crimp, 2011; Dawson, 2015; KFF, 2014). In an effort to address their concerns, a group of statisticians (Byar et al., 1990) advocated for randomization in AIDS trials, but also clearly articulated a limited set of conditions for which randomization may not be appropriate. While a universally poor prognosis was one condition, it could not be the only one; rather, Byar et al. argued, all five must apply for uncontrolled trials to be warranted (see Box 2-5).

These considerations support the view that equipoise is applicable to emergency contexts and that it is therefore ethically acceptable to offer participants the chance to participate in a trial that begins in and is designed to disturb a state of equipoise (Nelson et al., 2015).

Determining an Ethical Comparator

Debate about clinical trial designs during the Ebola epidemic also focused on what might constitute an ethical comparator for the evaluation of novel interventions. The choice of comparator is important because it provides the benchmark against which novel interventions are assessed. If a sick person receives a novel intervention and his or her condition improves or worsens, the benefit or harm cannot be attributed to the intervention unless we know what would have happened to that person without the intervention. Because we cannot know the answer to this counterfactual directly, we compare the effect of giving a novel intervention to some patients against a comparator group.

Substantial confusion can arise in the discussion of study comparators because some commonly used terms are themselves either misleading or are frequently used in ways that can be confusing. For example, the claim that a novel intervention will be compared against a placebo control is sometimes taken to be synonymous with the claim that it will be compared against “no treatment.” In this instance potential trial participants may believe that those in the comparator arm will not receive any medical care or treatment of any kind. However, this is rarely if ever the case, as both arms will typically receive standard supportive care. Similarly, the statement that a novel intervention is being compared against a placebo is often used to describe two very different situations. The first is what might be called a “placebo-

only” comparison, in which members of the investigational arm receive no therapeutic interventions other than the novel intervention being tested and members of the comparator arm receive no therapeutic intervention other than an inert substance that is delivered in the same manner and looks like the novel intervention. In a “placebo-add-on” design, each person in the investigational and comparator arms of the study receives a standardized treatment package as part of the baseline of his or her care and treatment (see Box 2-6 for further discussion on standard care) (Gupta and Verma, 2013). Members of the investigational arm then receive that investigational agent “on top of” this baseline of care, and members of the comparator arm receive a placebo on top of this same baseline package of care.

During the Ebola epidemic, some stakeholders objected to a placebo controlled design, unequivocally stating that trials “should not include a placebo: exposed and vulnerable people in Ebola-affected and low-resource settings shouldn’t be led to think they are either being treated or protected when they’re not” (MSF, 2014b). Objectors to the use of a placebo also argued that it could be unethical or logistically implausible to administer a placebo treatment to such sick patients, for example, “giving 12 to 24 placebo tablets to a vomiting Ebola patient or a 6-hours-lasting placebo infusion to a patient with coagulopathy.”⁶ While RCTs do not require the use of a placebo, placebos are used to facilitate blinding and thereby control for other factors that may influence patient outcomes, such as the conduct of caregivers⁷ (Vickers and de Craen, 2000). The committee determined that such considerations do not warrant the a priori rejection of the use of a placebo but rather should be taken into consideration within the specific context of a trial.

Resistance to studies that would compare a new intervention to a placebo control may have stemmed partly from a misperception that participants in such studies would be denied all care, including such supportive interventions as aggressive rehydration and management of electrolyte abnormalities. Such a “placebo-only” design would have been unethical, but a placebo-add-on design would have been both ethically permissible and scientifically desirable.

No therapeutics trial that was conducted in the three countries in 2014–2015 used a placebo in the standard-of-care study arm (a placebo add-on); rather when a concurrent control was used, for example in the

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⁶ Personal communication, Annick Antierens, Médecins Sans Frontières, March 25, 2015. Trial designs in epidemic emergencies: The perspective of caretakers and aid workers, based on the experience in the 2014–2015 Ebola outbreak.

⁷ An additional consideration is that of the “placebo effect.” The placebo effect is a beneficial effect, produced by a placebo drug or treatment, that cannot be attributed to the properties of the placebo itself, and must therefore be due to the patient’s belief in that treatment (Oxford English Dictionary, 2016).

ZMapp trial, it was compared to a standard-of-care arm alone. However, it is possible that the initial discussion of including a placebo polarized the debate about randomized trials. Those who argued against RCTs may have mistakenly believed that patients randomized to the control group would receive no care, rather than the standard of care. In reality, at the

beginning of the epidemic, given the capacity of the health care system and infrastructure and the conditions of working in containment in a hastily constructed facility, the standard of care that was generally available was quite limited. However, the clinical trials that used a standard-of-care arm made a concerted effort to provide the best possible supportive care available. For example, the PREVAIL II trial of ZMapp (which had the advantage of starting later when better supportive care was available) had an “optimized-standard-of-care” control arm in which patients received IV fluids, monitoring of electrolytes and key biochemical parameters, and maintenance of oxygenation and blood pressure support and treatment for other infections when they were identified (Davey, 2016). The PREVAIL II trial also demonstrated that individuals would consent to participation in an RCT when it was clearly explained to them. Nelson et al. wrote that “to build trust, all efforts should be made to improve the local standard of care to include early rapid diagnostic testing, the provision of intravenous fluids, and electrolyte management—all of which are known to be effective in reducing the mortality of Ebola. However, the provision of such resources reinforces the need for a concurrent control group, as such interventions are likely to affect mortality” (Nelson et al., 2015) (see Chapter 6 for further discussion on community engagement). While the availability of treatments remained somewhat variable based on trial site, the patients in the standard-of-care arm and the active arm received the same supportive care, with the only difference between the groups being the provision of the investigational medicinal product. Most of the Ebola trials that were conducted provided all trial participants with supportive care, including IV fluids, hemodynamic or electrolyte monitoring or both, and adjunctive medications (e.g., antimalarials, antibiotics) (Dunning et al., 2016a,c; MSF, 2015; PREVAIL II Writing Group, 2016; Sissoko et al., 2016; van Griensven et al., 2016).

Authoritative research ethics guidance documents hold that, as a general rule, research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive intervention should receive an established effective intervention. However, there are some circumstances under which it may be ethically acceptable to compare a novel intervention against a placebo-only comparator. As stated in CIOMS guidelines, such a placebo may be used when

• there is no established effective intervention;
• withholding an established effective intervention would expose subjects to, at most, temporary discomfort or delay in relief of symptoms; and
• use of an established effective intervention as comparator would not yield scientifically reliable results and use of placebo would

Guideline 33 of the Declaration of Helsinki (2013) also states that the benefits, risks, burdens, and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances:

• Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or
• Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option (WMA, 2013).

Given the severity of Ebola and the likely effects of leaving severe dehydration untreated, a placebo-only trial would not meet the above exceptions and, therefore, would not have been ethically acceptable. Because a placebo-add-on design would not deny any study participant access to currently accepted treatment for Ebola, such comparator arms would be ethically permissible so long as the provision of the placebo add-on would be feasible and could be performed safely. The committee determined that testing a novel intervention against a standard-of-care comparator without a placebo add-on is less desirable from a methodological point of view, but is also ethically acceptable, particularly where administering a placebo involves risk to providers or patients (e.g., because of the difficulty of injecting highly infectious patients). Whether IV fluids are actually provided is another issue. As Lamontagne et al. observed, “A common assumption is that a lack of material resources constitutes the dominant barrier to clinical care. That is not the case. Intravenous catheters, fluids, and electrolyte replacement are readily available but thus far are being used much too sparingly. . . . There is a historical bias against aggressive interventions, including intravenous cannulation, for many transmissible illnesses. Percutaneous injury to health care workers does carry substantial risk, but such risks are not specific to Ebola” (Lamontagne et al., 2014, p. 1566).

On this point, it is worth considering the implications of a standard of care or placebo control group with some level of the risk of serious harm to

subjects, researchers, or caregivers. For some therapies, for example, using IVs for rehydration or administering a placebo in infected people presented risks to caregivers, as administering an IV involves potential risk from an accidental needle stick to the person doing the infusion. However, as it became common to provide IV fluids as part of standard supportive care the evidence suggests the marginal increase in risk was modest. In March 2015 Partners In Health stated that “responders started putting IVs in children more regularly to resuscitate and rehydrate them. In some cases, they used intraosseous lines (inserted into the bone) if insertion into a vein wasn’t possible. . . . The more aggressive use of hydration has certainly dropped mortality rates” (Partners In Health, 2015). The result was that IV rehydration became standard care for all patients at the Maforki Ebola Treatment Unit in Port Loko, Sierra Leone. In areas where IV rehydration was already the standard of care and the health care team had experience, the additional risk to researchers and caregivers to administer an IV placebo, if deemed necessary, would be limited, although needle-stick injury is a well-described hazard for transmission of Ebola (Guardian, 2015). The greater exposure risk may actually result from the more extensive bedside monitoring and direct contact with patients or with the equipment used for supportive care, such as respirators. During the Ebola-TKM trial, monitoring occurred over the 2-hour infusion period, with additional assessment of vital signs before, during, and at 1, 2, 4, and 8 hours after the end of infusion (Dunning et al., 2016c). For these reasons the committee determined that the additional risk involved with administering an IV placebo is minimal because IV fluid replacement is considered standard of care for Ebola and all patients with dehydration should be receiving fluids, whether they are in the treatment or the control arm of a study.

It might, however, be challenging to allocate the manpower required to monitor a patient receiving a placebo or IV for an extended period of time. It can be argued that unless researchers are able to provide all of the necessary resources to conduct a trial properly and not interrupt clinical care routines, they ought not to proceed. A call for more volunteers to carry out protocol requirements would be relevant, but it may also be insensitive or naïve to simply call for more manpower. The priority is to set up enough facilities and staff to deliver a site-specific optimized standard of care. With that in place, RCTs are more palatable and readily implemented.

In principle, there is the danger that providing an enhanced standard of care even in the control arm might push people to enroll in trials (McMillan and Conlon, 2004); however, it is unclear whether this was a factor in community members’ decisions to enroll in Ebola trials.

Limited Product Availability

Supplies of some of the experimental therapies being considered for Ebola were limited, and this influenced perspectives on the appropriateness of RCTs under these circumstances. Objectors to RCTs believed that RCTs would deprive some patients of access to treatment. Proponents of RCTs countered that “given the scarcity of the drug, a finite number of patients will receive access regardless of what study design is used” (Joffe, 2014, p. 1300), and they maintained that RCTs would actually be a fair and ethical way to allocate resources while gathering data that could help future Ebola patients (Cox et al., 2014). Further, supporters of randomization noted that “alternative means for prioritizing access, such as first-come first-served and sickest first, are themselves ethically unsatisfactory” (Joffe, 2014, p. 1300) and would fail to generate interpretable evidence.

The argument for randomization seems especially strong in the case of a limited supply of product. If there were, for example, just 10 doses of an experimental therapy available, would it be rational to give it to the first 10 people who showed up and agreed to its administration when this may sacrifice the ability to learn something about its efficacy and safety? Would the decision be different if there were 100 doses? In contrast, if an intervention is in surplus and randomization is applied, it might appear to some observers that the researchers are “withholding” the intervention from some patients. All trial designs need to enroll enough subjects to reach interpretable endpoints and there needs to be enough available product for the patients randomized to the experimental treatment. However, even small randomized studies can provide a provisional assessment of efficacy that a first-come/first-served approach cannot, unless the effect is very dramatic. If not enough doses to conduct a suitable trial are available, the use of a randomized lottery system to distribute the available doses would still be preferential because it would be the fairest possible way to distribute scarce resources and retain the potential to generate useful information. The Ebola report of the Presidential Commission for the Study of Bioethical Issues presented two competing perspectives on obligations to Africans confronting Ebola (Presidential Commission for the Study of Bioethical Issues, 2015):

1. Identify safe, effective interventions as efficiently and reliably as possible.
2. Provide access to the potential benefits of experimental interventions to as many people as possible using scientifically valid research designs.

For scarce interventions during the epidemic, like ZMapp, there may be no conflict between these two obligations. But where the intervention

may be given to a large number of people (e.g., vaccines), there may be controversy over a randomized trial because there must be a risk of infection distributed across the population to be able to assess efficacy, and some subjects will be denied the potential benefit of the product. On the other hand, they are spared the potential adverse effects of the vaccine. Many still recall the widespread administration of an experimental vaccine in the United States to protect against the emerging influenza A H1N1 New Jersey 1976 strain that provided no protection because the anticipated epidemic did not happen; however, there was a sharp increase in the number of individuals with Guillain-Barre syndrome in the weeks following immunization, and 25 deaths were attributed to the vaccine (Langmuir, 1979).

Community Trust

Some argued that mistrust of health care workers by the community would deter trial enrollment and the generation of meaningful data (CIOMS Guideline 1) (Caplan et al., 2015). They also argued that the sharing of drugs (to ensure that more people had access to the active agent, as seen in early HIV trials with AZT [Farber, 2015]) might compromise trial results. However, previous experiences in confronting the HIV epidemic revealed that controlled conditions of a randomized trial are possible even in developing country settings, and even where there is a sense of urgency about addressing an emerging epidemic (Lane et al., 2016). These concerns, in combination with the violence and mistrust the affected population had shown toward both ETUs and health care workers, led some to assume that randomization would be locally unacceptable (Adebamowo et al., 2014; McCoy, 2014). Waldman and Neiburg expanded on this, emphasizing that the confusion and volatility of the situation would make it challenging for individuals to understand what the standard of care was (Waldman and Nieburg, 2015). They worried that the foreign care providers would be perceived as providing potentially lifesaving treatments, thus enhancing therapeutic misperceptions. At the very least, this situation would make fully informed consent challenging. “RCTs will not work without community trust,” Caplan et al. wrote, “yet implementing them risks eroding that trust” (Caplan et al., 2015, p. 7).

It is critically important, however, that researchers not make assumptions about how communities perceive prospective research activities. In order to lay the groundwork for ethical research, there has to be truthful engagement with the community about the tradeoffs inherent to clinical trials so they can make an informed decision about the trial designs that can be implemented. If trial teams rush to enter a community in order to rapidly implement a trial without having a proper engagement strategy, it can backfire, as observed during the latter months of 2014. When the teams

can engage the community and provide clearly articulated information about the various aspects of trial designs, community buy-in for research is possible, as documented by the experience in West Africa. For example, the PREVAIL team demonstrated their ability to propose and implement an RCT in Liberia in early 2015 (Wilson et al., 2016). Respect for communities requires that their members are engaged in a process of dialogue and exchange with the investigators about the need for research, the nature of the uncertainty to be addressed, what is known about the status of the interventions to be used, and the merits of possible trial designs. As the committee heard through testimony in their meeting in Liberia, communities, even those that were previously unexposed to clinical trials, are capable of understanding components of research when it is explained. In a context of scarcity, need, and heightened mistrust, such conversations can be challenging. But they are an indispensable component of ethically sound research and are critical to treating study communities as full partners in the effort to find the means to advance their health needs.

However, if after substantial and genuine community discussion and engagement there is still extensive opposition to trials that involve randomization, it becomes reasonable to consider alternative trial approaches. When this course is taken there must be a commitment to avoid supporting any design that is unlikely to produce sufficiently reliable evidence in order to offset the many risks, costs, and burdens associated with research. The study design proposed by Cooper et al., using a single-arm study at the outset and then moving to a randomized trial if the results are promising but neither exceptional nor limited, is an effort to address the concerns of such communities while recognizing that views about the acceptability of randomization may evolve as evidence accumulates and it is clear that an intervention is or is not highly efficacious (Cooper et al., 2015). Such multistage study designs may represent prudent options in such circumstances, when despite engagement and information exchanges, communities or the health authorities in a country will not accept the inclusion of an add-on control group in a clinical trial. Research must be conducted in a responsible and locally acceptable fashion, with attention paid to the local communities’ values, beliefs, and priorities. Failing to conduct research in this manner risks more than the success of the research project; it can also jeopardize the trust and relationships that allow clinical care to be delivered to the community. (See Chapter 6 for further discussion of community engagement.)

CONCLUSIONS

The features of the early days of the Ebola epidemic—high mortality rate, rumors, fears, and uncertainty—were part of the context in which stakeholders had to evaluate the designs for clinical trials during the sum-

mer of 2014, when the need for and the opportunity to conduct clinical trials became fully apparent. Specifically, the desire to find a highly effective treatment that could be deployed in the epidemic at hand, the belief that the mortality rates from Ebola were extremely high, the potential conflict between research and patient care, and the perception that communities would not agree to study designs in which they were denied access to potentially helpful investigational agents no doubt played a strong role in the support for nonrandomized, uncontrolled study designs.

In evaluating the single-arm trials that used historical data for comparison (the design of many of the therapeutics trials, described in detail in Chapter 3), there are two important questions. First, can the trial as designed answer the research questions that it is asking? In this regard, such designs seem most reasonable when there are preliminary data from preclinical or clinical trials that are highly suggestive of efficacy, the natural history of the disease is uniform and well understood, and there is a stable and high mortality rate. This type of design would then be used to address the goal of identifying a highly efficacious intervention that could effectively stop the epidemic. However, such designs cannot reliably identify moderately effective interventions, or identify any potential serious adverse events of the interventions that were distinct from those of the disease itself, particularly given the minimal natural history on Ebola. The second question is whether the questions asked by the study were the right ones (e.g., whether a single-arm trial design to find a highly efficacious medicinal product in the context of Ebola was a reasonable one), or whether it would be preferable at the outset of future outbreaks to employ study designs that are capable of generating information that can support incremental progress in understanding and addressing Ebola or another similar infectious disease.

Each issue discussed in this chapter highlights an important aspect of research involving human participants that must be addressed to ensure that the design and conduct of a study is ethically acceptable. Reconciling the demands of these requirements in specific cases can be challenging. In an emergency, research must be responsive to the particular health needs that arise in that context, while being designed and conducted so as to ensure that the rights, interests, and autonomy of study participants are respected. To reiterate, to be ethically acceptable, research must have a realistic prospect of generating information that constitutes an adequate basis for learning. In the case of an emerging infectious disease outbreak, ethically acceptable research must provide the information needed to put stakeholders in a better position to understand and make decisions regarding the use of new interventions and to address similar outbreaks in the future (CIOMS, 2016). In this regard, there is a strong, default presumption in favor of the strongest research design that is feasible to implement, considering both logistical constraints and cultural acceptance together with

the highest scientific standards of excellence. The ideal output from research is to obtain maximum scientific benefit by generating valid interpretable knowledge that can be applied to the affected population in current and future outbreaks.

Given the complexity of conducting research in low-resource settings during an infectious disease outbreak, it is also essential that research designs be feasible and can be implemented under the constraints of the outbreak and the response to it. The reality is that what is feasible may change over the course of the epidemic (e.g., as caseloads rise or fall, more facilities, health care workers and resources become available, knowledge grows, and process efficiencies are realized). Similarly, the risk–benefit balance of trial designs may change over time, depending on how the epidemic, standard of care, and treatment alternatives evolve. Thus, as an ethical matter in emergencies involving great uncertainty about key parameters of the disease, trial design decisions should be subject to close monitoring and potential reconsideration or adaptation. These decisions are not restricted to a single point during the study, but must be revisited as needed as the outbreak evolves over time. In this regard, trials must be designed in ways that permit periodic reassessment of the original design decisions to ensure that they still make the most sense, both ethically and scientifically. Context matters.

While the Ebola epidemic was unique in many respects, the ethical issues raised were not unprecedented and have been encountered in previous events and epidemics, including HIV, severe acute respiratory syndrome (SARS) and tuberculosis (KFF, 2014). Much can be learned from prior debates over research involving desperately ill patients, research conducted during humanitarian or public health emergencies, research in emergency room situations and with an unconscious patient, and research in resource-poor settings (Wainberg et al., 2014). Similarly, lessons learned from the Ebola epidemic will provide insights for the future. The issues that influenced choices about trial design during the Ebola epidemic—community mistrust, the feasibility of a standard-of-care-only arm, the early high mortality rate, limited product availability, and the potential conflicts between research and care—are likely to recur in future epidemics. However, the perceived ethical or logistical hurdles that these issues present are not sufficiently compelling to override the benefits of randomized trials. Rather, RCTs may be seen as the most ethical trial design in a context such as the Ebola epidemic because they offer the fastest route to identifying beneficial treatments while minimizing the risks of exposure to potentially harmful investigational agents.

Researchers have an ethical obligation to undertake efforts to help ensure that RCTs are locally acceptable. Community engagement, in particular, is an essential element to the conduct of successful clinical trials; a

community that is informed of the risks and benefits of RCTs and is engaged in the planning process from the beginning is more likely to actively participate in research efforts. Failing to conduct clinical research in a way that considers and addresses community concerns jeopardizes the success of the entire research enterprise. It can also jeopardize trust and relationships that permit clinical care to be delivered, and for vaccine trials, it can jeopardize trust in the whole immunization system. The stakes are very high.

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