Integrating Clinical Research into Epidemic Response The Ebola Experience (2017) / Chapter Skim
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2 Conducting Clinical Research During an Epidemic
2 Conducting Clinical Research During an Epidemic
Pages 37-82
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From page 37... ...
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)
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From page 38... ...
. Some of the perceptions around the effectiveness of investigational agents were influenced by the disparate clinical care international workers received.
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From page 39... ...
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)
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From page 40... ...
. 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
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From page 41... ...
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.
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From page 42... ...
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.
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From page 43... ...
• 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.
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From page 44... ...
, 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)
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From page 45... ...
. 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)
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From page 46... ...
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.
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From page 47... ...
. Randomized Controlled Trials The gold standard for a clinical trial continues to be the randomized controlled trial (RCT)
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From page 48... ...
Each of these trial designs involves randomization. There are many procedures for the random assignment of participants to treatment groups in clinical trials.
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From page 49... ...
. 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.
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From page 50... ...
Trial designs in epidemic emergencies: The perspective of caretakers and aid workers, based on the experience in the 2014–2015 Ebola outbreak.
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From page 51... ...
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)
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From page 52... ...
. 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.
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From page 53... ...
.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]
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From page 54... ...
. 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)
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From page 55... ...
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]
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From page 56... ...
. 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.
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From page 57... ...
(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.
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From page 58... ...
and in fact during the Ebola epidemic, trials did or intended to include pregnant women and children to various degrees. As examples, the Guinea ring vaccination trial actively enrolled children; the EBOVAC vaccine trial planned to enroll children at a later phase of the trial; three therapeutic trials (to study brincidofovir, favipiravir, and ZMapp)
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From page 59... ...
The exclu sion of pregnant woman from clinical trials of experimental agents may later ex pose the fetus to unnecessary risks from medicinal products previously approved based on studies only in adult males and nonpregnant females. Evidence gained in clinical trials would be particularly valuable because physiological changes in the pregnant woman may alter drug pharmacokinetics, making a drug's metabo lism, efficacy, and optimal dosing different from that in men and women who are not pregnant (Feghali et al., 2015)
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From page 60... ...
. When conducting clinical trials in children, the goal is to balance ethical concerns with the moral imperative to understand how drugs are metabolized and affect children specifically.
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From page 61... ...
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-ofcare 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.
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From page 62... ...
. 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)
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From page 63... ...
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.
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From page 64... ...
SOURCE: Byar et al., 1990. 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.
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From page 65... ...
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 benefi cial 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)
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From page 66... ...
. For example, given the setting and infrastructure, the Ebola epidemic was not a situation in which the best available standard of supportive care anywhere in the world could have been provided.
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From page 67... ...
. 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.
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From page 68... ...
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)
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From page 69... ...
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.
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From page 70... ...
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.
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From page 71... ...
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.
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From page 72... ...
(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
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From page 73... ...
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.
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From page 74... ...
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.
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From page 75... ...
https:// www.scientificamerican.com/article/ebola-free-for-all-could-trigger-bad-science-and wasted-efforts (accessed January 20, 2017)
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From page 76... ...
2015. Evaluating clinical trial designs for investi gational treatments of Ebola virus disease.
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From page 77... ...
Science, August 7. http://www.sciencemag.org/news/2014/08/how-two-us-patients changed-debate-about-using-untested-ebola-drugs (accessed January 25, 2017)
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From page 78... ...
2016. Conducting clinical trials in outbreak settings: Points to consider.
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From page 79... ...
2015. Right job, wrong tool: A commentary on designing clinical trials for Ebola virus disease.
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2013. Exclusion of pregnant women from industry-sponsored clinical trials.
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From page 81... ...
2014b. Ethical issues related to study design for trials on therapeutics for Ebola virus disease.
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From page 82... ...
2013. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects.
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