key: cord-0888455-gzubomiz authors: Lanini, Simone; Zumla, Alimuddin; Ioannidis, John P A; Caro, Antonino Di; Krishna, Sanjeev; Gostin, Lawrence; Girardi, Enrico; Pletschette, Michel; Strada, Gino; Baritussio, Aldo; Portella, Gina; Apolone, Giovanni; Cavuto, Silvio; Satolli, Roberto; Kremsner, Peter; Vairo, Francesco; Ippolito, Giuseppe title: Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa? date: 2015-04-14 journal: Lancet Infect Dis DOI: 10.1016/s1473-3099(15)70106-4 sha: 7738dbffafaefd40ae2b91ef52c3c127655f92e7 doc_id: 888455 cord_uid: gzubomiz The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24 900 cases and about 10 300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled trials (RCT) for Ebola-related research might be both unethical and infeasible and that potential interventions should be assessed in non-randomised studies on the basis of compassionate use. However, non-randomised studies might not yield valid conclusions, leading to large residual uncertainty about how to interpret the results, and can also waste scarce intervention-related resources, making them profoundly unethical. Scientifically sound and rigorous study designs, such as adaptive RCTs, could provide the best way to reduce the time needed to develop new interventions and to obtain valid results on their efficacy and safety while preserving the application of ethical precepts. We present an overview of clinical studies registered at present at the four main international trial registries and provide a simulation on how adaptive RCTs can behave in this context, when mortality varies simultaneously in either the control or the experimental group. The crushing Ebola virus disease outbreak that has devastated parts of west Africa is the largest recorded in history and represents an unprecedented challenge for health policy, research, and ethics. 1 Although Ebola has aff ected people of all ages and both sexes, many of the people aff ected by the epidemic are young adults (aged 15-44 years) 2 who represent the social and economic backbone of already fragile local communities. The best available fi gures to estimate the size of the outbreak are chilling and underline a strong geographical inequity that shows the uneven capability of diff erent countries to aff ord interventions, to contain transmission, and to care for infected people. 2, 3 In the three most aff ected countries (Guinea, Liberia, and Sierra Leone), the eff ort to contain human-to-human transmission has been grossly insuffi cient. As of March 25, 2014 , WHO 4 reported 24 907 Ebola virus disease cases and 10 326 deaths (41% mortality): 3429 cases from Guinea (2263 deaths), 9602 cases from Liberia (4301 deaths), and 11 841 cases from Sierra Leone (3747 deaths). Other cases have been reported from Mali (eight cases, six deaths), Nigeria (20 cases, eight deaths), Senegal (one case), Spain (one case), UK (one case), and USA (four cases, one death). 4 Faced with such an exceptional event, WHO declared that it "is ethical to off er unproven interventions with as yet unknown effi cacy and adverse eff ects, as potential treatment or prevention". 5 Although this is a reasonable statement under the circumstances, some experts argued that well designed randomised controlled trials (RCTs) are both unethical and infeasible in the present circumstances and that researchers should fi rst try to ascertain which intervention is effi cacious by doing observational or non-comparative studies. 6 We argue that this represents an inferior strategy and that instead, RCTs should be used from the early stages of human experimentation of candidate Ebola interventions. 7, 8 What has been done until now The most sensible, and ethically acceptable, strategy for planning interventions during the largest Ebola virus disease outbreak ever recorded should have been to favour clinical studies located in the most aff ected areas to assess whether new therapeutic options could help those who are in the greatest need-ie, patients with acute Ebola virus disease-although little was done in this vein. Of the 34 clinical studies submitted to the four main international registries (fi gure 1): 20 are enrolling healthy participants (only one is located in the main outbreak area), one is an observational study, two are studies launched to assess isolation measures in contacts, and only 11 (a third) are studies aimed to assess the effi cacy of new interventions for patients with acute Ebola virus disease. The analysis of these 11 studies is even more dissatisfying. Only two are RCTs and only one is located in the outbreak area but is not yet recruiting. The other nine studies are aimed at assessing effi cacy against non-randomised controls-three of these studies are enrolling participants at present. Table 1 outlines the study design and enrolment status of each study, as of March 1, 2015, and table 2 reports present knowledge about the potential safety and effi cacy of the experimental interventions under investigation. 14 months after the start of the outbreak-which has caused more than 10 300 deaths as of March 25, 2015, 4the best evidence base for Ebola virus disease treatment is a handful of anecdotal experiences in high-resource settings, 11, 13, 20, 21 which are hardly reproducible in Africa. The unrealistic notion that three uncontrolled studies (one of which is testing herbal remedies against supportive therapy) could succeed in showing an intervention to have substantial eff ectiveness against one of the deadliest human infections shows the exceptional scarcity of trial investments made so far in the face of the an outbreak that is still not under control. Even if somehow the present epidemic is eventually contained (something that is far from certain), the world will still be totally unprepared for the next epidemic that could strike again at any time in an equally explosive manner. RCTs are widely deemed to be the most important vehicle for generating evidence about the effi cacy and safety of novel interventions. The ethical basis of RCTs relies on the principle of clinical equipoise (ie, no genuine evidence exists that an experimental treatment is better than the standard of care) and individual uncertainty (ie, clinical investigators and enrolled patients are substantially uncertain about the merits of the experimental treatment). By providing a virtually unbiased comparator, RCTs guarantee, at best, robustness of results about both the effi cacy and safety of investigational drugs. Thus, since the inception of RCTs, researchers have acknowledged that until an intervention has been proven benefi cial, randomisation is the most ethical approach and provides the best answer soonest. 7, [22] [23] [24] [25] [26] The idea that RCTs are ethically unjustifi ed in the present Ebola outbreak might be based on several widespread misconceptions. The fi rst is a somewhat fatalistic assumption that case fatality rates always exceed 70% because no standard of care exists that can substantially aff ect the clinical outcomes of patients with Ebola virus disease. 6 This assumption is incorrect because enough evidence exists from previous 27 and present Ebola outbreaks 2 that standard supportive therapy can signifi cantly reduce mortality. 28, 29 Remarkably, reported case fatality rates range widely between less than 50% to more than 70% according to the diff erent countries where patients are treated. 2, 7 This variability is probably because of the application of supportive therapy and other intangible diff erences across studies and settings. The second is the overoptimistic assumption that drug effi cacy in preclinical studies unequivocally translates into signifi cant benefi ts towards the clinical outcomes of patients. 30 The third is that in phase 1 and 2 research, nonrandomised designs are preferable, merely because they are widely used 8 or easily accepted by local communities. We believe that when ethical aspects of non-randomised studies are considered in the midst of the most terrifying Ebola virus outbreak ever recorded several topical answers arise. 31 First, how will non-randomised studies aff ect global capability to manage present and future Ebola outbreaks? Second, will non-randomised studies guarantee a reliable assessment of safety of new treat ments? Third, will non-randomised studies have an immediate eff ect of ameliorating health-care standards in the location where the study is set, when general improvements in patient care might be as important for reducing mortality as any experi mental intervention? Fourth, are non-randomised trials ethical for testing treatments that still do not have a line of mass-scale production and thus can only be used for a few, selected patients? Finally, which kinds of socalled alternative study designs should be approved, which kinds should not be acceptable, and, most importantly, what will the selection criteria be for distinguishing between these choices? Previous experiences with the severe acute respiratory syndrome outbreak and H1N1 pandemic infl uenza 32 suggest that these issues can be reasonably met by well designed RCTs, whereas no guarantee is provided by the possibly disorganised implementation of non-randomised studies based on subjective perceptions rather than scientifi cally sound and rigorous methods. In the present situation of perceived impotence and absence of reliable estimates about the real effi cacy of present medical interventions, no guarantee exists that the effi cacy and safety of the new therapies can be assessed without a comparable control group-only randomisation can provide this guarantee. 7,33 Non-randomised studies will inevitably produce contrasting results with the risk of fostering uncertainty among experts while ultimately jeopardising the eff ort to produce clear and feasible clinical guidance. Similar to other investigators, 34 we think that well designed RCTs with adaptive study design 35 should be endorsed in this crisis and preferred to non-randomised designs for several reasons. First, no unequivocal data about the case fatality rates of Ebola virus disease exist. The most reliable estimates from WHO range between 46% in Nigeria (ie, the most affl uent setting) to 72% in Liberia (ie, the least affl uent setting). 2 In such circumstances, non-randomised studies will provide clinicians with no reliable means to assess promptly the safety and effi cacy of new treatments, thus making room for larger ethical dilemmas than those arising from random allocation of interventions. Unless a new treatment has great eff ectiveness (eg, by decreasing mortality to close to 0% in series of hundreds of patients), we might continue to have substantial uncertainty about whether a treatment works at all for many years after the trial fi nishes. If a treatment does confer such great eff ectiveness, an RCT should be able to detect and document the eff ectiveness very quickly. However, if eff ectiveness is only slight, external com parators (both concurrent or historical) in observ ational series or non-comparative studies could be severely biased because of high and undocumented patient heterogeneity and will probably diff er systematically between patients who received treatment and patients who did not. By contrast, interim analyses in RCTs can, at best, inform clinical investigators on whether to proceed with the same randomised allocation, either shifting all patients to an intervention group with an eff ective treatment or stopping the Personal View treatment with a potentially unsafe drug. 7 The focus of an interim analysis is to respond rapidly to high quality data emerging from an RCT, rather than in an RCT without an interim analysis wherein researchers blindly treat and hope for a positive outcome. Second, non-randomised or compassionate use of various interventions might happen anyhow. The challenge is not to encourage additional compassionate use and so-called hints and guesses, but to put together a robust RCT agenda. In fact, for proposed inter ventions that do not have an established line of large-scale production, and whose availability is very restricted (eg, ZMapp), use in non-randomised studies, instead of RCTs, is not straightforward. Such use wastes the already small sample size of potential RCTs that could have been done with the restricted available stock and thus negates the chances of being able to understand whether these treatments are eff ective or are not. 33 Third, as recommended by WHO, 5, 34 well designed RCTs will ensure that all patients receive at least the best feasible care, which at present is standard supportive care, 28, 29 and that "investigational therapeutic or prophylactic options should not divert attention or resources from the public health measures that remain the main priority in outbreak control". 5 In this view, RCTs should be designed to have a control group with standard supportive care (as deemed feasible in the sites where the trials are done) and an experimental group, consisting of one or more new drugs in addition to the standard care. Moreover clinical centres should be able to implement infection control measures in advance to prevent health-care associated transmission of infection. The sponsors of such studies should provide the clinical facilities and adequate resources to ensure that the standard supportive care meets minimum requirements of good clinical practice. The rigorous implementation and monitoring of interventions that are agreed by consensus as being practicable in the context of local care, would help to set minimum ethically acceptable practices for treatment and infection control. By contrast, the deregulated scenario, where any new drugs with unproven effi cacy can be used, provides no such guarantee. Of course, we do not advocate that resources for RCTs should be drawn from the restricted Fourth, as also acknowledged by others, 36 some non-randomised clinical study designs could even undermine present thinking. Particularly, when scarcely available treatment is given to consecutive series of patients without them being randomly assigned to a treatment group; the patients selected might be systematically diff erent from their historical or contemporary control groups and the selection rules might choose sicker patients than the population average who might have the worst probability of responding, thus potentially condemning to failure even treatments that could have been eff ective in earlier stages of the disease than were treated. Finally, in the present context of emergency, much of the information about the outcome of patients who receive the so-called new treatment might not be systematically collected and analysed in the absence of a clear study framework. The major challenge in the present Ebola crisis is not whether RCTs should be used or not, but how their effi ciency can be increased, producing the desirable answers faster. In view of the idea that a scientifi cally sound and rigorous method does not compromise ethics but in fact is the prerequisite to implement ethical precepts by production of valid and reproducible results, 31 we propose that adequate and well controlled studies can be safely done in the present Ebola outbreak and argue that the adaptive RCT approach is better than approaches proposed at present (table 1) . Adaptive RCTs, particularly, can reasonably overcome the main objections raised against randomisation in emergencies and related to the ethical issue that a substantial number of patients would not receive a treatment with potentially (extraordinary) eff ectiveness. As acknowledged by the European Medicines Agency, "adaptive design would be best utilised as a tool for planning clinical trials in areas where it is necessary to cope with diffi cult experimental situations". 37 To lend support to our idea we tested the performance of an ideal two-arm adaptive RCT aimed at assessing the effi cacy of the addition of a specifi c investigational drug to the present standard of care (ie, supportive therapy) by comparison with the standard of care Panel: Randomised controlled trial description A priori assumption Scenario 1: π1=50% and π2=30% Scenario 2: π1=60% and π2=40% Scenario 3: π1=70% and π2=50% Effi cacy (as diff erence): π2 -π1=-20% Effi cacy (as ratio): odds ratio between 0·43 and 0·44-ie, alone. The RCT design and simulation has been done according to requisites for "generally well understood adaptive designs with valid approaches to implementation". 38 The proposed RCT will have a maximum sample size of 210 participants and two interim analyses, allowing early cessation for effi cacy (group sequential design) and toxicity stopping rules (decided by an independent data monitoring committee). The simulation was done to show how the RCT will behave in response to the simultaneous variation of the reported mortality in either treatment or control group. The full description of the RCT is reported in the panel and the results of the simulations are reported in fi gure 2. Consistent with our hypothesis, an extraordinary unexpected effi cacy of the experimental treatment will result in a very early RCT cessation. For example, if mortality in the experimental group is only 10% the probability of stopping the RCT at the fi rst interim analysis will be 98·1%, 87·6%, and 61·7% for mortality in the control equal to 70%, 60%, and 50%, respectively (see fi gure 2A). With such an extraordinary effi cacy no RCT will go beyond the second interim analysis (see fi gure 2B). Moreover, if a priori hypotheses are confi rmed the chance that a signifi cant eff ect will be reported at the second interim analysis is still about 50% (see fi gure 2B). As the likelihood of the study cessation is positively associated with the mortality in the control group, very few patients (in absolute terms) who did not receive such an extraordinary intervention will actually die. In view of the availability of a reliable comparator, interim analyses in RCTs are much stronger than analyses in non-comparative studies to inform investigators about any unexpected toxic eff ects of the investigational drug. A singular confi rmation of our argument is provided by the preliminary results (interim analysis) of the JIKI trial (NCT02329054; table 1) presented at the last Conference on Retroviruses and Opportunistic Infections, held in Seattle in February, 2015. 18 JIKI is a non-comparative, proof-of-concept trial aimed to enrol 225 participants to assess the benefi t of high-dose favipiravir in reducing mortality and decreasing Ebola viral load in patients with acute Ebola virus disease. At present JIKI is the most ambitious trial in progress and since the start of enrolment, on Dec 17, 2014, the investigators have enrolled 80 participants after just 36 days. The main results presented were that mortality was positively associated with Ebola viral load; that favipiravir was generally well tolerated; and that a nonsignifi cant trend for reduced mortality was reported in those with the lowest Ebola viral load who received the drug by comparison with historical controls, whereas an opposite trend was reported in those with the highest Ebola viral load who received the drug. In view of the absence of an extraordinary effi cacy or a reliable comparator, the analysis provided hardly any conclusive evidence. An association between mortality and Ebola viral load and the good tolerability of favipiravir are all expected fi ndings, whereas researchers remain uninformed about the effi cacy of favipiravir. These results leave ethical uncertainty for the researchers about whether to continue the study as it is, change the enrolment according to baseline viral load, or to interrupt the study and divert resources for tests of new experimental drugs. Should the JIKI trial have been designed within an adaptive framework, the maximum sample size would have been reduced (210 vs 225) and, having gone through an adaptation iteration, the researchers would have been able to discuss truly comparative evidence for this kind of treatment by the time 80 patients had been assessed. In our opinion this trial exemplifi es the idea that when considerations related to the urgency of actions are preferred over scientifi c hypotheses the eff orts to obtain new evidence could be jeopardised without the realisation of any ethical advantage. Adaptive study designs remain attractive because of their fl exibility, which could provide several practical and ethical advantages compared with standard RCT design. The primary goal of adaptive trials is to minimise the harm to study participants by exposing fewer participants to the burden and risks of research, and to benefi t more participants with the favourable treatment, by reducing time to obtain conclusive evidence compared with conventional RCTs. Nevertheless this fl exibility comes at a cost. Several issues could hinder the implementation of adaptive RCTs and reduce the internal and external validity of these studies. 39 First, adaptive trial designs are more complex to implement and analyse than standard RCTs. 34, 37, 38 Second, adaptive study designs seem most suitable for situations where endpoints can be quickly and reliably assessed. This restricted suitability implies that adaptive RCTs might be unable to assess long-term outcomes. Third, results of interim analyses might infl uence decisions of the data and safety monitoring boards, researchers, and study participants. Finally, adaptive designs usually include multiple interim analyses, which often leads to an infl ated type-I error; as such the adaptive framework should be kept as simple as possible. 35 However, a prudent adaptive design including a small number of clinical centres, a restricted number of interim analyses, and a well understood and validated adaptive framework could easily address all these issues. 37, 38 Conclusions For life-threatening diseases under the conditions of suboptimum standards of care 40 (such as with the present Ebola outbreak) RCTs that take a very long time to do would not be straightforward or would be unacceptable. 33, 39 However, dependence on non-randomised studies to assess the effi cacy and harms of interventions might be even worse than RCTs. New RCT designs, such as adaptive designs, can provide the best solution for researchers to obtain robust evidence on the merits of candidate interventions. All authors contributed equally to the Personal View. SK is part of a consortium (VEBCON) funded by the WHO/Wellcome Trust to do phase 1 studies on a VSV-ZEBOV vaccine. EG reports personal fees from Janssen-Cilag, Abbot Diagnostics, Gilead Sciences, ViiV Healthcare, and BMS Europe, grants from Gilead Sciences, and non-fi nancial support from BMS Europe, outside the submitted work. All other authors declare no competing interests. This must be the year we beat Ebola in West Africa WHO Ebola Response Team. 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