COVID-19, SARS, MERS and Ebola: a comparative analysis registration of intervention clinical trials

which caused a in a short the to obtain suggestions in the on performing and this and and

guidance on how to perform appropriate emergency clinical trials, design a scientifically based clinical trial program and focus on researching drugs or vaccines that have great potential.

Introduction
An outbreak of pneumonia occurred in Wuhan, China, on Dec 2019. A novel coronavirus isolated from the bronchoalveolar lavage fluid of a patient was identified as the cause of the outbreak [1]. On Jan 30, 2020, the WHO (World Health Organization) declared the Corona Virus Disease 2019 (COVID- 19) epidemic as a Public Health Emergency of International Concern [2] and now it became a global pandemic. As of March 23, 2020, WHO reported 294,110 confirmed cases worldwide, including 12,944 deaths in 187 countries, areas or territories, and assessed the risk of COVID-19 at a very high level [3]. COVID-19 is the cause of a sudden outbreak, has a high transmission rate, is an infectious disease with a high mortality rate, and so far, no therapeutic drugs are available [4]. Severe acute respiratory syndrome (SARS) suddenly appeared in 2002 in the Guangdong province, China. By July 2003 and after a total of 8,096 reported cases, including 774 deaths in 27 countries, the death rate was 9.6% [5]. Middle East Respiratory Syndrome (MERS) was found in patients in Saudi Arabia in September 2012, and caused severe respiratory diseases and kidney failure [6]. As of November 2020, WHO reported 2494 confirmed cases of MERS and up to 858 (34.4%) deaths [7]. Ebola first occurred in Africa, with an average mortality rate of 50% in previous outbreaks [8].
The above data show that these viruses have a high transmission capacity and mortality, which raised global concern and seriously affected public health safety. However, the treatment methods are often unknown and lagging, thus, it is necessary to urgently launch clinical trials to explore effective treatment protocols. Under the emergency, a large number of COVID-19 clinical trials have been registered. Therefore, the clinical trial data of three viruses with similar emergency background, such as SARS, MERS, and Ebola, were systematically analyzed and compared with COVID- 19 (Fig 2). Vaccines & Prevention B.V. and the University of Oxford, accounting for 24 (24.7%), 9 (9.3%) and 6 (6.2% ), respectively (Fig 4).  (17) in the positive drug control group, and 8.8% (14) in the standard treatment control group. (Table 4) The cumulative sample size of the 203 intervention trials was 30,601, and among them, 26146 subjects were involved in the 159 drug intervention trials. Among the 159 trials, the sample size ranged from 10 to 1000 (including both ends). There is 117 samples with the sample size between 10 and 100 among 203 intervention trials, accounting for 57.6%; 84 samples among 159 drug intervention trials have a sample size between 10 and 100, accounting for 52.8%. The largest sample size of 1000 patients was in the "single-arm study of Chinese medicine in the prevention and treatment of novel coronavirus pneumonia (COVID-19)".

Major drugs used in COVID-19 clinical trials
The 159 COVID-19 clinical trials with drug intervention were analyzed. A total of 50 types of chemical and biological agents and nearly 30 types of TCM were used. Most of the chemical drugs and biological preparations are on the market except for the unlisted drugs such as Remdesivir, Azvudine tablets, ASC09/ritonavir tablets, and GD31. The top three used chemical drugs were anti-HIV drugs, antimalarial drugs, and anti-influenza drugs, and among them Lopinavir/Ritonavir, Hydroxychloroquine, Hloroquine, and Abidor were used on 15.1% (24), 13.8% (22) and 5.0% (8), respectively. The biological products used were mainly interferon, with a frequency of 8.2%. Other monoclonal drugs such as Carrillizumab, Adamumab, Meplazumab, and Bevacizumab were also used.

Research design of MERS drug clinical trial
Only 3 MERS drug clinical trials were registered, accounting for 23.1% of the intervention trials, and all were RCT. One protocol was a patient-based evaluation of Lopinavir/Ritonavir and interferon phase III, the first patients of this trial was enrolled in November 2016. Although only 194 patients were plan to be recruited, the recruitment process progressed slowly and they are still in the recruitment phase [9]. The other two were phase I clinical trials with healthy subjects. One of these was the first human trial using two monoclonal antibodies, REGN3048 and REGN3051 [10] to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of the combined use of these two antibodies. The study involving 48 healthy adult subjects was completed but the results of the clinical trials have not been announced. The other, using a biological product such as fully human polyclonal IgG antibody (sab-301), completed a placebo-controlled study regarding the safety, tolerability, and pharmacokinetics of 38 healthy adults [11] (Table 5).

Research design of Ebola drug clinical trials
A total of 19 Ebola drug intervention clinical trials were available, 84.2% (16) were in phase I or II, 11 (57.9%) were RCT, 6 were double-blind RCT and placebo-controlled, accounting for 31.6% of the drug trials. Six specific chemicals were tested in the Ebola clinical trials, including Remdesivir, Favipiravir, Brincidofovir, Avi-7537, TKM and BCX4430, and four antibodies, including REGN-EB3, MAb114, ZMAPP, and GamEMab. However, 8 of the 19 trials were interrupted or withdrawn, accounting for 42.1% (Table 5, Table 6). Van Griensven J et al reported that 84 subjects received plasma from Ebola survivors with an unknown neutralizing antibody levels, and no serious adverse reactions were observed, but the survival rate of the experimental group was not significantly improved [22]. This may be related to the lack of moderate antibody levels, and further research is needed to evaluate the effectiveness of antibodies at a high level [23]. The use of plasma may be an option for critically ill patients, but there are many problems and risks, including epidemiological, virological, immunological, and ethical ones [24]. COVID-19 registered 7 clinical trials regarding plasma therapy and 18 clinical trials regarding cell therapy and also focused on carrying psychological intervention studies for medical staff and patients [25][26]. TCM and integrated Chinese and western medicine also accounted for a large proportion of the treatment plan, making a huge contribution during the SARS period [27]. In terms of intervention methods, COVID-19 used more types of interventions, but to establish which one it is effective or not requires the support of more data.

Discussion
We focused our analysis on the interventional drug clinical trial design, since COVIS-19 is mainly an exploratory trial of marketed drugs, with the purpose of obtaining effective data. Most of the trials registered to solve MERS and Ebola were designed using drugs for drug development, requiring phase validation of safety and efficacy. In the absence of a clear and effective treatment regimen for COVID-19, the blank control group and the control group with basic treatment were the most used, which was consistent with the clinical trial design of MERS and Ebola [9,14]. Although we have positive drug controls in the COVID-19 group, neither a standard, nor a recognized effective treatment regimen was obtained, just an exploration of different interventions. The proportion of COVID-19 placebo-controlled trials (14.5%) was lower than that of MERS (100%) and Ebola (31.6%). Although the cumulative sample size of COVID-19 was large, it is mainly distributed in the range of 10 to 100, which is still small, thus resulting in a waste of research resource (for example human subjects) and in a failure to achieve the expected results and meet the statistical requirements. Nature reported that if China's COVID-19 trials are not designed with strict standards on study parameters, such as control groups, randomization and the measures of clinical outcomes, the efforts will be in vain. [28].
The drugs used in 159 COVID-19 drug clinical trials were analyzed, and showed that a wide variety of drugs were used. Many trials, such as the ones using Lopinavir/Ritonavir, Hydroxychloroquine, Chloroquine, and Abidor, were repeated and resulting in a waste of resources. A retrospective study reported by Chen jun et al. did not find that Lopinavir/Ritonavir and Abidor had the ability of improving symptoms or shortening the time of negative transformation of the respiratory virus nucleic acid [29]. A recently RCT open-label study showed that in hospitalized adult patients with severe COVID-19, no benefit was observed using the Lopinavir-Ritonavir treatment beyond the standard care [30]. Currently, only Chloroquine, Remdesivir, Famivir and Abidol resulted effective against COVID-19 in vitro [31][32]. Many other drugs may be used directly on patients without in vitro experiments, with a consequent risk for many patients to receive ineffective or even adverse treatments. A total of 42.1% of the 19 clinical trials on Ebola drugs were concluded or withdrawn, and so far no drugs have been approved for the market. Thus, it is foreseeable that a large proportion of clinical trials on COVID-19 may not produce satisfactory results.
Gilead's Remdesivir nucleoside analog received the highest level of attention in ongoing clinical trials.
Remdesivir is a broad spectrum antiviral drug, Remdesivir proved on SARS -CoV, and MERS -CoV showed an inhibiting effect in vitro and in animal models [5]. Compared with the effect of biological antibody drugs in the other two groups (MAb114 is 35.1% 33.5%, REGN EB3) [15], tentative analyzes revealed that the 28-day mortality of the Remdesivir group was 53.1%, which did not show any advantagenor significantly reduced the average mortality rate of Ebola disease (about 50%) [8].
However, in N Engl J Med, Michelle l. et al. reported that the first confirmed COVID-19 patient's symptoms were improved after 1 day of using Remdesivir under emergency conditions, and no drugrelated adverse reactions were found [33]. The Remdesivir protocol in the United States is designed with an adaptive approach and a data safety oversight board. This flexible trial design and data management is important for subject protection and risk management and has been used in several trial designs for the Ebola and MERS. Many of the Ebola and MERS trials were conducted by national research institutions such as the NIAID or by large pharmaceutical companies, which can pool resources and maintain uniform standards. Therefore, China should learn from these good designs and management experiences in conducting clinical trials on COVID-19.
The ethics of clinical trials and the quality of research during outbreaks are also representing a concern. The spread of the virus created panic in some subjects, and the review of the ethics committee and the subject's knowledge raise sufficient concern in these trials. Some procedures can be simplified to initiate clinical trials during specific periods of virus outbreaks, but the standards of clinical trial ethics and research quality cannot be lowered because of the outbreak [34]. The research team of the joint prevention and control mechanism of new coronavirus pneumonia under the state council of China issued"the notice on standardizing medical institutions to carry out clinical research on drug treatment of new coronavirus pneumonia" [35]. WHO also evaluated many COVID-19 clinical trials, and suggested that experts from other countries together with Chinese experts draft the COVID-19 clinical trial protocols [28], to regulate COVID-19 clinical trials in an appropriate manner.        Organizations that registered ≥ 3 protocols among 97 Ebola clinical trials

Supplementary Files
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