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The World Is Waiting, Use Sequential Analysis and Get Us the Evidence-Based Treatment We Need for COVID-19

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The World Is Waiting, Use Sequential Analysis and Get Us the Evidence-Based Treatment We Need for COVID-19 Libyan Journal of Medicine ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/zljm20 The world is waiting, use sequential analysis and get us the evidence-based treatment we need for COVID-19 Adel El Taguri & Aisha NASEF To cite this article: Adel El Taguri & Aisha NASEF (2020) The world is waiting, use sequential analysis and get us the evidence-based treatment we need for COVID-19, Libyan Journal of Medicine, 15:1, 1770518, DOI: 10.1080/19932820.2020.1770518 To link to this article: https://doi.org/10.1080/19932820.2020.1770518 © 2020 The Author(s). published by informed UK Limited Taylor & Francis Group, LLC Published online: 27 May 2020. Submit your article to this journal Article views: 1764 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=zljm20 LIBYAN JOURNAL OF MEDICINE 2020, VOL. 15, 1770518 https://doi.org/10.1080/19932820.2020.1770518 The world is waiting, use sequential analysis and get us the evidence-based treatment we need for COVID-19 Adel El Taguria,b and Aisha NASEFc,d aNational Center for Accreditation of Health Establishments-, Tripoli-Libya, Libya; bCommunity Medicine Department, Faculty of Medicine-University of Tripoli, Tripoli-Libya, Libya; cAuthority of Natural Science Research and Technology, Tripoli-Libya, Libya; dScientific Council of Laboratory Medicine, Medical Specialty council, Tripoli-Libya, Libya ABSTRACT ARTICLE HISTORY In spite of the relatively high morbidity and mortality, there is no approved medication yet for Received 3 May 2020 COVID-19. There are more than 200 ongoing trials on different drugs or vaccines, but new Accepted 12 May 2020 medications may take until 2021 to develop. Defining the optimal number of patients to be KEYWORDS included in a study is a considerable challenge in these interventional researches. Ethical Sequential analysis; COVID- considerations prompt researchers to minimize the number of patients included in a trial. This 19; clinical trials; treatment gains particular importance when the disease is rare or lethal which is particularly so in the case of COVID-19. It is of paramount importance to explore some of the available tools that could help accelerate the adoption of any or some of the many proposed modalities for the treatment of diseases. These tools should be effective, yet efficient, for rapid testing of such treatments. Sequential analysis has not been frequently used in many clinical trials where it should have been used. None of the authors in published literature, as far as we know, used sequential analysis techniques to test potential drugs for COVID-19. In addition to its useful- ness when the results of new forms of treatment are quickly needed, other important benefit of sequential analysis includes the ability to reach a similar conclusion about the utility of a new drug without unduly exposing more patients to the side effect of the old drug, in particularly, for the treatment of a rare disease. 1. Introduction As there is no approved medication yet, there is an urgent need for specific treatment targeting COVID- The novel coronavirus disease (COVID-19), the latest in 19 [3]. Research into potential treatments for COVID- the series of emerging coronavirus diseases, was first 19 started in January 2020. Several antiviral and other identified in December 2019 in the city of Wuhan. It has drugs in various stages of clinical trials are being since spread globally resulting in one of the most challen- tested [4,5]. Currently, there are more than 200 ging recorded pandemics in the history of mankind. Until ongoing trials on different drugs or vaccines [6]. It is now, the disease had infected more than four million and widely presumed that new medications may take until claimed the lives of more than a quarter of million people. 2021 to develop. The WHO recommended volunteers The World Health Organization (WHO) had take part in trials of the effectiveness and safety of declared this outbreak on 30 January 2020 as potential treatments [7]. Ethically we should ensure a Public Health Emergency of International Concern that certain statistical standards are met in the drug’s (PHEIC) and a Pandemic on 11 March 2020. Local clinical trials and that the drug will not have an undue transmission of the disease has been recorded in harmful adverse effect on humans. most countries across all six WHO regions. Defining the optimal number of patients to be The relatively high morbidity and mortality included in a study is a considerable challenge in inter- launched the hunt for an effective treatment modality vention research. In small samples, because of a lack of directed either at the virus itself or at its different statistical power, indeterminate results are expected. On complications [1]. the other hand, traditional trials entail the risk of still Far from being perfect, patients are given empirical including patients at a time when enough information antibiotics, antiviral therapy (Oseltamivir, Remdesivir, is already available to answer the trial question. Ethical Ribavirin, Sofosbuvir, Lopinavir/Ritonavir, Favipiravir considerations prompt researchers to minimize the num- ….), fluids, immunosuppressive and systemic corticos- ber of patients included in a trial. This is, even so, when teroids, and invasive mechanical ventilation, in addi- the disease is rare or lethal [8]. That is particularly so in the tion, to support for other vital organs [2,3]. case of COVID-19. CONTACT Adel El Taguri [email protected] National Center for Accreditation of Health Establishments, Sabaa Street, Ain Zara, Tripoli, Libya © 2020 The Author(s). published by informed UK Limited Taylor & Francis Group, LLC This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 A. EL TAGURI AND A. NASEF Traditional comparative clinical trials are difficult to Table 1. Rational and advantages for using sequential analy- conduct when large sample sizes are required, as recruit- sis design in clinical trials. ment may be challenging and increase study duration. ● Overcoming the disadvantages of enrolling more than necessary patients to achieve statistically significant results thereby low- In addition, the power to evaluate efficacy in relevant ering the number of subjects needed in a trial. subgroups may be limited. Costs may be so high that ● Elimination of unnecessary costs by achieving economy in sam- trials either not performed [9]ornotcompleted[10]. ple size. ● Potentially life-saving reductions in the time needed to establish As more new drugs are to be discovered, traditional a drug’s safety. ● designs come at their limits. It would be of paramount Saving participants from unknown risks. ● Increased efficiency by potentially detecting differences sooner importance to explore some of the tools, whether new than traditional sampling. or already known, that could help accelerate the adop- ● Availability of information about the effect of interventions can be made as soon as enough information is assembled to end the tion of the many proposed modalities for the treatment inclusion into the trial. of diseases as COVID-19. These tools should be effec- ● Ensuring ethical and moral consideration. ● Reduction of the costs of clinical trials lead to lower cost of tive, yet efficient, for rapid testing of such treatments. treatments and consequent reduction in the overall cost of OneofthesetoolsistheSequentialAnalysis.Itis health care [16,17]. ● a method of continuous periodic assessment during an Improved patient care. experiment, where a decision can be taken early at cutoff points. It is a useful method for optimizing the sample size 19’ AND ‘Vaccine’). The search yielded 189 articles. in clinical trials and is a promising technique for rare or Out of these, 26 were obtained when ‘COVID-19’ urgent studies [9,11]. Sequential designs should be con- AND ‘vaccine’ only are used. Using ‘COVID-19’ AND sidered when it is ethically undesirable to continue rando- ‘Clinical study’ OR ‘COVID-19’ AND ‘Clinical trials’ mizing vulnerable subjects at a time when enough yielded 59 different articles. information has accumulated to decide which treatment We also searched the literature using the following is superior. It could be used to decide about the optimal keywords: (‘sequential trial’ OR ‘sequential design’ OR treatment strategy in the clinical setting when results ‘sequential experiment’ OR ‘sequential analysis’ OR should be obtained with a minimum number of patients ‘sequential test’ OR ‘triangular trial’ OR ‘triangular test’ [12,13]. Although these approaches were developed as OR ‘sequential probability ratio’ OR ‘boundaries approach’ early as the 1960 s, they are relatively unknown. The OR ‘adaptive designs’ OR sequential probability ratio test sequential probability ratio test (SPRT) is the term that is (SPRT) OR “repeated significance testing (RST). used currently for this particular form of statistical analysis In addition, we searched the literature using these where the sample is not fixed in advance and stopped as keywords with (AND ‘Clinical Study’,OR‘Clinical Trial’, soon as significant results are observed according to pre- OR ‘Controlled Clinical Trial’). Our search yielded defined rule. Sequential analysis has not been frequently 20,562 different manuscripts in the last decade that used in many clinical trials where it should have been cited these different terms related to the tool, out of used [14]. which 19,971 were in the English language. Among It is generally considered unethical to continue ran- these, 7343 were published in the last 5 years. Only domizing patients and thus exposing half of them to an 767 of them were clinical trials and/or clinical studies, inferior or least desirable intervention, when the already while 1921 were review articles.
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