Sudan Journal of Medical Sciences Volume 16, Issue no. 3, DOI 10.18502/sjms.v16i3.9697 Production and Hosting by Knowledge E Review Article Exploring the Power and Promise of In Silico Clinical Trials with Application in COVID-19 Infection Abdelrahman H. Abdelmoneim1, Safinaz I. Khalil2,3, Hiba Awadelkareem Osman Fadl4,5, Ayesan Rewane6, and Sahar G. Elbager7 1Clinical Immunology Resident, Sudan Medical Specialization Board, Khartoum, Sudan 2Department of Pharmacology, Faculty of Medicine, University of Medical Sciences and Technology, Khartoum, Sudan 3Department of Pharmacology, Alfajr College of Science and Technology, Khartoum, Sudan 4Department of Hematology, Faculty of Medical Laboratory Sciences, Al-Neelain University, Khartoum, Sudan 5Deapartment of Medical Laboratory, Sudanese Medical Research Association (SMRA), Khartoum, Sudan 6Department of Allergy and Immunology, Rush University Medical Center, Chicago, Illinois, USA 7Department of Hematology, Faculty of Medical Laboratory Sciences, University of Medical Sciences and Technology, Khartoum, Sudan ORCID: Abdelrahman H. Abdelmoneim: https://orcid.org/0000-0002-5037-8488 Safinaz I. Khalil: https://orcid.org/0000-0003-3843-0447 Hiba Awadelkareem Osman Fadl: https://orcid.org/0000-0002-3614-1994 Sahar G. Elbager: https://orcid.org/0000-0002-3891-6968 Abstract Background: COVID-19 pandemic has dramatically engulfed the world causing catastrophic damage to human society. Several therapeutic and vaccines have been suggested for the disease in the past months, with over 150 clinical trials currently running or under process. Nevertheless, these trials are extremely expensive and require a long time, which presents the need for alternative cost-effective methods to tackle this urgent requirement for validated therapeutics and vaccines. Bearing this in mind, here we assess the use of in silico clinical trials as a significant development in the field of clinical research, which holds the possibility to reduce the time and cost needed for clinical trials on COVID-19 and other diseases. Methods: Using the PubMed database, we analyzed six relevant scientific articles regarding the possible application of in silico clinical trials in testing the therapeutic and investigational methods of managing different diseases. Results: Successful use of in silico trials was observed in many of the reviewed evidence. Conclusion: In silico clinical trials can be used in refining clinical trials for COVID-19 infection. Keywords: in silico, clinical trials, COVID-19, SARS-CoV-2, vaccine How to cite this article: Abdelrahman H. Abdelmoneim, Safinaz I. Khalil, Hiba Awadelkareem Osman Fadl, Ayesan Rewane, and Sahar G. Elbager (2021) “Exploring the Power and Promise of In Silico Clinical Trials with Application in COVID-19 Infection,” Sudan Journal of Medical Sciences, vol. 16, Issue no. 3, pages 355–370. DOI 10.18502/sjms.v16i3.9697 Page 355 Corresponding Author: Abdelrahman H. Abdelmoneim; email: abduhamza009@gmail.com Received 19 June 2021 Accepted 07 August 2021 Published 30 September 2021 Production and Hosting by Knowledge E Abdelrahman H. Abdelmoneim et al.. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Editor-in-Chief: Prof. Mohammad A. M. Ibnouf http://www.knowledgee.com mailto:abduhamza009@gmail.com https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. 1. Introduction Computer simulations have been used in airplane and car design with great perfor- mance and accuracy for years [1, 2]. Recently, companies and researchers have started to pay more attention to the use of computational modeling in areas like fluid dynamics, ventricular septal deceives, and movement mechanics of hip implants [3, 4]. The general commissioner of the American Food and Drug Administration (FDA) in 2017 recognized computer simulation as a possible solution for approved medical instruments. Further- more, in 2016, a guide for reporting Computational Modeling Studies in Medical Device Submissions was issued by the FDA to provide clear recommendations for organizing and submission of these studies [5]. Randomized clinical trials represent almost two-thirds of the approximately $2.6 billion needed to develop a new drug [6], it is a very long and expensive method for designing and validating new therapies and technologies with a very disturbing high failure rate [7]. Furthermore, real clinical trials may indicate a drug to be ineffective, however, it rarely indicates the reason behind this failure. This leads to the rejection of the drug despite the possibility of it working with small modifications [8]. From here, the possibility of other methods like in silico simulation with coherent abilities to provide fast and accurate results seems very promising especially in times of pandemic like the current COVID-19 where time is a very limited resource. The term in silico clinical trial (ISCT) was first coined in 2011 by the Virtual Physiological Human (VPH) Institute which defined it as: The use of individualized computer simulation in the development or regula- tory evaluation of a medicinal product, medical device, or medical interven- tion. It is a subdomain of “in silico medicine, the discipline that encompasses the use of individualized computer simulations in all aspects of the preven- tion, diagnosis, prognostic assessment, and treatment of disease.” Since then, the concept of changing clinical evidence with in silico evidence is slowly being more accepted, which was made evident by the FDA acceptance of in silico simulation as a possible replacement for animal studies in the assessment of artificial pancreas technologies [9, 10]. In silico trials can be used for the noninvasive assessment of medical conditions. For example, in vivo computed tomography data were used to create individualized models that accurately predict the changes in vertebrae bone strength in mice [11], and the incidence of spine and hip fracture in humans [12]. From these observations, we DOI 10.18502/sjms.v16i3.9697 Page 356 Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. contemplate that ISCTs can be used for choosing the specific mode of therapy with the appropriate doses for individual COVID-19 patients, depending on their individualized parameters like immunodeficiency and renal impairment. This will be a significant step in the path of individualized medicine. Furthermore, since this information can be available within hours to minutes to the clinical provider, this acts as a significant bonus when compared with the classical clinical trial. This work aims to discuss the possible use of in silico trials in the design and testing of therapeutic and preventive measures to either reduce, refine, or partially replace human clinical trials done on the common disease with a focus on the possible applications of these methodologies in COVID-19 trials. 2. Materials and Methods 2.1. Types and phases of clinical trials Clinical trials have been for a long time the golden tool for validating the efficiency of new drugs and biomedical products. It is a very long and complicated procedure containing five basic phases: 1. Preclinical phase: done in animals to understand the physiological action of the drug and four clinical trials in humans to assess the appropriate dose and duration of the drug and acquire data about short- and long-term side effects [13]. Figure 1 shows a schematic representation of the clinical trials pathway to further elucidate the relation between the different phases. Although randomized clinical trials are the gold standard for evaluating the effec- tiveness and safety of the new medication and biomedical products, nonrandomized studies could still provide valuable and reliable input especially in fields such as foren- sic mental health where the randomized clinical trial may be inappropriate, therefore assisting in the decision for accepting or rejecting the new products or procedures [14]. 2.2. COVID-19 conventional therapeutic clinical trials In the past months since COVID-19 appeared from Wuhan, China, and spread around the world, over 3876 clinical studies have been recorded globally on clinical trial registries, including over 500 randomized controlled trials. DOI 10.18502/sjms.v16i3.9697 Page 357 Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. Figure 1: Preclinical and clinical trial phases. FDA: Food and Drug Administration (https://www.fda.gov/) Such rapid development and inauguration of clinical trials are remarkable but presents challenges, including the possibility for replication and rivalry [15]. The most common therapeutic agent being trialed presently is hydroxychloroquine (261 trials with some trials planning to recruit over 25,000 participants), followed by antiinfective and antiparasitic agents as illustrated in Figure 2. Figure 2: Distribution of the most common therapeutic clinical trials on COVID-19, as reported by clinicaltrials.gov. Currently, there are many contestant drugs in preclinical and early phase development and these form a pipeline for future large clinical trials if current applicant therapies prove ineffective or unsafe [15]. With 15% of patients complaining of the severe form of the disease, hospitals being stunned worldwide, and a global mortality rate of 5.7%, new modes of therapy are instantly needed. New interventional clinical trials for COVID-19 treatment encompass the recycling of an old antiviral drug formerly used to treat the Ebola virus known as DOI 10.18502/sjms.v16i3.9697 Page 358 https://www.fda.gov/ Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. Remdesivir or the combination of two antivirals: Ritonavir + Lopinavir, which has been used in the past to treat the HIV infection. Additionally, active clinical trials comprise the use of drugs approved for different therapeutic indications, as in the case of using monoclonal antibodies against interleukin-6 receptor (anti-IL-6R). This recycling strategy established on the reuse of approved drugs is commonly stated as drug repurposing and is largely effective, as verified by instances of repurposing treatments in cancer and other human diseases [16]. ISCTs could be very cost-effective in testing all possible therapeutic drugs for COVID- 19 as it provides a fast and reliable method for acquiring data about the efficiency of these therapeutics with no or minimal human involvement. 2.3. COVID-19 vaccine clinical trials The ideal design SARS-CoV-2 vaccine must address the need of vaccinating both the general population and high-risk individuals. Furthermore, the designed vaccines must adhere to the basic standard for vaccines like non-allergenicity, antigenicity, potency, and ability to induce both cellular and humoral response among others [17, 18]. At the time of writing this paper, and according to the WHO, there were 47 COVID-19 vaccine candidates around the world under clinical evaluation at different stages. Most of these (14 trials) were using a protein subunit platform. Furthermore, there are 155 trials currently under preclinical evaluation with the majority (55 trials) using protein subunit platforms [19]. Figure 3 illustrates the distribution of these vaccines. A B Figure 3: (A) The number of COVID-19 vaccine candidates in preclinical evaluation trials. (B) The number of COVID-19 vaccines clinical trials in clinical evaluation. DOI 10.18502/sjms.v16i3.9697 Page 359 Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. 2.4. Artificial intelligence and COVID-19 Artificial intelligence (AI) has been useful in designing drugs and vaccines against several organisms, including bacteria and viruses that are known to cause severe infections. In particular, AI has a great outlook on developing vaccines against dis- eases such as HIV and malaria that have been problematic [20–23]. The SARS-Cov-2 is a single-stranded, enveloped RNA virus which has several antigenic proteins: the matrix (M) protein, nucleocapsid (N) protein, envelope (E) protein, and spike (S) surface glycoprotein [24]. The S protein has two subunits S1 and S2, majorly responsible for the viral fusion and binding, respectively. It is the primary focus of the development of serology tests and vaccines for the disease. Understanding the complete sequence of the S glycoprotein has been explored to design a multi-epitope vaccine with VaxiJen, ToxinPred, and IEDB servers. This resultant in silico vaccine was shown to have an excellent ability to stimulate a robust immune response against the virus [25]. 2.5. ISCTs 2.5.1. Earlier applications The process of developing new biomedical products requires three steps: design, preclinical assessment, and clinical assessment; all of which can be enriched by the use of in silico simulations [10]. In silico trials can be used to refine clinical trials and reduce the number and duration of animals and humans involved in this experimentation. For example, when a surrogate measurement is used in the in silco trial, the reproducibility of the in vivo studies is highly improved, and hence the numbers required for statistical significance will be reduced, as illustrated in the study by Orwoll et al., where bone fracture endpoint was replaced with a bone strength endpoint [26]. Another use is where individualized models can partially replace animals or humans in a trial. An example of this is the approval by the FDA of the complete replacement of experiments on animals (dogs) with a UVA/PADOVA diabetes type I simulator for the assessment of new artificial pancreas technologies [27]. DOI 10.18502/sjms.v16i3.9697 Page 360 Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. 2.5.2. Future applications Regular use of in silico software may become the common theme in medical research, where simulation could be provided for a large number of virtual patients ( <1000) in a matter of minutes to hours, with tools to validate and replicate these trials. Depending on the result of these in silico trials, new drugs and biomedical products can be approved by health agencies without the need for major human involvement in traditional randomized clinical trials. Table 1 summarizes the difference between ISCT and traditional clinical trials. TABLE 1: Comparison between in silico and randomized clinical trials. Types of trial Cost Duration Human risk Need for validation Type of disease understudy Traditional randomized clinical trial Expensive Several years Low to moderate human risk Current gold standard with no need for validation Better in common disease and for detecting common side effects for drugs or procedures In silico clinical trial Relatively cheaper Minutes to hours No human risks Currently need validation in most cases with subsequent small-size random clinical trials Good for both common and rare diseases and rare side effects 2.6. Available ISCT software 2.6.1. Simulo Simulo is a user-friendly clinical trial simulator developed by SGS Exprimo. It uses Monte Carlo simulations and R code to assess study designs and compare different dosing strategies using mixed-effects models. This will help in the optimization of the steps of the clinical trial and the prediction of the probability of success, the optimal dose, the cost-effectiveness, and finally to go or not to go decisions. There are two available versions of the software – the basic free version and the expert version. While the basic version is suitable for small projects and demonstration purposes, the expert version provides more advanced tools like validation algorithms, which make it more acceptable for scientific publication (https://exprimo.com/simulo). This software was used in 2018 in a study done by Murad Melhem and colleagues to model neutrophil response to granulocyte colony-stimulating factor (G-CSF) in patients DOI 10.18502/sjms.v16i3.9697 Page 361 https://exprimo.com/simulo Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. with chemotherapy-induced neutropenia [28]. The successful use of this software in this work is encouraging and shows that it can be useful in other diseases like the current COVID-19 disease. 2.7. Highly Efficient Clinical Trials Simulator (HECT) HECT is a web-based clinical trial simulator for the planning of adaptive trials (a type of trial that is more flexible than conventional clinical trials), written with statistical software R, with a friendly user graphical interface. This simulator allows the user to set multiple clinical trial parameters and investigate different settings such as varying treatment effects, control response, and adherence. It is open-source and is most useful for clinical trial investigators who don’t have the specialized statistical capacity or access to a commercial trial simulator. An important note here is that the simulation code in this software has been validated against six clinical trials designed by the designer of the software [29] (https://mtek.shinyapps.io/hect/). 2.8. Previous studies on ISCTs In total, six ISCTs were retrieved from the PubMed database. These trials were used for common diseases such as breast cancer, diabetes, and tuberculosis. The first trial simulates a clinical trial of immunotherapies in metastatic breast cancer, which was carried out by Hanwen Wang and colleagues. In this study, a quantitative systems pharmacology model was built to integrate immune cancer cell interactions in patients with breast cancer, simulating central, peripheral, tumor-draining lymph node and tumor compartments. The proposed model provides a platform that can be further adapted to other types of immunotherapy which may contribute to the optimization of breast cancer treatment. The other in silico trial was carried out by Susan G. Hilsenbeck and C. Kent Osborne in breast cancer, where they identified the role of adjuvant tamoxifen in progesterone-positive breast cancer. Regarding the non-small cell lung cancer, an ISCT was taken, comparing the photon and proton radiotherapy effect on this patient group, which showed a reduction of the integral dose (ID) and the dose to the Organ at Risk (OAR) with protons therapy instead of photons even with dose escalation. In addition, simulation of clinical trials was conducted to identify and individualize optimal isoniazid doses in children with tuberculosis, where they concluded that in children, isoniazid should be optimized based upon disease process, age, and acetylation status. DOI 10.18502/sjms.v16i3.9697 Page 362 https://mtek.shinyapps.io/hect/ Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. Additionally, another ISCT was done, this time testing bioactive substance effect on healthy smokers. In this study, the result could explain the synergistic action mecha- nisms of the Sanghuang–Danshen (SD) bioactive in the regulation of vascular endothe- lial dilation, confirming the SD potential effect in releasing the vascular stiffness and decreasing blood pressure in healthy smokers. Finally, an ISCT with the University of Virginia tested the use of inhaled insulin using Type I Diabetes Simulator which in this study provides superior postprandial control and smaller risks of hypoglycemic events [30–35]. Table 2 summarizes these trials. TABLE 2: Summary of six ISCTs. Authors Num. of virtual patients Disease understudy Medication or device Main outcome Roberto Visentin and colleagues [30] 100 Type 1 diabetes militias Inhaled technosphere insulin (Afrezza) Relative to insulin lispro, postmeal dosing, or split dosing of inhaled insulin, in combination with an appropriate titration rule, can achieve superior postprandial glucose control. Prakash M. Jeena and colleagues [31] 10,000 Tuberculosis in children Isoniazid None of the isoniazid routine doses (between 2.5 and 40 mg/kg/day) would achieve 80% effective concentration in most of the children (<90%). Hanwen Wang and colleagues [32] 18 Metastatic breast cancer Anti-CTLA-4 and anti-PD-L1 immunotherapies In combination therapy, the reduction in tumor size is moderately enhanced, compared to the anti-PD-L1 monotherapy. Furthermore, the proposed model display the potential to make predictions of tumor response of individual patients when sufficient clinical measurements are provided. Susan G. Hilsenbeck and C. Kent Osborne [33] 50,000 Progesterone receptor(–/+) breast cancer Arimidex and Tamoxifen In PR– cases, initial therapy with an aromatase inhibitor is superior to tamoxifen. In PR+ cases, tamoxifen is only modestly inferior to Arimidex at the outset, with a higher survival rate at 7.5 years. Erik Roelofs and colleagues [34] 25 Non-small cell lung cancer Photon and proton radiotherapy When compared with photon, passive scattered conformal proton therapy (PSPT) will provide a larger dose to the tumor tissue with less damage to at-risk organs. Yeni Lim and colleages [35] 72 Vascular stiffness in healthy smokers Sanghuang– Danshen (SD) bioactive Compared to a placebo alone, SD consumption at 900 mg/day for four weeks improves pulse wave velocity (p = 0.0497), and reduces systolic blood pressure, therefore reducing vascular stiffness in healthy smokers. DOI 10.18502/sjms.v16i3.9697 Page 363 Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. 3. Results Only six relevent ICTs were through PubMed. These trials were conducted for common diseases such as breast cancer, diabetes, and tuberculosis. The first trial simulateed a clinical trial of immunotherapies in metastatic breast cancer, which was carried out by Hanwen Wang and colleagues. In this study, a quantitative systems pharmacology model was built to integrate immune cancer cell interactions in patients with breast cancer, simulating central, peripheral, tumor-draining lymph node, and tumor compartments. The proposed model provides a platform that can be further adapted to other types of immunotherapy which may contribute to the optimization of breast cancer treatment. The other ICT was carried out by Susan G Hilsenbeck and C Kent Osborne in breast cancer, where they identified the role of adjuvant tamoxifen in progesterone-positive breast cancer. Table 2 summarizes the main aspects of the involved trials 4. Discussion 4.1. Validation of ISCTs Validation of ISCTs is the procedure that evaluates the degree of how much the computer model and simulation agenda is capable of imitating a reality of interest. It is a necessary step before application in clinical studies. This step can be done either through comparison with existing literature or through standardizing the methodology used in these trials. Assessing these two factors will help in proving the model integrity and hence the reliability of the ISCT [36, 37]. 4.2. Limitation of ISCTs Resistance from the research professionals with limited interest in physics and math- ematics, and the difficulty in simulating the complex physiological systems with the specialized advanced technical requirement to create new simulator software are the major hurdle of ISCT simulations. DOI 10.18502/sjms.v16i3.9697 Page 364 Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. 4.3. Proposed ISCT protocol for COVID-19 vaccine Building on the previous evidence, we believe ISCTs could be a plausible option in the current COVID-19 pandemic, as the software and models needed can be tested and validated against the preliminary results of the current COVID-19 clinical trials. Specially designed models or an already available one like the model designed by Renz et al. simulating human alveolar macrophage with SARS-CoV-2 [38] can be used as a basis for the in silico trials. Furthermore, the Universal Immune System Simulator (UISS) platform which is an agent-based simulator is suggested by Giulia Russo and colleagues as a good choice for vaccine design studies [39]. Other platforms like Simulo and HECT can also be used in the current COVID-19 ISCTs with the following suggested parameters: 1. Type of trials: adaptive randomized ISCTs. 2. Number of patients: 10,000 virtual patients, between 6 and 59 years old who will receive two dosages of the vaccine or placebo. 3. Dataset: data for comparison and validation can be retrieved from open online databases like UK datasevice or specialized research centers. 4. Duration: 5 years. 5. Drug: multi-epitope peptide vaccine using spike protein as an immunogenic target. 6. Primary end target results: number of patients with positive and negative RT-PCR, death rate. 7. Secondary end target results: number of patients with documented allergies or vaccine side effects. 4.4. Study limitation The lack of standardized systemic review with appropriate statistical measurement in this work may undermine the acquired results and conclusion, however, the significance of this conclusion should not be overlooked. 5. Conclusion ISCTs can truly transform the war against the COVID-19 pandemic. It is an attractive and applicable tool to accelerate the rate of approval for new therapeutics and vaccines for DOI 10.18502/sjms.v16i3.9697 Page 365 Sudan Journal of Medical Sciences Abdelrahman H. Abdelmoneim et al. common and rare diseases. Furthermore, it is probably the most cost-effective method to reduce, refine, and partially replace COVID-19 conventional clinical trials ensuring both relevant results and minimal human risks. Acknowledgements The authors would like to thank Israa Isam for helping in designing Figure 1. Ethical Considerations Not required. Competing Interests The authors declare that they have no conflict of interest regarding this paper. Availability of Data and Material All relevant data of this study are available to any interested researchers upon reason- able request to the corresponding author. Funding None. References [1] Krus, P., Braun, R., Nordin, P., et al. (2012). Aircraft system simulation for preliminary design. Paper presented at the 28th International Congress of the Aeronautical Sciences. Retrieved from: https://www.researchgate.net/publication/ 233919742_Aircraft_System_Simulation_for_Preliminary_Design [2] Janoško, I., Polonec, T., Kuchar, P., et al. (2017). Computer simulation of car aero- dynamic properties. Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis, vol. 65, no. 5, pp. 1505–1514. 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DOI 10.18502/sjms.v16i3.9697 Page 370 Introduction Materials and Methods Types and phases of clinical trials COVID-19 conventional therapeutic clinical trials COVID-19 vaccine clinical trials Artificial intelligence and COVID-19 ISCTs Earlier applications Future applications Available ISCT software Simulo Highly Efficient Clinical Trials Simulator (HECT) Previous studies on ISCTs Results Discussion Validation of ISCTs Limitation of ISCTs Proposed ISCT protocol for COVID-19 vaccine Study limitation Conclusion Acknowledgements Ethical Considerations Competing Interests Availability of Data and Material Funding References