Drug repurposing for inclusion of COVID-19-related indication: field study of the European Medicines Agency’s response to the pandemic

Drug repurposing for inclusion of COVID-19-related indication: field study of the European Medicines Agency’s response to the pandemic | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Drug repurposing for inclusion of COVID-19-related indication: field study of the European Medicines Agency’s response to the pandemic Antonio Ivanov, Violeta Getova-Kolarova, Ines Hababa-Ivanova, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6472930/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract As one of the biggest challenges for healthcare in the 21st century, COVID-19 placed a sustained and intense demand on the European Medicines Agency resources and required constant adaptation and mobilization of different regulatory processes. In this situation drug repurposing appeared as a promising potential approach in quickly emerging health crises due to its main advantage of reducing time and cost for addition of new indications since it uses products proven to be of high quality, safe and effective. The European Medicines Agency authorised total of 8 products for the SARS-CoV-2 infection, 3 (37.5%) of which used this mechanism for development (Veklury, RoActemra and Kineret). The application of drug repurposing by these medicines highlights the importance of the life cycle stage at which repositioning is undertaken. This resulted in different volumes of data submitted in the respective European Public Assessment Reports. The participation of organisations other than the MAH in key stages in the drug development process of repurposed products once again shows the need to regulate this interaction. Biological sciences/Drug discovery Biological sciences/Drug discovery/Business strategy in drug development Biological sciences/Drug discovery/Drug regulation Biological sciences/Drug discovery/Drug safety repurposing COVID-19 EMA crisis management clinical trials drug safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION The infection caused by the SARS-CoV-2 virus, declared by the World Health Organization (WHO) as COVID-19 pandemic on 11.03.2020 due to its increasing spread, is one of the biggest health crises of the 21st century. During the first years of the pandemic the efforts and resources of the entire global healthcare system were directed towards discovering ways for influencing and preventing the disease, thus granting authorization to a multitude of vaccines and medicines. This was further emphasized by factors such as unusually high economic incentives for treatment development, as well as accelerated and eased regulatory procedures for authorization. Since the first effective treatment would yield the highest economic benefits, the time pressure factor was exceptional for many of the stakeholders. ( 1 ) Repurposing (or repositioning) is the mechanism for detection of new uses of authorized medicinal products or investigational products outside their original indication/s. The way is by combining the knowledge of the human genome sequence and that some diseases share common biological mechanisms. In addition, the concept of pleiotropic drugs and the systematic understanding of molecule-target interactions play a crucial role in identifying new candidates. The experimental approaches of repurposing suffer from lack of efficacy and with the advance of computational power the ligand-based, target-based and machine learning-based mechanisms are developing as leaders. Apart from some inherent drawbacks of the drug repurposing as lower affinity of the target-molecule interaction due to molecular optimization and using data with lower accuracy and consistency this approach has many advantages. One of the most important is increasing the speed and success rate of research and development efforts by operating with medicinal products that have been proven as effective and safe. Another important positive effect is lowering the overall costs in time and money for development by using already generated data during the research programs. This eliminates the necessity of conducting large pre-clinical and clinical programs. Finally, drug repurposing has potential in battling emerging health crises again by producing a medicinal product, which is safe and effective enough to prevent human losses and lower the general risk for the public health in the first stages of an epidemic/pandemic situation. ( 2 ) The European Medicines Agency (EMA) as part of the European Medicines Regulatory Network (EMRN) has established itself as key player in the process of authorizing pandemic vaccines and therapeutic agents and monitoring their safety. EMA has a key role also in crisis coordination activities, management of medicines shortages, provision of information on COVID-19 medicines and generation of reliable real-world evidence (RWE). The uninterrupted work of the Agency was made possible thanks to the development of crisis management plan in 2006 and its adjustments after health crises like the 2009 H1N1 influenza pandemic. ( 3 ) Despite this, as every health crisis has its specifics, COVID-19 pandemic posed difficulties like need for constant adaptation to emerging scientific data, remote working, communicating uncertainty in real time and counteracting misinformation by providing authoritative reference data and reports. In this turbulent period, waiting for a full data package in marketing authorization submissions would have significantly delayed access to much needed medicines. Moreover, significant reduction in deaths and hospitalizations was observed after the authorization of medicines and vaccines against the SARS-CoV-2 infection. There are many lessons learned and some of them refer to the ways used for collecting data for drug approvals. This includes the drawbacks from the fragmented nature of clinical trials, which are often small, underpowered, or with suboptimal design. The need of large, well-designed trials, including platform trials, that can provide the robust data needed to support decision-making is clear. Randomized controlled trials remain essential for clinical development of new vaccines or therapies, also in a pandemic context but they can benefit from complementary evidence from clinical practice through the analysis of RWE. ( 4 ) By conducting this research and analysis, we aim to study the effects of repurposing in the drug development during the COVID-19 pandemic, synthesize the advantages and disadvantages, and identify external factors that may influence this method in the setting of health crisis. MATERIALS AND METHODS We have carried out research of the European Public Assessment Reports (EPARs) for authorized medicinal products available in the COVID-19 section on the European Medicines Agency website in Jul-2024. The methodology of the conducted analysis does not include analysis of vaccines. Their repositioning is largely based on heterologous and non-specific effects for a general improvement of the body's defenses, the precise mechanism of which is not fully discovered. In addition, the basic concept of these therapeutic agents is active immunization for prevention, which necessitates hyperactive specificity to the disease-causing agent and a reduction in the potential for repositioning. The first EPARs to add an indication related to COVID-19 were used for the analysis and specific sections were selected as a study subject: For evaluation of the quality data - "Discussion on chemical, pharmaceutical and biological aspects", "Conclusions on the chemical, pharmaceutical and biological aspects" and "Recommendation for future quality development" For evaluation of the preclinical phase of drug development - "Non-clinical aspects" For evaluation of the clinical phase of drug development - "Clinical aspects" For evaluation of the safety data - "Risk Management Plan" The comparative part of the analysis was focused primarily on the qualitative and quantitative aspects of the different sections between Kineret® (anakinra) and the rest authorized medicinal products. We have identified Kineret® (anakinra) as classic example of the use of repositioning due to its of history of use of over 22 years and being authorized in 6 different therapeutic indications. In addition, we have included RoActemra and Veklury as a second line in the analysis since they are also authorized for use in patients with COVID-19 infection using repurposing. RESULTS At the time of the study, eight medicinal products were authorized in the EU with COVID-19 as an indication, shown chronologically as per the date of issue of the MA in Table 1 : Table 1 Chronological list of medicinal products receiving marketing authorization for indication related to SARS-CoV-2 Medicinal product Date of MA issue - Difference from declaring COVID-19 pandemic in days Repurposed medicinal product Veklury (remdesivir) Conditional MA: 03/07/2020 − 115 MA: 08/08/2022 − 881 Yes Ronapreve (casirivimab/imdevimab) MA: 12/11/2021 − 612 No Regkirona (regdanvimab) MA: 12/11/2021 − 612 No RoActemra (tocilizumab) MA: 07/12/2021 − 637 Yes Kineret (anakinra) MA: 17/12/2021 − 647 Yes Xevudy (sotrovimab) MA: 17/12/2021 − 647 No Paxlovid (PF-07321332/ritonavir) Conditional MA: 28/01/2022 − 689 MA: 24/02/2023 − 1081 No Evusheld (tixagevimab/cilgavimab) MA: 25/03/2022 − 744 No Extremely rapid development of the first drug (Veklury) can be observed when comparing the dates for granting MA. It received a Conditional MA only 115 days after WHO declared the pandemic. Ronapreve, Regkirona, RoActemra, Kineret and Xevudy were next to receive MAs. The difference between the dates of issue for each of these five medicinal products can be considered relatively negligible compared to the number of days since the COVID-19 pandemic was announced. In this group, two of the drugs also used repositioning as drug development approach, demonstrating its importance in addressing health crises. Paxlovid is a combination of drug molecules (nirmatrelvir/ritonavir) and is the second antiviral product for treatment of COVID-19 to be granted a marketing authorization (MA) in the EU. A comparison between Veklury and Paxlovid shows a difference of 574 and 200 days for receiving conditional MA and complete MA respectively, highlighting remdesivir as the first antiviral molecule ready for use for treatment of SARS-CoV-2 infection. It is worth noting that this is observed amid the use of ritonavir as part of the Paxlovid combination, which has history of established use, but the use of newly developed molecule PF-07321332 (nirmatrelvir) requires robust demonstration of efficacy and safety. The authorization of medicinal products by regulatory agencies aims to maintain high levels of quality, efficacy and safety standards. Examination of the quality summary sections of the assessment report also shows a distinction between repositioned and innovative therapies. The first important observation is the complete absence of submitted information on quality of the repositioned products Kineret and RoActemra, both of which have an established use in the EU. This fact allows the CHMP to consider these parts of the dossier acceptable without requiring additional data than the currently available. The assessment report for Veklury shows a total of 11 issues identified in quality documentation that require specific obligations during remdesivir manufacturing. In addition, 3 recommendations for future quality development are also described. This is amidst the fact that Veklury has not been authorised for use in EU prior to the COVID-19 pandemic, but it has history of development in similar therapeutic indications and therefore can be categorised as repurposed. Information on quality requirements in EPARs for the remaining medicinal products is summarized in Table 2 . Table 2 Summary of the Quality sections for non-repurposed medicinal products Medicinal product Issues identified in quality documentation that require specific obligations Recommendations for future quality development Ronapreve - 3 Regkirona - 1 Xevudy - 5 Paxlovid 4 18 Evusheld - 13 In regards to non-clinical aspects, the medicinal products approved for use in SARS-CoV-2 virus infection showed similar results to the Quality section analysis. In Kineret and RoActemra there is again absence of new data submissions in the analyzed section of the evaluation reports, which is considered acceptable by the EMA due to long-standing use of the medicines. The remaining drugs, including Veklury, provide in-depth preclinical programs that investigate multiple aspects such as ADME (Absorption, Distribution, Metabolism, Excretion) characterization and different types of toxicity in a wide range of cell models and animal species. The analysis of „Clinical aspects“ section of the Scientific discussion showed that the drug product with the lowest number of conducted clinical trials (CTs) is Kineret ( 2 ), where a COVID-19 related indication is added through repurposing. (Fig. 1 ) The other product using this approach, RoActemra shows 5 conducted CTs, on par with Ronapreve and Xevudy. Unlike the latter, however, the repositioned product submits dominantly completed CTs (4/80%), while the innovative drugs report 3/60% and 1/20%, respectively. A total of 8 CTs are included in the EPAR of the third repositioned representative - Veklury. Although this is a large number, it should be noted that 4/50% of them were conducted in the period 2015–2019 and were Phase I CTs to assess safety, tolerability, metabolism, excretion and pharmacokinetics of remdesivir. For this reason, Veklury is classified as a repositioned medicinal product, as these are already accumulated data. However, it is necessary to include it in the submission due to the absence of a marketing authorization at the time of issuing EPAR. For the Clinical aspects section total number of subjects in clinical trials is another important parameter, part of the EPAR analysis. Again, Kineret shows the smallest number of participants (1606) compared to the other repositioned products Veklury and RoActemra ranking 3rd (2462) and 5th (5706) respectively in terms of number of subjects enrolled in the clinical program (Fig. 2 ). Analysis of clinical trials distribution by phases also provides evidence of the effect of repositioning. For innovative products, there is a dominance of initial phases such as Phase I (particularly pronounced for Paxlovid and Regkirona), as these therapies have not been authorized for use and need to provide positive data to demonstrate tolerability. (Fig. 3 ) For the repositioned product RoActemra, there is a dominance of Phase III CTs. Thus demonstrates the effect of using a proven to be safe product, which does not require conduct of additional Phase 1 safety and tolerability trials. For Kineret, only one Phase I trial was conducted to collect data in the new indication, and this result is consistent with Evusheld and Ronapreve. In addition, although 4 Phase I CTs for Veklury are included in the EPAR, their aim was to demonstrate safety and tolerability of the molecule in general rather than specifically in the indication associated with COVID-19. It is also interesting to note the impact of the COVID-19 pandemic on clinical trials with platform/adaptive designs or using a master protocol. Out of 41 total CTs included in EPARs, 6 (15%) are conducted such designs. Examples of clinical trials with platform/adaptive designs for authorized medicines with SARS-CoV-2 indication are presented in Fig. 4 . Safety is also part of the three most important features in the authorization of a medicinal product and is included in the EPAR, being described by a Summary of safety concerns; Risk minimization measures (RMMs) and the Pharmacovigilance plan. For comparing the drug development and life cycle of repositioned and innovative medicines, the most comprehensive information is provided by the Pharmacovigilance plan as it describes the on-going and planned additional pharmacovigilance activities. The „Safety concerns“ section can be considered specific to each drug molecule and cannot reflect the different drug development methods, whereas the „Risk minimization measures“ section combines information from the previous two sections. Figure 5 presents a summary of the quantitative and qualitative results when compare only the Pharmacovigilance plan of all medicinal products. DISCUSSION The analysis of EPARs showed that the authorized medicines for treatment of Covid-19 comprise of one RNA polymerase inhibitor (Veklury), one interleukin-1 receptor antagonist (Kineret), one combination of antivirals (Paxlovid), three monoclonal antibodies (Regkirona, RoActemra, Xevudy) and two combinations of monoclonal antibodies (Ronapreve, Evusheld). While the study did not show a dramatic difference in the time to obtain MA, large impact of repositioning as drug development mechanism in response to an emerging health crisis was observed. On one hand, this is demonstrated by 3 out of 8 medicines (37.5%) being authorized using this approach. On the other hand, the first authorized medicinal product to include COVID-19-related indication is also a repositioning product and receives a MA 497 days before the next authorized ones. This occurs in the light of EMA’s still evolving regulatory initiatives for scientific advice for drug development program that would subsequently favor the expeditious authorization of the remaining drugs. The absence of major gaps in the timing of granting MA can be explained with the global scale and strength of the health crisis, which imposes directing enormous health care resources to drug development in this indication, as shown by von Delft and colleagues. ( 5 ) A major reason for the fast Conditional MA issue for Veklury is the use of drug repositioning in its development. Although unapproved, the product is an antiviral therapy under development and proven safe in a number of preclinical studies and clinical trials. Another major reason is the expedited regulatory procedures by the EMA and the use of so-called "rolling review", where data for a drug product is submitted by the Applicant and reviewed by the EMA "as it becomes available". This has been shown by Marinus et al., which describe the calling of extraordinary CHMP meetings and closer EMA-Applicant communication as main advantages of rolling review assessment which helps clarify the characteristics of the medicinal product. ( 6 ) The study on the Quality section of the EPAR reinforces repositioning as a mechanism for rapid and accessible medicinal product development by using available data on product quality. Anakinra and RoActemra demonstrate full use of already collected quality data without providing data generated specifically for the new MA procedure. On the other hand, Veklury, Paxlovid, Evusheld, Regkirona, Ronapreve, and Xevudy provide large data packages using time- and money-consuming tests. Farid and colleagues, in their study of costs in the biopharmaceutical industry, report $ 40 million in expenses to develop and optimize the manufacturing which is crucial for proof of quality. ( 7 ) Moreover, the additional financial resources required for post-approval quality improvement or addressing regulatory agency obligations/recommendations can also influence and raise the whole investment and the risk associated with it. The difference in the number of regulatory obligations/recommendations between representatives from the antibody MPs group and the antiviral group can be explained by the different parameters monitored in quality control. The antibodies are subjected to detailed characterization (physico-chemical, structural, immunological and functional) during different stages of development, production and storage by specific analytical methods, which can ensure batch-to-batch repeatability. In addition, antiviral substances are developed as solid dosage forms, which may require the inclusion of additional excipients to further stabilize and ensure proper delivery into the body. Veklury, although using repositioning, also submits a large volume of quality data due to performing “drug rescue” as type of repositioning during the clinical development phase prior to MA issue. While overall Veklury has a large number of quality obligations/recommendations (14 in total) compared to the antibody MPs group, this number is lower than the other medicinal product in the antiviral group (Paxlovid) with a total of 22. The results of the summary sections of the quality in the EPAR also reinforce the advantages of repositioning. However, a correlation was found between the phase of the drug life cycle at which repositioning was undertaken and the amount of quality data submitted. The analysis shows that the EMA accepts the applications of authorized and repositioned products without the need for additional data, whereas repurposing an unauthorized product in its clinical phase can result in the need for a significant amount of data – close to that of innovative products. A distinct advantage is again observed for the already authorized medicinal products, while no significant difference is found between the volume and complexity of the preclinical programs, e.g. Veklury vs innovative products. The latter observation may be explained by the fact that although data collection is available for a drug with still ongoing development, it is focused on a particular indication and may be difficult to adapt to new emerging disease. Similar to quality requirements, the efficacy of repositioning in preclinical data is variable, with the main factor being the stage of the life cycle at which repositioning is undertaken. Other important factors may also include the accumulated knowledge of the new disease and the similarities between the indications for which medicinal product is being developed and repositioned, respectively. Sultana and colleagues confirm these factors as well, and their work further reinforces the need for good interaction between industry and academia in order to make precise use of limited resources during a health crisis. ( 8 ) In addition, by using the proven to be safe drug molecule, repositioning allows conducting a smaller number of CTs directly targeting the desired indication which was the case for Veklury and its four Phase II/III trials. Another important comparison is with Paxlovid, which has larger clinical program including 2 CTs more than Veklury and further reinforces the effect of repositioning. Thus, due to the use of a repositioned drug being developed for similar indications (SARS-CoV-1 and MERS-CoV), the drug regulator grants authorization with efficacy data in the indication of the new MA application without requirements for conducting additional Phase 1 trials. . Comparison between the clinical programs of repurposed and innovative drugs underlines also the importance of academia and nonprofit organizations in repurposing. It is important to note that all clinical trials with Anakinra were sponsored by an organization other than a pharmaceutical company (Hellenic Institute for the Study of Sepsis), whereas the CT with the largest number of patients in Veklury (RECOVERY) was sponsored by Oxford University. In contrast, the clinical program of innovative drugs is almost entirely sponsored by pharmaceutical companies. The only exception is the ACTIV-3-TICO trial for Xevudy, which received public and private funding, with a design using a master protocol incorporating several subtests with different characteristics. This phenomenon is confirmed by Greenblatt et al., which show that industry sponsorship played a limited role in supporting drug repurposing in the COVID-19 pandemic. Most of the sponsorship for clinical trials of repurposed drugs came from academic institutions, especially for drugs with generic competitors already on the market. ( 9 ) Regarding clinical trial design, the findings of our study are in line with these of Vanderbeek and colleagues who confirm the expansion in the use of complex and adaptive designs precisely during the pandemic. Their review shows a several fold increase in adaptive clinical trials over the 2001–2019 period. ( 10 ) The authors describe the ability to simultaneously compare a large number of therapies, rapidly add an investigational product, and even change the indication through a protocol amendment as key drivers of this phenomenon. In the largest clinical trial with the SARS-CoV-2 indication, the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial saw 11 approved drugs out of 14 participating. ( 11 ) Some of the benefits of conducting clinical trials with such designs match the goals of repositioning. Deloitte highlight as pros the reduction of risk to clinical programs through rapid testing of hypotheses and scientific questions and detecting early signals of failure without spending unnecessary resources. In addition, complex design reduces the time, cost of conducting the overall clinical program, and mediates the accumulation of real-world data/evidence. ( 12 ) The comparative analysis of the clinical safety section of the EPAR strongly indicates the impact of repositioning as a method of drug development and the use of a medicinal products which are proven to be safe. Kineret shows a total absence of additional studies, part of the Pharmacovigilance plan and RoActemra - two non-interventional studies (NIS) of registry type, which are intended to research drug safety information for use in diseases other than SARS-CoV-2 infection. These two observations provide evidence of the clear advantage of extending the application of a product with an established use, as there are usually no imposed additional drug safety monitoring activities, nor activities specific to the new indication. Additional activities are listed in the EPARs of all other products, and in most cases, these represent NISs (registry type). It is also important to note that pregnancy use studies are planned or underway for all remaining drugs, once again demonstrating the small amount of information collected in the course of CTs for this population, also mentioned by Vousden and colleagues. ( 13 ) Thus, in an urgent health crisis, repositioning may emerge as the drug development strategy of choice in similar populations for which a sufficient amount of data is not traditionally collected in CTs. Similar to the analysis of other parts of the evaluation reports, the results of the one on safety reinforce the importance of the life cycle phase of the medicinal product at which the repurposing is undertaken. Drug safety can be considered the most sensitive for this aspect of repositioning which is evident from the large number of additional activities specifically in Veklury, some of which are self-imposed by the regulator compared to the other products. In contrast to quality, where Veklury has a large number of obligations/recommendations compared to the antibody MPs group, but less compared to Paxlovid from the antiviral group, Veklury has the largest number of additional safety activities among all products. Difference between drug classes (antiviral antibodies) as well as the indications for which they are approved (prevention or treatment of COVID-19) may lead to differences in clinical program data, quality and safety in published European Public Assessment Reports and may be a possible limitation to our study. In addition, we reviewed only the first EPARs adding an indication related to SARS-CoV-2, with no follow-up of subsequent evaluation reports to update the information when administered in this indication. CONCLUSION The pandemic caused by SARS-CoV-2 virus demonstrates the impact of repositioning with total of 37.5% therapies authorized by the EMA based on such approach. The data on several medicinal products clearly demonstrates the advantages of using a molecule proven qualitative, safe and efficacious for development of new indications without the need of additional data and large amount of clinical research. In addition, the importance of the life cycle stage of the drug product at which repositioning has been undertaken was also highlighted during this health crisis. Our study showed that product that was developed but did not receive a marketing authorization may need to submit significantly larger quality, safety and efficacy data package in the evaluation report compared to medicines with established use using repurposing. Nevertheless, product which is repositioned prior to receiving authorization can become the first available to patients using regulatory mechanism like scientific advice, rolling review, etc. With 50% of the medicines authorized for COVID-19-related indication included in clinical trials with platform/adaptive design or using master protocol we confirm the recent trend of their higher utilization. Finally, yet importantly, the involvement in drug development and clinical trials of organizations other than the MAH is represented clearly, which once again confirms the need to regulate this interaction for more efficiency. Declarations DATA AVAILABILITY STATEMENT The original contributions presented in the study are included in the Article/Supplementary Material, further inquiries can be directed to the corresponding author. AUTHOR CONTRIBUTIONS Conceptualization: IG, VG-K; Writing—original draft preparation AI, VG-K, IH; Writing—review and editing VG-K, IG; Visualization: AI; Supervision: IG. Funding acquisition: IG, VG-K; Methodology: AI, VG-K. All authors made a significant contribution to the work and approved the submitted version. FUNDING This study is financed by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0004-C01. CONFLICT OF INTEREST The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Hanisch M, Rake B. Repurposing without purpose? Early innovation responses to the COVID-19 crisis: Evidence from clinical trials. R&D Management. 2021;51(4):393–409. Jourdan J, Bureau R, Rochais C, Dallemagne P. Drug repositioning: a brief overview. J Pharm Pharmacol. 2020 Sep;72(9):1145–51. COVID-19 lessons learned.pdf [Internet]. [cited 2025 Jan 8]. Available from: https://www.ema.europa.eu/en/documents/report/covid-19-lessons-learned-joint-report-response-public-health-emergency_en.pdf Cavaleri M, Sweeney F, Gonzalez-Quevedo R, Carr M. Shaping EU medicines regulation in the post COVID-19 era. The Lancet Regional Health – Europe [Internet]. 2021 Oct 1 [cited 2025 Jan 8];9. 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Facilitating participation in clinical trials during pregnancy. BMJ. 2023 Feb 6;380:e071278. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6472930","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":453861102,"identity":"1b3c8dbe-9ecb-439f-9af9-11be27317855","order_by":0,"name":"Antonio Ivanov","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYNACAwYGNgjLRo4fRCUU4FPOjKIlzViyAaTFgJAWBDicuOEA1F5cgH92/8HHBQU2dn0Syc8efGw7bGx8fnXihwcGDPL8YgewapG4c5jZeIZBWnKbRJq54cy2dDmzG283SwAdZjhzdgJ2a24ks0nzGBxOZuM5YCbNc8ba2OzG2Q0gLQkGt7FrkUdoOf4NqIU5cfOMs5t/4NNiANVix8beA7SlwjlxA3/vNry2GN5INjbmMUhLAGopk5xRkWYscYN3m0WCgQROv8jdSHz4mOePjb18M/s2iQ8GwKjsP7v55o8KG3l+aRzeh4LEBjhTAqxSAq9yELBHMPkPEFQ9CkbBKBgFIwsAADyvWU04pv2lAAAAAElFTkSuQmCC","orcid":"","institution":"Medical University of Sofia","correspondingAuthor":true,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Ivanov","suffix":""},{"id":453861103,"identity":"e7b5e07e-8ef8-40d3-a0f1-f02e55186d58","order_by":1,"name":"Violeta Getova-Kolarova","email":"","orcid":"","institution":"Medical University of Sofia","correspondingAuthor":false,"prefix":"","firstName":"Violeta","middleName":"","lastName":"Getova-Kolarova","suffix":""},{"id":453861104,"identity":"5ae89799-7ee0-444a-a672-8265c6d37d5e","order_by":2,"name":"Ines Hababa-Ivanova","email":"","orcid":"","institution":"Medical University of Sofia","correspondingAuthor":false,"prefix":"","firstName":"Ines","middleName":"","lastName":"Hababa-Ivanova","suffix":""},{"id":453861105,"identity":"041aeb26-2152-4ee1-b25a-dfd6bc58acf0","order_by":3,"name":"Ilko Getov","email":"","orcid":"","institution":"Medical University of Sofia","correspondingAuthor":false,"prefix":"","firstName":"Ilko","middleName":"","lastName":"Getov","suffix":""}],"badges":[],"createdAt":"2025-04-17 15:08:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6472930/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6472930/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82365608,"identity":"50edf71d-564d-434a-918a-8a7153570300","added_by":"auto","created_at":"2025-05-09 12:43:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":118276,"visible":true,"origin":"","legend":"\u003cp\u003eClinical trials included in EPAR\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6472930/v1/46509c04df5cfab36d3f58bd.png"},{"id":82365613,"identity":"19df7280-d57a-476d-9816-b7360d3d8f8a","added_by":"auto","created_at":"2025-05-09 12:43:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":164644,"visible":true,"origin":"","legend":"\u003cp\u003eTotal number of clinical trial subjects included in EPAR\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6472930/v1/332a3a135863c43b94756cd1.png"},{"id":82365999,"identity":"6684cd80-6863-4a47-8749-1ade34c16ab9","added_by":"auto","created_at":"2025-05-09 12:51:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":53113,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of clinical trials included in the EPAR focused on phase\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6472930/v1/4c87d436dcd5b5acfe9908cd.png"},{"id":82366000,"identity":"3f743be9-2fc3-4f27-9cea-95c873b73064","added_by":"auto","created_at":"2025-05-09 12:51:29","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":87130,"visible":true,"origin":"","legend":"\u003cp\u003eClinical trials with platform/adaptive design or using master protocol included in EPAR\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6472930/v1/35cb6fcd7b8d5f8e68d09c70.png"},{"id":82365617,"identity":"bcec0ee5-f6b0-4dc4-bb5e-949f1816807e","added_by":"auto","created_at":"2025-05-09 12:43:29","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1045671,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of additional pharmacovigilance activities in EPAR’s Pharmacovigilance plans of analysed medicinal products\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6472930/v1/89603b4f33717699bf4f6d7d.png"},{"id":83491671,"identity":"7447654b-006a-41ab-9ce8-1f4cc0ef01d7","added_by":"auto","created_at":"2025-05-27 10:08:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1789302,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6472930/v1/13b6f15d-c300-4c6f-9134-7a2e3ff83f5f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Drug repurposing for inclusion of COVID-19-related indication: field study of the European Medicines Agency’s response to the pandemic","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe infection caused by the SARS-CoV-2 virus, declared by the World Health Organization (WHO) as COVID-19 pandemic on 11.03.2020 due to its increasing spread, is one of the biggest health crises of the 21st century. During the first years of the pandemic the efforts and resources of the entire global healthcare system were directed towards discovering ways for influencing and preventing the disease, thus granting authorization to a multitude of vaccines and medicines. This was further emphasized by factors such as unusually high economic incentives for treatment development, as well as accelerated and eased regulatory procedures for authorization. Since the first effective treatment would yield the highest economic benefits, the time pressure factor was exceptional for many of the stakeholders. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eRepurposing (or repositioning) is the mechanism for detection of new uses of authorized medicinal products or investigational products outside their original indication/s. The way is by combining the knowledge of the human genome sequence and that some diseases share common biological mechanisms. In addition, the concept of pleiotropic drugs and the systematic understanding of molecule-target interactions play a crucial role in identifying new candidates. The experimental approaches of repurposing suffer from lack of efficacy and with the advance of computational power the ligand-based, target-based and machine learning-based mechanisms are developing as leaders. Apart from some inherent drawbacks of the drug repurposing as lower affinity of the target-molecule interaction due to molecular optimization and using data with lower accuracy and consistency this approach has many advantages. One of the most important is increasing the speed and success rate of research and development efforts by operating with medicinal products that have been proven as effective and safe. Another important positive effect is lowering the overall costs in time and money for development by using already generated data during the research programs. This eliminates the necessity of conducting large pre-clinical and clinical programs. Finally, drug repurposing has potential in battling emerging health crises again by producing a medicinal product, which is safe and effective enough to prevent human losses and lower the general risk for the public health in the first stages of an epidemic/pandemic situation. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe European Medicines Agency (EMA) as part of the European Medicines Regulatory Network (EMRN) has established itself as key player in the process of authorizing pandemic vaccines and therapeutic agents and monitoring their safety. EMA has a key role also in crisis coordination activities, management of medicines shortages, provision of information on COVID-19 medicines and generation of reliable real-world evidence (RWE). The uninterrupted work of the Agency was made possible thanks to the development of crisis management plan in 2006 and its adjustments after health crises like the 2009 H1N1 influenza pandemic. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Despite this, as every health crisis has its specifics, COVID-19 pandemic posed difficulties like need for constant adaptation to emerging scientific data, remote working, communicating uncertainty in real time and counteracting misinformation by providing authoritative reference data and reports. In this turbulent period, waiting for a full data package in marketing authorization submissions would have significantly delayed access to much needed medicines. Moreover, significant reduction in deaths and hospitalizations was observed after the authorization of medicines and vaccines against the SARS-CoV-2 infection. There are many lessons learned and some of them refer to the ways used for collecting data for drug approvals. This includes the drawbacks from the fragmented nature of clinical trials, which are often small, underpowered, or with suboptimal design. The need of large, well-designed trials, including platform trials, that can provide the robust data needed to support decision-making is clear. Randomized controlled trials remain essential for clinical development of new vaccines or therapies, also in a pandemic context but they can benefit from complementary evidence from clinical practice through the analysis of RWE. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eBy conducting this research and analysis, we aim to study the effects of repurposing in the drug development during the COVID-19 pandemic, synthesize the advantages and disadvantages, and identify external factors that may influence this method in the setting of health crisis.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eWe have carried out research of the European Public Assessment Reports (EPARs) for authorized medicinal products available in the COVID-19 section on the European Medicines Agency website in Jul-2024. The methodology of the conducted analysis does not include analysis of vaccines. Their repositioning is largely based on heterologous and non-specific effects for a general improvement of the body's defenses, the precise mechanism of which is not fully discovered. In addition, the basic concept of these therapeutic agents is active immunization for prevention, which necessitates hyperactive specificity to the disease-causing agent and a reduction in the potential for repositioning.\u003c/p\u003e \u003cp\u003eThe first EPARs to add an indication related to COVID-19 were used for the analysis and specific sections were selected as a study subject:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eFor evaluation of the quality data - \"Discussion on chemical, pharmaceutical and biological aspects\", \"Conclusions on the chemical, pharmaceutical and biological aspects\" and \"Recommendation for future quality development\"\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFor evaluation of the preclinical phase of drug development - \"Non-clinical aspects\"\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFor evaluation of the clinical phase of drug development - \"Clinical aspects\"\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFor evaluation of the safety data - \"Risk Management Plan\"\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe comparative part of the analysis was focused primarily on the qualitative and quantitative aspects of the different sections between Kineret\u0026reg; (anakinra) and the rest authorized medicinal products. We have identified Kineret\u0026reg; (anakinra) as classic example of the use of repositioning due to its of history of use of over 22 years and being authorized in 6 different therapeutic indications. In addition, we have included RoActemra and Veklury as a second line in the analysis since they are also authorized for use in patients with COVID-19 infection using repurposing.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eAt the time of the study, eight medicinal products were authorized in the EU with COVID-19 as an indication, shown chronologically as per the date of issue of the MA in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e:\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChronological list of medicinal products receiving marketing authorization for indication related to SARS-CoV-2\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedicinal product\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDate of MA issue -\u003c/p\u003e \u003cp\u003eDifference from declaring COVID-19 pandemic in days\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRepurposed medicinal product\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVeklury\u003c/p\u003e \u003cp\u003e(remdesivir)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConditional MA: 03/07/2020\u0026thinsp;\u0026minus;\u0026thinsp;115\u003c/p\u003e \u003cp\u003eMA: 08/08/2022\u0026thinsp;\u0026minus;\u0026thinsp;881\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRonapreve (casirivimab/imdevimab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA: 12/11/2021\u0026thinsp;\u0026minus;\u0026thinsp;612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegkirona (regdanvimab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA: 12/11/2021\u0026thinsp;\u0026minus;\u0026thinsp;612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRoActemra\u003c/p\u003e \u003cp\u003e(tocilizumab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA: 07/12/2021\u0026thinsp;\u0026minus;\u0026thinsp;637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKineret\u003c/p\u003e \u003cp\u003e(anakinra)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA: 17/12/2021\u0026thinsp;\u0026minus;\u0026thinsp;647\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eXevudy\u003c/p\u003e \u003cp\u003e(sotrovimab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA: 17/12/2021\u0026thinsp;\u0026minus;\u0026thinsp;647\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaxlovid\u003c/p\u003e \u003cp\u003e(PF-07321332/ritonavir)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConditional MA: 28/01/2022\u0026thinsp;\u0026minus;\u0026thinsp;689\u003c/p\u003e \u003cp\u003eMA: 24/02/2023\u0026thinsp;\u0026minus;\u0026thinsp;1081\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvusheld (tixagevimab/cilgavimab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA: 25/03/2022\u0026thinsp;\u0026minus;\u0026thinsp;744\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eExtremely rapid development of the first drug (Veklury) can be observed when comparing the dates for granting MA. It received a Conditional MA only 115 days after WHO declared the pandemic. Ronapreve, Regkirona, RoActemra, Kineret and Xevudy were next to receive MAs. The difference between the dates of issue for each of these five medicinal products can be considered relatively negligible compared to the number of days since the COVID-19 pandemic was announced. In this group, two of the drugs also used repositioning as drug development approach, demonstrating its importance in addressing health crises. Paxlovid is a combination of drug molecules (nirmatrelvir/ritonavir) and is the second antiviral product for treatment of COVID-19 to be granted a marketing authorization (MA) in the EU. A comparison between Veklury and Paxlovid shows a difference of 574 and 200 days for receiving conditional MA and complete MA respectively, highlighting remdesivir as the first antiviral molecule ready for use for treatment of SARS-CoV-2 infection. It is worth noting that this is observed amid the use of ritonavir as part of the Paxlovid combination, which has history of established use, but the use of newly developed molecule PF-07321332 (nirmatrelvir) requires robust demonstration of efficacy and safety.\u003c/p\u003e \u003cp\u003eThe authorization of medicinal products by regulatory agencies aims to maintain high levels of quality, efficacy and safety standards. Examination of the quality summary sections of the assessment report also shows a distinction between repositioned and innovative therapies. The first important observation is the complete absence of submitted information on quality of the repositioned products Kineret and RoActemra, both of which have an established use in the EU. This fact allows the CHMP to consider these parts of the dossier acceptable without requiring additional data than the currently available. The assessment report for Veklury shows a total of 11 issues identified in quality documentation that require specific obligations during remdesivir manufacturing. In addition, 3 recommendations for future quality development are also described. This is amidst the fact that Veklury has not been authorised for use in EU prior to the COVID-19 pandemic, but it has history of development in similar therapeutic indications and therefore can be categorised as repurposed. Information on quality requirements in EPARs for the remaining medicinal products is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of the Quality sections for non-repurposed medicinal products\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedicinal product\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIssues identified in quality documentation that require specific obligations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRecommendations for future quality development\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRonapreve\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegkirona\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eXevudy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaxlovid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e18\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvusheld\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn regards to non-clinical aspects, the medicinal products approved for use in SARS-CoV-2 virus infection showed similar results to the Quality section analysis. In Kineret and RoActemra there is again absence of new data submissions in the analyzed section of the evaluation reports, which is considered acceptable by the EMA due to long-standing use of the medicines. The remaining drugs, including Veklury, provide in-depth preclinical programs that investigate multiple aspects such as ADME (Absorption, Distribution, Metabolism, Excretion) characterization and different types of toxicity in a wide range of cell models and animal species.\u003c/p\u003e \u003cp\u003eThe analysis of \u0026bdquo;Clinical aspects\u0026ldquo; section of the Scientific discussion showed that the drug product with the lowest number of conducted clinical trials (CTs) is Kineret (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), where a COVID-19 related indication is added through repurposing. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) The other product using this approach, RoActemra shows 5 conducted CTs, on par with Ronapreve and Xevudy. Unlike the latter, however, the repositioned product submits dominantly completed CTs (4/80%), while the innovative drugs report 3/60% and 1/20%, respectively. A total of 8 CTs are included in the EPAR of the third repositioned representative - Veklury. Although this is a large number, it should be noted that 4/50% of them were conducted in the period 2015\u0026ndash;2019 and were Phase I CTs to assess safety, tolerability, metabolism, excretion and pharmacokinetics of remdesivir. For this reason, Veklury is classified as a repositioned medicinal product, as these are already accumulated data. However, it is necessary to include it in the submission due to the absence of a marketing authorization at the time of issuing EPAR. For the Clinical aspects section total number of subjects in clinical trials is another important parameter, part of the EPAR analysis. Again, Kineret shows the smallest number of participants (1606) compared to the other repositioned products Veklury and RoActemra ranking 3rd (2462) and 5th (5706) respectively in terms of number of subjects enrolled in the clinical program (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Analysis of clinical trials distribution by phases also provides evidence of the effect of repositioning. For innovative products, there is a dominance of initial phases such as Phase I (particularly pronounced for Paxlovid and Regkirona), as these therapies have not been authorized for use and need to provide positive data to demonstrate tolerability. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) For the repositioned product RoActemra, there is a dominance of Phase III CTs. Thus demonstrates the effect of using a proven to be safe product, which does not require conduct of additional Phase 1 safety and tolerability trials. For Kineret, only one Phase I trial was conducted to collect data in the new indication, and this result is consistent with Evusheld and Ronapreve. In addition, although 4 Phase I CTs for Veklury are included in the EPAR, their aim was to demonstrate safety and tolerability of the molecule in general rather than specifically in the indication associated with COVID-19.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIt is also interesting to note the impact of the COVID-19 pandemic on clinical trials with platform/adaptive designs or using a master protocol. Out of 41 total CTs included in EPARs, 6 (15%) are conducted such designs. Examples of clinical trials with platform/adaptive designs for authorized medicines with SARS-CoV-2 indication are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSafety is also part of the three most important features in the authorization of a medicinal product and is included in the EPAR, being described by a Summary of safety concerns; Risk minimization measures (RMMs) and the Pharmacovigilance plan. For comparing the drug development and life cycle of repositioned and innovative medicines, the most comprehensive information is provided by the Pharmacovigilance plan as it describes the on-going and planned additional pharmacovigilance activities. The \u0026bdquo;Safety concerns\u0026ldquo; section can be considered specific to each drug molecule and cannot reflect the different drug development methods, whereas the \u0026bdquo;Risk minimization measures\u0026ldquo; section combines information from the previous two sections. Figure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e presents a summary of the quantitative and qualitative results when compare only the Pharmacovigilance plan of all medicinal products.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe analysis of EPARs showed that the authorized medicines for treatment of Covid-19 comprise of one RNA polymerase inhibitor (Veklury), one interleukin-1 receptor antagonist (Kineret), one combination of antivirals (Paxlovid), three monoclonal antibodies (Regkirona, RoActemra, Xevudy) and two combinations of monoclonal antibodies (Ronapreve, Evusheld).\u003c/p\u003e \u003cp\u003eWhile the study did not show a dramatic difference in the time to obtain MA, large impact of repositioning as drug development mechanism in response to an emerging health crisis was observed. On one hand, this is demonstrated by 3 out of 8 medicines (37.5%) being authorized using this approach. On the other hand, the first authorized medicinal product to include COVID-19-related indication is also a repositioning product and receives a MA 497 days before the next authorized ones. This occurs in the light of EMA\u0026rsquo;s still evolving regulatory initiatives for scientific advice for drug development program that would subsequently favor the expeditious authorization of the remaining drugs. The absence of major gaps in the timing of granting MA can be explained with the global scale and strength of the health crisis, which imposes directing enormous health care resources to drug development in this indication, as shown by von Delft and colleagues. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eA major reason for the fast Conditional MA issue for Veklury is the use of drug repositioning in its development. Although unapproved, the product is an antiviral therapy under development and proven safe in a number of preclinical studies and clinical trials. Another major reason is the expedited regulatory procedures by the EMA and the use of so-called \"rolling review\", where data for a drug product is submitted by the Applicant and reviewed by the EMA \"as it becomes available\". This has been shown by Marinus et al., which describe the calling of extraordinary CHMP meetings and closer EMA-Applicant communication as main advantages of rolling review assessment which helps clarify the characteristics of the medicinal product. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe study on the Quality section of the EPAR reinforces repositioning as a mechanism for rapid and accessible medicinal product development by using available data on product quality. Anakinra and RoActemra demonstrate full use of already collected quality data without providing data generated specifically for the new MA procedure. On the other hand, Veklury, Paxlovid, Evusheld, Regkirona, Ronapreve, and Xevudy provide large data packages using time- and money-consuming tests. Farid and colleagues, in their study of costs in the biopharmaceutical industry, report \u003cspan\u003e$\u003c/span\u003e40\u0026nbsp;million in expenses to develop and optimize the manufacturing which is crucial for proof of quality. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Moreover, the additional financial resources required for post-approval quality improvement or addressing regulatory agency obligations/recommendations can also influence and raise the whole investment and the risk associated with it. The difference in the number of regulatory obligations/recommendations between representatives from the antibody MPs group and the antiviral group can be explained by the different parameters monitored in quality control. The antibodies are subjected to detailed characterization (physico-chemical, structural, immunological and functional) during different stages of development, production and storage by specific analytical methods, which can ensure batch-to-batch repeatability. In addition, antiviral substances are developed as solid dosage forms, which may require the inclusion of additional excipients to further stabilize and ensure proper delivery into the body.\u003c/p\u003e \u003cp\u003eVeklury, although using repositioning, also submits a large volume of quality data due to performing \u0026ldquo;drug rescue\u0026rdquo; as type of repositioning during the clinical development phase prior to MA issue. While overall Veklury has a large number of quality obligations/recommendations (14 in total) compared to the antibody MPs group, this number is lower than the other medicinal product in the antiviral group (Paxlovid) with a total of 22. The results of the summary sections of the quality in the EPAR also reinforce the advantages of repositioning. However, a correlation was found between the phase of the drug life cycle at which repositioning was undertaken and the amount of quality data submitted. The analysis shows that the EMA accepts the applications of authorized and repositioned products without the need for additional data, whereas repurposing an unauthorized product in its clinical phase can result in the need for a significant amount of data \u0026ndash; close to that of innovative products.\u003c/p\u003e \u003cp\u003eA distinct advantage is again observed for the already authorized medicinal products, while no significant difference is found between the volume and complexity of the preclinical programs, e.g. Veklury vs innovative products. The latter observation may be explained by the fact that although data collection is available for a drug with still ongoing development, it is focused on a particular indication and may be difficult to adapt to new emerging disease. Similar to quality requirements, the efficacy of repositioning in preclinical data is variable, with the main factor being the stage of the life cycle at which repositioning is undertaken. Other important factors may also include the accumulated knowledge of the new disease and the similarities between the indications for which medicinal product is being developed and repositioned, respectively. Sultana and colleagues confirm these factors as well, and their work further reinforces the need for good interaction between industry and academia in order to make precise use of limited resources during a health crisis. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn addition, by using the proven to be safe drug molecule, repositioning allows conducting a smaller number of CTs directly targeting the desired indication which was the case for Veklury and its four Phase II/III trials. Another important comparison is with Paxlovid, which has larger clinical program including 2 CTs more than Veklury and further reinforces the effect of repositioning. Thus, due to the use of a repositioned drug being developed for similar indications (SARS-CoV-1 and MERS-CoV), the drug regulator grants authorization with efficacy data in the indication of the new MA application without requirements for conducting additional Phase 1 trials. .\u003c/p\u003e \u003cp\u003eComparison between the clinical programs of repurposed and innovative drugs underlines also the importance of academia and nonprofit organizations in repurposing. It is important to note that all clinical trials with Anakinra were sponsored by an organization other than a pharmaceutical company (Hellenic Institute for the Study of Sepsis), whereas the CT with the largest number of patients in Veklury (RECOVERY) was sponsored by Oxford University. In contrast, the clinical program of innovative drugs is almost entirely sponsored by pharmaceutical companies. The only exception is the ACTIV-3-TICO trial for Xevudy, which received public and private funding, with a design using a master protocol incorporating several subtests with different characteristics. This phenomenon is confirmed by Greenblatt et al., which show that industry sponsorship played a limited role in supporting drug repurposing in the COVID-19 pandemic. Most of the sponsorship for clinical trials of repurposed drugs came from academic institutions, especially for drugs with generic competitors already on the market. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eRegarding clinical trial design, the findings of our study are in line with these of Vanderbeek and colleagues who confirm the expansion in the use of complex and adaptive designs precisely during the pandemic. Their review shows a several fold increase in adaptive clinical trials over the 2001\u0026ndash;2019 period. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) The authors describe the ability to simultaneously compare a large number of therapies, rapidly add an investigational product, and even change the indication through a protocol amendment as key drivers of this phenomenon. In the largest clinical trial with the SARS-CoV-2 indication, the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial saw 11 approved drugs out of 14 participating. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) Some of the benefits of conducting clinical trials with such designs match the goals of repositioning. Deloitte highlight as pros the reduction of risk to clinical programs through rapid testing of hypotheses and scientific questions and detecting early signals of failure without spending unnecessary resources. In addition, complex design reduces the time, cost of conducting the overall clinical program, and mediates the accumulation of real-world data/evidence. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe comparative analysis of the clinical safety section of the EPAR strongly indicates the impact of repositioning as a method of drug development and the use of a medicinal products which are proven to be safe. Kineret shows a total absence of additional studies, part of the Pharmacovigilance plan and RoActemra - two non-interventional studies (NIS) of registry type, which are intended to research drug safety information for use in diseases other than SARS-CoV-2 infection. These two observations provide evidence of the clear advantage of extending the application of a product with an established use, as there are usually no imposed additional drug safety monitoring activities, nor activities specific to the new indication. Additional activities are listed in the EPARs of all other products, and in most cases, these represent NISs (registry type). It is also important to note that pregnancy use studies are planned or underway for all remaining drugs, once again demonstrating the small amount of information collected in the course of CTs for this population, also mentioned by Vousden and colleagues. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) Thus, in an urgent health crisis, repositioning may emerge as the drug development strategy of choice in similar populations for which a sufficient amount of data is not traditionally collected in CTs.\u003c/p\u003e \u003cp\u003eSimilar to the analysis of other parts of the evaluation reports, the results of the one on safety reinforce the importance of the life cycle phase of the medicinal product at which the repurposing is undertaken. Drug safety can be considered the most sensitive for this aspect of repositioning which is evident from the large number of additional activities specifically in Veklury, some of which are self-imposed by the regulator compared to the other products. In contrast to quality, where Veklury has a large number of obligations/recommendations compared to the antibody MPs group, but less compared to Paxlovid from the antiviral group, Veklury has the largest number of additional safety activities among all products.\u003c/p\u003e \u003cp\u003eDifference between drug classes (antiviral antibodies) as well as the indications for which they are approved (prevention or treatment of COVID-19) may lead to differences in clinical program data, quality and safety in published European Public Assessment Reports and may be a possible limitation to our study. In addition, we reviewed only the first EPARs adding an indication related to SARS-CoV-2, with no follow-up of subsequent evaluation reports to update the information when administered in this indication.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe pandemic caused by SARS-CoV-2 virus demonstrates the impact of repositioning with total of 37.5% therapies authorized by the EMA based on such approach. The data on several medicinal products clearly demonstrates the advantages of using a molecule proven qualitative, safe and efficacious for development of new indications without the need of additional data and large amount of clinical research. In addition, the importance of the life cycle stage of the drug product at which repositioning has been undertaken was also highlighted during this health crisis. Our study showed that product that was developed but did not receive a marketing authorization may need to submit significantly larger quality, safety and efficacy data package in the evaluation report compared to medicines with established use using repurposing. Nevertheless, product which is repositioned prior to receiving authorization can become the first available to patients using regulatory mechanism like scientific advice, rolling review, etc. With 50% of the medicines authorized for COVID-19-related indication included in clinical trials with platform/adaptive design or using master protocol we confirm the recent trend of their higher utilization. Finally, yet importantly, the involvement in drug development and clinical trials of organizations other than the MAH is represented clearly, which once again confirms the need to regulate this interaction for more efficiency.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the Article/Supplementary Material, further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: IG, VG-K; Writing\u0026mdash;original draft preparation AI, VG-K, IH; Writing\u0026mdash;review and editing VG-K, IG; Visualization: AI; Supervision: IG. Funding acquisition: IG, VG-K; Methodology: AI, VG-K.\u003c/p\u003e\n\u003cp\u003eAll authors made a significant contribution to the work and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is financed by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project №\u0026nbsp;BG-RRP-2.004-0004-C01.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHanisch M, Rake B. Repurposing without purpose? Early innovation responses to the COVID-19 crisis: Evidence from clinical trials. R\u0026amp;D Management. 2021;51(4):393\u0026ndash;409. \u003c/li\u003e\n\u003cli\u003eJourdan J, Bureau R, Rochais C, Dallemagne P. Drug repositioning: a brief overview. J Pharm Pharmacol. 2020 Sep;72(9):1145\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eCOVID-19 lessons learned.pdf [Internet]. [cited 2025 Jan 8]. Available from: https://www.ema.europa.eu/en/documents/report/covid-19-lessons-learned-joint-report-response-public-health-emergency_en.pdf\u003c/li\u003e\n\u003cli\u003eCavaleri M, Sweeney F, Gonzalez-Quevedo R, Carr M. Shaping EU medicines regulation in the post COVID-19 era. The Lancet Regional Health \u0026ndash; Europe [Internet]. 2021 Oct 1 [cited 2025 Jan 8];9. Available from: https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00169-1/fulltext\u003c/li\u003e\n\u003cli\u003evon Delft A, Hall MD, Kwong AD, Purcell LA, Saikatendu KS, Schmitz U, et al. Accelerating antiviral drug discovery: lessons from COVID-19. Nat Rev Drug Discov. 2023 Jul;22(7):585\u0026ndash;603. \u003c/li\u003e\n\u003cli\u003eMarinus R, Mofid S, Mpandzou M, K\u0026uuml;hler TC. Rolling Reviews During COVID-19: The European Union Experience in a Global Context. Clinical Therapeutics. 2022 Mar 1;44(3):352\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eFarid SS, Baron M, Stamatis C, Nie W, Coffman J. Benchmarking biopharmaceutical process development and manufacturing cost contributions to R\u0026amp;D. MAbs. 12(1):1754999. \u003c/li\u003e\n\u003cli\u003eSultana J, Crisafulli S, Gabbay F, Lynn E, Shakir S, Trifir\u0026ograve; G. Challenges for Drug Repurposing in the COVID-19 Pandemic Era. Front Pharmacol [Internet]. 2020 Nov 6 [cited 2025 Jan 8];11. Available from: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.588654/full\u003c/li\u003e\n\u003cli\u003eGreenblatt W, Gupta C, Kao J. Drug Repurposing During The COVID-19 Pandemic: Lessons For Expediting Drug Development And Access. https://doi.org/101377/hlthaff202201083 [Internet]. 2023 Mar 6 [cited 2025 Jan 8]; Available from: https://www.healthaffairs.org/doi/10.1377/hlthaff.2022.01083\u003c/li\u003e\n\u003cli\u003eVanderbeek AM, Bliss JM, Yin Z, Yap C. Implementation of platform trials in the COVID-19 pandemic: A rapid review. Contemporary Clinical Trials. 2022 Jan 1;112:106625. \u003c/li\u003e\n\u003cli\u003eAbani O, Abbas A, Abbas F, Abbas M, Abbasi S, Abbass H, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet. 2021 May 1;397(10285):1637\u0026ndash;45. \u003c/li\u003e\n\u003cli\u003eDeloitte Insights [Internet]. [cited 2025 Jan 8]. Master protocols. Available from: https://www2.deloitte.com/content/www/us/en/insights/industry/life-sciences/master-protocol-clinical-trial-drug-development-process.html\u003c/li\u003e\n\u003cli\u003eVousden N, Haynes R, Findlay S, Horby P, Landray M, Chappell L, et al. Facilitating participation in clinical trials during pregnancy. BMJ. 2023 Feb 6;380:e071278. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"repurposing, COVID-19, EMA, crisis management, clinical trials, drug safety","lastPublishedDoi":"10.21203/rs.3.rs-6472930/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6472930/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAs one of the biggest challenges for healthcare in the 21st century, COVID-19 placed a sustained and intense demand on the European Medicines Agency resources and required constant adaptation and mobilization of different regulatory processes. In this situation drug repurposing appeared as a promising potential approach in quickly emerging health crises due to its main advantage of reducing time and cost for addition of new indications since it uses products proven to be of high quality, safe and effective. The European Medicines Agency authorised total of 8 products for the SARS-CoV-2 infection, 3 (37.5%) of which used this mechanism for development (Veklury, RoActemra and Kineret). The application of drug repurposing by these medicines highlights the importance of the life cycle stage at which repositioning is undertaken. This resulted in different volumes of data submitted in the respective European Public Assessment Reports. The participation of organisations other than the MAH in key stages in the drug development process of repurposed products once again shows the need to regulate this interaction.\u003c/p\u003e","manuscriptTitle":"Drug repurposing for inclusion of COVID-19-related indication: field study of the European Medicines Agency’s response to the pandemic","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 12:43:24","doi":"10.21203/rs.3.rs-6472930/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c69a2473-52e4-40d3-962f-1509579ca420","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48264492,"name":"Biological sciences/Drug discovery"},{"id":48264493,"name":"Biological sciences/Drug discovery/Business strategy in drug development"},{"id":48264494,"name":"Biological sciences/Drug discovery/Drug regulation"},{"id":48264495,"name":"Biological sciences/Drug discovery/Drug safety"}],"tags":[],"updatedAt":"2025-05-27T10:08:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 12:43:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6472930","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6472930","identity":"rs-6472930","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}