On 11 March 2020, the World Health Organisation (WHO) declared the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a pandemic, stating that it was “deeply concerned by the alarming levels of spread and severity of the disease, and the equally alarming levels of inaction1. The WHO had already issued a warning about the disease in a report on the joint WHO-China mission, which was published in February 20202. This report provided a series of recommendations for preventing, detecting, and isolating cases, monitoring disease progression, carrying out public health prevention activities, and managing media coverage. This report only refers to nonpharmacological support measures, except in the recommendations made to China, in which it suggests “establish a centralized research program to fast-track the most promising rapid diagnostics and serologic assays, the testing of potential antivirals and vaccine candidates, and Chinese engagement in selected multi-country trials”.

Before the pandemic was officially recognised as such, very few studies had been published on the use of drug therapy in coronavirus infection3. At that time, several antivirals and other drugs were tested in clinical trials (CTs) in China, but no significant scientific evidence of their efficacy was achieved.

When the first cases of SARS-CoV-2 infection appeared in Spain, the healthcare professionals' approach to treating these patients was characterised by uncertainty and a focus solely on clinical aspects. As in other European countries (e.g. France and Italy), off-label drugs were administered in Spain without robust evidence of their efficacy. These drugs included hydroxychloroquine, lopinavir/ritonavir, azithromycin and, later, remdesivir, in line with recommendations from the scientific community and health authorities. These drugs are used in routine clinical practice to treat various diseases and have well-known safety profiles, in terms of both adverse reactions and potential drug interactions. Some of these effects are serious, particularly given that many of the patients treated were elderly or had pre-existing conditions4–6. In line with these recommendations, the Spanish Agency for Medicines and Health Products (AEMPS) made great efforts to ensure that these drugs were available in Spanish hospitals, as they were already being used to treat affected patients.

Controlled CTs are the most reliable method to yield high-quality scientific evidence. The results obtained from scientific research help determine optimal therapeutic strategies. This information is disseminated through national registries (e.g. the Spanish Clinical Trials Registry in Spain) and by publishing the results, which is legally required by Royal Decree 1090/20157. For this reason, health authorities in all countries, particularly in Spain and the United Kingdom, urged the initiation of CTs, initially using drugs that were already being employed empirically. Noteworthy initiatives included the WHO Solidarity trial8 and the UK National Health Service's Recovery trial9, the results of which were published shortly after completion. In addition, new research projects involving other drugs were initiated that, from the outset, called for the inclusion of as many patients as possible. The main objectives were to provide patients with new therapeutic options and to obtain drug efficacy and safety data that would confirm favourable risk–benefit ratios.

In Spain, approximately 17% of drug research is noncommercial or academic in nature10. However, during the COVID-19 pandemic, numerous independent or noncommercial CTs were conducted, sponsored by collaborative groups, scientific societies, hospital foundations, or independent researchers. All those involved made great efforts to evaluate, authorise, implement, and develop the CTs, with the work of independent researchers being particularly noteworthy. This effort was not only financial, requiring significant public funding, but also organisational, involving the rapid evaluation and approval of protocol submissions and the rushed initiation of CTs in hospitals. The CT units played a decisive role by quickly adapting their standard operating procedures and participating in resource allocation11,12.

According to the Organisation for Economic Co-operation and Development and major pharmaceutical companies, Spain was among the countries that conducted the most CTs on SARS-CoV-2 at the height of the pandemic12. Now that some time has passed, a number of questions remain. How many of these trials have been completed? How many studies have published their results, even if they were negative? What problems arose during their implementation? In short, was the effort involved in setting them up worthwhile? Against this backdrop, the present study aimed to analyse CTs involving drugs for SARS-CoV-2 infection that were conducted in Spain during the pandemic, and to describe the publication and completion rates of these trials.

A meta-epidemiological, analytical, retrospective study of the characteristics, completion rates, and publication of CTs involving drugs intended for the prophylaxis and treatment of SARS-CoV-2 infection approved in Spain between March 2020 and August 2021.

During the study period, 191 CTs involving drugs were approved, 12 of which were excluded because they were phase I studies of paediatric populations. Ten CTs involved vaccines as a therapeutic option. The principal objective of most of the 179 CTs was therapeutic repurposing (72.1%). In addition, 45 studies (25.1%) involved new drugs not previously approved by the AEMPS for any disease. One CT had a dual objective, combining drug repurposing and new molecules (WHO Solidarity Trial)8. Only 6 studies (2.8%) were conducted with drugs classified as cell therapies.

Of the 179 CTs, 67.2% were Spanish, 71.0% were multicentre, and 64.8% had noncommercial sponsors. Most CTs were phase III (48.1%) or phase II (44.7%) (Table 2). Regarding methodology, the comparative design stood out, having been employed in 93.9% of the studies. The majority of the trials focussed on treatment (91.1%) and 10.6% addressed disease prophylaxis. A total of 21.2% of trials were terminated prematurely. The main reasons were recruitment difficulties (36.6%), withdrawal of consent (26.8%), and lack of efficacy (21.9%). By the cut-off date of November 2024, 41.1% had issued a final report and 31.3% had published results in scientific journals (71.9% in the first quartile).

Statistically significant associations were found between the availability of the final report and the following variables: being an international study (54.7% vs 45.3%; p < 0.001); being a multicentre study (84.0% vs 16.0%; p = 0.002); having a commercial sponsor (64.2% vs 35.8%; p < 0.001); comparing treatment with placebo (54.7% vs 45.3%; p = 0.001); focussing on drug repurposing (57.3% vs 42.7%; p < 0.001); and not undergoing early closure (69.3% vs 30.7%; p = 0.009).

Only 49 of the 179 CTs were published in indexed journals. Associations were found between publication and variables related to the study design: being multicentre (85.7% vs 14.3%; p = 0.004), phase III (58.9% vs 41.1%; p = 0.049), and Spanish (53.6% vs 46.4%; p = 0.01). The majority of CTs published in the first quartile were international (58.5% vs 41.5%; p = 0.002).

Notable findings regarding outcome-related variables included the availability of a final report (64.3% vs 35.7%; p < 0.001) and the absence of premature termination (89.3% vs 10.7%; p = 0.02).

The main characteristics of the studies (N = 82) that began during the first wave of COVID (March–June 2020) were as follows: not being international (82.9% vs 17.1%; p < 0.001), having noncommercial sponsors (80.5% vs 19.5%; p < 0.001), not being placebo-controlled (73.2% vs 26.8%; p < 0.001), and focussing on drug repurposing (84.1% vs 15.9%; p = 0.001).

The characteristics of studies approved during the second wave (N = 62) were as follows: not being international (61.3% vs 38.7%; p < 0.001), having commercial sponsors (90.3% vs 9.7%; p < 0.001), being placebo-controlled (66.1% vs 33.9% p = 0.04), and focussing on drug repurposing (70.9% vs 29.1%; p = 0.001). The characteristics during the third, fourth, and fifth waves (N = 35) were as follows: being international studies (61.5% vs 38.5%; p < 0.001), having commercial sponsors (68.8% vs 31.2%), being placebo-controlled (78.8% vs 21.2%; p < 0.001); and evaluating new molecules (59.4% vs 40.6%; p =  0.003) (Fig. 1; Table 2).

Figure 1.

Number of CTs initiated in each wave of the pandemic.

The need for effective and safe treatments for COVID-19 led to the large-scale initiation of CTs. According to recent data, over 2700 CTs related to SARS-CoV-2 were registered globally on ClinicalTrials.gov13. In Spain, 191 studies were registered in the SCTR. These figures reflect the effort undertaken by the scientific and healthcare community to advance knowledge in this field.

Various published reviews identified significant limitations in the quality, impact, design, and publication of CTs14. They found that many CTs had significant methodological limitations that compromised their scientific value. These limitations included inconsistent designs, small sample sizes, an absence of control groups, unblinded patients and physicians, and nonrandomised designs15. Another key factor in these studies was the lack of coordination between different bodies16. The lack of quality was most pronounced during the first wave, when there was an urgent need for additional knowledge and increased pressure on healthcare systems16,17.

Dal-Ré and Mahillo-Fernández18 reviewed 159 CTs that were not sponsored by the pharmaceutical industry and were conducted across various Western European countries over 1 year (May 2020–May 2021). Overall, 44% of the CTs exhibited at least 1 indicator of low methodological quality. For this reason, the results obtained in these trials made it difficult to reproduce them and draw firm conclusions. For example, one CT evaluated the effectiveness of hydroxychloroquine combined with macrolides, but the results were not statistically rigorous19. Publications such as these contributed to the initial confusion regarding treatment, which ultimately forced numerous scientific journals to retract them due to weak methodological rigour and questionable ethical clarity20.

In addition to the methodological shortcomings mentioned above, we found that a significant proportion (68.7%) of CTs registered in Spain did not publish their results in a scientific journal. This figure is similar to the results of other reviews, including that by Fincham et al., which reported a nonpublication rate of 70.1%21. It should be emphasised that failing to publicly share the results of a CT can be considered detrimental to healthcare professionals, regulatory authorities, and patients. Publication bias, whether positive or negative, hinders the accumulation of evidence.

The methodological characteristics of CTs conducted in Spain are similar to those of international research studies. Regarding design, most of the studies conducted during this period were controlled randomised CTs to ensure the internal validity of the results. One such design is exemplified by the WHO Solidarity trial8.

Regarding the treatment control arm, our results show that a placebo was used as the main comparator in 40.8% of the studies. This figure is higher than the 29.1% reported by Silva et al22.

The main barriers to the development of CTs were recruitment difficulties, lack of efficacy, and funding, much like those reported by Cook et al. in their Canadian study23. In addition to the aspects mentioned above, consideration must also be given regarding the impact of publishing the CTs conducted. Of the studies analysed, only 31.3% published their results in a scientific journal, compared to the 53% reported by Showell et al24. This percentage contrasts with the legal requirement to publish the results of CTs, whether positive or negative, as set out in current legislation7.

On the other hand, 89.2% of the published research appeared in first-quartile indexed journals. This figure is very similar to the 80% reported in the Annual Cancer Research Report25. This situation raises ethical concerns regarding data transparency, as many studies remained unfinished or as preprint repositories26. In turn, this research has the potential to influence decisions on healthcare policy. An example of this possibility was the prescription of dexamethasone to reduce mortality from SARS-CoV-2 respiratory infection as reported in the RECOVERY trial27. The failure to publish data from scientific studies can raise significant mistrust.

Various authors and health authorities have pointed out the importance of the quality of the evidence produced by these trials. London and Kimmelman28 proposed 5 conditions that clinical research must meet in the context of a health emergency in order to increase knowledge and be socially relevant. In March 2020, the European Medicines Agency and the US Food and Drug Administration published guidelines to support clinical research during the pandemic. The aim was to record any deviations from protocols and provide recommendations to ensure patient safety and maintain the integrity of CTs29,30. The AEMPS published recommendations based on the European guidelines and adapted to Spanish legislation31.

This study was subject to a number of limitations. First, the time available for reviewing the publications was limited due to the acute nature of COVID-19 infection, and the time lag between selecting the studies (August 2021) and commencing the literature search (November 2024).

Another relevant limitation was the lack of detailed information regarding the early termination of certain CTs. Some studies were suspended, cancelled, or terminated prematurely, without providing clear explanations. In such cases, the information was supplemented using the scientific publications themselves or secondary sources, such as the SCTR maintained by the AEMPS. This lack of transparency made it difficult to correctly interpret the reasons behind these decisions and their potential impact.

During the COVID-19 pandemic, Spain experienced a moderate increase in the number of CTs involving drugs, driven by the worldwide urgency to identify effective alternatives. In the first wave of the epidemic, most CTs focused on drug repurposing, with the majority being multicentre, Spanish, or sponsored by noncommercial bodies. As the pandemic progressed, research was dominated by complex, international studies involving commercial sponsors and designs focussed on new therapies.

The findings suggest that there were a substantial number of clinical studies that were never published in scientific journals. This results in research inefficiency, providing little scientific value and failing to advance knowledge, which is particularly critical in times of high uncertainty. In order to minimise lost opportunities, transparency must be improved by updating scientific registries and fulfilling the obligation to make the results publicly available. Finally, any limiting factors that could lead to failure to publish should be identified so that they can be minimised before studies are designed, funded, and scientifically evaluated. This approach can be applied in situations such as the SARS-CoV-2 pandemic as well as in routine clinical research.

All authors declare that this is an original work, has not been previously published, and is not under consideration by any other journal. They also confirm that they have each made a significant contribution to the manuscript and approved the final version. The applicable ethical standards for research have been followed. No data that could identify patients were used or published.

Tejedor-Tejada Eduardo: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Formal analysis, Data curation. González-Pérez Cristina: Writing – review & editing, Writing – original draft, Validation, Formal analysis, Data curation. Goyache Goñi María del Puy: Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation. Suñé-Martín María Pilar: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Data curation, Conceptualization. Serrano-Alonso María: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Data curation, Conceptualization. Rafael Sánchez-del Hoyo: Validation, Supervision, Methodology, Formal analysis.

None declared.

Eduardo Tejedor-Tejada: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Formal analysis, Data curation. Cristina González-Pérez: Writing – review & editing, Writing – original draft, Validation, Formal analysis, Data curation. María del Puy Goyache Goñi: Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation. María Pilar Suñé-Martín: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Data curation, Conceptualization. María Serrano-Alonso: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Data curation, Conceptualization. Rafael Sánchez-del Hoyo: Validation, Supervision, Methodology, Formal analysis.