Challenges in conducting efficacy trials for new COVID-19 vaccines in developed countries.

The protection from COVID-19 vaccination wanes a few months post-administration of the primary vaccination series or booster doses. New COVID-19 vaccine candidates aiming to help control COVID-19 should show long-term efficacy, allowing a possible annual administration. Until correlates of protection are strongly associated with long-term protection, it has been suggested that any new COVID-19 vaccine candidate must demonstrate at least 75% efficacy (although a 40%-60% efficacy would be sufficient) at 12 months in preventing illness in all age groups within a large randomized controlled efficacy trial. This article discusses four of the many scientific, ethical, and operational challenges that these trials will face in developed countries, focusing on a pivotal trial in adults. These challenges are (1) the comparator and trial population; (2) how to enroll sufficient numbers of adult participants of all age groups considering that countries will recommend COVID-19 booster doses to different populations; (3) whether having access to a comparator booster for the trial is actually feasible; and (4) the changing epidemiology of severe acute respiratory syndrome coronavirus 2 across countries involved in the trial. It is desirable that regulatory agencies publish guidance on the requirements that a trial like the one discussed should comply with to be acceptable from a regulatory standpoint. Ideally, this should happen even before there is a vaccine candidate that could fulfill the requirements mentioned above, as it would allow an open discussion among all stakeholders on its appropriateness and feasibility.

Posting of clinical trial results and other critical information from completed medicines trials on ClinicalTrials.gov.

PURPOSE: Clinical trials transparency requires trial registration and the posting of results on a public register. US regulations also require the posting of protocols and statistical analysis plans (SAPs). For US Federal agency funded trials to be started on or after 21 January 2019, informed consent forms (ICFs) must also be posted. Posting these documents is not mandatory in other countries. We aimed to assess compliance with US regulations of trials conducted in the US or in other countries with respect to ICFs, protocols, SAPs, and results. METHODS: This cross-sectional analysis (27 April 2023) comprised completed medicines trials to be started on or after 21 January 2019 registered on ClinicalTrials.gov. Trial data were registered by funder type (i.e., 'US federal agencies', industry, and 'all others') and development phase. RESULTS: Of 5,584 trials, 40% were conducted solely in the US. 47% and 12% of US and non-US trials had posted results. Some 40% of US trials had posted protocols and SAPs as did 9% of trials conducted in other countries. Only 10% (US) and 2% (other countries) of trials had posted ICFs. When the margin of the last 2 and 12 months after primary completion date were considered in the analysis, ICF posting rate did not change, but posting results increased to 64% for US trials. 'US Federal agencies' funded trials were significantly more likely to post ICFs than industry [OR 23.9 (12.5-45.7; <.001)] or 'all others' [OR 3.16 (1.79-5.56; <.001)]. CONCLUSION: Future interventions should be considered to encourage timely posting of trial results and information.

Equipoise, standard of care and consent: responding to the authorisation of new COVID-19 treatments in randomised controlled trials.

In response to the COVID-19 pandemic, large-scale research and pharmaceutical regulatory processes have proceeded at a dramatically increased pace with new and effective, evidence-based COVID-19 interventions rapidly making their way into the clinic. However, the swift generation of high-quality evidence and the efficient processing of regulatory authorisation have given rise to more specific and complex versions of well-known research ethics issues. In this paper, we identify three such issues by focusing on the authorisation of molnupiravir, a novel antiviral medicine aimed at reducing the ability of SARS-CoV-2 to multiply in the body, for clinical use by the National Health Service in England and the concomitant testing of molnupiravir through the large-scale Platform Adaptive trial of Novel antiviRals for eArly treatMent of COVID-19 In the Community randomised control trial. By analysing the ways in which the authorisation and clinical use of molnupiravir complicate standard approaches to clinical equipoise, standard of care and participant consent in the PANORAMIC randomised control trial, we will explain some of ethical implications for clinical trials that aim to study the efficacy and safety of new COVID-19 and other therapeutics when conditional authorisation has already been granted and when such treatments have already been made available to patients by national health providers.

Heterologous COVID-19 Vaccination in Spain: A Case Study of Individual Autonomy in the Real World.

In Spain, 1.5 million essential < 60-year-old workers were vaccinated with a first AstraZeneca vaccine dose. After assessing the cases of thrombosis with thrombocytopenia associated to this vaccine, the European Medicines Agency (EMA) supported the administration of 2 doses of the AstraZeneca vaccine with no age restrictions. Nevertheless, Spain decided not to administer the second dose of this vaccine to < 60-year-olds. The government sponsored a clinical trial (CombiVacS) to assess the immunogenicity response to a Pfizer/BioNTech vaccine dose in adults primed with the AstraZeneca vaccine. The positive results backed the Public Health Commission and the Spanish Ministry of Health to offer the Pfizer/BioNTech vaccine as the booster. Nevertheless, regional public health authorities-responsible for administering vaccines-believed that, following the EMA's decision, an AstraZeneca booster dose should be given. The public confrontation of these 2 positions forced the Spanish Health Ministry to request the signature of an informed consent form to those individuals willing to receive the AstraZeneca vaccine booster and rejecting the Pfizer/BioNTech vaccine dose. Eventually, it was decided that these essential workers could choose the vaccine but signing an informed consent form. All relevant information was posted on the Ministry of Health and regional health authorities' websites and provided to potential vaccine recipients at vaccination sites. Most individuals (≥ 75%) chose the AstraZeneca vaccine: perhaps because they likely trusted the EMA more than the CombiVacS results. This unprecedented and massive exercise of individual autonomy about the choice of COVID-19 vaccines from 2 different platforms has shown that adequately informed persons can autonomously weigh their options, regardless of government decisions. Exercising individual autonomy may contribute to the success of future COVID-19 booster vaccination campaigns.

The PRECIS-2 tool seems not to be useful to discriminate the degree of pragmatism of medicine masked trials from that of open-label trials.

PURPOSE: To assess, with all available trial information, whether the assessment of the PRECIS-2 nine domains could provide a clear distinction between medicine masked pragmatic randomized controlled trials (pRCTs) and open-label pRCTs. METHODS: A search was conducted of participant-level pRCTs on medicines published on 25 influential medical journals in July 2018-December 2019. All pre-licensing (phases 1-3) and cluster pRCTs were excluded. All trials' available reports were searched through the published article information, Google Scholar, and trial websites. Instead of providing a score to each PRECIS-2 domain, these were classified as E (explanatory), N (neutral), or P (pragmatic). RESULTS: Of 128 pRCTs, 18 (14%) were participant-level pRCTs on medicines. The full trial protocol was available for 14 trials; 12 had published the protocol and nine had additional reports published. All trials were prospectively registered, and none was funded by industry. Ten and eight were masked and open-label trials, respectively. Masked pRCTS had 34% of pragmatic and 60% of explanatory domains; open-label pRCTS had 45% pragmatic and 45% explanatory domains. Among the 10 masked trials, only one had a majority of five pragmatic domains; among the eight open-label trials, four had a majority of six or five pragmatic domains. "Follow-up" was considered explanatory in the 18 pRCTs; "primary analysis" was pragmatic in 17 pRCTs. CONCLUSION: The PRECIS-2 tool seems not to be sensitive enough to clearly discriminate between medicine masked pRCTs and open-label pRCTs. When conducting systematic reviews, it is suggested that the PRECIS-2 tool should not be used to support placing masked trials in the pragmatic side of the explanatory/pragmatic continuum.

Articles provided insufficient information to conduct an appropriate retrospective assessment of the pragmatic/explanatory features of medicine trials with the PRECIS-2 tool.

PURPOSE: To assess whether, in the retrospective assessment of the pragmatic/explanatory features of pragmatic randomized controlled trials (pRCTs), the nine PRECIS-2 domain scores using the information provided in articles were modified after using the information reported in other publicly available sources. METHODS: This is a cross-sectional study of participant-level pRCTs published in July 2018 to December 2019 in the four highest-impact general medicine journals. The articles described the main results of pRCTs assessing medicines in one or more arms that were not in the pre-licensing phases. The information reported in trial full protocols, published protocols, and other publications, registries, and trial websites were assessed and scored, and compared with that previously obtained after reviewing the information reported in the articles. RESULTS: Out of 76 articles on pRCTs, 13 (17%) were included in the analysis. All were two-arm trials, assessing medicines only (n = 7), medicine vs device (n = 2), medicine vs surgery (n = 1), or medicine vs placebo (n = 3). Seven were open-label trials, and six had any type of masking. All except one had the full protocol available and/or published protocol; seven had other types of publication available. The assessment of the nine PRECIS-2 domains with the information reported in the 13 articles was changed in all trials after using the information included in other additional available sources. Between one (n = 1 article) and six (n = 2) domains were modified in each pRCT. The domains that most commonly changed were "organization" (n = 12), "recruitment" (n = 11), and "follow-up" (n = 8). "Primary outcome" and "primary analysis" were not modified in any trial. Eight percent of all domains could not be assessed due to inadequate or lack of information in seven articles; those were "recruitment" (n = 3), "organization" (n = 3), "setting" (n = 2), and "flexibility:adherence" (n = 1). CONCLUSION: Articles describing the trial main results are usually insufficient for the appropriate retrospective assessment of the pragmatic/explanatory features of a pRCT by authors not involved in the conduct of the trial. To address this issue, editors should require the submission of the original full protocol and final full protocol with the history of amendments to be published as supplementary material to the article.

Reasons for and time to retraction of genetics articles published between 1970 and 2018.

INTRODUCTION: Between 0.02% and 0.04% of articles are retracted. We aim to: (a) describe the reasons for retraction of genetics articles and the time elapsed between the publication of an article and that of the retraction notice because of research misconduct (ie, fabrication, falsification, plagiarism); and (b) compare all these variables between retracted medical genetics (MG) and non-medical genetics (NMG) articles. METHODS: All retracted genetics articles published between 1970 and 2018 were retrieved from the Retraction Watch database. The reasons for retraction were fabrication/falsification, plagiarism, duplication, unreliability, and authorship issues. Articles subject to investigation by company/institution, journal, US Office for Research Integrity or third party were also retrieved. RESULTS: 1582 retracted genetics articles (MG, n=690; NMG, n=892) were identified . Research misconduct and duplication were involved in 33% and 24% of retracted papers, respectively; 37% were subject to investigation. Only 0.8% of articles involved both fabrication/falsification and plagiarism. In this century the incidence of both plagiarism and duplication increased statistically significantly in genetics retracted articles; conversely, fabrication/falsification was significantly reduced. Time to retraction due to scientific misconduct was statistically significantly shorter in the period 2006-2018 compared with 1970-2000. Fabrication/falsification was statistically significantly more common in NMG (28%) than in MG (19%) articles. MG articles were significantly more frequently investigated (45%) than NMG articles (31%). Time to retraction of articles due to fabrication/falsification was significantly shorter for MG (mean 4.7 years) than for NMG (mean 6.4 years) articles; no differences for plagiarism (mean 2.3 years) were found. The USA (mainly NMG articles) and China (mainly MG articles) accounted for the largest number of retracted articles. CONCLUSION: Genetics is a discipline with a high article retraction rate (estimated retraction rate 0.15%). Fabrication/falsification and plagiarism were almost mutually exclusive reasons for article retraction. Retracted MG articles were more frequently subject to investigation than NMG articles. Retracted articles due to fabrication/falsification required 2.0-2.8 times longer to retract than when plagiarism was involved.

Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic?

INTRODUCTION: Pragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as "pragmatic" or "naturalistic". We focused on 89 of these trials that assessed medicines (drugs or biologics). DISCUSSION: 36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term 'pragmatic' to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as 'pragmatic' and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic). CONCLUSIONS: To allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real-world practice.

Public preferences on written informed consent for low-risk pragmatic clinical trials in Spain.

AIMS: Pragmatic randomized clinical trials (pRCTs) collect data that have the potential to improve medical care significantly. However, these trials may be undermined by the requirement to obtain written informed consent, which can decrease accrual and increase selection bias. Recent data suggest that the majority of the US public endorses written consent for low-risk pRCTs. The present study was designed to assess whether this view is specific to the US. METHODS: The study took the form of a cross-sectional, probability-based survey, with a 2 × 2 factorial design, assessing support for written informed consent vs. verbal consent or general notification for two low-risk pRCTs in hypertension, one comparing two drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. The primary outcome measures were respondents' personal preference and hypothetical recommendation to a research ethics committee regarding the use of written informed consent vs. the alternatives. RESULTS: A total of 2008 adults sampled from a probability-based online panel responded to the web-based survey conducted in May 2016 (response rate: 61%). Overall, 77% of respondents endorsed written consent. In both scenarios, the alternative of general notification received significantly more support (28.7-37.1%) than the alternative of verbal consent (12.7-14.0%) (P = 0.001). Forty per cent of respondents preferred and/or recommended general notification rather than written consent. CONCLUSIONS: The results suggested that, rather than attempting to waive written consent, current pRCTs should focus on developing ways to implement written consent that provide sufficient information without undermining recruitment or increasing selection bias. The finding that around 40% of respondents endorsed general notification over written consent raises the possibility that, with educational efforts, the majority of Spaniards might accept general notification for low-risk pRCTs.

Patients' beliefs regarding informed consent for low-risk pragmatic trials.

BACKGROUND: The requirement to obtain written informed consent may undermine the potential of pragmatic randomized clinical trials (pRCTs) to improve evidence-based care. This requirement could compromise trials statistical power or even force it to close them down prematurely. However, recent data from the U.S. and Spain suggest that a majority of the public endorses written consent for low-risk pRCTs. The present manuscript assesses whether this view is shared by patients. METHODS: This was a cross-sectional, probability-based survey, with a 2 × 2 factorial design, assessing support for written informed consent versus verbal consent or general notification for two low-risk pRCTs in hypertension, one comparing 2 drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. This web-based survey was conducted in May 2016. Two-thousand and eight adults who were representative of the Spanish population participated in the survey (response rate: 61%). Of these 2008 respondents, 338 indicated that they had been diagnosed with hypertension and were being treated with prescription medicines for this condition at the time of responding to the survey. The primary outcome measures were respondents' personal preference and recommendation to a research ethics committee regarding the use of written informed consent versus verbal consent or general notification. RESULTS: Overall, 74% of the 338 patient respondents endorsed written consent. In both scenarios, general notification received significantly more support (30.6%-44.7%) than verbal consent (13.3%-17.6%). 43% of respondents preferred and/or recommended general notification rather than written consent. CONCLUSIONS: As in the survey of the general public, more patients endorsed written consent than the alternative option. However, two factors suggest that a different approach to written consent should be investigated for low-risk pRCTs: a) a substantial minority of respondents supported general notification, b) data from the US have shown that most patients who prefer written consent are willing to forego it if obtaining written consent makes the trial too difficult to be conducted; and c) 2016 CIOMS guidelines endorse waivers of consent when the trial fulfills specific conditions. Surveys in other EU countries are needed to assess what patients believe towards pRCTs. If similar results to that reported in this study are found, it is foreseeable that with educational efforts, general notification could be an acceptable and widespread approach to the conduct of low-risk pRCTs.