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.

The definition of research misconduct should be stated in the abstract when reporting research on research misconduct.

Research integrity is the cornerstone for a reliable and trustworthy science. Research misconduct is classically defined as fabrication, falsification, or plagiarism. To be considered as such, the action must have been committed with the intent to mislead or deceive. There are many other research misbehaviors such as duplication, fake-peer review or lack of disclosure of conflicts of interest, that are often included in the definition of research misconduct in codes, policies, and professional documents. The definition of research misconduct varies among countries and institutions, the seriousness and intentionality of the action. This variability is also present in research articles on the prevalence of research misconduct because it is common for each author to use a different definition, creating confusion for readers. We argue that the definition of research misconduct used in a study should be stated already in the abstract, particularly because not all publications are in open access, so that readers can fully understand what the study found concerning research misconduct without needing to have access to the full article.

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.

Adaptive, platform trials assessing therapies for hospitalized COVID-19 patients: Informed consent forms omitted a few important elements of information.

Background: The information provided to participants of adaptive platform trials assessing therapies for COVID-19 inpatients is unknown. We aim to evaluate it by reviewing participant information sheets/informed consent forms (PIS/ICFs). Methods: We searched the Cochrane COVID-19 Study Register and ClinicalTrials.gov (28 March 2022) to identify non-industry-sponsored adaptive platform phase 2+ trials with publicly available protocols and PIS/ICFs, selecting versions closest to the initial one. We assessed the elements of information included in the Good Clinical Practice guidelines and the Declaration of Helsinki as present, absent, or deficient (incompletely described). Results: We included PIS/ICFs of 11 trials (ACCORD-2, ACTIV-1IM, Bari-SolidAct, CATALYST, Discovery, HEAL-COVID, ITAC, RECOVERY, REMAP-COVID, Solidarity and TACTIC-R), which were 4-32 pages long (median (md) = 11). Between two and 11 (md = 6) of the 25 different elements of information assessed were omitted or deficiently described in the PIS/ICFs of the 11 trials. Information about providing trial results, investigators' conflicts of interest, post-study provisions, payment to and anticipated expenses for participants, number of participants, and on whether participants will receive new information that could impact their decision on staying in the trial, were omitted or deficiently described in at least five PIS/ICFs. Conclusions: Investigators failed to include a few important elements of information in the trial's PIS/ICF deemed relevant by international standards. In protocols of future trials, investigators should explain why elements of information specified in the Good Clinical Practice guidelines and/or by the Declaration of Helsinki were omitted from the PIS/ICFs.

How WHO Solidarity Plus trial participants in countries on four continents are informed in writing.

Background: It is unknown if changes have been made to the original participant's information sheet/informed consent form (PIS/ICF) provided by the WHO Solidarity Plus team when it was transferred to participating countries. Methods: National principal investigators from 30 countries were asked if the original PIS/ICF was edited in their countries and, if so, to share with us the one used to recruit participants. We assessed whether the 25 different elements of information from the good clinical practice guidelines and the Declaration of Helsinki were present in, deficiently described, or absent from the PIS/ICFs. Results: Nineteen national principal investigators responded: eight (Argentina, Brazil, Ethiopia, Georgia, Iran, Lebanon, Lithuania, and Malaysia) stated that no edits were introduced to the original PIS/ICF; eight (Canada, Colombia, Philippines, India, Ireland, Pakistan, Portugal, and Switzerland) added some elements of information in the national PIS/ICF; and three (Italy, Peru, and Spain) reported not participating in the trial. None of the elements included in the original PIS/ICF were omitted from the edited PIS/IFC. Six elements of information were omitted and five deficiently described in the original PIS/ICF. The number of elements omitted from the edited PIS/ICFs varied (range = 2-5). Nine PIS/ICFs incompletely described or omitted the informing of study participants about the study results, while five deficiently described or omitted the anticipated expenses for trial participation. Information concerning whom to contact for more information or in case of injury was deficient in six PIS/ICFs. Unlike the original PIS/ICF, all edited PIS/ICFs informed participants about the existence of compensation or treatment for any injury related to the trial. Conclusions: WHO should consider adding three of the omitted elements in PIS/ICFs of future multinational similar trials.