The winding 12-month journey of the AstraZeneca COVID-19 vaccine since its first administration to humans.

The deficiently designed and conducted initial clinical development plan and the occurrence of thrombotic thrombocytopenia cases, have marked the 12-month journey of the AstraZeneca coronavirus disease 2019 (COVID-19) vaccine after it was first administered to humans. When it was authorized, there were no available efficacy data in the elderly. However, this age group was included in the product labelling based on immunogenicity data. The lack of safety and efficacy data in the elderly that was acknowledged in the product information, triggered most European Union (EU) countries to limit the administration of this vaccine to certain age groups. In February-March/2021, after the results of observational studies supported the vaccine effectiveness in the elderly, several countries broadened its use to this age group. When trust on the vaccine was ramping up, unusual blood clot cases were described in Europe, which led 24 countries around the world to temporarily halt its administration. These cases were first described as thrombotic thrombocytopenia in late March. In mid-April, the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) updated the product information and confirmed the positive benefit/risk ratio of the vaccine, recommending its use with no age restrictions. The World Health Organization (WHO) coincided with this approach. However, several countries decided to limit its use to certain age groups. The EMA listed thrombotic thrombocytopenia as a "very rare" adverse reaction. Although, the AstraZeneca vaccine was conceived in early 2020 to be a worldwide leader in the fight against COVID-19, its use was abandoned by the African Union, Denmark, and Israel. However, this vaccine has shown its usefulness in many settings across the world.

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.

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.

High heterogeneity on the accepted vaccines for COVID-19 certificates in European countries.

BACKGROUND: We aimed to elucidate which vaccines were accepted by European countries as valid proof of vaccination against COVID-19 for international travelers. METHOD: On 27-September-2021 a cross-sectional study was conducted on VisaGuide.World, that reports on valid vaccines for international travelers. Other databases, lay press and regulatory agencies were also checked. The main outcome measure was which of the vaccines included on the WHO emergency use listing (EUL) [ChAdOx1 (Vaxzevria, Covishield),BNT162b2,mRNA-1273,Ad26.CoV2.S,BBIBP-CorV,CoronaVac] and Sputnik V, were accepted in each country. The influence of the vaccines approved for COVID-19 vaccination programs on the vaccines recognized as proof of vaccination was assessed. RESULTS: There was a remarkable heterogeneity on the vaccines accepted as proof of vaccination among 46 countries. Russia accepted only one. Cyprus, Greece and Slovenia accepted all vaccines considered. Eleven countries accepted the seven WHO EUL vaccines: eight EU countries, plus Iceland, Norway and Switzerland. Seven EU countries accepted only the four EMA-authorized vaccines. Considering Covishield as equivalent to Vaxzevria, 69% of countries recognized only vaccinated travelers who received any of the vaccines approved for vaccination programs in the country of arrival as valid. CONCLUSION: Vaccines accepted as proof of vaccination should be harmonized. Accepting any of the WHO EUL vaccines would be a scientifically sound objective.

Availability of oral antivirals against SARS-CoV-2 infection and the requirement for an ethical prescribing approach.

The first two oral antivirals, molnupiravir and nirmatrelvir-ritonavir, are now becoming available in many countries. These medicines will be indicated to treat mild-to-moderate COVID-19 in non-hospitalised patients who are at high risk of progressing to severe COVID-19. These antivirals should be prescribed within 5 days of symptom onset, and after SARS-CoV-2 infection has been confirmed. However, the availability of these antivirals will be scarce for some time due to manufacturing constraints. Each country should establish a policy on the conditions under which these antivirals can be prescribed. Such a policy should be based on the fulfilment of five ethical elements: transparency, relevance, appeals, enforcement, and fairness. Following the principles of distributive justice, molnupiravir and nirmatrelvir-ritonavir should be prescribed according to a hierarchy of predicted efficacy, ideally on the basis of an evidence-based scoring system. The placebo-controlled randomised trials that supported the temporary authorisation of these two antivirals were conducted in unvaccinated patients with COVID-19, so an evidence-based prescription practice would only use these drugs for unvaccinated patients until further data become available. However, in the countries that authorised these antivirals in 2021 (the UK and the USA), both vaccinated and unvaccinated patients meeting particular requirements have access to these antivirals. Due to the complexity of prioritisation, national health authorities should start issuing their draft policies as soon as possible and these policies should be regularly updated. The effectiveness of these antivirals against the omicron variant of SARS-CoV-2 must be urgently assessed. Once implemented, molnupiravir and nirmatrelvir-ritonavir must show their effectiveness and safety in the real world, and health systems must be adequately adapted for the correct use of these antivirals.

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.

Ongoing and future COVID-19 vaccine clinical trials: challenges and opportunities.

Large-scale deployment of COVID-19 vaccines will seriously affect the ongoing phases 2 and 3 randomised placebo-controlled trials assessing SARS-CoV-2 vaccine candidates. The effect will be particularly acute in high-income countries where the entire adult or older population could be vaccinated by late 2021. Regrettably, only a small proportion of the population in many low-income and middle-income countries will have access to available vaccines. Sponsors of COVID-19 vaccine candidates currently in phase 2 or initiating phase 3 trials in 2021 should consider continuing the research in countries with limited affordability and availability of COVID-19 vaccines. Several ethical principles must be implemented to ensure the equitable, non-exploitative, and respectful conduct of trials in resource-poor settings. Once sufficient knowledge on the immunogenicity response to COVID-19 vaccines is acquired, non-inferiority immunogenicity trials-comparing the immune response of a vaccine candidate to that of an authorised vaccine-would probably be the most common trial design. Until then, placebo-controlled, double-blind, crossover trials will continue to play a role in the development of new vaccine candidates. WHO or the Council for International Organizations of Medical Sciences should define an ethical framework for the requirements and benefits for trial participants and host communities in resource-poor settings that should require commitment from all vaccine candidate sponsors from high-income countries.