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Intro: VLA2001 is a highly-purified, inactivated whole-virus SARS-CoV-2 vaccine based on a dual-adjuvant system of Alum and CpG1018 for induction of a robust immune response. The vaccine was designed using a well-established technology platform and has received full marketing authorization in Europe. In a pivotal Phase 3 trial, VLA2001 demonstrated superior neutralizing antibody geometric mean titers (GMT) to the comparator, AstraZeneca's AZD1222, as well as non-inferior seroconversion rates two weeks after priming. The extension of the Phase 3 trial evaluated safety and immunogenicity of homologous and heterologous booster vaccinations of VLA2001. Method(s): This is a randomized observer-blind controlled, pivotal trial conducted in the UK in participants aged >=18 years who were randomly assigned 2:1 to receive two doses of VLA2001 or AZD1222, 28 days apart. A booster with VLA2001 was administered to eligible participants at 7 to 8 months after priming. The primary safety outcome was the frequency and severity of any adverse event following the booster vaccination. The primary immunogenicity outcomes were the GMT and fold increase of neutralizing antibodies against SARS-CoV-2 two weeks after the booster vaccination. The study is registered under NCT04864561. Finding(s): A booster dose of VLA2001 is well-tolerated in both AZD1222 and VLA2001 primed participants. High neutralizing antibody titers and fold- increases were generated two weeks following a booster of VLA2001. Cross- neutralizing serological responses against Delta and the Omicron BA.4/BA.5 variants of concern are elicited following a homologous or heterologous booster dose in VLA2001 or AZD1222 primed participants, respectively. Additionally, VLA2001 induced broad T-cell responses with antigen-specific IFN-gamma producing T-cells against the Spike, the Nucleocapsid and the Membrane protein. Conclusion(s): Homologous and heterologous booster doses of VLA2001 demonstrated a favorable tolerability profile irrespective of priming and induced broadly reactive neutralizing antibodies against the ancestral virus and variants of concern, including the currently circulating BA.4/BA.5.Copyright © 2023
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One aspect that is of great interest and subject to debate among European (EU) inspectors is the risk-based approach adopted to determine which marketing authorization holders (MAHs) should be inspected before others. As per GVP module III, pharmacovigilance inspection planning should be based on systematic and risk-based approach methodologies. Nevertheless, these evaluations shall be the result of cooperation between national competent authorities and the European Medicines Agency (EMA) to avoid duplications wherever possible and to maximize the use of the available resources to achieve common goals. As of today, a risk-based approach is used for inspection planning by all Member States (MSs), most relying on data collected by means of customized national risk-assessment questionnaires and by information which may be already available at the Agency's premises [e.g. data from PSMF, PSUR, signals, assessors, EudraVigilance, XEVMPD, National databases, number and type of Marketing Authorizations (MAs) and Company's portfolio changes from last inspection, number of critical deviations detected in the last inspection conducted]. During the COVID-19 pandemic, onsite inspections were stopped and, taking into account national and European legislation, the AIFA's Inspection offices revised their way to conduct inspections by implementing distant assessments for good manufacturing practice (GMP) and remote inspections for good pharmacovigilance practice (GVP) and good clinical practice (GCP) (Phase 1 facilities, Sponsor/CROs). In these circumstances, distant assessments and remote inspections can represent a suitable means to verify compliance against the different GMP, GCP and GVP applicable requirements. During the COVID-19 pandemic pharmacovigilance inspections continued, though some required adjustments to the inspection plans which had been prepared before the COVID-19 emergency (e.g. plans previously established for the years 2019 and 2020). The remote inspection capabilities were developed fairly quickly and each inspectorate developed an internal procedure to support this kind of inspection. In many instances, MAHs and third parties involved in their PV systems were shown to be ready to sustain these remote inspections with great professionalism and preparation. Under these circumstances, the inspectors were able to successfully complete the inspection as per the full planned agenda in the same way as the inspection would have been conducted if it were on site. It is worth noting that no specific findings or clear changes (e.g. number, category and classification of findings) were detected that could be considered directly attributable to the remote nature of the conducted inspections. This result further confirms that the risk-based approaches used by AIFA to prepare annual inspection plans worked properly to tackle these remote inspection modalities, allowing the identification of criticalities of pharmacovigilance systems in use at the MAHs in the same way they would have been detected if the inspections were on site. The majority of the detected findings regarded the management of ADRs and computerized systems, followed by deviations concerning the PSMF, the quality system, audit, training, standard operating procedures and signal management.
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EudraVigilance, as a system for managing and analysing information on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area, is always improving and changing to comply with the latest trends as well as applicable regulatory guidelines. In recent years, the system faced multiple challenges: continuous implementation of E2B(R3) standards for reporting;introduction of EVDAS access for Marketing Authorization Holders and of course the COVID-19 pandemic, which resulted in an enormous surge in reports coming into the system, as well as increased demand of public access to data via the ADR reports portal. Since the access to EVDAS has been granted to MAHs, there was a limit of five users per organization. Due to the stabilization of the system, this has now been increased to 10. Another new rule is the implementation of European Directorate for the Quality of Medicines & HealthCare (EDQM) codes for pharmaceutical dose forms and route of administration while reporting ICSRs. This poses a certain challenge for organizations, as they need to download and implement the terms onto their databases on a periodic basis. Changes to Article 57 Database (XEVMPD), another component of EudraVigilance, are also worth mentioning. While the information about medicinal products is preparing for transition to ISO IDMP standards, MAHs and Sponsors still have the obligation to send information about authorized and development medicinal products to XEVMPD. The platform runs on an older version of the Internet Explorer browser, which Microsoft stopped providing support for in June 2022. The European Medicines Agency provided a workaround using Microsoft Edge or by downloading extensions for other browsers that emulate the Internet Explorer mode. Not only EudraVigilance is being updated and modernized, internal EMA tools such as Service Desk are also keeping up with the pace and are being transferred from their current JIRA platform to ServiceNow (SNOW). We also cannot forget the changes post Brexit. MAHs are using the ICSR Submission Portal for transmission of ICSRs to MHRA, and since the beginning of October 2022, SUSARs from Clinical Trials are also submitted via this portal.
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At the end of 2019, an outbreak of a new coronavirus began in the city of Wuhan (Hubei Province) in the People's Republic of China. The outbreak turned into a pandemic. In the shortest possible time, national and international manufacturers developed preventive COVID-19 vaccines, and the population was vaccinated. During pandemics, accelerated approval of vaccines is an important factor that shortens the time to market with the aim of mass vaccination. The experience of rapidly developing and introducing vaccines into routine practice is not only important for managing the current pandemic, but also valuable in case of extremely likely future ones. The aim of this study was to analyse the main issues associated with assessing the safety and efficacy of vaccines for COVID-19 prevention during their registration and widespread use amid the pandemic and ongoing SARS-CoV-2 evolution. The vaccines for COVID-19 prevention were developed and introduced into healthcare practice very rapidly and under the circumstances of the pandemic, and the use of these vaccines has surfaced a number of concerns requiring further research. The most important issues identified in the performed analysis include, but are not limited to the need for accelerated assessment of the safety and immunogenicity of new vaccines;the lack of immune correlates of protection against SARS-CoV-2;the waning of antibody immunity over time, motivating the need to determine revaccination and post-recovery vaccination timelines;and the emergence of mutant SARS-CoV-2 variants. One of noteworthy aspects is the need to develop recommendations for updating the strain composition of registered COVID-19 vaccines. According to the conclusions, the level of herd immunity, including vaccine-induced protection, plays a certain role in virus evolution during the pandemic. If COVID-19 becomes seasonal, which is a probable scenario, regular revaccination can be essential.Copyright © 2023 Safety and Risk of Pharmacotherapy. All rights reserved.
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The rapid spread of SARS-CoV-2 worldwide has triggered intense activity in the field of biotechnology, leading to the development and regulatory approval of multiple COVID-19 vaccines in less than 1 year while raising sustained scrutiny as to the ethical issues associated with this process. This article pursues a twofold objective. First, it reconstructs and provides a thorough overview of the different steps, from clinical trial design to regulatory procedures, underpinning the "fast-tracking" of COVID-19 vaccine R&D and approval. Second, drawing on a review of published literature, the article identifies, outlines, and analyzes the most ethically challenging aspects related to such process, including concerns around vaccine safety, issues in study design, the enrollment of study participants, and the challenges in obtaining valid informed consent. By scrutinizing relevant aspects of COVID-19 vaccine development and regulatory processes leading to market authorization, this article ultimately aims to provide a comprehensive overview of the regulatory and ethical issues underpinning the roll-out of this key pandemic-containment technology worldwide.
Subject(s)
COVID-19 , Vaccines , Humans , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , SARS-CoV-2 , PandemicsABSTRACT
At the end of 2019, an outbreak of a new coronavirus began in the city of Wuhan (Hubei Province) in the People's Republic of China. The outbreak turned into a pandemic. In the shortest possible time, national and international manufacturers developed preventive COVID-19 vaccines, and the population was vaccinated. During pandemics, accelerated approval of vaccines is an important factor that shortens the time to market with the aim of mass vaccination. The experience of rapidly developing and introducing vaccines into routine practice is not only important for managing the current pandemic, but also valuable in case of extremely likely future ones. The aim of this study was to analyse the main issues associated with assessing the safety and efficacy of vaccines for COVID-19 prevention during their registration and widespread use amid the pandemic and ongoing SARS-CoV-2 evolution. The vaccines for COVID-19 prevention were developed and introduced into healthcare practice very rapidly and under the circumstances of the pandemic, and the use of these vaccines has surfaced a number of concerns requiring further research. The most important issues identified in the performed analysis include, but are not limited to the need for accelerated assessment of the safety and immunogenicity of new vaccines;the lack of immune correlates of protection against SARS-CoV-2;the waning of antibody immunity over time, motivating the need to determine revaccination and post-recovery vaccination timelines;and the emergence of mutant SARS-CoV-2 variants. One of noteworthy aspects is the need to develop recommendations for updating the strain composition of registered COVID-19 vaccines. According to the conclusions, the level of herd immunity, including vaccine-induced protection, plays a certain role in virus evolution during the pandemic. If COVID-19 becomes seasonal, which is a probable scenario, regular revaccination can be essential.
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Objectives: In France, patients can benefit an early access to innovation, ahead of the marketing authorization or final reimbursement since 1992. This early access program (EAP) was reformed on July 1, 2021. As of this date, the eligibility criteria, the timelines and the process have evolved. Now, EAP is assessed by the Haute Autorite de Sante (HAS) including the Transparency Committee (TC), which is responsible of reimbursement decision. Our study consisted of a descriptive analysis of EAP first decisions. Method(s): We conducted a retrospective analysis of all HAS decisions published between July 1, 2021 and Avril 21, 2022. Result(s): Among 46 EAP decisions published, 37% concerned medicines without marketing authorization (MA) and 63% concerned medicines with a MA. The most represented therapeutic area was oncology (46%) and 17% decisions were related to COVID-19 therapies. The average time from dossier submission to EAP decision publication was 69 days, with an increasing trend in 2022 compared to 2021 (85 vs 43 days). Most evaluated medicines (65%) had comparative phase III results at the time of their evaluation. The main reasons for denying an EAP were the lack of a presumption of innovation (18%), the identification of appropriate comparators (16%), and the lack of a presumption of efficacy and safety (15%). EAP was granted for 37/46 (79%) of treatments. Of these, 25/37 medicines were evaluated for reimbursement in France. The TC granted ASMR III (12/37), ASMR IV (3/37) and AMSR V (6/37). Conclusion(s): Since the reform, evaluation for EAP is conducted according to TC requirements and became a very important preparatory step for reimbursement. Pharmaceutical companies must ensure consistency between EAP and reimbursement dossiers and think about their market access strategy earlier. Copyright © 2022
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Objectives: To review and analyze the new early access authorization program in France launched in July 2021. Method(s): Treatments that were processed under the early access authorization program between July 2021 and June 2022 were analyzed. The assessments were examined for therapy area, processing timeline, and data used in the evaluation. Result(s): As of 30 June 2022, 55 of the 66 decisions (83%) that have been published by HAS were granted early access, and 11 (17%) applications were refused. Among those granted early access, 37 (67%) already had a marketing authorization (MA), of which 25 (68%) had conditional MA and 11 (30%) were granted orphan status;18 (33%) applied to the program before obtaining regulatory approval (pre-MA). Among the treatments granted early access after MA, one received ASMR II, 15 received ASMR III, 2 Received ASMR IV, 5 received ASMR V rating, and 13 had not been evaluated for the indication. The average time taken for the processing of all applications (receipt of complete file to date of adoption) was 65 days (range, 1-121);mean time for ANSM opinion on the product's presumed efficacy and safety in the absence of MA was 55 days (range, 4-112). Oncology drugs accounted for 21 (39%) of applications. Most decisions were based on phase 2-3 clinical data for technologies with or without MA. Only two positive, pre-MA early access authorization requests used phase 1 clinical data for treatments indicated in pre-exposure prophylaxis of coronavirus 2019 and unresectable or metastatic triple-negative breast cancer. Contributions from stakeholders, including patient and user groups, were involved in 39 (59%) applications (both pre-MA and post-MA). Conclusion(s): Overall, the time taken to evaluate the early access applications is significantly lower compared with the 3-month examination period stipulated by the program, facilitating a quick access to patients with high unmet need. Copyright © 2022
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Objectives: The publication of the French Social Security Financing Act for 2021 enacted the reform of the authorizing procedure for early and derogatory access to medicinal products by regrouping former derogatory access processes into 2 distinct pathways: pre/post-marketing authorization early access (EA) and compassionate access. The reform is effective since July 2021 and the HAS (Haute Autorite de Sante) is now responsible for evaluating EA requests based on a set of pre-defined criteria. We aimed at analyzing all EA opinions issued by the HAS since July 2021. Method(s): A review of HAS early access opinions was conducted. All published opinions since the reform was implemented and up to March 2022 were included. Outcomes of interest included: number of positive opinions, therapeutic areas, percentage of eligibility criteria met, market authorization (MA) status, indication, and mean/median review time. Result(s): A total of 34 opinions was extracted with the main therapeutic areas being oncology (n=12;35%), infectiology (n=11;32%, of which 10 were related to COVID-19) and rare diseases (n=4;12%). Additionally, 13 requests (38%) were submitted pre-MA and 21 (62%) post-MA. Out of the 34 opinions, 26 were approved (76%), with a mean/median time of 53/51 days (56/55 days when excluding infectiology-related opinions) and 8 were rejected (24%), with a mean/median time 56/51 days (62/54 days when excluding infectiology-related opinions). All approved opinions matched the 'severe disease' and 'invalidating' criteria, and only 65%, 88% and 96% matched the 'rare disease', 'no existing treatment' and 'innovation' criteria respectively. Conclusion(s): The reform allows for a faster access to treatment for patients. The reform will also improve HAS review time for reimbursement dossiers if an early access request is submitted beforehand. An update of the reform further describing HAS criteria for EA has recently been published in April 2022. Copyright © 2022
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Several vaccine strategies are in use against the SARS-CoV2 virus which causes COVID-19. There are three major approaches to vaccine development: Using the whole virus (live virus, inactivated virus, or viral vector vaccines), using immunogenic parts of the virus, or using the genetic material of the virus. As of April 29, 2022, 10 vaccines with different mechanisms of action have received EUL by WHO.1 In the United States, 3 vaccines have received either emergency use authorization or FDA approval.2 The timing and number of injections in the primary series and timing and need for booster doses of these vaccines depend on the age of the person, underlying immunocompromised status.4 The vaccines have overall been demonstrated to be safe and effective in preventing COVID-19 infection and also in preventing serious COVID-19 infection. However they are rarely associated with some serious side effects. Thrombosis with thrombocytopenia syndrome (TTS) after Johnson & Johnson/ Janssen adenoviral vector vaccine is a rare complication that appears to affect women between the ages of 30 and 49 years. It has also been described with the Oxford/Astra Zeneca vaccine. Based on the available data there is no increased risk for TTS after mRNA vaccination, although cases of immune thrombocytopenia have bene reported after the Pfizer/ BioNTech and Moderna vaccines.3,4 An increased risk of Guillain-Barré syndrome has also been associated with this the Janssen vaccine.3 Myocarditis and pericarditis, particularly in male adolescents and young adults have been associated with the Pfizer and Moderna mRNA vaccines.5 Currently, antibody testing either post infection or post vaccination are not recommended for various reasons.6, 7 Preexposure prophylaxis with a combination of 2 long-acting antibodies, tixagevimab-cilgavimab target the receptor binding domain of the SARS-CoV-2 spike protein and inhibit virus attachment. In December 2021, the US FDA provided emergency use authorization for preexposure prophylaxis of COVID- 19 in patients 12 years or older weighing at least 40 kg, not currently infected with COVID-19 or have a known recent exposure and either have moderate to severe immunocompromise due to a medical condition or receipt of immunosuppressive treatments and may not mount an adequate immune response to COVID-19 vaccines, or in whom available vaccines are not recommended due to prior severe adverse reaction.8 This consists of 2 consecutive intramuscular injections at the same visit and the effi cacy appears to last for up to 6 months. It was granted marketing authorization in the EU in March 2022.
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ATMPs - a new era A boy from Hungary, Zente, was one and a half years old when the crowd-funding campaign to finance his life-saving medicine Zolgensma concluded with a happy end. He was the third European patient that received the new gene therapy, which replaces the function of the missing or nonworking survival motor neuron 1 (SMN1) gene with a new, working copy of a human SMN gene that helps motor neuron cells work properly and survive. From a European perspective, it has been almost 15 years by now since regulatory framework for advanced therapy medicinal products (ATMPs) had been established to ensure the free movement of these medicines within the European Union, to facilitate their access to the EU market, and to foster the competitiveness of European pharmaceutical companies in the field. Zolgensma has been approved in the EU in May 2020. The FDA expects it will be reviewing and approving up to 20 cell and gene therapies each year until 2025. Rapid development of technology and better understanding of the manufacturing challenges are not the only prerequisites of the growth. Assessment of products like Zolgensma requires very specific knowledge and often an adaptive approach from regulators. They have to gain enough experience and need to be able to summarize knowledge in guidelines that would help developers of products that are substantially different from traditional medicines. FDA issued seven new guidelines in January 2020, in which, for example, they highlight the importance of long-term follow-up for gene therapies that offer one-time fix for inherited diseases and where pre-market studies may have limited value. 2. Regulatory tools These examples may already show that rapid change in technology leads to new kinds of medicines that require a properly adapted regulatory system. Patients would expect state-of-the-art medicines within the shortest possible time frame, however, authorities are traditionally more cautious. Still, there are several various initiatives from the EMA and the FDA to foster early access to medicines. Some of these have been available for a longer time. EMA's accelerated assessment reduces the timeframe for review of innovative applications of medicines with major public health interest. Conditional marketing authorisation grants authorization before a complete dataset is available, and compassionate use allows the use of an unauthorized medicine for patients with an unmet medical need. A more recent regulatory tool of EMA is the priority medicines scheme (PRIME) that aims to enhance support for the development of medicines that are expected to make a real difference to patients. Early dialogue between EMA and the developers is a crucial part of the tool, together with accelerated assessment and continuous scientific advice and protocol assistance. Up to now, 282 applications for PRIME eligibility have been assessed by the CHMP of which 95 have received a green light. Most of the applicants are small and medium size enterprises, and the major therapeutic area is oncology. FDA has similar programs, such as the Fast Track, Breakthrough Therapy and Priority Review designations, and is also aiming to facilitate and accelerate development and marketing authorization of key medicines. By 2018, about 70% of new drug approvals by the FDA were expedited, compared to about 50% in 2010. The result is a growing pro-portion of medicines authorized with less premarket evidence, a trade-off, that most patients with fatal or debilitating disease would likely accept. Nevertheless, conditional approval requires a strong post-marketing attention from regulators, and lack of enough evidence sometimes leads to difficult decisions. In April 2019 a fast-tracked cancer drug, Lartruvo was withdrawn because a large study was not able to prove a favourable benefit-risk profile, which was established previously on a smaller patient population. The regulators approach is not expected to be changed, but experience from such cases would gradually be built into the decision-making process. In addition to this real world evidence (RWE) and patient recorded outcomes may also help in decision making. 3. Digital revolution The rapid development of biotechnology is not the only area where an adaptive regulatory approach is needed. Digital medicine is a new field, as smartphones and sensors open up new ways of generating data. For example, collecting and analysing RWE seems to be a good solution for single arm studies where randomized trials are not feasible. FDA has approved easy-to-use devices that are able to track several physiological systems of our body, which in turn can give a boost to developments in this field. In addition to these simpler devices, digital revolution in terms of artificial intelligence (AI) and cognitive machine learning is another challenge that our regulatory systems should tackle. It has been recently announced that a new drug candidate, a long-acting and potent serotonin 5-HT1A receptor agonist, which was created using an artificial intelligence platform, will enter into clinical study. There are also numerous radiological applications based on AI, including computer aideddetection and diagnosis software, where images are analysed, and clinically relevant findings suggested to aid diagnostic decisions. Many of these new developments require a tailored approach from regulators to find a way for authorization within the existing regulatory framework. The fact, that many of these new developments are carried out by academic research groups or small companies without extensive regulatory experience, adds an extra layer of difficulty. To meet this challenge, EMA and the Heads of Medicines Agencies have established the EU-Innovation Network, to support medicine innovation and early development. As a milestone of its function, beginning in 1 February 2020 a pilot for simultaneous scientific advice is starting, where the applicants will receive a consolidated advice from the participating agencies. Innovative products often require specific expertise;therefore this new form of advice is also extremely beneficial for regulators as they are able to learn from each other and broaden their knowledge. 4. Conclusions The rapid development of pharmaceutical and digital technology requires a concerted action from all stakeholders. Or, as we all experience, a global pandemic can be an important driving force of the evolution of regulatory policies. Appropriate usage of currently available regulatory tools and a continuous discussion between academia, industry and regulators would be the only way to ensure quick access to state-of-the-art, safe and efficacious medicines, and medical devices. It is clearly shown currently by the concerted action of various stakeholders and series of rolling reviews which led to the expedited authorization of COVID-19 vaccines.
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Introduction Pfizer-BioNTech collaboration started in 2018 in order to develop mRNA flu vaccine. Because of the covid19 pandemic the two companies started to focus on mRNA vaccine development for the prevention of covid19 infection. In March they signed the Letters of Intent. Initially there were four vaccine candidates including unmodified mRNA, nucleoside-modified mRNA and self-amplifying mRNA. For further development the nucleoside- modified mRNA was chosen. In April Phase 1/2 study was completed in Germany and in May in the USA. Two 30 μg doses 3 weeks apart induced neutralizing antibody titers comparable to natural infection and strong CD4+ and CD8+ Tcell responses were observed. Phase 2b/3 clinical trial started in July involving more than 43.000 participants in 153 sites. The result showed 95% efficacy with mild and moderate local and systemic events. For safety reason all participants will be followed for 2 years after the second dose. Based on rolling review regulatory agencies were able to approve within a short period of time in December 2020, first MHRA in UK, then FDA authorized for Emergency Use and EMA granted Conditional Marketing Authorization on 21 December 2021 for 16 years old and older. The first shipments were sent all European countries on 27 December. Direct shipments to vaccination centers on ultra-low temperature (minus 9060 degree of centigrade) using dry ice. Each thermal shipping container has a temperature monitoring device. All shipments are tracked via GPS monitoring device to ensure end-to-end distribution within required temperatures. In May EMA granted an extension of indication for covid-19 vaccine to include in children aged 12-15. The effect of vaccine was investigated in 2260 children aged 12-15, about half of them received dummy injection. Of the 1,005 children receiving the vaccine, none developed COVID-19 compared to 16 children out of the 978 who received the dummy injection. This means that, in this study, the vaccine was 100% effective at preventing COVID-19. The most common side effects in children aged 12 to 15 are similar like those in people aged 16 and above. They include pain at the injection site, tiredness, headache, muscle and joint pain, chills and fever. These effects are usually mild or moderate and improve within a few days from the vaccination. EMA granted approval for booster dose (third dose) for immune weakened people 28 days after the second dose, and 6 months after the second dose for 18 years of age and older. Approval is based on the clinical program evaluating the safety, tolerability and immunogenicity of a booster dose of covid-19 vaccine. A booster dose of the vaccine elicited significantly higher neutralizing antibody titers against the initial SARS-CoV-2 virus (wild type), as well as the Beta and Delta variants, when compared with the levels observed after the two-dose primary series. The reactogenicity profile within seven days after the booster dose was typically mild to moderate, and the frequency of reactions was similar to or lower than after dose two. The efficacy is this trial was 95,6%. In October 2021 FDA authorized for emergency use of covid-19 for children 5 through 111 years of age. For this age group, the vaccine is to be admin-istered in a two-dose regimen of 10 μg (0,2 ml) doses given 21 days apart. EUA is supported by clinical data showing a favorable safety profile and high vaccine efficacy of 90.7% in children 5 through 11 years of age during a period when Delta was the prevalent strain. In 2021 we have already distributed 1,8B doses to 146 countries by end of September. In 2022 we plan to distribute 4B doses. (Figure Presented).
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Background: SB5, a biosimilar to reference adalimumab (ADL), received EU marketing authorisation in 2017, based on pre-clinical and clinical phase I and III studies that demonstrated bioequivalence and comparable efficacy, safety and immunogenicity to ADL. Objectives: The real-world study 'PROPER' is designed to provide insights into outcomes of the transition from ADL to SB5 outside the randomised, controlled, clinical trial setting. Methods: Under an umbrella design, 1000 patients with immune-mediated infammatory disease were enrolled at centres in Belgium, Germany, Ireland, Italy, Spain and the UK, and followed for 48 weeks post-transition. Eligible patients with a diagnosis of rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), ulcerative colitis or Crohn's disease had been transitioned to SB5 as part of routine treatment following a minimum of 16 weeks' treatment with ADL. Data were captured from patient charts retrospectively for 24 weeks prior to and prospectively and/or retrospectively up to 48 weeks after SB5 initiation. This analysis of the rheumatology cohort reports clinical characteristics, disease scores, persistence on SB5, clinical management and safety up to the closing date of November 30th, 2021. Results: Of the 496 patients included in this analysis, the majority were enrolled in UK (n=174), Germany (n=145) and Spain (n=73);Italy, Ireland and Belgium enrolled 45, 44 and 15 patients respectively. At study close, 487 patients had completed 48 weeks of follow-up;397 of those remained on SB5 throughout. Methotrexate was received as concomitant therapy by 37% of patients and 20% had received a biologic therapy prior to reference ADL. Most patients (89.3% of RA, 92.1% of axSpA, 97.3% of PsA) transitioned to SB5 at the same dose regimen received for ADL. Clinical characteristics, SB5 dose and fare are detailed in Table 1, disease scores in Figure 1. Fifteen patients each experienced one unrelated Serious Adverse Event (SAE): 2 in the axSpA cohort [tachycardia, intracranial haemorrhage];6 in the PsA cohort [myocardial infarct (2), breast carcinoma, COVID-19, gallbladder calculus, dyspnoea];7 in the RA cohort [facial numbness, depression, COVID-19, pneumonia, diverticulitis, parvovirus, coronary occlusion]. Tw o patients reported SAEs considered causally related to SB5: Herpes zoster and pneumonia (RA cohort), and ALS with worsening (PsA cohort). Conclusion: This analysis of a large, contemporary cohort of EU patients with established RA, axSpA or PsA shows treatment effectiveness maintained at 48 weeks after switching from ADL to SB5, with most patients continuing on SB5 Q2W throughout. Episodes of fare were uncommon, and the importance of patient-reported symptoms in recognition of fare is evident. No new safety signals were observed.
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Introduction/ Background: While over 6 billion doses of Covid19 vaccines have been administered globally, only 2% of people in Africa have been vaccinated. This uncomfortable reality lead to the establishment of a mRNA vaccine technology transfer and training Hub in South Africa under the COVAX initiative lead by WHO and MPP. Methods: Afrigen Biologics is establishing a technology transfer and training hub for COVID-19 mRNA-based vaccines. In the absence of a technology transfer agreement with the holders of mRNA vaccine technology, Afrigen and its University partners are developing a firstgeneration vaccine, a fast follow-on of mRNA-1273 (Moderna vaccine). The Afrigen-based vaccine technology transfer program will provide sufficient transfer of know-how to allow a competent tech transfer recipient manufacturer in Africa and other LIMCs to successfully manufacture and release mRNA vaccines at scale to support clinical development, national/regional marketing authorization and WHO prequalification, and sustainable supply to meet local and regional vaccine demand. Results: The mRNA Hub at Afrigen has reached key milestones in terms of completion of the facility and start up phase of equipment supply, training of Afrigen core staff in drug substance and drug product production at lab scale. The development of a stable genetic construct that allows transcription of an mRNA molecule at bench scale as well as the encapsulation in a lipid nano particle is underway. This presentation will provide an overview of the progress of the mRNA Hub, its workplan as well as the long-term research and development program and the partnerships supporting the Hub. Impact: The mRNA vaccine technology transfer Hub has created a public private partnership model for sustainable vaccine manufacturing on the African continent. Supported and enabled by the African Union and the African CDC, the mRNA Hub is well positioned to become one of the pillars of the African vaccine manufacturing strategy. Conclusion: The Covid19 pandemic has unleashed significant energy to ensure that Africa implement programs that will ensure sustainable supply of vaccines and preparedness for future pandemics. The Hub and Spoke model is one of the interventions that has the potential to create local innovation and contribute to the supply of vaccines.
ABSTRACT
Introduction: The retina is a highly specialized sense organ subjected to constant exposure to systemic toxins and oxidative stress. The frequency and etiology of drug-induced retinopathy, as well as the number of new potential drugs involved, are largely unknown. Objective: Describe the most frequent drug-induced retinal disorders and the drugs implicated gathered through the spontaneous report registry of the Spanish System of Pharmacovigilance (SSP). Methods: All spontaneous reported cases describing Retinal structural change, deposit and degeneration, Retinopathies not elsewhere classified, and Retinal bleeding and vascular disorders (excluded retinopathy) (MedDRA-HLT) in the SSP database from 1983 to January 2022 were selected. Medical devices and marketing authorisation holder cases were excluded. The variables studied were age and sex of the patients, characteristics of adverse drug reactions (ADRs) (seriousness, outcome) and suspect drugs (active substance, anatomical therapeutic chemical code, previous knowledge of drug-reaction association, rechallenge and existence of alternative causes). Results: Out of 175 spontaneous reports (0.1% of the spontaneous reports in the SSP database) that describe 210 ocular ADRs and/or adverse events, the most frequent (MedDRA-HLT) were retinal bleeding and vascular disorders (111, 52.9%), ocular structural change, deposit and degeneration (59, 28.1%) and vision disorders (12, 5.7%). For MedDRA-PT;retinal vein thrombosis (38, 18.1%), retinal detachment (22, 10.5%) and retinal hemorrhage (20, 9.5%). In only 8 cases (3.8%) drug administration was ophthalmic. Patient's median age was 57.65 (IQR 48-67.5) years;68.6% (120) were adults and 56.6% (99) were women. 153 reports (87.4%) were serious. 10.9% (19) cases resolved after withdrawal of the suspect drug and 12.6% (22) resolved with sequelae. A total of 220 drugs were suspected, of which 55 (25%) were COVID-19 vaccines -vector vaccine ChAdOx1 nCoV-19/AZD1222, Oxford-AstraZeneca (27) and mRNA vaccine BNT162b2, Pfizer- BioNTech (23)-, followed by sex hormones (21), immunostimulants (16) and antiprotozoals (14). Of the 175 reports, 56% (98) were poorly or unknown ADR associations. Alternative causes were excluded in 46 (26.3%) cases of which 12 (26%) were poorly or unknown ADR associations and no cases had a positive rechallenge. Conclusion: Our study shows that drug-induced retinopathy is an infrequent but serious complication. In the SSP database more than half of ADRs were retinal bleeding and vascular disorders. A quarter of the suspected drugs were new COVID-19 vaccines, followed by other drugs for which retinal disorders are well known. Although striking, it is important to contextualize this data in the current situation, considering the particularities of pharmacovigilance in vaccines, the massive rollout campaign and the nascent and evolving data on COVID-19 vaccines. Thus, further studies are needed to confirm such associations. Moreover, clinicians should be aware of drug-induced retinal disorders, even when not listed in the product information leaflet.
ABSTRACT
Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.