Immunogenic responses in the context of biological medicines regulatory assessment

Tese de mestrado, Regulação e Avaliação do Medicamento e Produtos de Saúde, 2021, Universidade de Lisboa, Faculdade de Farmácia.As atividades regulamentares são cruciais para a avaliação da eficácia e segurança dos medicamentos biológicos, uma vez que, devido à sua origem e modo de ação, a ocorrência de reações imunogénicas é mais propícia aquando da utilização deste tipo de medicamentos. Assim, de forma a garantir a segurança dos doentes, é extremamente importante desenvolver estudos imunogénicos adequados. A Food and Drug Administration e a Agência Europeia do Medicamento desenvolveram guidelines que visam auxiliar os titulares na realização de estudos de imunogenicidade, sendo em geral, a metodologia utilizada por ambas as agências semelhante. O tipo de proteína terapêutica e o método de administração podem influenciar o aparecimento de anticorpos anti-medicamento (ADAs) e/ou anticorpos neutralizantes (nAbs) responsáveis pela ocorrência de reações imunogénicas. Para os medicamentos biológicos com atividade direcionada (grupo 1), foram detetados níveis mais elevados de ADAs (U(45)=154.000;p<0.05;M=0.08;DP=0.119) e nAbs (U(45) = 189.000; p < 0.05; M = 0.02; DP = 0.045) para os anticorpos monoclonais. Relativamente ao método de administração, os medicamentos com administração intravítrea apresentam uma diferença estatisticamente significativa para ADAs (H(45) = 11.078; p < 0.05); M = 0.21; DP = 0.082, e a administração intravenosa para nAbs (H(45) = 7.073; p < 0.05); M = 0.02; DP = 0.056. Quanto ao grupo com atividade enzimática ou reguladora (grupo 2), as enzimas e hormonas apresentaram diferenças estatisticamente significativas para os ADAs (H(33) = 43.950; p < 0.05); M = 0.20; DP = 0.252, bem como a administração subcutânea (H(33) = 43.950; p < 0.05); M = 0.10; DP = 0.265. Não foram identificadas diferenças significativas para os nAbs neste grupo. Foi notificado um total de 47 reações adversas para medicamentos do grupo 1 e 31 para medicamentos do grupo 2. As reações adversas imunogénicas notificadas com mais frequência para o grupo 1 foram reações no local de injeção, anafilaxia, hipersensibilidade e pirexia. Para medicamentos administrados por via intravenosa e subcutânea, a reação adversa mais frequente foi anafilaxia. Para os medicamentos do grupo 2 a hipersensibilidade e as reações anafiláticas foram as que apresentaram maior frequência. As reações de hipersensibilidade parecem estar mais relacionadas com a administração intravenosa enquanto a administração subcutânea está mais frequentemente associada a reações anafiláticas. Embora os Relatórios Públicos de Avaliação de medicamentos aprovados mais recentemente apresentem um maior número de dados relativos à imunogenicidade, continua a ser necessário harmonizar estes resumos, uma vez que a informação não é apresentada da mesma forma para todos os medicamentos. Deve ser dada mais atenção às hormonas e enzimas, uma vez que não foram detetados tanto ADAs como nAbs durante os estudos de imunogenicidade efetuados durante os ensaios clínicos. Além disso, relativamente às atividades de farmacovigilância pós- comercialização, devem ser feitos mais esforços por profissionais de saúde e pacientes para melhor identificar o medicamento biológico assim como o número de lote.The regulatory activities are crucial in the evaluation of the efficacy and safety of biological medicines. Due to their origin and mode of action, immunogenic reactions are more likely to occur when biological medicines are used. Therefore, in order to ensure patient safety, it is extremely important to develop adequate immunogenic studies. Both Food and Drug Administration and European Medicines Agency issued guidelines that aim to assist Marketing Authorisation Holders to develop immunogenicity studies, being, in general, its methodology similar. The type of therapeutic protein and method of administration may influence the emergence of Anti-drug antibodies (ADAs) and/or neutralizing antibodies (nAbs) which can trigger immunogenic responses. For the biologicals with targeting activity (group 1), higher levels of ADAs (U(45 ) = 154.000; p < 0.05; M = 0.08; SD = 0.119 ) and nAbs (U(45) = 189.000; p < 0.05; M = 0.02; SD = 0.045) were detected for mAbs. Regarding the method of administration, medicinal products with intravitreal administration showed a significant difference for ADAs (H(45) = 11.078; p < 0.05); M = 0.21; SD = 0.082, and intravenous administration for nAbs (H(45) = 7.073; p < 0.05); M = 0.02; SD = 0.056. As regards to the group with enzymatic or regulatory activity (group 2), the products enzymes and hormones showed significant differences for ADAs (H(33) = 43.950; p < 0.05; M = 0.20; SD = 0.252) as well as the subcutaneous administration (H(33) = 43.950; p < 0.05); M = 0.10; SD = 0.265. No significant differences were identified for nAbs within this group. A total of 47 possible adverse reactions were reported for medicines with targeting activity and 31 for medicines with enzymatic or regulatory activity. The most frequent adverse reactions reported for the System Organ Classes (SOC) “Immune system disorders” within the first group were injection site reactions, anaphylaxis, hypersensitivity, and pyrexia. For medicines administered intravenously and subcutaneously the most frequent adverse reaction was anaphylaxis. For medicines belonging to the group with enzymatic or regulatory activity, the hypersensitivity and anaphylactic reactions were the ones with higher frequency. Hypersensitivity reactions seem to be more related with intravenous administration while subcutaneous administration is more commonly associated with anaphylactic reactions. Although the most recent European Public Assessment Reports have the information well presented, MAHs need to harmonize the summaries of immunogenicity, since the information is not presented in the same manner for all medicines (period of sampling, preexisting antibodies, placebo and active control group), and for some of the medicine’s immunogenicity studies have not even been carried out. More attention should be given to medicines such as hormones and enzymes since most of these products have not detected neither ADAs nor nAbs. Additionally, regarding post-marketing pharmacovigilance activities, more efforts should be carried out by healthcare professionals and patients to better identify the biological medicinal product and batch number

In COVID-19 Health Messaging, Loss Framing Increases Anxiety with Little-to-No Concomitant Benefits: Experimental Evidence from 84 Countries

The COVID-19 pandemic (and its aftermath) highlights a critical need to communicate health information effectively to the global public. Given that subtle differences in information framing can have meaningful effects on behavior, behavioral science research highlights a pressing question: Is it more effective to frame COVID-19 health messages in terms of potential losses (e.g., "If you do not practice these steps, you can endanger yourself and others") or potential gains (e.g., "If you practice these steps, you can protect yourself and others")? Collecting data in 48 languages from 15,929 participants in 84 countries, we experimentally tested the effects of message framing on COVID-19-related judgments, intentions, and feelings. Loss- (vs. gain-) framed messages increased self-reported anxiety among participants cross-nationally with little-to-no impact on policy attitudes, behavioral intentions, or information seeking relevant to pandemic risks. These results were consistent across 84 countries, three variations of the message framing wording, and 560 data processing and analytic choices. Thus, results provide an empirical answer to a global communication question and highlight the emotional toll of loss-framed messages. Critically, this work demonstrates the importance of considering unintended affective consequences when evaluating nudge-style interventions

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Author Correction: A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

Correction to: Nature Human Behaviour https://doi.org/10.1038/s41562-021-01173-x, published online 2 August 2021. In the version of this article initially published, the following authors were omitted from the author list and the Author contributionssection for “investigation” and “writing and editing”: Nandor Hajdu (Institute of Psychology, ELTE Eötvös Loránd University, Budapest,Hungary), Jordane Boudesseul (Facultad de Psicología, Instituto de Investigación Científica, Universidad de Lima, Lima, Perú), RafałMuda (Faculty of Economics, Maria Curie-Sklodowska University, Lublin, Poland) and Sandersan Onie (Black Dog Institute, UNSWSydney, Sydney, Australia & Emotional Health for All Foundation, Jakarta, Indonesia). In addition, Saeideh FatahModares’ name wasoriginally misspelled as Saiedeh FatahModarres in the author list. Further, affiliations have been corrected for Maria Terskova (NationalResearch University Higher School of Economics, Moscow, Russia), Susana Ruiz Fernandez (FOM University of Applied Sciences,Essen; Leibniz-Institut fur Wissensmedien, Tubingen, and LEAD Research Network, Eberhard Karls University, Tubingen, Germany),Hendrik Godbersen (FOM University of Applied Sciences, Essen, Germany), Gulnaz Anjum (Department of Psychology, Simon FraserUniversity, Burnaby, Canada, and Department of Economics & Social Sciences, Institute of Business Administration, Karachi, Pakistan)

Author correction: A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic

Correction to: Nature Human Behaviour https://doi.org/10.1038/s41562-021-01173-x, published online 2 August 2021. In the version of this article initially published, the following authors were omitted from the author list and the Author contributionssection for “investigation” and “writing and editing”: Nandor Hajdu (Institute of Psychology, ELTE Eötvös Loránd University, Budapest,Hungary), Jordane Boudesseul (Facultad de Psicología, Instituto de Investigación Científica, Universidad de Lima, Lima, Perú), RafałMuda (Faculty of Economics, Maria Curie-Sklodowska University, Lublin, Poland) and Sandersan Onie (Black Dog Institute, UNSWSydney, Sydney, Australia & Emotional Health for All Foundation, Jakarta, Indonesia). In addition, Saeideh FatahModares’ name wasoriginally misspelled as Saiedeh FatahModarres in the author list. Further, affiliations have been corrected for Maria Terskova (NationalResearch University Higher School of Economics, Moscow, Russia), Susana Ruiz Fernandez (FOM University of Applied Sciences,Essen; Leibniz-Institut fur Wissensmedien, Tubingen, and LEAD Research Network, Eberhard Karls University, Tubingen, Germany),Hendrik Godbersen (FOM University of Applied Sciences, Essen, Germany), Gulnaz Anjum (Department of Psychology, Simon FraserUniversity, Burnaby, Canada, and Department of Economics & Social Sciences, Institute of Business Administration, Karachi, Pakistan)

A global test of brief reappraisal interventions on emotions during the COVID-19 pandemic

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion regulation strategy which modifies how one thinks about a situation. Participants from 87 countries/regions (N = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vs. both control conditions) had consistent effects in reducing negative emotions and increasing positive emotions across different measures. Reconstrual and repurposing had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world to build resilience during the pandemic and beyond

In COVID-19 Health Messaging, Loss Framing Increases Anxiety with Little-to-No Concomitant Benefits: Experimental Evidence from 84 Countries.

The COVID-19 pandemic (and its aftermath) highlights a critical need to communicate health information effectively to the global public. Given that subtle differences in information framing can have meaningful effects on behavior, behavioral science research highlights a pressing question: Is it more effective to frame COVID-19 health messages in terms of potential losses (e.g., "If you do not practice these steps, you can endanger yourself and others") or potential gains (e.g., "If you practice these steps, you can protect yourself and others")? Collecting data in 48 languages from 15,929 participants in 84 countries, we experimentally tested the effects of message framing on COVID-19-related judgments, intentions, and feelings. Loss- (vs. gain-) framed messages increased self-reported anxiety among participants cross-nationally with little-to-no impact on policy attitudes, behavioral intentions, or information seeking relevant to pandemic risks. These results were consistent across 84 countries, three variations of the message framing wording, and 560 data processing and analytic choices. Thus, results provide an empirical answer to a global communication question and highlight the emotional toll of loss-framed messages. Critically, this work demonstrates the importance of considering unintended affective consequences when evaluating nudge-style interventions

In COVID-19 health messaging, loss framing increases anxiety with little-to-no concomitant benefits: Experimental evidence from 84 countries

The COVID-19 pandemic (and its aftermath) highlights a critical need to communicate health information effectively to the global public. Given that subtle differences in information framing can have meaningful effects on behavior, behavioral science research highlights a pressing question: Is it more effective to frame COVID-19 health messages in terms of potential losses (e.g., "If you do not practice these steps, you can endanger yourself and others") or potential gains (e.g., "If you practice these steps, you can protect yourself and others")? Collecting data in 48 languages from 15,929 participants in 84 countries, we experimentally tested the effects of message framing on COVID-19-related judgments, intentions, and feelings. Loss- (vs. gain-) framed messages increased self-reported anxiety among participants cross-nationally with little-to-no impact on policy attitudes, behavioral intentions, or information seeking relevant to pandemic risks. These results were consistent across 84 countries, three variations of the message framing wording, and 560 data processing and analytic choices. Thus, results provide an empirical answer to a global communication question and highlight the emotional toll of loss-framed messages. Critically, this work demonstrates the importance of considering unintended affective consequences when evaluating nudge-style interventions