Attention for sex in COVID-19 trials: a review of regulatory dossiers.

An under-representation of women and a lack of sex-specific analyses in COVID-19 trials has been suggested. However, the higher number of men than women who are severely affected by COVID-19 and the restricted information in scientific publications may have biased these suggestions. Therefore, we evaluated sex proportionality and sex-specific efficacy and safety data in trials of COVID-19 treatments and vaccines using both publicly available regulatory documents and confidential documents used by regulators in their review of medicinal products. Included were two treatments (ie, remdesivir and dexamethasone) and four vaccines (ie, BNT162b2 mRNA (BioNTech/Pfizer), mRNA-1273 (Moderna), ChAdOx1-S (AstraZeneca) and Ad26.COV2-S (Janssen)) that received marketing authorisation by the European Commission at the time of the study conduct. An under-representation of women was shown in three of the nine data sets for one treatment (ie, remdesivir), but the proportion of women included was representative in each of the data sets for the other five products. This indicates that there is no structural under-representation of women in the COVID-19 trials. Currently, sex-specific efficacy data are available for five of the six assessed products and sex-specific safety data are available for half of the products only. It is important that this information will also be made available for the other products. There are only small differences in efficacy and safety between men and women which are likely to be of limited clinical relevance. Sex-specific efficacy information can generally be found in the publicly available regulatory documents other than the Summary of Product Characteristics, for which more awareness might be required.

Bell's palsy and influenza(H1N1)pdm09 containing vaccines: A self-controlled case series.

BACKGROUND: An association between AS03 adjuvanted pandemic influenza vaccine and the occurrence of Bell's palsy was found in a population based cohort study in Stockholm, Sweden. To evaluate this association in a different population, we conducted a self-controlled case series in a primary health care database, THIN, in the United Kingdom. The aim of this study was to determine whether there was an increased risk of Bell's palsy following vaccination with any influenza vaccine containing A/California/7/2009 (H1N1)-like viral strains. Secondly, we investigated whether risks were different following pandemic influenza A(H1N1)pdm09 vaccines and seasonal influenza vaccines containing the influenza A(H1N1)pdm09 strain. METHODS: The study population comprised all incident Bell's palsy cases between 1 June 2009 and 30 June 2013 identified in THIN. We determined the relative incidence (RI) of Bell's palsy during the 6 weeks following vaccination with either pandemic or seasonal influenza vaccine. All analyses were adjusted for seasonality and confounding variables. RESULTS: We found an incidence rate of Bell's palsy of 38.7 per 100,000 person years. Both acute respiratory infection (ARI) consultations and pregnancy were found to be confounders. When adjusted for seasonality, ARI consultations and pregnancies, the RI during the 42 days after vaccination with an influenza vaccine was 0.85 (95% CI: 0.72-1.01). The RI was similar during the 42 days following seasonal vaccine (0.96, 95%CI: 0.82-1.13) or pandemic vaccine (0.73, 95%CI: 0.47-1.12). CONCLUSION: We found no evidence for an increased incidence of Bell's palsy following seasonal influenza vaccination overall, nor for monovalent pandemic influenza vaccine in 2009.

Pandemic influenza vaccine & narcolepsy: simulations on the potential impact of bias.

Several studies have identified an association between Pandemrix(TM), an AS03 adjuvanted pandemic influenza A(H1N1) vaccine, and narcolepsy, a rare and under-diagnosed sleep disorder with a median onset-to-diagnosis interval of ten years. This paper reviews potential sources of bias in published studies and aims to provide, through simulation, methodological recommendations for assessment of vaccine safety signals. Our simulation study showed that in the absence of an association between the vaccine and the outcome, presence of detection bias and differential exposure misclassification could account for elevated risk estimates. These may play a major role, particularly in alert situations when observation times are limited and the disease has a long latency period. Estimates from the case-control design were less inflated than those from the cohort design when these biases were present. Overall, these simulations provide useful insights for the design and interpretation of future studies.

A review of the changes to the licensing of influenza vaccines in Europe.

In 2014, the European Committee for Medicinal Products for Human Use (CHMP) published a draft regulatory guideline for the evaluation of influenza vaccines. Following a public consultation round, the final guidance will be published in the near future. Here, we highlight the main changes in the clinical section in this guideline and discuss the background to these changes and whether the new consolidated guidance document can be expected to achieve a better understanding of the performance of seasonal, zoonotic and pandemic influenza vaccines during the regulatory licensing process. The new influenza guideline reflects a changed approach to the regulatory assessment of influenza vaccines, resulting in the abolition of serological criteria, known as the CHMP criteria, which have been the mainstay for evaluating the influenza vaccine immunogenicity for several decades. The new guideline adopts a more diversified approach to the measurement and reporting of the immune response to influenza vaccines and sets a requirement to conduct clinical outcome trials in young children. Importantly, more emphasis is placed on the post-licensure monitoring of the benefit risk of influenza vaccines, including a request for continuous monitoring of efficacy and enhanced safety surveillance. Despite the improvements these new requirements will expectedly bring to the regulatory assessment of influenza vaccines, major challenges remain which cannot be overcome by new guidance alone. Ongoing initiatives in which academia, manufacturers, public health institutes and regulators work together to address these challenges are central to the development of robust tools to evaluate and monitor performance of influenza vaccines in the future.

Effectiveness of MF59™ adjuvanted influenza A(H1N1)pdm09 vaccine in risk groups in the Netherlands.

BACKGROUND: The aim of the present study was to estimate the effectiveness of the MF59™-adjuvanted influenza A(H1N1)pdm09 vaccine against medically attended influenza-like illness and RT-PCR confirmed influenza in the at-risk population and persons over 60 in the Netherlands. METHODS: We conducted a retrospective cohort study in a Dutch based GP medical record database between 30 November 2009 and 1 March 2010 to estimate the vaccine effectiveness against influenza-like illness. Within the cohort we nested a test negative case-control study to estimate the effectiveness against laboratory confirmed influenza. RESULTS: The crude effectiveness in preventing diagnosed or possible influenza-like illness was 17.3% (95%CI: -8.5%-36.9%). Of the measured covariates, age, the severity of disease and health seeking behaviour through devised proxies confounded the association between vaccination and influenza-like illness. The adjusted vaccine effectiveness was 20.8% (95%CI: -5.4%, 40.5%) and varied significantly by age, being highest in adults up to 50 years (59%, 95%CI: 23%, 78%), and non-detectable in adults over 50 years. The number of cases in the nested case control study was too limited to validly estimate the VE against confirmed influenza. CONCLUSIONS: With our study we demonstrated that the approach of combining a cohort study in a primary health care database with field sampling is a feasible and useful option to monitor VE of influenza vaccines in the future.

The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns.

BACKGROUND: In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. METHODS: We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. RESULTS: Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. CONCLUSIONS: The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Safety of pandemic H1N1 vaccines in children and adolescents.

During the 2009 influenza A (H1N1) pandemic several pandemic H1N1 vaccines were licensed using fast track procedures, with relatively limited data on the safety in children and adolescents. Different extensive safety monitoring efforts were put in place to ensure timely detection of adverse events following immunization. These combined efforts have generated large amounts of data on the safety of the different pandemic H1N1 vaccines, also in children and adolescents. In this overview we shortly summarize the safety experience with seasonal influenza vaccines as a background and focus on the clinical and post marketing safety data of the pandemic H1N1 vaccines in children. We identified 25 different clinical studies including 10,505 children and adolescents, both healthy and with underlying medical conditions, between the ages of 6 months and 23 years. In addition, large monitoring efforts have resulted in large amounts of data, with almost 13,000 individual case reports in children and adolescents to the WHO. However, the diversity in methods and data presentation in clinical study publications and publications of spontaneous reports hampered the analysis of safety of the different vaccines. As a result, relatively little has been learned on the comparative safety of these pandemic H1N1 vaccines - particularly in children. It should be a collective effort to give added value to the enormous work going into the individual studies by adhering to available guidelines for the collection, analysis, and presentation of vaccine safety data in clinical studies and to guidance for the clinical investigation of medicinal products in the pediatric population. Importantly the pandemic has brought us the beginning of an infrastructure for collaborative vaccine safety studies in the EU, USA and globally.