Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development

This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.Copyright © 2023, Matrix Medical Communications. All rights reserved.

Apropos of menstrual changes and abnormal uterine bleeding after COVID-19 vaccination.

It is news of 28 October 2022 that the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency has recommended to add heavy menstrual bleeding among the side effects of unknown frequency inside the package insert of nucleoside-modified messenger ribonucleic acid vaccines to prevent coronavirus disease 2019 (COVID-19). The decision has been made in the light of the numerous reports of unexpected menstrual changes or abnormal uterine bleeding following COVID-19 vaccination. Here we advance a possible involvement of the particular adenohypophyseal microcirculation in these strange and still unexplained events.

Epidemiology of Pemphigus.

Pemphigus is an epidemiologically heterogeneous group of autoimmune bullous diseases comprising pemphigus vulgaris (PV), pemphigus foliaceus, paraneoplastic pemphigus, IgA pemphigus, and pemphigus herpetiformis. Recently, our knowledge about the frequency of pemphigus, which is highly variable between different populations, has considerably expanded, and the first non-HLA genes associated with PV have been identified. In addition, a variety of comorbidities, including other autoimmune diseases, hematological malignancies, and psoriasis, have been described in this variant. Here, initial data about the impact of COVID-19 on this fragile patient population are discussed and perspectives for future epidemiological studies are outlined.

When and How to Use Covariate Adjustment to Improve Precision in Randomized Trials

Background In May 2021, the US Food and Drug Administration (FDA) released a revised draft guidance for industry on ''Adjustment for Covariates in Randomized Clinical Trials for Drugs and Biological Products.'' This guidance discusses adjustment for covariates in the statistical analysis of randomized clinical trials in drug development programs. It specifically focuses on the use of prognostic baseline factors to improve precision for estimating treatment effects. The impact depends on the specifics of the trial, but typical sample size reductions range from 5-25% (at no cost). Despite regulators such as the FDA and the European Medicines Agency recommending covariate adjustment, it remains highly underutilized leading to inefficient trials in many disease areas. This is especially true for binary, ordinal, and time-to-event outcomes, which are quite common in COVID-19 trials and are, moreover, prevalent as primary outcomes in many disease areas (e.g. Alzheimer's disease and stroke). Research and guidance on this topic could therefore not be more timely. In response to the FDA draft guidance on covariate adjustment, this session invites experts who represent a variety of viewpoints, coming from academia and Pharmaceutical industry. The aim of this session is to provide insight into the state-of-the-art methods at a high level and from a practical perspective. We moreover want to discuss the main obstacles that lead to the underutilization of covariate adjustment, all of which we aim to surmount in this session. Finally, we want to discuss the connections of the different talks to the FDA draft guidance and provide options for better practice. Talk by Min Zhang ''Covariate adjustment for randomized clinical trials when covariates are subject to missingness.'' One practical issue that may have limited the use of covariate adjustment is that covariates are often subject to missingness. Existing statistical methodologies often ignore this issue and assume covariates are completely observed. We discuss conditions under which robust covariate adjustment can be achieved when the missingness of covariates is present. We study various methods for handling missing data and compare their performances in terms of robustness and efficiency through comprehensive simulation studies. Recommendations on strategies for handling missing covariates to achieve robust covariate adjustment are provided. Talk by Mark van der Laan on ''Targeted Learning of causal effects in randomized Trials with continuous time-to-event outcomes.'' Targeted maximum likelihood estimation (TMLE) provides a general methodology for estimation of causal parameters in the presence of high-dimensional nuisance parameters. Generally, TMLE consists of a twostep procedure that combines data-adaptive nuisance parameter estimation with semi-parametric efficiency and rigorous statistical inference obtained via a targeted update step. In this talk, we demonstrate the practical applicability of TMLE for standard survival and competing risks settings where event times are not confined to take place on a discrete and finite grid. We demonstrate TMLE updates that simultaneously target point-treatment-specific survival curves and treatmentcause- specific subdistributions in the competing risk setting, across treatment and time points. We consider the case that we only observe baseline covariates as well as the case that we also track time-dependent covariates that potentially inform censoring/drop-out. This results in estimates that are not only fully efficient, but also respect the natural monotonicity of survival functions and cause-specific subdistributions. It moreover makes sure that the sum of subdistributions and survival equals 1. We propose a super-learner for the causespecific conditional hazards that incorporate many possible Cox models as well as a variety of highly adaptive Lasso estimators. Asymptotic theoretical guarantees are given and finite-sample robust performance is demonstrated with simulations. We illustrate the usage of the considered methods for a ovo Nordisk Leader study as well as for publicly available data from a trial on adjuvant chemotherapy for colon cancer. Talk by Kelly Van Lancker on ''Combining Covariate Adjustment with Information Monitoring and Group Sequential Designs to Improve Randomized Trial Efficiency'' In this talk, we focus on the knowledge gap in statistical methodology that leads to the underutilization of covariate adjustment. A first obstacle is the uncertainty of its efficiency gain and corresponding sample size reduction at the design stage;an incorrect projection of a covariate's prognostic value risks an over- or underpowered future trial. A second open problem is the incompatibility of many covariate-adjusted estimators with the commonly used group sequential, information-based designs (GSDs). To overcome these challenges, we suggest combining covariate adjustment with information monitoring and continuing the trial until the required information level is surpassed. Since adjusted estimators typically have smaller variance than standard estimators, the information accrues faster leading to faster trials. Building on this, we propose a new statistical method that orthogonalizes estimators in order to (1) have the independent increments property needed to apply GSDs and (2) simultaneously improve (or leave unchanged) the variance at each analysis. Such a method is needed in order to fully leverage prognostic baseline variables to speed up clinical trials without sacrificing validity or power. We prove that this method has properties such as the independent increments, consistency, asymptotic normality, and correct type I error and power, and evaluate its performance in simulations and data analyses. Discussion by Frank Bretz This talk will discuss connections between the three previous presentations in the session and recommendations in the May 2021 FDA revised draft guidance for industry document on ''Adjustment for Covariates in Randomized Clinical Trials for Drugs and Biological Products.'' It will moreover touch on the broad impact of covariate adjustment for the pharmaceutical industry and provide advice on better practice.

Update on EudraVigilance and on MHRA ICSR Submission Portal

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.

Correcting Disparities in Adolescent Access to Medicines by Promoting Age-Inclusive Research

The average time between regulatory approval and labeling of an innovative medicine for adults and children is nearly a decade.1 Often this is the result of poorly integrated adult and pediatric studies within medicines development programs, which consequently leads to prolonged off-label pediatric use. Furthermore, the conduct of studies in children after adult market approval becomes difficult if not impossible. Experiences during the SARS-CoV-2 pandemic have heightened awareness of this disparity. The fact that most children have been less severely affected by COVID-19 combined with reluctance to include children in early phases of investigational research has contributed to delays in evaluation of potential treatments for those children who present with more severe forms of the disease.2 Our study sought to understand how adolescent inclusion in adult trials is positioned in regulatory guidance since such documents set critical expectations for trial design and regulatory decision-making for innovative medicines. The authors conducted multiple sequential PubMed searches in November 2019 (and repeated in August 2021) utilizing a variety of grouped search terms-including ''pediatric,'' ''paediatric,'' ''adolescent,'' ''adolescence,'' ''regulatory guidance,'' ''guidance,'' ''FDA guidance,'' ''regulatory guideline,'' ''guideline,'' ''EMA guideline,'' and/or ''meta-analysis.'' The searches failed to return any results showing that an analysis of regional regulatory guidance specific to age-inclusive research has been published. It is our understanding that this study represents the first comprehensive analysis of age-inclusive language within regulatory guidance for two globally important health agencies, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The study utilized a qualitative analysis approach to review FDA and EMA regulatory guidance documents assessing their recommendations about adolescent inclusion in clinical trials. The study found that regulatory guidance contained recommendations supporting adolescent inclusion in 32% of FDA and 15% of EMA documents, while 14% and 21%, respectively, were found to be exclusionary. In both regions, more than half of all guidance documents were silent regarding the applicability of adolescentinclusive trial methodologies. Analysis by therapeutic area revealed FDA guidance for infectious diseases and EMA guidance for conditions requiring blood products was the most permissive. A more inclusive approach was identified to disease guidance published by the FDA Oncology Center of Excellence. Our study has identified important opportunities for enhancement of regulatory guidance which, if addressed, can facilitate inclusion of adolescent patients in adult trials to accelerate adolescent access to life-changing medicines. Regulatory guidance plays a critical role in improving the type and the quality of data generated in clinical trials which inform medicines use in diverse patient populations. As pediatric policy reforms have led to significant experience with pediatric medicines development, this should be leveraged to update existing regulatory guidance, fostering scientifically justified inclusion of adolescents in adult clinical trials.

The evolving landscape of pulmonary arterial hypertension clinical trials

Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.Copyright © 2022 Elsevier Ltd

Starting the conversation on gene therapy for phenylketonuria: Current perspectives of patients, caregivers, and advocates.

Phenylketonuria (PKU) is a rare genetic condition caused by inborn error(s) in the gene for the enzyme phenylalanine hydroxylase. Resulting loss of phenylalanine (Phe) metabolism requires strict dietary therapy and/or medication to prevent toxic accumulation of Phe. Novel investigational therapies, including gene therapies that aim to address underlying causes of PKU, are now entering clinical trials. However, perceptions of this technology in the PKU community have not been assessed. We conducted a qualitative survey recruiting adult patients, caregivers, and patient advocates from the US and 3 EU countries to assess the impact of living with PKU and the perceptions of gene therapy. Telephone interviews were conducted for up to 60 min following a standardized discussion guide. Interviewers classified each participant by their level of knowledge regarding gene therapy as either: low (little or no prior awareness); moderate (awareness of gene therapy as a concept in PKU); or high (working knowledge of gene therapy, e.g., vectors). In total, 33 participants were recruited (patients, n = 24; caregivers, n = 5; advocates, n = 4). The patient sample was well balanced among age groups, sex, and US/EU geographies. The participants' experiences and burden of living with PKU were largely negative, characterized by frustrations with current management consistent with prior reports. Most participants (n = 18/33) were identified as displaying moderate gene-therapy knowledge, 10/33 as displaying high knowledge, and 5/33 as displaying low knowledge. Both positive and negative perceptions were observed; positive perceptions were often linked to "hope" that gene therapy may represent a cure, whereas negative perceptions were linked to the "uncertainty" of outcomes. High knowledge of gene therapy appeared to trend with negative perceptions; 7/10 participants from this group reported high levels of concern over gene therapy. In contrast, participants who displayed low knowledge reported low (n = 3/5) or moderate (n = 2/5) concern, with predominantly positive perceptions. These data highlight the need for education around the theoretical risk:benefit profile of gene therapy. Despite current unknowns around gene therapy, our study demonstrates the important role of healthcare providers as educators who can use available data to provide balanced information to patients and caregivers.

Antibodies to watch in 2023.

In this 14th installment of the annual Antibodies to Watch article series, we discuss key events in commercial monoclonal antibody therapeutics development that occurred in 2022 and forecast events that might occur in 2023. As of mid-November, 12 antibody therapeutics had been granted first approvals in either the United States or European Union (tebentafusp (Kimmtrak), faricimab (Vabysmo), sutimlimab (Enjaymo), relatlimab (Opdualag), tixagevimab/cilgavimab (Evusheld), mosunetuzumab (Lunsumio), teclistamab (TECVAYLI), spesolimab (SPEVIGO), tremelimumab (Imjudo; combo with durvalumab), nirsevimab (Beyfortus), mirvetuximab soravtansine (ELAHERE™), and teplizumab (TZIELD)), including 4 bispecific antibodies and 1 ADC. Based on FDA action dates, several additional product candidates could be approved by the end of 2022. An additional seven were first approved in China or Japan in 2022, including two bispecific antibodies (cadonilimab and ozoralizumab). Globally, at least 24 investigational antibody therapeutics are undergoing review by regulatory agencies as of mid-November 2022. Our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline grew by ~20% in the past year to include nearly 140 investigational antibody therapeutics that were designed using a wide variety of formats and engineering techniques. Of those in late-stage development, marketing application submissions for at least 23 may occur by the end of 2023, of which 5 are bispecific (odronextamab, erfonrilimab, linvoseltamab, zanidatamab, and talquetamab) and 2 are ADCs (datopotamab deruxtecan, and tusamitamab ravtansine).

Regulatory Science Challenges - Encouraging Innovation Through an Adaptive Regulatory System

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.

Vaccine Development in Global Pandemic Time

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).

A PHASE III, RANDOMISED, DOUBLE-BLIND, ACTIVE-CONTROLLED CLINICAL TRIAL to COMPARE BAT1806/BIIB800, A PROPOSED TOCILIZUMAB BIOSIMILAR, with TOCILIZUMAB REFERENCE PRODUCT in SUBJECTS with MODERATE to SEVERE RHEUMATOID ARTHRITIS with AN INADEQUATE RESPONSE to METHOTREXATE THERAPY

Background: BAT1806/BIIB800 is a proposed biosimilar to reference tocili-zumab (TCZ). A Phase III randomised, double-blind, active-controlled clinical trial was conducted as part of a biosimilar development programme. Objectives: To evaluate the efficacy, pharmacokinetics (PK), safety and immu-nogenicity of BAT1806/BIIB800 in comparison with EU-sourced TCZ in subjects with moderate to severe rheumatoid arthritis with inadequate response to meth-otrexate (MTX). Methods: The study was conducted at 55 centres in China and Europe, between June 2018 and January 2021. Eligible subjects were randomised in a 2:1:1 ratio to one of three treatment groups: (1) BAT1806/BIIB800 up to Week 48, (2) TCZ up to Week 48, or (3) TCZ up to Week 24, followed by BAT1806/BIIB800 from Week 24 to Week 48, administered intravenously every 4 weeks at a dose of 8mg/kg. The primary endpoint was the proportion of subjects achieving an ACR20 response at timepoints pre-specifed to meet the requirements of different Regulatory Agencies: Week 12, for EMA;Week 24, for FDA and NMPA. Equivalence margins applied to differences in ACR20 response rates in the BAT1806/BIIB800 and TCZ treatment groups were pre-specifed as follows: +/-14.5% for EMA (95% confdence interval (CI));-12.0%,15% for FDA (90% CI);+/-13.6% for NMPA (95% CI). Secondary endpoints included pharmacokinetics, safety and immunogenicity. The ICH E9(R1) estimands framework including intercurrent events (related or unrelated to the COVID19 pandemic) was implemented for the ACR20 evaluation. A logistic regression model including 'region' (China and Eastern Europe) and 'previous biologic or targeted synthetic DMARD use' (Yes/No) as captured in Interactive Web Response System as stratifcation factors was utilised to assess equivalence for the primary endpoint. The difference in response rates was estimated and corresponding confdence intervals were derived to assess equivalence for the primary endpoint. This presents results up to Week 24. Results: In total, 621 subjects were randomised to receive BAT1806/BIIB800 (N=312), TCZ (N=155), or TCZ followed by BAT1806/BIIB800 (N=154). The groups were comparable in terms of baseline demographics and disease characteristics, including age, gender, disease activity and disease duration. The estimated proportions of subjects achieving an ACR20 response in the BAT1806/BIIB800 vs. the TCZ groups, respectively, were 68.97% vs. 64.82% at Week 12 and 69.89% vs. 67.94% at Week 24. The estimated difference between ACR response rates was 4.15% (95% CI-3.63, 11.93) at week 12, and 1.94% (90% CI-4.04, 7.92;95% CI-5.18, 9.07) at Week 24. The CIs for the estimated differences between the treatment groups were within the pre-defned equivalence margins (Figure 1). The treatment groups were comparable in terms of serum trough levels, incidence of TEAEs and ADA/NAb positivity (Table 1). Conclusion: BAT1806/BIIB800 has demonstrated equivalent efficacy at Week 12 and Week 24 and a similar PK, safety and immunogenicity profile as reference tocilizumab up to Week 24.

COVID-19 VACCINES IN CANCER PATIENTS

Clinical trials prior to licensing of COVID-19 vaccines collected key information on effectiveness and safety in general population. During rollout of COVID 19 vaccines, larger and diverse populations is vaccinated. Certain groups, e.g. immunocompromised patients or pregnant women, have not been included in pivotal clinical trials or number of patients included was small. Only approximately 4 percent of the patients enrolled in the phase III trial of Pfizer COVID-19 vaccine had a malignancy of any type, and these patients were not analyzed separately to assess vaccine efficacy;patients with cancer were not enrolled on the Moderna COVID-19 vaccine trial. In the Janssen COVID-19 vaccine phase III trial, only 0.5 percent of patients had cancer. Licensure of a vaccine that is rolled out to a large population in a short time requires not only regular spontaneous reporting but also cohort event monitoring to obtain more in-depth information on the safety of the vaccines. A large-scale cohort event monitoring system is very useful for newly introduced vaccines or for new target groups, in addition to existing spontaneous reporting systems and healthcare database studies (i.e. secondary data), as it is complementary to these systems in several ways. It generates more comprehensive safety data, e.g. on disease course and impact of the adverse events. Moreover, in contrast to spontaneously reported data, the denominator of the studied cohort is known (in real time) so that adverse drug reactions frequencies can be calculated. Therefore, European medicines agency stared study Cohort event monitoring to assess safety of COVID-19 vaccines using patient reported event in several European countries including Croatia to collect more data especially in immunocompromised patient, pregnant woman and patients with allergy in medical history. In Croatia all vaccinated adults can be included up to 6 days after the first or the third dose (more info: http://www.halmed.hr). Clinical Guidances suggest that all individuals with active or prior cancer who are eligible for vaccination according to local allocation priorities be fully vaccinated to prevent SARS-CoV-2 infection. Immunocompromised patients may have attenuated immunogenicity to the COVID vaccines, but vaccination is still recommended in immunocompromised populations. For individuals undergoing hematopoietic cell transplantation (HCT) or cellular therapies such as chimeric antigen receptor (CAR)-T-cell therapy, clinical guidances usually suggest waiting at least three months for vaccination, if possible. Given the potential for a blunted immune response to vaccination, it is important to counsel immunocompromised patients on maintaining personal protective measures despite vaccination.

Updated principles of prevention, diagnosis and treatment of COVID-19 in children in Poland - recommendations for paediatricians and family medicine doctors

Since late 2021, we have observed a significant increase in the proportion of children infected with SARS-CoV-2. The course of the disease in children is usually sparsely symptomatic or asymptomatic. However, the predominance of new virus variants makes children more likely to become symptomatically ill and require hospitalisation. This paper aims to update recommendations for managing a child with COVID-19 in out- and inpatient settings. Current options for prevention and antiviral treatment are discussed, noting the limited availability of therapy for children. In most children with COVID-19, the basis for treatment remains symptomatic and supportive therapy and measures to reduce SARS-CoV-2 infection spread.