Oral presentations & e-posters session (Eastern Europe, East Africa, Middle East, Asia, Australia & New Zealand)

Patient Safety & Pharmacovigilance

K.A. Nikolaou¹, C. Kani², F. Bacopoulou^2,3, S.L. Markantonis¹

¹Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece

²University Research Institute of Maternal and Child Health & Precision Medicine, and UNESCO Chair in Adolescent Health Care, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

³Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

Background: Immune checkpoint inhibitor (ICI) combinations are currently first-line treatment options for clear-cell renal cell carcinoma (ccRCC). Moreover, ICIs are recommended for platinum-refractory urothelial carcinoma (PRUC). ICIs have been associated with a new type of toxicity, immune-related adverse events (AEs).

Aim: To compare the safety of first-line treatments for ccRCC and second-line ICIs versus chemotherapy for PRUC. Also, to estimate the economic impact of first-line ICI combinations for ccRCC, on the Greek National Health System (ESY).

Methods: CENTRAL, PubMed and clinicaltrials.gov were searched to identify randomized controlled trials (RCTs) with safety outcomes for the treatments studied. Review Manager software was used for statistical analysis. For the economic analysis, data were collected from the Price Bulletin of Medicines for Human Use.

Results: Nine RCTs were selected for the systematic review of ccRCC and two for the systematic review of PRUC. The meta-analysis of first-line treatments for ccRCC suggests that ICI combinations have a lower risk of “treatment-related AEs” than sunitinib (OR=0.53, 95%CI:0.38-0.73). The meta-analysis of second-line regimens for PRUC suggests that ICIs have a lower risk of “AEs” than chemotherapy (OR=0.32, 95%CI:0.17-0.60). The economic analysis estimated that pembrolizumab+axitinib included an additional cost of 55,154.74€ per patient per year compared with nivolumab+ipilimumab, for first-line treatment of patients with ccRCC, and an additional cost of 64,575.65€ per patient for the median progression-free survival of each treatment for the intermediate- and poor-risk population.

Conclusions: First-line regimens for ccRCC that include ICIs seem to have a lower risk of AEs than sunitinib. The ICIs, atezolizumab, pembrolizumab, seem to have a lower incidence of toxicity than chemotherapy in patients with PRUC, but more studies need to be conducted for safer conclusions. ESY expenditure seems to be lower with nivolumab+ipilimumab compared to pembrolizumab+axitinib for patients with ccRCC, without taking into account rebates applied.

Pharmaceutical Medicine

Viviane Klingmann¹, Sibylle Reidemeister², Ingrid Klingmann³, Manfred Wargenau⁴

¹Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany

²Novartis Pharma AG, Global Drug Development /Technical Research & Development, Basel, Switzerland

³Pharmaplex bv, Wezembeek-Oppem, Belgium

⁴M.A.R.C.O. GmbH & Co. KG, Institute for Clinical Research and Statistics, Düsseldorf, Germany

Introduction: Paediatric medicine development needs to be facilitated and shortened. Justification of the formulation selection is a challenging element in paediatric development negotiations with authorities as no―scientifically sound, with broadly recognised acceptability―assessment methods exist.

Objective: Enabling frontloading of oral formulation selection with a standardised, statistically sound acceptability assessment method before entering the paediatric efficacy and safety studies.

Methods: In statistically powered paediatric patient studies with placebo-containing oral formulations, performed with standardised investigator-observed assessment methods and defined evaluation criteria for swallowability and palatability in children, statistically significant differences between the acceptability of several oral formulations were detected (Klingmann et al. [1-6]). To further strengthen discrimination, a new composite endpoint acceptability method was established combining a deglutition score and palatability assessment. The data from studies [5,6] investigating mini-tablets, oblong tablets, orodispersible films and syrup were used to evaluate the suggested acceptability assessment tool for the composite endpoint and to demonstrate its validity, expediency and applicability. A factor analysis was applied for each formulation and the results for acceptability defined as composite endpoint were calculated for the different formulations. Each outcome category of acceptability was then related to the outcome of the factor analysis as expressed by the linear combination for the main component.

Results: A high association between acceptability categories and the results from factor analysis was recognized. Comparison of the acceptability categories with regard to the main component by analysis of variance yielded a p-value < 0.0001. All formulations showed highly consistent results. Conclusion: The suggested acceptability as composite endpoint can be regarded as a valid approach representing the result of the factor analysis and providing high validity and reliability of the suggested approach for assessing acceptability as composite endpoint. It is highly suitable and efficient to select different preferences of oral formulations before entering indication-specific efficacy or safety studies.

References:

1. Spomer N, Klingmann V et al., Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study, Arch Dis Child, 2012; 97:283-286.
2. Klingmann V et al., Favourable acceptance of mini-tablets compared to syrup: a randomised controlled trial in small children, J Pediatr, 2013; 163:1728-1732.
3. Klingmann V et al., Acceptability of uncoated mini-tablets in neonates - a randomized controlled trial, J Pediatr, 2015;167:893-896.
4. Klingmann V et al., Acceptability of multiple uncoated mini-tablets in infants and toddlers: A randomized controlled trial, J Pediatr, 2018; 201:202-207.
5. Klingmann, V et al., Acceptability of an orodispersible film compared to syrup in neonates and infants: A randomized controlled trial. Eur J Pharm Biopharm, 2020; 151:239-245.
6. Münch J et al., Acceptability of Small-Sized Oblong tablets in Comparison to Syrup and Mini-tablets in Infants and Toddlers: A Randomized Controlled Trial. Eur J Pharm Biopharm, 2021; 166:126-134.

Regulatory Science, Regulatory Affairs, Ethical, Legal, Social related issues

Georgia Livieri^1,4, Eleni Mangina², Evangelos Protopapadakis³, Andrie Panayiotou⁴

¹Ethics Research Associate, Cardiovascular Epidemiology and Genetics Research Lab

²College of Science, UCD College of Science, Dublin, Ireland

³National and Kapodistrian University of Athens, Faculty of Philosophy, Athens, Greece

⁴Cyprus International Institute for the Environmental and Public Health, Faculty of Health Sciences, Limassol, Cyprus

Pharmaceutical companies have been challenged either with regards to the rising development costs or the satisfaction of the need to discover new approaches in differentiating the candidate drugs. Digitalization has been spreading with a rapid pace throughout Europe affecting both healthcare and pharmaceutical sectors. Recent advances in digital health technology, including wearables, sensors, in-home clinical devices, have given space to several data endpoints leading these devices to be proved as a valuable tool in clinical trials’ programs of the modern era. Specifically, vast amounts of data are being collected, processed and analyzed, coming either from the phase of development and production of medicines or from patient treatments and its subsequent outcomes. Due to covid-19 pandemic and social distancing measures, a huge demand in alternatives for in-person care, including virtual trials, telemedicine and remote patient monitoring, has been promoted, as multiple stakeholders seemed to be benefited at a wide range. Therefore, there is an urgent need for the “capitalization” of pharma industry in the new digital era of healthcare and for the integration of digital technologies across its value chain, contributing to the overall support of its clients. However, several issues, emerging from the digital transformation in healthcare, need to be tackled. Despite the offered opportunities, this study aims to address the gaps and challenges raised by the digital technology use in drug developers, being gathered from a philosophical perspective.

RWD / Real World Evidence/ Big Data/ Pharmacoepidemiology

Foteini Dermiki-Gkana, Panagiotis Nikolaos Lalagkas, Christos Kontogiorgis, Theodoros Constantinides

Laboratory of Hygiene and Environmental Protection, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece

Background: The outbreak of COVID-19 pandemic had a severe psychological impact on the Greek population due to the fear of COVID-19 disease, death, the social isolation, and the extended periods of quarantines during the period 2020-2021.

Aim: The significant negative impact of COVID-19 pandemic crisis on the mental health of Greeks has enforced the execution of a study focusing on psychiatric drugs’ (antidepressants (N06A), anxiolytics (N05B) and hypnotics/sedatives (N05C)) consumptions and the investigation of the mental disorders being responsible for this.

Methods: We analyzed community pharmacies’ sales data of 31 psychiatric medicines, provided by the IQVIA HELLAS database, to calculate their annual consumption for the years 2019 and 2020, expressed in "Number of Daily Doses (DDDs) per 1,000 inhabitants per day”. Furthermore, for the same time period, we estimated their use per diagnosis of mental disorder (ICD-10 codes) using the National Organization of Health Care Provision (EOPYY) database.

Results: The consumption of antidepressants, anxiolytics and hypnotics/sedatives increased in 2020 compared to 2019 by 7.2%, 8.1% and 2.6%, respectively. In 2020, the highest use (51,6 DDDs/1,000 inhabitants/day) was observed for the selective Serotonin Reuptake Inhibitors (N06AB) and more specifically for the active substance escitalopram (N06AB10). Regarding anxiolytics, benzodiazepines (N05BA) showed the highest consumption (37.3 DDDs/1,000 inhabitants/day) in 2020. Alprazolam (N05BA12) was the most widely prescribed medicine and recorded an increase of 13,6% from 2019 to 2020. Furthermore, by analyzing the reason of these psychiatric drugs’ prescriptions, it was found that Depressive disorders F32 and F33, Other anxiety disorders (F41) and Sleep disorders not due to a substance or known physiological condition (F51) were the most common diagnoses on the prescriptions of psychiatric drugs. Finally, the number of patients with Anxiety disorders (F41), who received anxiolytics and sedatives/hypnotics was increased 5% and 3% respectively from 2019 to 2020.

Conclusions: We observed an increasing trend in the consumption of antidepressants, anxiolytics, and hypnotics/sedatives during the COVID-19 pandemic (2020) compared to pre-pandemic period (2019). Moreover, we observed that four mental disorders were the main reason for the higher consumption of psychiatric medicines.

Translational Research & Precision Medicine

Daniela Fazzotta, Thomas D. Szucs, Annette Mollet

Faculty of Medicine, University of Basel, Switzerland

Background: Cell and gene therapies (CGTs) are highly specialized one-time technologies with curable potential targeting rare diseases, previously difficult-to-treat, or untreatable diseases.

Objective: The scope of this study was to promote objective value assessment of CGTs by investigating three rare diseases: spinal muscular atrophy (SMA), hemophilia A (Hem A), and sickle cell disease (SCD).

Methods: A systematic review of reports published between January 1, 2000, and September 30, 2021, was conducted on PubMed. For the set criteria 25 eligible studies on 17 interventions were found.

Results: Hem A with inhibitors (for patients developing inhibitors against rFVIII) reported the highest SOC costs: While lifetime cost-estimates per patient reached up to USD 99.21 million for SOC with BPA Prophylaxis (at 21.28 LYs, 15.21 QALYs), they were only USD 9.27 million for intervention with Hypothetical Gene Therapy (at 21.28 LYs, 15.41 QALYs), generating per-patient-cost-savings of roughly USD 90 million in favor of the US health system. Cost-savings per patient without inhibitors were less but still reached up to roughly USD 9.8 million (rFVIII Prophylaxis $23.47m vs $13.69m for Valoctogene Roxa-parvovec gene therapy [at 23.56 LYs, 17.31 QALYs vs 26.53 LYs, 19.09 QALYs, respectively]). Similarly, in SCD the per-patient cost-savings with CGTs reached up to roughly USD 6.4 million (Hydroxyurea $8.75m vs $2.37m hypothetical gene therapy [at not reported LYs/QALYS vs 26.4 LYs, 29.9 QALYs for gene therapy]). Finally, in SMA, CGTs generated cost-savings of roughly up to USD 2.4 million per patient (Nusinersen $6.32m vs $3.93m gene therapy Onasemnogene Abeparvovec [at 7.11 LYs, 5.29 QALYs vs 20.09 LYs, 13.33 QALYs, respectively]), see Table 1.

Conclusion: The results demonstrate that CGTs are significantly less expensive (up to $90m per-person) compared to lifelong chronic SOC treatments while generating significantly more health gains (SMA: +14.18 LY/+12.18 QALYs, BSC vs Onasemnogene).

Patient Centricity in Research & Development and Health Technology Assessment

A. Chantzaras¹, A. Margetis¹, C. Kani¹, V. Koutsiouris², F. Bacopoulou¹

¹Health Technology Assessment and Reimbursement Committee, Ministry of Health, Athens, Greece

²Ministry of Health, Athens, Greece

Objectives: The purpose of the present study was to evaluate the type of medicinal products and the pace of recommendations issued by the Health Technology Assessment (HTA) Committee in Greece over 4 years, from its establishment in 2018 until 2022.

Methods: Data regarding new medicinal products/extensions of indications were collected from the HTA Committee’s database and other publicly available sources. Analyses were carried out with respect to the legal basis of approval of the medicinal products. A secondary analysis by ATC1 level was also performed.

Results: During the study period, 140 new active substances, 37 orphan medicinal products, and 44 vaccines/biosimilars were submitted to the Greek HTA Committee. Another 92 applications referred to known/well established/hybrid products, whereas 36 applications pertained to fixed combinations. Most medicinal products belonged to the category of antineoplastic and immunomodulating agents (ATC-1 L) (25.98%) followed by alimentary tract and metabolism agents (ATC-1 A) (14.2%). Total recommendations during the study period were 216 (36.1%, 29.2%, 18.1%, 10.6%, and 6%, for new active substances, known/well established/hybrid products, biosimilars/vaccines, fixed combinations, and orphans, respectively).

Conclusions: The majority of HTA recommendations referred to new active substances, with antineoplastic and immunomodulatory effects. These findings corroborate the products’ assessment plan outlined in the European HTA regulation and underline the emergence of the new era of immuno/oncology treatments.

Translational Research & Precision Medicine

Kokkali¹, A. Tsonis¹, C. Kani², F. Bacopoulou^2,3, S.L. Markantonis¹

¹Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece

²University Research Institute of Maternal and Child Health & Precision Medicine, and UNESCO Chair in Adolescent Health Care, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

³Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

Background: Most European countries have adopted Health Technology Assessment (HTA) practices to support decision-making processes in health care at a policy level. Two CAR T-cell therapies have been recently approved in Greece for the treatment of patients with acute lymphoblastic leukemia (ALL) and relapsed or refractory lymphomas (DLBCL, PMBCL), tisagenlecleucel and axicabtagene ciloleucel.

Aim: To study the phase III clinical trials on which the approval of the CAR T-cell therapies was based, and critically evaluate the benefits and risks of both treatments. Also, to estimate the total cost of CAR T-cell treatment in Greece and review reimbursement schemes, proposed or implemented by health organizations worldwide, and to propose a suitable reimbursement model for Greece.

Methods: Efficacy and safety data on tisagenlecleucel and axicabtagene ciloleucel from EMA evaluation reports and published clinical trials were collected. Completed studies were assessed for the magnitude of clinical benefit of each therapy (ESMO-MCB scale) and the risk of bias (Cochrane Collaboration tool). Finally, the cost of each therapy was estimated.

Results: Only 7 of the 49 clinical trials found in the literature had published results. ALL patients showed a positive response to treatment (ORR 33.9%-81.3%), but ultimately the magnitude of the clinical benefit was moderate (Grade 2) and the clinical trials were of low quality. The cost of therapy per patient for ALL with tisagenlecleucel, and DLBCL or PMBCL with axicabtagene ciloleucel, was estimated to be high, but comparable (295,282.47€ and 286,260.78€, respectively). The lowest cost was for DLBCL treatment with tisagenlecleucel (278,815.24€).

Conclusion: Both CAR T-cell therapies provide an important actual clinical benefit and a moderate improvement in added benefit over conventional chemotherapy regimens. Outcomes-based staged payments, in line with other European countries, may be the most acceptable reimbursement approach for these therapies in Greece. Despite their high cost these health benefits might be cost effective.