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. 2021 Nov;35(6):749-764.
doi: 10.1007/s40259-021-00498-3. Epub 2021 Oct 12.

Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project

Gianluca Trifirò  1 , Valentina Isgrò  2 , Ylenia Ingrasciotta  3 , Valentina Ientile  3 , Luca L'Abbate  2 , Saveria S Foti  4 , Valeria Belleudi  5 , Francesca Poggi  5 , Andrea Fontana  6 , Ugo Moretti  2 , Riccardo Lora  2 , Alberto Sabaini  7 , Ilenia Senesi  8 , Carla Sorrentino  9 , Maria R Puzo  10 , Angela Padula  11 , Mariano Fusco  12 , Roberta Giordana  13 , Valentina Solfrini  14 , Aurora Puccini  14 , Paola Rossi  15 , Stefania Del Zotto  16 , Olivia Leoni  17 , Martina Zanforlini  18 , Domenica Ancona  19 , Vito Bavaro  19 , Donatella Garau  20 , Stefano Ledda  21 , Salvatore Scondotto  22 , Alessandra Allotta  22 , Marco Tuccori  23 , Rosa Gini  24 , Giampaolo Bucaneve  25 , David Franchini  26 , Anna Cavazzana  27 , Valeria Biasi  27 , Stefania Spila Alegiani  28 , Marco Massari  28 ; VALORE Project Collaborators
Collaborators, Affiliations

Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project

Gianluca Trifirò et al. BioDrugs. 2021 Nov.

Abstract

Background: Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings.

Objective: The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID.

Methods: A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010-2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association.

Results: From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015-2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively.

Conclusion: The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010-2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings.

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Conflict of interest statement

In the last 3 years, Gianluca Trifirò has served on advisory boards/seminars funded by several pharmaceutical companies marketing biologics originators and biosimilars on topics unrelated to this paper; he was the scientific director of a Master program on pharmacovigilance, pharmacoepidemiology, and real-world evidence at University of Messina, which received non-conditional grants from various pharmaceutical companies; he coordinated a pharmacoepidemiology team at the University of Messina until October 2020, which received funding for conducting observational studies from various pharmaceutical companies; he is also scientific coordinator of the academic spin-off “INSPIRE srl,” which received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.), based on funding from pharmaceutical companies. None of these listed activities are related to the topic of the manuscript. Ylenia Ingrasciotta is the CEO of the academic spin-off “INSPIRE srl” of the University of Messina, which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.). Rosa Gini is the head of the Pharmacepidemiology Unit of ARS Toscana. The budget of her unit is partially supported by contracts with pharmaceutical companies whose products are studied in the VALORE project. Such studies are compliant with the ENCePP Code of Conduct. Valentina Isgrò, Valentina Ientile, Luca L’Abbate, Saveria Serena Foti, Valeria Belleudi, Francesca Poggi, Andrea Fontana, Ugo Moretti, Riccardo Lora, Alberto Sabaini, Ilenia Senesi, Carla Sorrentino, Maria Rosalia Puzo, Angela Padula, Mariano Fusco, Roberta Giordana, Valentina Solfrini, Aurora Puccini, Paola Rossi, Stefania Del Zotto, Olivia Leoni, Martina Zanforlini, Domenica Ancona, Vito Bavaro, Donatella Garau, Stefano Ledda, Salvatore Scondotto, Alessandra Allotta, Marco Tuccori, Giampaolo Bucaneve, David Franchini, Anna Cavazzana, Valeria Biasi, Stefania Spila Alegiani, and Marco Massari have no conflicts of interest that are directly relevant to the content of this article.

Figures

Fig. 1
Fig. 1
VALORE project multi-database network using common data model. id index date, atc anatomical therapeutic chemical
Fig. 2
Fig. 2
Age-adjusted yearly prevalence of use (per 1000 people) of biological drugs approved for immune-mediated inflammatory diseases, stratified by region in the period 2010–2019. Age adjustment was performed using standardized direct method, based on calendar year-specific Italian population for the following age categories: < 18, 18–44, 45–64, and ≥ 65 years
Fig. 3
Fig. 3
Cumulated number of biological drug users (left) and person-years (PYs) of biological drug exposure (right) during the study period 2010–2019, stratified by regions
Fig. 4
Fig. 4
Cumulated number of biological drug users (left) and person-years (PYs) of biological drug exposure (right) during the study period 2010–2019, stratified by single molecule
Fig. 5
Fig. 5
Distribution of infliximab (A), adalimumab (B), and etanercept (C) originator/biosimilar use in the years 2015–2019, stratified by region and calendar year, and total number of users of those individual biological drugs, stratified by originator/biosimilar use (D). Biosimilar users: one or more dispensing of biosimilar only; originator users: one or more dispensing of originator only; originator + biosimilar users: one or more dispensing of biosimilar and one or more dispensing of originator
Fig. 6
Fig. 6
Approximate power curves to estimate the required amount of drug exposure (PYs) to detect a statistically significant ratio of 1.5 (weak association), 2 (moderate association), 4 (strong association), and 6 (very strong association) between the IR of a given safety outcome in users of biological drugs approved for IMIDs vs. the general population, using one-sided significant level α = 0.05 and a power of 80% (β = 0.2). Note: The following background IRs were considered based on scientific literature: 175 for 100,000 PYs for congestive heart failure, 95 for 100,000 PYs for tuberculosis, 10.4 for 100,000 PYs for optic neuritis, 382 for 100,000 PYs for neoplasms, 164.1 for 100,000 PYs for SARS-CoV-2 infection, 4312 for 100,000 PYs for severe infections. IMID immune-mediated inflammatory diseases, IR incidence rate, PYs person-years, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
Fig. 7
Fig. 7
Minimum detectable relative risk for important pregnancy-related adverse events associated to biological drug users in pregnant women
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