The effect of exposure misclassification in spontaneous ADR reports on the time to detection of product-specific risks for biologicals: a simulation study.

BACKGROUND AND OBJECTIVE: The availability of accurate product-specific exposure information is essential in the pharmacovigilance of biologicals, because differences in the safety profile may emerge between products containing the same active substance. In spontaneous adverse drug reaction (ADR) reports, drug exposure may, however, be misclassified, that is, attributed to the incorrect product. The aim of this study was to explore the effect of exposure misclassification on the time to detection of product-specific risks in spontaneous reporting systems. METHODS: We used data simulations to explore the effect of exposure misclassification. We simulated an active substance-specific subset of a spontaneous reporting system and used the proportional reporting ratio for signal detection. The effect of exposure misclassification was evaluated in three test cases representing product-specific ADRs that may occur for biologicals and studied in relative terms by varying the model parameters (market share and relative risk). RESULTS: We found that exposure misclassification results in the largest delay in identification of risks that have a weak association (relative risk < 2 or 3) with the product of interest and in situations where the product associated with the unique risk has a large (>50%) market share. The absolute public health impact of exposure misclassification, in terms of cases/time to detection, varied considerably across the test cases. CONCLUSION: Exposure misclassification in ADR reports may result in a delayed detection of product-specific risks, particularly in the detection of weak drug-event associations. Our findings can help inform the future implementation and refinement of product-specific and batch-specific signal detection procedures.

Associations between patient and disease characteristics and severe adverse events during immune checkpoint inhibitor treatment: An observational study.

AIM: With increasing use of immune checkpoint inhibitors (ICIs) more patients will develop severe and potentially life-threatening immune-related adverse events (irAEs). So far, predictive models for the occurrence of grade ≥3 irAEs are lacking. Therefore, we analysed associations between patient and disease characteristics, and the occurrence of grade ≥3 irAEs. METHODS: Patients with cancer who were treated with anti-PD-1 (+/-anti-CTLA-4) between July 2015 and February 2020, and who were prospectively included in the MULTOMAB-trial, were eligible for this cohort study. Time to and occurrence of grade ≥3 irAEs according to CTCAE v5.0 were retrospectively registered. The associations between patient and disease characteristics and irAE occurrence were analysed using the competing risk cox-regression model of Fine and Gray. Analyses were performed separately in patients treated with monotherapy (anti-PD-1) and combination therapy (anti-PD-1 + anti-CTLA-4). Subgroup analyses were performed in tumour types with the highest number of patients; melanoma and NSCLC. RESULTS: Out of 641 patients, 106 patients (17%) experienced grade ≥3 irAEs. None of the analysed factors were associated with grade ≥3 irAE occurrence in the monotherapy (n = 550) or the combination therapy (n = 91) groups, nor in the subgroup analyses. Of interest, none of the patients with NSCLC with a WHO performance status of 0 (n = 34) experienced grade ≥3 irAEs. Most common NSCLC histology types were adenocarcinoma (n = 99/55%) and squamous cell carcinoma (n = 39/22%). CONCLUDING STATEMENT: This study shows that patient and disease characteristics are not able to predict the occurrence of serious AEs in patients treated with ICIs.

Identifiability of Biologicals in Adverse Drug Reaction Reports Received From European Clinical Practice.

Biologicals are established treatment options that require pharmacovigilance adapted to their specific nature, including the need for products to be identifiable up to the specific manufacturer in reports of adverse drug reactions (ADRs). This study explored the identifiability of 10 classes of similar and related biologicals up to the level of the manufacturer in ADR reports received from European clinical practice between 2011 and June 2016. Adequate identifiers were reported for 96.7% of the suspected biologicals, ranging from 89.5% for filgrastim to 99.8% for interferon beta-1a. The product identifiability remained consistently high over time for classes of biologicals for which biosimilars were introduced during follow-up. The overall batch traceability was, however, only ensured for 20.5% of the suspected biologicals and needs further improvement. This study shows that the European system for identification of ADRs to the level of the manufacturer is robust, allowing for the timely detection of potential product-specific safety signals for biologicals.

Traceability of Biologics in The Netherlands: An Analysis of Information-Recording Systems in Clinical Practice and Spontaneous ADR Reports.

INTRODUCTION AND OBJECTIVE: Pharmacovigilance requirements for biologics mandate that EU Member States shall ensure that any biologic that is the subject of a suspected adverse drug reaction (ADR) is identifiable by brand name and batch number. Recent studies showed that brand name identification is well established, whereas batch numbers are (still) poorly reported. We evaluated information-recording systems and practices in the Dutch hospital setting to identify determinants for brand name and batch number recording as well as success factors and bottlenecks for traceability. METHODS: We surveyed Dutch hospital pharmacists with an online questionnaire on systems and practices in hospitals for recording brand names and batch numbers. Additionally, we performed an analysis of the traceability of recombinant biologics in spontaneous ADR reports (received between 2009 and 2014) from the Netherlands Pharmacovigilance Centre Lareb. RESULTS: The survey showed that brand names are not routinely recorded in the clinical practice of Dutch hospitals, whereas batch numbers are poorly recorded. Seventy-six percent of the 1523 ADR reports for recombinant biologics had a traceable brand name whereas 5% of these reports contained a batch number. The results suggest a possible relationship between the availability of brand and batch number information in clinical practice and the inclusion of this information in ADR reports for biologics. CONCLUSION: The limited traceability of brand names and batch numbers in ADR reports may be primarily caused by the shortcomings in the recording of information in clinical practice. We recommend efforts to improve information-recording systems as a first step to improve the traceability of biologics in ADR reporting.

Traceability of biologicals: present challenges in pharmacovigilance.

INTRODUCTION: Traceability is important in the postmarketing surveillance of biologicals, since changes in the manufacturing process may give rise to product- or batch-specific risks. With the expected expansion of the biosimilar market, there have been concerns about the ability to trace individual products within pharmacovigilance databases. AREAS COVERED: The authors discuss the present challenges in the traceability of biologicals in relation to pharmacovigilance, by exploring the processes involved in ensuring traceability. They explore both the existing systems that are in place for the recording of exposure information in clinical practice, as well as the critical steps involved in the transfer of exposure data to various pharmacovigilance databases. EXPERT OPINION: The existing systems ensure the traceability of biologicals down to the manufacturer within pharmacy records, but do not support the routine recording of batch information. Expected changes in supply chain standards provide opportunities to systematically record detailed exposure information. Spontaneous reporting systems are the most vulnerable link in ensuring traceability, due to the manual nature of data transfer. Efforts to improve the traceability should, in the short term, be focused toward encouraging health professionals and patients to systematically record and report detailed exposure information. Long-term solutions lie in expanding the accessibility to, and increasing the electronic exchange of exposure data.

[Research into the risk of malignancy from biologicals: utility of meta-analysis hampered]. / Kankerrisico van biologicals vaststellen? Beperkingen in bruikbaarheid van meta-analyse.

Safety meta-analyses could play an important role in capturing fragmented safety data from underpowered clinical studies. Their utility, however, is hampered by the same constraints surrounding clinical studies, including limited external validity, inconsistent classification and the underreporting of safety data. When long-term adverse effects are studied, like the risk of malignancy associated with the use of inhibitors of tumour necrosis factor (TNF) alpha, particular scrutiny should be exercised in deciding whether the individual trials included have allowed sufficient follow-up time for the safety endpoint to occur.

Traceability of biopharmaceuticals in spontaneous reporting systems: a cross-sectional study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases.

BACKGROUND: Adverse drug reactions (ADRs) of biopharmaceuticals can be batch or product specific, resulting from small differences in the manufacturing process. Detailed exposure information should be readily available in systems for postmarketing safety surveillance of biopharmaceuticals, including spontaneous reporting systems (SRSs), in which reports of ADRs are collected. OBJECTIVE: The aim of this study was to explore the current status of traceability of biopharmaceuticals in the US and the EU up to patient level in SRSs. DESIGN AND SETTING: A cross-sectional study was conducted over the period 2004-2010, including ADR reports from two major SRSs: the FDA Adverse Event Reporting System (FAERS) in the US and EudraVigilance (EV) in the EU. MAIN OUTCOME MEASURES: The availability of batch numbers was determined for biopharmaceuticals, and compared with small molecule drugs. For biopharmaceuticals for which a biosimilar has been approved for marketing in the EU, the identifiability of the product (i.e. the possibility of distinguishing the biosimilar from the reference biopharmaceutical) was determined. RESULTS: A total of 2,028,600 unique ADR reports were identified in the FAERS, reporting a total of 591,380 biopharmaceuticals (of which 487,065 were suspected). In EV there were 2,108,742 unique ADR reports, reporting a total of 439,971 biopharmaceuticals (356,293 suspected). Overall, for 24.0 % of the suspected biopharmaceuticals in the FAERS and 7.4 % of the suspected small molecule drugs (p < 0.001) batch numbers were available. A similar pattern was seen in EV: for 21.1 % of the suspected biopharmaceuticals batch numbers were available, compared with only 3.6 % of the small molecule drugs (p < 0.001). In both SRSs, consumers were most likely to report a batch number for suspected biologicals (36.3 % in the FAERS and 40.7 % in EV). A total of 13,790 biopharmaceuticals (9,759 suspected) for which a biosimilar has been approved in the EU were identified in EV. For 90.4 % of these biopharmaceuticals and 96.2 % of the suspected biopharmaceuticals the product was clearly identifiable. CONCLUSION: This study underlines the need for improving traceability of biopharmaceuticals, in particular with respect to individual batches, allowing better identification and monitoring of postmarketing safety issues related to biopharmaceuticals.