Comment on ‘Evaluation of the Reported Rates of Severe Hypersensitivity Reactions Associated with Ferric Carboxymaltose and Iron(III) Isomaltoside 1000 in Europe Based on Data from EudraVigilance and VigiBase™ Between 2014 and 2017’

Indirect methods of comparison of the safety of ferric derisomaltose, iron sucrose and ferric carboxymaltose in the treatment of iron deficiency anemia

“…Despite the inclusion of non-comparative studies, the present analysis still represents a marked improvement on approaches that rely on combining data from PV and market share data, where agreement between events and exposure is extremely tenuous, doubly so when relying on proprietary market share data, which is not subject to any external scrutiny from peer reviewers, clinicians or marketing authorization holders [13,42]. Even in the case where exposure estimates could be derived from a source congruent with the event incidence data, previous analyses of HSR incidence after IV iron administration have also been confounded by highly selective use of preferred terms for HSRs and misaligned reporting periods, thereby conflating heightened post-launch vigilance and genuinely elevated incidence of HSRs [13,14,43]. The present analysis is not affected by any of these issues, utilizing only prospective data to ensure agreement between exposure and event counts, and classifying all events using SMQs to ensure that HSRs were recorded consistently using validated and pre-specified definitions [44].…”

“…For instance, recent studies have relied on spontaneous reporting of adverse reactions and market share data in an attempt to compare hypersensitivity reaction (HSR) rates as recorded in pharmacovigilance (PV) databases [13]. Such studies are fundamentally flawed, with the underreporting and differential reporting of spontaneous adverse reactions resulting in scientifically invalid and potentially misleading conclusions [14]. Furthermore, the use of discrete data sources for the numerator and denominator in rate, risk, hazard, or odds derivations violates the foundational principles of quantitative epidemiology to the extent that it is almost guaranteed to result in erroneous outcomes.…”

Evaluation of the reported rates of hypersensitivity reactions associated with iron dextran and ferric carboxymaltose based on global data from VigiBase™ and IQVIA™ MIDAS® over a ten-year period from 2008 to 2017

“…The amount of time a product has been on the market is relevant to this study because reporting rates of spontaneously reported adverse reactions tend to be highest in the introductory phase of a new drug, and to subsequently decrease over time (the 'Weber effect') [36]. Consequently, it can be hypothesized that studies of spontaneously reported adverse reactions show bias in favour of formulations which have been on the market for longer [37]. FCM was launched in 2007 (EU approval, 2007; US approval 2013), and the present study ran from 2008 to 2017.…”

Authors’ reply to Schaffalitzky de Muckadell and colleague’s Comment on “Evaluation of the Reported Rates of Severe Hypersensitivity Reactions Associated with Ferric Carboxymaltose and Iron (III) Isomaltoside 1000 in Europe Based on Data from EudraVigilance and VigiBase™ between 2014 and 2017”

“…We write in response to the letter by Schaffalitzky de Muckadell and Strom [ 1 ] on behalf of Pharmacosmos, the manufacturer of the iron (III) isomaltoside 1000 product. This letter contains a number of criticisms regarding the method used in our article Evaluation of the Reported Rates of Severe Hypersensitivity Reactions Associated with Ferric Carboxymaltose and Iron (III) Isomaltoside 1000 in Europe Based on Data from EudraVigilance and VigiBase™ between 2014 and 2017 [ 2 ].…”

“…Thus, it is difficult to comment on the calculation presented in the letter for a broader definition of hypersensitivity events, as the underlying exposure data have not been presented in the letter, invalidating any comparison. The letter [ 1 ] suggests, without providing quantitative reasoning, that the use of iron (III) isomaltoside 1000 would be underestimated. In fact, for both substances, 100, 500, and 1000 mg vials are available and were included in the analysis.…”