Abstract

Objective To investigate whether published results of industry funded trials of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion match underlying trial data by comparing three different data sources: individual participant data, internal industry reports, and publicly available journal publications and conference abstracts.

Data collection and synthesis The manufacturer of rhBMP-2 products (Medtronic; Minneapolis, MN) provided complete individual participant data and internal reports for all its studies of rhMBP-2 in spinal fusion. We identified publications and conference abstracts through comprehensive literature searches. We compared outcomes provided in the individual participant data against outcomes reported in publications. For effectiveness outcomes, we compared meta-analyses of randomised controlled trials based on each of the three data sources. For adverse events, meta-analysis of the published aggregate data was not possible and we compared the number and type of adverse events reported between data sources.

Results 32 publications reported outcomes from 11 of the 17 existing manufacturer sponsored studies. For individual randomised controlled trials, 56% (9/16) to 88% (15/17) of effectiveness outcomes known to have been collected were reported in the published literature. Meta-analyses of effectiveness data were almost identical for pain outcomes and similar for fusion across the three data sources. A minority of adverse event data known to have been collected were reported in the published literature. Several journal articles reported only “serious,” “related,” or “unanticipated” adverse events, without defining these terms. Others reported a small proportion of the collected adverse event categories. Around 23% (533/2302) of the total adverse events collected in published randomised controlled trials have been reported in the literature, with randomised controlled trials evaluating the licensed preparation (Infuse) reporting around 11% (122/1108) of collected adverse events.

Conclusions The published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. This did not lead to substantially different results for meta-analysis of effectiveness outcomes. In contrast, reporting of adverse event data in trial publications was inadequate and inconsistent to the extent that any systematic review based solely on the publicly available data would not be able to properly evaluate the safety of rhBMP-2. Analysis of individual participant data enabled the most complete, detailed, and in-depth analysis and was not more resource intensive than extracting, collating, and analysing aggregate data from multiple trial publications and conference abstracts. Confidential internal reports presented considerably more adverse event data than publications, and in the absence of individual participant data access to these reports would support more accurate and reliable investigation, with less time and effort than relying on incomplete published data.

Discussion

Controversy around use of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion began with suggestions that inadequate peer review and editorial oversight were responsible for an apparent absence of adverse events from early peer reviewed publications of industry sponsored studies. A subsequent investigation led by the editor in chief of The Spine Journal¹⁴ found fewer reported adverse events in academic publications of industry sponsored studies than in related study data available in FDA summaries and public meeting documents. The FDA materials available for that investigation appear to be partial outcome data from a subset of industry funded studies evaluating Infuse/LT-CAGE, Infuse/MASTERGRAFT, and AMPLIFY rhBMP-2 matrix preparations. Our investigation was able to explore this issue in greater depth having individual participant data on all recorded effectiveness and safety outcomes as well as internal reports provided for all Medtronic funded studies of rhBMP-2 for spinal fusion. Given their previous confidentiality, high degree of detail, and availability for all known studies, we consider the combination of individual participant data and internal reports to be the most comprehensive and trustworthy source of Medtronic trial evidence available to date.

Source: BMJ