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Adverse events under-reported

Posted on 18 June 2013

York research reveals incomplete reporting of adverse events for bone growth product

Adverse events linked to a product used to promote bone growth are incompletely and inadequately reported in the published literature, reveals new research from the Centre for Reviews and Dissemination (CRD) at the University of York.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a controversial orthobiologic agent used to promote bone growth in spinal surgery. Concerns about the product stemmed from suspicions of under reporting of harms in the publications arising from industry-funded studies.

Systematic reviews provide the best means of informing health decision making, but rely on the availability and integrity of the trial data on which they are based. If unfavourable results are not placed in the public domain then the evidence base is biased, undermining systematic reviews and the decisions that depend on them.

In 2011, Yale University brokered an unprecedented agreement with the manufacturer, Medtronic, to release all its patient-level clinical trial data for unrestricted independent scrutiny and re-analysis. Yale then appointed two teams, CRD and Oregon Health & Science University, to separately conduct systematic reviews and individual participant data (IPD) meta-analyses of the company’s data.

As part of this project, the CRD research team investigated whether the published results of industry-funded trials of rhBMP-2 matched the patient-level data and whether systematic reviews based only on publically available data differed from those incorporating additional confidential data.

Published online in the BMJ, the researchers have found that the published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. While this did not substantially influence effectiveness outcomes, reporting of adverse event data in trial publications was sparse and inconsistent, such that any analysis based solely on the publicly available data could not properly evaluate the safety of rhBMP-2.

Far fewer total adverse events were reported across publications than were collected in the IPD. Several journal articles reported only “serious”, “related”, or “unanticipated” adverse events, without defining these terms. Around 18.5% of adverse events recorded in the patient-level research data from randomised trials have been reported in the entire published literature; this figure was 10.5% for RCTs of rhBMP-2 in its licensed preparation (INFUSE®).

CRD Director, Professor Lesley Stewart said “Having unprecedented access to all the individual participant data enabled a robust evaluation of the benefits and harms of this product and confirmed that adverse events were only partially reported in the published literature. This underscores the importance that the full results of all trials, positive, negative or inconclusive, are made available for systematic review and decision making.”

She added “This has been a ground breaking study in which we have been delighted to partner with Yale. Medtronic also deserve credit for helping pioneer this move towards greater openness and transparency.”