The trouble with calling for an investigation to clear your name is, as Oscar Wilde could have told you, that it only works if you’re innocent. In 2011, researchers looking at Medtronic’s spine fusion product Infuse suggested that it was less safe and effective than company-funded research suggested, and furthermore that this research had been biased. Consequently Medtronic gave the nod – and $2.5m – to two trials to prove both company and product beyond reproach.
Now the results are in, and they have done no such thing. One study has shown that Infuse is no better than bone grafting and carries an increased risk of cancer, and also reported that the earlier Medtronic-funded Infuse trials were indeed biased. Infuse was approved in the US in 2002 and accounts for 3% of Medtronic’s revenue, bringing in $528m worldwide in fiscal 2013. Sales were already on a downward trend, and this could well now accelerate.
Yoda: increased, cancer risk is
Infuse is a formulation of a synthetic bone growth factor, recombinant human bone morphogenetic protein-2 (rhBMP-2), and is implanted during spinal surgery. rhBMP-2 has been linked with adverse events including retrograde ejaculation, radiculitis and cancer.
Two years ago, research was published claiming that complication rates with Infuse were greater than shown in the previously reported medical literature. Medtronic engaged and funded the Yale University Open Data Access (Yoda) project, an effort to disseminate trial data and improve transparency, to see off this criticism.
Under Yoda’s umbrella, Oregon Health and Science University and the University of York reviewed the entire body of scientific evidence regarding the safety and effectiveness of Infuse. The Oregon group concluded that Infuse had similar rates of successful fusion as iliac crest bone autografting, the gold standard treatment for spinal fusion, in which bone harvested from the hip is used to fix the spine.
More damagingly, the Oregon researchers wrote that rhBMP-2 was associated with an increased chance of cancer, with a 24-month risk ratio of 3.45, although the actual event rates were low.
The York group echoed the efficacy findings but said that cancer data were inconclusive. Both groups published their research in Annals of Internal Medicine, and in accordance with Yoda’s transparency agenda both papers were published in full for free.
The York-based researchers did not structure their study to assess bias in the earlier Medtronic-sponsored trials, but the Oregon researchers did, and reported that the publications misrepresented the effectiveness and harms of Infuse through selective reporting, underreporting and duplicate publication.
The bottom line is that the research will reduce sales of Infuse, particularly for off-label use. Infuse is approved for anterior lumbar interbody fusion procedures in adults with degenerative disc disease, for tibial fractures in adults and for oral-maxillofacial surgery.
However, it has been far more widely prescribed, with analysts from Wells Fargo saying that, before a steep decline prompted by the 2011 reports, the majority of its sales came from off-label use. The main off-label uses to which Infuse was put were posterior lumbar interbody fusion or transforaminal lumbar interbody fusion.
And that decline has been steep; in June 2011 the New York Times estimated that Medtronic had earned $900m from Infuse in the previous fiscal year.
Both Yoda research groups stopped short of recommending against Infuse. Instead they said that clinicians should explain the findings to patients to allow them to make informed choices, balancing the increased cancer risk against the second surgery necessitated by iliac crest grafting.
Medtronic’s 2014 guidance suggests that Infuse sales will be flat or decline by around 5% – an improvement over the decline of 15% seen in 2013. Wells Fargo, by contrast, estimate that Infuse sales will fall 20% in 2014.
The investigation Medtronic began as a way to improve its fortunes may yet make things worse.