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Looking Back at INFUSE: 2002 to Today

In mid-June, two independent research groups released a long-awaited review of trial data regarding the use of Medtronic’s INFUSE recombinant human bone morphogenetic protein-2 (rhBMP-2). The following timeline summarizes events that brought us here from the product’s initial clearance.

 July 2002:

Under a PMA, FDA approves Medtronic Sofamor Danek’s INFUSE Bone Graft/LT-Cage Lumbar Tapered Fusion Device, a proprietary formulation of rhBMP-2, for use in anterior lumbar interbody spinal fusion to treat skeletally-mature patients with degenerative disc disease at a single level from L2-S1.

 June 2003:

Analysis of 679 patients from four prospective groups finds that INFUSE, used with the LT-Cage, delivered statistically better spinal fusion results, with less pain and blood loss, shorter recovery times and fewer complications than autograft.

 April 2004:

INFUSE receives additional approval for treatment of acute, open tibial shaft fractures in skeletally-mature patients that have been stabilized with intramedullary nail fixation after appropriate wound management.

 April 2004:

Aetna acknowledges INFUSE as “medically necessary” for spinal fusion procedures if certain medical standards are met.

 July 2006:

Medtronic agrees to pay $40 million to the U.S. to settle civil allegations that Medtronic Sofamor Danek paid kickbacks to doctors to induce use of its spinal products.

 March 2007:

INFUSE receives additional approval for oral-maxillofacial indication as an alternative to autogenous bone graft for sinus augmentations and localized alveolar ridge augmentations.

 February 2007:

Two whistleblowers file a complaint alleging that 120 spine surgeons and 18 medical device distributors were involved in a scheme to promote Medtronic products by offering bribes. This is a second suit brought by one plaintiff; the government declined to intervene in a first case, which was dismissed.

 July 2008:

FDA issues a warning that rhBMP may be linked to life-threatening complications when used without approval in the cervical spine.

 July 2008:

Medtronic reports largest revenue quarter ever for INFUSE, attributed to contribution of clearance to market two smaller kit sizes (for certain spinal fusion and oral maxillofacial procedures).

 July 2008:

A qui tam suit alleges that a number of spine surgeons and distributors may have colluded with Medtronic Sofamor Danek, engaging in violations of Medicare regulations designed to restrict reimbursement for products. Unlawful practices alleged include improper on-label purchase/promotion of products influenced through the use of kickbacks/consulting fees, etc., and improper off-label promotion of products such as INFUSE.

 September 2008:

INFUSE is honored with the Prix Galien USA 2008 Award for Best Biotechnology Product.

 November 2008:

Medtronic receives a subpoena from the U.S. Department of Justice regarding off-label use of INFUSE.

 December 2008:

A suit filed in a U.S. Federal court is reportedly the 1st to allege that use of INFUSE was responsible for the death of a patient. In this case, the product was implanted in a cervical procedure.

 December 2008:

Two former employees file a whistleblower suit against the company, alleging that Medtronic signed consulting and royalty agreements with seven surgeons to use INFUSE in applications not cleared by FDA.

 March 2009:

A whistleblower lawsuit filed in 2007 by former employees is dismissed. The court rules that the allegations did not constitute a whistleblower suit, and blocks a motion to file an amended complaint.

 FY2009 (ended April 2009):

INFUSE revenue reports at ~$839 million.

 May 2009:

A study on INFUSE is retracted by the Journal of Bone and Joint Surgery due to false claims made by the author.

 June 2009:

Medtronic states that it made ~$0.8 million in direct payments between 2001 and 2009 and ~$0.6 million in indirect payments from 2001 to 2007 to a military surgeon who was accused of falsifying a medical journal study involving INFUSE. Further, Medtronic noted that it did not participate in the collection or analysis of the study data, preparation of the manuscript for the article or its submission for publication, nor did it fund the study. The company is subpoenaed by the U.S. Attorney for Massachusetts, seeking documents related to the former U.S. Army surgeon. Prosecutors also seek information about contracts, research grants, speaking and education programs, and payments for certain named physicians.

 October 2009:

An investigative panel concludes that evidence is insufficient to indicate that the orthopaedic military surgeon had falsified data for a study of INFUSE. Other actions by the surgeon, such as listing doctors as study co-authors without their permission, amounted to “research misconduct.”

 FY2010 (ended April 2010):

INFUSE revenue reports at $867 million.

 FY2011 (ended April 2011):

INFUSE revenue reports at $884 million.

 May 2011:

Study results suggest that use of INFUSE may increase the risk of infertility in men following some procedures.

 May 2011:

Omar Ishrak is appointed Chairman and CEO of Medtronic, replacing the retiring William Hawkins.

 June 2011:

The U.S. Senate and Department of Justice open an investigation of off-label use of INFUSE and of reports that doctors with financial ties to Medtronic were aware of serious complications arising from use of INFUSE, yet did not report these in clinical literature.

 June 2011:

The entire issue of The Spine Journal is dedicated to INFUSE and Medtronic in >10 articles. Eugene Carragee, spine surgeon from Stanford University, serves as editor. Carragee and staff present a host of criticisms, from unreported/underreported side effects common with use of INFUSE to the tens of millions of dollars in royalties received from Medtronic by study authors, who were co-inventors of Medtronic products. Noted side effects included unwanted bone growth, infections, nerve damage, increased risk of cancer and retrograde ejaculation in males.

 August 2011:

Medtronic pays $2.5 million, commissioning Yale University to analyze INFUSE data from 1996 to 2012 from individual patients, all Medtronic-sponsored studies, related internal documents, documents from FDA and other published research. Harlan Krumholz, director of the Yale Center for Outcome Research & Evaluation, organizes the project that selects two groups to undertake the independent reviews: Oregon Health & Science University (OHSU) and the University of York (UY) in the U.K.

 March 2012:

Medtronic agrees to pay $85 million to settle a shareholder suit alleging failure to disclose that more than 85% of INFUSE sales arose from off-label use.

 FY2012 (ended April 2012):

INFUSE revenue reports at $800 million.

 May 2012:

U.S. Department of Justice and the U.S. Attorney’s Office close an investigation of INFUSE, finding no wrongdoing.

 October 2012:

Findings stated in a U.S. Senate finance committee report suggest that Medtronic edited studies by outside researchers about INFUSE, claiming the product to be superior to competing product.

 FY2013 (ended April 2013):

INFUSE sales reports at ~$528 million.

 June 2013:

In an investor meeting, Medtronic stands by FY2014 projected INFUSE sales growth of flat to down in mid-single-digits.

 June 2013:

Annals of Internal Medicine publishes results from York and Oregon. OHSU group determines no clinical benefit to use of INFUSE vs. the gold standard, iliac crest bone graft. Further, the group finds that certain studies, funded by Medtronic, did underreport problems with use of INFUSE. UY determines that INFUSE use will more likely cause vertebrae to fuse. While patients report less pain, the UY team indicates that the difference is not statistically significant and may have been due to placebo effect. Both groups discover a slight increase in cancers in INFUSE patients.

The OHSU and UY summaries are accompanied by editorial from Dr. Daniel Resnick of the University of Wisconsin and Dr. Kevin Bozic of University of California. The authors suggest that INFUSE should not be used with a posterior in cervical or lumbar procedures, but may be an acceptable choice for its FDA-cleared indication, anterior lumbar interbody fusion, as well as in patients whose iliac crest bone graft is not optimal.

 June 2013:

Medtronic and the Australia Therapeutic Goods Administration initiate a recall of unused lots of the INFUSE LT-Cage Bone Graft Kits, which contain Integra LifeSciences’s Absorbable Collagen Sponge. In April, Integra communicated a deviation in production that may result in the sponge having endotoxin levels slightly higher than product specification. No injury or adverse events have been reported regarding this recall.

 Fall 2013:

Results expected from retrospective analysis of large, national payer database investigating the incidence of cancer in real-world use of INFUSE.

Sources: Company press releases, investor meeting, articles in the public domain.

Photo courtesy of Medtronic Inc.