Preclinical studies of the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) on tumorogenicity, dosing and antibody response during pregnancy should be conducted by Medtronic/Sofamor Danek, FDA's Orthopedic & Rehabilitation Devices Panel recommended Jan. 10.

Voting unanimously (10-0) to recommend Medtronic's InFuse bone graft/ LT-Cage lumbar tapered fusion device for PMA approval, the panelists suggested the three pre-clinical studies as post-approval conditions.

The theoretical possibility that BMP-2, a genetically-engineered protein that stimulates bone growth, can cause complications during pregnancy or tumorogenicity was initially raised by FDA reviewers. In asking the panel to discuss those issues, the agency stressed its concern was "not based on any adverse events reported during the use of the device under review," according to a review document.

"While antibody assays were performed on all enrolled subjects, no adverse events related to these questions were reported, e.g. birth defects or cancer," FDA noted. "These questions are based on non-clinical studies reported in the literature that indicate that the potential for these concerns exists."

Although the panel recommended a pre-clinical study to determine the antibody response during pregnancy, it declined to endorse a proposed condition that would have required the company to maintain a patient registry of pregnant women.

University of Texas Health Science Center's Barbara Boyan, PhD, emphasized how difficult it would be for the registry to generate enough data to become statistically significant.

"The numbers of patients who are going to accrue over five years and the number of anticipated pregnancies is probably at the low end of where you are going to be able to detect teratogenicity for sure, and even fetal loss," she pointed out. "The chance of actually reaching numbers where you can say with confidence it's not teratogenic is vanishingly small." Boyan argued that such a registry would be expensive and difficult to maintain.

As an alternative, the panel believed that mouse studies would more adequately reflect the potential for the mother to develop antibodies as an immune response to the rhBMP-2, which would cross the placenta and disrupt normal embryogenesis.

The mouse studies also would address the possibility that fetal expression of BMP-2 could trigger a maternal immune response, thereby causing adverse effects in the mother.

University of California-Davis' Hari Reddi, PhD, stressed the importance of observing the immune response in pregnant mice before implantation, at implantation, after the first skeletal elements begin to form, and during joint formation and spine formation of the embryo.

In addition to a non-clinical study recommending antibody response during pregnancy, the panel recommended two other studies evaluating tumorogenicity and dosing. Concerning tumorogenicity, the panel approved a recommendation stating the the postmarket study should "assess the potential for BMP-2 to promote growth in primary tumor oscillates which have been analyzed for BMP-2 receptors."

The dosing study should examine the mouse model "with equal dosing of the rhBMP-2 and multiple dosing over long periods of time to complement the data we have already heard, which was a single large dose at a single time," the panel advised.

In their recommendation, panel members referred to preclinical trial data by Genetics Institute, a unit of American Home Products' Wyeth-Ayerst that discovered and developed the rhBMP-2. The data examined the potential effects of rhBMP-2 to stimulate tumor cell line proliferation at 10, 100 and 1000 ng/mL. The company found that human osteosarcoma cell lines were unaffected by treatment.

Nonetheless, panel members believed that the preclinical studies were insufficient to ensure that BMP-2 lacks the potential to cause cancer. "If the mouse has a longevity of two years, I don't buy the study in which they say, 'We give thousands times the dose, and the mouse was fine at six months.' That's not a useful study in cancer research," Reddi said.

Instead, he recommended a non-clinical study that examines dosing over a longer period of time. Boyan and Betty Diamon, MD, University of Kansas Medical School, added that any clinical study should be conducted in animals rather than in the more variable cell lines.

Clinical investigators for the InFuse have noted the difficulties associated with repeatedly injecting a mouse with BMP. In lower-order animals, BMP is excreted out of the body within two weeks if it is submitted intravenously. If it is injected through the skin, bone will form. In addition, clinical investigators note that BMP differentiates cells instead of multiplying them, leading to the possibility that it may actually inhibit cancer.

The panel's "approvable" vote for the InFuse mirrored FDA's favorable statistical analysis of Medtronic/Sofamor Danek's pivotal study results. Medtronic's 16-site, 270-patient, prospective, randomized pivotal study compared the fusion device with an iliac crest autograft/tapered cage as a control. Primary effectiveness was measured by radiographic fusion, a pain/disability questionnaire, and neurological status.

The trial's goal was to evaluate safety and effectiveness of anterior lumbar interbody fusion of the device to treat patients with symptomatic degenerative disc disease.

At 12 months postoperative, the experimental and control arm success rates were 59.7% and 60.8%, respectively. At 24 months, those rates were 58.8% and 56.3%. The overall success rate at 24 months for the InFuse treatment group was found to be statistically equivalent to the autograft group.

In addition, the InFuse group showed a statistically significant improvement over the autograft group in terms of fusion rates. At 24 months, 94.5% of the InFuse group successfully fused compared with 88.7% for the autograft group (¹ Also see "Medtronic InFuse Favored By Study Data, New Payment Code In The Offing" - Medtech Insight, 5 November, 2001., p. 6).

The main advantage of the InFuse is that it eliminates pain from a second procedure to harvest the patient's hip-bone. All of the autograft bone patients in the study reported hip donor site pain. In addition, Medtronic notes that InFuse decreases hospital stay and reduces the period before patients can return to work. With InFuse, rhBMP-2 powder is reconstituted with sterile water and soaked into an absorbable collagen sponge. The sponge is then placed inside two LT-Cage lumbar tapered devices, which the surgeon implants between the vertebrae of the spine. While the rhBMP-2 was developed by American Home Products, the absorbable collagen sponge is made by Integra Lifesciences. Sofamor Danek's LT-Cage was approved via PMA in September 2000 for both laparoscopic and open surgical approaches.

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