FDA orthopedic panel favors approval of synthetic bone graft for foot and ankle fusion
The Orthopaedic and Rehabilitation Devices Panel of the FDA voted on May 12 in favor of having the agency approve BioMimetic Therapeutic Inc.s premarket approval application for Augment Bone Graft, a bone graft substitute product.
The device, which is part biologic and part scaffold, is intended to augment healing in various kinds of foot and ankle fusions when a grafting procedure is called for, such as tibiotalar, tibiocalcaneal, talonavicular and calcaneocuboid fusions. Augment Bone Graft consists of two components packaged together that are combined in the operating room just before the procedure the resorbable ß-TCP or beta-tricalcium phosphate matrix and a growth factor called rhPDGF-BB or recombinant human platelet-derived growth factor B homodimer.
The product eliminates the need for a second surgery to harvest autologous bone, therefore there is not donor site morbidity (e.g., pain, infection, etc.), BioMimetic Therapeutics stated in premarket approval (PMA) documents submitted to the FDA.
The product received marketing approval in Canada in 2009 for similar indications.
Todays panel meeting represents a major milestone for the company, and one that our investigators and BioMimetic team have worked tirelessly to achieve over the last several years, Samuel E. Lynch, DMD, DMSc, president and chief executive officer of BioMimetic Therapeutics, stated in a company release. Many years ago, my colleagues and I first imagined the possibilities of using PDGF as a broad multi-factorial stimulator of musculoskeletal tissue repair. It is exciting to see that our hypothesis culminated today with a favorable advisory panel recommendation, which is an important step on the path to approval for this novel and important option for the treatment of hindfoot and ankle fusions. It is also gratifying to see the overwhelming support for the distribution of augment in the market place, and we expect to be ready to commercialize immediately upon approval from the FDA, which we expect within the coming 6 months.
In the clinical study that comprised BioMimetic Therapeutics PMA submission, patients were treated by clinicians at 37 centers in the United States and Canada. Investigators randomized 434 patients using a 2:1 (augment:control) pattern, for the intent to treat analysis. Twenty patients withdrew after failing the intraoperative screening step and 17 patients were later excluded due to major protocol violations. This left 397 patients in what the sponsor called the modified intent-to-treat group, of which there were 260 patients in the augment group and 137 patients in the autologous graft group.
The company based its safety analyses on the 414 patients enrolled in the PMA study following randomization, according to the sponsors presentation.
The primary study endpoint was fusion based on CT. However, the FDA questioned this key study endpoint because this method of analysis did not include validation information with respect to traditional radiographic methods, the FDA stated in its panel questions document.
As secondary endpoints, study patients were evaluated and compared with patients with autograft bone using measures such as the Foot Function Index, the American Orthopaedic Foot and Ankle Society (AOFAS) score, Visual Analog Scale for pain and SF-12.
The 18-member panel, which consisted of orthopedic surgeons, cancer and environmental health experts, statisticians, pharmaceutical scientists and a radiologist, debated the growth factor components safety profile during the meeting. The sponsor stressed in its presentation that PDGF is a naturally occurring molecule.
In addition, panel members tried to piece together holes they believe existed in the statistical analysis portion in the sponsors noninferiority study.
The panel members voted 12 to 6, with no abstentions, in favor of the products safety. They voted 10 to 8, with no abstentions, in favor of the products effectiveness and they voted 10 to 8, with no abstentions, indicating they were assured that the products benefits outweighed its risks as an alternative to autograft in hindfoot and ankle fusion applications.
Select patients needed graft augmentation
Temporary voting member of the panel Glenn B. Pfeffer, MD, past president of the AOFAS, voted yes to recommend approval of the device, noting that users should be aware that patients in the sponsors study were carefully selected.
Its very important when you publish the study, which I imagine you will, that you emphasize that this is not a consecutive group of patients and to give as many examples as you can of the types of fusions you were doing. Its one thing to pass this through the FDA. Its another thing to have orthopedic surgeons use it, he said.
Two orthopedic surgeons who recommended against approval were Raj D. Rao, MD, and William L. Rohr Jr., MD.
I didnt see clinically significant results evident in the sponsors study, Rao said during his final comments.
I see a product that is not fulfilling an unmet need, and so to me we ought to have good evidence that product is clearly safe and efficacious, Rohr said, adding the products growth factor was poorly characterized in the study.
Additional studies identified
The panels vote included recommendations for potential pre- and post-approval studies, should the FDA approve the augment product.
I believe those of us who participated in this study are confident that the data generated by this research demonstrate that augment is a safe and effective product, which offers an attractive risk-benefit ration for our patients, Christopher W. DiGiovanni, MD, a principal investigator for the trial, stated in a BioMimetic Therapeutics press release. The product, if approved, would provide our specialty an alternative means of enhancing osteointegration while simultaneously eliminating the potential risk and morbidity associated with autogenous bone graft harvest, he stated. DiGiovanni is professor and program director of the department of orthopedic surgery at the Warren Alpert School of Medicine, Brown University in Providence, R.I.
FDA could render its decision regarding approval within 3 to 6 months of the panel meeting date, according to BioMimetic Therapeutics release. by Susan M. Rapp
- Disclosures: Pfeffer, Rao and Rohr have no relevant financial disclosures.
The FDA panel recommended the use of Augment Bone Graft as the first combination product utilizing rh-PDGF-BB to be indicated for use as an alternative to autograft in hindfoot/ankle fusion procedures that require supplemental graft material. The threshold of the study was to show noninferiority to autograft, which it did (and the FDA panel vote reflects). Efficacy, which also passed with a narrow vote, was more in question as the study does not compare either group to a no graft control.
Since so little graft was required (1 cc to 3 cc) in one third of the cases, was it required at all to obtain fusion? All the cases were primary fusions, which in many cases require no graft at all. Finally, if 1 cc worked in some cases, why was so little required? Is there a recommended dose?
I look forward to the final decision by the FDA. To avoid an additional invasive procedure, harvesting a graft, is an achievement.
Carol C. Frey, MD
Foot & Ankle Section Editor,
Manhattan Beach, Calif.
Disclosure: She has no relevant financial disclosures.