Sam Lynch, founder, president and CEO of BioMimetic Therapeutics, Inc., had heard enough.
Lynch, D.M.D., D.M.Sc., had been in the audience all day on May 12 as FDA staffers and some members of the FDA Orthopedic and Rehabilitation Devices Panel tried to rip apart his company’s Augment Bone Graft clinical study.
Augment is designed to be used by orthopedic surgeons during ankle surgery, specifically hindfoot and ankle fusion procedures, as a replacement for autograft bone harvesting. BioMimetic is seeking a premarket application (PMA) approval.
More on the specifics of Augment and the clinical study later.
Trial Questioned
“The trial has no meaning, ” said Brent Blumenstein, Ph.D., a statistical consultant and long-serving member of the Panel. Lynch had also listened to the FDA point out the risk for “potential” for cancer formation in patients receiving Augment based on a Black Box warning for a Johnson & Johnson product called Regranex. Augment contains the same PDGF molecule as Regranex. Regranex is FDA approved for use as a foot ulcer treatment. In addition, Lynch’s team had to spend the day responding to questions about the way adverse events were defined and reported in the study, shifting primary study endpoints, the appropriateness of CT scans and the effectiveness of bone grafting itself.
Lynch’s “Hail Mary”
The panel was about to vote when Lynch made an unscheduled and impassionate presentation to the panel.
Sam Lynch, D.M.D., D.M.Sc.
BioMimetic Therapeutics, Inc.“Please, ” he pleaded, “judge our product by our clinical evidence, not some other product.” Lynch told the panelists that the company’s recombinant human platelet-derived growth factor (rh-PDGF) had been in clinical use for over five years, in 250, 000 patients as a dental product (sold under the brand name GEM 21S). Furthermore, Lynch pointed out, 600 patients in the U.S., Canada and Europe had already been treated with Augment and not one significant adverse event was ever reported.
Lynch felt compelled to speak directly to the panel to address items brought up during the meeting. As the leader of the team and given how the day had gone, Lynch thought it was his responsibility to make the final argument, and if necessary, “take the bullet” if the panel voted against approval. Considering how the day had gone, that outcome would not have been surprising.
Biologic FDA Woes
The FDA has not been a friendly place for biologic products intended for surgery. Recently the agency denied Medtronic’s application to have its bone morphogenic protein product, Amplify, approved for spine fusion surgery and before that the FDA panel failed to recommend Stryker’s bone morphogenic protein, OP-1, also for spine surgery.
The financial markets, in anticipation of yet another panel biologics rejection, had sold off BioMimetic’s stock —driving it down to 40% to $8.00 from $14.00—when word of the FDA’s concerns with the company’s PMA was made public.
It was under those circumstances that Dr. Sam Lynch stood up and made his speech at the end of a brutal day in front of the panel.
Safe, Effective and Beneficial
The final vote was 12-6 in favor of approving Augment as a safe treatment for ankle surgery. The panel members spoke publicly about their votes. Panelists and clinicians Glenn Johnson, M.D., and Sam Nasser, M.D., Ph.D, both said they were swayed by Lynch’s summation and were openly critical of the FDA for not presenting the safety record of the company’s dental product. When the panel was discussing adverse reaction definitions, Nassar said he thought the agency came in to the meeting with an agenda. Mark Malkerson, the agency’s representative on the panel, gamely told the panel that the agency would endeaver to do better in the future.
The panel went on to vote 10-8 that Augment for ankle fusion surgery was effective and, finally, voted 10-8 that this PDGF biologic product when used by surgeons in hindfoot and ankle surgery, delivered benefits that outweighed the risks.
A contentious and long day had come dramatically to an end.
Lynch and the BioMimetic’s team had swayed a particularly large panel with 18 voting and three non-voting members.
Panel Deliberations
As is customary, the day of the FDA Panel meeting began with a presentation by the company and was followed by a full bore attack by the FDA. In fairness, the FDA staff is required to play “devil’s advocate” and give panel members reasons to find shortcomings with the company’s PMA and clinical trial data. The panel is made up of clinicians, academicians and statisticians who are charged with reading and considering the voluminous materials, testimony and then to openly debate the merits of the application and criticisms.
In our experience with panels, statisticians almost always find enough faults with the applicant’s clinical trials to deem the study “meaningless.” It’s usually left to the clinicians who have the responsibility of treating patients, to provide the “real” world perspective for the FDA.
And so it was with Augment.
The Challenge
Ironically, it was a clinician, William Rohr, M.D., an orthopedic surgeon from California who took the panel on an early tangent over the effectiveness of bone graft in general. BioMimetic set out to prove that Augment was not inferior to autologous bone graft in promoting fusion. Its primary benefit is that the use of the product spared patients from undergoing a second ankle surgery to harvest bone.
In Rohr’s view, Augment was being recommended by BioMimetic for a questionable procedure (bone graft fusion), which could open up new potential risks (cancer) for little or no benefit (bone graft harvest site pain).
It was left to the other surgeons on the panel to forcefully argue that while using bone graft to promote fusion in the ankle was not a preferred choice, for patients with various comorbities such as diabetes, obesity and aging bones, using bone grafts was the gold standard. Several panelists even argued that the absence of pain by not having a second operation to harvest their graft was irrelevent.
Due to the relatively low number of ankle surgery patients in the study (434), the dropping of 37 patients for major protocol violations or not treated at all, caused the statisticians to declare the study underpowered. Again, the clinicians spoke up and said they found the reasons for excluding the 37 patients as reasonable.
Clinical Trial
BioMimetic’s clinical trial for using Augment in ankle surgery was approved by the FDA in 2007. The company enrolled 434 patients for treatment in a Pivotal Randomized Controlled Trial (RCT) at 37 centers in the U.S. and Canada. It was the largest RCT ever for the foot and ankle. The company’s PMA was accepted for review by the FDA in 2010.
The primary endpoint was the percent of patients whose ankles successfully fused at six months (a 50% osseous bridging via CT). Secondary endpoints were clinical, functional, radiologic, quality of life, and safety outcomes.
The data was not perfect. While six-month data showed that Augment was non-inferior to autografts, Augment failed to show non-inferiority at the 36-week and 52-week follow-up points. The results were close and hurt by the unavailability of some patients for follow-up. The long-term follow-up points caused the spine surgeon on the panel, Raj Rao, M.D., to comment that biologics may not stay as robust over time and degradation of the bone quality is possible.
Augment Bone Graft
Augment is a blend of calcium phosphate (beta-TCP), bovine collagen and human platelet derived growth factor.
Augment’s beta tri-calcium phosphate is the scaffold upon which bone is expected to grow after surgery. The human platelet derived growth factor (rhPDGF-BB) is the signaling protein that triggers new bone growth in the ankle. The conclusion of the study was that the matrix plus the biologic accelerated fracture healing and enhanced joint fusion with no evidence of ectopic bone formation (a plus over Infuse) and no evidence of toxicity.
Augment’s PDGF is created using recombinant DNA technology which is more than two decades old and has been used by spine surgeons and other physicians in hundreds of thousands of patients globally.
Platelet-derived growth factor (PDGF) is a naturally occurring protein and one of the primary growth factors released when platelets activate and degranulate in response to injury. PDGF is responsible for triggering a number of cellular events critical to bone growth and healing.
Treatment for Arthritis, Ankle Pain or Fracture
Surgeons often recommend a fusion of the foot or ankle when a patient presents with debilitating end stage arthritis of the ankle, hindfoot and midfoot. For patients with diabetes or osteoporosis or fracture, there is a high risk that the bones following surgery will not heal completely. That is known as a nonunion. Typically, surgeons have relied on a second ankle surgery, an autograft procedure to harvest chips of healthy bone, to then implant into the surgery site and, hopefully, improve healing. Often surgeons harvest this bone from the patient’s hip, tibia or heel. When that happened, patients can experience a number of post surgery complications and, according to the eight published studies, 27% will complain of chronic donor site pain.
BioMimetic’s success with GEM 21S, indicated for periodontal bone defects and gum tissue recession, and approved by the FDA in 2005, gave the company confidence the material could be used for other orthopedic indications.
If approved by the FDA, Augment Bone Graft would be the first, new recombinant protein technology for orthopedics introduced to the market in nearly a decade and the first and only cost effective fully synthetic bone growth factor replacement for autograft with Level 1 data supporting its safety and efficacy.
Since we started with Dr. Lynch, we’ll let him finish.
“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.”
Lynch should thank the clinicians.
