Biologics – Where’s the Damn Evidence?

So-called “stem cell” therapies are the worst. Platelet rich plasma (PRP) products, living cell allografts and off-the-shelf demineralized bone matrix (DBM) are not so far behind.

The problem?

Scant evidence of clinical efficacy.

In the eternal struggle between hype and science, hype, it seems, is winning.

Consider the comments of the outgoing NASS President Jeff Wang, M.D., Ph.D. as he addressed surgeons at the 2019 North American Spine Society (NASS) annual meeting.

The Controversy Hiding in Plain Sight

“The controversy that I think exists in biologics is the one that people are ignoring,” said Dr. Wang. “I think the biggest controversy is the lack of evidence for non-BMP [bone morphogenetic protein] biologics.”

This was the case, he said, before BMP was commercialized, during the launch of recombinant BMP and still to this day. In fact, said Dr. Wang, sales of non-BMP biologic products to physicians are more dependent on the size of a company’s sales force than the size of their commitment to clinical evidence.

To make his point, he cited a rat study from about ten years ago.

“Here’s a rat model where three different commercially available demineralized bone matrices were tested. One of these DBMs fused 60% of the time in rats. One fused 0% of the time. And one fused 80% of the time. Which do you think sold the most at the time of this study?”

“The one that sold the most out of these three products was the one that was affiliated with the spine company with the largest sales force. The second highest selling product was the one associated with the second largest company and its sales force. And the lowest selling of these three was affiliated with the smallest company.”

“Sales of these DBM products were really connected to the size of the sales force. Not clinical evidence. That’s a problem.”

To be sure, BMP has had its fair share of controversy, as Dr. Wang also noted.

“With the BMP controversies,” said Wang, “we were talking about the quality, and possible industry influence of the large number of studies looking at BMP.”

“What we’re not talking about is the fact that many of the other biologics have really no evidence to support their use. Looking at a literature search of human studies of graft extenders from a few years ago, the researchers found thousands of articles. How many were human trials?”

“I got nineteen.”

Nineteen?!

Ethically, We Should Demand Evidence

Dr. Wang described a moment when he asked a company about their living cell allograft products.

“I remember in 2009, living cell allografts came out and surgeons were using them. I saw one of these products at a booth back then and I went up and said to the person ‘this is very interesting, can you show me some animal studies, some data that shows that it works.’ I’ll never forget the response. The person in the booth said, ‘We don’t have any, but we’d like to get some.’”

“They didn’t do any studies! They just started selling it. What’s worse is that surgeons were using them. Even today, the data is quite lacking.”

“A lot of surgeons are ignoring the data. That’s a problem. We talk a lot about BMPs. How are they made? Correct me if I’m wrong, they’re made in the lab from cells.”

“How are these non-BMP biologics made? They are made out of people. These DBMs are people who’ve passed away and donated their body. Processing companies take the bone, demineralize it, concentrate the proteins that are in bone and that is what makes up these products.”

“Ethically, we should demand evidence.”

So-called “Stem Cell” Therapies

Two years ago, Leigh Turner, Ph.D. (an investigator with the Center for Bioethics at the School of Public Health in the University of Minnesota) and Paul Knoepfler, Ph.D. (with the Institute of Pediatric Regenerative Medicine at Shriner’s Hospital for Children and a member of the Department of Cell Biology at the University of California, Davis campus) counted the number of stem cell clinics in the United States.

Turner and Knoepfler found 351 U.S. businesses engaging in direct-to-consumer marketing of stem cell interventions at 570 clinics. Five states were hotspots for stem cell clinics—California (113 clinics), Florida (104 clinics), Texas (71), Colorado (37), Arizona (36) and New York (21).

After doing our own Google search, we’d guess that the number of such clinics have probably doubled since Turner and Knoepfler published their study in 2016.

What Are So-called “Stem Cells” Supposed to Do?

If these clinics are to be believed (and the FDA’s warning letter from August 2017 would suggest the majority are full of BS), the “stem cells” they inject in patients will:

• Relieve pain and improve function in arthritic large joints
• Relieve soft tissue inflammation
• Grow bone
• Treat spinal cord injuries
• Treat immunological conditions
• Ameliorate cardiac disease and pulmonary disorders
• Treat ophthalmologic disease and injury
• Relieve urological disorders
• Treat Alzheimer’s
• Treat essential tremor diseases
• Address necrotic bone
• Provide a facelift
• Augment breasts
• Enhance sex

To be blunt, marketing has gotten way ahead of the science.

Rules of the Road for Mixed Cell Therapies

The American Academy of Orthopaedic Surgeons (AAOS) convened a symposium on the subject of living cell implants and issued recommendations covering nomenclature, standards for measuring and reporting the composition of these therapies and their clinical outcomes and registries and clinical trial networks to accelerate rigorous assessment and optimization of regenerative therapies for musculoskeletal diseases.

They urged physicians to:

• Refer to minimally manipulated cell products and tissue derived culture-expanded cells as “cell therapy” not ‘stem cell’ therapy.
• Inform patients that these therapies are largely untested and uncharacterized.

They urged suppliers to conduct rigorous studies of their non-BMP biologics which:

• Use AAOS symposium checklists as a guide for study design and reporting.
• Disclose the detailed composition of PRP and cell-based therapies.
• Identify the biologic activity target (e.g., cell proliferation, anti-inflammatory, antifibrotic effect) for their non-BMP biologic.

The Unique Case of Medtronic’s Infuse™

The paucity of clinical evidence for today’s wave of living cell implants and other biologics stands in sharp contrast to the enormous body of clinical evidence behind BMP — specifically Medtronic’s Infuse™.

Since it was approved by the FDA in 2002, the spine research community jumped on this landmark biologic and generated hundreds of studies and wrote thousands of clinical papers, from level I on down to case studies, some with Medtronic financial support, but most not, and submitted them to dozens of peer-reviewed publications.

This body of evidence about BMP is significant and has, we think, served the physician community well. It is quite likely true that Infuse® is THE single most studied biologic in the history of spine and orthopedics.

Brett Knappe, Ph.D., VP of Biologics at Medtronic, told OTW: “The safe and effective use of Infuse is backed by years of scientific development, clinical trials and two decades on the market with more than 2,000,000 patients treated.”

Medtronic is still investing in BMP clinical trials having recently announced one for TLIF [transforaminal lumbar interbody fusion] indications and another for PLF [posterior lumbar fusion].

Medtronic’s new campaign—”Think Twice Fuse Once”—which was front and center at NASS, parallels AAOS’ new guidelines and urges physicians to ensure that biologic use is informed by the needs of the patient, the site, the procedure, and is based on strong data and evidence.

SeaSpine’s Drop the Mic Moment at NASS

Other companies are also putting evidence at the center of their biologics marketing.

One that deserves special notice is SeaSpine, Inc.

SeaSpine, using their scientific advisory board, designed a simple test for bone formation which can be used for either BMP or non-BMP biologics.

“We wanted to isolate the elements which can form bone, regardless of the biologic implant”, said Frank Vizesi, Ph.D. Vice President, Orthobiologics Research & Development, and Clinical Affairs at SeaSpine.

“We designed a study to test whether demineralized bone matrix (DBM) with or without BMP proteins can form bone. With growth factors, we got abundant bone formation in an athymic rat muscle pouch model. Without growth factors we got NO bone formation.”

Simple. As far as it goes. SeaSpine and their surgeon advisors then took it a step further, teaming up with Jeff Wang and his research team at USC.

“Nobody had presented data which isolates the elements of living cell-based implants to prove the cell component actually forms bone,” said Dr. Vizesi.

The study: “What drives spinal fusion within graft materials: cells or growth factors?”, by Aidin Abedi MD[1], Blake Formanek BA¹, Nick Russell PhD[2], Frank Vizesi PhD², Scott Boden MD[3], Jeffrey C. Wang MD¹ and Zorica Buser PhD¹, was presented to spine surgeons and a group of Wall Street analysts and institutional investors at the 2019 annual meeting of the North American Spine Society.

“So, the first question a surgeon might have is ‘are the cells alive?’. There is plenty of data that says they are. But is that the right question?”

The right question, said Vizesi, was “do the cells DO anything?”

Using the well-validated athymic rat model, the study team took 2 of the 3 top selling living cell-based bone grafting products and tested them with cells and then without cells.

It was, of course, a variation on the well-known athymic rat model test of DBM.

As Dr. Vizesi explained to OTW: “We tested with and without the cells. So, with the cells these products should work better for bone formation. It’s not complicated.”

What the investigators found, and what they presented at NASS, was that neither of the living cell-based products (which out-sell classic DBM) produced an increase in the rate of bone formation and, therefore, fusion.

As Dr. Vizesi told OTW, “Whether with cells or without cells, the amount of bone formation was the same.” Meaning that the cells didn’t add anything to the fusion. If that’s the case, then they might actually be diluting the performance of the products.

“Our basic conclusion is that it is the DBM that is causing an increase in bone formation and fusion.”

Not living cells.

As we’ve said many times, biologics is complicated. There is more work to do.

Still, this study is a drop-the-mic moment.

The Regulators are Closing In

Under the FDA’s Human Cell and Tissue (361) rules, human tissues may be processed for clinical use and commercialized IF their use is homologous and safe—no disease transmission, principally.

In practical terms that means rigorous, validated processing and no therapeutic benefit marketing claims.

Only biologic products with a biologics license (BLA) or pre-market approval (PMA) may claim a therapeutic benefit.

A recent study found that a depressingly large amount of non-BMP marketing emanating from clinics and suppliers alike had crossed that FDA imposed marketing claims and practices line.

Every clinic that is promoting non-BMP biologics should carefully review its claims, both implicit and explicit.

The good news is that AAOS and other surgeon societies are providing guidance so that clinics and suppliers can stay on the right side of both medicine and, critically, the law.

Still, forewarned is forearmed.

[1] Keck School of Medicine, University of Southern California

[2] SeaSpine, Inc

[3] Emory University School of Medicine