A Biologics Boom: What Are the Rules?

The name of orthopaedics is used to market PRP and stem cells for all kinds of ailments

Aid the swirl of competing claims about platelet-rich plasma (PRP), stem cells, and other biologic therapies stands the orthopaedic surgeon, like a lighthouse, to guide the public and patients who are hoping to benefit from the claims made about these agents. As the physicians who manage conditions for which biologics are commonly heralded as breakthroughs and wonder therapies, orthopaedic surgeons find themselves in roles both of trusted bulwarks separating fact from fantasy and of healing practitioners who welcome new treatments that are proven to benefit their patients.

At the AAOS 2018 Annual Meeting, a panel of clinicians and researchers had the task of cutting through the fog for a surgeon audience at a symposium titled “Use and Misuse of Biologics.”

Symposium moderator William J. Maloney, MD, having just finished his term as Academy president, summed up the biologics scene in the United States as “an explosion of mom-and-pop shops with little or no regulation.” Noting that most of the several hundred U.S. establishments that feature stem cells and PRP offer treatment for orthopaedic conditions, Dr. Maloney said, “Whether we like it or not, orthopaedics is in the middle of it. There is a concern in the orthopaedic community that we need to stay on top of this as an Academy and as a profession.”

Noting that the retailing of biologics “is a cash business—and it’s expensive,” with prices that vary greatly, he declared, “We are at a crossroads. Is this going to become mainstream therapy with good evidence behind it, or is it snake oil? Some of the literature indicates high patient satisfaction, but there’s very little data. What we do know is that these products are relatively safe, but the quality of data for efficacy is poor.”


According to William M. Mihalko, MD, PhD, many of the enterprises that offer platelet-rich plasma and stem cell therapies use “orthopaedics” in their name but are not operated or staffed by orthopaedic surgeons.

18 million hits

William M. Mihalko, MD, PhD, of the Campbell Clinic, offered an overview of the biologics landscape. He, too, characterized the proliferation of centers providing PRP and stem cell treatments as explosive. In 2015, he counted 351 such shops, but that number has surely mushroomed. “My latest check came up with 18 million hits when I Googled ‘stem cell centers,’” he said. “It’s impossible to know how many are open now.”

Dr. Mihalko explained that some centers offering biologics for orthopaedic conditions advertise treatment for the full gamut of bone and joint ailments: arthritis, general hip and knee pain, plantar fasciitis, “tennis and golfer’s elbow,” tendon tears, rotator cuff injuries, and general low back pain. He noted that many centers use “orthopaedics” in their name but are not operated or staffed by orthopaedic surgeons; they may advertise with phrases like, “Hope that we can keep you off the orthopaedic surgeon’s operating table.”

Biologics clinics also may claim relief for many nonorthopaedic conditions, including migraines, diabetes, hair loss, Parkinson’s disease, multiple sclerosis, and macular degeneration.

Typically, for orthopaedic conditions, the centers use products derived from peripheral blood for PRP and from bone marrow aspirate, adipose tissue harvest, and cell isolation for stem cells. Of businesses advertising stem cell treatment, about two-thirds market interventions using autologous adipose-derived stem cells, half promote what they describe as autologous stem cells obtained from bone marrow, and 4 percent market stem cells purportedly obtained from peripheral blood.

Dr. Mihalko explained that the stem cell products actually approved by the U.S. Food and Drug Administration (FDA) are either cord blood or placental remnant products and are typically indicated for some type of pediatric cancer therapy. “None are approved for any type of orthopaedic use,” he said. “Why do these centers think they can use these without oversight?” he asked. The answer lies in the Public Health Service Act, Section 361. “If you are using the HCT/P (human cells, tissues, and tissue-based products) that are minimally manipulated and homologous only, you can proceed without FDA approval,” he said.

Still, many centers will make the claim: “We use FDA-approved devices,” Dr. Mihalko said. The asterisk: “That’s just to obtain the bone marrow. How they are using the bone marrow aspirate is not FDA approved.”

Murky marketing

Noting that the FDA is well aware of how the truth is shaded in the marketing of PRP and stem cells, Dr. Mihalko said the agency has promised to step up enforcement of regulations and efforts against illegal claims. It has provided guidance to patients in public statements to the effect of, “Outside the United States, all bets are off; you are basically with no oversight,” he said. “Within the United States, they specify that even if someone is spinning down or obtaining stem cells from your body, you still need to ask your treating physician, ‘Is this an FDA-approved product or therapy? Is it part of a new therapy?’ If so, you should be signing a consent for institutional review board (IRB) approval.”

The way clinical trials are presented to the public is murky and often misleading. “Many centers use the fact that they have clinical trials registered,” Dr. Mihalko said, noting that some 18 U.S. companies had registered trials that were “patient sponsored” on ClinicalTrials.gov, meaning that the patients receiving the treatment paid for it—which isn’t the case in more legitimate studies.

Dr. Mihalko noted that ClinicalTrials.gov is not monitored by the FDA and that many trials that are registered as patient sponsored never have data entered into the database. “Often, there is no IRB listed or patients being recruited,” he said. He searched the site and found that of 13 studies listed, three were completed, four were actively recruiting, and five were active but not recruiting, with one not yet recruiting.


William M. Mihalko, MD, PhD, said: “While there may be promise in certain cell-based therapies, we currently do not have the evidence to tell our patients they can expect good outcomes or avoid surgery.”
Courtesy of Artem Egorov

Referring to a study that contacted 271 of 317 centers that marketed directly to consumers, Dr. Mihalko said that 36 provided patient satisfaction rates, with:

  • 10 centers reporting good results in 70 percent to 79 percent of cases
  • 15 centers reporting good results in 80 percent to 89 percent of cases
  • 10 centers reporting good results in 90 percent to 100 percent of cases
  • One center reporting good results in 50 to 59 percent of cases

The mean cost of treatment for stem cells and/or PRP was $5,156, with a range of $1,500 to $12,000. Dr. Mihalko called a center in his hometown of Memphis, Tenn., and was given a quote of $3,500 for treatment of knee arthritis and was told the center had treated “hundreds of patients” successfully, with no further specifics.

Dr. Mihalko surveyed the published data regarding stem cells and PRP for just one condition, knee arthritis, and reported that the state of the evidence is not strong in support of efficacy. A recent meta-analysis of stem cell injection therapy for knee arthritis scanned 420 reports in the literature, of which six had level III evidence or stronger. Some had promising results, but the placebo effect could not be ruled out. Overall, the analysis revealed moderate confidence for safety but low evidence for efficacy. “These results are far different from what many centers advertise,” Dr. Mihalko said.

For PRP, recent meta-analyses identified 19 higher-quality investigations. Comparisons of the studies are somewhat difficult, he said, because of differences among the treatments, including the number of injections (1–2, or 3), inclusion or exclusion criteria, and differing outcome scores. Seven studies reported good response to treatment, and four reported a bad response.

In summary, Dr. Mihalko said, “For many stem cell centers, the appropriate avenues of legitimate clinical research, informed consent, and physician-directed use are not always followed. Many sponsored legitimate studies are ongoing that are well controlled and have IRB approval, but others are not. We may want to be more active in policing the clinical marketplace to make certain that false hope under guise of an ‘Orthopaedic Stem Cell Center’ does not create risk and expense for patients under the disguise of our medical specialty. While there may be promise in certain cell-based therapies, we currently do not have the evidence to tell our patients they can expect good outcomes or avoid surgery.”

Editor’s note: This article is the first of a two-part series. The next installment will focus on clinical applications for PRP in orthopaedics in the August issue of AAOS Now.

Terry Stanton is the senior science writer for AAOS Now. He can be reached at tstanton@aaos.org.

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