Exciting Orthobiologic Products Must Be Viewed through Regulatory and Guideline Lens

The field of orthobiologics is rapidly advancing. Orthobiologics are typically defined as biological substances used to treat acute or chronic musculoskeletal problems.

At the AAOS 2024 Annual Meeting, Jason L. Dragoo, MD, FAAOS, chair of the AAOS Devices, Biologics, and Technology Committee and vice chair of academic affairs at the University of Colorado, moderated the symposium titled “Optimizing the Care of Your Patients Using Biologics.” Conducted in collaboration with the Biologic Association, the event explored the optimization of biologics in orthopaedic surgery.

Attendees of the symposium were treated to a series of in-depth presentations on the cutting-edge uses of biologics, including platelet-rich plasma (PRP), micro-fragmented adipose tissue, peripheral blood stem cells, bone marrow aspirate concentrate, and more. The final two presenters of the day put all the compelling new developments into context in the current regulatory environment and within AAOS Clinical Practice Guidelines (CPGs).

Regulatory considerations
Despite the excitement regarding biologic products, “Talking about FDA regulations is about as exciting as watching paint dry,” said Stephen C. Weber, MD, FAAOS, assistant professor at Johns Hopkins School of Medicine, “but they are things we need to know as practicing orthopaedists to not get into trouble.”

The FDA definition of biologic products encompasses a wide range, such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. However, Dr. Weber explained that biologics exist in a grey area, which can complicate how they are regulated.

FDA jurisdiction for biologics can fall under the Center for Biologics Evaluation and Research, be considered devices in some cases (e.g., viscosupplementation until 2018), or fall under the Center for Drug Evaluation and Research. Combination products can fall under more than one of those areas.

“One of the big questions—and this is where orthopaedists get into trouble—is, ‘What are these human cellular and tissue products?’” Dr. Weber said. In some cases, they fall into Public Health Service Act section 361 (human cells, tissues, and cellular- and tissue-based products); in other cases, they fall into section 351 (biological products that do not meet FDA’s criteria for being regulated under section 361).

“361 products are what we all like; they are not regulated per se, other than in basic ways,” Dr. Weber said. However, “if it is in the 351 category, then giving these to patients right now is a violation of federal guidelines without an approved Investigational Device Exemption.”

It is important that clinicians are educated about the products they are using and the federal regulations related to them. In some cases, the FDA has sought permanent injunctions against stem cell providers. In 2020, AAOS created the Biologics Dashboard, an online tool designed to help orthopaedic surgeons navigate the approval status of biologic-based interventions.

Dr. Weber also noted that many of the 351 products were legally marketed under enforcement discretion until June 1, 2021, but the products are now required to obtain a Biologic Licensing Application to continue being legally marketed. These include stem cells, stromal vascular fraction adipose tissue, exosomes, Wharton’s jelly, and manipulated amniotic products. If the Centers for Medicare & Medicaid Services was billed for those products, it plans to “claw back” the money. “They have prosecuted people as well if they didn’t get clawbacks,” Dr. Weber cautioned. “Seek legal council if you have given these products.”

The regulation of biologics continues to provide challenges for practicing surgeons, but Dr. Weber encouraged attendees to stay informed and obtain appropriate informed consent from patients. “Healthy skepticism is still the key,” Dr. Weber said. “Don’t be the first and don’t be the last.”

AAOS guidance
Karl C. Roberts, MD, FAAOS, FAOA, chair of the AAOS Evidence-Based Quality and Value Committee, closed the symposium by explaining the challenges of addressing orthobiologics in CPGs. “The goal of CPGs is to decrease variability in care, identify evidence-based treatments that can improve quality of care, and help educate our physicians and patients,” Dr. Roberts said. “The problem is it requires good evidence.”

Despite a lack of evidence on biologics, there has been a rapid adoption of these therapies inside and outside orthopaedics. When AAOS CPGs are written, they require rigorous methodology, management of conflicts of interest, and a concept of best-evidence synthesis. With a lack of evidence or heterogenous evidence, a recommendation cannot be made.

Additionally, CPGs are always just a snapshot in time. They are time and resource intensive, often taking 1 to 3 years, and must rely on synthesis of evidence published prior to their creation, which can exclude the most up-to-date data.

“CPGs are often criticized because rationale for recommendations often only cites a few studies, but that represents the best of all evidence,” Dr. Roberts said. He walked attendees through several examples in recent CPGs related to use of certain biologics, such as PRP, that could not be recommended or were given only moderate or limited recommendations.

“As we try to overcome the challenges of performing research and obtaining high-quality evidence, registry data are critical,” Dr. Roberts said. “There is a need for a biologics registry to advance this field forward.”

Additional speakers
The symposium included several presentations on optimizing the efficacy and dosing of orthobiologics:

• David Karli, MD, FAAOS, founder and CEO of Greyledge Technologies, discussed dose- and indication-specific autologous cell therapies.
• Shane Shapiro, MD, of Mayo Clinic, discussed the effects of diet and exercise on biologics.
• Daniel Saris, MD, PhD, of Mayo Clinic, discussed dosing of mesenchymal stromal cells.
• Xiaoning Yuan, MD, PhD, of Uniformed Services University, discussed the use of personalized biologics and multimodal medicine.
• Bert Mandelbaum, MD, FAAOS, of Cedars-Sinai Kerlan-Jobe Institute, updated attendees on adjuvant therapy.
• Dr. Dragoo presented information on behalf of Scott Rodeo, MD, FAAOS, of Hospital for Special Surgery, who was unable to attend, on PRP responders versus non-responders.
• Kenneth Zaslav, MD, FAAOS, of the Cartilage Repair Center at Northwell Health, discussed current activities of the Biologic Association.

The symposium also highlighted modern indications for orthobiologics:

• Khay-Yong Saw, MB, ChB, MCh Orth, FRCS, of Kuala Lumpur Sports Medicine Center, discussed peripheral blood stem cells.
• Don Buford, MD, FAAOS, of Texas Orthobiologics, gave an overview of bone marrow aspirate concentrate.
• Dr. Dragoo covered modern indications for use of adipose tissue.
• Dr. Mendelbaum covered interosseous treatment for avascular necrosis, bone marrow lesions, and osteoarthritis.

Leah Lawrence is a freelance medical writer for AAOS Now.