Regenerative orthopedics: where is it heading? New FDA policy framework

Regenerative orthopedics: where is it heading? New FDA policy framework H   Dao

Hà Dao, PhD, CCRP, CRA School Montreal

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Many researchers and practitioners in the field believe that regenerative medicine is the future of orthopedics. While orthopedic surgeons continue to face challenges in healing musculoskeletal lesions, regenerative medicine is appealing to patients because of its ability to foster the natural healing process and even to allow for the regrowth of lost or damaged tissues. Over the last decade, the evolution of regenerative medicine has been fueled by advances in cell biology and nanotechnology.

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How does regenerative orthopedics work?

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The success of different regenerative strategies relies on the dynamic interplay of three key components: cell type, scaffold and bioactive agents. In orthopedic medicine, mesenchymal stem cells (MSC) are the most commonly utilized cell type. This tendency can be explained by MSCs’ impressive ability to differentiate into multiple tissue lineages, including the formation of bone, cartilage, muscle, fat, tendon or ligament and other connective tissues.

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Inclusion of appropriate bioactive molecules such as growth factors is of great interest due to their important roles in wound healing. These proteins trigger a variety of cell signaling pathways such as cell survival, migration, proliferation and differentiation. In some cases, the introduction of antibiotics is also considered to treat or prevent musculoskeletal infections.

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Of utmost importance, cells and growth factors need an appropriate environment to sustain and optimize their functions. The scaffold, which usually involves a 3D network of natural or synthetic polymers, serves as 3D guide and mechanical support on which tissues grow and organize. Recent designs have been developed to mimic the microenvironment of the native tissue (so-called extracellular matrix or ECM). These scaffolds include further biological cues present in the ECM to enhance attachment, such as cell adhesion ligands.

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One major advantage of regenerative medicine is that the resulting product can be highly customized to a specific patient by using his or her own cells, thus resolving issues related to both autografts (tissues transplanted from one spot to another on the person’s body) and allografts (tissues transplanted from one person to another), such as donor-site morbidity and rejection respectively. Furthermore, medical imaging technologies (CT and MRI) can help create 3D images of replacement tissues. These images are then used as molds for subsequent 3D bioprinting to fabricate scaffolds perfectly tailored to the patient’s anatomy. Currently, both inkjet and microextrusion techniques are being actively applied to “print” a wide range of tissues.1

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Current market and trends

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The market for bone and joint regenerative medicine has grown quickly over the last few years. The global market was valued at $ 2.6 billion in 2012 and hit $ 4.2 billion in 2015.2,3 According to the most recent analysis and forecast report by iHealthcareAnalyst, the global bone and joint regenerative medicine market is predicted to reach nearly $ 8.2 billion by 2021 at a Compound Annual Growth Rate (CAGR) of 11.7% from 2017 to 2021.4 North America currently occupies the biggest space in this market, followed by Europe.

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The increasing incidence of bone and joint diseases and injuries is the major driver for the orthopedic regenerative medicine market and research. Disease prevalence increases with age, and people are now living longer. The rise in injuries related to sport activities and road accidents also increases demand for bone and cartilage repair products. In May 2017, the WHO estimated that approximately 1.25 million people die each year in road accidents worldwide.5 The American Orthopaedic Society for Sports Medicine also published research data showing that over 3.5 million children aged 14 and younger receive medical treatment each year due to sport injuries.6

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Current challenges

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In over two decades since the emergence of regenerative medicine, only a few therapies have received US Food and Drug Administration (FDA) clearance or approval to use in orthopedics, despite great promises and extensive efforts from preclinical and clinical research. Examples are shown in Table 1.

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Table 1. FDA-approved orthopedic regenerative medicine products

Name Biological Agent Approved use
Carticel, MACI Autologous chondrocytes Cartilage defects from acute or repetitive trauma
Celution Cell extraction Transfer of autologous adipose stem cells
Infuse, Infuse Bone Graft, InductOs BMP-2 Tibia fracture and non-union, and lower spin fusion
Osteogenic Protein-1 BMP-7 Tibia non-union

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The biggest hurdle delaying the process of introducing new regenerative medicines to the market probably comes from regulatory constraints. The rapid expansion of the field has outpaced the regulations that govern it; scientists and industrial sponsors have been provided with little guidance on the best way to proceed. Increasing complexity of product design poses greater challenges to translation from the laboratory to the operating room. For example, an acellular scaffold should require substantially less time and fewer resources to get regulatory approval than a stem cell-based scaffold. Stem cell use often requires tight control to ensure their safety-efficacy profile after transplantation. So far, the list of approved cellular and gene therapy products on the FDA website includes only 15 entries.

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New FDA policy framework for regenerative medicine

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Good news came in November 2017. A new FDA policy framework. for regenerative medicine released two new draft guidance documents, one on expedited approvals for regenerative medicines for serious conditions and the other on medical devices used with regenerative therapies. “We’re adopting a risk-based and science-based approach that builds upon existing regulations to support innovative product development while clarifying the FDA’s authorities and enforcement priorities”, FDA Commissioner Scott Gottlieb said in a statement. “This will protect patients from products that pose potential significant risks, while accelerating access to safe and effective new therapies”.

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Besides regulatory barriers, challenges in regenerative product development are considerable. For orthopedics, mechanical properties and durability are paramount for a successful device. Ideally, the rate of scaffold resorption needs to be compatible with the rate of native tissue replacement. This property is neither easy to obtain nor to predict, and varies among patients, while screening a huge number of combinations of the three key components of regenerative products requires elaborate work in the laboratory. There is still concern about the potential long-term side effects of MSC transplantation.

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Clinical research on regenerative orthopedics is ongoing, but many trials were conducted with small patient numbers, lack of randomization and an absence of control groups, making it hard to determine the efficacy of these new therapies. In addition, comparing results across existing studies is difficult due to the lack of protocol standardization. When a protocol requires biopsies, these trials present unique challenges compared to traditional small molecule clinical trials.

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In a discussion recently published on Clinical Leader, Iovance Biotherapeutics revealed that they have to deal with multiple departments within the hospital along with different contract and budget personnel. The site activation process thus becomes quite time-consuming. Many hospitals were built when cell therapies did not exist and have no appropriate infrastructure specialized for this field. Setting up and running a Good Manufacturing Practices (GMP) facility for regenerative medicine in a public hospital includes other challenges that have been reviewed by Lazzari et al.7 on Future Medicine. Iovance also stressed that partnering with a Contract Manufacturing Organization capable of performing GMP work on patient cells plays a key role in cell therapy trials, especially for a smaller company.

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Promises from clinical research

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Many studies on orthopedic regenerative medicine at both the preclinical and clinical stages have been done. The potential therapies of stem cell use make it the most commonly studied field in orthopedics, although application of cell-free scaffolds has been also explored. Table 2 summarizes some clinical studies published over the last few years. The outcomes demonstrate a significant potential of stem cell therapies in treating a wide range of orthopedic injuries and conditions such as non/delayed unions (bone fractures that fail to heal), cartilage defects, osteogenesis imperfecta (OI) or osteoarthritis (OA).

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Table 2. Recent orthopedic regenerative trials.

Year of publishing
Disease Patients

number

Cell source Outcome
2013 8 Non-union 12 (+12 controls)

Autologous

MSC

Reduced union time (3 to 1.5 months) in MSC-treated group vs. control
2013 9 Non-union 52 MSCs Follow-up time ≥1 year: significantly improved radiographic healing and rapidity of healing in patients receiving all 3 elements (MSCs, a scaffold, and Bone Morphogenetic Protein) vs. patients receiving 1 element
2013 10 Non-union 8

Autologous

MSC

Successful bone union
2014 11 Non-union 7 Autologous hematopoietic stem cells Fracture healing in 5 (71%) of 7 patients at 12 weeks vs. 18% (2 of 11 patients) in the historical control group
2007 12 Cartilage defect 3

Autologous

MSC

Improved clinical symptoms; cartilage repair
2014 13 Osteonecrosis 10 Autologous bone marrow-derived MSCs 2-year follow-up: 7 of 9 patients (1 excluded) had no further disease progression
2002 14 OI 6 Allogeneic bone marrow MSCs Growth acceleration
2014 15 OI 2 Fetal liver-derived MSC Lack of new fractures and improved growth and mobility; lower MSC dose more effective
2012 16 OA 6

Autologous

MSC

Increased cartilage thickness, increased repair tissue and decreased subchondral edema
2013 17 OA 28 (+28 controls)

Autologous

MSC

Improved short-term clinical parameters and cartilage compared to control
2015 18 OA 27 Modified allogeneic chondrocytes Significantly improved clinical scores (reduced pain and stiffness, increased physical function)
2014 19 Rotary cuff repair surgery 45 (+45 controls) Bone marrow-derived MSCs 100% of MSC patients (vs. 67% of controls) had healed by 6 months; 39 of 45 MSC patients (vs. 20 of 45 controls) had intact rotary cuffs during the next 10 years

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Promising results from preclinical and clinical research augur a bright future for orthopedic regenerative medicine. However, there is much work to be done in order to bridge the gap from research to practice. Better knowledge on product design and behavior as well as better regulation is essential to move the field forward. The regulatory authorities are making the first big strides to help streamline and accelerate the approval process of promising regenerative therapies. In the coming years, we hope to see in the market more stem cell-based bone and cartilage grafts that are resorbable, custom-made, and affordable, in order to meet patient demand in this area.

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References

  1. Paxton NC, Powell SK, Woodruff MA. Biofabrication: The future of regenerative medicine. Techniques in Orthopaedics 2016, 31, 190-203.
  2. Research and Markets: Regenerative medicine market (bone and joint) – Global industry analysis to 2019 for the $6.4 billion industry. Check out at: https://www.businesswire.com/news/home/20140811005341/en/Research-Markets-Regenerative-Medicine-Market-Bone-Joint
  3. Regenerative medicine market: Tissue engineering technology will remain key to overall growth: Global industry analysis and opportunity assessment, 2015-2019. Check out at: https://www.futuremarketinsights.com/reports/regenerative-medicine-market
  4. Global bone and joint regenerative medicines market US$ 8.2 billion by 2021. Check out at: https://www.ihealthcareanalyst.com/global-regenerative-medicines-market/
  5. Road traffic injuries. Fact sheet – updated May 2017. Check out at: http://www.who.int/mediacentre/factsheets/fs358/en/
  6. Press release: American Medical Society for Sports Medicine, Apr 01, 2010. Check out at: https://www.amssm.org/young-athletes-overuse-th-p-79.html?StartPos=&Type
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