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FDA Regulatory Challenges for Antimicrobial Orthopedic Devices

Preventing and managing orthopedic-associated infections is one of the major challenges in orthopedic surgery.

Mehdi Kazemzadeh-Narbat, Ph.D., Associate Director, Regulatory Affairs, MCRA LLC11.17.21

Orthopedic implants are susceptible to the bacteria attachment and development of infection. Preventing and managing orthopedic-associated infections is one of the major challenges in orthopedic surgery despite the maintenance of strict hygiene protocols and modern surgical techniques. In addition, treating orthopedic infections has become further complicated by the emergence of multi drug-resistant organisms that cannot be managed with traditional antibiotics and prophylaxis. The growth of adhered bacteria to the implant substrate results in the colonization and formation of biofilm, which is up to 1,000 times more resistant than planktonic cells. Bacteria resistance and biofilm formation are the leading causes of orthopedic implant failures. Approximately 14.8 percent of total hip arthroplasty (THA) and 25.2 percent of total knee arthroplasty (TKA) revisions result from infection.^1,2 Considering that current U.S. reimbursement models usually do not cover complications like infection, the estimated $100,000 treatment costs for orthopedic infections rests with the patient, physician, hospital, or healthcare service.^2,3 The current standard of care for treating acute periprosthetic joint infection is debridement, antibiotics/irrigationa, and implant retention (DAIR) procedure.⁴

Strategies for Preventing Infections in Orthopedic Devices
Several antimicrobial strategies have been applied to prevent infection in joint arthroplasty prostheses, bone void fillers, bone cements, spinal implants, and fracture fixation devices. These strategies mainly are classified into bactericidal or superhydrophobic/anti-fouling.^5,6 Bacteriocidal orthopedic devices kill bacteria either upon contact or by releasing antimicrobial agents. The common antimicrobial agents used in orthopedic implants include silver, zinc, copper, nitric oxides, selenium, carbon nanostructures, antibiotics, and polycations like quaternary ammonium compounds, chitosan, and antimicrobial peptides (AMPs).^5,7 Superhydrophobic or anti-fouling coating repel or prevent bacteria adherence to the implant surface. For example, modifying the Ti substrate with PEG-based antifouling agent, or certain features such as nanopillars or nano-scale topographies ranging from 20 to 80 nm reportedly may prevent bacteria attachment.^8,9 Some recent developing technologies try to eradicate the biofilm through electrical or magnetic forces such as application of cathodic voltage-controlled electrical stimulation,¹⁰ or non-invasive high-frequency alternating magnetic fields.¹¹

FDA Regulatory Challenges
The industry’s first challenge is to define the regulatory pathway for an orthopedic device with antimicrobial agent. The FDA Office of Combination Products (OCP) assigns the classification based on a product’s primary mode of action (PMOA). According to the OCP, if antimicrobial activity is attributed to physical interaction and does not include chemical or metabolization action, the product is assigned to CDRH as a device. An example of such physical-based antimicrobial activity is antimicrobial properties due to surface topography, anti-fouling, or electrostatic interaction. However, if the PMOA is attributed to the device but the antimicrobial activity associates with chemical action or metabolization, the product is considered a combination product and multiple centers are involved in the review with the CDRH as the lead center. An example of this scenario is the combination of gentamicin with bone void fillers. In case the PMOA is attributable to the antimicrobial component of the combination product, the product is assigned to the Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) as the lead center with CDRH consultation. An example of this situation is drug delivery systems such as antibiotic beads.

The major challenge for antimicrobial orthopedic device developers is the huge gap in regulatory science between the industry and FDA. A workshop on orthopedic device-related infections was held on Nov. 13, 2020, in which the agency expressed an unmet need for developing alternatives to the current standard of care for orthopedic infection.¹² However, despite recognizing the priority of novel antimicrobial technologies, FDA has not yet recognized sufficient standards or published guidance documents to introduce special controls or provide adequate clear knowledge for establishing antimicrobial safety and effectiveness. ^13,14

From the FDA’s perspective, antimicrobial orthopedic devices face complex challenges in demonstrating safety and effectiveness. It is insufficient for a sponsor to merely provide evidence of in-vitro antimicrobial properties to the FDA. Antimicrobial orthopedic device approval hinges on performing a risk assessment and proposing special controls to address the risks. Generally, coming to an agreement with the agency regarding the risk assessment and special controls occurs through multiple pre-submissions (Q-subs). Some of the risks and challenges that should be addressed through special controls include maintaining antimicrobial activity without impairing biocompatibility; toxicity; developing bacteria resistance; bone growth and osteointegration interference; burst release; lack of stable, steady release over the intended use; ability to disintegrate or eradicate biofilm matrix; and sufficient mechanical stability on the implant surface.⁵

Some of the FDA’s more ambiguous expectations are the definitions of antibacterial, antimicrobial, and anti-biofilm. Based on the MCRA’s past interactions, FDA does not consider less than 3 log bioburden reduction of bacteria colony-forming unit (CFU) as an active antibacterial activity, but in some cases up to 6 log reduction has been requested. Another consideration is the proper selection of testing bacteria in accordance with intended use. Since the prevalence of bacteria strains responsible for infection in different devices such as fracture fixation, hip, knee, or spinal implants are dissimilar, the choice of bacteria should be confirmed by the FDA before starting testing. The agency usually recommends companies identify the device’s worst-case scenario and clinically relevant infection to be simulated using resistant forms of at least three Gram-positive and three Gram-negative bacteria. If an antimicrobial claim is made, testing should be expanded to other forms of infection causing pathogens such as fungi. Anti-biofilm claims may require further testing to show the device can disrupt the biofilm matrix and eradicate the planktonic bacteria. For the worst-case scenario of biofilm, companies may be requested to evaluate the challenging forms of biofilm with resistant and persister dormant cells for pre-clinical testing. Moreover, the sponsor should provide the agency with some forms of visual assessment such as scanning electron microscopy (SEM) or confocal microscopy to illustrate the device’s ability to disrupt biofilms.

Pre-Clinical Testing
To demonstrate the safety and effectiveness of novel antimicrobial orthopedic devices the FDA recommends adequate in-vitro, in-vivo, or ex-vivo, or clinical data. Because of the complex nature of orthopedic infections, the agency believes bench testing is insufficient and cannot necessarily be translated to in-vivo; therefore, animal study is usually recommended to demonstrate safety and effectiveness. Some recommended in-vitro anti-microbial testing include time-kill test, Agar Disk-Diffusion assay, antimicrobial release profile over time, adhesion testing (e.g., for anti-fouling claims), resistance testing (e.g., Mu50 susceptibility), minimum inhibitory concentration (MIC), and minimum effective concentration (MEC) values determination in accordance with FDA-recognized test methods developed by the Clinical and Laboratory Standards Institute (CLSI) such as M02, M07, and M100.

There are insufficient guidance documents published by the FDA for antimicrobial medical devices. The only guidance document, published in 2007, “Premarket Notification [510(k)] Submissions for Medical Devices that Include Antimicrobial Agents” has been withdrawn by the Agency. Another FDA guidance document is specific instructions on susceptibility test, “Coordinated Development of Antimicrobial Drugs and Antimicrobial Susceptibility Test Devices.” The agency also appears to accept the unrecognized standard, “ASTM E2149 Standard Test Method for Determining the Antimicrobial Activity of Antimicrobial Agents Under Dynamic Contact Conditions.“

Biocomaptibility of antimicrobial associated orthopaedic devices is a challenging topic. To demonstrate biocomaptibility, the Agency recommends companies conduct a biological risk assessment in accordance with ISO 10993 series of standards and a 2020 FDA guidance document, “Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process“. The biocomaptibility end points for permanent antimicrobial orthopedic implants include cytotoxicity; sensitization, irritation or intracutaneous reactivity; acute systemic toxicity; material-mediated pyrogenicity; subacute/subchronic toxicity; genotoxicity; implantation; chronic toxicity; and carcinogenicity. For some of these end points (i.e., systemic toxicity as well as genotoxicity and carcinogenicity risks), FDA accepts the use of chemical characterization and toxicological risk assessment approach in accordance with ISO 10993-18, ISO 10993-17, and ISO 21726 in lieu of biological testing. Another safety concern for antimicrobial orthopedic devices is the application of nanoparticles relative to their size and tolerable intake. For example the agency has reported cytotoxicity and adverse effects on the osteogenic differentiation for human bone marrow stem cells at silver nanoparticle concentrations of 10 µg/mL.¹⁵ FDA defines the particles with the size range of approximately 1 nanometers(nm) to 100 nm in at least one external dimension, or an internal or surface structure as nanoparticles and believe they may be able to cross biological membrane barriers and have harmful effects due to the potential interaction with organs and cellular compartments. Therefore, their safety assessment including absorption, distribution, metabolism, and excretion parameters should be evaluated. The FDA has published several guidance documents about the application of nanotechnolgy, which can be found on its website.¹⁶

References

Dr. Kazemzadeh-Narbat is a former FDA medical device reviewer and joined MCRA in 2020. Dr. Kazemzadeh-Narbat is a biomedical engineer with five years of FDA experience in medical device regulation; he worked at CDRH as a pre-market and post-market lead reviewer of orthopedic and dental devices. At MCRA, he provides guidance on regulatory strategies and submissions development across various therapies.