Preclinical Studies for Dental Bone Graft Devices – 510(k) Submissions

On 28 March 2024, the US Food and Drug Administration (FDA) issued a draft guidance for manufacturers of dental bone grafting devices. The document, entitled “Animal Studies for Dental Bone Grafting Material Devices – Premarket Notification (510(k)) Submissions”, explains the circumstances under which preclinical studies are required and provides specific recommendations for the use of these studies to meet the special control requirements for these Class II devices.

Scope of the Guidance

The devices covered by this guidance include materials for oral/maxillofacial indications that are synthetic or of animal or human origin (i.e., product codes LYC, NMP, and NUN), but exclude grafts that are combined with a drug or biologic and demineralized bone matrix (DBM), as well as bone grafting materials for non-oral/maxillofacial indications (e.g., spinal or orthopaedic applications). This guidance complements an existing guidance document issued in 2005, “Dental Bone Grafting Material Devices – Class II Special Controls” and the FDA’s “General Considerations for Animal Studies Intended to Evaluate Medical Devices”.

The document outlines how to evaluate the biological performance of such devices through preclinical studies and describes the data that should be included in a 510(k) submission. Some of these recommendations were included in the previous FDA guidance on Class II Special Controls, which included a short section on in vivo performance, but the current guidance provides much more detail, including technical and reporting recommendations to help develop a compliant protocol.

Choosing the Right Preclinical Model

Emphasis is placed on the choice of preclinical model, which should be clinically relevant. The FDA clearly states that small preclinical models are not recommended and that skeletally mature canine or porcine models should be used as they are more representative of human physiology and anatomy. The FDA provides additional information on the choice of model, which should be representative of the full range of proposed indications for use; studies should use anatomical sites consistent with the intended use or represent a worst-case scenario covering all indications. When a device is intended for use in an intra-oral environment, there are specific anatomical differences and challenges that differ significantly from other bone-related environments, therefore cranial/calvarial or orthopaedic preclinical studies are generally not sufficient and intra-oral models should be used. The critical size defect model, which was mentioned without detail in the 2005 guideline, is better described in this guideline. The use of a critical size defect model is recommended for all indications where the clinical defect to be filled may be of critical size, to ensure that the full range of intended use is assessed.

Study Design Considerations

The guidance also provides study design considerations such as sample size, choice of controls, or study duration. Study endpoints are provided, including detailed technical recommendations for consistent assessment of bone formation and device resorption using radiography, histology, and histomorphometry. The FDA also recommends considering the addition of microCT, which was not mentioned in the 2005 guidance, as it can provide additional three-dimensional (3D) detail and quantitative information on device microarchitecture and tissue ingrowth. Finally, the need for supportive biomechanical testing on explanted specimens to demonstrate the quality of the newly formed bone, which was mentioned in the 2005 guidance, is no longer required. It is considered that radiographic, histological, and histomorphometric data are generally sufficient to demonstrate adequate biomechanical properties of the newly formed bone.

The FDA also offers recommendations for Sponsors who intend to combine the preclinical study evaluating in vivo performance with the biocompatibility endpoint of implantation conducted per ISO 10993-6. The FDA recommends that if biocompatibility assessment is included within the same preclinical study intended to evaluate device performance, justifications should be provided and discussed during a pre-submission meeting to justify the use of any different preparation methods, assessments, and procedures that are modified from ISO 10993-6.

Aiming for Consistency and Efficiency

The guidance reflects the current FDA review practices and aims to promote consistency, facilitating efficient review of these submissions. However, this guidance only provides recommendations, and each study protocol will need to be tailored based on device characteristics, mechanism of action, indications for use, and objectives of performance and safety. Simultaneously, the ethical principles of reduction, replacement, and refinement must be balanced. Additionally, regulatory least burdensome principles must be applied, with the goal of using the minimum number of preclinical models necessary to generate valid scientific data. The FDA also mention that manufacturers are encouraged to take advantage of the Q-Submission Program and submit the preclinical study protocol to help ensure that it adequately addresses safety and performance concerns for the 510(k) submission.

How Can NAMSA Help?

Designing a compliant preclinical study is key for a successful 510(k). We understand the challenges of defining the optimal preclinical study and are poised to be your partner in helping with study design, the Q-submission process, study execution, and reporting. Our preclinical and regulatory experts will guide you through these challenges, ensuring precision and alignment with the FDA and global requirements.