Guide to Understanding FDA Preclinical Study Requirements for Medical Devices

The development of a medical device is a rigorous process that requires compliance with regulatory standards to ensure both safety and performance. Before testing a device in people, researchers must determine if it has potential to cause harm when used clinically. These studies are referred to as “preclinical” studies – or more simply put – studies prior to use in humans. These studies can be performed either in vitro (conducted outside living organisms, usually in test tubes or petri dishes), or in vivo (research conducted on living organisms). In most cases both are needed for regulatory approval.

Preclinical studies comprise a variety of study types including safety and performance testing of a finished device, R&D studies, efficacy studies, toxicity studies, and biocompatibility studies of device materials. For the purposes of this article, we will focus on safety and performance studies. 

Preclinical safety and performance studies are an essential step in the development process, providing a bridge between in vitro testing and human clinical trials. The US Food and Drug Administration (FDA) has detailed requirements for preclinical studies. Understanding these requirements is critical for developers seeking regulatory approval. This article provides an overview of the FDA’s preclinical requirements, discusses key considerations for designing preclinical studies to evaluate their safety and performance, and highlights best practices for meeting these standards.

Table of Contents

• Importance of Preclinical Studies
• Key FDA Guidelines
• Compliance and Use of Standards
• Ethical Considerations
• Interaction with the FDA
• Designing In Vivo Studies for FDA Compliance
• Conclusion
• Frequently Asked Questions (FAQ)

The Necessity and Importance of Preclinical Studies

Preclinical studies are a fundamental step in the medical device development process. Per US FDA guidance, in vivo research generally provides an initial assessment of how a medical device interacts with biological systems, including physiological, pathological, and toxicological effects of the device, and how the biological system may affect the device. These studies are often conducted to support medical device premarket regulatory submissions. The primary purpose of a preclinical study submitted in support of a regulatory submission is for the applicant to demonstrate safety of the final finished version of the device. As possible, endpoints to evaluate performance in a model that mimics clinical use are often added. Proof of concept studies are typically conducted separately at an earlier stage.

Although breakthroughs are being developed in alternative testing methods, preclinical models are still often essential to demonstrate that the device under investigation is sufficiently safe for early human experience (e.g. to support an Investigational Device Exemption application) or to demonstrate device safety in support of a regulatory submission.

Preclinical studies on medical devices help address several critical questions including:

• How does the device interact with biological system overtime?
• What is the effect of the environment on the device?
• What is the biological response of the host to the device?
• Does the device cause any local or systemic adverse effects such as inflammation, toxicity or thrombosis?
• Are there any safety risks associated with the device’s materials, components, design, degradation, particulate debris, or energy output?
• Does the device perform as intended in a living system ?
• Are there any identified safety or performance concerns predictive of how a device might perform when used in human patients for the intended medical use ? 

These studies play a critical role in demonstrating compliance with FDA regulations, particularly for devices subject to the Premarket Approval (PMA) or 510(k) clearance pathways. Generally, safety and performance preclinical studies are designed to replicate the clinical use of a final finished device as intended to be used in humans.  Hence the study design needs to be customized for the device and/or specific clinical indication, requiring extensive discussions during planning with various stakeholders (regulatory, biocompatibility experts, KOLs and clinical experts, veterinarians, engineers…) to design a regulatory compliant study based on the least burdensome approach.

Start with the regulatory strategy

Before designing a medical device preclinical study, it is important to confirm the classification of the product and the associated regulatory pathway, define intended use and associated risks. This effort informs overall study design and endpoints which will need to be evaluated. 

Step 1: Classify your device

The regulatory pathway chosen can have a significant impact on the design of a pre-clinical study. For example, if a 510K is pursued, the main objective of the preclinical study will be to demonstrate substantial equivalence to the predicate device, whereas the objective will be different in the case of a de novo or PMA where no predicate is available. Similarly, the selection of the control group (predicate, negative control, state-of-the-art treatment) will depend in part on the FDA device classification.

Step 2: Define the intended use

The FDA recommends that the preclinical study be designed to ensure that the test environment simulates (to the extent possible) a clinical setting that reflects the intended use and proposed labelling of the device. The definition of the indication/intended use will therefore be critical to the choice of preclinical model and should be clearly defined prior to the definition of an preclinical model that should cover the full range of intended use. Some useful FDA guidance documents and statements related to intended use can be found here:

• Determination of Intended Use for 510(k) Devices – Guidance for CDRH Staff (Update to K98-1)
• FDA Clarifies Types of Evidence Relevant to Determining the “Intended Use” of FDA-Regulated Products
• FDA Final Rule on Medical Device Intended Use

Step 3: Identify the risks linked to your device

Your preclinical study should be designed to investigate the risks identified for the device or device type for the same intended use. It is therefore important that the manufacturer carries out a risk analysis in advance and defines how the preclinical study can address some of the identified risks that cannot be adequately addressed by alternative methods. This might be materials, biocompatibility (as discussed below), long term performance and associated safety, the placement/delivery procedures, or other device-specific factors. Here are some useful links: 

• FDA Guidance: Factors to Consider Regarding Benefit Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions
• FDA Guidance: Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process

Return to Top

Key FDA Guidelines for Preclinical Studies

The FDA provides some guidelines and expectations for preclinical studies to ensure robust and reliable data generation.

In 2023, the FDA published a guidance document entitled “General Considerations for Animal Studies Intended to Evaluate Medical Devices“. The FDA has developed this guidance to assist industry in conducting and reporting the results of preclinical studies for medical devices. The intent of this draft guidance is to provide a reference of best practices for designing evaluation strategies, conducting and presenting preclinical study data to demonstrate that the device under investigation is sufficiently safe for early human experience, while incorporating modern animal care and use strategies.

Good Laboratory Practice (GLP) Requirements

The FDA requires that preclinical studies, including safety endpoints, be conducted in accordance with Good Laboratory Practice (GLP) regulations outlined in 21 CFR Part 58. These regulations govern how preclinical studies are designed, performed, recorded and reported, ensuring the quality and integrity of preclinical studies. It is therefore crucial to select a GLP facility to conduct such studies.

Key GLP requirements include:

• Establishment of a detailed protocol defining objectives, procedures, materials and data collection methods.
• Establishment of a quality assurance program to monitor compliance
• Use of validated protocols and standard operating procedures (SOP’s)
• Use of appropriate facilities and qualified equipment
• Ensuring adequate training of personnel
• Maintain detailed records of study design, animal care and test results.

Biocompatibility Endpoints

It is recommended that some biocompatibility endpoints be included in the design of preclinical studies based on the ISO 10993 series, where appropriate. Specific biocompatibility endpoints that may be addressed in preclinical studies include:

• Systemic toxicity based on ISO 10993-11
• Hemocompatibility based on ISO 10993-4
• Implantation / local tissue effects based on ISO 10993-6

The design of preclinical studies should be carefully adapted to meet ISO 10993 requirements. The use of different preparation methods, assessments and procedures that deviate from the ISO 10993 series should be justified in the protocol and is recommended to be discussed at a presubmission meeting with FDA. The FDA provide useful information on the application of  the ISO 10993 series here.

Return to Top

Compliance and Use of Standards in Medical Device Study Design

In addition to “horizontal” biocompatibility standards applicable for all medical devices, device-specific (vertical) ISO standards, ASTM or FDA guidance documents also provide information on the risks associated with specific device types and may provide guidance on the design of the model and preclinical studies. For example, some FDA guidance documents such as the one describing preclinical studies for dental bone grafts that clearly mention the need for a critical size defect, some expected timelines, control groups or endpoints. ASTM are sometimes developed specifically to support pre-clinical evaluation of a particular type of device, such as ASTM F2884-21 describing in vivo evaluation of spinal fusion, or ASTM F2901-19  describing tests to evaluate potential neurotoxicity of medical devices, that is often referred to for devices within the neurologic space.

In some rare cases, an ISO vertical standard may also provide some preclinical recommendations, such as ISO 25539-2:2020 that will provide some information about the expected endpoints for preclinical studies dealing with endovascular devices, or ISO 5840-1:2021 that will provide guidelines for preclinical in vivo evaluation of heart valve substitutes, in order to predict their safety and performance.

It is also recommended to explore the publicly available data on the FDA website and identify the strategy used by others for predicate or approaching premarket devices.

Finally, an extensive literature search should be conducted to support protocol development. 

Ethical Considerations

The use of preclinical models raises important ethical concerns. Researchers must adhere to strict regulatory requirements and ethical guidelines to ensure humane treatment and to minimize the use of animals wherever possible. Ethical considerations are paramount in the design of animal studies. Developers should follow the “3Rs” principle:

• Replace animal models with non-animal methods wherever possible
• Reduce the number of animals used without compromising scientific validity
• Refine procedures to minimize pain and distress

It should be emphasized that animal welfare is not only an ethical consideration, but is also law in compliance with the Animal Welfare Act. The FDA has more information on this topic that you should review here.

Adherence to these principles is not only an ethical obligation but also a regulatory requirement and ensures the integrity of the data collected. One way (but not the only one) to verify a CRO’s adherence to these principles is to verify its accreditation with AAALAC, a not-profit organization that promotes the humane treatment of animals in science through a voluntary accreditation program that ensures that accredited facilities meet regulatory standards and go the extra mile to achieve excellence in animal care and use. NAMSA is accredited by AAALAC.

Return to Top

Interaction with the FDA – Use the Q-submission Program

Each study protocol is uniquely designed and tailored based on the device characteristics, mechanism of action, indications for use, and performance and safety goals, while balancing the ethical principles of reduction, replacement, and refinement and the regulatory principles of least burdensome, with the goal of using the minimum number of animals necessary to generate valid scientific data.

This is why FDA encourages manufacturers to take advantage of the Q-Submission Program (Q-Sub) and submit the preclinical study protocol to the FDA to ensure that it adequately addresses safety and performance concerns and is consistent with FDA expectations prior to initiation of the study. This protocol should provide sufficient detail for the FDA to evaluate the adequacy of the study to support clinical safety and performance. A study synopsis is generally considered insufficient by the FDA that will not be able to not provide adequate feedback. Q-Sub is very valuable in planning as the FDA will provide feedback within 75 days, free of charge, including a possible meeting to discuss any outstanding questions or clarifications to the feedback. 

The submitted protocol should typically include:

• Device description and purpose of the study
• Objectives and endpoints
• Animal model description and justification
• Procedural approach and justification
• Test methodology
• Control condition(s) and justification
• Study duration and justification
• Group size, justification and statistical methods
• Quality Assurance
• Success Criteria for evaluation of endpoints

Return to Top

Designing In Vivo Studies for FDA Compliance

Designing preclinical in vivo studies requires careful planning and adherence to regulatory standards. Below are some critical considerations for ensuring FDA compliance.

Selecting the Appropriate Preclinical Model

The choice of preclinical model is one of the most important aspects for a successful preclinical study. The species selected should closely mimic human anatomy and physiology as it relates to the product under investigation, while considering its limitations. The FDA recommends that the final study report include scientific justification that the animals enrolled are robustly representative of the human patient population to support that the data are translatable to clinical safety. For larger devices which are meant to be used in humans, large preclinical safety studies often generate the most clinically relevant safety data when they evaluate the clinical device implanted and used according to clinical use/labelling. If a device can be scaled down (examples: trimmable bandages, injectable devices, certain grafts or patches) smaller species such as rabbits or rodents may be utilized.  

Factors to consider include:

• Relevance: Does the preclinical model replicate the clinical condition and the complex biological interactions between the device and tissues to allow evaluation of the identified clinical risks?
• Size and anatomy: Is the size of the model compatible with the dimensions and intended use of the device?
• Physiology: Is the metabolism/coagulation system/healing characteristics of the selected model close enough to the patient?
• Age and longevity: Will the model survive long enough to assess long-term effects? Will the model grow during the study? Should the model be juvenile or adult?

For example, the use of juvenile sheep is recommended for testing a bioprosthetic heart valve, as they are of an appropriate size and are known to calcify easily and rapidly, which is one of the risks to be assessed in vivo for this device type. Conversely, skeletally mature models should be used in orthopedic studies to minimize innate healing, which is faster in young models and would bias the evaluation of safety and performance. 

The FDA recommends that pilot preclinical studies be conducted prior to preclinical  safety studies, in particular if a significant learning curve is expected that would significantly increase the variability of model response. Such studies are also highly recommended to optimize the GLP study design, to verify the suitability of the model, to support some of the justifications and to avoid any surprises during the conduct of the GLP study.

Further information on preclinical model choice and considerations may be found in this FDA guidance here.

Define Sample Size and Study Duration

The FDA expects manufacturers to justify, based on scientific principles, that their sample size and study duration are adequate to generate valid safety data. Studies that are too small may fail to detect safety problems, while studies with too many test subjects may raise ethical concerns.

• Sample size: Justification may be based on pilot study and experience with the model and known variability, may be based on statistical power analysis, or may be based on standards such as ISO 10993-6 or 11 or other guidance/standard that specify expected comparisons. 
• Duration of the study: The duration of the study should be consistent with the intended clinical use of the device. For example, if local tissue effects based on ISO 10993-6 is one of the endpoints which is often the case, the last time point should demonstrate a steady state tissue reaction; for implants, this will typically require a minimum of 13 to 26 weeks of implantation depending on the tissue implanted.
• Number of time points: The study will also often include a short term to evaluate the acute response to the implant. For degradable implants, in most cases FDA will require to see almost complete degradation with healing of the implanted tissue returning to normal, as well as short term and mid-term type points to show the kinetics of degradation and associated tissue reaction overtime.

Medical Device Implantation Strategy and Test/Control Group Considerations

It should be emphasized that the finished version of the device intended for use in human patients should be used to ensure that the data most supportive of safety in clinical use are implanted. This is an expectation of FDA for GLP Safety and Performance Testing. In some cases, a device designed for human anatomy won’t fit into a preclinical model. One option is to modify the device specifically to fit into the preclinical model. If a different version of the device or implantation method is being evaluated (e.g. use of a scaled-down version to fit the anatomy of the model or use of a different implantation site), a description of any differences from the clinical version, including justification of why any changes would not be expected to affect the strength of the safety data generated, should be included to demonstrate that the final clinical design does not present any new risks to the patient compared to the design studied in preclinical models. In cases where modifications to the device are necessary for the study, it is highly recommended to have discussions with FDA through the Q-submission process previously discussed. 

The inclusion of control groups strengthens the validity of study results and in most cases are either required and/or highly recommended to evaluate endpoints in a study. Control groups allow a clear assessment of the effects of the device relative to baseline conditions or interpretation of tissue response or sequelae associated with a standard therapy treatment procedure. For example, if a study is designed according to ISO 10993-6, local tissue effects should be assessed by comparing the tissue response induced by a test sample with that induced by control materials used in medical devices whose clinical acceptability and biocompatibility characteristics have been established (typically the predicate device in case of a 510K). In addition, in some cases a negative and/or positive control group will be required to verify the suitability of the preclinical model (e.g. to demonstrate that a bone defect does not heal spontaneously and to allow evaluation of the bone healing performance of a bone graft). A negative control group is also required if compliance with ISO 10993-11 is claimed.  

Endpoints and Acceptance Criteria

The FDA recommends that pre-defined acceptance criteria be included in the protocol to aid interpretation of clinical safety. Clear objectives and acceptance criteria for each objective should be established in the protocol prior to study initiation. The study report should clearly indicate which criteria were met during the study to demonstrate risk reduction.  Examples of acceptance criteria might include:

• No adverse events attributed to the test device
• Device is a non-irritant
• Device does not cause systemic or downstream adverse tissue response

These are just a few generic examples. There are many other considerations for evaluating endpoints based on the risk profile of a test device. 

Many endpoints may be evaluated in studies depending on the risks associated with the device, as well as techniques to capture potential clinical sequalae of those risks.  For example, several parameters can be used to evaluate safety, including clinical and macroscopic observations, clinical pathology, imaging techniques such as angiography, Ultrasonography, X-rays, MRI, computerized tomography, or other device-specific functional assessment.

Histopathology is a key endpoint in almost all studies. This endpoint is particularly important as histopathology requiring tissue sampling cannot be obtained from human patients in clinical trials. Histology of implanted and surrounding tissues provides an understanding of the interactions between a device and tissues, which are dynamic and change over time.

Histopathological assessment of systemic organs is also key in the evaluation of systemic or downstream effects of an implant generated by leachables, degradation products, particles or thromboembolisms. A protocol for necropsy, tissue sampling, staining techniques and analysis of the implant site, as well as surrounding and downstream tissues, should be developed with the assistance of the study pathologist, who should be board-certified based on FDA requirements. Several techniques are available depending on the type of tissue/implant and objectives. Qualitative and semi-quantitative standard histopathology after resin or paraffin embedding can be supplemented by quantitative histomorphometry, immunohistochemistry, specific labelling or scanning electron microscopy and combined with other imaging techniques such as micro-computed tomography or quantitative angiography. 

Return to Top

Conclusion

Preclinical safety and performance preclinical studies are a critical part of the medical device development process. By understanding and complying with FDA requirements, developers can generate robust data to support the safety and performance of their devices. Key takeaways include:

• Start with the regulatory process for appropriate classification, intended use, and control group(s) selection
• Adherence to GLP regulations
• Identify appropriate FDA guidance documents, ISO or ASTM standards, or other applicable consensus standards that apply to the device type.
• Engage with the FDA early to clarify study expectations and develop a collaborative relationship which will carry through the regulatory submission.
• Justify the selected model, duration, sample sizes and ethical considerations.
• Ensure thorough and clear documentation and transparent reporting based on GLP requirements to prevent questions during the regulatory review by FDA.

Designing a compliant preclinical study is key to a successful submission to the FDA. By prioritizing scientific rigor and regulatory compliance and with the support of an experienced CRO, manufacturers can successfully navigate the preclinical phase and advance their devices towards clinical testing and regulatory approval.

At NAMSA, we understand the challenges of defining the optimal medical device preclinical study and are ready to partner with you in its design, quality submission process, study execution and reporting. Our preclinical and regulatory experts will guide you through these challenges, ensuring precision and alignment with FDA and global requirements.

Return to Top