On October 14, 2015, the Food and Drug Administration (FDA) released a draft guidance document, General Considerations for Animal Studies for Medical Devices, discussing designing evaluation strategies for and reporting the results of animal studies for medical devices. While the guidance is in draft and therefore not yet in effect, the FDA clarifies that the document reflects its existing approach on this topic, rather than announcing new policy. Though the draft guidance is intended to replace the FDA’s July 2010 final guidance titled Guidance for Industry and FDA Staff: General Considerations for Animal Studies for Cardiovascular Devices when finalized, the newly issued draft guidance applies to all medical devices, making the guidance far broader in scope than the guidance being replaced.
The guidance reflects recent trends that have been observed by industry including the FDA’s strong preference for studies to be conducted under Good Laboratory Practice (GLP) requirements and for the collection of histopathology data. The recommendations outlined in the draft guidance are considerably detailed, and while largely consistent with the GLP requirements in 21 C.F.R. Part 58, the draft guidance provides additional details as to the recommended content, format, and organization of both the test protocols and reports as well as the development and conduct of the study. The agency also stressed its availability and willingness to review animal study plans or justifications for not conducting animal studies through the pre-submission process.
The FDA’s recommendations in the guidance are broken down into three areas, as further discussed below:
- development of an animal study protocol
- study methods and conduct; and
- reporting results
Determining Whether an Animal Study Is Necessary
The guidance states that the primary purposes in recommending the collection of animal study data is to collect evidence of safety of the device, as well as performance and handling, emphasizing that these are related concepts for many devices. Evaluations of efficacy of proof or principle can also be evaluated as secondary objective in these studies.
When determining whether an animal study is necessary to evaluate the device and designing an appropriate animal study, companies should begin by engaging in a risk analysis to identify potential risks of the device as well as any known risks of the device type. Companies should test evaluable risks on the benchtop, to the extent feasible, using the final design iteration. If the risk analysis suggests that an animal study is necessary, companies should then assess whether an established animal model for the type of device being tested exists or if a new approach might be needed for testing or physiological reasons (in which case the FDA recommends contacting the agency to discuss it further). To the extent possible, companies should use endpoints, time points, and methods reported for similar devices, though if the study calls for new endpoints, time points, and methods, the company should identify them in the protocol. The FDA also recommends examining whether or not what is known about the device would indicate high variability of animal responses as a result of factors such as investigator training and familiarity with the device or inherent challenges in the placement or tolerance of the device. The guidance provides a decision tree in Appendix B to assist companies in determine whether an animal study is necessary and appropriate to evaluate the device. The agency does acknowledge that studies may not be necessary or appropriate for certain devices and encourages companies to discuss these situations with the agency in a pre-submission.
Designing and Developing an Animal Study Protocol
The animal study protocol should be designed to address identified risks with the device and prescribe the frequency and type of monitoring, interventions, and outcome assessments based on the known risks and predicted outcomes of use of the device. The study design should include acceptance criteria for each step required for the use of the device, and the FDA’s draft guidance recommends applying a semi-objective rating scale (e.g., Likert scale) for each acceptance criterion. To fully quantify the risks of the device, the draft guidance further recommends the use of control groups within the study. Where a control is not utilized, an explanation as to why a control group is not needed should be prospectively included in the study protocol. FDA also states in the draft guidance that the responsible use of animals optimizes the use of all animal tissue, and accordingly, the agency recommends that complete gross and microscopic organ and tissue evaluations are performed on fresh tissue.
The study should simulate the clinical setting as much as possible. To ensure that the study reflects the clinical application of the device, the study should utilize an animal model that is generally accepted for the study of the device type. Companies should document a rationale for the selection of a particular animal model and how it simulates the clinical setting. Any limitations of the animal model should be described. Additionally, any accessory devices anticipated for use of the device clinically should be incorporated into the animal study evaluation and the acceptance criteria should evaluate compatibility with these products.
Study designs should consider the adequacy of controls, timing and route of intervention, and methods to minimize bias (e.g., blinding, randomization, use of controls, sample size based on expected magnitude of the biological response, reporting missing data, and clearly stated statistical considerations). The FDA emphasizes that planning of the study should include appropriate personnel and that the study has appropriate oversight to ensure that the study is designed and executed in a way to collect useful data. Interim data should be considered to determine whether additional observations are needed to ensure the useful data are not lost.
Study sample sizes should be statistically justified, however the draft guidance states that in studies evaluating higher risk implants, a relatively large number of animals may be required to establish device safety. Specifically, animal studies involving higher species (e.g., sheep, goat, non-human primate) generally have three to nine animals per group/time point.
While the guidance recognizes that companies may perform multiple animals studies on multiple versions of the device during the device development process, the FDA emphasizes that the pivotal study should utilize the final design of the device. However, if the final design is not used, a rationale should be provided for why the final clinical design presents no new risks to the patient compared to the design studied in animals.
Study Methods and Conduct
The FDA has confirmed in this guidance its strong preference for conducting animal studies in accordance with GLP as described in 21 C.F.R. Part 58. To the extent that studies were not performed in accordance with these regulations, the deviations from the regulations will need to be carefully explained to the agency to support that there were sufficient controls in place and that complete and accurate test data have been collected and reported.
The draft guidance offers specific recommendations for the conduct of animal studies, including the following key points:
- Sufficient research controls should be in place to ensure the quality and integrity of the data, namely to minimize variability between test and control animals. Specific recommended research controls are provided in Appendix C of the draft guidance.
- Standard operating procedures should be adopted for animal identification, animal quarantine, and conditioning to ensure animal wellness.
- Animals should be monitored for food, water, and basic husbandry as animal weight loss can be particularly difficult to interpret in terms of device relatedness. Monitoring should include assessments of appetite, food and water intake; micturition and bowel movements are important, particularly when animals are pen-housed.
- Facilities should be free of contaminants, including potentially poisonous plants in agricultural settings, organic metals, or contaminants in the soil, and feed and water must be analyzed periodically.
- Published guidelines should be consulted on maintaining an appropriate environment for well-being of animal research models. (Appendix F of the draft guidance)
- Monitoring protocols should be developed with attending veterinary staff and recorded in current standards of veterinary medicine record-keeping such as the subjective/objective assessment and plan (SOAP) format.The guidance provides specific recommendations for monitoring parameters and time periods for such observations in both acute and chronic studies in the guidance document. Animal wellness should be evaluated through use of problem-oriented veterinary medical records including the development of postoperative, interim, and terminal clinical pathology assessments. Downstream and systemic effects of the device should also be assessed. The FDA suggests identifying key biologic response variables at regional sites, locations adjacent to the implant site, and along all paths to and from the point of implantation or use to develop active means of surveying the impact of your device on the body.
- The draft guidance also provides specific recommendations for conduct of specific post-mortem analysesincluding radiographic imaging, scanning electron microscopy (SEM), histomorphometric analysis, and local and downstream tissue assessments.
The FDA recommends frequent interaction between personnel involved in planning the study and those performing the study to ensure that study facilities have the proper equipment, supplies, and resources for the study.
Reporting Animal Study Data
The FDA also states that the final study report should meet the requirements of 21 C.F.R. § 58.185. As above, a consistent message of the draft Guidance is the FDA’s desire for sponsors to comply to the extent possible with GLP requirements. Here, consistent with that goal, the report should be structured in a manner that allows for efficient evaluation of the device safety and performance. Any instances of unexpected morbidity or mortality should be fully explained and evaluated to determine whether or not they were device-related, supported by testimonials and evidence. The agency recommends a specific format for presentation of animal study test reports, outlined in Appendix D of the draft guidance, though the FDA notes that study reports should include additional information to demonstrate compliance with 21 C.F.R Part 58.
When summarizing animal studies in a submission to the FDA (e.g., pre-submission, 510(k), IDE), the FDA recommends providing information on the protocol design details, including the following:
- a rationale for the model selected and any limitations of the animal model
- the purpose of the evaluation and what elements of the risk analysis will be addressed
- the general animal study methodology used and study
- the study schedule and assessments performs
- any amendments and deviations from the original protocol
- descriptions of any standard operating procedures in place and followed during the study
- information demonstrating that the quality assurance unit is independent and impartial with respect to the inspection of the data and the reporting of the results
- rationale for the transition, if any, from pilot, validation, or proof of concept animal studies to pivotal animal studies; and any design changes implemented after completion of all animal studies.
Additionally, the key parameters for each study should be provided in tabular format, including the following information: the study groups, the number of animals in each group, identification of animals corresponding to study group allocation, study duration, the device design iteration used, and a summary of study outcomes. These summary descriptions submitted to the FDA should be accompanied by a signed and dated copy of the final study report.
Companies may submit comments on the draft guidance until January 12, 2016. Electronic comments should be submitted to http://www.regulations.gov.